PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND

Abstract

The present inventors found cyclic peptide compounds that interact with Ras, and pharmaceutical compositions containing the cyclic peptide compounds or salts thereof, or solvates thereof.

Description

TECHNICAL FIELD

The present invention relates to cyclic peptide compounds having a Ras inhibitory effect, and the cyclic peptide compounds or salts thereof, or solvates thereof; pharmaceutical compositions, or therapeutic agents or preventive agents for a disease, containing the cyclic peptide compounds or salts thereof, or solvates thereof; and use thereof in the manufacture of medicaments for treatment or prevention of a disease.

BACKGROUND ART

Ras is a protein belonging to the small GTPase family, and Kras, Nras, and Hras are known. Ras is in an inactive state or an active state according to whether it is bound to GTP or GDP. It is activated by the exchange reaction from GDP to GTP by GEFs (guanine nucleotide exchange factors) and inactivated by the hydrolysis reaction of GTP by GAP₈ (GTPase-activating proteins) (NPL 1). Activated Ras induces cell proliferation, survival, and differentiation by activating various downstream signals in the MAPK pathway, PI3K/Akt pathway, RAL pathway, and such, and the constitutive activation of Ras plays an important role in the development and progression of cancer. In cancer, it is known that the Ras-RAF-MEK-ERK pathway is activated by the activation of an upstream signal of Ras, constitutive activation of Ras, and/or activating mutations of Ras (NPL 2). These activating mutations of Ras have been found in numerous cancer types. G12, G13, and Q61 are known as hot spots of Ras mutation, and G12 is frequently found mutated in Kras and Q61 in Nras. These mutations are also known to be associated with the prognosis of patients (NPL 3).

When it comes to access to a tough target, as typified by inhibition of a protein-protein interaction, medium sized molecules (having a molecular weight of 500 to 2000) may be superior to low molecular weight compounds. Also, medium sized molecules may be superior to antibodies in that they can migrate into cells. Among biologically active medium sized molecules, peptide drugs are highly valuable molecular species, with more than 40 peptide drugs being already commercially available (NPL 4). Representative examples of such peptide drugs include cyclosporin A and polymyxin B, which are peptides containing some non-natural amino acids. A non-natural amino acid refers to an amino acid that is not naturally encoded on mRNA. It is highly interesting that non-natural amino acids that are not encoded on mRNA are contained in naturally-occurring cyclosporin A and polymyxin B.

Since the discovery of the pharmaceutical utility of naturally-occurring peptides, peptides having pharmacological activity and bioabsorbability have been attracting attention, and those having a molecular weight of about 500 to 2000 have been actively researched (NPL 5).

There is a report on conditions for medium molecular weight peptides to have increased membrane permeability and metabolic stability, which may contribute to improving their biokinetics (conditions necessary for satisfying drug-likeness) (PTL 1).

Moreover, as for the conditions that may contribute to improving the biokinetics of medium molecular weight peptides, conditions necessary for cyclic peptides to satisfy drug-likeness have been shown (PTL 2).

Peptides that bind to Ras have been found, and the binding site between a cyclic peptide and Ras has been studied by X-ray structural analysis (NPL 6, NPL 7, NPL 8, and NPL 9). Also, cyclic peptides that apparently inhibit binding between Ras and SOS have been found (PTL 3). Moreover, a competition assay for binding with Ras has suggested that some cyclic peptides inhibit binding between a particular compound and Ras (PTL 4).

CITATION LIST

Patent Literature

• [PTL 1] WO 2013/100132
• [PTL 2] WO 2018/225864
• [PTL 3] WO 2012/122059
• [PTL 4] WO 2017/181061

Non-Patent Literature

• [NPL 1] Nat. Rev. Drug Discov. 2014 November; 13(11):828-851.
• [NPL 2] Nat. Rev. Drug Discov. 2014 December; 13(12):928-942.
• [NPL 3] Nat. Rev. Drug Discov. 2016 November; 15(11):771-785.
• [NPL 4] Future Med. Chem. 2009, 1, 1289-1310.
• [NPL 5] Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 7, 821-836.
• [NPL 6] Biochem. Biophys. Res. Commun. 2017, 484, 605-611.
• [NPL 7] Bioorg. Med. Chem. Lett. 2017, 27, 2757-2761.
• [NPL 8] ACS Med. Chem. Lett. 2017, 8, 732-736.
• [NPL 9] ACS Cent. Sci. 2020, 6, 1753-1761.

SUMMARY OF INVENTION

Technical Problem

The present invention provides pharmaceutical compositions containing compounds effective for cancers associated with Ras mutations or abnormalities of Ras genes, and cyclic peptide compounds or salts thereof, or solvates thereof; pharmaceutical compositions, or therapeutic agents or preventive agents for a disease, containing the cyclic peptide compounds or salts thereof, or solvates thereof; use thereof in the manufacture of medicaments for treatment or prevention of a disease; and the like.

• • PTL 1 and PTL 2 describe drug-like peptides, but do not describe a peptide having an antitumor effect on cancers including cancers associated with Ras mutations or abnormalities of Ras genes.
  • PTL 3 describes the inhibition of binding between Ras and SOS, and PTL 4 describes a peptide competing with a compound that binds to Ras. However, none of these documents shows any pharmacological action, especially action on tumor cells. These documents do not describe drug-like peptides, either.
  • NPL 1 shows the relationship between Ras and cancer in detail. This document describes molecules that bind to Ras. Although their efficacy was shown in preclinical studies, no compound was shown to be effective as a drug specifically on Ras-mutant cancer. Also, no drug-like cyclic peptide is disclosed.
  • NPL 2 provides detailed descriptions about Ras and the RAF-MEK-ERK pathway, which is downstream of Ras. Although this document suggests the possibility of treating Ras-mutant cancer with RAF, MEK, and ERK inhibitors, it does not show any compound that directly inhibits Ras.
  • NPL 3 describes a compound that binds to the GTP/GDP binding site of Ras and inhibits the function of Ras, and the mechanism thereof. This document describes the interaction with the GTP/GDP binding site in detail, but does not show pharmacological action, especially action on tumor cells.
  • NPL 4 describes peptides that are used as drugs, but does not describe a drug-like peptide or a peptide useful for Ras-mutant cancer.
  • NPL 5 describes the molecular form and pharmacokinetics of cyclic peptides, but does not describe a compound useful for Ras-mutant cancer.
  • NPLs 6 to 9 describe peptides that bind to Ras, but their action on tumor cells is limited, and, in addition, a drug-like peptide is not described.

Despite the fact that cancers associated with Ras mutations or abnormalities of Ras genes have no effective treatment and the unmet medical need is strong, a drug that directly inhibits Ras and exhibits a clinical therapeutic effect has not been developed yet. Also, a peptide that satisfies drug-likeness has not been found.

The present invention is directed to a group of breakthrough peptide compounds that directly bind to Ras and inhibit its interaction with SOS, whereby they suppress the activation of Ras and inhibit the proliferation of cancer cells associated with Ras mutations or abnormalities of Ras genes, and pharmaceutical compositions containing such a group of peptide compounds.

Solution to Problem

As a result of dedicated research for seeking cyclic peptide compounds having Ras inhibitory activity, for the first time, the present inventors found cyclic peptide compounds that interact with Ras in a novel and characteristic manner. Specifically, it was found for the first time that the cyclic peptide compounds of the present invention interact with at least one amino acid residue selected from the group consisting of Val8, Gly10, Lys16, Glu37, Leu56, Gln70, Tyr71, and Glu98 of Ras. The inventors also found that those cyclic peptide compounds inhibit the binding between Ras and SOS. In addition, the inventors found that the cyclic peptide compounds have, as a pharmacological effect, a proliferation inhibitory effect on cancer cells associated with Ras mutations or abnormalities of Ras genes. Furthermore, amino acid sites in Ras proteins that interact with the cyclic peptide compounds were found.

The present invention encompasses the following in one non-limiting specific embodiment:

[1] A pharmaceutical composition containing a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof:

wherein,

• • L₁ is a single bond, or —CHM₁-, (CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and in are each independently 1 or 2,
  • R₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylC₁-C₆, alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₁ and P₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and Q₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and M₁, together with the carbon atom to which R₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁ and P₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₅ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁ is hydrogen or C₁-C₆ alkyl, and
  • except when R₁ and M₁ form a 3- to 8-membered alicyclic ring, M₁ is hydrogen,
  • R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C₁-C₆ alkylsulfonyl, or
  • R₂ and P₂, together with the carbon atom to which R₂ is attached and the nitrogen atom to which P₂ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₂ and Q₂, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, P₂ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₂ is hydrogen or C₁-C₆ alkyl,
  • R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₂-C₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), or
  • R₃ and P₃, together with the carbon atom to which R₃ is attached and the nitrogen atom to which P₃ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₃ and Q₃. together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₃ and P₃ form a 4- to 7-membered saturated heterocyclic ring, P₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₃-C₈ cycloalkyl, each of-which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C₁-C₆ aminoalkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino is optionally substituted with one or more halogens), except when R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₃ is hydrogen or C₁-C₆ alkyl,
  • R₄ is hydrogen or C₁-C₆ alkyl, or
  • R₄ and P₄, together with the carbon atom to which R₄ is attached and the nitrogen atom to which P₄ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₄ and Q₄, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₄ and Q₄ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₄ is hydrogen or C₁-C₆ alkyl, R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆, alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, and C₁-C₆ alkylsulfonyl, or R together with R forms C₄-C₆ alkylene, or
  • R₅ and P₅, together with the carbon atom to which R, is attached and the nitrogen atom to which P₅ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₅ and Q₅, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₅ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₅ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₅ and Q₅ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₅ is hydrogen or C₁-C₆ alkyl,
  • R₆ is hydrogen or C₁-C₆ alkyl, or
  • R₆ and P₆, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₅ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₆ and Q₆, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₆ and P₆ form a 4- to 7-membered saturated heterocyclic ring, P₆ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₆ and Q₆ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₆ is hydrogen or C₁-C₆ alkyl,
  • R₇ is C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, C₁-C₆ alkylsulfonyl, and SF₅, or
  • R₇ and P₇, together with the carbon atom to which R₇ is attached and the nitrogen atom to which P₇ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₇ and Q₇, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₇ and P₇ form a 4- to 7-membered saturated heterocyclic ring, P₇ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆, alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q % is hydrogen or C₁-C₆ alkyl,
  • R₈ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, 5- to 10-membered heteroarylC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, cyano, amino (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkylidene, protected 4- to 7-membered heterocycloalkylidene, 4- to 7-membered heterocyclyl, and protected 4- to 7-membered heterocyclyl, or R₈ together with R₅ forms C₄-C₈ alkylene, or
  • R₈ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS₈, and S₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₇-C₁₄ aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy), or 5- to 10-membered heteroarylC₁-C₆ alkyl, or
  • R₈ and Q₈, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₈ and P₈ form a 4- to 7-membered saturated heterocyclic ring, P₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl, C₇-C₁₄ aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen or C₁-C₆ alkyl), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₉ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₉ and P₉, together with the carbon atom to which R₉ is attached and the nitrogen atom to which P₉ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₉ and P₉ form a 4- to 7-membered saturated heterocyclic ring, P₉ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₉ is hydrogen or C₁-C₆ alkyl,
  • R₁₀ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C₁-C₆ alkylsulfonyl, or
  • R₁₀ and P₁₀, together with the carbon atom to which R₁₀ is attached and the nitrogen atom to which P₁₀ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₀ and Q₁₀, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁₀ and P₁₀ form a 4- to 7-membered saturated heterocyclic ring, P₁₀ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₀ and Q₁₀ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₀ is hydrogen or C₁-C₆ alkyl, and
  • L₁₁ is a single bond, or —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and m are each independently 1 or 2,
  • R₁₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or aminocarbonyl (wherein the amino is —NH₂, mono C₂-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C₁-C₆ alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or R₁₁ is a peptide chain comprising 1 to 4 amino acid residues, or
  • R₁₁ and P₁₁, together with the carbon atom to which R₁₁ is attached and the nitrogen atom to which P₁₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and Q₁₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and M₁₁, together with the carbon atom to which R₁₁ is attached and the carbon atom to which M₁₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, P₁₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₁ is hydrogen or C₁-C₆ alkyl,
  • except when R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring, M₁₁ is hydrogen,
  • wherein, when L₁₁ is a single bond, L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, and when L₁₁ is —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, L₁₁ is a single bond, and
  • at least three of P₁ to P₁₁ are not hydrogen.[2]

The pharmaceutical composition according to [1], wherein the cyclic peptide compound is represented by formula (2) below:

wherein,

• • R₁ is C₁-C₆ alkyl,
  • P₁ is C₁-C₆ alkyl,
  • R₂ is C₁-C₆ alkyl,
  • P₂ is hydrogen,
  • R₃ is hydrogen or C₁-C₆ alkyl,
  • P₃ is C₁-C₆ alkyl,
  • R₄ is hydrogen, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is C₁-C₆ alkyl,
  • R₅ is C₃-C₈ cycloalkylC₁-C₆ alkyl or C₇-C₁₄ aralkyl optionally substituted with C₁-C₆ alkyl,
  • P₅ is C₁-C₆ alkyl,
  • R₆ is hydrogen,
  • P₆ is C₁-C₆ alkyl,
  • R₇ is C₇-C₁₄ aralkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl,
  • Q₇ is hydrogen,
  • P₂ is hydrogen,
  • R₈ and P₈, together with the nitrogen atom to which P₈ is attached and the carbon atom to which R₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with C₁-C₆ alkoxy,
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring,
  • P₉ is hydrogen,
  • R₁₀ is C₃-C₈ cycloalkyl,
  • P₁₀ is C₁-C₆ alkyl,
  • R₁₁ is di-C₁-C₆ alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl,
  • M₁₁ is hydrogen, and
  • P₁₁ is C₁-C₆ alkyl.[3]

The pharmaceutical composition according to [2], wherein the cyclic peptide compound is represented by formula below:

wherein,

• • R₃ is hydrogen or methyl,
  • R₄ is hydrogen and P₄ is methyl, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form an azetidine ring,
  • R₅ is cyclohexylmethyl or 4-methylbenzyl,
  • P₅ is methyl or ethyl,
  • R_7A, R_7B, and R_7C are independently selected from the group consisting of hydrogen, fluorine, chlorine, and trifluoromethyl,
  • R_8A is hydrogen or ethoxy,
  • R₁₀ is cyclopentyl or cyclohexyl, and
  • R_11A and R_11B are both methyl, or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a piperidine ring or a morpholine ring.[4]

The pharmaceutical composition according to any one of [1] to [3], wherein the cyclic peptide compound is selected from the group consisting of:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacycltetratriacontine-2,1′-cyclopentane]-15-carboxamide,
• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, and
• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.[5]

The pharmaceutical composition according to any one of [1] to [4], wherein the cyclic peptide compound is:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.[6]

The pharmaceutical composition according to any one of [1] to [4], wherein the cyclic peptide compound is:

• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.[7]

The pharmaceutical composition according to any one of [1] to [4], wherein the cyclic peptide compound is:

• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.[8]

The pharmaceutical composition according to any one of [1] to [4], wherein the cyclic peptide compound is:

• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.[8-1]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N 5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof.

[8-2]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N 5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof.

[8-3]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof.

[8-4]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

[8-5]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof

[8-6]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof

[8-7]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof

[8-8]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

[8-9]

A pharmaceutical composition comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or solvate thereof

[8-10]

A pharmaceutical composition comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or hydrate thereof.

[8-11]

A pharmaceutical composition comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or hydrate thereof

[8-12]

A pharmaceutical composition comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.

[8-13]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or solvate thereof

[8-14]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or hydrate thereof

[8-15]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or hydrate thereof.

[8-16]

A pharmaceutical composition comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

[9]

The pharmaceutical composition according to any one of [1] to [8] and [8-1] to [8-16], wherein the pharmaceutical composition is a RAS inhibitor.

[10]

The pharmaceutical composition according to [9], wherein the Ras inhibitor is one or more Ras inhibitors selected from the group consisting of Kras inhibitors, Nras inhibitors, and Hras inhibitors.

[11]

The pharmaceutical composition according to any one of [1] to [10], wherein the pharmaceutical composition is for treating or preventing cancer.

[12]

The pharmaceutical composition according to [11], wherein the cancer is solid cancer or hematological cancer.

[13]

The pharmaceutical composition according to [11] or [12], wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[14]

The pharmaceutical composition according to any one of [11] to [13], wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine body cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[15]

The pharmaceutical composition according to any one of [11] to [14], wherein the cancer is associated with an abnormality of a Ras gene.

[16]

The pharmaceutical composition according to [15], wherein the abnormality of a Ras gene is a mutation in the coding region of the Ras gene and/or an amplification of the copy number of the Ras gene.

[17]

The pharmaceutical composition according to [15] or [16], wherein the Ras gene is one or more Ras genes selected from the group consisting of Kras gene, Nras gene, and Hras gene.

[18]

The pharmaceutical composition according to [17], wherein the Ras gene is Kras gene.

[19]

The pharmaceutical composition according to any one of [11] to [18], wherein the cancer is associated with generation of a mutant Ras protein and/or increased generation of a Ras protein.

[20]

The pharmaceutical composition according to [19], wherein the cancer is associated with generation of a mutant Ras protein.

[21]

The pharmaceutical composition according to [19] or [20], wherein the mutant Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant Hras proteins.

[22]

The pharmaceutical composition according to [21], wherein the mutant Ras protein is a mutant Kras protein.

[23]

The pharmaceutical composition according to any one of [19] to [22], wherein the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences set forth in SEQ ID Nos: 6, 7, or 8.

[24]

The pharmaceutical composition according to any one of [19] to [23], wherein the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence set forth in SEQ ID No: 6.

[25]

The pharmaceutical composition according to any one of [19] to [23], wherein the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L as compared to the amino acid sequence set forth in SEQ ID No: 7.

The pharmaceutical composition according to any one of [19] to [23], wherein the mutant Ras protein is a mutant Hras protein and has an amino acid mutation of G13R as compared to the amino acid sequence set forth in SEQ ID No: 8.

A therapeutic agent or preventive agent for a disease, comprising a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof:

wherein,

• • L₁ is a single bond, or —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and m are each independently 1 or 2,
  • R₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₁ and P₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and Q₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and M₁, together with the carbon atom to which R₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁ and P₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁ is hydrogen or C₁-C₆ alkyl, and
  • except when R₁ and M₁ form a 3- to 8-membered alicyclic ring, M₁ is hydrogen,
  • R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C₁-C₆ alkylsulfonyl, or
  • R₂ and P₂, together with the carbon atom to which R₂ is attached and the nitrogen atom to which P₂ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₂ and Q₂, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, P₂ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NI-12, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₂ is hydrogen or C₁-C₆ alkyl,
  • R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₆ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), or
  • R₃ and P₃, together with the carbon atom to which R₃ is attached and the nitrogen atom to which P₃ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₃ and Q₃, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₃ and P₃ form a 4- to 7-membered saturated heterocyclic ring, P₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C₁-C₆ aminoalkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino is optionally substituted with one or more halogens),
  • except when R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₃ is hydrogen or C₁-C₆ alkyl,
  • R₄ is hydrogen or C₁-C₆ alkyl, or
  • R₄ and P₄, together with the carbon atom to which R₄ is attached and the nitrogen atom to which P₄ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₄ and Q₄, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂. mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₄ and Q₄ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₄ is hydrogen or C₁-C₆ alkyl,
  • R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₆-C₁₀ aryloxyC₁-C₈ alkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, and C₁-C₆ alkylsulfonyl, or R₅ together with R₈ forms C₄-C₈ alkylene, or
  • R₅ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₅ and Q₅, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₅ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₅ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₅ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₅ is hydrogen or C₁-C₆ alkyl,
  • R₆ is hydrogen or C₁-C₆ alkyl, or
  • R₆ and P₈, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₆ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₆ and Q₆, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₆ and P₆ form a 4- to 7-membered saturated heterocyclic ring, P₆ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₆ and Q₆ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₆ is hydrogen or C₁-C₆ alkyl,
  • R₇ is C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄, aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, C₁-C₆ alkylsulfonyl, and SF₅, or
  • R₇ and P₇, together with the carbon atom to which R; is attached and the nitrogen atom to which P₇ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₇ and Q₇, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₇ and P, form a 4- to 7-membered saturated heterocyclic ring, P₇ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₇ is hydrogen or C₁-C₆ alkyl,
  • R₈ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylC₁-C₆ alkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₁-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, 5- to 10-membered heteroarylC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, amino (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkylidene, protected 4- to 7-membered heterocycloalkylidene, 4- to 7-membered heterocyclyl, and protected 4- to 7-membered heterocyclyl, or R₈ together with R₅ forms C₄-C₅ alkylene, or
  • R₈ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS₈, and S₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₇-C₁₄ aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C₁-C₈ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy), or 5- to 10-membered heteroarylC₁-C₆ alkyl, or R₈ and Q₈, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₈ and P₈ form a 4- to 7-membered saturated heterocyclic ring, P₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl, C₇-C₁₄ aralkyl, 5- to 1-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen or C₁-C₆ alkyl), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₉ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₇-C₄ aralkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₉ and P₉, together with the carbon atom to which R₉ is attached and the nitrogen atom to which P₉ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₉ and P₉ form a 4- to 7-membered saturated heterocyclic ring, P₉ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆, alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₉ is hydrogen or C₁-C₆ alkyl,
  • R₁₀ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C₁-C₆alkylsulfonyl, or
  • R₁₀ and P₁₀, together with the carbon atom to which R₁₀ is attached and the nitrogen atom to which P₁₀ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₀ and Q₁₀, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁₀ and P₁₀ form a 4- to 7-membered saturated heterocyclic ring, P₁₀ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₀ and Q₁₀ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₀ is hydrogen or C₁-C₆ alkyl, and
  • L₁₁ is a single bond, or —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₁₂)_m—, wherein n and n are each independently 1 or 2,
  • R₁₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₇-C₄ aralkyl, or aminocarbonyl (wherein the amino is —NH₂, mono C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C₁-C₆ alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or R₁₁ is a peptide chain containing 1 to 4 amino acid residues, or
  • R₁₁ and P₁₁, together with the carbon atom to which R₁₁ is attached and the nitrogen atom to which P_n is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and Q₁₁, together with the carbon atom to which they are attached, from a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and M₁₁, together with the carbon atom to which R₁₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, P₁₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₁ is hydrogen or C₁-C₆ alkyl,
  • except when R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring, M₁₁ is hydrogen, wherein, when L₁ is a single bond, L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, and when L₁ is —CHM₂-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, L₁₁ is a single bond, and at least three of P₁₁ to P₁₁ are not hydrogen.[28]

The therapeutic agent or preventive agent according to [27], wherein the cyclic peptide compound is represented by formula (2) below:

wherein,

• • R₁ is C₁-C₆ alkyl,
  • P₁ is C₁-C₆ alkyl,
  • R₂ is C₁-C₆alkyl,
  • P₂ is hydrogen,
  • R₃ is hydrogen or C₁-C₆ alkyl,
  • P₃ is C₁-C₆ alkyl,
  • R₄ is hydrogen, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is C₁-C₆ alkyl,
  • R₅ is C₃-C₈ cycloalkylC₁-C₆ alkyl or C₇-C₁₄ aralkyl optionally substituted with C₁-C₆ alkyl,
  • P₅ is C₁-C₆ alkyl,
  • R₆ is hydrogen,
  • P₆ is C₁-C₆ alkyl,
  • R₇ is C₇-C₁₄ aralkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl,
  • Q₇ is hydrogen,
  • P₇ is hydrogen,
  • R₈ and P₈, together with the nitrogen atom to which P₈ is attached and the carbon atom to which R₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with C₁-C₆ alkoxy,
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring,
  • P₉ is hydrogen,
  • R₁₀ is C₃-C₈ cycloalkyl,
  • P₁₀ is C₁-C₆ alkyl,
  • R₁₁ is di-C₁-C₆ alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl,
  • M₁₁ is hydrogen, and
  • P₁₁ is C₁-C₆ alkyl.[29]

The therapeutic agent or preventive agent according to [28], wherein the cyclic peptide compound is represented by formula below:

wherein,

• • R₃ is hydrogen or methyl,
  • R₄ is hydrogen and P₄ is methyl, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form an azetidine ring,
  • R₅ is cyclohexylmethyl or 4-methylbenzyl,
  • P₅ is methyl or ethyl,
  • R_7A, R_7B, and R_7C are independently selected from the group consisting of hydrogen, fluorine, chlorine, and trifluoromethyl,
  • R_8A is hydrogen or ethoxy,
  • R₁₀ is cyclopentyl or cyclohexyl, and
  • R_11A and R_11B are both methyl, or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a piperidine ring or a morpholine ring.

The therapeutic agent or preventive agent according to any one of [27] to [29], wherein the cyclic peptide compound is selected from the group consisting of:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-8-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4, 7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoroethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, and
• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

The therapeutic agent or preventive agent according to any one of [27] to [30], wherein the cyclic peptide compound is:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

The therapeutic agent or preventive agent according to any one of [27] to [30], wherein the cyclic peptide compound is:

• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

The therapeutic agent or preventive agent according to any one of [27] to [30], wherein the cyclic peptide compound is:

• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.

The therapeutic agent or preventive agent according to any one of [27] to [30], wherein the cyclic peptide compound is: (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

A therapeutic agent or preventive agent for a disease, comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof.

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof

[34-8]

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

[34-9]

A therapeutic agent or preventive agent for a disease comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or solvate thereof.

[34-10]

A therapeutic agent or preventive agent comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or hydrate thereof.

[34-11]

A therapeutic agent or preventive agent for a disease comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or hydrate thereof.

[34-12]

A therapeutic agent or preventive agent for a disease comprising (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.

[34-13]

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22-1)-undecaone or salt thereof, or solvate thereof.

[34-14]

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or hydrate thereof.

[34-15]

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or hydrate thereof.

[34-16]

A therapeutic agent or preventive agent for a disease comprising (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

[35]

The therapeutic agent or preventive agent according to any one of [27] to [34] and [34-1] to [34-16], wherein the therapeutic agent or preventive agent is a RAS inhibitor.

[36]

The therapeutic agent or preventive agent according to [35], wherein the Ras inhibitor is one or more Ras inhibitors selected from the group consisting of Kras inhibitors, Nras inhibitors, and Hras inhibitors.

[37]

The therapeutic agent or preventive agent according to any one of [27] to [36], wherein the therapeutic agent or preventive agent is for treating or preventing cancer.

[38]

The therapeutic agent or preventive agent according to [37], wherein the cancer is solid cancer or hematological cancer.

[39]

The therapeutic agent or preventive agent according to [37] or [38], wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[14]

The therapeutic agent or preventive agent according to any one of [37] to [39], wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine body cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[41]

The therapeutic agent or preventive agent according to any one of [37] to [40], wherein the cancer is associated with an abnormality of a Ras gene.

[42]

The therapeutic agent or preventive agent according to [41], wherein the abnormality of a Ras gene is a mutation in the coding region of the Ras gene and/or an amplification of the copy number of the Ras gene.

[43]

The therapeutic agent or preventive agent according to [41] or [42], wherein the Ras gene is one or more Ras genes selected from the group consisting of Kras gene, Nras gene, and Hras gene.

[44]

The therapeutic agent or preventive agent according to [43], wherein the Ras gene is Kras gene.

[45]

The therapeutic agent or preventive agent according to any one of [37] to [44], wherein the cancer is associated with generation of a mutant Ras protein and/or increased generation of a Ras protein.

[46]

The therapeutic agent or preventive agent according to [45], wherein the cancer is associated with generation of a mutant Ras protein.

[47]

The therapeutic agent or preventive agent according to [45] or [46], wherein the mutant Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant Hras proteins.

[48]

The therapeutic agent or preventive agent according to [47], wherein the mutant Ras protein is a mutant Kras protein.

[49]

The therapeutic agent or preventive agent according to any one of [45] to [48], wherein the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences set forth in SEQ ID Nos: 6, 7, or 8.

[50]

The therapeutic agent or preventive agent according to any one of [45] to [49], wherein the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence set forth in SEQ ID No: 6.

[51]

The therapeutic agent or preventive agent according to any one of [45] to [49], wherein the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G 13D, G13V, Q61K, and Q61 L as compared to the amino acid sequence set forth in SEQ ID No: 7.

[52]

The therapeutic agent or preventive agent according to any one of [45] to [49], wherein the mutant Ras protein is a mutant Iras protein and has an amino acid mutation of C13R as compared to the amino acid sequence set forth in SEQ ID No: 8.

[53]

A cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof, for use in treatment or prevention of a disease:

wherein,

• • L₁ is a single bond, or —CHM₁, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and in are each independently 1 or 2,
  • R₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ aikoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₁ and P₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and Q₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and M₁, together with the carbon atom to which R₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁ and P₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₈ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁ is hydrogen or C₁-C₆ alkyl, and
  • except when R₁ and M₁ form a 3- to 8-membered alicyclic ring, M₁ is hydrogen,
  • R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C₁-C₆ alkylsulfonyl, or
  • R₂ and P₂, together with the carbon atom to which R₂ is attached and the nitrogen atom to which P₂ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₂ and Q₂, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, P₂ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₂ is hydrogen or C₁-C₆ alkyl,
  • R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₁-C₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), or
  • R₃ and P₃, together with the carbon atom to which R₃ is attached and the nitrogen atom to which P₃ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₃ and Q₃, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₃ and P₃ form a 4- to 7-membered saturated heterocyclic ring, P₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C₁-C₆ aminoalkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino is optionally substituted with one or more halogens),
  • except when R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₃ is hydrogen or C₁-C₆ alkyl,
  • R₄ is hydrogen or C₁-C₆ alkyl, or
  • R₄ and P₄, together with the carbon atom to which R₄ is attached and the nitrogen atom to which P₄ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₄ and Q₄, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₄j and Q₄ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₄ is hydrogen or C₁-C₆ alkyl,
  • R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl. C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, and C₁-C₆ alkylsulfonyl, or R₅ together with R₈ forms C₄-C₈ alkylene, or
  • R₅ and P₅, together with the carbon atom to which R₅ is attached and the nitrogen atom to which P₅ is attached, form a 4- to 7-membered saturated heterocyclic ring, or R₈ and Q₈, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₅ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₅ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₈ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₆ is hydrogen or C₁-C₆ alkyl, or
  • R₆ and P₆, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₆ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₆ and Q₆, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₆ and P₆ form a 4- to 7-membered saturated heterocyclic ring, P₆ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₆ and Q, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₆ is hydrogen or C₁-C₆ alkyl,
  • R₇ is C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, C₁-C₆ alkylsulfonyl, and SF₅, or
  • R₇ and P₇, together with the carbon atom to which R₇ is attached and the nitrogen atom to which P₇ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₇ and Q₇, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₇ and P₇ form a 4- to 7-membered saturated heterocyclic ring, P₇ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₇ is hydrogen or C₁-C₆ alkyl,
  • R₈ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, 5- to 10-membered heteroarylC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C₁-C₆ alkyl, C₁C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆, haloalkoxy, cyano, amino (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkylidene, protected 4- to 7-membered heterocycloalkylidene, 4- to 7-membered heterocyclyl, and protected 4- to 7-membered heterocyclyl, or R₈ together with R₅ forms C₄-C₈ alkylene, or
  • R₈ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS₈, and S₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₇-C₁₄ aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy), or 5- to 10-membered heteroarylC₁-C₆ alkyl, or
  • R₈ and Q₈, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₈ and P₈ form a 4- to 7-membered saturated heterocyclic ring, P₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₈ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl, C₇-C₁₄ aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen or C₁-C₆ alkyl), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₈ and _Q8 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₉ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₁ cycloalkylC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₉ and P₉, together with the carbon atom to which R₉ is attached and the nitrogen atom to which P₉ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₄ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₉ and P₉ form a 4- to 7-membered saturated heterocyclic ring, P₉ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₉ is hydrogen or C₁-C₆ alkyl,
  • R₁₀ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C₁-C₆ alkylsulfonyl, or
  • R₁₀ and P₁₀, together with the carbon atom to which R₁₀ is attached and the nitrogen atom to which P₁₀ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₀ and Q₁₀, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁₀ and P₁₀ form a 4- to 7-membered saturated heterocyclic ring, P₁₀ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₀ and Q₁₀ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₀ is hydrogen or C₁-C₆ alkyl, and
  • L₁₁ is a single bond, or —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and m are each independently 1 or 2,
  • R₁₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or aminocarbonyl (wherein the amino is —NH₂, mono C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C₁-C₆ alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or R₁₁ is a peptide chain containing 1 to 4 amino acid residues, or
  • R₁₁ and P₁₁, together with the carbon atom to which R₁₁ is attached and the nitrogen atom to which P₁₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and Q₁₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and M₁₁, together with the carbon atom to which R₁₁ is attached and the carbon atom to which M₁₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, P₁₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₁ is hydrogen or C₁-C₆ alkyl,
  • except when R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring, M₁₁ is hydrogen,
  • wherein, when L₁₁ is a single bond, L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, and when L₁₁ is —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, L₁₁ is a single bond, and
  • at least three of P₁ to P₁₁ are not hydrogen.[54]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [53], wherein the cyclic peptide compound is represented by formula (2) below:

wherein,

• • R₁ is C₁-C₆ alkyl,
  • P₁ is C₁-C₆ alkyl,
  • R₂ is C₁-C₆ alkyl,
  • P₂ is hydrogen,
  • R₃ is hydrogen or C₁-C₆ alkyl,
  • P₃ is C₁-C₆ alkyl,
  • R₄ is hydrogen, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is C₁-C₆ alkyl,
  • R₅ is C₃-C₈ cycloalkylC₁-C₆ alkyl or C₇-C₁₄ aralkyl optionally substituted with C₁-C₆ alkyl,
  • P₅ is C₁-C₆ alkyl,
  • R₆ is hydrogen,
  • P₆ is C₁-C₆ alkyl,
  • R₇ is C₇-C₁₄ aralkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl,
  • Q₇ is hydrogen,
  • P₇ is hydrogen,
  • R₈ and P₈, together with the nitrogen atom to which P₈ is attached and the carbon atom to which R₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with C₁-C₆ alkoxy,
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring,
  • P₉ is hydrogen,
  • R₁₀ is C₃-C₈ cycloalkyl,
  • P₁₀ is C₁-C₆ alkyl,
  • R₁₁ is di-C₁-C₆ alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl,
  • M₁₁ is hydrogen, and
    • P₁₁ is C₁-C₆ alkyl.[55]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [54], wherein the compound is represented by formula below:

wherein,

• • R₃ is hydrogen or methyl,
  • R₄ is hydrogen and P₄ is methyl, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form an azetidine ring,
  • R₅ is cyclohexylmethyl or 4-methylbenzyl,
  • P₅ is methyl or ethyl,
  • R_7A, R_7B, and R_7C are independently selected from the group consisting of hydrogen, fluorine, chlorine, and trifluoromethyl,
  • R_8A is hydrogen or ethoxy,
  • R₁₀ is cyclopentyl or cyclohexyl, and
  • R_11A and R_11B are both methyl, or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a piperidine ring or a morpholine ring.[56]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [53] to [55], wherein the compound is selected from the group consisting of:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacycltetratriacontine-2,1′-cyclopentane]-15-carboxamide,
• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, and
• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.[57]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of to [56], wherein the compound is:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.[58]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [53] to [56], wherein the cyclic peptide compound is:

• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.[59]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [53] to [56], wherein the cyclic peptide compound is:

• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.[60]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [53] to [56], wherein the cyclic peptide compound is:

• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.[60-1]

(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof, for use in treatment or prevention of a disease.

[60-2]

(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4, 7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof, for use in treatment or prevention of a disease.

[60-3]

(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof, for use in treatment or prevention of a disease.

[60-4]

(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-1-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide, for use in treatment or prevention of a disease.

[60-5]

(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof, for use in treatment or prevention of a disease.

[60-6]

(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof, for use in treatment or prevention of a disease.

[60-7]

(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylacetyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof, for use in treatment or prevention of a disease.

[60-8]

(5S,8S,11S,15S,1S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylacetyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide, for use in treatment or prevention of a disease.

[60-9]

(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or solvate thereof, for use in treatment or prevention of a disease.

[60-10]

(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or hydrate thereof, for use in treatment or prevention of a disease.

[60-11]

(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or hydrate thereof, for use in treatment or prevention of a disease.

[60-12]

(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyanopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, for use in treatment or prevention of a disease.

[60-13]

(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or solvate thereof, for use in treatment or prevention of a disease.

[60-14]

(5S,8S,1S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or hydrate thereof, for use in treatment or prevention of a disease.

[60-15]

(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or hydrate thereof, for use in treatment or prevention of a disease.

[60-16]1

(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone, for use in treatment or prevention of a disease.

[61]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [53] to [60] and [60-1] to [60-16], wherein the compound is a Ras inhibitor.

[62]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [61], wherein the Ras inhibitor is one or more Ras inhibitors selected from the group consisting of Kras inhibitors, Nras inhibitors, and Hras inhibitors.

[63]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [53] to [62], wherein the disease is cancer.

[64]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [63], wherein the cancer is solid cancer or hematological cancer.

[65]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [63] or [64], wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[66]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [63] to [65], wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine body cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL. (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[67]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [63] to [66], wherein the cancer is associated with an abnormality of a Ras gene.

[68]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [67], wherein the abnormality of a Ras gene is a mutation in the coding region of the Ras gene and/or an amplification of the copy number of the Ras gene.

[69]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [67] or [68], wherein the Ras gene is one or more Ras genes selected from the group consisting of Kras gene, Nras gene, and Hras gene.

[70]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [69], wherein the Ras gene is Kras gene.

[71]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [63] to [70], wherein the cancer is associated with generation of a mutant Ras protein and/or increased generation of a Ras protein.

[72]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [71], wherein the cancer is associated with generation of a mutant Ras protein.

[73]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [71] or [20], wherein the mutant Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant Hras proteins.

[74]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to [73], wherein the mutant Ras protein is a mutant Kras protein.

[75]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [71] to [74], wherein the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences set forth in SEQ ID Nos: 6, 7, or 8.

[76]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [71] to [75], wherein the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence set forth in SEQ ID No: 6.

[77]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to any one of [71] to [75], wherein the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G3D, G13V, Q61K, and Q61L as compared to the amino acid sequence set forth in SEQ ID No: 7.

[78]

The cyclic peptide compound or salt thereof, or solvate thereof for use according to to any one of [71] to [75], wherein the mutant Ras protein is a mutant Hras protein and has an amino acid mutation of G13R as compared to the amino acid sequence set forth in SEQ ID No: 8.

[79]

A method for treating or preventing a disease, the method comprising administering to a subject a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof

wherein,

• • L₁ is a single bond, or —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_mS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and m are each independently 1 or 2,
  • R₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₆ alkyl, or C₃-C₆ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₁ and P₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and Q₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and M₁, together with the carbon atom to which R₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when Rr and P₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁ is hydrogen or C₁-C₆ alkyl, and
  • except when R₁ and M₁ form a 3- to 8-membered alicyclic ring, M₁ is hydrogen,
  • R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C₁-C₆ alkylsulfonyl, or
  • R₂ and P₂, together with the carbon atom to which R₂ is attached and the nitrogen atom to which P₂ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₂ and Q₂, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, P₂ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₂ is hydrogen or C₁-C₆ alkyl,
  • R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), or
  • R₃ and P₃, together with the carbon atom to which R₃ is attached and the nitrogen atom to which P₃ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₃ and Q₃, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁ and P₃ form a 4- to 7-membered saturated heterocyclic ring, P₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C₁-C₆ aminoalkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino is optionally substituted with one or more halogens),
  • except when R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₃ is hydrogen or C₁-C₆ alkyl,
  • R₄ is hydrogen or C₁-C₆ alkyl, or
  • R₄ and P₄, together with the carbon atom to which R₄ is attached and the nitrogen atom to which P₄ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₄ and Q₄, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₄ and Q₄ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₄ is hydrogen or C₁-C₆ alkyl,
  • R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆, alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, and C₁-C₆ alkylsulfonyl, or R₅ together with R₈ forms C₄-C₆ alkylene, or
  • R₅ and P₅, together with the carbon atom to which R is attached and the nitrogen atom to which P₅ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₅ and Q₅, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₈ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₅ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₄ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₆ is hydrogen or C₁-C₆ alkyl, or
  • R₆ and P₆, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₆ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₆ and Q₆, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₆ and P₆ form a 4- to 7-membered saturated heterocyclic ring, P₆ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R(and Q₆ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₆ is hydrogen or C₁-C₆ alkyl,
  • R₇ is C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₁-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, C₁-C₆ alkylsulfinyl, and SF₅, or
  • R₇ and P₇, together with the carbon atom to which R₇ is attached and the nitrogen atom to which P₇ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₇ and Q₇ together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₇ and P₇ form a 4- to 7-membered saturated heterocyclic ring, P₇ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₇ is hydrogen or C₁-C₆ alkyl,
  • R₈ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyC₁-C₆ alkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, 5- to 10-membered heteroarylC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, amino (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkylidene, protected 4- to 7-membered heterocycloalkylidene, 4- to 7-membered heterocyclyl, and protected 4- to 7-membered heterocyclyl, or R₈ together with R₈ forms C₄-C₈ alkylene, or
  • R₈ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS₈, and S₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₇-C₁₄ aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy), or 5- to 10-membered heteroarylC₁-C₆ alkyl, or
  • R₈ and Q₈, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₈ and P₈ form a 4- to 7-membered saturated heterocyclic ring, P₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl, C₇-C₄ aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen or C₁-C₆ alkyl), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₉ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₆ cycloalkylC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₉ and P₉, together with the carbon atom to which R₉ is attached and the nitrogen atom to which P₉ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₉ and P₉ form a 4- to 7-membered saturated heterocyclic ring, P₉ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₉ is hydrogen or C₁-C₆ alkyl,
  • R₁₀ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C₁-C₆ alkylsulfonyl, or
  • R₁₀ and P₁₀, together with the carbon atom to which R₁₀ is attached and the nitrogen atom to which P₁₀ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₀ and Q₁₀, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁₀ and P₁₀ form a 4- to 7n-membered saturated heterocyclic ring, P₁₀ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₀ and Q₁₀ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₀ is hydrogen or C₁-C₆ alkyl, and
  • L₁₁ is a single bond, or —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₁)_m—, wherein n and in are each independently 1 or 2,
  • R₁₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or aminocarbonyl (wherein the amino is 4NH₂, mono C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C₁-C₆ alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆alkylsulfonyl, or R₁₁ is a peptide chain containing 1 to 4 amino acid residues, or
  • R₁₁ and P₁₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and Q₁₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and M₁₁, together with the carbon atom to which R₁₁ is attached and the carbon atom to which M₁₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, P₁₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₁ is hydrogen or C₁-C₆ alkyl,
  • except when R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring, M₁₁ is hydrogen,
  • wherein, when L₁₁ is a single bond, L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, (CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, and when L₁ is —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, L₁₁ is a single bond, and at least three of P₁ to P₁₁ are not hydrogen.[80]

The method according to [79], wherein the cyclic peptide compound is represented by formula (2) below:

wherein,

• • R₁ is C₁-C₆ alkyl,
  • P₁ is C₁-C₆ alkyl,
  • R₂ is C₁-C₆ alkyl,
  • P₂ is hydrogen,
  • R₁ is hydrogen or C₁-C₆ alkyl,
  • P₃ is C₁-C₆ alkyl,
  • R₄ is hydrogen, or
  • R₄ and P₄, together With the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is C₁-C₆ alkyl,
  • R₅ is C₃-C₈ cycloalkylC₁-C₆ alkyl Or C₂-C₁₄ aralkyl optionally substituted with C₁-C₆ alkyl,
  • P₅ is C₁-C₆ alkyl,
  • R₆ is hydrogen,
  • P₆ is C₁-C₆ alkyl,
  • R₇ is C₇-C₁₄ aralkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl,
  • Q₇ is hydrogen,
  • P₇ is hydrogen,
  • R₈ and P₈, together with the nitrogen atom to which P_K is attached and the carbon atom to which R₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with C₁-C₆ alkoxy,
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring,
  • P₉ is hydrogen,
  • R₁₀ is C₃-C₈ cycloalkyl,
  • P₁₀ is C₁-C₆ alkyl,
  • R₁₁ is di-C₁-C₆ alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl,
  • M₁₁ is hydrogen, and
  • P₁₁ is C₁-C₆ alkyl.[81]

The method according to [80], wherein the cyclic peptide compound is represented by formula below:

wherein

• • R₃ is hydrogen or methyl,
  • R₄ is hydrogen and P₄ is methyl, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form an azetidine ring,
  • R₅ is cyclohexylmethyl or 4-methylbenzyl,
  • P₅ is methyl or ethyl,
  • R_7A, R_7B, and R_7C are independently selected from the group consisting of hydrogen, fluorine, chlorine, and trifluoromethyl,
  • R_8A is hydrogen or ethoxy,
  • R₁₀ is cyclopentyl or cyclohexyl, and
  • R_11A and R_11B are both methyl, or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a piperidine ring or a morpholine ring.[82]

The method according to any one of [79] to [81], wherein the cyclic peptide compound is selected from the group consisting of:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, and
• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.[83]

The method according to any one of [79] to [82], wherein the cyclic peptide compound is:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-Cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.[84]

The method according to any one of [79] to [82], wherein the cyclic peptide compound is:

• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.[85]

The method according to any one of [79] to [82], wherein the cyclic peptide compound is:

• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.[86]

The method according to any one of [79] to [82], wherein the cyclic peptide compound is:

• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.[86-1]

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof.

[86-2]

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,2 3aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4, 7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof.

[86-3]

A method for treating or preventing a disease, the method comprising administering to a Subject (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4, 7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof.

[86-4]

A method for treating or preventing a disease, the method comprising administering to a Subject (5S,8S,11S,15S,18S,23As,29S,35S,37As)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4, 7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

[86-5]

A method for treating or preventing a disease, the method comprising administering to a Subject (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof.

[86-6]

A method for treating or preventing a disease, the method comprising administering to a Subject (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof.

[86-7]1

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-21H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof

[86-8]

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

[86-9]

A method for treating or preventing a disease, the method comprising administering to a subject (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or solvate thereof

[86-10]

A method for treating or preventing a disease, the method comprising administering to a subject (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or hydrate thereof

[86-11]

A method for treating or preventing a disease, the method comprising administering to a subject (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or hydrate thereof

[86-12]

A method for treating or preventing a disease, the method comprising administering to a subject (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.

[86-13]

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or solvate thereof

[86-14]

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or hydrate thereof

[60-15]

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or hydrate thereof.

[86-16]

A method for treating or preventing a disease, the method comprising administering to a subject (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

[87]

The method according to any one of [79] to [86] and [86-1] to [86-16], wherein the cyclic peptide compound or salt thereof, or solvate thereof is a Ras inhibitor.

[88]

The method according to [87], wherein the Ras inhibitor is one or more Ras inhibitors selected from the group consisting of Kras inhibitors, Nras inhibitors, and 1Hras inhibitors.

[89]

The method according to any one of [79] to [88], wherein the disease is cancer.

[90]

The method according to [89], wherein the cancer is solid cancer or hematological cancer.

[91]

The method according to [89] or [90], wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[92]

The method according to any one of [89] to [91], wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine body cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[93]

The method according to any one of [89] to [92], wherein the cancer is associated with an abnormality of a Ras gene.

[94]

The method according to [93], wherein the abnormality of a Ras gene is a mutation in the coding region of the Ras gene and/or an amplification of the copy number of the Ras gene.

[95]

The method according to [93] or [94], wherein the Ras gene is one or more Ras genes selected from the group consisting of Kras gene, Nras gene, and Hras gene.

[96]

The method according to [95], wherein the Ras gene is Kras gene.

[97]

The method according to any one of [89] to [96], wherein the cancer is associated with generation of a mutant Ras protein and/or increased generation of a Ras protein.

[98]

The method according to [97], wherein the cancer is associated with generation of a mutant Ras protein.

[99]

The method according to [97] or [98], wherein the mutant Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant Hras proteins.

[100]

The method according to [99], wherein the mutant Ras protein is a mutant Kras protein.

[101]

The method according to any one of [97] to [100], wherein the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences set forth in SEQ ID Nos: 6, 7, or 8.

[102]

The method according to any one of [97] to [101], wherein the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence set forth in SEQ ID No: 6.

[103]

The method according to any one of [97] to [101], wherein the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L as compared to the amino acid sequence set forth in SEQ ID No: 7.

[104]

The method according to any one of [97] to [101], wherein the mutant Ras protein is a mutant Hras protein and has an amino acid mutation of G13R as compared to the amino acid sequence set forth in SEQ ID No: 8.

[105] Use of a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof, in the manufacture of a medicament for treating or preventing a disease:

wherein,

• • L₁ is a single bond, or —CHM₁, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and in are each independently 1 or 2,
  • R₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₆ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₁ and P₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and Q₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and M₁, together with the carbon atom to which R₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁ and P₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₈ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁ is hydrogen or C₁-C₆ alkyl, and
  • except when R₁ and M₁ form a 3- to 8-membered alicyclic ring, M₁ is hydrogen,
  • R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C₁-C₆ alkylsulfonyl, or
  • R₂ and P₂, together with the carbon atom to which R₂ is attached and the nitrogen atom to which P₂ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₂ and Q₂, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, P₂ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₂ is hydrogen or C₁-C₆ alkyl,
  • R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), or
  • R₃ and P₃, together with the carbon atom to which R₃ is attached and the nitrogen atom to which P₃ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₃ and Q₃, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₃ and P₃ form a 4- to 7-membered saturated heterocyclic ring, P₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₃-C₈ cycloalkyl, each of-which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C₁-C₆ aminoalkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino is optionally substituted with one or more halogens),
  • except when R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₃ is hydrogen or C₁-C₆ alkyl,
  • R₄ is hydrogen or C₁-C₆ alkyl, or
  • R₄ and P₄, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₄ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₄ and Q₄, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₄j and Q₄ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₄ is hydrogen or C₁-C₆ alkyl,
  • R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl. C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, and C₁-C₆ alkylsulfonyl, or R₅ together with R₈ forms C₄-C₈ alkylene, or
  • R₅ and P₅, together with the carbon atom to which R₅ is attached and the nitrogen atom to which P₅ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₅ and Q₅, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₅ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₅ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₈ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₆ is hydrogen or C₁-C₆ alkyl, or
  • R₆ and P₆, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₆ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₆ and Q₆, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₆ and P₆ form a 4- to 7-membered saturated heterocyclic ring, P₆ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₆ and Q₆ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₆ is hydrogen or C₁-C₆ alkyl,
  • R₇ is C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, C₁-C₆ alkylsulfonyl, and SF₅, or
  • R₇ and P₇, together with the carbon atom to which R₇ is attached and the nitrogen atom to which P₇ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₇ and Q₇, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₇ and P₇ form a 4- to 7-membered saturated heterocyclic ring, P₇ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₇ is hydrogen or C₁-C₆ alkyl,
  • R₈ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, 5- to 10-membered heteroarylC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆, haloalkoxy, cyano, amino (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkylidene, protected 4- to 7-membered heterocycloalkylidene, 4- to 7-membered heterocyclyl, and protected 4- to 7-membered heterocyclyl, or R₈ together with R₅ forms C₄-C₈ alkylene, or
  • R₈ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS₈, and S₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₇-C₁₄ aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy), or 5- to 10-membered heteroarylC₁-C₆ alkyl, or
  • R₈ and Q₈, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₈ and P₈ form a 4- to 7-membered saturated heterocyclic ring, P₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₈ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl, C₇-C₁₄ aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen or C₁-C₆ alkyl), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl,
  • R₉ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₁ cycloalkylC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C-Cc, alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₉ and P₉, together with the carbon atom to which R₉ is attached and the nitrogen atom to which P₉ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₉ and P₉ from a 4- to 7-membered saturated heterocyclic ring, P₉ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₉ is hydrogen or C₁-C₆ alkyl,
  • R₁₀ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₆ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C₁-C₆ alkylsulfonyl, or
  • R₁₀ and P₁₀, together with the carbon atom to which R₁₀ is attached and the nitrogen atom to which P₁₀ is attached, form a 4- to 7-membered saturated heterocyclic ring, or R₁₀ and Q₁₀, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁₀ and P₁₀ form a 4- to 7-membered saturated heterocyclic ring, P₁₀ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₀ and Q₁₀ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₀ is hydrogen or C₁-C₆ alkyl, and
  • L₁₁ is a single bond, or —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and m are each independently 1 or 2,
  • R₁₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or aminocarbonyl (wherein the amino is —NH₂, mono C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C₁-C₆ alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or R₁₁ is a peptide chain containing 1 to 4 amino acid residues, or
  • R₁₁ and P₁₁, together with the carbon atom to which R₁₁ is attached and the nitrogen atom to which P₁₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and Q₁₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and M₁₁, together with the carbon atom to which R₁₁ is attached and the carbon atom to which M₁₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, P₁₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₁ is hydrogen or C₁-C₆ alkyl,
  • except when R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring, M₁₁ is hydrogen,
  • wherein, when L₁ is a single bond, L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, and when L₁ is —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, L₁₁ is a single bond, and
  • at least three of P₁ to P₁₁ are not hydrogen.[106]

Use according to [105], wherein the cyclic peptide compound is represented by formula (2) below:

wherein,

• • R₁ is C₁-C₆ alkyl,
  • P₁ is C₁-C₆ alkyl,
  • R₂ is C₁-C₆ alkyl,
  • P₂ is hydrogen,
  • R₃ is hydrogen or C₁-C₆ alkyl,
  • P₃ is C₁-C₆ alkyl,
  • R₄ is hydrogen, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is C₁-C₆ alkyl,
  • R₅ is C₃-C₈ cycloalkylC₁-C₆ alkyl or C₇-C₁₄ aralkyl optionally substituted with C₁-C₆ alkyl,
  • P₅ is C₁-C₆ alkyl,
  • R₆ is hydrogen,
  • P₆ is C₁-C₆ alkyl,
  • R₇ is C₇-C₁₄ aralkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl,
  • Q₇ is hydrogen,
  • P₂ is hydrogen,
  • R₈ and P₈, together with the nitrogen atom to which P₈ is attached and the carbon atom to which R₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with C₁-C₆ alkoxy,
  • R₃ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring,
  • P₉ is hydrogen,
  • R₁₀ is C₃-C₈ cycloalkyl,
  • P₁₀ is C₁-C₆ alkyl,
  • R₁₁ is di-C₁-C₆ alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl,
  • M₁₁ is hydrogen, and
  • P₁₁ is C₁-C₆ alkyl.

[107] Use according to [106], wherein the cyclic peptide compound is represented by formula below:

wherein

• • R₃ is hydrogen or methyl,
  • R₄ is hydrogen and P₄ is methyl, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form an azetidine ring,
  • R₅ is cyclohexylmethyl or 4-methylbenzyl,
  • P₅ is methyl or ethyl,
  • R_7A, R_7B, and R_7C are independently selected from the group consisting of hydrogen, fluorine, chlorine, and trifluoromethyl,
  • R_8A is hydrogen or ethoxy,
  • R₁₀ is cyclopentyl or cyclohexyl, and
  • R_11A and R_11B are both methyl, or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a piperidine ring or a morpholine ring.

[108] Use according to any one of [105] to {107}, wherein the cyclic peptide compound is selected from the group consisting of:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacycltetratriacontine-2,1′-cyclopentane]-15-carboxamide,
• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, and
• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-Undecaone.

[109] Use according to any one of [105] to [108], wherein the cyclic peptide compound is: (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

[110] Use according to any one of [105] to [108], wherein the cyclic peptide compound is: (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

[111] Use according to any one of [105] to [108], wherein the cyclic peptide compound is: (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.

[112] Use according to any one of [105] to [108], wherein the cyclic peptide compound is: (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

[112-1]

Use of (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-indecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-2]

Use of (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-a]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-3]

Use of (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-4]

Use of (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide, in the manufacture of a medicament for treating or preventing a disease.

[112-5]

Use of(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-21H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-6]

Use of (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-2,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-7]

Use of (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-8]

Use of (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide, in the manufacture of a medicament for treating or preventing a disease.

[112-9]

Use of (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or solvate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-10]

Use of (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-11]

Use of (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-12]

Use of (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, in the manufacture of a medicament for treating or preventing a disease.

[112-13]

Use of (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or solvate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-14]

Use of (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-15]

Use of (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or hydrate thereof, in the manufacture of a medicament for treating or preventing a disease.

[112-16]

Use of(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone, in the manufacture of a medicament for treating or preventing a disease.

[113]

Use according to any one of [105] to [112] and [112-1] to [112-16], wherein the cyclic peptide compound or salt thereof, or solvate thereof is a Ras inhibitor.

[114]

Use according to [113], wherein the Ras inhibitor is one or more Ras inhibitors selected from the group consisting of Kras inhibitors, Nras inhibitors, and Hras inhibitors.

[115]

Use according to any one of [105] to [114], wherein the disease is cancer.

[116]

Use according to [115], wherein the cancer is solid cancer or hematological cancer.

[117]

Use according to [115] or [116], wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[118]

Use according to any one of [115] to [117], wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine body cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[119]

Use according to any one of [115] to [118], wherein the cancer is associated with an abnormality of a Ras gene.

[120]

Use according to [119], wherein the abnormality of a Ras gene is a mutation in the coding region of the Ras gene and/or an amplification of the copy number of the Ras gene.

[121]

Use according to [119] or [120], wherein the Ras gene is one or more Ras genes selected from the group consisting of Kras gene, Nras gene, and Hras gene.

[122]

Use according to [121], wherein the Ras gene is Kras gene.

[123]

Use according to any one of [115] to [122], wherein the cancer is associated with generation of a mutant Ras protein and/or increased generation of a Ras protein.

[124]

Use according to [123], wherein the cancer is associated with generation of a mutant Ras protein.

[125]

Use according to [123] or [124], wherein the mutant Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant Bras proteins.

[126]

Use according to [125], wherein the mutant Ras protein is a mutant Kras protein.

[127]

Use according to any one of [123] to [126], wherein the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences set forth in SEQ ID Nos: 6, 7, or 8.

[128]

Use according to any one of [123] to [127], wherein the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence set forth in SEQ ID No: 6.

[129]

Use according to any one of [123] to [127], wherein the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, GI3D, G13V, Q61K, and Q61L as compared to the amino acid sequence set forth in SEQ ID No: 7.

[130]

Use according to any one of [123] to [127], wherein the mutant Ras protein is a mutant Hras protein and has an amino acid mutation of G13R as compared to the amino acid sequence set forth in SEQ ID No: 8.

[131]

A cyclic peptide compound or salt thereof, or solvate thereof, comprising 8 to 15 amino acid residues that binds to a Ras protein containing the amino acid sequence set forth in SEQ ID No: 9, wherein the compound comprises

• • i) at least three N-substituted amino acid residues,
  • ii) at least one non-N-substituted amino acid residue, and
  • iii) a cyclic moiety containing at least eight amino acid residues, andwherein
  • iv) the compound interacts with at least one amino acid selected from the group consisting of Val8, Gly10, Lys16, Glu37, Leu56, Gln70, Tyr71, and Glu98 of the Ras protein.[132]

The cyclic peptide compound or salt thereof, or solvate thereof according to [131], wherein

• • the compound interacts with at least one amino acid selected from the group consisting of Val7, Val9, Ala11, Xaa12, Thr58, Ala59, Gly60. Xaa61, Glu62, Glu63, Tyr64, Arg68, Asp69, Met72, Arg73, Phe78, Asp92, Xaa95, Tyr96, Gln99, Ile100, Arg102, and Val103 of the Ras protein,
  • the Xaa12 is an amino acid selected from the group consisting of Gly, Asp, Cys, Ser, Val, Ala, and Arg,
  • the Xaa61 is an amino acid selected from the group consisting of Gln, His, Lys, and Leu, and/or
  • the Xaa95 is an amino acid selected from the group consisting of Gln, His, and Leu.[133]

The cyclic peptide compound or salt thereof, or solvate thereof according to [131] or [132], wherein

• • the compound interacts with at least one amino acid selected from the group consisting of Val9, Thr58, Xaa61, Glu62, Tyr64, Arg68, Met72, Asp92, Xaa95, Tyr96, Gln99, Arg102, and Val103 of the Ras protein,
  • the Xaa61 is an amino acid selected from the group consisting of Gln, His, Lys, and Leu, and/or
  • the Xaa95 is an amino acid selected from the group consisting of Gln, His, and Leu.[134]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [131] to [133], wherein

• • the compound interacts with at least one amino acid selected from the group consisting of Thr58, Xaa61, Arg68, Gln99, and Arg102 of the Ras protein, and
  • the Xaa61 is an amino acid selected from the group consisting of Gin, His, Lys, and Leu.[135]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [131] to [134], wherein the compound interacts with at least one amino acid selected from the group consisting of Gly10, Leu56, Tyr71, and Glu98 of the Ras protein.

[136]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [131] to [135], wherein

• • the compound further interacts with at least two amino acids selected from the group consisting of Thr58, Xaa61, Arg68, Gln99, and Arg102 of the Ras protein, and
  • the Xaa61 is an amino acid selected from the group consisting of GLn, His, Lys, and Leu.[137]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [131] to [136], wherein the compound interacts with at least two amino acids selected from the group consisting of Gly10, Leu56, Tyr71, and Glu98 of the Ras protein.

[138]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [131] to [137], wherein the Ras protein is one or more Ras proteins selected from the group consisting of Kras protein, Nras protein, and Hras protein.

[139]

The cyclic peptide compound or salt thereof, or solvate thereof according to [138], wherein the Ras protein is Kras protein.

[140]

The cyclic peptide compound or salt thereof, or solvate thereof according to [131] or [139], wherein the Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant Hras proteins.

[141]

The cyclic peptide compound or salt thereof, or solvate thereof according to [139] or

[140], wherein

• • the Ras protein is a mutant Kras protein,
  • Xaa12 is an amino acid selected from the group consisting of Asp, Cys, Ser, Val, and Ala, and/or
  • Xaa61 is an amino acid selected from His or Lys.[142]

The cyclic peptide compound or salt thereof, or solvate thereof according to [139], wherein

• • the Ras protein is a mutant Nras protein,
  • Xaa12 is an amino acid selected from Asp or Cys, and/or
  • Xaa61 is an amino acid selected from Lys or Leu.[143]

The cyclic peptide compound or salt thereof, or solvate thereof according to [131] to [142], wherein

• • the cyclic peptide compound is composed of eleven amino acid residues,
  • one of the amino acid residues is an amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group, wherein the amino acid residue is optionally N-substituted and is linked to the adjacent amino acid residue on the C-terminal side via the carbonyl group,
  • an amino acid residue located four amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group is a N-substituted amino acid residue, and
  • an amino acid residue located seven amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group contains —(CH₂)_x—O_y—(CH₂)_z1—C₆-C₁₀ aryl or —(CH₂)_x—O_y—(CH₂)_z2-5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C₁-C₄ alkyl, C₂-C₄ alkynyl, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, C₁-C₄ alkoxy, —CN, C₁-C₃ alkylsulfonyl, hydroxy, and SF₅, wherein
  • x is 1, 2, or 3,
  • y is 0 or 1,
  • z1 is 0, 1, 2, or 3, and
  • z2 is 1, 2, or 3,
  • provided that the sum of x, y, and z1 or z2 is 1 to 4.[144]

The cyclic peptide compound or salt thereof, or solvate thereof according to [143], wherein an amino acid residue located seven amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group is Hph(4-CF3-3-Cl).

[145]

The cyclic peptide compound or salt thereof, or solvate thereof according to [143] or [144], wherein an amino acid residue located four amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group is MeCGly or Aze(2).

[146]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [143] to [145], wherein an amino acid residue located seven amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group interacts with one or more selected from Tyr71, Leu56, and Glu37 of the Ras protein.

[147]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [143] to [146], wherein an amino acid residue located four amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group interacts with Glu98 of the Ras protein.

[148]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [143] to [147], wherein amino acid residues located seven amino acid residues ahead and amino acid residues located eight amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group each interact with one or more selected from Tyr71, Leu56, Glu37, Lys16, and Gly10 of the Ras protein, respectively.

[149]

The cyclic peptide compound or salt thereof, or solvate thereof according to any one of [131] to [148], wherein the compound is selected from the group consisting of:

• (488) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (872) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-ethoxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (2187) (6S,9S,15S,18S,21S,24S,27S,30R,34S)-15-benzyl-21-[(3-chlorophenyl)methyl]-9-[(4-chlorophenyl)methyl]-24,27-bis[(3-fluoro-4-hydroxy-phenyl)methyl]-10,16,30,31-tetramethyl-6-[(1S)-1-methylpropyl]-18-(2-methylsulfonylethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone, and
• (2188) (3S,6S,9S,12S,15S,18S,21S,24S,28S,31S)-18,21-dibutyl-12-[(2-chlorophenoxy)methyl]-6-[(5-fluoro-3-pyridyl)methoxymethyl]-4,10,24,25-tetramethyl-15-[(1S)-1-methylpropyl]-3,9-bis(3-pyridylmethyl)-28-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,29-decazabicyclo[29.3.0]tetratriacontane-2,5,8,11,14,17,20,23,26,30-decone.[149-1]

A hydrate of the cyclic peptide compound according to any one of [131] to [148], wherein the compound is selected from the group consisting of:

• (488) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (872) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl] ]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-ethoxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (2187) (6S,9S,15S,18S,21S,24S,27S,30R,34S)-15-benzyl-21-[(3-chlorophenyl)methyl]-9-[(4-chlorophenyl)methyl]-24,27-bis[(3-fluoro-4-hydroxy-phenyl)methyl]-10,16,30,31-tetramethyl-6-[(1S)-1-methylpropyl]-18-(2-methylsulfonylethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone, and
• (2188) (3S,6S,9S,12S,15S,18S,21S,24S,28S,31S)-18,21-dibutyl-12-[(2-chlorophenoxy)methyl]-6-[(5-fluoro-3-pyridyl)methoxymethyl]-4,10,24,25-tetramethyl-15-[(1S)-1-methylpropyl]-3,9-bis(3-pyridylmethyl)-28-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,29-decazabicyclo[29.3.0]tetratriacontane-2,5,8,11,14,17,20,23,26,30-decone.[150]

A pharmaceutical composition comprising the cyclic peptide compound or salt thereof, or solvate thereof according to any one of [131] to [149].

[151]

The pharmaceutical composition according to [150], wherein the pharmaceutical composition is a RAS inhibitor.

[152]

The pharmaceutical composition according to [151], wherein the Ras inhibitor is one or more Ras inhibitors selected from the group consisting of Kras inhibitors, Nras inhibitors, and Hras inhibitors.

[153]

The pharmaceutical composition according to any one of [150] to [152], wherein the pharmaceutical composition is for treating or preventing cancer.

[154]

The pharmaceutical composition according to [153], wherein the cancer is solid cancer or hematological cancer.

[155]

The pharmaceutical composition according to [153] or [154], wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[156]

The pharmaceutical composition according to any one of [153] to [155], wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine body cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[157]

The pharmaceutical composition according to any one of [153] to [156], wherein the cancer is associated with an abnormality of a Ras gene.

[158]

The pharmaceutical composition according to [157], wherein the abnormality of a Ras gene is a mutation in the coding region of the Ras gene and/or an amplification of the copy number of the Ras gene.

[159]

The pharmaceutical composition according to [157] or [158], wherein the Ras gene is one or more Ras genes selected from the group consisting of Kras gene, Nras gene, and Hras gene.

[160]

The pharmaceutical composition according to [159], wherein the Ras gene is Kras gene.

[161]

The pharmaceutical composition according to any one of [153] to [160], wherein the cancer is associated with generation of a mutant Ras protein and/or increased generation of a Ras protein.

[162]

The pharmaceutical composition according to [161], wherein the cancer is associated with generation of a mutant Ras protein.

[163]

The pharmaceutical composition according to [161] or [162], wherein the mutant Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant Hras proteins.

[164]

The pharmaceutical composition according to [163], wherein the mutant Ras protein is a mutant Kras protein.

[165]

The pharmaceutical composition according to any one of [161] to [164], wherein the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences set forth in SEQ ID Nos: 6, 7, or 8.

[166]

The pharmaceutical composition according to any one of [161] to [165], wherein the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence set forth in SEQ ID No: 6.

[167]

The pharmaceutical composition according to any one of [161] to [163] and [165], wherein the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L as compared to the amino acid sequence set forth in SEQ ID No: 7.

[168]

The pharmaceutical composition according to any one of [161] to [163] and [165], wherein the mutant Ras protein is a mutant 1-ras protein and has an amino acid mutation of G13R as compared to the amino acid sequence set forth in SEQ ID No: 8.

[169]

The pharmaceutical composition according to any one of [149] to [167], comprising a cyclic peptide compound or salt thereof, or solvate thereof, selected from the group consisting of:

• (488) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (872) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-ethoxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-buty)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (2187) (6S,9S,15S,18S,21S,24S,27S,30R,34S)-15-benzyl-21-[(3-chlorophenyl)methyl]-9-[(4-chlorophenyl)methyl]-24,27-bis[(3-fluoro-4-hydroxy-phenyl)methyl]-10,16,30,31-tetramethyl-6-[(1S)-1-methylpropyl]-18-(2-methylsulfonylethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone, and
• (2188) (3S,6S,9S,12S,15S,18S,21S,24S,28S,31S)-18,21-dibutyl-12-[(2-chlorophenoxy)methyl]-6-[(5-fluoro-3-pyridyl)methoxy methyl]-4,10,24,25-tetramethyl-15-[(1S)-1-methylpropyl]-3,9-bis(3-pyridylmethyl)-28-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,29-decazabicyclo[29.3.0]tetratriacontane-2,5,8,11,14,17,20,23,26,30-decone.[169-1]

The pharmaceutical composition according to any one of [149] to [167], comprising a hydrate of a cyclic peptide compound selected from the group consisting of:

• (488) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-1,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (872) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-ethoxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (2187) (6S,9S,15S,18S,21S,24S,27S,30R,34S)-15-benzyl-21-[(3-chlorophenyl)methyl]-9-[(4-chlorophenyl)methyl]-24,27-bis[(3-fluoro-4-hydroxy-phenyl)methyl]-10,16,30,31-tetramethyl-6-[(1S)-1-methylpropyl]-18-(2-methylsulfonylethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone, and
• (2188) (3S,6S,9S,12S,15S,18S,21S,24S,28S,31S)-18,21-dibutyl-12-[(2-chlorophenoxy)methyl]-6-[(5-fluoro-3-pyridyl)methoxy methyl]-4,10,24,25-tetramethyl-15-[(1S)-1-methylpropyl]-3,9-bis(3-pyridylmethyl)-28-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,29-decazabicyclo[29.3.0]tetratriacontane-2,5,8,11,14,17,20,23,26,30-decone.

In the numbering above, numbers cited by dependent items include the branch numbers of those numbers, unless otherwise noted. For example, it is indicated that [2] cited in dependent items includes its branch numbers [2A], [2B], and [2C], and also that, for example, [95] cited in dependent items includes its branch numbers [95-1] to [95-53], along with [95]. The same applies to other numberings.

Effects of the Invention

The present invention can provide novel cyclic peptide compounds having anti-cancer action, and pharmaceutical compositions containing the cyclic peptide compounds or salts thereof, or solvates thereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 schematically shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 488, as shown in Example 6-2. The human Kras G12D mutant is shown as a ribbon representation, while compound 488 and guanosine diphosphate (GDP) are shown as black and gray stick representations, respectively.

FIG. 2 schematically shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 872, as shown in Example 6-3. The human Kras G12D mutant is shown as a ribbon representation, while compound 872 and GDP are shown as black and gray stick representations, respectively.

FIG. 3 schematically shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 1201, as shown in Example 6-4. The human Kras G12D mutant is shown as a ribbon representation, while compound 1201 and GDP are shown as black and gray stick representations, respectively.

FIG. 4-(1) schematically shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 2187, as shown in Example 6-5. Two molecules contained in the asymmetric unit are shown. FIG. 4-(2) shows a structure in which the molecules 1 and 2 are superimposed with all atoms of the human Kras G12D mutant. The human Kras G12D mutant is shown as a ribbon representation, while compound 2187 and GDP are shown as black and gray stick representations, respectively.

FIG. 5 schematically shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 2188, as shown in Example 6-6. The human Kras G12D mutant is shown as a ribbon representation, while compound 2188 and GDP are shown as black and gray stick representations, respectively.

FIG. 6 schematically shows a characteristic interaction site of the X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 488. The human Kras G12D mutant is represented as gray ribbon and stick representations, and compound 488 is shown as a black stick representation. Dotted lines represent interatomic distances.

FIG. 7 schematically shows a characteristic interaction site of the X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 872. The human Kras G12D mutant is represented as gray ribbon and stick representations, and compound 872 is shown as a black stick representation. Dotted lines represent interatomic distances.

FIG. 8 schematically shows a characteristic interaction site of the X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 1201. The human Kras G12D mutant is represented as gray ribbon and stick representations, and compound 1201 is shown as a black stick representation. Dotted lines represent interatomic distances.

FIG. 9 schematically shows a characteristic interaction site of the X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 2187. The human Kras G12D mutant is represented as gray ribbon and stick representations, and compound 2187 is shown as a black stick representation. Dotted lines represent interatomic distances.

FIG. 10 schematically shows a characteristic interaction site of the X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 2188. The human Kras G12D mutant is represented as gray ribbon and stick representations, and compound 2188 is shown as a black stick representation. Dotted lines represent interatomic distances.

FIG. 11 schematically shows the amino acid sites where and the extent to which each of the cyclic peptide compounds 488, 872, 1201, 2187, and 2188 interacts with the human Kras G12D mutant. Amino acids containing one or more atoms positioned at a distance of 3.0 Å or less from any atom in the cyclic peptide compound are shown in black, amino acids containing one or more atoms positioned at a distance of farther than 3.0 Å and 4.0 Å or less are shown in shaded, and amino acids containing one or more atoms positioned at a distance of farther than 4.0 Å and 5.0 Å or less are shown in gray.

DESCRIPTION OF EMBODIMENTS

Abbreviations

The abbreviations used herein are as follows.

• • AA: Ammonium acetate
  • Alloc group: Allyloxycarbonyl group
  • Boc group: tert-Butoxycarbonyl group
  • Cbz group: Benzyloxycarbonyl group
  • CSA: (+)-10-Camphorsulfonic acid
  • DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene
  • DCC: N,N′-Dicyclohexylcarbodiimide
  • DCM: Dichloromethane
  • DCE: 1,2-Dichloroethane
  • DEAD: Diethyl azodicarboxylate
  • DMA: N,N-Dimethylacetamide
  • DMF: N,N-Dimethylformamide
  • DIAD: Diisopropyl azodicarboxylate
  • DIC: N,N′-Diisopropylcarbodiimide
  • DIPEA: N,N-Diisopropylethylamine
  • DMAP: N,N-Dimethyl-4-aminopyridine
  • t-Bu group: tert-Butyl group
  • dtbbpy: 4,4′-Di-tert-butyl-2,2′-dipyridyl
  • EDTA: Ethylenediaminetetraacetic acid
  • FA: Formic acid
  • Fmoc group: 9-Fluorenylmethyloxycarbonyl group
  • NMP: N-Methyl-2-pyrrolidone
  • TBME: t-Butyl methyl ether
  • TES: Triethylsilane
  • TFA: Trifluoroacetic acid
  • TFE: 2,2,2-Trifluoroethanol
  • THF: Tetrahydrofuran
  • THP: Tetrahydropyranyl
  • TMSC: Trimethylsilyl chloride
  • HFIP: 1,1,1,3,3,3-Hexafluoroisopropyl alcohol
  • HOAt: 1-Hydroxy-7-azabenzotriazole
  • HOBt: 1-Hydroxybenzotriazole
  • HOOBt: 3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine
  • IPAC: Isopropyl acetate
  • oxyma: Ethyl cyano(hydroxyimino)acetate
  • PPTS: Pyridinium p-toluenesulfonate
  • Pis: 2-Phenylisopropyl
  • WSCI—HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • TIPS: Triisopropylsilane
  • TfOH: Trifluoromethanesulfonic acid
  • HATU: O-(7-Aza-1H-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DMSO: Dimethylsulfoxide
  • Fmoc-C₁: (9H-Fluoren-9-yl)methyl carbonochloridate
  • Fmoc-OSu: 9-Fluorenylmethyl N-succinimidyl carbonate
  • Ns group: o-Nitrobenzenesulfonyl group
  • Trt group: Triphenylmethyl group
  • Troc group: 2,2,2-Trichloroethoxycarbonyl group

As used herein, unless otherwise noted, “Ras gene” may be abbreviated simply as “Ras”, but the two are used interchangeably. Similarly, “Ras protein” may also be indicated simply as “Ras”, but the two are used interchangeably.

As used herein, “amino acid residue” constituting the cyclic peptide compound may be referred to simply as “amino acid”. Also, “cyclic peptide compound” may be referred to as “peptide compound” or simply as “compound”

“One or more” herein means one or two or more. When “one or more” is used in a context relating to the substituent of a group, the phrase means a number encompassing one to the maximum number of substituents permitted by that group. Specific examples of “one or more” include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and/or a greater number.

As used herein, the meaning of the term “and/or” includes any combination of “and” and “or” as appropriate. Specifically, for example, “A, B, and/or C” includes the following seven variations; (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B, and C.

As used herein, “to” indicating a range includes values at both ends of the range, and for example, “A to B” means a range that is A or more and B or less.

As used herein, the term “about”, when used in combination with a numerical value, means a value range of +10% and −10% of that numerical value.

(Definitions of Functional Groups and the Like)

Examples of “halogen atoms” herein include F, Cl, Br, and I.

“Alkyl” herein means a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, and has a subset of hydrocarbyl or hydrocarbon group structures not containing either a heteroatom (which refers to an atom other than carbon and hydrogen atoms) or an unsaturated carbon-carbon bond but containing hydrogen and carbon atoms in its backbone. The alkyl includes linear and branched alkyls. Specifically, the alkyl has 1 to 20 carbon atoms (C₁-C₂₀, hereinafter “C_p-C_q” means that the number of carbon atoms is p to q), and is preferably C₁-C₁₀ alkyl, and more preferably C₁-C₆ alkyl. Specific examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

“Alkenyl” herein means a monovalent group having at least one double bond (two adjacent SP² carbon atoms). Depending on the configuration of a double bond and a substituent (if present), the geometrical form of the double bond can be entgegen (F) or zusammen (Z) as well as cis or trans configuration. The alkenyl includes linear and branched alkenyls. The alkenyl is preferably C₂-C₁₀ alkenyl, and more preferably C₂-C₆ alkenyl, and specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans forms), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

“Alkynyl” herein means a monovalent group having at least one triple bond (two adjacent SP carbon atoms). The alkynyl includes linear and branched alkynyls. The alkynyl is preferably C₂-Cia alkynyl, and more preferably C₂-C₆ alkynyl, and specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2′-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

“Cycloalkyl” herein means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes a monocyclic ring, a bicyclo ring, and a spiro ring. The cycloalkyl is preferably C₁-C₈ cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

“Aryl” herein means a monovalent aromatic hydrocarbon ring, and is preferably C₆-C₁₀ aryl. Specific examples of the aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl).

“Heterocyclyl” herein means a non-aromatic cyclic monovalent group containing 1 to hetero atoms in addition to carbon atoms. The heterocyclyl may have a double and/or triple bond within the ring, a carbon atom within the ring may be oxidized to form carbonyl, and heterocyclyl may be a monocyclic ring or a condensed ring. The number of atoms constituting the ring is preferably 4 to 10 (4- to 10-membered heterocyclyl), and more preferably 4 to 7 (4- to 7-membered heterocyclyl). Specific examples of the heterocyclyl include azetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydro pyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiazinane, thiadiazolidinyl, azetidinyl, oxazolidone, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazole, thietanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, sultam, and 2-oxaspiro[3.3]heptyl.

“Protected heterocyclyl” herein means a group in which one or more functional groups, such as an amino group, contained in the above-defined “heterocyclyl” are protected with a protecting group, and is preferably 4- to 7-membered protected heterocyclyl. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocyclyl include Boc-protected azetidine.

“Heterocycloalkylidene” herein means a divalent group obtained by removing two hydrogen atoms from one carbon atom of the above-defined “heterocyclyl”, in which a free valence forms a part of a double bond. The heterocycloalkylidene is preferably 4- to 7-membered heterocycloalkylidene, and specific examples include tetrahydropyran-4-ylidene and azetidin-3-ylidene.

“Protected heterocycloalkylidene” herein means a group in which one or more functional groups, such as an amino group, contained in the above-defined “heterocycloalkylidene” are protected with a protecting group, and is preferably 4- to 7-membered protected heterocycloalkylidene. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocycloalkylidene include Boc-protected azetidin-3-ylidene.

“Heteroaryl” herein means an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a monocyclic ring, may be a condensed ring formed with another ring, or may be partially saturated. The number of atoms constituting the ring is preferably 5 to 10 (5- to 10-membered heteroaryl) and more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of the heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridyl.

“Alkoxy” herein means an oxy group to which the above-defined “alkyl” is bonded, and is preferably C₁-C₆ alkoxy. Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

“Alkenyloxy” herein means an oxy group to which the above-defined “alkenyl” is bonded, and is preferably C₂-C₆ alkenyloxy. Specific examples of the alkenyloxy include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans forms), 3-butenyloxy, pentenyloxy, and hexenyloxy.

“Cycloalkoxy” herein means an oxy group to which the above-defined “cycloalkyl” is bonded, and is preferably C₃-C₈ cycloalkoxy. Specific examples of the cycloalkoxy include cyclopropoxy, cyclobutoxy, and cyclopentyloxy.

“Aryloxy” herein means an oxy group to which the above-defined “aryl” is bonded, and is preferably C₆-C₁₀ aryloxy. Specific examples of the aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

“Amino” herein means —NH₂ in a narrow sense and —NRR′ in a broad sense, wherein R and R′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R′, together with the nitrogen atom to which they are attached, form a ring. The amino is preferably —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, 4- to 8-membered cyclic amino, or the like.

“Monoalkylamino” herein means a group corresponding to the above-defined “amino” wherein R is hydrogen and R′ is the above-defined “alkyl”, and is preferably mono-C₁-C₆ alkylamino. Specific examples of the monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

“Dialkylamino” herein means a group corresponding to the above-defined “amino” wherein R and R′ are independently the above-defined “alkyl”, and is preferably di-C₁-C₆ alkylamino. Specific examples of the dialkylamino include dimethyldiamino and diethylamino.

“Cyclic amino” herein means a group corresponding to the above-defined “amino” wherein R and R′, together with the nitrogen atom to which they are attached, form a ring, and is preferably 4- to 8-membered cyclic amino. Specific examples of the cyclic amino include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.

“Protected amino” herein means an amino group protected with any protecting group. Specific examples of the protected amino include amino protected with a protecting group such as Boc, Fmoc, Cbz, Troc, or Alloc.

“Aminocarbonyl” herein means a carbonyl group to which the above-defined “amino” is bonded, and is preferably —CONH₂, mono-C₁-C₆ alkylaminocarbonyl, di-C₁-C₆ alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl. Specific examples of the aminocarbonyl include —CONH₂, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl.

“Alkenyloxycarbonyl” herein means a carbonyl group to which the above-defined “alkenyloxy” is bonded, and is preferably C₂-C₆ alkenyloxycarbonyl. Specific examples of the alkenyloxycarbonyl include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans forms), 3-butenyloxycarbonyl, pentenyloxycarbonyl, and hexenyloxycarbonyl.

“Alkylsulfonyl” herein means a sulfonyl group to which the above-defined “alkyl” is bonded, and is preferably C₁-C₆ alkylsulfonyl. Specific examples of the alkylsulfonyl include methylsulfonyl.

“Hydroxyalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with hydroxyl groups, and is preferably C₁-C₆ hydroxyalkyl. Specific examples of the hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

“Haloalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with halogen, and is preferably C₁-C₆ haloalkyl, and more preferably C₁-C₆ fluoroalkyl. Specific examples of the haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.

“Cyanoalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with cyano, and is preferably C₁-C₆ cyanoalkyl. Specific examples of the cyanoalkyl include cyanomethyl and 2-cyanoethyl.

“Aminoalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “amino”, and is preferably C₁-C₆ aminoalkyl. Specific examples of the aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, and 4-aminobutyl.

“Carboxyalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with carboxy, and is preferably C₂-C₆ carboxyalkyl. Specific examples of the carboxyalkyl include carboxymethyl.

“Alkenyloxycarbonylalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “alkenyloxycarbonyl”, and is preferably C₂-C₆ alkenyloxycarbonyl C₁-C₆ alkyl, and more preferably C₂-C₆ alkenyloxycarbonyl C₁-C₂ alkyl. Specific examples of the alkenyloxycarbonylalkyl include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.

“Alkoxyalkyl” herein means a group in which one of more hydrogens of the above-defined “alkyl” are replaced with the above-defined “alkoxy”, and is preferably C₁-C₆ alkoxy C₁-C₆ alkyl, and more preferably C₁-C₆ alkoxy C₁-C₂ alkyl. Specific examples of the alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

“Cycloalkylalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “cycloalkyl”, and is preferably C₃-C₈ cycloalkyl C₁-C₆ alkyl, and more preferably C₃-C₆ cycloalkyl C₁-C₂ alkyl. Specific examples of the cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

“Cycloalkoxylalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “cycloalkoxy”, and is preferably C₃-C₈ cycloalkoxy C₁-C₆ alkyl, and more preferably C₃-C₆ cycloalkoxy C₁-C₂ alkyl. Specific examples of the cycloalkoxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.

“Heterocyclylalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “heterocyclyl”, and is preferably 4- to 7-membered heterocyclyl C₁-C₆ alkyl, and more preferably 4- to 7-membered heterocyclyl C₁-C₂ alkyl. Specific examples of the heterocyclylalkyl include 2-(tetrahydro-21-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.

“Alkylsulfonylalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “alkylsulfonyl”, and is preferably C₁-C₆ alkylsulfonyl C₁-C₆ alkyl, and more preferably C₁-C₆ alkylsulfonyl C₁-C₂ alkyl. Specific examples of the alkylsulfonylalkyl include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.

“Aminocarbonylalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “aminocarbonyl”, and is preferably aminocarbonyl C₁-C₆ alkyl, and more preferably aminocarbonyl C₁-C₄ alkyl. Specific examples of the aminocarbonylalkyl include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, and 4-(dimethylaminocarbonyl)butyl.

“Aryloxyalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “aryloxy”, and is preferably C₆-C₁₀ aryloxy C₁-C₆ alkyl, and more preferably C₆-C₁₀ aryloxy C₁-C₂ alkyl. Specific examples of the aryloxyalkyl include phenoxymethyl and 2-phenoxyethyl.

“Aralkyl (arylalkyl)” herein means a group in which one or more hydrogen atoms of the above-defined “alkyl” are replaced with the above-defined “aryl”, and is preferably C₁-C₄ aralkyl, and more preferably C₁-C₁₀ aralkyl. Specific examples of the aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

“Aralkoxy” herein means an oxy group to which the above-defined “aralkyl” is bonded, and is preferably C₇-C₁₄ aralkoxy, and more preferably C₇-C₁₀ aralkoxy. Specific examples of the aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

“Aralkoxyalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “aralkoxy”, and is preferably C₁-C₁₄ aralkoxy C₁-C₆ alkyl, and more preferably C₇-C₁₄ aralkoxy C₁-C₂ alkyl. Specific examples of the aralkoxyalkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.

“Heteroarylalkyl” herein means a group in which one or more hydrogen atoms of the above-defined “alkyl” are replaced with the above-defined “heteroaryl”, and is preferably 5- to 10-membered heteroaryl C₁-C₆ alkyl, and more preferably 5- to 10-membered heteroaryl C₁-C₂ alkyl. Specific examples of the heteroarylalkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

“Heteroarylalkoxy” herein means an oxy group to which the above-defined “heteroarylalkyl” is bonded, and is preferably 5- to 10-membered heteroaryl C₁-C₆ alkoxy, and more preferably 5- to 10-membered heteroarylC₁-C₂ alkoxy. Specific examples of the heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.

“Heteroarylalkoxyalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “heteroarylalkoxy”, and is preferably 5- to 10-membered heteroaryl C₁-C₆ alkoxy C₁-C₆ alkyl, and more preferably 5- to 10-membered heteroaryl C₁-C₂ alkoxy C₁-C₂ alkyl. Specific examples of the heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl.

“Heterocycloalkylidenealkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “heterocycloalkylidene”, and is preferably 4- to 7-membered heterocycloalkylidene C₁-C₆ alkyl, and more preferably 4- to 7-membered heterocycloalkylidene C₁-C₂ alkyl. Specific examples of the heterocycloalkylidenealkyl include tetrahydro-4H-pyran-4-ylidenemethyl and azetidin-3-ylidenemethyl.

“Alkoxyalkenyl” herein means a group in which one or more hydrogens of the above-defined “alkenyl” are replaced with the above-defined “alkoxy”, and is preferably C₁-C₆ alkoxy C₂-C₆ alkenyl. Specific examples of the alkoxyalkenyl include (E)-4-methoxybut-2-en-1-yl.

“Aminocarbonylalkenyl” herein means a group in which one or more hydrogens of the above-defined “alkenyl” are replaced with the above-defined “aminocarbonyl”, and is preferably aminocarbonyl C₂-C₆ alkenyl. Specific examples of the aminocarbonylalkenyl include (E)-3-(dimethylaminocarbonylcarbonyl)-prop-2-en-1-yl.

“Haloalkoxy” herein means a group in which one or more hydrogens of the above-defined “alkoxy” are replaced with halogen, and is preferably C₁-C₆ haloalkoxy. Specific examples of the haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

“Alkylene” herein means a divalent group derived by further removing any one hydrogen atom from the above “alkyl”, and is preferably C₄-C₈ alkylene. Specific examples of the alkylene include —CH₂—, —(CH₂)—, —(CH₂)₃—, —CH(CH₃)CH₂—, —C(CH₃)₂—, —(CH₂)₄—, —CH(CH₃)CH₂CH₂—, —C(CH₃)₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂C(CH₃)₂—, —CH—CH₂CH(CH₃)—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, and —(CH₂)—.

“Alicyclic ring” herein means a non-aromatic hydrocarbon ring, The alicyclic ring may have an unsaturated bond within the ring, and may be a polycyclic ring having two or more rings. A carbon atom constituting the ring may be oxidized to form carbonyl. The alicyclic ring is preferably a 3- to 8-membered alicyclic ring, and specific examples include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.

“Saturated heterocyclic ring” herein means a non-aromatic heterocyclic ring containing 1 to 5 hetero atoms in addition to carbon atoms and not containing a double bond and/or a triple bond within the ring. The saturated heterocyclic ring may be a monocyclic ring, or may form a condensed ring with another ring, e.g., an aromatic ring such as a benzene ring. The saturated heterocyclic ring is preferably a 4- to 7-membered saturated heterocyclic ring, and specific examples include an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, and an indoline ring.

“Peptide chain” herein refers to a peptide chain in which 1, 2, 3, 4, or more natural amino acids and/or non-natural amino acids are connected by an amide bond and/or an ester bond. The peptide chain is preferably a peptide chain comprising 1 to 4 amino acid residues, and more preferably a peptide chain consisting of 1 to 4 amino acid residues.

“Optionally substituted” herein means that a group may be substituted with any substituent.

“Optionally protected” herein means that a group may be protected with any protecting group.

“One or more” herein means one or two or more. When “one or more” is used in a context relating to the substituent of a group, the phrase means a number encompassing one to the maximum number of substituents permitted by that group. Specific examples of “one or more” include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and/or a greater number.

The compounds disclosed herein can be salts thereof, and preferably chemically or pharmmaceutically acceptable salts thereof. Also, the compound disclosed herein or a salt thereof can be a solvate thereof, and preferably a chemically or pharmaceutically acceptable solvate thereof. Examples of salts of the compound disclosed herein include hydrochloride; hydrobronide; hydroiodide; phosphate; phosphonate; sulfate; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate; alkali metal salts such as a sodium salt and a potassium salt; alkaline earth metal salts such as a magnesium salt and a calcium salt; and ammonium salts such as an ammonium salt, an alkylammonium salt, a dialkylammonium salt, a trialkylammonium salt, and a tetraalkylammonium salt. These salts are produced by, for example, bringing the compound into contact with an acid or a base usable in the production of pharmaceutical products. In the present invention, a solvate of a compound refers to a phenomenon in which solute molecules strongly attract solvent molecules in a solution and form one molecular group, and is called a hydrate when the solvent is water. The solvate of the compound disclosed herein is preferably a hydrate, and specific examples of such hydrates include mono- to deca-hydrates, preferably mono- to penta-hydrates, and more preferably mono- to tri-hydrates. The solvate of the compound disclosed herein includes not only a solvate formed of a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, or 2-propanol), or dimethylformamide, but also a solvate formed of a plurality of solvents.

The term “amino acid” as used herein includes natural and unnatural amino acids. The term “natural amino acid” as used herein refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, or Pro. Examples of the unnatural amino acid include, but are not particularly limited to, n-amino acids, -amino acids, D-amino acids, N-substituted amino acids, α, α-disubstituted amino acids, amino acids having side chains that are different from those of natural amino acids, and hydroxycarboxylic acids. Amino acids herein may have any conformation. There is no particular limitation on the selection of amino acid side chain, but in addition to a hydrogen atom, it can be freely selected from, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and a cycloalkyl group. One or two non-adjacent methylene groups in such a group are optionally substituted with an oxygen atom, a carbonyl group (—CO—), or a sulfonyl group (—SO₂—). Each group may have a substituent, and there are no limitations on the substituent. For example, one or more substituents may be freely and independently selected from any substituents including a halogen atom, an O atom, an S atom, an N atom, a B atom, an Si atom, or a P atom. Examples include an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group, and cycloalkyl group. In a non-limiting embodiment, amino acids herein may be compounds having a carboxy group and an amino group in the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included in amino acids).

The main chain amino group of an amino acid may be unsubstituted (an NH₂ group) or substituted (i.e., an —NHR group, where R represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl which may have a substituent, one or two non-adjacent methylene groups in such a group may be substituted with an oxygen atom, a carbonyl group (—CO—), or a sulfonyl group (—SO₂—), and the carbon chain bonded to the N atom and the carbon atom at the position a may form a ring, as in proline). The R substituent is selected as the substituent in the aforementioned amino acid side chain is selected. When the main chain amino group is substituted, the R is included in the “amino acid side chain” as used herein. Such amino acids in which the main chain amino group is substituted are herein called “N-substituted amino acids.” Preferred examples of the “N-substituted amino acids” as used herein include, but are not limited to, N-alkylamino acids, N—C₁-C₆ alkylamino acids, N—C₁-C₄ alkylamino acids, and N-methylamino acids.

“Amino acids” as used herein which constitute a peptide compound include all isotopes corresponding to each amino acid. The isotope of the “amino acid” refers to one having at least one atom replaced with an atom of the same atomic number (number of protons) and different mass number (total number of protons and neutrons). Examples of isotopes contained in the “amino acid” constituting the peptide compounds disclosed herein include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, and a chlorine atom, which respectively include ²H and H; ¹³C and ¹⁴C; ¹⁵N; ¹⁷O and ¹⁸O; ³¹P and ³²P; ³⁵S; ¹⁸F; and ³⁶Cl.

Substituents containing a halogen atom as used herein include a halogen-substituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, or aralkyl group. More specific examples include fluoroalkyl, difluoroalkyl, and trifluoroalkyl.

Substituents containing an O atom include groups such as hydroxy (—OH), oxy (—OR), carbonyl (—C═O—R), carboxy (—CO₂H), oxycarbonyl (—C═O—OR), carbonyloxy (—O—C═O—R), thiocarbonyl (—C═O—SR), carbonylthio (—S—C═O—R), aminocarbonyl (—C═O—NHR), carbonylamino (—NH—C═O—R), oxycarbonylamino (—NH—C═O—OR), sulfonylamino (—NH—SO₂—R), aminosulfonyl (—SO₂—NHR), sulfamoylamino (—NH—SO₂—NHR), thiocarboxyl (—C═O—SH), and carboxylcarbonyl (—C═O—CO₂H).

Examples of oxy (—OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy. The alkoxy is preferably C₁-C₄ alkoxy and C₁-C₂ alkoxy, and particularly preferably methoxy or ethoxy.

Examples of carbonyl (—C═O—R) include formyl (—C═O—H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and aralkylcarbonyl.

Examples of oxycarbonyl (—C═O—OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.

Examples of carbonyloxy (—O—C═O—R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.

Examples of thiocarbonyl (—C═O—SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and aralkylthiocarbonyl.

Examples of carbonylthio (—S—C═O—R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, and aralkylcarbonylthio.

Examples of aminocarbonyl (—C═O—NHR) include alkylaminocarbonyl (examples of which include C₁-C₆ or C₁-C₄ alkylaminocarbonyl, in particular, ethylaminocarbonyl and methylaminocarbonyl), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, and aralkylaminocarbonyl. Additional examples include compounds in which the H atom bonded to the N atom in —C═O—NHR is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

Examples of carbonylamino (—NH—C═O—R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. Additional examples include compounds in which the H atom bonded to the N atom in —NH—C═O—R is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

Examples ofoxycarbonylamino (—NH—C═O—OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino. Additional examples include compounds in which the 11 atom bonded to the N atom in —NH—C═O—OR is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

Examples of sulfonylamino (—NH—SO₂—R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. Additional examples include compounds in which the H atom attached to the N atom in —NH—SO₂—R is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

Examples of aminosulfonyl (—SO₂—NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylanrinosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. Additional examples include compounds in which the H atom attached to the N atom in —SO₂—NHR is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

Examples of sulfamoylamino (—NH—SO₂—NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylanrino, heteroarylsulfamoylamino, and aralkylsulfamoylamino. The two H atoms bonded to the N atoms in —NH—SO₂—NHR may be further replaced with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

Substituents containing an S atom include groups such as thiol (—SH—), thio (—S—R), sulfinyl (—S═O—R), sulfonyl (—SO₂—R), and sulfo (—SO₃H).

Examples of thio (—S—R) include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and aralkylthio.

Examples of sulfonyl (—SO₂—R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

Substituents containing an N atom include groups such as azido (—N₃, also called “azido group”), cyano (—CN), primary amino (—NH₂), secondary amino (—NH—R; also called monosabstituted amino), tertiary amino (—NR(R′); also called disubstituted amino), amidino (—C(═NH)—NH₂), substituted amidino (—C(═NR)—NR′R″), guanidino (—NH—C(═NH)—NH₂), substituted guanidino (—NR—C(═NR′″)—NR′R″), aminocarbonylamino (—NR—CO—NR′R″), pyridyl, piperidino, morpholino, and azetidinyl.

Examples of secondary amino (—NH—R; monosubstituted amino) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

Examples of tertiary amino (—NR(R′); disubstituted amino) include amino groups having any two substituents each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)amino, where any two such substituents may form a ring. Specific examples include dialkylamino, in particular, C₁-C₆ dialkylamino, C₁-C₄ dialkylamino, dimethylamino, and diethylamino. The term “C_p-C_q dialkylamino group” as used herein refers to an amino group substituted with two C_p-C_q alkyl groups, where the two C_p-C_q alkyl groups may be the same or different.

Examples of substituted amidino (—C(═NR)—NR′R″) include groups in which three substituents R, R′, and R″ on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.

Examples of substituted guanidino (—NR—C(═NR′″)—NR′R″) include groups in which R, R′, R″, and R′″ are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these substituents form a ring.

Examples of aminocarbonylamino (—NR—CO—NR′R″) include groups in which R, R′, and R″ are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these substituents form a ring.

Herein, an “amino acid residue” constituting the peptide compound may be simply referred to as an “amino acid”.

In an embodiment, the present invention relates to a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof.

In formula (1), the ring is composed of 11 amino acid residues. Herein, the amino acid residue having P₁, Q₁, R₁, and L₁ in the formula may be referred to as core 1, the amino acid residue having P₂, Q₂, and R₂ as core 2, the amino acid residue having P₃, Q₃, and R₁ as core 3, the amino acid residue having P₄, Q₄, and R₄ as core 4, the amino acid residue having P₈, Q₅, and R₅ as core 5, the amino acid residue having P₆, Q₆, and R₆ as core 6, the amino acid residue having P₂, Q₂, and R₂ as core 7, the amino acid residue having P₈, Q₈, and R₈ as core 8, the amino acid residue having P₉, Q₉, and R₉ as core 9, the amino acid residue having P₁₀, Q₁₀, and R₁₀ as core 10, and the amino acid residue having P₁₁, Q₁₁, R₁₁, and L₁₁ as core 11.

In an embodiment, in formula (1), L₁ is a single bond or is —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, and L₁₁ is a single bond or is —CHM₁₁-, —(C₁₂)S(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein one of L₁ and L₁₁ is a single bond. That is, when L₁ is a single bond, L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, and when L₁ is a single bond, L₁ is —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)₁S(O)₂(CH₂)_m—. M₁ is hydrogen except when R₁ and M₁ form a 3- to 8-membered alicyclic ring, and M₁₁ is hydrogen except when R u and M₁₁ form a 3- to 8-membered alicyclic ring.

When L₁ or L₁ is —(CH₂)_nS(CH₂)_m—, specific examples of —(CH₂)_nS(CH₂)_m— include —CH₂SCH₂—, —CH₂CH₂SCH₂—, —CH₂SCH₂CH₂—, and —CH₂CH₂CH₂CH₂—.

When L₁ or L₁₁ is —(CH₂)_nS(O)(CH₂)_m—, specific examples of —(CH₂)_nS(O)(CH₂)_m—include —CH₂S(O)CH₂—, —CH₂CH₂S(O)CH₂—, —CH₂S(O)CH₂CH₂—, and —CH₂CH₂S(O)CH₂CH₂—.

When L₁ or L₁₁ is —(CH₂)_nS(O)₂(CH₂)_m—, specific examples of —(CH₂)_nS(O)₂(CH₂)_m—include —CH₂S(O)₂CH₂—, —CH₂CH₂S(O)₂CH₂—, —CH₂S(O)₂CH₂CH₂—, and —CH₂CH₂S(O))₂CH₂CH₂—.

In an embodiment, in formula (1), R₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl.

When core 1 is α-amino acid (i.e., L₁ is a single bond), R₁ is preferably C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkylsulfonylC₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl (wherein the C₁-C₆ alkoxyC₁-C₆ alkyl is optionally substituted with one or more halogens, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), or hydroxy), C₃-C₈ cycloalkyl, C₃-C₆ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl.

In this embodiment, R₁ is more preferably C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₁-C₄ hydroxyalkyl, methylsulfonylC₁-C₂ alkyl, C₂-C₃ alkynyl; C₁-C₆ alkoxyC₁-C₂ alkyl optionally substituted with one or more fluorines, mono-C₁-C₄alkylaminocarbonyl, or hydroxy; C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₂ alkyl, or C₃-C₆ cycloalkoxyC₁-C₂ alkyl.

In this embodiment, specific examples of R₁ include methyl, ethyl, i-propyl, n-propyl, 2-methylpropyl, 1-methylpropyl, n-butyl, n-hexyl, 3-methylbutyl, 2-methylbutyl, n-pentyl, but-3-yn-1-yl, propargyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(t-butylamino)-2-oxoethoxy)methyl, 3,3-difluorobutyl, n-propoxymethyl, hydroxymethyl, 2,2,2-trifluoroethyl, 5,5-difluoropentyl, methoxymethyl, 3-methylbutoxymethyl, 1-hydroxyethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, 1-methoxyethyl, 2-methoxyethyl, 2-methylsulfonylethyl, cyclohexyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl, and cyclopropoxymethyl.

When core 1 is β-amino acid (i.e., L₁ is —CHM₁-), R₁ is preferably hydrogen.

In an embodiment, in formula (1), R₁ and P₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₁ and P₁ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₁ and Q₁, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), when core 1 is β-amino acid, R₁ and M₁, together with the carbon atom to which R₁ is attached and the carbon atom to which M₁ is attached, can form a 3- to 8-membered alicyclic ring.

When R₁ and M₁ form a 3- to 8-membered alicyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.

In an embodiment, in formula (1), when core 1 is β-amino acid, M₁ is hydrogen except when R₁ and M₁ form a 3- to 8-membered alicyclic ring.

In an embodiment, in formula (1), except when R₁ and P₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

P₁ is preferably hydrogen or C₁-C₆ alkyl. Specific examples of such P₁ include hydrogen, methyl, ethyl, and n-propyl.

In an embodiment, except when R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

When core 1 is α-amino acid, specific examples of core 1 include MeAla, Ala, Pic(2), MeLeu, MeCha, MeVal, EtAla, nPrAla, MeSer(tBuOH), MeSer(NtBu-Aca), MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly(cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, Val, Leu, MeAOC(2), MeNva(5-F2), MeHle, MeIle, MeSer(nPr), MeSer(cPr), MeSer, MeAbu(4-F3), MeHnil, MeH-Ini(7-F2), MePRA, MeSer(Me), MeSer(iPen), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), MeMet(O2), Mekhxy(2), and EtLeu.

When core 1 is β-amino acid, specific examples of core 1 include bAla and bMeAla.

In an embodiment, in formula (1), R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₁-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C₁-C₆ alkylsulfonyl.

R₂ is preferably C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkylsulfonylC₁-C₆ alkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl optionally substituted with one or more halogens, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl.

R₂ is more preferably C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₁-C₄ hydroxyalkyl, methylsulfonylC₁-C₂ alkyl, C₂-C₆ alkenyl, C₂-C₃ alkynyl, C₁-C₆ alkoxyC₁-C₂ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₂ alkyl, or C₃-C₆ cycloalkoxyC₁-C₂ alkyl.

Specific examples of R₂ include methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-methylpropyl, 1-methylpropyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, pentan-3-yl, n-propoxymethyl, cyclopropoxymethyl, hydroxymethyl, 2,2,2-trifluoroethyl, 5,5-difluoropentyl, methoxymethyl, 3-methyl-butoxy-methyl, 2-hydroxyethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, cyanomethyl, 1-methoxyethyl, 2-methoxyethyl, 2-methylsulfonylethyl, allyl, 3-methylbut-2-en-1-yl, propargyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, and cyclopropylmethyl.

In an embodiment, in formula (1), R₂ and P₂, together with the carbon atom to which R₂ is attached and the nitrogen atom to which P₂ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₂ and Q₂, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, P₂ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino). P₂ is preferably hydrogen.

In an embodiment, except when R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₂ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

Specific examples of core 2 include Ala, Val, Leu, Ile, Nle, PRA, Chg, Cha, Ala(cPent), Ala(cBu), Ala(cPr), Gly(cPent), Gly(cBu), Gly(cPr), Hle, Ser(nPr), Ser(cPr), Ser, Abu(4-F3), Ahp(2), Abu, Nva, Hnl(7-F2), Ser(Me), Ser(iPen), Thr, Algly, Pregly, Ser(cBu), Ser(Tfe), Ala(CN), Thr(Me), Hse(Me), Met(O2), and Nva(3-Et).

In an embodiment, in formula (1), R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

R₃ is preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyC₁-C₆ alkyl (wherein the C₁-C₆ alkoxyC₁-C₆ alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino) or hydroxy), aminocarbonylC₁-C₆ alkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl.

R₃ is more preferably hydrogen, C₁-C₆ alkyl, C₁-C₄. hydroxyalkyl, C₁-C₆ alkoxyC₁-C₂ alkyl optionally substituted with mono-C₁-C₄ alkylaminocarbonyl or hydroxy, mono-C₁-C₄ alkylaminocarbonylC₁-C₂ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₂ alkyl, benzyl, or phenethyl.

Specific examples of R₃ include hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-methylpropyl, 3-methylbutyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(tert-butylamino)-2-oxoethoxy)methyl, n-propoxymethyl, cyclopropoxymethyl, 3-methylbutoxymethyl, 1-hydroxyethyl, 3-methylamino-3-oxo-propyl, cyclohexyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, and phenethyl.

In an embodiment, in formula (1), R₃ and P₃, together with the carbon atom to which R₃ is attached and the nitrogen atom to which P₃ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₃ and P₃ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₃ and Q₃, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₃ and P₃ form a 4- to 7-membered saturated heterocyclic ring, P₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₃-C₆ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

P₃ is preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ aminoalkyl (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), or C₁-C₆ cycloalkyl. P₃ is more preferably hydrogen, C₁-C₆ alkyl, C₁-C₄ alkoxyC₁-C₂ alkyl, 4- to 8-membered cyclic aminoC₁-C₂ alkyl optionally substituted with one or more halogens, or C₃-C₆ cycloalkyl. Specific examples of such P₃ include hydrogen, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, 2-ethoxyethyl, and 2-(4,4-difluoro-1-piperidyl)ethyl.

In an embodiment, except when R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₃ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

Specific examples of core 3 include MeAla, Ala, Pic(2), MeLeu, MeCha, MeVal, EtAla, MeSer(tBuOH), MeSer(NtBu-Aca), MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, MeNle, MeSer(nPr), MeSer(cPr), MeSer(iPen), MeThr, Abu, MeGly, EtGly, Gly, nBuGly, iPrGly, cPrGly, nPrGly, iBuGly, (EtOEt)NGly, 2-(pip-4-F2)-EtGly, Pro, Aze(2), MeGln(Me), MePhe, and MeHph.

In one embodiment, in formula (1), R₄ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen or C₁-C₄ alkyl. Specific examples of R₄ include hydrogen and methyl.

In an embodiment, in formula (1), R₄ and P₄, together with the carbon atom to which R₄ is attached and the nitrogen atom to which P₄ is attached, can form a 4- to 7-membered saturated heterocyclic ring (preferably, 4- or 5-membered saturated heterocyclic ring).

When R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₄ and Q₄, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₄ and Q₄ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

P₄ is preferably C₁-C₆ alkyl or C₁-C₆ alkoxyC₁-C₆ alkyl.

P₄ is more preferably hydrogen, C₁-C₆ alkyl, or C₁-C₄ alkoxyC₁-C₂ alkyl. Specific examples of P₄ include methyl, ethyl, n-propyl, n-butyl, i-propyl, i-pentyl, and 2-ethoxyethyl.

In an embodiment, except when R₄ and Q₄ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₄ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

Specific examples of core 4 include MeAla, Pic(2), MeGly, EtGly, nBuGly, nPrGly, (EtOEt)NGly, Pro, Aze(2), and iPenGly.

In an embodiment, in formula (1), R₈ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, and C₁-C₆ alkylsulfonyl.

R₅ is preferably C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₁-C₆ alkylsulfonylC₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl optionally substituted with one or more halogens, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl (wherein the C₇-C₁₄ aralkyl is optionally substituted with one or more halogens, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or cyano), C₁-C₆ aryloxyC₁-C₆ alkyl optionally substituted with one or more halogens, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl.

R₅ is more preferably C₁-C₆ alkyl, C₇r-C₆ fluoroalkyl, C₁-C₄ hydroxyalkyl, C₂-C₃ alkenyl, C₂—C, alkynyl, methylalkylsulfonylC₁-C₂ alkyl, C₁-C₆ alkoxyC₁-Q₂ alkyl optionally substituted with one or more fluorines, C₃-C₆ cycloalkyl, C₁-C₆ cycloalkylC₁-C₂ alkyl, C₃-C₆ cycloalkoxyC₁-C₂ alkyl, benzyl or phenethyl optionally substituted with one or more halogens, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyano, phenoxyC₁-C₂ alkyl optionally substituted with one or more halogens, benzyloxyC₁-C₂ alkyl, and 5- to 6-membered heteroarylC₁-C₂ alkyl.

Specific examples of R₅ include methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, propargyl, 3,3-difluorobutyl, n-propoxymethyl, cyclopropoxymethyl, hydroxymethyl, 2,2,2-trifluoroethyl, 5,5-difluorobutyl, methoxymethyl, 3-methylbutoxy methyl, 1-hydroxyethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, 1-methoxyethyl, 2-methoxyethyl, 2-methylsulfonylethyl, (2-chlorophenoxy)methyl, allyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopentylmethyl, cyclohexylmethyl, cyclobutylmethyl, cyclopropylmethyl, pyridin-3-ylmethyl, phenethyl, 4-chlorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-ethynylbenzyl, 2-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, 4-(trifluoromethyl)benzyl, 4-methoxybenzyl, 2-(trifluoromethoxy)benzyl, 3-(trifluoromethoxy)benzyl, 4-(trifluoromethoxy)benzyl, 3,4-difluorobenzyl, 4-iodobenzyl, benzyl, 3-fluorobenzyl, and 4-fluorobenzyl.

In an embodiment, in formula (1), R₅ together with R₈ can form C₄-C₈ alkylene. C₄-C₈ alkylene is preferably —(CH₂)₈—.

In an embodiment, in formula (1), R₅ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₅ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₈ and P₈ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₅ and Q₅, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₅ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₅ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₈ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —Ni, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

P₈ is preferably hydrogen or C₁-C₂ alkyl, and specific examples include hydrogen, methyl, and ethyl.

In an embodiment, except when R₅ and Q₅ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₅ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

Specific examples of core 5 include MeAla, MeLeu, MeCha, MeVal, MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeCGly(cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, MeNya(5-F2), MeHle, Melle, MeSer(nPr), MeSer(cPr), MeSer, MeAbu(4-F3), MeHnl, MeHnl(7-F2), MePRA, MeSer(Me), MeSer(iPen), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), MeMet(O2), MePhe, MeHph, MePhe(4-C₁), MeThr(Bn), EtPhe(4-C₁), MePhe(2-CN), MePhe(3-CN), MePhe(4-CN), MePhe(2-F), MePhe(3-F), MePhe(4-F), MePhe(2-C₁), MePhe(3-C₁), MePhe(3-Br), MePhe(4-Br), MePhe(2-Me), MePhe(3-Me), MePhe(4-Me), MePhe(2-CF3), MePhe(3-CF3), MePhe(4-CF3), MeTyr(Me), MePhe(2-OCF3), MePhe(3-OCF3), MePhe(4-OCF3), MeSer(Ph-2-C₁), MeAlgly, MePhe(34-F2), MeAla(3-Pyr), MePhe(4-1), EtCha, EtPhe(4-Me), EitPhe(4-CF3), and Phe(4-Me).

In an embodiment, in formula (1), R₆ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen or C₁-C₃ alkyl. Specific examples of R₆ include hydrogen and methyl.

In an embodiment, in formula (1), R₆ and P₆, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₆ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₆ and P₆s form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₆ and Q₆, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₆ and Q₆ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₆ and P₆ form a 4- to 7-membered saturated heterocyclic ring, P₆ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxyamino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

P₆ is preferably C₁-C₆ alkyl or C₃-C₈ cycloalkyl, and more preferably C₁-C₄ alkyl or C₃-C₆ cycloalkyl. Specific examples of such P₆ include methyl, ethyl, and cyclopropyl.

In an embodiment, except when R₆ and Q₆ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₆ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

Specific examples of core 6 include MeAla, MeGly, EtGly, cPrGly, D-Pro, D-MeAla, and D-Pic(2).

In an embodiment, in formula (1), R₇ is C₆-C₁; aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, C₁-C₆ alkylsulfonyl, and SF₅.

R₇ is preferably C₆-C₁₀ aryloxyC₁-C₆ alkyl (wherein the C₆-C₁₀ aryloxyC₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl), C₇-C₁₄ aralkyl (wherein the C₇-C₁₄ aralkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkynyl, cyano, C₁-C₆ alkylsulfonyl, and SF₅), C₇-C₁₄ aralkoxyC₁-C₆ alkyl optionally substituted with one or more halogens, or 5- to 10-membered heteroarylC₁-C₆ alkyl (wherein the 5- to 10-membered heteroarylC₁-C₆ alkyl is optionally substituted with one or more halogens, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy).

R₇ is preferably —(CH₂)_x—O_y—(CH₂)_z1—C₆-C₁₀ aryl or —(CH₂)_x—O_y—(CH₂)_z2-5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C₁-C₄ alkyl (preferably methyl), C₂-C₄ alkynyl (preferably ethynyl), C₁-C₃haloalkyl (preferably difluoromethyl, triifluoromethyl), C₁-C₃ haloalkoxy (preferably difluoromethoxy, trifluoromethoxy), C₁-C₄ alkoxy (preferably methoxy, ethoxy, isopropoxy, n-butoxy, t-butoxy), —CN, C₁-C₃ alkylsulfonyl (preferably methylsulfonyl), and SF₅, wherein x is 1, 2, or 3, y is 0 or 1, z1 is 0, 1, 2, or 3, and z2 is 0, 1, 2, or 3, provided that the sum of x, y, and z1 or z2 is 1 to 4. Such —(CH₂)_x—O_y—(CH₂)_z1—C₆-C₁₀ aryl or —(CH₂)_x—O_y—(CH₂)_z2-5- to 10-membered heteroaryl is preferably —CH₂—C₆-C₁₆ aryl or —(CH₂)₂—C₆-C₁₆ aryl, which is optionally substituted with the above-mentioned group(s). When —(CH₂)_x—O_y—(CH₂)_z1—C₆-C₁₀ aryl has a substituent, the substituent is preferably on C₆-C₁₀ aryl in the group, and when —(CH₂)_x—O_y—(CH₂)_z2-5- to 10-membered heteroaryl has a substituent, the substituent is preferably on 5- to 10-membered heteroaryl in the group.

Specific examples of R₇ include ((4-chlorobenzyl)oxy)methyl, 2-(4-chlorophenoxy)ethyl, 2-(3,4-dichlorophenoxy)ethyl, 2-(4-(trifluoromethylphenoxy))ethyl, (4-chlorophenoxy)methyl, ((3-chlorobenzyl)oxy)methyl, ((2-chlorobenzyl)oxy)methyl, 3-iodobenzyl, 3-chlorobenzyl, 3-methylbenzyl, 3-fluorobenzyl, 3,5-difluorobenzyl, 4-methylphenethyl, 4-(trifluoromethyl)phenethyl, 3-chloro-5-fluorobenzyl, 3-cyanobenzyl, 3-(trifluoromethoxy)benzyl, benzyl, 4-fluorophenethyl, 2-fluoro-4-(trifluoromethyl)phenethyl, 3-chlorophenethyl, 4-chlorophenethyl, 3-fluoro-4-(trifluoromethyl)phenethyl, 2,3,4,5,6-pentafluorophenethyl, 2,4,5-trifluorophenethyl, 2,5-difluorophenethyl, 2-fluoro-4-chlorophenethyl, 2,4-difluorophenethyl, 2-fluoro-6-chlorophenethyl, 2,4,6-trifluorophenethyl, 3-chloro-4-(trifluoromethyl)phenethyl, 3-trifluoromethylphenethyl, 4-(pentafluoro-6-sulfanyl)phenethyl, 3,5-difluoro-4-(trifluoromethyl)phenethyl, 3-methoxybenzyl, 3,5-dichlorobenzyl, 3-chloro-4-fluorobenzyl, phenethyl, 3,4-dichlorophenethyl, 3-bromobenzyl, 4-fluorobenzyl, 2-fluoro-5-iodobenzyl, 2-chloro-5-iodobenzyl, 3-ethynylbenzyl, 3-fluorophenethyl, 3-phenylpropyl, 2-fluorobenzyl, 2-fluoro-3-iodobenzyl, 2-fluoro-3-bromobenzyl, 3-iodo-5-fluorobenzyl, 3-iodo-5-chlorobenzyl, 3-bromo-5-fluorobenzyl, 2-bromo-5-iodobenzyl, 2-methyl-5-iodobenzyl, 2-fluoro-5-methylbenzyl, 2-chloro-5-bromobenzyl, 2-methyl-5-bromobenzyl, ²,3-difluorobenzyl, 2,5-difluorobenzyl, 2,6-difluorobenzyl, 3-fluoro-4-(difluoromethoxy)phenethyl, 3-cyano-4-(trifluoromethyl)phenethyl, 3-methoxy-4-(trifluoromethyl)phenethyl, 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl, 3-chloro-4-(trifluoromethoxy)phenethyl, 3-fluoro-4-(trifluoromethoxy)phenethyl, 4-(methylsulfonyl)phenethyl, 3-fluoro-4-(difluoromethyl)phenethyl, 3,4,5-trichlorophenethyl, 3,4-dichloro-5-methoxyphenethyl, 3,4-dichloro-5-cyanophenethyl, 3,4-dichloro-5-isopropoxyphenethyl, 3,4-dichloro-5-(n-butoxy)phenethyl, 3,4-dichloro-5-(t-butoxy)phenethyl, 3-(4-(trifluoromethyl)phenyl)propyl, (5-chlorothiophen-2-yl)methyl, (5-bromothiophen-2-yl)methyl, (5-bromopyridin-3-yl)methyl, 2-(6-(trifluoromethyl)pyridin-3-yl)ethyl, 2-(quinolin-6-yl)ethyl, 2-(1-methyl-1H-indol-6-yl)ethyl, 2-(1-methyl-1H-indol-5-yl)ethyl, 2-(6-methoxypyridin-3-yl)ethyl, 2-(benzofuran-5-yl)ethyl, 2-(6-(difluoromethyl)pyridin-3-yl)ethyl, 2-(5-(trifluoromethyl)pyridin-2-yl)ethyl, and 2-(quinolin-7-yl)ethyl.

In an embodiment, in formula (1), R₇ and P₇, together with the carbon atom to which R₇ is attached and the nitrogen atom to which P₇ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₇ and P₇ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₇ and Q₇, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R. and P₇ form a 4- to 7-membered saturated heterocyclic ring, P₇ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NI-Hz, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino). P₇ is preferably hydrogen.

In an embodiment, except when R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q; is hydrogen, C₁-C₆ alkyl, or C₇-C₁₄ aralkyl, and is preferably hydrogen.

Specific examples of core 7 include Phe(3-Cl), Phe(3-Me), Phe(3-F), Phe(35-F2), Hph(4-Me), H4ph(4-CF3), Phe(3-Cl-5-F), Phe(3-J), Phe(3-CN), Phe(3-OCF3), Phe, Hph(4-F), Hph(4-CF3-2-F), Hph(3-Cl), Hph(4-Cl), Hph(4-CF3-3-F), Hph(F5), Hph(245-F3), Hph(2-F-5-Cl), Hph(2-F-4-Cl), Hph(24-F2), Hph(2-F-6-Cl), Hph(246-F3), Hph(4-CF3-3-C), Hph(3-CF3), Hph(4-SF5), Hph(4-CF3-35-F2), Phe(3-OMe), Phe(35-Cl2), Phe(3-Cl-4-F), -Iph, -Iph(34-Cl2), Phe(3-Br), Phe(4-F), Phe(2-F-5-I), Phe(2-Cl-5-I), Ala(2-Thie-5-Cl), Ala(2-Thie-5-Br), (Me)Phe(3-1), Phe(3-C #C), Hph(3-F), Phe3, Phe(2-F), Phe(2-F-3-I), Phe(2-F-3-Br), Phe(3-1-5-F), Phe(3-1-5-Cl), Ala(3-Pyr-5-Br), Phe(3-Br-5-F), Phe(2-Br-5-1), Phe(2-Me-5-I), Phe(2-F-5-Br), Phe(2-Cl-5-Br), Phe(2-Me-5-Br), Phe(23-F2), Phe(25-F2), Phe(26-F2), H-ph(3-F-4-OCHF2), Hph(3-CN-4-CF3), Hph(3-OMe-4-CF3), Abu(3-Pyr-4-CF3), Abu(34-Cate(CF2)), HTph(3-Cl-4-OCF3), Hph(3-F-4-OCF3), Abu(6-Quino), Abu(1-Me-6-Indo), Abu(I-Me-5-fndo), Abu(3-Pyr-4-OMe), Abu(5-Bzfr), Abu(3-Pyr-4—CHF2), Abu(2-Pyr-4-CF3), -Iph(4-SO₂Me), Hph(3-F-4-CHF2), Abu(7-Quino), Hph(345-Cl3), Hlph(34-Cl2-5-OMe), Hph(34-Cl2-5-CN), Hph(34-Cl2-5-OiPr), Hph(34-Cl2-5-OnBu), Hph(34-Cl2-5-OtBu), Phe3(4-CF3), Ser(Bn-4-Cl), Hse(Ph-4-Cl), Hse(Ph-34-Cl2), Hse(Ph-4-CF3), Ser(Ph-4-Cl), Ser(Bn-3-Cl), and Ser(Bn-2-Cl).

In an embodiment, in formula (1), R₈ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₈ alkyl, C₆-C₁(aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₁-C₁₄ aralkoxyC₁-C₆ alkyl, 5- to 10-membered heteroarylC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, amino (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkylidene, protected 4- to 7-membered heterocycloalkylidene, 4- to 7-membered heterocyclyl, and protected 4- to 7-membered heterocyclyl.

R₈ is preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ carboxyalkyl, C₁-C₆ aminoalkyl (wherein the amino is —NH₂, protected amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogen atoms), aminocarbonylC₁-C₆ alkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogen atoms), optionally protected 4- to 7-membered heterocyclylC₁-C₆ alkyl, optionally protected 4- to 7-membered heterocycloalkylideneC₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl (wherein the C₁-C₆ alkoxyC₁-C₆ alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino) or hydroxy), C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₂-C₆ alkynyl, C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl (wherein the C₇-C₁₄ aralkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and cyano), 5- to 10-membered heteroarylC₁-C₆ alkyl (wherein the 5- to 10-membered heteroarylalkyl is optionally substituted with one or more groups selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and cyano), or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl optionally substituted with one or more halogen atoms.

R₈ is more preferably hydrogen. C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ carboxyalkyl, protected aminoC₁-C₄ alkyl, mono-C₁-C₄ alkylaminocarbonylC₁-C₂ alkyl, di-C₁-C₄ alkylaminocarbonylC₁-C₂ alkyl, 4- to 8-membered cyclic aminocarbonylC₁-C₂ alkyl optionally substituted with one or more fluorine atoms, 4- to 8-membered cyclic aminoC₁-C₂ alkyl optionally substituted with one or more fluorine atoms, optionally protected 4- to 7-membered heterocyclylC₁-C₂ alkyl, optionally protected 4- to 7-membered heterocycloalkylideneC₁-C₂ alkyl, mono-C₁-C₄ alkylaminocarbonylmethyloxyC₁-C₂ alkyl, C₁-C₄ alkoxyC₁-C₂ alkyl optionally substituted with hydroxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₂ alkyl, C₂-C₆ alkenyl, C₂-C₃ alkynyl, C₂-C₃ alkenyloxycarbonylC₁-C₂ alkyl, phenoxyC₁-C₂ alkyl; benzyl or phenethyl optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, and cyano; 5- to 6-membered heteroarylC₁-C₂ alkyl optionally substituted with one or more groups selected from the group consisting of methyl, trifluoromethyl, methoxy, and cyano; or 5- to 6-membered heteroarylmethoxyC₁-C₂ alkyl optionally substituted with one or more halogen atoms.

In an embodiment, R₈ is preferably —(CH₂)_x—O_y—(CH₂)z-C₆-C₁₀ aryl or —(CH₂)_XO_y—(CH₂)_z2-5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C₁-C₄ alkyl (preferably methyl), C₂-C₁ alkynyl (preferably ethynyl), C₁-C₃ haloalkyl (preferably difluoromethyl, trifluoromethyl), C₁-C₃ haloalkoxy (preferably trifluoromethoxy), C₁-C₄ alkoxy (preferably methoxy), —CN, C₁-C₃ alkylsulfonyl (preferably methylsulfinyl), hydroxy, and SF₅, wherein provided that the sum of x, y, and z1 or z2 is 1 to 4, x is 1, 2, or 3, y is 0 or 1, z1 is 0, 1, 2, or 3, and z2 is 1, 2, or 3. When —(CH₂)O_y—(CH₂)_z1—C₆-C₁₀ aryl has a substituent, the substituent is preferably on C₆-C₁₀ aryl in the group, and when —(CH₂)_x—O_y—(CH₂)_z2-5- to 10-membered heteroaryl has a substituent, the substituent is preferably on 5- to 10-membered heteroaryl in the group.

Specific examples of R₈ include hydrogen, methyl, ethyl, i-propyl, n-propyl, n-butyl, 2-methylpropyl, 1-methylpropyl, neopentyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(tert-butylamino)-2-oxoethoxy)methyl, 3,3-difluorobutyl, n-propoxymethyl, 3-methylbutoxymethyl, 1-hydroxyethyl, 2-methoxyethyl, 2-methylbutyl, 5,5-difluoropentyl, 3-methylamino-3-oxo-propyl, ((5-fluoropyridin-3-yl)methoxy)methyl, 4-(((allyloxy)carbonyl)amino)butyl, 2-hydroxy-2-oxoethyl, (5-fluoripyridin-3-yl)methyl, 2-(3,3-difluoropiperidinyl)ethyl, 2-(4,4-difluoropiperidinyl)-2-oxo-ethyl, 2-(allyloxy)-2-oxo-ethyl, phenoxymethyl, hydroxymethyl, 2-(tetrahydro-4H-pyran-4-ylidene)ethyl, 2-(tetrahydro-21-pyran-4-yl)ethyl, 2-(1-(t-butoxycarbonyl)azetidin-3-ylidene)ethyl, 2-(1-(t-butoxycarbonyl)azetidin-3-yl)ethyl, 2-(3,3-difluoro-azetidin-1-yl)-2-oxoethyl, 2-(3,3-difluoro-azetidin-1-yl)-ethyl, 3-(dimethylamino)-3-oxopropyl, 3-(3,3-difluoro-azetidin-1-yl)-3-oxopropyl, 3-(azetidin-1-yl)-3-oxopropyl, 2-(piperidinyl)-2-oxo-propyl, 3-(pyrrolidin-1-yl)-3-oxopropyl, 3-(morpholin-1-yl)-3-oxopropyl, 2-(dimethylamino)-2-oxoethyl, 2-(azetidinyl)-2-oxo-ethyl, 2-(piperidinyl)-2-oxo-ethyl, 2-(pyrolidinyl)-2-oxo-ethyl, 2-(morpholin-1-yl)-2-oxoethyl, allyl, 2-methylallyl, 3-methylbut-2-en-1-yl, pent-4-en-1-yl, propargyl, 3-allyloxy-3-oxo-propyl, cyclohexyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, phenethyl, 4-chlorobenzyl, 3-cyanobenzyl, 4-ethynylbenzyl, 2-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-methoxybenzyl, 3-(trifluoromethoxy)benzyl, 4-(trifluoromethoxy)benzyl, 3,4-difluorobenzyl, 4-iodobenzyl, 4-fluorobenzyl, 4-difluoromethylbenzyl, 3-fluoro-4-hydroxybenzyl, 4-(trifluoromethyl)benzyl, 2-trifluoromethylbenzyl, 2-methoxybenzyl, 3-trifluoromethylbenzyl, 2-(trifluoromethoxy)benzyl, 3-methoxybenzyl, 3-iodobenzyl, 3-fluorobenzyl, pyridin-3-ylmethyl, thiazol-4-ylmethyl, (6-cyanopyridin-3-yl)methyl, (6-methoxypyridin-3-yl)methyl, (6-trifluoromethylpyridin-3-yl)methyl, (5-methylpyridin-3-yl)methyl, (5-methoxypyridin-3-yl)methyl, (pyridin-4-yl)methyl, (6-methylpyridine-3-yl)methyl, 2-(pyridin-3-yl)ethyl, and 2-(pyridin-4-yl)ethyl.

In an embodiment, in formula (1). R₈, together with R₅, can form C₄-C₈ alkylene. C₄-C₈ alkylene is preferably —(CH₂)₈—.

In an embodiment, in formula (1), R₈ and P₈ together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, can form a 4- to 7-membered saturated heterocyclic ring (preferably 4- or 5-membered saturated heterocyclic ring). The 4- to 7-membered saturated heterocyclic ring may be condensed with a saturated carbocyclic ring or an aromatic ring. The 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogen atoms), or OS₈. Here, S is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₇-C₁₄ aralkyl (wherein the aralkyl is optionally substituted with one or more halogen atoms, C₁-C₆ alkyl, C₁-C₆ (alkoxy, or C₁-C₆ haloalkoxy), or 5- to 10-membered heteroarylC₁-C₆ alkyl.

When R₈ and P₈ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring. These saturated heterocyclic rings may be condensed with a 3- to 8-membered saturated carbocyclic ring (preferably a cyclohexane ring) or a 6- to 10-membered aromatic ring (preferably a benzene ring). When the 4- to 7-membered saturated heterocyclic ring has one or more substituents, the 4- to 7-membered saturated heterocyclic ring is preferably substituted one or more halogen atoms, hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroarylC₁-C₆ alkoxy, C₇-C₁₄ aralkoxy (wherein the C₇-C₁₄ aralkoxy is optionally substituted with one or more halogen atoms, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy), 4- to 8-membered cyclic amino optionally substituted with one or more halogen atoms, or 5- to 10-membered heteroaryl. More preferable examples of the substituent of the 4- to 7-membered saturated heterocyclic ring include halogen, hydroxy, oxo, ethoxy, 2-hydroxyethyl, phenyl, difluoroethoxy; benzyloxy optionally substituted with one or more substituents independently selected from the group consisting of one or more halogen atoms, methyl, trifluoromethyl, methoxy, and difluoromethoxy; 5- to 6-membered heteroarylmethoxy, 4- to 8-membered cyclic amino optionally substituted with one or more fluorine atoms, phenyl, and 5- to 6-membered heteroaryl.

In an embodiment, in formula (1), R₈ and Q₈, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₈ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₂-C₈ alkenyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl, C₇-C₁₀ aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen or C₁-C₆ alkyl), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

P₈ is preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, (wherein the C₁-C₆ alkoxyC₁-C₆ alkyl is optionally substituted with one or more halogen atoms, hydroxy, di-C₁-C₆ alkylaminocarbonyl, C₁-C₆ alkoxy, or amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino)), aminocarbonylC₁-C₆ alkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogen atoms), C₁-C₆ aminoalkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogen atoms or C₁-C₆ alkyl), C₂-C₆ alkenyl, C₂-C₆ hydroxyalkenyl, aminocarbonylC₂-C₆ alkenyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), C₁-C₆ alkoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl optionally substituted with one or more halogen atoms, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl optionally substituted with one or more halogen atoms, C₇-C₁₄ aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl.

P₈ is more preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl; C₁-C₄ alkoxyC₁-C₂ alkyl optionally substituted with one or more fluorine atoms, hydroxy, dimethylaminocarbonyl, methoxy, amino, methylamino, or dimethylamino; dimethylaminocarbonylC₁-C₄ alkyl, aminoC₁-C₄ alkyl (wherein the amino is —NH₂), 4- to 8-membered cyclic aminoC₁-C₄ alkyl optionally substituted with one or more fluorines or methyl, C₂-C₃ alkenyl, C₂-C₆ hydroxyalkenyl, dimethylaminocarbonylC₂-C₃ alkenyl, methoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl optionally substituted with one or more fluorine atoms, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₂ alkyl, phenyl optionally substituted with one or more halogen atoms, benzyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heteroarylC₁-C₂ alkyl.

Specific examples of P₈ include hydrogen, methyl, ethyl, n-butyl, allyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-(dimethylaminocarbonylmethoxy)ethyl, 2-(2-hydroxy-2-methylpropoxy)ethyl, 4-aminobutyl, 2-piperazin-1-ylethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(2,2,2-trifluoroethoxy)ethyl, 2-(2-methoxyethoxy)ethyl, 2-(2,2-difluoroethoxy)ethyl, 2-(2-aminoethoxy)ethyl, 2-[2-(methylamino)ethoxy]ethyl, 2-[2-(dimethylamino)ethoxy]ethyl, 5-hydroxypentyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, benzyl, (E)-3-(dimethylaminocarbonyl)-prop-2-en-1-yl, (E)-5-hydroxypent-2-en-1-yl, (E)-4-hydroxy-4-methyl-pent-2-en-1-yl, (E)-5-hydroxy-5-methyl-hex-2-en-1-yl, (E)-4-methoxybut-2-en-1-yl, 3-(dimethylaminocarbonyl)propyl, 2,2-difluorospiro[3.3]heptan-6-yl, 3-thienyl, 3-pyridylmethyl, 2-oxaspiro[3.3]heptan-6-yl, oxetan-3-ylmethyl, 2-(azetidin-3-yl)ethyl, 2-(4,4-difluoro-1-piperidyl)ethyl, and 3-(4,4-difluoro-1-piperidyl)propyl.

In an embodiment, except when R₈ and Q₈ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₈ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

Specific examples of core 8 include MeAla, Ala, Pic(2), MeLeu, EtAla, MeSer(tBuOH), MeSer(NtBu-Aca), MeAla(cPent), MeAla(cPr), MeNva, MeNle, Val, Leu, MeNya(5-F2), MeSer(nPr), MeHnl(7-F2), MeSer(iPen), MeThr, MeHse(Me), Ile, Nle, PRA, Chg, Abu, Hnl(7-F2), Ser(iPen), Algly, Pregly, EtGly, nBuGly, (EtOEt)NGly, Pro, Aze(2), MeGln(Me), MePhe, MePhe(4-C₁), MePhe(3-CN), MePhe(4-CN), MePhe(2-F), MePhe(3-F), MePhe(4-F), MePhe(2-C), MePhe(3-Cl), MePhe(3-Br), MePhe(4-Br), MePhe(2-Me), MePhe(3-Me), MePhe(4-Me), MeTyr(Me), MePhe(3-OCF3), MePhe(4-OCF3), MeAlgly, MePhe(34-F2), MeAla(3-Pyr), MePhe(4-I), Phe(4-Me), D-MeAla, Phe(3-Me), Phe, Hph, Phe(4-F), Phe(2-F), Hyp(Et), Tle, Pro(4-F2), Ser(tBuOH), Ser(NtBu-Aca), Ser(3-F-5-Me-Pyr), Glu(OAl), Oic, Hyp, cisHyp, Lys(Alloc), Phe(4—CHF2), Hyp(Bzl), cisHyp(Et), Hyp(Bzl(2-Cl)), cisHyp(Bzl(2-Cl)), cisHyp(Bzl(3-C₁)), cisHyp(Bzl(4-C₁)), Hyp(Bzl(3-Cl)), Hyp(Bzl(4-Cl)), Hyp(Bzl(2-Me)), Hyp(Bzl(3-Me)), Hyp(Bzl(3-OMe)), Hyp(Bzl(4-Me)), Hyp(Bzl(4-OCHF2)), cislyp(Bzl(2-Me)), cisHyp(Bzl(3-Me)), cisHyp(Bzl(3-OMe)), cisHyp(Bzl(4-Me)), cisHyp(Bzl(4-OCHF2)), Methagly, MeAsp, Pro(4-keto), Pic(2)(4-Oxo), Mor(3), Thiopro, MeAla(4-Thz), MeSer(3-F-5-Me-Pyr), MeTyr(3-F), MeAla(3-Pyr-4-CN), Ahpe(2), Hyp(3-Me-Pyr), cisHyp(3-Me-Pyr), cisHyp(Et(2-F2)), Hyp(Et(2-F2)), Tyr(Me), Phe(4-CF3), Phe(4-C), Phe(2-CF3), Phe(2-Cl), Phe(2-Me), Phe(2-OMe), Phe(3-CF3), MeAbu(pip-3-F2), MeAsn(pip-4-F2), Pro(4-pip-4-F2), cisPro(4-pip-4-F2), MeAsp(OAl), Pro(4R-Tri), Pro(4S-Tri), Ser(Ph), IDC, Pro(4R-Ph), Pro(4S-Ph), MeAla(3-Pyr-4-OMe), MeAla(3-Pyr-4-CF3), MeAla(3-Pyr-5-Me), MeAla(3-Pyr-5-OMe), MeAla(4-Pyr), MeAla(3-Pyr-4-Me), Hyp(3-thie-Me), PhGly, cisHyp(2-EtOH), Hyp(2-EtOH), Phe(2-OCF3), BnGly, (3-Thienyl)Gly, (Ph-3-C₁)Gly, (Ph-4-Cl)Gly, (F2cBucBu)Gly, (OxeMe)Cly, (OxecBu)Cly, D-Ala, D-MeSer(iPen), D-MeSer, D-Mor(3), D-MePhe, D-MeAbu, MePhe(4—CHF2), MeAbu(3-Pyr), MeAbu(4-Pyr), MeAbu(THPdene), MeAbu(THP), MeAbu(BocAzedene), MeAbu(BocAze), (pip(4-F2)Et)Gly, (pip(4-F2)nPr)Gly, (Et(2-F2)OEt)Gly, (MeOEtOEt)Gly, (Et(2-F3)OEt)Gly, (4-pyr-Et)Gly, (3-pyr-Et)Gly, (4-pyr-Me)Gly, (3-pyr-Me)Gly, AllylGly, (HOEt)Gly, (HOiPrallyl)Gly, (DMFallyl)Gly, (HOEtallyl)Gly, (5-OH-nPent)Gly, MeAsn(Aze-3-F2), MeAbu(Aze-3-F2), (Me2NCOnPr)Gly, (HOtBuallyl)Gly, (HOtBuOEt)Gly, (DMAOEt)Gly, (MeOMeallyl)Gly, MeGln(Me2), MeGln(Aze-3-F2), MeGln(Aze), MeGln(pip), MeGln(pyrro), MeGln(mor), MeAsn(Me2), MeAsn(Aze), MeAsn(pip), MeAsn(pyrro), MeAsn(mor), MePhe(3-OMe), MePhe(3-I), EtPhe(2-C₁), (4-Me-piz-Et)Gly, (Aze(3)Et)Gly, (H2NEtOEt)Gly, (H2NnBu)Gly, (Me2NEtOEt)Gly, (MeNEtOEt)Gly, and (piz-Et)Gly.

In an embodiment, in formula (1), R₉ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₇—CH aralkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl.

R₉ is preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl (wherein the C₁-C₆ alkoxyC₁-C₆ alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), hydroxy, or 5- to 10-membered heteroaryl optionally substituted with one or more halogen atoms), C₃-C₆ cycloalkylC₁-C₆ alkyl, or C;7-C₁₄ aralkyl (wherein the C₇-C₁₄ aralkyl is optionally substituted with one or more groups independently selected from the group consisting of one or more halogen atoms, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and cyano).

R₉ is more preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₂-C₃ alkenyl; C₁-C₆ alkoxyC₁-C₂ alkyl optionally substituted with mono-C₁-C₁₀ alkylaminocarbonyl, hydroxy, or 5- to 6-membered heteroaryl optionally substituted with one or more fluorine atoms; and benzyl or phenethyl optionally substituted with one or more groups independently selected from the group consisting of C₃-C₆ cycloalkylC₁-C₂ alkyl, halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, and cyano.

More specific examples of R₉ include hydrogen, methyl, ethyl, i-propyl, 2-methylpropyl, 2,2,2-trifluoroethyl, 5,5-difluoropentyl, methoxymethyl, n-propoxymethyl, 3-methylbutoxymethyl, 3-(dimethylamino)₃-oxopropyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(tert-butylamino)-2-oxoethoxy)methyl, (5-fluoropyridin-3-yl)methyl, allyl, cyclohexylmethyl, benzyl, phenethyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 4-methoxybenzyl, 2-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl, 4-(trifluoromethyl)benzyl, 2-(trifluoromethoxy)benzyl, 3-(trifluoromethoxy)benzyl, and 4-(trifluoromethoxy)benzyl.

In an embodiment, in formula (1), R₉ and P₉, together with the carbon atom to which R₉ is attached and the nitrogen atom to which P₉ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₉ and P₉ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₉ and Q₉, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₉ and P₉ form a 4- to 7-membered saturated heterocyclic ring, P₉ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino). P₉ is preferably hydrogen or C₁-C₆ alkyl, and more preferably hydrogen, methyl, n-propyl, or n-butyl.

In an embodiment, except when R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₉ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen or methyl.

Regarding R₈ and Q₉, preferably, R₉ is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₇-C₁₄ aralkyl, and Q₉ is C₁-C₆ alkyl; or R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

Specific examples of core 9 include MeAla, Ala, MeLeu, MeCha, MeVal, MeSer(tBuOH), MeSer(NtBu-Aca), Val, Leu, MeSer(nPr), MeHnl(7-F2), MeSer(iPen), Ser(nPr), Abu(4-F3), Abu, Ser(Me), Gly, nBuGly, nPrGly, MePhe, MeHph, MePhe(4-Cl), MePhe(2-F), MePhe(3-F), MePhe(4-F), MePhe(2-C₁), MePhe(3-C₁), MePhe(2-Me), MePhe(4-Me), MePhe(2-CF3), MePhe(3-CF3), MePhe(4-CF3), MeTyr(Me), MePhe(2-OCF3), MePhe(3-OCF3), MePhe(4-OCF3), D-Pro, Phe, Ser(NtBu-Aca), MeSer(3-F-5-Me-Pyr), D-Ala, MeGln(Me2), MeAib, Aib, cLeu, cHex, cVal, (Me)Phe, MecLeu, D-(Me)Abu, D-(Me)Algly, 1-ACPrC, (Me)Abu, (Me)Algly, (Me)Leu, Athpc, MePhe(2-OMe), Me(Me)Phe, D-Val, and D-Algly.

In an embodiment, in formula (1), R₁₀ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyC₁-C₈ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C₁-C₆ alkylsulfonyl.

R₁₀ is preferably C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkylsulfonylC₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆alkyl optionally substituted with one or more halogen atoms, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₂-C₄ aralkyl.

R₁₀ is more preferably C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₄ hydroxyalkyl, methylsulfonylC₁-C₂ alkyl, C₂-C₃ alkynyl, C₁-C₄ alkoxyC₁-C₂ alkyl optionally substituted with one or more fluorine atoms, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₂ alkyl, C₃-C₆ cycloalkoxyC₁-C₂ alkyl, benzyl, or phenethyl.

More specific examples of R₁₀ include methyl, ethyl, n-propyl, i-propyl, 2-methylpropyl, 1-methylpropyl, n-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, propargyl, 3,3-difluorobutyl, 5,5-difluoropentyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, n-propoxymethyl, 1-hydroxyethyl, cyclopropoxymethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, 2-methylsulfonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, and phenethyl.

In an embodiment, in formula (1), R₁₀ and P₁₀, together with the carbon atom to which R₁₀ is attached and the nitrogen atom to which P₁₀ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₁₀ and P₁₀ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₁₀ and Q₁₀, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₁₀ and Q₁₀ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), except when R₁₀ and P₁₀ form a 4- to 7-membered saturated heterocyclic ring, P₁₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino). P₁₀ is preferably hydrogen or C₁-C₂ alkyl, and specific examples include hydrogen and methyl.

In an embodiment, except when R₁₀ and Q₁e form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₀ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

Specific examples of core 10 include MeAla, MeLeu, MeCha, MeVal, MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly(cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, Val, Leu, MeNva(5-F2), MeHle, MeIle, MeSer(nPr), MeSer(cPr), MeHnl, MeHnl(7-F2), MePRA, MeSer(Me), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), MeMet(02), Ile, Nle, Chg, Ala(cBu), Gly(cPent), Hle, Nva, Phe, and 1Hph.

In an embodiment, in formula (1), R₁₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or aminocarbonyl (wherein the amino is —NH₂, mono C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C₁-C₆ alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl; or R₁₁ is a peptide chain containing 1 to 4 amino acid residues. When R₁₁ is a peptide chain containing 1 to 4 amino acid residues, the 1 to 4 amino acid residues constituting the peptide chain may be natural amino acid residues or non-natural amino acid residues, and may be the same or different.

When core 11 is α-amino acid (i.e., L₁₁ is a single bond), R₁₁ is preferably hydrogen, C₁-C₆ alkoxyC₁-C₆ alkyl optionally substituted with hydroxy, or C₁-C₁₄ aralkyl optionally substituted with one or more halogen atoms.

When core 11 is α-amino acid, R₁₁ is more preferably hydrogen, C₁-C₆ alkoxyC₁-C₂ alkyl optionally substituted with hydroxy, or benzyl optionally substituted with fluorine, and specific examples include hydrogen, (2-hydroxy-2-methyl-propyloxy)methyl, benzyl, 3-fluorobenzyl, and 4-fluorobenzyl.

When core 11 is β-amino acid (i.e., L₁₁ is —CHM₁₁-), R₁₁ is preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl (wherein the C₁-C₆ alkoxyC₁-C₆ alkyl is optionally substituted with hydroxy or aminocarbonyl (wherein the amino is —NH₂. mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino)), C₇-C₁₄ aralkyl optionally substituted with one or more halogen atoms, or aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, and the cyclic amino may be further substituted with one or more halogen atoms, one or more oxo groups, one or more C₁-C₆ alkyl groups, or 4- to 7-membered heterocyclyl).

When core 11 is β-amino acid, R₁₁ is more preferably hydrogen, C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₆ alkoxyC₁-C₂ alkyl optionally substituted with mono-C₁-C₄ alkylaminocarbonyl, dimethylaminocarbonyl; 4- to 8-membered cyclic aminocarbonyl optionally substituted with one or more fluorine atoms, C₁-C₄ alkyl, or 4- to 7-membered heterocyclyl; benzyl or phenethyl.

When core 11 is β-amino acid, specific examples of R₁ include hydrogen, methyl, isobutyl, trifluoromethyl, allyl, prop-2-yn-1-yl, (isopentyloxy)methyl, {2-(t-butylamino)-2-oxoethoxy}methyl, dimethylaminocarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, 3,3-dimethylpyrrolidinylcarbonyl, 3,3,4,4-tetrafluoropyrrolidinylcarbonyl, 4-methylpiperidinylcarbonyl, 4-(t-butyl)-piperidinylcarbonyl, 3,3,4,4,5,5-hexafluoropiperidinylcarbonyl, 3,3-difluoropiperidinylcarbonyl, 4,4-difluoropiperidinylcarbonyl, piperidinylcarbonyl, morpholinocarbonyl, oxazolidin-3-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, 1,1-dioxidethiomorpholinylcarbonyl, 1-(oxetan-3-yl)-piperazin-4-ylcarbonyl, and phenethyl.

When L₁₁ of core 11 is —(CH₂)_mS(CH₂)_m, —(CH₂)_nS(O)(CH₂)_m, or —(CH₂)_nS(O)₂(CH₂)_m, R₁₁ is preferably aminocarbonyl (wherein the amino is —NH₂, Mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

In an embodiment, in formula (1), R₁₁ and P₁₁, together with the carbon atom to which R₁₁ is attached and the nitrogen atom to which P₁₁ is attached, can form a 4- to 7-membered saturated heterocyclic ring.

When R₁₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

In an embodiment, in formula (1), R₁₁ and Q₁₁, together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

When R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

In an embodiment, in formula (1), when core 11 is β-amino acid, R₁₁ and M₁₁, together with the carbon atom to which R₁₁ is attached and the carbon atom to which M₁₁ is attached, can form a 3- to 8-membered alicyclic ring.

When R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring, the 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.

In an embodiment, in formula (1), when core 11 is β-amino acid, M₁₁ is hydrogen except when R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring.

In an embodiment, in formula (1), except when R₁₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₈ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

P₁₁ is preferably hydrogen or C₁-C₆ alkyl. Specific examples of such P₁₁ include hydrogen, methyl, ethyl, and n-propyl.

In an embodiment, except when R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₁ is hydrogen or C₁-C₆ alkyl, and preferably hydrogen.

In an embodiment, R₁₁ is preferably —CONR_11AR_11B, wherein R_11A and R_11B are each independently hydrogen or C₁-C₆ alkyl (preferably methyl), or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a 4- to 8-membered saturated heterocyclic ring. The 4- to 8-membered saturated heterocyclic ring is optionally substituted with one or more groups independently selected from the group consisting of one or more halogen atoms (preferably fluorine), one or more oxo groups, one or more C₁-C₆ alkyl groups (preferably C₁-C₄ alkyl), and 4- to 7-membered heterocyclyl (preferably oxetan-3-yl).

When core 11 is α-amino acid, specific examples of core 11 include MeSer(tBuOH), MeGly, MePhe, MePhe(3-F), MePhe(4-F), and D-MePhe.

When core 11 is β-amino acid, specific examples of core 11 include bAla, bMeAla, 2-ACHxC, 2-ACPnC, 3-CF3-bAla, Asp-mor, Asp-mor(26-bicyc), Asp-mor(SO2), Asp-NMe2, Asp-oxz, Asp-pip, Asp-pip(345-F6), Asp-pip(4-Me), Asp-pip-tBu, Asp-piz(oxe), Asp-pyrro, Asp-pyrro(34-F4), Asp-pyrro(3-Me2), D-(Propargyl)Gly-(C#CH2), D-3-Abu, D-3-MeAbu, D-Gly(Allyl)-(C#CH2), D-Hph-(C#CH2), D-Leu-(C#CH2), D-MeAsp-pyrro, D-MeLeu-(C#CH2), D-Pic(2)-(C#CH2), D-Pro-(C#CH2), D-Ser(iPen)-(C#CH2), D-Ser(NtBu-Aca)-(C #CH₂), EtAsp-pip, MeAsp-aze, MeAsp-mor, MeAsp-mor(26-bicyc), MeAsp-mor(SO2), MeAsp-NMe2, MeAsp-oxz, MeAsp-pip, MeAsp-pip(345-F6), MeAsp-pip(3-F2), MeAsp-pip(4-F2), MeAsp-pip(4-Me), MeAsp-piz(oxe), MeAsp-pyrro, MeAsp-pyrro(34-F4), MeAsp-pyrro(3-Me2), and nPrA sp-pip.

When L₁₁ is —(CH₂)_nS(CH₂)_m, —(CH₂)_nS(O)(CH₂)_m, or —(CH₂)_nS(O)₂(CH₂)_m—, specific examples of core 11 include MeCys(AcOH)—NMe2.

In an embodiment, in formula (1), at least three of P₁ to P₁₁ are not hydrogen.

In an embodiment, in formula (1), at least three, at least four, at least five, or at least six of P₁ to P₁₁ are preferably C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is preferably methyl or ethyl.

In an embodiment, the present invention can be a compound having formula (1) wherein one of —CO-L₁- and —CO-L₁₁- is replaced with —(CH₂)_nC≡CCH₂S(CH₂)_m—, —(CH₂)_nCH═CHCH₂S(CH₂)_m—, or —(CH₂)_n+3S(CH₂)_m—, wherein n is 1, 2, or 3, and m is 1 or 2. —S— may be oxidized to be —S(O)— or —S(O)₂—. Here, when —CO-L₁- is replaced with —(CH₂)C≡CCH₂S(CH₂)_m—, —(CH₂)n_CH═CHCH₂S(CH₂)_m—, or —(CH₂)_n+3S(CH₂)_m—, L₁₁ is a single bond, and when —CO-L₁₁- is replaced with —(CH₂)_nC≡CCH₂S(CH₂)_m—, —(CH₂)_nCH═CHCH₂S(CH₂)_m—, or —(CH₂)_n+3S(CH₂)_m—, L₁ is a single bond. Groups other than L₁ and L₁₁ in formula (1) are as described above.

In an embodiment, the present invention relates to a cyclic peptide compound represented by formula (1′) below or a salt thereof, or a solvate thereof.

In formula (1′),

• • L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_n—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)(CH₂)_m—,
  • n and m are each independently 1 or 2, the definitions of R₂ to R₁₁, P₂ to P₁₁, Q₂ to Q₁₁, and M₁₁ are the same as the definitions of R₂ to R₁₁, P₂ to P₁₁, Q₂ to Q₁₁, and M₁₁ in formula (1), respectively.

In formula (1′), the ring is composed of 10 amino acid residues. As in formula (1), the amino acid residue having P₂, Q₂, and R₂ in the formula may be referred to as core 2, the amino acid residue having P₃, Q₃, and R₃ as core 3, the amino acid residue having P₄, Q₄, and R₄ as core 4, the amino acid residue having P₅, Q₅, and R₅ as core 5, the amino acid residue having P₆, Q₆, and R₆ as core 6, the amino acid residue having P₇, Q₇, and R₇ as core 7, the amino acid residue having P₈, Q₈, and R₈ as core 8. the amino acid residue having Pa, Q₉, and R₉ as core 9, the amino acid residue having P₁₀, Q₁₀, and R₁₀ as core 10, and the amino acid residue having P₁₁, Q₁₁, R₁₁, and L₁₁ as core 11.

In an embodiment, in formula (1′), L₁₁ is —CHM₁₁-, —(CH₂)S(CH₂)_m—, (CH₂)_nS(O)(CH₂)_m—, or (CH₂)_nS(O)₂(CH₂)_m—. M₁₁ is the same as M₁₁ in formula (1).

When L₁₁ is —CHM₁₁-, M₁₁ can be hydrogen, or M₁₁ can, together with R₁₁, the carbon atom to which R₁₁ is attached, and the carbon atom to which M₁₁ is attached, form a 3- to 8-membered alicyclic ring. The 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.

When L₁₁ is —(CH₂)_nS(CH₂)_m—, specific examples of —(CH₂)_nS(CH₂)_m— include —CH₂SCH₂—, —CH₂CH₂SCH₂—, —CH₂SCH₂CH₂—, and —CH₂CH₂SCH₂CH₂—.

When L₁₁ is —(CH₂)_nS(O)(CH₂)_m—, specific examples of —(CH₂)_nS(O)(CH₂)_m— include —CH₂S(O)C₂—, —CH₂CH₂S(O)CH₂—, —C₂S(O)CH₂CH₂—, and —Ch₂CH₂S(O)CH₂CH₂—.

When L₁₁ is —(CH₂)_nS(O)₂(CH₂)_m—, specific examples of —(CH₂)_nS(O)₂(CH₂)_m— include —CH₂S(O)₂CH₂—, —CH₂CH₂S(O)₂CH₂—, —CH₂S(O)₂CH₂CH₂—, and —CH₂CH₂S(O)₂CH₂CH₂—.

When L₁₁ is —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m, or —(CH₂)_nS(O)₂(CH₂)_m—, R₁₁ is preferably aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino).

When L₁₁ is —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m, or —(CH₂)_nS(O)₂(CH₂)_m—, R₁₁ is more preferably —CONR_11AR_11B, wherein R_11A and R_11B are each independently hydrogen or C₁-C₆ alkyl (preferably methyl), or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a 4- to 8-membered saturated heterocyclic ring. The 4- to 8-membered saturated heterocyclic ring is optionally substituted with one or more groups independently selected from the group consisting of one or more halogen atoms (preferably fluorine atom(s)), one or more oxo groups, one or more C₁-C₆ alkyl groups (preferably C₁-C₄ alkyl group(s)), and 4- to 7-membered heterocyclyl (preferably oxetan-3-yl). Specific examples of R₁₁ include dimethylaminocarbonyl.

When L₁₁ is —(C₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₁)_m, or —(CH₂)_nS(O)₂(C₁₂)_m—, Q₁ is preferably hydrogen or C₁-C₆ alkyl, and more preferably hydrogen.

When L₁₁ is —(CH₂)_nS(CH₂)_m—, —(C₁₂)_nS(O)(CH₂)_m, or —(CH₂)_nS(O)₂(CH₂)_m—, P₁₁ is preferably hydrogen or C₁-C₆ alkyl. Specific examples of such P₁₁ include hydrogen, methyl, ethyl, and n-propyl.

When L₁₁ is —(CH₂)S(CH)_m—, CH₂)_nS(O)(CH₂)., or —(CH₂)_nS(O)₂(C₂)_m—, specific examples of core 11 include MeCys(AcOH)—NMe2.

Preferable groups in each of cores 2 to 11 in formula (1′) may be the same as the preferable groups in each corresponding core in formula (1). Further, the specific amino acids listed above as cores 2 to 11 of formula (1) can be used as amino acids of each corresponding core of formula (1′).

Specific examples of the cyclic peptide compound represented by formula (1′) include the following:

• (2172) (3S,9S,18S,24R,27S,33S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-27-cyclopentyl-N,N,7,10,13,16,25,28-octamethyl-2,5,8,11,14,17,20,26,29,32-decaoxospiro[22-thia-1,4,7,10,13,16,19,25,28,31-decazabicyclo[31.3.0]hexatriacontane-30,1′-cyclopentane]-24-carboxamide, and
• (2173) (3S,9S,18S,24R,27S,33S)-18,27-bis[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]—N,N,7,10,13,16,25,28-octamethyl-9-[(4-methylphenyl)methyl]-2,5,8,11,14,17,20,26.,29,32-decaoxospiro[22-thia-1,4,7,10,13,16,19,25,28,31-decazabicyclo[31.3.0]hexatriacontane-30,1-cyclopentane]-24-carboxamide.

In an embodiment, the present invention can be a cyclic peptide compound represented by formula (2) below that further specifies formula (1) above.

The definition of each group in formula (2) is the same as the definition of each group in formula (1). The cyclic peptide compound represented by formula (2) preferably has each of the following groups.

• • R₁ is C₁-C₈ alkyl (preferably C₁-C₄ alkyl, and more preferably methyl or 2-methylpropyl), and P₁ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₂ is C₁-C₆ alkyl (preferably C₃-C₆ alkyl, and more preferably 1-methylpropyl), and P₂ is hydrogen or C₁-C₆ alkyl (preferably hydrogen or C₁-C₃ alkyl, and more preferably hydrogen or methyl), and/or
  • R₃ is hydrogen or C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and P₃ is hydrogen or C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₄ is hydrogen, and P₄ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), or R₄ and P₄, together with the carbon atom to which R₄ is attached and the nitrogen atom to which P₄ is attached, form a 4- to 7-membered saturated heterocyclic ring (preferably, an azetidine ring, a pyrrolidine ring, or a piperidine ring, and more preferably an azetidine ring or a pyrrolidine ring), and/or
  • R₅ is C₁-C₆ alkoxyC₁-C₆ alkyl (preferably C₂-C₆alkoxy C₁-C₂ alkyl, and more preferably C₃-C₈ alkoxymethyl); C₇-C₁₄ aralkyl (preferably benzyl or phenethyl, and more preferably benzyl) optionally substituted with a group independently selected from the group consisting of halogen (preferably fluorine or chlorine), C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), C₁-C₆ haloalkyl (preferably C₁-C₃ fluoroalkyl, and more preferably trifluoromethyl), and C₁-C₆ alkoxy (preferably C₁-C₃ alkoxy, and more preferably methoxy); C₃-C₈ cycloalkyl (preferably C₃-C₆ cycloalkyl, and more preferably C₅-C₆ cycloalkyl), or C₃-C₈ cycloalkylC₁-C₆ alkyl (preferably C₃-C₆ cycloalkylC₁-C₂ alkyl, more preferably C₅-C₆ cycloalkylmethyl, and even more preferably cyclohexylmethyl), and P₅ is C₁-C₂ alkyl (preferably methyl or ethyl), and/or
  • R₆ is hydrogen or C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and P₆ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl or ethyl), or R₆ and P₆, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₆ is attached, form a 4- to 7-membered saturated heterocyclic ring (preferably, an azetidine ring, a pyrrolidine ring, or a piperidine ring, and more preferably a pyrrolidine ring), and/or
  • R₇ is C₇-C₁₄ aralkyl (preferably benzyl or phenethyl) optionally substituted with 1 to 5 (preferably 1 to 3) groups independently selected from the group consisting of halogen (preferably fluorine, chlorine, or iodine) and C₁-C₆ haloalkyl (preferably C₁-C₃ fluoroalkyl, and more preferably trifluoromethyl), P₇ is hydrogen, and Q₇ is hydrogen, and/or
  • R₈ is C₁-C₆ alkyl (preferably C₁-C₄ alkyl, and more preferably 2-methylpropyl, isopropyl, or n-butyl), C₂-C₆ alkynyl (preferably C₂-C₃ alkynyl, and more preferably propargyl), 4- to 8-membered cyclic aminocarbonylC₁-C₆ alkyl (preferably 4- to 8-membered cyclic aminocarbonylC₁-C₂ alkyl, and more preferably 4- to 8-membered cyclic aminocarbonylmethyl) optionally substituted with 1 to 5 (preferably 1 to 3) fluorine atoms, 5- to 10-membered heteroarylC₁-C₆ alkyl (preferably 5- to 10-membered heteroarylC₁-C₂ alkyl, and more preferably 5- to 10-membered heteroarylmethyl), or C₇-C₁₄ aralkyl (preferably benzyl or phenethyl) optionally substituted with 1 to 3 halogen atoms (preferably chlorine), and P₈ is hydrogen, C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), 4- to 8-membered cyclic aminoC₁-C₆ alkyl optionally substituted with 1 to 5 (preferably 1 to 3) C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl) (preferably piperazylC₁-C₂ alkyl), 4- to 7-membered heterocyclylC₁-C₆ alkyl (preferably 4- to 7-membered heterocyclylC₁-C₂ alkyl, more preferably azetidylethyl), C₁-C₆ alkoxyC₁-C₆ alkyl substituted with amino (NH₂), C₁-C₆ alkylamino (preferably methylamino), or di-C₁-C₆ alkylamino (preferably dimethylamino) (preferably C₁-C₃ alkoxyC₁-C₂ alkyl, and more preferably ethoxyethyl), or amino (NH₂) C₁-C₆ alkyl; or R₈ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring (preferably an azetidine ring, a pyrrolidine ring, or a piperidine ring, and more preferably an azetidine ring or a pyrrolidine ring), wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (preferably fluorine) or C₁-C₆ alkoxy (preferably C₁-C₃ alkoxy, and more preferably methoxy or ethoxy), and/or
  • R₉ is benzyl, and Q₉ is hydrogen; or R₉ and Q₉ are each independently C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), or R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring (preferably a 3- to 6-membered alicyclic ring, more preferably a cyclobutane ring or a cyclopentane ring), and P₉ is hydrogen or C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₁₀ is C₁-C₆ alkyl (preferably C₁-C₄ alkyl, and more preferably isopropyl, 1-methylpropyl, or 2-methylpropyl) or C₃-C₈ cycloalkyl (preferably C₃-C₆ cycloalkyl, and more preferably cyclopentyl or cyclohexyl), and P₁₀ is hydrogen or C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₁₁ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), di-C₁-C₆ alkylaminocarbonyl (preferably di-C₁-C₃ alkylaminocarbonyl, and more preferably dimethylaminocarbonyl), or 4- to 8-membered cyclic aminocarbonyl (preferably azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, 4-morpholinylcarbonyl, or 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl), P₁₁ is hydrogen or C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and M₁₁ is hydrogen.

In an embodiment, the present invention can be a cyclic peptide compound represented by formula (3) below that further specifies formula (1) above.

definition of each group in formula (3) is the same as the definition of each group in formula (1). The cyclic peptide compound represented by formula (3) preferably has each of the following groups.

• • R₁ is hydrogen, P₁ is hydrogen or C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and M₁ is hydrogen, and/or
  • R₂ is hydrogen or C₁-C₆ alkyl (preferably C₃-C₆ alkyl, and more preferably 1-methylpropyl), and P₂ is hydrogen or C₁-C₆ alkyl (preferably hydrogen or C₁-C₃ alkyl, and more preferably hydrogen or methyl), and/or
  • R₃ is hydrogen, P₃ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₄ is hydrogen, P₄ is C₁-C₆ alkyl (preferably hydrogen or C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₅ is C₃-C₈ cycloalkylC₁-C₆ alkyl (preferably C₃-C₆ cycloalkylC₁-C₂ alkyl, and more preferably C₅—C, cycloalkylmethyl), and P₅ is C₁-C₂ alkyl (preferably methyl), and/or
  • R₆ is hydrogen, and P₆ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₇ is C₇-C₁₄ aralkyl (preferably benzyl or phenethyl, and more preferably benzyl) optionally substituted with 1 to 5 (preferably 1 to 3) groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl (preferably C₁-C₃ fluoroalkyl, and more preferably trifluoromethyl), and P₇ is hydrogen, and Q₇ is hydrogen, and/or
  • R₈ and P₈, together with the carbon atom to which R is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring (preferably an azetidine ring, a pyrrolidine ring, or a piperidine ring, and more preferably a pyrrolidine ring), and/or
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring (preferably a 3- to 6-membered alicyclic ring, and more preferably a cyclobutane ring or a cyclopentane ring), and P₉ is hydrogen, and/or
  • R₁₀ is C₃-C₈ cycloalkyl (preferably C₃-C₆ cycloalkyl, and more preferably cyclopentyl or cyclohexyl), and P₁₀ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl), and/or
  • R₁₁ is hydrogen, C₇-C₁₄ aralkyl (preferably benzyl or phenethyl, and more preferably benzyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (preferably fluorine), or C₁-C₆ alkoxyC₁-C₆ alkyl (preferably C₂-C₈ alkoxyC₁-C₂ alkyl, and more preferably C₃-C₈ alkoxymethyl) optionally substituted with one hydroxy group, and P₁₁ is C₁-C₆ alkyl (preferably C₁-C₃ alkyl, and more preferably methyl).

In an embodiment, the present invention can be a cyclic peptide compound represented by formula (4) below that further specifies formula (1) above.

R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (4) are the same as R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (2) above, respectively, and n and m are each independently 1 or 2. Moreover, —S— in formula (4) may be oxidized to be —S(O)— or —S(O)₂—.

In an embodiment, the present invention can be a cyclic peptide compound represented by formula (5) below that further specifies formula (1) above.

R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (5) are the same as R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (2) above, respectively, and n and in are each independently 1 or 2. Moreover, —S— in formula (5) may be oxidized to be —S(O)— or —S(O)₂—.

In an embodiment, the present invention can be formula (6) below wherein —CO-L₁- in formula (1) above is replaced with —(CH₂)_nC≡CCH₂S(CH₂)_m—, —(CH₂)_nCH═CHCH₂S(CH₂)_m—, or —(CH₂)_n+3S(CH₂)_m, and L₁₁ is a single bond.

R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (6) are the same as R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (2) above, respectively,

represents a single bond, a double bond, or a triple bond, n is 1, 2, or 3, and m is 1 or 2. Moreover, —S— in formula (6) may be oxidized to be —S(O)— or —S(O)—.

In an embodiment, the present invention can be formula (7) below wherein —CO-L₁₁- in formula (1) is replaced with —(CH₂)_nC≡CCH₂S(CH₂)_m—, —(CH₂)_nCH═CHCH₂S(CH₂)_m—, or —(CH₂)_n+3S(CH)_m—, and L₁ is a single bond.

R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (7) are the same as R₁ to R₁₁, P₁ to P₁₁, Q₇, and Q₉ in formula (2), respectively,

represents a single bond, a double bond, or a triple bond, n is 1, 2, or 3, and m is 1 or 2. Moreover, —S— in formula (7) may be oxidized to be —S(O)— or —S(O)₂—.

In an embodiment, the present invention can be a cyclic peptide compound represented by formula (8) below.

R₂ to R₁₁, P₂ to P₁₁, Q₇, and Q₉ in formula (8) are the same as R₂ to R₁₁, P₂ to P₁₁, Q₇, and Q₉ in the above-mentioned formula (1), respectively, and n and mi are each independently 1 or 2. Further, —S— in formula (8) may be oxidized to be —S(O)— or —S(O)₂—.

Specific examples of the cyclic peptide compound disclosed herein are as follows. The structural formulae of the following compounds (1) to (762), (764) to (845), (847) to (1027), (1029) to (1146), and (1148) to (2188) are shown in Table 39. That is, the numbers given to the following compounds correspond to the numbers given to the compounds shown in Table 39, respectively, and are described herein as “(the number given to the compound)” at the beginning of the IUPAC name.

• (1) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9,18-bis(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2) (8S,11S,17S,26S,29S,33R,36S)-17-(cyclohexylmethyl)-11-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-8,29,36-triisobutyl-6,15,18,21,24,30,33,34-octamethyl-26-[(1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (3) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-29-isobutyl-36-isopropyl-9,15,18,21,24,30,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (4) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,22,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (5) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-33-ethyl-11-isobutyl-N,N,5,6,12,16,19,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (6) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-[[6-(trifluoromethyl)₃-pyridyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (7) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylethyl)-11-isobutyl-18-isopropyl-8-(methoxymethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (8) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(cyclopentylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (9) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-2,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (10) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-[[6-(trifluoromethyl)-3-pyridyl]methyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (11) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(propoxymethyl)docosahydro-2-1,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (12) allyl N-[4-[(3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-9-yl]butyl]carbamate,
• (13) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-9-(2-phenylethyl)-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (14) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopropyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (15) (8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-chlorobenzyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (16) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (17) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-8-(2-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (18) (3S,9S,18S,21S,25R,28S,31S,34S)-31-benzyl-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-9,18-bis[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (19) (3S,9S,12S,18S,27S,30S,34R)-12-[2-(4-chlorophenyl)ethyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,6,6,10,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (20) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (21) (3S,6S,9S,12S,18S,27S,30S,34S)-6,9-dibenzyl-18-[(4-chlorophenyl)methyl]-12-[(3,5-difluorophenyl)methyl]-3-isopropyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (22) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopentyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (23) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-36-ethyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (24) (3S,6S,9S,13S,16S,19S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,22,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (25) (6S,12S,21S,24S,26aR,29aR,32S,35S,37aS)-35-benzyl-21-((S)-sec-butyl)-12-(4-chlorobenzyl)-32-isobutyl-10,13,16,19,24,25,33,36-octamethyl-6-(4-(trifluoromethyl)phenethyl)hexacosahydro-1H-cyclopenta[f1]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-5,8,11,14,17,20,23,26,31,34,37(37aH)-undecaone,
• (26) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (27) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-22-(isopentyloxymethyl)-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (28) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-(4-fluorophenyl)ethyl]-3,9-diisobutyl-4,6,6,10,16,19,22,25,30,31,34-undecanethiol-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (29) (3S,6S,9S,12S,18S,27S,30S,34S)-6,9-dibenzyl-12-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-16-ethyl-3-isopropyl-4,7,19,22,25,30,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (30) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (31) (4R,7S,13S,16S,22S,31S,34S)-22-(cyclohexylmethyl)-7,13-diisobutyl-4,8,10,10,14,20,23,26,29-nonamethyl-31-[(1S)-1-methylpropyl]-16-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,5,8,11,14,17,20,23,26,29,32-undecazabicyclo[32.4.0]octatriacontane-2,6,9,12,15,18,21,24,27,30,33-undecone,
• (32) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(prop-2-yn-1-yl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (33) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (34) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2, 1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (35) (8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (36) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(4-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (37) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(cyclopentylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (38) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11,35-bis(cyclohexylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-²H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (39) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H-22H)-undecaone,
• (40) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (41) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-19-(propoxymethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (42) (5S,8S,11S,15 R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(3-chlorobenzyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone, (43) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[(2-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (44) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (45) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-8-(cyclobutoxymethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (46) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-3,6,9-triisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (47) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (48) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (49) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (50) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (51) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-9-isobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (52) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-11-methylpropyl]-21-(2-methylsulfonylethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (53) N-tert-butyl-2-[[(3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,16,19,22,25,30,31-heptamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-6-yl]methoxy]acetamide,
• (54) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)-11-pentyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (55) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (56) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-7,10,13,16,21,22,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-26-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (57) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexymethyl)-9,16,22-triisobutyl-4,10,13,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (58) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-cyclohexyl-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (59) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-(cyclobutylmethyl)-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (60) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-(cyclopentylmethyl)-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cycyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (61) (8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8,36-diisobutyl-9,15,18,21,24,29,30,33,37-nonamethyl-26-[(1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (62) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(tri fluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (63) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-unidecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone, (64) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11,15-diisobutyl-5,6,12,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (65) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (66) (3S,9S,18S,21S,25R,28S,34S,36R)-28-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (67) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,22,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (68) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(cyclopropylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (69) (8S,11S,17S,26S,29S,33S,36S)-8-benzyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-unidecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (70) N-(tert-butyl)-2-(((5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-5-yl)methoxy)acetamide,
• (71) (3S,6S,10R,13S,16S,19S,22S,28S,34S)-16-benzyl-28-[(4-chlorophenyl)methyl]-19-isobutyl-13-isopropyl-6,7,10,14,17,20,26,29,32-nonamethyl-3-[(1S)-1-methylpropyl]-22-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,11,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,12,15,18,21,24,27,30,33-undecone,
• (72) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (73) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (74) (3S,9S,18S,21S,25R,28S,34S,36R)-9-(cyclohexylmethyl)-28-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (75) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclobutylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (76) (6′S,15′S,18′S,22′R,25′S,30a′S,36′S,38a′R)-15′-((S)-sec-butyl)-36′-(3-chloro-4-(trifluoromethyl)phenethyl)-6′-(cyclohexylmethyl)-18′-isobutyl-25′-isopropyl-7′,10′,13′,19′,22′,26′-hexamethyltetracosahydro-5′H-spiro[cyclopentane-1,28′-dipyrrolo[2,1-i2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,24′,27′,30′,35′,38′(21′H,29′H)-undecaone,
• (77) (8S,11S,15R,18S,23aS,29S,31aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-37-(cyclohexylmethyl)-18-isopropyl-6,11,12,15,19,38-hexamethyltetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (78) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(5,5-difluoropentyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (79) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopentyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (80) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-11-((R)-1-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (81) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclohexane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (82) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(2-chlorobenzyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (83) (3S,9S,12S,18S,27S,30S,34R)-3-butyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (84) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexymethyl)-8-(cyclopentylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (85) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (86) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-((2-hydroxy-2-methylpropoxy)methyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,41-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (87) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-bis(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (88) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (89) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-11-(but-3-yn-1-yl)-8-((S)-sec-butyl)₂₉-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(4-iodobenzyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (90) (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-36-phenyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (91) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-((R)-1-hydroxyethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (92) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoroethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-(5,5-difluoropentyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (93) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,25,29,31,31,32-undecamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (94) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(5,5-difluoropentyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (95) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]31-(cyclohexylmethyl)-16-cyclopentyl-22-[(3-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (96) (3S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-6,6,7,16,19,22,25,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (97) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-29-isobutyl-36-isopropyl-N,N,9,15,18,21,24,30,37-nonamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-33-carboxamide,
• (98) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-isobutyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-21H,41-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (99) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (100) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-cyclopropyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (101) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylethyl)-18-cyclopropyl-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (102) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,22,23,29,32-undecamethyl-6-[(1S)-11-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (103) (2aS,5S,11S,14S,20S,23S,30aS,33S,36S)-33-((S)-sec-butyl)-14-butyl-11-(3-chloro-4-(trifluoromethyl)phenethyl)-5-(4-chlorobenzyl)-20-isobutyl-4,7,16,17,17,22,35,36-octamethyl-23-(piperidine-1-carbonyl)tetracosahydroazeto[1,2-j]pyrido[1,2-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-3,6,9,12,15,18,21,25,31,34,37(1H,22H,27H)-undecaone,
• (104) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoroazetidin-1-yl)ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-19-(2,2,2-trifluoroethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (105) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (106) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclohexyl-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (107) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylethyl)-28-cyclopentyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (108) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (109) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-9-isopropyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (110) (3S,9S,18S,21S,25R,28S,34S)-21-but-3-ynyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-[(4-iodophenyl)methyl]-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (111) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptaethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-[[2-(trifluoromethoxy)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (112) (5S,8S,12S,15S,20aS,26S,32S,37aS)-5-((S)-sec-butyl)-26-(4-chlorophenethyl)-32-(cyclohexylmethyl)-8-isobutyl-15-isopropyl-9,13,16,30,33,36-hexamethyl-12-(piperidine-1-carbonyl)docosahydrospiro[azeto[1,2-g]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1-cyclopentan]-4,7,10,14,17,20,25,28,31,34,37(2H,111H,19H)-undecaone,
• (113) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-8,33,36-triisobutyl-29-isopropyl-9,15,18,21,24,30,37-heptamethyl-26-[(1S)-1-methylpropyl]-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (114) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-22-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (115) (8S,11S,15S,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-6,11,12,16,19,32,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (116) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]-16-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (117) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyl-35-(3-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (118) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-[(1R)-1-hydroxyethyl]-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (119) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylacetyl)-12-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (120) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-chlorobenzyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (121) (3S,9S,18S,21S,25R,28S,34S)-9-[(4-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (122) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (123) (3S,9S,18S,21S,25R,28S,34S)-16-butyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexymethyl)-21-isobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (124) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-9,30-diisobutyl-3-isopropyl-4,7,10,16,19,22,25,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (125) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-9-butyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-18-[(4-methoxyphenyl)methyl]-1,6,7,16,19,22,25,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (126) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(propoxymethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (127) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclobutyl-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (128) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,12,16,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (129) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-(propoxymethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (130) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoroazetidin-1-yl)ethyl]-9-isobutyl-19-(methoxymethyl)-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (131) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-22-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (132) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (133) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (134) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18,35-dicyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (135) (6′S,15′S,18′S,22′S,25′S,30a′S,36′S,38a′R)-15′-((S)-sec-butyl)-36′-(3-chloro-4-(trifluoromethyl)phenethyl)-6′-(cyclohexylmethyl)-25′-isopropyl-7′,10′,13′,18′,19′,23′,26′-heptamethyl-22′-(piperidine-1-carbonyl)tetracosahydro-5′1H-spiro[cyclopentane-1,28′-dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′, 8,11′,14′,17′,20′,24′,27′,30′,35′,38′(21′H,29′H)-undecaone,
• (136) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(cyclopropylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (137) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-22-ethyl-21-isobutyl-7,10,13,16,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (138) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-36-ethyl-25,25-difluoro-11-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (139) (5S,8S,12S,15S,20aS,26S,32S,37aS)-5-((S)-sec-butyl)-32-(cyclohexylmethyl)-26-(3-fluoro-4-(trifluoromethyl)phenethyl)-8-isobutyl-15-isopropyl-9,13,16,30,33,36-hexamethyl-12-(piperidine-1-carbonyl)docosahydrospiro[azeto[1,2-g]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1′-cyclopentan]-4,7,10,14,17,20,25,28,31,34,37(2H,11H,19H)-undecaone,
• (140) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (141) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-(2-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (142) (6′S,12′S,21′S,24′S,27a′R,34′S,39a′S)-21′-((S)-sec-butyl)-12′-(cyclohexylmethyl)-6′-(3-fluoro-4-(trifluoromethyl)phenethyl)-24′-isobutyl-34′-isopropyl-10′,13′,16′,19′,25′,35′-hexamethylhexacosahydrospiro[cyclopentane-1,37′-pyrido[1,2-e1]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,23′,26′,33′,36′,39′(38′H)-undecaone,
• (143) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-[[3-(trifluoromethoxy)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (144) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-5,6,12,16,19,33,36-heptamethyl-11-pentyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (145) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-(5,5-difluoropentyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (146) (9′S,12′S,16R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-36′-(4-fluorobenzyl)-7′,12′13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′1H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(1511,23′t)-undecaone,
• (147) (8S,11S,15S,18S,23aS,25S,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-6,12,16,19,33,36-hexamethyl-25-phenyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,2.2H)-undecaone,
• (148) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-(methoxymethyl)-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (149) (3S,9S,18S,21S,25R,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-31-ethyl-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29,31-octamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (150) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (151) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′,37′-heptamethyl-36′-(4-methylbenzyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (152) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-9-isobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (153) (3S,9S,12S,18S,27S,30S,34R)-12-[2-(3-chlorophenyl)ethyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,6,6,10,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (154) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexymethyl)-9-[2-(3,3-difluoroazetidin-1-yl)ethyl]-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-(propoxymethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (155) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-5,12,16,19,33,36-hexamethyl-11-pentyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (156) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-29-isobutyl-36-isopropyl-8,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (157) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-8-cyclobutyl-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (158) (6S,9S,13R,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-9-isopropyl-4,10,13,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]=−2,5,8,11,15,18,21,24,27,30,33-undecone,
• (159) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-9-(2-methoxyethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (160) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-ethyl-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (161) (3S,9S,18S,21S,25S,28S,34S)-21-but-3-ynyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-[(4-iodophenyl)methyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-3,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (162) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-28-(2-methylsulfonylethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (163) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,12,16,19,33,36-hexamethyl-11-pentyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-Undecaone,
• (164) (3S,9S,18S,21S,25S,28S,34S)-18-allyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (165) (3S,9S,12S,18S,27S,30S,34R)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (166) (3S,9S,12S,18S,27S,30S,34S)-18-(cyclohexylmethyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-9-(p-tolylmethyl)-1,4,7,10,13,16,19,222,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (167) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (168) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-6-[(2-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (169) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-31-(cyclohexylmethyl)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-22-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (170) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-1,6,6,16,19,22,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (171) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8-[(3,4-difluorophenyl)methyl]-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (172) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-(cyclopropylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (173) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (174) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-8-(2-(methylsulfonyl)ethyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (175) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-35-(2-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (176) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (177) (8S,11S,17S,26S,29S,33S,36S)-11-[2-(4-chlorophenyl)ethyl]-17-(cyclohexylmethyl)-8-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-29-isobutyl-36-isopropyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (178) (6S,9S,13R,16S,22S,25S,31S,34S)-31-(cyclohexylmethyl)-25-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-4,10,13,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (179) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(3-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (180) 3-((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-15-(piperidine-1-carbonyl)tetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-5-yl)-N-methylpropananide,
• (181) (5S,8S,12R,15S,20aS,26S,32S,34aS,38aS)-5-((S)-sec-butyl)-26-(3-chloro-4-(trifluoromethyl)phenethyl)-32-(cyclohexylmethyl)-8-isobutyl-15-isopropyl-9,12,16,30,33-pentamethyldocosahydro-25H-spiro[bis(azeto)[1,2-g:1′,2′-j]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1′-cyclopentan]-4,7,10,14,17,20,25,28,31,34,38(2H,11H,19H,34aH)-undecaone,
• (182) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (183) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclobutyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (184) (3S,6S,9S,12S,18S,27S,30S,34S)-6,9-dibenzyl-18-[(4-chlorophenyl)methyl]-12-[(3-fluorophenyl)methyl]-3-isopropyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25 28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (185) (6′S,9′S,13′R,16′S,21a′S,27′S,33′S,38a′S)-6′-((S)-sec-butyl)-27′-(3-chloro-4-(trifluoromethyl)phenethyl)-33′-(cyclohexylmethyl)-9′-isobutyl-16′-isopropyl-10′,13′,17′,31′,34′,37′-hexamethyldocosahydro-1¹H-spiro[cyclopentane-1,19′-dipyrrolo[1,2-g:1′,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,15′,18′,21′,26′,29′,32′,35′,38′(12H,201′H,38a′H)-undecaone,
• (186) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′F(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(3-chlorobenzyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (187) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (188) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-22-[(4-methoxyphenyl)methyl]-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (189) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-30-isopropyl-4,10,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,25,28,31-undecazabicyclo[32.4.0]octatriacontane-6,1′-cyclopentane]-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (190) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-6-isobutyl-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8, 1,14,17,20,23,26,29,32-undecone,
• (191) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,22,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (192) (S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-8-(n-tolylethyl)-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (193) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-18-((S)-sec-butyl)-29-(3-dichloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-8-(pentan-3-yl)hexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (194) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-36′-(3-fluorobenzyl)-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′1H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (195) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluromethyl)phenethyl)-35-(cyclopropylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (196) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-22-ethyl-28-isopropyl-7,10,13,16,21,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3 0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (197) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopropyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (198) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-28-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (199) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (200) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-(cyclopropylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (201) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (202) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(3-chloro-5-fluoro-phenyl)methyl]-18-(4-chlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (203) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-25,25-difluoro-11-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (204) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-7-cyclopropyl-21-isobutyl-28-isopropyl-10,13,16,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (205) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-8,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (206) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-9-[(4-fluorophenyl)methyl]-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (207) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-chlorobenzyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (208) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-28-(2,2,2-trifluoroethoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (209) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5,12,16,19,33,36-hexamethyl-11-pentyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (210) (3S,9S,18S,21S,2′R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-16-ethyl-21-isobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.1]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (211) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1 i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,113,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (212) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclobutylethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23, 27,30,33-undecone,
• (213) (4R,7S,13S,16S,22S,31S,34S)-16-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-(cyclohexylmethyl)-7,13-diisobutyl-4,8,14,20,23,26,29-heptamethyl-31-[(1S)-1-methylpropyl]spiro[1,5,8,11,14,17,20,23,26,29,32-undecazabicyclo[32.4.0]octatriacontane-10,1′-cyclopentane]-2,6,9,12,15,18,21,24,27,30,33-undecone,
• (214) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-1,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (215) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-22-butyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxohexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (216) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(2-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-13-carboxamide,
• (217) (8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8,29,36-triisobutyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (218) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexymethyl)-8-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-29-isobutyl-36-isopropyl-N,N,9,15,18,21,24,30,34,37-decamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-6,9,12,15,1821,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-33-carboxamide,
• (219) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-3,9-diisobutyl-4,6,6,10,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (220) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptan-ethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (221) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (222) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-19-(2,2,2-trifluoroethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (223) (3S,9S,18S,21S,25R,28S,31R,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-31-ethyl-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29,31-nonamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (224) (3S,6S,9S,12S,18S,27S,30S,34S)-6,9-dibenzyl-12-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-25-ethyl-3-isopropyl-4, 7,16,19,22,30,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (225) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-cyclopentyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (226) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclobutoxymethyl)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-.1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-.31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (227) (6′S,12′S,21′S,23a′S,31′R,34′S,39a′S)-21′-((S)-sec-butyl)-12′-(4-chlorobenzyl)-34′-isobutyl-10′,13′,16′,19′31′,35′-hexamethyl-6′-(4-(trifluoromethyl)phenethyl)tetracosahydrospiro[cyclopentane-1,37′-pyrido[1,2-a]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,23′,29′,33′,36′,39′(23a′H,30′H,38′H)-undecaone,
• (228) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-((R)-1-hydroxyethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (229) (3S,9S,18S,21S,25S,28S,34S)-9-[(4-chlorophenyl)methyl]-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (230) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-(cyclobutylethyl)-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (231) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclohexane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (232) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,7,16,19,22,25,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (233) 2-[[(3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3-isobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-9-yl]methoxy]—N-tert-butyl-acetamide,
• (234) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopropylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (235) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-35-(2-(methylsulfonyl)ethyl)-15-(piperidine-1-carbonyl)docosahydro-21H,41-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (236) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (237) (3S,9S,18S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-25-[(3-fluorophenyl)methyl]-7,10,13,16,26,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,24,27,30,33-undecone,
• (238) 3-[[(3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (239) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (240) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexymethyl)-9-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-6-ethyl-30-isobutyl-3-isopropyl-1,4,10,16,19,22,25,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (241) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (242) (3S,9S,18S,21S,25R,28S,31S,34S)-31-allyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29,31-octamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-Undecone,
• (243) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl- N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(3-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (244) (3S,9S,18S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-25-[(2-hydroxy-2-methyl-propoxy)methyl]-7,10,13,16,23,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,24,27,30,33-undecone,
• (245) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (246) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-7,10,13,16,21,22,26,29-octamethyl-18[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (247) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (248) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexymethyl)-21-(cyclopropylmethyl)-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (249) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (250) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-22-(isopentyloxymethyl)-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (251) (7S,10S,16S,25S,28S,32S,35S)-102-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-(cyclohexylmethyl)-7-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-28-isobutyl-35-isopropyl-8,14,17,20,23,29,33,36-octamethyl-25-[(1S)-1-methylpropyl]-32-(piperidine-1-carbonyl)-5,8,11,14,17,20,23,26,29,33,36-undecazaspiro[3.33]heptatriacontane-6,9,12,15,18,21,24,27,30,34,37-undecone,
• (252) 3-[[(3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-12-yl]methyl]benzonitrile,
• (253) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-chlorobenzyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (254) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-((2,2,2-trifluoroethoxy)methyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (255) (9′S,12′S,16′S,19′S,24a′S,26′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclohexyl-36′-(cyclohexylmethyl)-12′-isobutyl-7′,13′,17′,20′,34′,37′-hexamethyl-26′-phenyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (256) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (257) (3S,9S,12S,18S,27S,30S,34R)-9-butyl-18-[(4-chlorophenyl)methyl]-19-ethyl-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-1,6,6,7,16,22,25,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (258) (3S,9S,18S,21S,25R,28S,34S)-9-[(4-chlorophenyl)methyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (259) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-6-[(2-methoxyphenyl)methyl]-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (260) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-((R)-1-hydroxyethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-21H,41-H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (261) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (262) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (263) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)-11-pentyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (264) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexymethyl)-22-ethyl-28-isopropyl-7,10,13,16,21,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (265) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-(2-phenylethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (266) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexymethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (267) (8S,11S,15R,18S,23aS,29S,31aR,38S,40aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-38-(cyclohexylmethyl)-18-isopropyl-6,11,12,15,19,39-hexamethyltetracosahydro-2H,4H,28H-spiro[azeto[2,1-u]pyrido[2,1-o]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,37,40(14H,22H,31aH)-undecaone,
• (268) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopropane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (269)(3S,9S,18S,21S,25R,28S,34S)-28-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (270) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-cyclobutyl-35-(cyclohexylmethyl)-18-cyclopentyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (271) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (272) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (273) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-prop-2-ynyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (274) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,22,23,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-13-carboxamide,
• (275) (3S,9S,18S,21S,25R,28S,31R,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-31-ethyl-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29,31-octamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (276) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (277) (8R,1S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-8,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-unidecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (278) 2-((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-15-(piperidine-1-carbonyl)tetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-8-yl)acetonitrile,
• (279) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (280) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-cyclopropyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (281) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (282) (8S,11S,17S,26S,29S,33S,36S)-8-[(3-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7, 10,13,16,19,22,25,28,31,35,38-undecone,
• (283) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-(2-methylsulfonylethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (284) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-28-prop-2-ynyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (285) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,21-bis(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(15)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (286) (4R,7S,13S,16S,22S,31S,34S)-22-[(4-chlorophenyl)methyl]-7,13-diisobutyl-4,8,10,10,14,20,23,26,29-nonamethyl-31-[(1S)-1-methylpropyl]-16-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,5,8,11,14,17,20,23,26,29,32-undecazabicyclo[32.4.0]octatriacontane-2,6,9,12,15,18,21,24,27,30,33-undecone,
• (287) (3S,9S,18S,21S,25S,28S,31R,34S)-31-allyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29,31-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (288) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,22,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (289) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-35-(propoxymethyl)tetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (290) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclobutylmethyl)-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (291) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-5,6,11,12,15,19,21,21,22,33,36-undecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (292) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (293) (5S,8S,11S,15S,18S,23aS,29S,31aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-37-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,38-heptamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-a][1,4,7,10,13,16,19,22,25,28,31 ]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (294) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-8,9,15,18,21,24,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (295) (3S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (296) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (297) (6′S,9′S,13′S,16′S,25′S,31′S,33a′S,37a′S,38a′S)-16′-((S)-sec-butyl)-31′-(3-chloro-4-(trifluoromethyl)phenethyl)-6′-cyclohexyl-25′-(cyclohexylmethyl)-13′-isobutyl-5′,8′,12′,18′,21′,24′,27′-heptamethyl-9′-(piperidine-1-carbonyl)hexacosahydro-4′H-spiro[cyclopentane-1,3′-[1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine[10,9-a]indol]-1′,4′,7′,11′,14′,17′,20′,23′,26′,29′,32′(2′H,8′H)-undecaone,
• (298) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (299) (3S,9S,18S,21S,25R,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.4.0]octatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (300) (3S,9S,18S,21S,25R,28S,34S)-21-but-3-ynyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-[(4-iodophenyl)ethyl]-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (301) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (302) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (303) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isopentyl-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (304) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-8-((2,2,2-trifluoroethoxy)methyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (305) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-16,28-diisopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (306) allyl 3-[(3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3-isobutyl-4,7,16,19,22,25,30,31-octamethyl-271-[(S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-9-yl]propanoate,
• (307) (9′S,12′S,16′S,19′S,24a′S,30′S,33′R,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,17′,20′,33′,34′,37′-octamethyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (308) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isopentyl-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (309) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclobutoxymethyl)-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (310) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-(3,4-difluorobenzyl)-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (311) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (312) (3S,9S,12S,18S,27S,30S,34S)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (313) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (314) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-N,N,5,6,12,16,19,21,33,36-decamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxohexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (315) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (316) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-35-(propoxymethyl)tetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (317) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-N,N,9,15,18,21,24,29,30,34,37-undecamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-33-carboxamide,
• (318) (5S,8S,12S,15S,20aS,26S,32S,34aS,38aS)-5-((S)-sec-butyl)-26-(3-chloro-4-(trifluoromethyl)phenethyl)-32-(cyclohexylmethyl)-8-isobutyl-15-isopropyl-9,13,16,30,33-pentamethyl-12-(piperidine-1-carbonyl)docosahydro-25H-spiro[bis(azeto)[1,2-g:1′,2′-j]pyrrolo[1,2-v] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1′-cyclopentan]-4,7,10,14,17,20,25,28,31,34,38(2H,11H,19H,34aH)-undecaone,
• (319) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (320) (3S,9S,12S,18S,27S,30S,34S)-18-(cyclohexylmethyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (321) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,21-bis(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (322) (3S,9S,18S,21S,25R,28S,31S,34S,36R)-31-benzyl-9-[(4-chlorophenyl)methyl]-36-ethoxy-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (323) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-1,6,6,7,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (324) (10′S,13′S,17′S,20′S,25a′S,31′S,37′S,39a′S)-10′-((S)-sec-butyl)-37′-(cyclohexylethyl)-31′-(3,4-dichlorophenethyl)-13′-isobutyl-20′-isopropyl-8′,14′,18′,21′,35′,38′-hexamethyl-17′-(piperidine-1-carbonyl)tetracosahydro-2′H,6′H-spiro[cyclopentane-1,23′-pyrido[2,1-u]pyrrolo[2,1-i]][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-6′,9′,12′,15′,19′,22′,25′,30′,33′,36′,39′(16′H,24′H)-undecaone,
• (325) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopropylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (326) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (327) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (328) (3S,9S,18S,21S,25S,28S,34S)-9-[(4-chlorophenyl)methyl]-10-ethyl-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,13,16,22,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (329) (3S,9S,8S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-16-(2-ethoxyethyl)-21-isobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (330) (3S,9S,12S,18S,27S,30S,34S)-9-[(4-chlorophenyl)methyl]-18-(cyclohexylmethyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (331) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(3,3-difluoroazetidin-1-yl)ethyl]-6-isobutyl-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (332) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-9,27-bis[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (333) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-18-cyclopentyl-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (334) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (335) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-22-(o-tolylmethyl)-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (336) (3S,9S,12S,18S,27S,30S,34S)-18-(cyclohexylmethyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (337) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (338) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-22-[(5-methyl-3-pyridyl)methyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (339) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (340) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22,31-bis(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (341) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (342) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-11-pentyltetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (343) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-11-pentyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (344) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (345) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (346) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(p-tolylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (347) (6′S,12′S,21′S,24′S,26a′R,29a′R,32′S,37a′S)-21′-((S)-sec-butyl)-6′-(3-chloro-4-(trifluoromethyl)phenethyl)-12′-(cyclohexylmethyl)-24′-isobutyl-32′-isopropyl-10′,13′,16′,19′,25′,33′-hexamethylhexacosahydrospiro[cyclopentane-1,35′-cyclopenta[f1]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′8′,11′,14′,17′,20′,23′,26′,31′,34′,37′(36′1)-undecaene,
• (348) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (349) (5S,8S,11S,15S,18S,23aS,29S,31aR,38S,40aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-38-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,39-heptamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H,41H,281-spiro[azeto[2,1-u]pyrido[2,1-o]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,37,40(14H,22H,31aH)-undecaone,
• (350) (8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-29-isobutyl-36-isopropyl-9,15,18,21,24,30,33,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (351) (3S,6S,9S,12S,18S,27S,30S)-6-benzyl-18-F[(4-chlorophenyl)methyl]-9-isobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (352) (2aS,5S,11S,14S,20S,23S,30aS,33S)-33-((S)-sec-butyl)-14-butyl-11-(3-chloro-4-(trifluoromethyl)phenethyl)-5-(4-chlorobenzyl)-20-isobutyl-4,7,16,17,17,22,35-heptamethyl-23-(piperidine-1-carbonyl)tetracosahydroazeto[1,2-j]pyrido[1,2-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-3,6,9,12,15,18,21,25,31,34,37(1H,221-H,27H)-undecaone,
• (353) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (354) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,21,21,33,36-nonamethyl-35-(4-methylbenzyl)tetracosahydro-211-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (355) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(thiazol-4-ylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (356) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (357) 2-[[(3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (358) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-(cyclopropylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (359) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]]ethyl]-28-cyclopentyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (360) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (361) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,9,10,13,16,21,22,25,29-decamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (362) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (363) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (364) (3S,9S,18S,21S,2′R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (365) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (366) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (367) (3S,9S,18S,21S,25S,28S,34S)-3-[2-3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (368) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (369) (3S,9S,18S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-7,10,13,16,23,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,24,27,30,33-undecone,
• (370) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (371) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (372) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-7,16,19,22,25,30,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (373) 3-[[(3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-12-yl]methyl]benzonitrile,
• (374) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (375) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (376) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-9-[[3-(trifluoromethyl)phenyl]]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (377) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (378) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,22,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (379) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[2-(3,3-difluoro-1-piperidyl)ethyl]-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (380) (3S,6R,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-6,7,10,13,16,21,22,26,29-nonamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (381) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (382) (3S,6S,9S,13S,16S,19S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,19,22,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (383) (3S,9S,18S,21S,25R,28S,31S,34S)-9-[(4-chlorophenyl)methyl]-31-(cyclohexylmethyl)-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (384) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(thiazol-4-ylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (385) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (386) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18,35-dicyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (387) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-11-((2,2,2-trifluoroethoxy)methyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (388) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-(4-fluorobenzyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (389) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoro-1-piperidyl)ethyl]-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (390) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (391) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-11-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i]][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,2-2H)-undecaone,
• (392) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-propyl-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (393) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-cyclopentyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (394) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-21-ethyl-11-isobutyl-18-isopropyl-5,6,12,16,19,21,33,36-octamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H-1-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (395) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-7-ethyl-21-isobutyl-28-isopropyl-10,13,16,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (396) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,35,36-decamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (397) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-11-(2-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (398) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-12-[2-(p-tolyl)ethyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (399) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-cyclopentyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (400) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclopentylmethyl)-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (401) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-36-ethyl-11-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (402) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (403) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxylmethyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (404) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (405) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,16,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]-13-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (406) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-1,4,7,16,19,22,25,30,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (407) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexymethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,4′-tetrahydropyran]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (408) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (409) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (410) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (411) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (412) (6′S,15′S,18′S,22′R,25′S,30a′S,36′S,38a′R)-15′-((S)-sec-butyl)-36′-(3-chloro-4-(trifluoromethyl)phenethyl)-6′-(cyclohexylmethyl)-25′-isopropyl-7′,10′,13′,18′,19′,22′,26′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,28′-dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,24′,27′,30′,35′,38′(21′H,29′H)-undecaone,
• (413) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-9-ethyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3 0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (414) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexymethyl)-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (415) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(propoxymethyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (416) (7S,10S,14R,17S,22aS,28S,34S,36aS,40aS)-7-((S)-sec-butyl)-28-(3-chloro-4-(trifluoromethyl)phenethyl)-34-(cyclohexylmethyl)-10-isobutyl-17-isopropyl-11,14,18,32,35-pentamethyltetracosahydro-27H-spiro[azeto[1,2-j]pyrido[1,2-g]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-20,1′-cyclopentan]-6,9,12,16,19,22,27,30,33,36,40(2H,13H,21H,36aH)-undecaone,
• (417) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (418) (6S,9S,13R,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-25-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-9-isopropyl-4,10,13,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (419) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-11-(2-(methylsulfonyl)ethyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (420) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexymethyl)-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (421) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-18-(cyclopropylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (422) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (423) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-19-ethyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,22,25,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (424) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (425) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(5,5-difluoropentyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (426) (3S,9S,12S,18S,27S,30S,34S)-9-[(2-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3-isopropyl-1,4,6,6,10,16,19,22,25,30,31-undecamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (427) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-[(1R)-1-hydroxyethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (428) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-36-phenyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (429) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-36′-isobutyl-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,123′H)-undecaone,
• (430) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (431) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3,5-dichlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (432) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (433) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-4,9,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-(3-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (434) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (435) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5-((isopentyloxy)methyl)-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (436) (3S,9S,12S,18S,27S,30S,34R)-25-butyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,6,6,10,16,19,22,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (437) (3S,9S,18S,21S,25S,28S,34S)-25-(azetidine-1-carbonyl)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,31,33-undecone,
• (438) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (439) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclohexane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (440) 2-[(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-18-yl]acetonitrile,
• (441) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(thiazol-4-ylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-13-carboxamide,
• (442) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-22-(2-phenylethyl)-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (443) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-6-ethyl-11-isobutyl-18-isopropyl-5,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (444) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-30-isobutyl-3-isopropyl-1,4,6,10,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (445) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(propoxymethyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (446) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclobutyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (447) (8S,11S,15S,18S,23aS,29S,31aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-37-(cyclohexylmethyl)-18-isopropyl-6,11,12,16,19,38-hexamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (448) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,4′-tetrahydropyran]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (449) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-22-(m-tolylmethyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (450) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexymethyl)-8-((R)-1-hydroxyethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′- cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (451) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclobutylmethyl)-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cycloheptane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (452) (8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-29-isobutyl-36-isopropyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (453) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,19,33,36-hexamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′- cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (454) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,25,26,29,31,31,32-dodecamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (455) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclobutylmethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (456) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]]ethyl]-21-cyclohexyl-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (457) (3S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-9-ethyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (458) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)-29-(4-(trifluoromethyl)phenethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (459) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-22-[(2-methoxyphenyl)methyl]-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (460) (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-36-(4,4-difluoro-1-piperidyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (461) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-118-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (462) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (463) (3S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexymethyl)-9-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-30-isobutyl-3-isopropyl-1,4,6,6,10,16,19,22,25,31-decamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (464) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-35-(2-chlorobenzyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (465) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-cyclobutyl-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-1,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (466) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (467) (3S,6S,9S,12S,18S,27S,30S,34S)-6,9-dibenzyl-18-[(4-chlorophenyl)methyl]-3-isopropyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-12-(m-tolylmethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (468) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopropane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (469) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (470) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-35-((isopentyloxy)methyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (471) (3S,9S,12S,18S,27S,30S,34R)-9-benzyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (472) (6S,9S,13S,16S,19S,22S,25S,31S,34S)-19-benzyl-22-butyl-31-(cyclohexylethyl)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,20,29,32-hexamethyl-6-1[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-Undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (473) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methyldipropyl]-34-(piperidine-1-carbonyl)-12-[[3-(trifluoromethoxy)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (474) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-(cyclopropylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (475) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (476) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (477) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-22-[(5-methyl-3-pyridyl)methyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (478) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-propyl-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (479) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-[[6-(trifluoromethyl)-3-pyridyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (480) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-(4-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (481) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (482) (3S,6R,9S,18S,21S,25R,28S,34S)-9-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (483) (3S,6S,9S,12S,18S,27S,30S,34S)-9-buty-18-[(4-chlorophenyl)methyl]-6-[(3-fluorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (484) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-(methoxymethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (485) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-8-((isopentyloxy)methyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (486) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (487) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluromethyl)phenethyl)-11-isobutyl-18-isopropyl-35-(methoxymethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (488) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (489) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′,37′-heptamethyl-36′-(pyridin-3-ylmethyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (490) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-cyclopropyl-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (491) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (492) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8-[(2-fluorophenyl)methyl]-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (493) (3S,6R,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-30-isobutyl-3-isopropyl-1,4,6,10,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (494) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (495) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)-18-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (496) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-((R)-1-hydroxyethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (497) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-8-((R)-1-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (498) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-11-carbonyl)-6-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (499) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-12-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-7,16,19,22,25,30,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (500) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(thiazol-4-ylethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (501) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (502) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3-isobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (503) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (504) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-13-ethyl-21-isobutyl-28-isopropyl-7,10,16,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (505) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (506) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (507) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,26,29,31,31,32-undecamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (508) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexymethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (509) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5,6,12,16,19,33,36-heptamethyl-11-pentyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (510) (3S,9S,18S,21S,25R,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-36-ethoxy-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (511) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopropylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (512) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-9-isobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazabicyclo[32.4.0]octatriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (513) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-9-[(5-fluoro-3-pyridyl)methoxymethyl]-3-isobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (514) (6′S,9′S,13′S,16′S,25′S,31 ′S,38a′S)-16′-((S)-sec-butyl)-31′-(3-chloro-4-(trifluoromethyl)phenethyl)-6′-cyclohexyl-25′-(cyclohexylmethyl)-13′-isobutyl-5′,8′,12′,18′,21′,24′,27′-heptamethyl-9′-(piperidine-1-carbonyl)-5′,6′,9′,10′,12′,13′,15′,16′,18′,19′,21′,22′,24′,25′,27′,28′,30′,31,38′,38a′-icosahydro-4′11-spiro[cyclopentane-1,3′-[1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontino[10,9-a]indol]-1′,4′,7′,11′,14′,17′,20′,23′,26′,29′,32′(2′1,8′H)-undecaone,
• (515)(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (516) (9′S,12′S,16′R,1′S,24a′S,30′S,33′R,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,16′,20′,33′,34′,37′-octamethyltetracosahydro-5′1H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (517) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-6-[(5-fluoro-3-pyridyl)methoxymethyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (518) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-21-(2,2,2-trifluoroethoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (519) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (520) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (521) (6S,9R,13S,16S,25S,31S,33aS,37aS,38aS)-16-((S)-sec-butyl)-25-(4-chlorobenzyl)-6-isobutyl-3,3,5,9,12,13,18,21,24,27-decamethyl-31-(4-(trifluoromethyl)phenethyl)octacosahydro-[1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontino[10,9-a]indol-1,4,7,11,14,17,20,23,26,29,32(8H)-undecaone,
• (522) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29,31,31-nonamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (523) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-(3,3-difluoropropyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (524) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclobutyl-18-cyclopentyl-11-isobutyl-5,6,12,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)-16-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (525) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-cloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-36-ethyl-1-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (526) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclohexyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (527) (6S,9S,13S,16S,22S,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (528) (3S,9S,18S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-25-[(4-fluorophenyl)methyl]-7,10,13,16,26,29-hexamethyl-18-[(S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,24,27,30,33-undecone,
• (529) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (530) (6′S,9′S,13′S,16′S,21a′S,27′S,33′S,38a′S)-6′-((S)-sec-butyl)-27′-(4-chlorophenethyl)-33′-(cyclohexylmethyl)-9′-isobutyl-16′-isopropyl-10′,14′,17′,31′,34′,37′-hexamethyl-13′-(piperidine-1-carbonyl)docosahydro-1H-spiro[cyclopentane-1,19′-dipyrrolo[1,2-g: 1′,2′-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,15′,18′,21′,26′,29′,32′,35′,38′(12′H,20′H,38a′H)-undecaone,
• (531) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-5,6,15,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (532) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-26-ethyl-7,10,13,16,21,22,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (533) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-18-cyclopropyl-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (534) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-8-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (535) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-[(1R)-1-methoxyethyl]-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (536) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-6-(cyclohexylmethyl)-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (537) (3S,9S,18S,21S,25R,28S,34S)₃-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,18-bis(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (538) (3S,6S,10R,13S,19S,22S,28S,34S)-28-[(4-chlorophenyl)methyl]-13,19-diisobutyl-6-isopropyl-7,10,14,20,26,29,32-heptamethyl-3-[(1S)-1-methylpropyl]-22-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,11,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-16,1′-cyclopentane]-2,5,8,12,15,18,21,24,27,30,33-undecone,
• (539) (3S,6R,9S,18S,21S,25R,28S,34S)-9-[(2-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (540) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (541) (3S,9S,18S,21S,25R,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-36-ethoxy-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (542) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-16-cyclopropyl-21-isobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (543) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-10-ethyl-21-isobutyl-7,13,16,22,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (544) (3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-36-hydroxy-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (545) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,110,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (546) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,10,16,19,22,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (547) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (548) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-28-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (549) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(4-chlorobenzyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′1H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (550) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-18-(cyclopropylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1 cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (551) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-21-prop-2-ynyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (552) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18,28-dicyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (553) (8S,11S,15S,18S,23aS,29S,31aR,38S,40aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-38-(cyclohexylmethyl)-18-isopropyl-6,11,12,16,19,39-hexamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H,41-1,28H-spiro[azeto[2,1-u]pyrido[2,1-o]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,37,40(14H,22H,31aH)-undecaone,
• (554) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-prop-2-ynyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (555) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (556) (3S,9S,12S,18S,27S,30S,34S)-9-[(2-fluorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (557) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,19,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(3-pyridylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (559) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-11-(prop-2-yn-1-yl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (560) (3S,9S,18S,21S,25R,28S,31S,34S)-9-[(4-chlorophenyl)methyl]-28-isobutyl-31-isopropyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropy]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (561) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-(cyclopropylmethyl)-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (562) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (563) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (564) 4-[[(3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (565) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-cyclopropyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-211′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (566) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-9-butyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-1,7,16,19,22,25,31,34-octamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (567) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (568) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-N,N,5,6,12,19,33,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (569) (6S,12S,21S,24S,26aR,30aR,33S,38aS)-21-((S)-sec-butyl)-6-(3-chloro-4-(trifluoromethyl)phenethyl)-12-(cyclohexylmethyl)-24-isobutyl-33-isopropyl-10,13,16,19,34-pentamethylhexacosahydro-5H-spiro[benzo[f1]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-36,1′-cyclopentan]-5,8,11,14,17,20,23,26,32,35,38(26aH,37H)-undecaone,
• (570) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-cyclopentyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (571) (5S,85S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (572) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluromethyl)phenethyl)-11,35-bis(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (573) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-methylbenzyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (574) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (575) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,22,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (576) (3S,9S,18S,21S,25R,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-9-cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,23,27,30,33-undecone,
• (577) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,28-bis(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (578) (3S,9S,18S,21S,25R,28S,34S)-9-[(4-chlorophenyl)methyl]-21-(cyclohexymethyl)-28-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (579) (3S,9S,18S,21S,25R,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (580) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-8-cyclobutyl-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (581) (6′S,12′S,21′S,23a′S,31′R,34′S,39a′S)-21′-((S)-sec-butyl)-6′-(3-chloro-4-(trifluoromethyl)phenethyl)-12′-(cyclohexylmethyl)-34′-isopropyl-10′,13′,16′,19′,31′,35′-hexamethyltetracosahydrospiro[cyclopentane-1,37′-pyrido[1,2-a]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,23′,29′,33′,36′,39′(23a′H,30′H,38′1)-undecaone,
• (582) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-6-[(2-hydroxy-2-methyl-propoxy)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (583) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-29-(cyclohexylmethyl)-8,36-diisobutyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (584) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-(4-fluorobenzyl)-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-21H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (585) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-(cyclobutoxymethyl)-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (586) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopentyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (587) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (588) (3S,6S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-6-isopropyl-4,7,10,16,19,22,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (589) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (590) 3-[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-8-yl]—N-methyl-propanamide,
• (591) (3S,9S,18S,21S,25S,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29,31-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (592) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-8-[(6-methoxy-3-pyridyl)methyl]-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (593) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4, 7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (594) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (595) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-30-(cyclohexylmethyl)-3,9-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropy]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (596) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-9-(o-tolylmethyl)-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (597) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-36′-(3,4-difluorobenzyl)-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (598) (5S,8S,11S,15R,18S,21R,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-21-isopropyl-5,6,12,15,19,33,36-heptamethyl-35-(4-methylbenzyl)tetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (599) (8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (600) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclohexane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (601) (8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-6,11,12,15,19,32,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (602) (3S,9S,12S,18S,27S,30S,34R)-22-butyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,6,6,10,16,19,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (603) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-[(1R)-1-hydroxyethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (604) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-19-benzyl-25-[(3-iodophenyl)methyl]-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,9,10,14,20,22,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(pyrrolidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (605) (3S,9S,18S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-25-[(2-hydroxy-2-methyl-propoxy)methyl]-7,10,13,16,26,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,24,27,30,33-undecone,
• (606) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (607) (8S,11S,17S,26S,29S,33S,36S)-11-[2-(4-chlorophenyl)ethyl]-8-[(2-chlorophenyl)methyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(pyrrolidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (608) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (609) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-12-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-3-isopropyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-9-(n-tolylmethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (610) (8S,11S,17S,26S,29S,33S,36S)-17-[(4-chlorophenyl)methyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (611) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(tri fluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (612) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-2-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-3-isopropyl-4,7,9,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-unidecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (613) (3S,6S,9S,12S,18S,27S,30S,34S)-6,12-dibenzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (614) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-22-[(6-methoxy-3-pyridyl)methyl]-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-11-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (615) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-30-(cyclohexylmethyl)-3,9-diisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (616) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(2-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1. methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (617) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-22-(2-phenylethyl)-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (618) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-(4-fluorophenyl)ethyl]-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (619) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,9,16,19,22,25,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (620) (3S,9S,18S,21S,25S,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-31-ethyl-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29,31-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (621) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-9-isobutyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]Spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (622) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,12,16,19,33,36-heptamethyl-11-pentyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (623) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-9-(methoxymethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (624) (3S,6S,9S,12S,18S,27S,30S,34S)-9-[(2-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3-isopropyl-1,4,6,10,16,19,22,25,30,31-decamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (625) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chlorophenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (626) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,17′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (627) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-18-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (628) (5S,8S,11S,5R,18S,23aS,29S,35S,37aS)-8((S)-sec-buty)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (629) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, (630) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (631) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(5,5-difluoropentyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (632) (6S,12S,21S,23aS,31R,34S,37S,39aS)-37-benzyl-21-((S)-sec-butyl)-12-(4-chlorobenzyl)-34-isobutyl-10,13,16,19,31,35,38-heptamethyl-6-(4-(trifluoromethyl)phenethyl)tetracosahydro-1H-pyrido[1,2-a]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-5,8,11,14,17,20,23,29,33,36,39(23aH,30H,39aH)-undecaone,
• (633) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-3-(3-phenylpropyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (634) (3S,9S,18S,21S,25S,28S,31S,34S,36R)-31-benzyl-9-[(4-chlorophenyl)methyl]-36-ethoxy-3-[(3-iodophenyl)methyl]-28-isobutyl-7,10,13,16,21,22,29,32-octamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (635) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-16-[2-(4,4-difluoro-1-piperidyl)ethyl]-21-isobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (636) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-11-(methoxymethyl) 5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,414-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (637) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (638) (6S,9S,13S,16S,22S,25S,31S,34S)-22-[(2-fluorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (639) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-((R)-1-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (640) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (641) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29,31,31-nonamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (642) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-8-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (643) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-(cyclopentylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (644) (3S,9S,18S,21S,25R,28S,31S,34S)-31-allyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29,31-nonamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (645) (6S,9S,13R,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-16,22-diisobutyl-9-isopropyl-4,10,13,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-25-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (646) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[2-(4-fluorophenyl)ethyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (647) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-tri fluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (648) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,15,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (649) (4R,7S,13S,16S,22S,31S,34S)-22-(cyclohexylmethyl)-16-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-7,13-diisobutyl-4,5,10,10,11,20,23,26,29-nonamethyl-31-[(1S)-1-methylpropyl]-1,5,8,11,14,17,20,23,26,29,32-undecazabicyclo[32.4.0]octatriacontane-2,6,9,12,15,18,21,24,27,30,33-undecone,
• (650) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(2-methoxyethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (651) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-ethyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (652) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (653) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(5,5-difluoropentyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (654) (3S,9S,18S,21S,2′R,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (655) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(3,3-difluoroazetidin-1-yl)ethyl]-3-isopropyl-6-(methoxymethyl)-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (656) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-(4-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (657) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-12-[(3-chloro-5-fluoro-phenyl)methyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (658) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-30-isopropyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (659) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-29-(3-phenylpropyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (660) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-21-isopropyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxohexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (661) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-((isopentyloxy)methyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (662) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[36-oxa-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.4.0]octatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (663) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (664) (3S,9S,18S,21S,25R,28S,34S)-9-[(4-chlorophenyl)methyl]-28-isobutyl-7,10,13,16,21,22,25,29,31,31-decamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (665) (3S,9S,18S,21S,25R,28S,31R,34S)-31-allyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29,31-octamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (666) (9′S,12′S,16′R,19′S,24a′S,30′S,32a′R,38′S,40a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-38′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,16′,20′,39′-hexamethylhexacosahydro-5′1-spiro[cyclopentane-1,22-tripyrrolo[2,1-i:2′,1′-o:2″,1″-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′8′,11′,14′,18′,21′,24′,29′,32′, 37′,40′(15′H,23′H)-undecaone,
• (667) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-12-ethyl-11-isobutyl-18-isopropyl-5,6,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (668) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (669) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-prop-2-ynyl-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (670) (6′S,12′S,21′S,23a′S,31′S,34′S,39a′S)-21′-((S)-sec-butyl)-12′-(cyclohexylmethyl)-6′-(3-fluoro-4-(trifluoromethyl)phenethyl)-34′-isopropyl-10′,13′,16′,19′,32′,35′-hexamethyl-31′-(piperidine-1-carbonyl)tetracosahydrospiro[cyclopentane-1,37′-pyrido[1,2-a]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,23′,29,33′,36′,39′(23a′H,30′H,38′H)-undecaone,
• (671) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-35-benzyl-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-21,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (672) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclobutyl-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (673) (5S,8S,11S,15 R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl- l-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (674) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (675) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-6-(isopentyloxymethyl)-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1i-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (676) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-(cyclopropoxymethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (677) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-N,N,5,6,12,19,33,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (678) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (679) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexymethyl)-9-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-(2,2,2-trifluoroethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (680) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-chlorobenzyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (681) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(2-fluorophenyl)methyl]-3,30-diisobutyl-6,18-bis[(4-methoxyphenyl)methyl]-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (682) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-22-[2-(3,3-difluoro-1-piperidyl)ethyl]-16-isopropyl-3,4,9,10,14,17,23,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (683) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1i-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (684) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (685) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluorophenethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (686) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-31-(cyclohexylmethyl)-25-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-3,4,10,13,14,19,19,20,29,32-decamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (687) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (688) 2-[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]acetic acid (689) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-(cyclopropylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (690) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (691) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclopentylmethyl)-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (692) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(propoxymethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (693) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (694) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (695) (3S,9S,18S,21S,25R,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (696) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-6-(o-tolylmethyl)-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (697) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4, 7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (698) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-21H,41-H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (699) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-(cyclobutoxymethyl)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (700) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,19,33,36-hexamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (701) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (702) (3S,6R,9S,12S,18S,27S,30S,34S)-9-[(2-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3-isopropyl-1,4,6,10,16,19,22,25,30,31-decamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (703) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-22-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31 (p-tolylmethyl)1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (704) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (705)(3S,9S,18S,21S,25R,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21,31-diisobutyl-28-isopropyl-7,10,13,16,22,25,29,31-octamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (706) (3S,9S,12S,18S,27S,30S,34S)-9-[(2-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (707) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(cyclopropylmethyl)-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (708) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (709) (6S,9S,13S,16S,21aS,27S,33S,35aS,39aS)-6-((S)-sec-butyl)-27-(3-chloro-4-(trifluoromethyl)phenethyl)-33-(cyclohexylmethyl)-9-isobutyl-16-isopropyl-10,14,17,31,34-pentamethyl-13-(piperidine-1-carbonyl)docosahydro-1H,26H-spiro[azeto[1,2-j]dipyrrolo[1,2-g:1′,2′-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-19,1′-cyclopentan]-5,8,11,15,18,21,26,29,32,35,39(12H,20H,35aH,39aH)-undecaone,
• (710) 3-[[(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (711) (3S,9S,12S,18S,27S,30S,34S)-18-(cyclohexylmethyl)-9-[(4-fluorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (712) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (713) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (714) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,25,26,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (715) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,19,22,23,29,32-dodecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (716) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)-18-prop-2-ynyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (717) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (718) (8S,11S,17S,26S,29S,33S,36S)-8-[(4-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (719) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-13-(azetidine-1-carbonyl)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-11-piperidyl)-2-oxo-ethyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (720) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-chlorobenzyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (721) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (722) (3S,6S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-6,7,10,13,16,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (723) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-(cyclobutylmethyl)-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (724) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclohexyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (725) (8S,11S,15S,18S,23aS,31S,37S,39aS)-8-((S)-sec-butyl)-31-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-37-(cyclohexylmethyl)-11-isobutyl-6,12,16,19,35,38-hexamethyl-15-(piperidine-1-carbonyl)-1,5,6,8,9,11,12,15,16,18,19,23a,24,31,32,34,35,37,38,39a-icosahydro-21H,4H-spiro[azeto[2′,1′:21,22][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontino[10,9-a]indole-21,1′-cyclopentan]-4,7,10,13,17,20,23,30,33,36,39(14H,22H)-undecaone,
• (726) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-33-ethyl-11-isobutyl-5,6,12,16,19,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (727) N-tert-butyl-2-[[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]methoxy]acetamide,
• (728) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.4.0]octatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (729) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-8-(3-methylbut-2-en-1-yl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (730) (8S,11S,17S,26S,29S,33S,36S)-8-butyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (731) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (732) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(2,2,2-trifluoroethoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (733) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-8-(cyclobutylmethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22, 25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (734) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22-1)-undecaone,
• (735) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(propoxymethyl)-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (736) (3S,6S,9S,13S,16S,19S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,19,22,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (737) (3S,9S,18S,21S,25S,28S,34S)-25-(4-tert-butylpiperidine-1-carbonyl)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (738) (3S,9S,18S,21S,25R,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (739) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-6-(propoxymethyl)-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (740) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-30-isopropyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (741) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18,21-diisopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (742) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21,28-diisobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,4′-tetrahydropyran]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (743) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-25-ethoxy-36-ethyl-11-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (744) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-(2-methoxyethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (745) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-allyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (746) (7′S,16′S,19′S,23′R,26′S,31a′S,37′S,39a′R)-16′-((S)-sec-butyl)-37′-(3-chloro-4-(trifluoromethyl)phenethyl)-7′-(cyclohexylmethyl)-26′-isopropyl-8′,11′,14′,19′,20′,23′,27-heptamethyltetracosahydro-2′H1,6′H-spiro[cyclopentane-1,29′-pyrido[2,1-o]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-6′,9′,12′,15′,18′,21′,25′,28′,31′,36′,39′(22′H,30′H)-undecaone,
• (747) (6′S,12′S,21′S,24′S,27a′R,34′S,39a′S)-21′-((S)-sec-butyl)-6′-(3-chloro-4-(trifluoromethyl)phenethyl)-12′-(cyclohexylmethyl)-24′-isobutyl-34′-isopropyl-10′,13′,16′,19′,25′,35′-hexamethylhexacosahydrospiro[cyclopentane-1,37′-pyrido[1,2-e1]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,23,26′,33′,36′,39′(38′H)-undecaone,
• (748) (3S,6R,9S,12S,18S,27S,30S,34S)-6-allyl-9-[(2-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (749) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′,37′-heptamethyl-36′-(4-(trifluoromethyl)benzyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′29′,32′,35′,38′(15′H,23′H)-undecaone,
• (750) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (751) (3S,9S,18S,21S,25R,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (752) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-9-isobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (753) (3S,9S,18S,25R,28S,34S)-25-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-7,10,13,16,23,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,24,27,30,33-undecone,
• (754) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-22-[(2-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (755) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclobutoxymethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (756) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-[(1R)-1-hydroxyethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (757) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-(3-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (758) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-12-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-Undecone,
• (759) N-tert-butyl-2-[[(8S,11S,17S,26S,29S,33S,36S)-17-[(4-chlorophenyl)methyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-33-yl]methoxy]acetamide,
• (760) (2aS,5S,11S,14S,20S,23S,30aS,33S)-33-((S)-sec-butyl)-14-butyl-11-(3-chloro-4-(trifluoromethyl)phenethyl)-5-(cyclohexylmethyl)-20-isobutyl-4,7,16,17,17,22,35-heptamethyl-23-(piperidine-1-carbonyl)tetracosahydroazeto[1,2-j]pyrido[1,2-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-3,6,9,12,15,18,21,25,31,34,37(1H,22H,27H)-undecaone,
• (761) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropy]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (762) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopentyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (764) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-9-tert-butyl-18-[(4-chlorophenyl)methyl]-3-isobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (765) (3S,9S,12S,18S,27S,30S,34S)-3,9-dibutyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-30-isobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (766) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-18-(prop-2-yn-1-yl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (767) 2-[[(3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (768) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isopentyl-5,12,16,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (769) (8S,11S,17S,26S,29S,33S,36S)-17-[(4-chlorophenyl)methyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(pyrrolidine-1-carbonyl)-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (770) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-22-[(5-methoxy-3-pyridyl)methyl]-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (771) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(cyclopropylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (772) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-9-cyclohexyl-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (773) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-choro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (774) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (775) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (776) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (777) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-9-isobutyl-3,4,10,13,14,17,23,29,32-nonamethyl-6-[(1S)-1-methylpropyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (778) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (779) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-6-(5,5-difluoropentyl)-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (780) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-13-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (781) (6S,9S,13S,16S,22S,25S,31S,34S)-22-[(2-chlorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (782) (6S,9S,13R,16S,19S,22S,25S,31S,34S)-19-benzyl-31-[(4-chlorophenyl)methyl]-25-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-22-isobutyl-16-isopropyl-4,9,10,13,17,20,23,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (783) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(3-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(QS)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (784) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-21-isopropyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxohexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (785) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,12,15,16,19,33-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (786) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-4,10,14,17,23,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-22-[(6-methyl-3-pyridyl)methyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (787) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(cyclopropylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (788) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,6,6,10,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (789) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-[(2-hydroxy-2-methyl-propoxy)methyl]-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7, 10,13,16,19,22,25,28,31,35,38-undecone,
• (790) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (791) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-22-[[2-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (792) allyl-2-[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]acetate,
• (793) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexymethyl)-9-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-3-isopropyl-6-(methoxymethyl)-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (794) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-(isopentyloxymethyl)-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (795) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-(3-fluorobenzyl)-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (796) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-(5,5-difluoropentyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (797) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (798) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11,15-diisobutyl-5,6,12,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (799) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (800) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-3,27-bis[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (801) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-13-isopentyl-28-isopropyl-7,10,16,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (802) (3S,9S,18S,21S,25R,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-9-(cyclohexylmethyl)-21,28-diisobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,4′-tetrahydropyran]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (803) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-(cyclobutoxymethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (804) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (805) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,19,23,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(thiazol-4-ylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (806) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isopentyl-5,6,12,16,19,33,36-heptamethyldocosahydro-²H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-1,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (807) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (808) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,30,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (809) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)-5-(propoxymethyl)docosahydro-²H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (810) 3-((5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-5-yl)-N-methylpropanamide,
• (811) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (812) (5S,8S,11S,15S,18S,23aS,31S,37S,39aS)-8-((S)-sec-butyl)-31-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-37-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,35,38-heptamethyl-15-(piperidine-1-carbonyl)-1,5,6,8,9,11,12,15,16,18,19,23a,24,31,32,34,35,37,38,39a-icosahydro-2H,4H-spiro[azeto[2′,1′:21,22][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontino[10,9-a]indole-21,1′-cyclopentan]-4,7,10,13,17,20,23,30,33,36,39(14H,22H)-undecaone,
• (813) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (814) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropy]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,21,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (815) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (816) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (817) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoroazetidin-1-yl)ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-19-(propoxymethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (818)(3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[2-(3,3-difluoro-1-piperidyl)ethyl]-9-isobutyl- N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (819) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-[[4-(trifluoromethoxy)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (820) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-[(1R)-1-methoxyethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (821) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexymethyl)-8-[(4-fluorophenyl)methyl]-36-isopropyl-9,15,18,21,2429,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (822) (5S,8S,11S,15S,18S,20aR,26S,29S,35S,37aS)-8-((S)-sec-butyl)-26-butyl-29-(3-iodobenzyl)-11,18-diisobutyl-5,6,12,16,33,36-hexamethyl-35-(4-methylbenzyl)-15-(piperidine-1-carbonyl)tetracosahydro-4H-azeto[2,1-u]pyrrolo[2,1-f][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,25,28,31,34,37(2H,14H)-undecaone,
• (823) (9′S,12′S,16′S,19′S,24a′S,30′S,32a′R,39′S,41a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-39′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,17′,20′,40′-hexamethyl-16′-(piperidine-1-carbonyl)hexacosahydro-5′H,29′H-spiro[cyclopentane-1,22′-pyrido[2,1-o]dipyrrolo[2,1-i:2′,1 u] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,38′,41′(15′H,23′H,32a′H)-undecaone,
• (824) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-22-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (825) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-(3,4-dichlorophenyl)ethyl]-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (826) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexymethyl)-9-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-6-isobutyl-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-11-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (827) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (828) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxohexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (829) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,21,33 36-decamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxohexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (830) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-9-[(3-fluorophenyl)methyl]-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (831) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-21H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (832) (3S,9S,12S,18S,27S,30S)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (833) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(141,2211)-undecaone,
• (834) (9′S,12′S,16′R,19′S,24a′S,30′S,32a′R,39′S,41a′S)-9′-((3S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-39′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,16′,20′,40′-hexamethylhexacosahydro-5′1,29′1-spiro[cyclopentane-1,22′-pyrido[2,1-o]dipyrrolo[2,1-i:2′,1′-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,38′,41′(15′H,23′H,32a′H)-undecaone,
• (835) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclobutoxymethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (836) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacycltetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (837) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (838) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(4-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,8,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[322.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (839) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (840) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (841) (6′S,12′S,21′S,23a′S,31′S,34′S,39a′S)-21′-((S)-sec-butyl)-6′-(4-chlorophenethyl)-12′-(cyclohexylmethyl)-34′-isopropyl-10′,13′,16′,19′,32′,35′-hexamethyl-31′-(piperidine-1-carbonyl)tetracosahydrospiro[cyclopentane-1,37′-pyrido[1,2-a]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,23′,29′,33′,36′,39′(23a′H,30′11,38′1)-undecaone,
• (842) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-1,6,6,7,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (843) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-8,29,36-triisobutyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (844) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-cyclopropyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (845) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclobutyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23, 27,30,33-undecone,
• (847) (4R,7S,13S,16S,22S,31S,34S)-22-[(4-chlorophenyl)methyl]-7,13-diisobutyl-4,8,14,20,23,26,29-heptamethyl-31-[(1S)-1-methylpropyl]-16-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,5,8,11,14,17,20,23,26,29,32-undecazabicyclo[32.4.0]octatriacontane-10,1′-cyclopentane]-2,6,9,12,15,18,21,24,27,30,33-undecone,
• (848) (11S,17S,26S,29S,33S,36S)-9-butyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (849) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21,28-dicyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (850) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-(methoxymethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (851) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-11-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,33,37-octamethyl-26-(1S)₁-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (852) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyl-5-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (853) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (854) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (855) (9′S,12′S,16′S,19′S,24a′S,32′S,38′S,40a′S)-9′-((S)-sec-butyl)-32′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclohexyl-38′-(cyclohexylmethyl)-12′-isobutyl-7′,13′,17′,20′,36′,39′-hexamethyl-16′-(piperidine-1-carbonyl)-1′,2′,3′,6′,7′,9′,10′,12′,13′,16′,17′,19′,20′,24a′,25′,32′,33′,35′,36′,38′,39′,40a′-docosahydro-5′H-spiro[cyclopentane-1,22′-pyrrolo[2′,1′:21,22][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontino[10,9-a]indol]-5′,8′,11′,14′,18′,21 ′,24′,31′,34′,37′,40′(15′H,23′H)-undecaone,
• (856) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,19,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(thiazol-4-ylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (857) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-cyclopentyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)₁-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (858) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-9-[[4-(difluoromethyl)phenyl]methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (859) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (860) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(4-fluorophenethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (861) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,3,26,29,32-undecone,
• (862) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-((R)-1-hydroxyethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (863) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,8-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7, 10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (864) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-13-(2-ethoxyethyl)-21-isobutyl-28-isopropyl-7,10,16,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (865) (3S,9S,18S,21S,25R,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-28-isopropyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (866) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4, 7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (867) 4-[[(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (868) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (869) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone
• (870) (3S,9S,18S,21S,25R,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-36,36-difluoro-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (871) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18,35-dicyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (872) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-ethoxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (873) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-cyclohexyl-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (874) (3S,9S,18S,21S, 25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopropyl-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.1]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (875) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-36-hydroxy-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (876) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (877) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,28-dicyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (878) (3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-6-(2-phenylethyl)-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (879) (3S,9S,18S,21S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (880) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclobutoxymethyl)-1-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (881) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(15)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (882) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (883) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (884) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (885) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclobutoxymethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (886) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9,16,22-triisobutyl-3,4,10,13,14,19,19,20,29,32-decamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (887) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-8-[(5-methoxy-3-pyridyl)methyl]-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (888) 4-[[(3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (889) N-tert-butyl-2-[[(3S,6S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-6-yl]methoxy]acetamide,
• (890) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22.,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (891) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (892) (8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (893) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (894) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)-18-(2,2,2-trifluoroethoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (895) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-19-ethyl-3,30-diisobutyl-1,6,6,7,16,22,25,31-octamethyl-27-[(1S)-11-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (896) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-11-pentyltetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (897) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-3-cyclohexyl-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (898) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (899) (11S,17S,26S,29S,33S,36S)-9-allyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (900) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (901) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]]ethyl]-9-(cyclohexylmethyl)-21-(cyclopentylmethyl)-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (902) (3S,9S,18S,21S,25R,28S,31S,34S)-9-[(4-chlorophenyl)methyl]-28,31-diisobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (903) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(4-chlorophenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (904) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (905) (3S,6S,10R,13S,19S,22S,28S,34S)-28-(cyclohexylmethyl)-22-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-6,13,19-triisobutyl-7,10,11,16,16,17,26,29,32-nonamethyl-3-[(1S)-1-methylpropyl]-1,4,7,11,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,12,15,18,21,24,27,30,33-undecone,
• (906) (7S,10S,16S,25S,28S,32S,35S)-7-[(2-chlorophenyl)methyl]-10-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-(cyclohexylmethyl)-35-isopropyl-8,14,17,20,23,28,29,33,36-nonamethyl-25-[(1S)-1-methylpropyl]-32-(pyrrolidine-1-carbonyl)-5,8,11,14,17,20,23,26,29,33,36-undecazaspiro[3.33]heptatriacontane-6,9,12,15,18,21,24,27,30,34,37-undecone,
• (907) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (908) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (909) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (910) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoro-1-piperidyl)ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.20]hexatriacontane-19,1-cyclopentane]-13-carboxamide,
• (911) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-(cyclobutylmethyl)-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (912) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-22-(m-tolylmethyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (913) (6S,9S,13R,16S,19S,22S,25S,31S,34S)-19-benzyl-31-[(4-chlorophenyl)methyl]-22-isobutyl-16-isopropyl-4,9,10,13,17,20,23,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-25-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (914) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-36-(4,4-difluoro-1-piperidyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (915) (3S,6S,9S,13S,16S,19S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,22,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (916) (8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(4-chlorophenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (917) (3S,9S,18S,21S,25S,28S,31R,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29,31-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (918) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18,35-dicyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-.2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (919) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,10,13,16,21,22,25 29-nonamethyl-18-[(1S)-1-methylpropyl]-9-(3-pyridylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (920) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[(4-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21.,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (921) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-5,12,16,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (922) (6S,9R,13S,16S,25S,31S,33aS,37aS,38aS)-16-((S)-sec-butyl)-25-(4-chlorobenzyl)-6,13-diisobutyl-3,3,5,9,12,18,21,24,27-nonamethyl-31-(4-(trifluoromethyl)phenethyl)octacosahydro-[1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontino[10,9-a]indol-1,4,7,11,14,17,20,23,26,29,32(8H.)-undecaone,
• (923) (8S,11S,17S,26S,29S,36S)-17-[(4-chlorophenyl)methyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,37-heptamethyl-26-[(1S)-1-methylpropyl]-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (924) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-18-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (925) (3S,9S,18S,21S,25S,28S,31S,34S,36R)-3-[(3-chlorophenyl)methyl]-9-[(4-chlorophenyl)methyl]-36-ethoxy-28-isobutyl-31-(isopentyloxymethyl)-7,10,13,16,21,22,29,32-octamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (927) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-1,4,7,16,19,22,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (928) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (929) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-35-((R)-1-methoxyethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (930) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopropylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (931) (6S,9S,13S,16S,22S,25S,31S,34S)-31-(cyclohexylmethyl)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1i-methylpropyl]-22-(2-phenylethyl)-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (932) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (933) (5S,8S,11S,15R,18S,21S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-21-isopropyl-5,6,12,15,19,33,36-heptamethyl-35-(4-methylbenzyl)tetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(1411)-undecaone,
• (934) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-6,18-bis[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (935) 2-[[(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (936) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-cyclobutyl-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (937)(3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1 cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (938) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (939) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-29-isobutyl-36-isopropyl-8,9,15,18,21,24,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (940) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-8-(isopentyloxymethyl)-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (941) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-(2-methoxyethyl)-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (942) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-4,9,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-(3-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (943) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropy]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (944) (3S,9S,18S,21S,25R,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-31-ethyl-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29,31-nonamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-Undecone,
• (945) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-8-[(3-fluorophenyl)methyl]-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1i-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (946) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-8-(prop-2-yn-1-yl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (947) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (948) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (949) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (950) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-[(5-fluoro-3-pyridyl)methoxymethyl]-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (951) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-36-ethyl-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (952) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2, 1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (953) (9′S,12′S,16′S,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(4-chlorophenethyl)-36′-(cyclohexylmethyl)-12′-isobutyl-19′-isopropyl-7′,13′,17′,20′,34′,37′-hexamethyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′11-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (954) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(3-chlorophenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (955) N-tert-butyl-2-[[(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-yl]methoxy]acetamide,
• (956) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-27-isopropyl-1,6,6,7,16,19,22,25,31,34-decamethyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (957) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,22,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (958) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (959) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-11-cyclobutyl-35-(cyclohexylmethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (960) (8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-6,12,16,19,33,36-hexamethyl-25-phenyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (961) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-11-(but-3-yn-1-yl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(4-iodobenzyl)-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (962) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (963) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (964) (9′S,12′S,16′S,19′S,24a′S,30′S,32a′R,38′S,40a′S)-9′-((S)-sec-buty)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-38′-(cyclohexylmethyl)-19′-isopropyl-7′,12′ 13,17′,20′,39′-hexamethyl-16′-(piperidine-1-carbonyl)hexacosahydro-5′11-spiro[cyclopentane-1,22′-tripyrrolo[2,1-i:2′,1′-o:2″,1″-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,37′,40′(15′H,23′-H)-undecaone,
• (965) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (966) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexymethyl)-8-cyclopentyl-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (967) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9,30-diisobutyl-3-isopropyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (968) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-(cyclobutylmethyl)-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (969) (3S,9S,12S,18S,27S,30S,34S)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32- undecone,
• (970) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-16,21-diisobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (971) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-11-(but-3-yn-1-yl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(4-iodobenzyl)-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (972) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-9,34-diisobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (973) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (974) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(³-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (975) 3-[[(3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-9-yl]methyl]benzonitrile,
• (976) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-29-(4-methylphenethyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (977) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (978) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3-isobutyl-4,7,9,10,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (979) (3S,9S,18S,21S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (980) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexymethyl)-21-cyclopropyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (981) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (982) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,23,29,32-decaamethyl-6,16-bis[(1S)-1-methylpropy]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(thiazol-4-ylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13 carboxamide,
• (983) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9,21-bis(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (984) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (985) (3S,9S,18S,21S,25R,28S,34S)-3- [2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (986) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,18-bis(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (987) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H1)-undecaone,
• (988) (7S,10S,14S,17S,22aS,28S,34S,36aS,40aS)-7-((S)-sec-butyl)-28-(3-chloro-4-(trifluromethyl)phenethyl)-34-(cyclohexylmethyl)-10-isobutyl-17-isopropyl-11,15,18,32,35-pentamethyl-14-(piperidine-1-carbonyl)tetracosahydro-27H-spiro[azeto[1,2-j]pyrido[1,2-g]pyrrolo[1,2-v][1,4, 7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-20,1 cyclopentan]-6,9,12,16,19,22,27,30,33,36,40(2H,131-1,21H,36aH)-undecaone,
• (989) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30-heptamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,9,32-undecone,
• (990) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-(2-fluorobenzyl)-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,113,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (991) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (992) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-25-(isopentyloxymethyl)-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (993) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,19,22,23,29,32-dodecamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (994) (6S,9S,13R,16S,19S,22S,25S,31S,34S)-19-benzyl-31-[(4-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22 -isobutyl-16-isopropyl-4,9,10,13,17,20,23,29,32-nonamethyl-6-[(1S)-1i-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (995) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-18-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (996) (1R,4S,7S,16S,22S,25S,31S,34R)-16-[(4-chlorophenyl)methyl]-25,31-diisobutyl-4-isopropyl-3,9,12,15,18,24,30-heptamethyl-7-[(1S)-1-methylpropyl]-22-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[3,6,9,12,15,18,21,24,27,30,33 undecazabicyclo[32.3.0]heptatriacontane-28,1′-cyclopentane]-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (997) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-6-[(4-fluorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (998)N-(tert-butyl)-2-((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexymethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-15-(piperidine-1-carbonyl)tetratriacontahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-5-yl)methoxy)acetamide,
• (999) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1000) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-13-carboxamide,
• (1001) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(p-tolylmethyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1002) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1003) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1004) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-36′-benzyl-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1005) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-propyl-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1006) (5S,8S,11S,15R,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25-ethoxy-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,113,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1007) (3S,9S,18S,25S,28S,34S)-25-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,26,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,23,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,24,27,30,33-undecone,
• (1008) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1009) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(2-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1010) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-21-isopropyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxohexatriacontahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (1011) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyl-35-(pyridin-3-ylmethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1012) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1013) (3S,9S,18S,21S,25R,28S,34S)-9-[(4-chlorophenyl)methyl]-21,28-diisobutyl-7,10,13,16,22,25,29,31,31-nonamethyl-18-[(1S)-11-methylpropy]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1014) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropy]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1015) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-benzyl-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1016) (5S,8S,11S,15S,18S,23aS,25S,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-25-phenyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1017) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1018) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-chlorobenzyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1019) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(cyclopropylmethyl)-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1020) (5S,8S,12R,15S,20aS,26S,32S,37aS)-5-((S)-sec-butyl)-26-(3-chloro-4-(trifluoromethyl)phenethyl)-32-(cyclohexylmethyl)-8-isobutyl-15-isopropyl-9,12,16,30,33,36-hexamethyldocosahydrospiro[azeto[1,2-g]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1′-cyclopentan]-4,7,10,14,17,20,25,28,31,34,37(2H,111-1,19H)-undecaone,
• (1021) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(pentafluoro-□⁶-sulfanyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1022) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33,36-dodecone,
• (1023) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-6-ethyl-11-isobutyl-5,12,15,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1024) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-29(3-fluoro-4-(trifluoromethyl)phenethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1025) (8R,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl] 17-(cyclohexylmethyl)-8-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1026) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-9-(isopentyloxymethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1027) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-propydocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-2,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1029) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1030) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1031)(3S,9S,18S,21S,25R,28S,31S,34S)-31-benzyl-9-(cyclohexylmethyl)-28-isobutyl-7,10,13,16,21,2 2,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1032) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21,25-diisobutyl-28-isopropyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4, 7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1033) (3S,9S,18S,21S,25R,28S,34S)-13-butyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,16,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1034) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,21,21,22,33,36-undecamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (1035) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-6-[(2-fluorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1036) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-cyclobutyl-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1037) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(methoxymethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1038) (3S,9S,18S,21S,25R,28S,31R,34S)-31-allyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29,31-nonamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1039) (3S,6,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1040) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1041) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexymethyl)-28-[(1R)-1-hydroxyethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1042) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isopentyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1043) (3S,9S,12S,18S,27S,30S,34S)-12-benzyl-9-butyl-18-[(4-chlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1044) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-6-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl] 12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1045) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-ethyl-29-isobutyl-8,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1046) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1047) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclobutyl 18-cyclopentyl-16-ethyl-11-isobutyl-5,6,12,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacycltetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1048) (3S,9S,18S,21S,25S,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-28-isobutyl-7,10,13,16,21,22,29,32-octamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1049) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-buty)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1050) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-12′-isobutyl-19′-isopropyl-7′,13′,16′,20′,34′,37′-hexamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′3,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1051) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-22-ethyl-28-isopropyl-7,10,13,16,21,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1052) (3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-[[3-(trifluromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1053) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-25-phenyl-15-(piperidine-11-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,2328,31,34,37(14H,22H)-undecaone,
• (1054) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-9-isopropyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1055) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)]-3-[2-(p-tolyl)ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1056) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1057) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1058) (6S,9S,13S,16S,19S,22S,25S,31S,34S)-19-benzyl-22-butyl-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-31-[(4-methoxyphenyl)methyl]-4,10,14,19,20,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1059) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-11-pentyltetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1060) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-fluorobenzyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1061) (3S,9S,18S,21S,25S,28S,34S)-9-[(4-chlorophenyl)methyl]-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1062) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-25,25-difluoro-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1063) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(4-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1064) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-18-cyclopentyl-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1065) (3S,6R,9S,18S,21S,25R,28S,34S)-9-[(4-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1066) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-35-isopropyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1067) (3S,9S,12S,18S,27S,30S,34R)-18-[(1R)-1-benzyloxyethyl]-3,9-diisobutyl-4,6,6,10,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1068) (3S,9S,18S,21S,25R,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21,31-diisobutyl-28-isopropyl-7,10,13,16,22,25,26,29,31-nonamethyl-18-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1069) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-8-isobutyl-29,36-diisopropyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1070) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1071) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(3-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1072) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-9-[(1R)-1-methoxyethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1073) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1074) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1075) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-9-[(3,4-difluorophenyl)methyl]-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1076) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1077) (9′S,12′S,16′R,19′S,24a,'S,3,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-36′-(2-fluorobenzyl)-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8,11′,14′,18′,21,24,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1078) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-30-isobutyl-3,6-diisopropyl-1,4,10,16,19,22,25,31-octamethyl-27-[(1S)-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1079) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[24-3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1080) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1081) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoro-1-piperidyl)ethyl]-9-isobutyl-N,N,3,4,10,14,17,19,23,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (1082) (6S,9S,13R,16S,21aS,27S,33S,35aS,39aS)-6-((S)-sec-butyl)-27-(3-chloro-4-(trifluoromethyl)phenethyl)-33-(cyclohexylmethyl)-9-isobutyl-16-isopropyl-10,13,17,31,34-pentamethyldocosahydro-111,2611-spiro[azeto[1,2-j]dipyrrolo[1,2-g:1′,2′-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-19,1′-cyclopentan]-5,8,11,15,18,21,26,29,32,35,39(12H,20H,35aH,39aH)-undecaone,
• (1083) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclopentyl-7′,12′,13′,16′,20′,34′,37′-heptamethyl-36′-(3-methylbenzyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1084) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9,30-diisobutyl-3-isopropyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1085) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,16,19,22,25,30,31-heptamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1086) (3S,9S,18S,21S,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-28-isobutyl-7,10,13,16,21,22,29,32-octamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1087) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-8-[(5-methyl-3-pyridyl)methyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1088) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]-9-(m-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1089) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.4.0]octatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33,36-dodecone,
• (1090) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-28-isobutyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]-3-[2-4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1091) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1092) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-9-(5,5-difluoropentyl)-3-isobutyl-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1093) (3S,9S,18S,21S,25S,28S,34R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[36-thia-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1094) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(2-methylsulfonylethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1095) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-6,6,7,16,19,22,25,31-octamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazabicyclo[32.4.0]octatriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1096) (9′S,12′S,16′S,19′S,24a′S,26′R,30′S,36′S,38a′S)-9′-((S)-sec-buty)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-cyclohexyl-36′-(cyclohexylmethyl)-12′-isobutyl-7′,13′,17′,20′,34′,37′-hexamethyl-26′-phenyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′1-1)-undecaone,
• (1097) (6′S,12′S,21′S,23a′S,31′R,34′S,39a′S)-21′-((S)-sec-butyl)-12′-(cyclohexylmethyl)-34′-isobutyl-11′,13′,16′,19′,31′,35′-hexamethyl-6′-(4-(trifluoromethyl)phenethyl)tetracosahydrospiro[cyclopentane-1,37′-pyrido[1,2-a]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,23′,29′,33′,36′,39′(23a′H,30′11,38′1)-undecaone,
• (1098) (5S,8S,11S,15S,18,23aS,29S,35S,37aS)-8,18-di((S)-sec-buty)-35-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1099) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18,35-dicyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1100) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-9-[(2-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1101) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-[(1R)-1-methoxyethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1102) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-(cyclopropoxymethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1103) (5S,8S,11S,15S,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,32,33,36-nonamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1104) (3S,6S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-9-[2-(3,3-difluoroazetidin-1-yl)ethyl]-3-isopropyl-1,4,10,16,19,22,25,30,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-6-(2,2,2-trifluoroethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8, 11,14,17,20,23,26,29,32-undecone,
• (1105) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-3-isopropyl-4,7,10,16,19,22,25,30,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1106) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4-H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1107) (8S,11S,17S,26S,29S,33R,36S)-17-[(4-chlorophenyl)methyl]-8,36-diisobutyl-29-isopropyl-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-11-[2-[4-(trifluoromethyl)phenyl]ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1108) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-9-isobutyl-19r-methoxymethyl)-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (1109) (3S,9S,18S,21S,25S,28S,31S,34S)-31-allyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29,31-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1110) (4R,7S,10S,13S,16S,22S,31S,34S)-10-benzyl-22-[(4-chlorophenyl)methyl]-13-isobutyl-7-isopropyl-4,8,11,14,20,23,26,29-octamethyl-31-[(15)-1-methylpropyl]-16-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,5,8,11,14,17,20,23,26,29,32-undecazabicyclo[32.4.0]octatriacontane-2,6,9,12,15,18,21,24,27,30,33-undecone,
• (1111) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4, 7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopropane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1112) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1113) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-propyl-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1114) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclobutylmethyl)-35-(cyclohexylmethyl)-8-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1115) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(isopentyloxymethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1116) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-cloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,44H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1117) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-N,N,5,12,16,19,33,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-11-pentyltetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1-cyclopentane]-15-carboxamide,
• (1118) (7′S,16′S,19′S,23′S,26′S,31a′S,37′S,39a′R)-16′-((S)-sec-butyl)-37′-(3-chloro-4-(trifluoromethyl)phenethyl)-7′-(cyclohexylmethyl)-26′-isopropyl-8′,11′,14′,19′,20′,24′,27′-heptamethyl-23′-(piperidine-1-carbonyl)tetracosahydro-2′H,6′H-spiro[cyclopentane-1,29′-pyrido[2,1-o]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-6′,9′,12′,15′,18′,21′,25′,28′,31′,36′,39′(22′H,30′H)-undecaone,
• (1119) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-18-[(4-chlorophenyl)methyl]-3-isobutyl-9-(isopentyloxymethyl)-4,7,16,19,22,25,30,31-octamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1120) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-33-ethyl-11-isobutyl-N,N,5,6,12,16,19,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1121) (9′S,12′S,16′S,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,17′,20′,34′,37′-heptamethyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′1-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1122) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-((2-hydroxy-2-methylpropoxy)methyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopenta]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1123) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-(5,5-difluoropentyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1124) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclobutylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1125) (8S,11S,17S,26S,29S,33S,36S)-8-benzyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1126) (1R,4S,7S,16S,22S,25S,31S,34R)-16-[(4-chlorophenyl)methyl]-25,31-diisobutyl-4-isopropyl-9,12,15,18,24,30-hexamethyl-7-[(1S)-1-methylpropyl]-22-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[3,6,9,12,15,18,21,24,27,30,33-undecazabicyclo[32.4.0]octatriacontane-28,1′-cyclopentane]-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1127) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-9-[[2-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1128) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclobutyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1129) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-22-[[2-(trifluoromethoxy)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1130) (3S,9S,18S,21S,25S,28S,31R,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-31-ethyl-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29,31-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1131) (5S,8S,11S,15S,1S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-22-propylhexatriacontahydro-21H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-15-carboxamide,
• (1132) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-11-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1133) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-27-cyclohexyl-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6, 7,16,19,22,25,31,34-decamethyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1134) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-(3-methylbut-2-enyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1135) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[2-(3,3-difluoro-1-piperidyl)ethyl]-9-isobutyl-N,N,3,4,10,14,17,19,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (1136) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)docosahydro-2H,41-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1137) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1138) (3S,9S,18S,21S,25S,28S,31R,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-31-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-Undecone,
• (1139) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-118-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,2932-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17 20,23,27 30,33-,
• (1140) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-12-ethyl-11-isobutyl-5,16,19,33,36-pentamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1141) (5S,8,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclopentylmethyl)-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1142) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-33-ethyl-11-isobutyl-5,6,12,16,19,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1143) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,3⁷aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1144) (3S,9S,18S,21S,25S,28S,34S,36R)-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1145) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-(cyclopentylmethyl)-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1146) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-12-ethyl-11-isobutyl-5,16,19,33,36-pentamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1148) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-N,N,5,6,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,41-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1149) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1150) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-25-(3,3-dimethylpyrrolidine-1-carbonyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1151) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-33-ethyl-11-isobutyl-5,6,12,16,19,36-hexamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1152) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-36-ethyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1153) (3S,6S,9S,13.,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclopentyl-9-isobutyl-3,4,10,13,17,22,23,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1154) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isopentyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1155) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(2-bromo-5-iodo-phenyl)methyl]-22-butyl-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1156) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-25-[(3-chloro-5-iodo-phenyl)methyl]-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1157) (3S,9S,18S,21S,25S,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-31-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1i-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1158) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1159) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-33-ethyl-11-isobutyl-5,6,12,16,19,36-hexamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1160) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexymethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1161) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyl-15-(4-methylpiperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1162) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-28-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1163) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1164) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,12,16,19,33,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1165) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1166) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-28-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1167) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-5,16,19,33,36-pentamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1168) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1169) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-18-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-9-prop-2-ynyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1170) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1171) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isopentyl-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1172) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-25-(4-methylpiperidine-1-carbonyl)-18,28-bis[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1173) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-(cyclopentylmethyl)-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1174) (5S,8S,11S,15S,18S,21R,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,21,33,36-octamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (1175) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1176) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacycltetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1177) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(5-bromo-2-fluoro-phenyl)methyl]-22-butyl-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1178) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22-1)-undecaone,
• (1179) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1180) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(oxazolidine-3-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1181) (5S,8S,11S,155,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(4-(oxetan-3-y)piperazine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1182) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropy]-25-(morpholine-4-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1183) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclopentylmethyl)-5 6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-1,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H-undecaone,
• (1184) (3S,9S,12S,18S,27S,30S,34S)-18-benzyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-9-prop-2-ynyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1185) (6′S,12′S,21′S,24′S,27a′R,33′S,38a′S)-21′-((S)-sec-butyl)-6′-(3-chloro-4-(trifluoromethyl)phenethyl)-33′-cyclohexyl-12′-(cyclohexylmethyl)-24′-isobutyl-10′,13′,16′,19′,25′,34′-hexamethyltetracosahydro-5′H-spiro[cyclopentane-1,36′-dipyrrolo[1,2-e1:1′,2′-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5,8′,11′,14′,17′,20′,23′,26′,32′,35′,38′(27′H,37′-H)-undecaone,
• (1186) (3S,9S,12S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,12,13,16,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1187) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-25-[(2,6-difluorophenyl)methyl]-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1188) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyl-15-(oxazolidine-3-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1189) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-22-ethyl-21-isobutyl-7,10,13,16,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1190) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-12-ethyl-11-isobutyl-5,6,16,19,33,36-hexamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1191) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylacetyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]-25-[4-(oxetan-3-yl)piperazine-1-carbonyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1192) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylacetyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1193) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-5,6,16,19,33,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1194) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1195) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(5-bromo-2-methyl-phenyl)methyl]-22-butyl-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1196) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1197) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1198) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-5,6,16,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1199) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1200) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobatyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1202) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,12,16,19,22,25,31-decamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1203) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7-ethyl-21-isobutyl-10,13,16,22,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1204) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1205) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-33-ethyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1206) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1207) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-methylpropyl]-25-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1208) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-12-ethyl-11-isobutyl-5,6,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1209) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)-15-(morpholine-4-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1210) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1211) (5S,8S,11S,15S,18S,21S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,21,33,36-octamethyl-15-(piperidine-1-carbonyl)tetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (1212) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(5-bromo-2-chloro-phenyl)methyl]-22-butyl-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1213) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1214) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1215) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-1-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,221-H)-undecaone,
• (1216) (3S,9S,12S,18S,27S,30S,34S)-12-[(5-bromo-2-thienyl)methyl]-9-butyl-18-[(4-chlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4, 7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,1922,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1218) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-33-ethyl-11-isobutyl-5,6,12,15,19,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1219) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-9-prop-2-ynyl-18-[[4-(trifluoromethoxy)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1220) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-5,6,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1221) (5S,8S,11S,15R,18S,21S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,21,33,36-octamethyl-35-(4-methylbenzyl)tetracosahydro-211-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (1222) (5S,8S,11S,15R,18S,21R,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,21,33,36-octamethyl-35-(4-methylbenzyl)tetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (1223) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isopentyl-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1224) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1225) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,8,12,15,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1226) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-9-ethyl-25-[(3-fluoro-5-iodo-phenyl)methyl]-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1227) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-13-ethyl-21-isobutyl-7,10,16,22,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1228) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1229) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-25-(3,3,4,4,5,5-hexafluoropiperidine-1-carbonyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1230) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-31-[(4-fluorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1231) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-buty)-35-(cyclohexylmethyl)-18-cyclopentyl-25-ethoxy-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1232) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1233) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-12-ethyl-11-isobutyl-5,16,19,33,36-pentamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1234) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-12-ethyl-11-isobutyl-5,6,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyirolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1235) (5S,8S,11S,15S,1S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1236) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′- ,cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1237) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isopentyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1238) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-15-(1,1-dioxidothiomorpholino-4-carbonyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1239) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,18,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1240) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(5-bromo-3-pyridyl)methyl]-22-butyl-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1241) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1242) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1243) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9-isobutyl-16-isopropyl-3,4,10,14,17,2,23,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1244) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13, 16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1245) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1246) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-31-[(4-methoxyphenyl)methyl]-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1247) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(oxazolidine-3-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1248) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3 5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1249) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-9-ethyl-25-[(2-fluoro-3-iodo-phenyl)methyl]-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1i-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1250) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1251) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1252) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-12-ethyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,16,19,33,36-heptamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1253) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1254) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1255) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-16-ethyl-21-isobutyl-7,10,13,22,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1256) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-buty-25-[(2,3-difluorophenyl)methyl]-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1257) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1258) (3S,6S,95,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1259) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1260) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1261) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-2,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(141,22H)-undecaone,
• (1262) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-12-ethyl- l-isobutyl-5,16,19,33,36-pentamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1263) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-25-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1264) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-25,25-difluoro-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1265) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-25-(3,3,4,4,5,5-hexafluoropiperidine-1-carbonyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1266) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-5,16,19,33,36-pentamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1267) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1268) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-buty-25-[(2,5-difluorophenyl)methyl]-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1269) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-N,N,5,12,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1270) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1271) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1272) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-33-ethyl-11-isobutyl-5,6,12,16,19,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1273) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-25-(3,3-dimethylpyrrolidine-1-carbonyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1274) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1275) (3S,9S,18S,21S,25S,28S,34S)-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,1,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1276) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-33-ethyl-11-isobutyl-18-isopropyl-5,6,12,16,19,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1277) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1278) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1279) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-25-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-21-isobutyl-7,10,13,16,22,29-hexamethyl-18,28-bis[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1280) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-15-(3,3-dimethylpyrrolidine-1-carbonyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1281) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1282) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-N,N,5,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1283) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(azetidine-1-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-25,25-difluoro-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1284) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1)-1-methylpropyl]-25-[4-(oxetan-3-yl)piperazine-1-carbonyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1285) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1286) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(2-fluoro-5-iodo-phenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1287) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-12-ethyl-11-isobutyl-N,N,5,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1288) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-31-[[4-(trifluoromethoxy)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1289) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isopentyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-21,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1290) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1291) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(4-methylpiperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1292) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isopentyl-N,N,5,12,16,19,33,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1293) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1294) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyl-15-(4-(oxetan-3-yl)piperazine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1295) (3S,9S,18S,21S,25S,28S,34S)-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1296) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1297) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25(morpholine-4-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1298) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-31-[[4-(trifluoroethoxy)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1299) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,12,16,19,33,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1300) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,33,35,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1301) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1302) (3S,9S,18S,21S,25S,28S,31S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-31-ethyl-21-isobutyl-7,10,13,16,22,26,29,31-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1303) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1304) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-bromo-2-fluoro-phenyl)methyl]-22-butyl-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1305) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(4-fluorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1306) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1307) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclopentyl-9-isobutyl-3,4,10,13,17,22,29,32-octamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1308) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1309) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1310) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isopentyl-5,12,16,19,33,36-hexamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1311) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1312) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1313) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-31-benzyl-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1314) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9-isobutyl-16-isopropyl-3,4,10,14,17,22,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1315) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,22,26,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1316) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9-isobutyl-16-isopropyl-3,4,10,14,17,22,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1317) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1318) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(5-chloro-2-thienyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1319) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1320) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclopentylmethyl)-5,12,16,19,33,36-hexamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1321) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1322) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1323) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-15-(3,3-dimethylpyrrolidine-1-carbonyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1324) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-12-ethyl-29-(3-fluoro-4-(trifluorodimethyl)phenethyl)-11-isobutyl-N,N,5,6,16,19,33,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4-H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1325) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1326) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isopentyl-5,12,16,19,33,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-Undecaone,
• (1327) (3S,9S,12S,18S,27S,30S,34S)-18-[(4-fluorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1, 6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)₁-methylpropyl]-34-(piperidine-1-carbonyl)-9-prop-2-ynyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1328) (3S,6S,9S,13R,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclopentyl-9-isobutyl-3,4,10,13,17,22,29,32-octamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1329) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(oxazolidine-3-carbonyl)docosahydro-2H1,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1330) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,414-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1331) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,12,15,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1332) (5S,8S,11S,14aR,20S,25aS,31S,37S,39aS)-8-((S)-sec-buty)-31-(3-chloro-4-(trifluoromethyl)phenethyl)-37-(cyclohexylmethyl)-11-isobutyl-20-isopropyl-5,6,12,21,35,38-hexamethyltetracosahydro-2H,4H-spiro[azeto[1,2-j]dipyrrolo[1,2-e1:′,2′-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-23,1′-cyclopentan]-4,7,10,13,19,22,25,30,33,36,39(14H,24H)-undecaone,
• (1333) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1334) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1335) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1336) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18,35-dicyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1337) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1338) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-33-ethyl-11-isobutyl-5,6,12,16,19,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1339) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1340) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-N,N,5,12,16,19,33,36-octamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1341) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1342) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-28-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1343) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-21-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1344) (6S,9S,13S,16S,22S,25S,31S,34S)-31-[(4-fluorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1345) (3S,9S,15S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,15,16,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1346) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-di fluoro-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-21H,41-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-5-carboxamide,
• (1347) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(4-methylpiperidine-1-carbonyl)-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1348) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25,25-difluoro-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1349) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-15-(1,1-dioxidothiomorpholino-4-carbonyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1350) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1351) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)-15-(pyrrolidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1352) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(2-chloro-5-iodo-phenyl)methyl]-18-[(4-chlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1353) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1354) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26-hexamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1355) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-Undecaone,
• (1356) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isopentyl-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1357) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1358) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-9-ethyl-25-[(5-iodo-2-methyl-phenyl)methyl]-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1359) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-5,12,16,19,33,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1360) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,12,16,19,33,36-hexamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1361) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-9-prop-2-ynyl-18-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1362) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1363) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1364) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1365) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-12-ethyl-11-isobutyl-N,N,5,6,16,19,33,36-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1366) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1367) (3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1368) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-5,6,12,16,19,33-hexamethyl-35-(4-methylbenzyl)-15-(morpholine-4-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-2,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1369) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1370) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1371) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-(cyclopentylmethyl)-5,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1372) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-bromo-5-fluoro-phenyl)methyl]-22-butyl-9-ethyl-16-isobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1i-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1373) (3S,9S,18S,21S,25R,28S,31S,34S,36S)-31-benzyl-9-[(4-chlorophenyl)methyl]-36-hydroxy-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1374) (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-hydroxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1375) (3S,9S,18S,21S,25R,28S,31S,34S,36R)-31-benzyl-9-[(4-chlorophenyl)methyl]-36-hydroxy-28-isobutyl-7,10,13,16,21,22,25,29,32-nonamethyl-18-[(1S)-1-methylpropyl]-3-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1376) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-hydroxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1377) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-4,9,10,13,14,19,19,20,29,32-decamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1378) (6S,9S,13R,16S,22S,25S,28R,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16,22-diisobutyl-4,9,10,13,14,19,19,20,28,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1379) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-3,4,10,13,14,19,19,20,29,32-decamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1380) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3,9-diisobutyl-1,6,6,7,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1381) (3S,9S,12S,15R,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-1,6,6,7,15,16,19,22,25,30,31,34-dodecamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1382) (6S,9S,13R,16S,2S,25S,28R,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-4,9,10,13,14,19,19,20,28,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1383) (6S,9S,13R,16S,22S,25S,28R,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-4,9,10,13,14,19,19,20,28,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-31 [[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1384) (3S,9S,12S,15R,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,15,16,19,22,25,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1385) (3S,9S,12S,15R,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-1,6,6,7,15,16,19,22,25,30,31,34-dodecamethyl-27-[(1S)-1-methylpropyl]-18-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1386) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-4,10,13,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.0.2.]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1387) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16,22-diisobutyl-4,9,10,13,14,19,19,20,29,32-decamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1388) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1389) (3S,9S,12S,15R,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3,9,30-triisobutyl-1,6,6,7,15,16,19,22,25,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1390) (3S,9S,12S,15R,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclohexylmethyl)-3,9-diisobutyl-1,6,6,7,15,16,19,22,25,30,31,34-dodecamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1391) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16,22-diisobutyl-3,4,9,10,13,14,19,19,20,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1392) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-4,9,10,13,14,19,19,20,29,32-decamethyl-6-[(1S)-1-methylpropyl]-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1393) (3S,9S,12S,15R,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,15,16,19,22,25,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-18-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1394) (6S,9S,13R,16S,22S,25S,28R,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-4,10,13,14,19,19,20,28,29,32-decamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1395) (6S,9S,13R,16S,22S,25S,28R,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-4,10,13,14,19,19,20,28,29,32-decamethyl-6-[(1S)-1-methylpropyl]-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1396) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-18-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1397) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-1,6,6,7,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-18-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1398) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-1,6,6,7,16,19,22,25,30,31,34-undecamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1399) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-3,4,9,10,13,14,19,19,20,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1400) (6S,9S,13R,16S,22S,25S,28R,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9,16,22-triisobutyl-4,10,13,14,19,19,20,28,29,32-decamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1401) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-3,4,10,13,14,19,19,20,29,32-decamethyl-6-[(1S)-1-methylpropyl]-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1402) (3S,6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,22-diisobutyl-3,4,9,10,13,14,19,19,20,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1403) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9,16,22-triisobutyl-4,10,13,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1404) (3S,9S,12S,18S,27S,30S,34S)-12-[(3-bromophenyl)methyl]-9-butyl-18-[(4-chlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1405) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-31-(cyclopentylmethyl)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-22-(2-methylallyl)-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1406) (3S,9S,12S,18S,27S,30S,34R)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-9-prop-2-ynyl-18-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1407) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(3-chlorophenyl)methyl]-18-[(4-chlorophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1408) (6S,9S,13R,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,13,14,19,19,20,29,32-nonamethyl-22-(3-methylbut-2-enyl)-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1409) (3S,9S,12S,18S,27S,30S,34S)-3-benzyl-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-30-isobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1410) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-30-isobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-3-propyl-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1411) (1S,7S,10S,14S,17S,26S,32S)-32-[(3-iodophenyl)methyl]-7,14-diisobutyl-3,4,4,9,13,19,22,25,28-nonamethyl-17-[(1S)-1-methylpropyl]-10-(piperidine-1-carbonyl)-3,6,9,13,16,19,22,25,28,31,34-undecazabicyclo[24.8.6]tetracontane-2,5,8,12,15,18,21,24,27,30,33-undecone,
• (1412) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-3,30-diisobutyl-12-[(3-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1413) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-31-(cyclobutylmethyl)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1414) (6S,9S,13S,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-22-(2-methylallyl)-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1415) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-bromophenyl)methyl]-22-butyl-31-(4-chlorophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1416) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-(cyclohexylmethyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1417) (6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-9-hexyl-25-[(3-iodophenyl)methyl]-16-isobutyl-31-[(4-methoxyphenyl)methyl]-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1418) (3S,9S,12S,18S,27S,30S,34R)-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31,34-decamethyl-9-(3-methylbut-2-enyl)-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1419) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-22-(3-methylbut-2-enyl)-6-[(1S)-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1420) (6S,9S,13S,16S,22S,25S,31S,34S)-22-butyl-31-(cyclohexylmethyl)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1421) (3S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-9-(2-methylallyl)-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1422) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-3-(cyclobutylmethyl)-12-[(3-iodophenyl)methyl]-30-isobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1423) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-(cyclopentylmethyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1424) (2aS,5S,11S,14S,20S,23S,30aS,33S,36S)-33-((S)-sec-butyl)-14-butyl-5-(cyclopentylmethyl)-11-(3-iodobenzyl)-20-isobutyl-4,7,16,17,17,22,35,36-octamethyl-23-(piperidine-1-carbonyl)tetracosahydroazeto[1,2-j]pyrido[1,2-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-3,6,9,12,15,18,21,25,31,34,37(1H,22H,27H)-undecaone,
• (1425) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-ynyl-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1426) (3S,9S,12S,18S,27S,30S,34S)-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-9-prop-2-ynyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1427) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,13,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-22-prop-2-ynyl-31-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1428) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-22-prop-2-vinyl-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1429) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-31-[(4-chlorophenyl)methyl]-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-22-(2-methylallyl)-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1430) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-30-isobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-3-(2-phenylethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1431) (3S,9S,12S,18S,27S,30S,34S)-9-allyl-18-[(4-chlorophenyl)methyl]-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1432) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-buty-31-(cyclopentylmethyl)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-3,4,10,14,19,19,20,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1433) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(3-iodophenyl)methyl]-30-isobutyl-3-isopentyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-18-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,2 3,26,29,32-undecone,
• (1434) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1435) (8R,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-ethyl-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1436) (8R,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-8-(isopentyloxymethyl)-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1437) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9-isobutyl-22-(isopentyloxymethyl)-16-isopropyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1438) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-22-ethyl-9-isobutyl-16-isopropyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,2629,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1439) (8R,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-cyclopentyl-8-ethyl-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1440) (8R,11S,17S,26S,29S,33S,36S)-111-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-cyclopentyl-29-isobutyl-8-(isopentyloxymethyl)-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7, 10,13,16,19,22,25,28,31,35,38-undecone,
• (1441) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-ethyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1442) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9-isobutyl-16-isopropyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1443) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-22-(isopentyloxymethyl)-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]=2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1444) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-22-(hydroxymethyl)-9-isobutyl-16-isopropyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1445) (3S,9S,18S,21S,25S,28S,34R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[36-oxa-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.4.0]octatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1446) (8R,11S,17S,26S,29S,33S,36S)-8-benzyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-cyclopentyl-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1447) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-alyl-25-[2-[3-chloro-4-(trichloromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-9-isobutyl-16-isopropyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1448) (8R,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-(hydroxymethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1449) (8S,11S,17S,26S,29S,33S,36S)-8-allyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,2730,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1450) (3S,6S,9S,12S,18S,27S,30S,34S)-6-benzyl-27-cyclohexyl-18-(5,5-difluoropentyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-4,6,10,16,19,22,25,31-octamethyl-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1451) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(5,5-difluoropentyl)-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1452) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21,28-diisobutyl-18-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1453) (3S,9S,12S,18S,27S,30S,34S)-27-cyclohexyl-18-(5,5-difluoropentyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31-nonamethyl-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1454) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1455) (3S,9S,12S,18S,27S,30S,34S)-18-(5,5-difluoropentyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1456) (3S,9S,12S,18S,27S,30S,34S)-18-(5,5-difluoropentyne)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-1,4,6,6,10,16,19,22,25,31-decamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19 22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1457) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(15)-i-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1458) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-18-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1459) (3S,9S,15S,1S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-15-ethyl-21-isobutyl-28-isopropyl-7,10,13,22,25,29-hexamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1460) (3S,9S,12S,18S,27S,30S,34R)-27-cyclohexyl-18-(5,5-difluoropentyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1461) (8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-6,11,12,15,19,32,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1462) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-6,11,12,15,19,33,36-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H-undecaone,
• (1463) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-6,11,12,15,19,33,36-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1464) (8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-24-ethyl-8-[(2-hydroxy-2-methyl-propoxy)methyl]-29,36-diisobutyl-17-(isopentyloxymethyl)-9,15,18,21,30,33,37-heptamethyl-26-[(l1S)-1-methylpropyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1465) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1466) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1467) N-tert-butyl-2-[[(3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,2 3,26,29,32-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-9-yl]methoxy]acetamide,
• (1468) (8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-6,12,15,19,32,33,36-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1469) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-28-ethyl-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1470) (6′S,15′S,18′S,22′R,25′S,30a′S,36′S,38a′R)-15′-((S)-sec-butyl)-36′-(3-chloro-4-(trifluoromethyl)phenethyl)-25′-cyclopentyl-7′,10′,13′,18′,19′,22′,26′-heptamethyl-6′-(4-(trifluoromethyl)benzyl)tetracosahydro-5′H-spiro[cyclopentane-1,28′-dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,24′,27′,30′,35′,38′(21′H,29′H)-undecaone,
• (1471) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1472) (6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-4-ethyl-22-[(2-hydroxy-2-methyl-propoxy)methyl]-9,16-diisobutyl-31-(isopentyloxymethyl)-10,13,17,19,19,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1473) (3S,9S,12S,18S,27S,30S,34R)-25-butyl-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-4,6,6,16,19,22,31,34-octamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1474) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-prop-2-ynyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1475) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,33,36-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1476) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-25-ethyl-30-[(2-hydroxy-2-methyl-propoxy)methyl]-3,9-diisobutyl-18-(isopentyloxymethyl)-4,6,6,10,16,19,22,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1477) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1478) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1479) (8S,11S,15R,18S,23aS,29S,31aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-37-(cyclohexylmethyl)-18-cyclopentyl-6,11,12,15,19,38-hexamethyltetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (1480) N-tert-butyl-2-[[(3S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-1,4,6,6,10,16,19,22,25,31-decamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-9-yl]methoxy]acetamide,
• (1481) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-6,11,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1482) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,32,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1483) (3S,9S,18S,21S,25R,28S,34S,36R)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-36-hydroxy-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1484) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-ethyl-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-4,6,6,10,16,19,2′,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1485) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1486) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1487) (6′S,15′S,18′S,22′R,25′S,30a′S,36′S,38a′R)-15′-((S)-sec-butyl)-36′-(3-chloro-4-(trifluoromethyl)phenethyl)-25′-cyclopentyl-18′-isobutyl-7′,10′,13′,19′,22′,26′-hexamethyl-6′-(4-methylbenzyl)tetracosahydro-5′H-spiro[cyclopentane-1,28′-dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazayclotetratriacontin]-5′,8′,11′,14′,17′,20′,24′,27′,30′,35′,38′(21′H,29′H)-undecaone,
• (1488) (8S,11S,15R,18S,23aS,29S,31aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-6,12,15,19,38-pentamethyl-37-(4-methylbenzyl)tetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (1489) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,29-hexamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1490) (3S,9S,18S,21S,25R,28S,34S)-18-butyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1491) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-5,6,11,12,15,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1492) N-tert-butyl-2-[[(8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-29,36-diisobutyl-17-(isopentyloxymethyl)-9,15,18,21,24,30,33,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]methoxy]acetamide,
• (1493) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-18-isopropyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1494) (8S,11S,15R,18S,23aS,29S,31aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-6,11,12,15,19,38-hexamethyl-37-(4-methylbenzyl)tetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (1495) N-tert-butyl-2-[[(2S,5S,14S,20S,23S,29S,32R)-20-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-7-ethyl-23,29-diisobutyl-14-(isopentyloxymethyl)-1,10,13,16,22,26,26,28,32-nonamethyl-5-[(1S)-1-methylpropyl]-3 6,9,12,15,18,21,24,27,30,34-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-2-yl]methoxy]acetamide,
• (1496) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-6,12,15,19,33,36-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1497) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1498) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1499) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1500) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-6,12,15,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1501) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17 20,23,27,30,33-undecone,
• (1502) N-tert-butyl-2-[[(3S,9S,12S,18S,27S,30S,34S)-3,30-diisobutyl-18-(isopentyloxymethyl)-1,4,6,6,10,16,19,22,25,31-decamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(piperidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-9-yl]methoxy]acetamide,
• (1503) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1504) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,32,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1505) (3S,9S,12S,18S,27S,30S,34R)-25-butyl-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-hydroxy-2-methyl-propoxy)methyl]-30-isobutyl-18-(isopentyloxymethyl)-3-isopropyl-4,6,6,10,16,19,22,31, 34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1506) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1507) (8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-6,11,12,15,19,32,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H1,22H)-undecaone,
• (1508) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1509) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-36,36-difluoro-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1510) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,110,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1511) (3S,9S,12S,18S,27S,30S,34R)-18-(cyclohexylmethyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-27-isopropyl-4,6,6,10,16,19,22,25,31,34-decamethyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1512) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,33,36-octamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1513) N-tert-butyl-2-[[(6S,9S,13R,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-4-ethyl-9,16-diisobutyl-31-(isopentyloxymethyl)-10,13,17,19,19,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontan-22-yl]methoxy]acetamide,
• (1514) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1515) (3S,9S,18S,21S,25R,28S,34S)-9-(5,5-difluoropentyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1516) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-ethyl-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-4,6,6,10,19,22,25,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1517) (8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-6,12,15,19,32,33,36-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1518) (3S,9S,18S,21S,25R,28S,34S)-28-butyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1519) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-25-ethyl-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-4,6,6,10,16,19,22,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4, 7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1520) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chlor-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1521) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-6,7,10,13,16,22,25,29-octamethyl-18-[(1S)-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1522) (8S,11S,15R,18S,23aS,29S,31aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-6,11,12,15,19,38-hexamethyl-37-(4-(trifluoromethyl)benzyl)tetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (1523) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1524) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1525) (6′S,15′S,18′S,22′R,25′S,30a′S,36′S,38a′R)-15′-((S)-sec-butyl)-36′-(3-chloro-4-(trifluoromethyl)phenethyl)-25′-cyclopentyl-7′,10′,13′,18′,19′,22′,26′-heptamethyl-6′-(4-methylbenzyl)tetracosahydro-5′H-spiro[cyclopentane-1,28′-dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,24′,27′,30′,35′,38′(21′H,29′H)-undecaone,
• (1526) (3S,9S,12S,18S,27S,30S,34R)-18-(5,5-difluoropentyl)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9,30-triisobutyl-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-11-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1527) (3S,9S,18S,21S,25R,28S,34S)-18-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1528) (3S,9S,12S,18S,27S,30S,34S)-25-ethyl-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-1,4,6,6,10,16,19,22,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-12-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1529) (3S,9S,18S,21S,25R,28S,34S,36S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-36-hydroxy-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1530) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-21-isobutyl-6,7,10,13,16,22,25,29-octamethyl-18-[(1S)-!-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1531) (8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-6,12,15,19,32,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1532) (3S,9S,12S,18S,27S,30S,34S)-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-1,4,6,6,10,16,19,22,25,31-decamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1533) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16, 22,25,29-heptamethyl-18-prop-2-ynyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1534) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1535) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1536) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,32,33,36-nonamethyl-35-(4-methylbenzyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1537) (5S,8S,1S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,19,33,36-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1538) N-tert-butyl-2-[[(2S,5S,14S,20S,23S,29S,32S)-2,23,29-triisobutyl-14-(isopentyloxymethyl)-1,7,10,13,16,22,26,26,28-nonamethyl-5-[(1S)-1-methylpropyl]-3,6,9,12,15,18,21,24,27,30,34-undecaoxo-20-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-32-yl]methoxy]acetamide,
• (1539) (8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-6,11,12,15,19,32,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1540) (5S,8S,11S,15R,18S,23aS,29S,31 aR,37S,39aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,11,12,15,19,38-heptamethyl-37-(4-methylbenzyl)tetracosahydro-2H,4H-spiro[azeto[2,1-u]dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,36,39(14H,22H)-undecaone,
• (1541) (3S,9S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-1,4,6,6,10,16,19,22,25,31-decamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1542) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-6,7,10,13,16,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1543) (6′S,15′S,18′S,22R,25′S,30a′S,36′S,38a′R)-15′-((S)-sec-butyl)-36′-(3-chloro-4-(trifluoromethyl)phenethyl)-6′-(cyclohexylmethyl)-25′-cyclopentyl-7′,10′,13′,18′,19′,22′,26′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,28′-dipyrrolo[2,1-i:2′,1′-o][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,17′,20′,24′,27′,30′,35′,38′(21′H,29′H)-undecaone,
• (1544) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1545) (3S,9S,18S,21S,25R,28S,34S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1546) (3S,9S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-hydroxy-2-methyl-propoxy)methyl]-3,30-diisobutyl-18-(isopentyloxymethyl)-4,6,6,10,16,19,22,25,31,34-decamethyl-27-[(1S)-11-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31 unidecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (1547) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(m-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1548) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-5-butyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1549) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1550) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(o-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1551) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-9-[(4-methoxyphenyl)methyl]-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1552) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-(cyclopentylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22-1)-undecaone,
• (1553) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-cyclopropyl-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1554) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5-cyclobutyl-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1555) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-[[3-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1556) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(3-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1557) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(3-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1558) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5,11-diisobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1559) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-6,11,12,16,19,33,36-heptamethyl-5-phenethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1560) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyl-5-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1561) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-5-benzyl-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1562) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1563) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1564) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyl-11-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1565) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1566) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-(cyclopentylmethyl)-18-isopropyl-6,11,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1567) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[2-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1568) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-11-butyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1569) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-ethyl-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1570) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(m-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1571) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(4-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1572) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[3-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1573) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl].-9-[[3-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1574) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5,35-bis(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1575) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-[[3-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1576) (3S,9S,18S,21S,25S,28S,34S)-9-[(4-bronophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1577) (5S,8S,11S,1S,1]8S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5-isopentyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1578) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,15,19,33,36-octamethyldocosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1579) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-[[2-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1580) (5S,8S,1S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5,35-bis(cyclohexylmethyl)-18-isopropyl-6,11,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1581) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5,35-bis(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-²H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1582) (3S,9S,18S,21S,25R,28S,34S)-9-[(2-chlorophenoxy)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1583) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1584) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(o-tolylmethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1585) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1586) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-cyclopropyl-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1587) (3S,9S,18S,21S,25R,28S,34S)-9-[(3-bromophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1588) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-9-[(4-methoxyphenyl)methyl]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1589) (3S,9S,18S,21S,25R,28S,34S)-9-[(2-chlorophenoxy)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1590) (3S,9S,18S,21S,25R,28S,34S)-9-[(4-bromophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1591) (3S,9S,18S,21S,25R,28S,34S)-9-[(2-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,?9-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1592) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,18-diisopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1593) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-ethyl-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1594) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1595) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-isopentyl-18-isopropyl-6,11,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,41-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1596) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-5-butyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1597) (3S,9S,18S,21S,25R,28S,34S)-9-[(3-bromophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1598) (3S,9S,18S,21S,25S,28S,34S)-9-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1i-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1599) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(2-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1600) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-a]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1601) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)-5-propyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1602) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(4-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1603) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5-(cyclobutylmethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1604) (3S,9S,18S,21S,25R,28S,34S)-9-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1605) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-9-[(4-methoxyphenyl)methyl]-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1606) (3S,9S,18S,21S,25R,28S,34S)-9-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1607) (5S,8S,10S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-ethyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,41H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1608) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(2-phenylethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1609) (3S,9S,18S,21S,25S,28S,34S)-9-[(2-chlorophenoxy)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1610) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(3-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1611) (3S,9S,18S,21S,25S,28S,34S)-9-[(3-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1612) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-(cyclopropylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,I-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1613) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-[[2-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1614) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(o-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1615) (3S,9S,18S,21S,25R,28S,34S)-9-[(2-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1616) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-11-butyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1617) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1618) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-(cyclopentylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,I-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14-1,22H)-undecaone,
• (1619) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5,11-diisobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1620) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1621) (3S,9S,18S,21S,25R,28S,34S)-9-[(3-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,?6,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1622) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5-cyclohexyl-35-(cyclohexylmethyl)-18-isopropyl-6,11,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,41-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1623) (3S,9S,18S,21S,25R,28S,34S)-9-[(3-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1624) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-5-phenethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1F-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1625) (3S,9S,18S,21S,25R,28S,34S)-9-[(4-bromophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1626) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(n-tolylmethyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1627) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(2-phenylethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1628) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-5-benzyl-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,19,33,36-hexamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1629) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1630) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropy]-25-(piperidine-1-carbonyl)-9-[[4-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1631) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(4-fluorophenyl)methyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1632) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1633) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[2-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1634) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropy]-9-(2-phenylethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1 cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1635) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-[[2-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1636) (3S,9S,18S,21S,25S,28S,34S)-9-[(2-chlorophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1637) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-[[3-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1638) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-ethyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1639) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-11-propyldocosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1640) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-[[3-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1641) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-[[2-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1642) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-(cyclopropylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22-1)-undecaone,
• (1643) (3S,9S,18S,21S,25S,28S,34S)-9-[(3-bromophenyl)methyl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1644) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclohexane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1645) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1646) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1647) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(3,3-difluoropropyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1648) (8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,15,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1649) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1650) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18,21-diisobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1651) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-isopentyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabiyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1652) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9,21-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1653) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1654) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1655) (3S,6R,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(4-fluorophenyl)methyl]-28-isopropyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1656) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-buyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1657) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11,18-diisobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1658) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1659) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-21-isobutyl-N,N,7,10,13,16,22,26,29-nonamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-carboxamide,
• (1660) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-(3,3-difluoropropyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1661) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,19,33,36-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1662) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1663) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1664) (5S,8S,11S,15S,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,32,33,36-nonamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1665) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-35-(2,2,2-trifluoroethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1666) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-cyclopropyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1667) (9′S,12′S,16′R,19′S,24a′S,30′S,32a′R,38′S,40a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-38′-(4-fluorobenzyl)-19′-isopropyl-7′,12′,13′,16′,20′,39′-hexamethylhexacosahydro-5′H-spiro[cyclopentane-1,22′-tripyrrolo[2,1-i:2′,1′-o:2″,1″-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,37′,40′(15′H,23′H)-undecaone,
• (1668) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-21-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1669) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-cyclopentyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23, 27,30,33-undecone,
• (1670) (8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1671) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18,21-bis[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1672) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclobutan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1673) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-1-spiro[azeto[2,1-a]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1674) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,35,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1675) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1676) (11S,17S,26S,29S,33S,36S)-9-benzyl-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1677) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopropyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1678) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-ethyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1679) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-Undecaone,
• (1680) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29,31,31-nonamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1681) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,9,10,13,16,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1682) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1683) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-35-benzyl-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-isopropyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1684) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,35-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1685) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1686) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-9,18-bis[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1687) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(hydroxymethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1688) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,25,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3 0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1689) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1690) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-(cyclopropoxymethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, -cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1691) (3S,6R,9S,18S,21S,25R,28S,34S)-9-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-isopropyl-6,7,10,13,16,21,22,25,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3 0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1692) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-pentyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1693) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-8-(3-pyridylmethyl)-33-(pyrrolidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1694) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methyldipropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1695) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopropane]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1696) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,1,116,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1697) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-8-isopentyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1698) (9′S,12′S,16′S,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-buty)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(4-fluorobenzyl)-19′-isopropyl-7′,12′,13′,17′,20′,34′,37′-heptamethyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′11,23′H)-undecaone,
• (1699) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1700) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-choro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(3,3-difluoropropyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1701) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1702) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-fluorobenzyl)-18-isopropyl-5,6,11,12,15,19,32,33,36-nonamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1703) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-4,9,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)-22-(3-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1704) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-11-(2,2,2-trifluoroethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(141, 22H)-undecaone,
• (1705) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-11-pentyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1706) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,15,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1707) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-choro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-18-pentyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1708) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclohexan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1709) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-35-isopentyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiroazeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1710) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1711) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1712) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-buty-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1713) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(hydroxymethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1714) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-36-ethyl-11-isobutyl-5,6,12,15,19,33-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,I-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1715) (9′S,12′S,16′S,19′S,24a′S,30′S,33′R,36′S,38a′S)-96((S)-sec-butyl)-30′-(3-cloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,17′,20′,33′,34′,37′-octamethyl-16′-(pyrrolidine-1-carbonyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1716) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclobutylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiroazeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1717) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1718) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(morpholine-4-carbonyl)-8-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1719) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1i-methylpropyl]-28-pentyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1720) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22.,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1721) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(hydroxymethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1722) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1723) (3S,9S,18S,21S,25S,28S,34S)-18-butyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1724) (5S,8S,11S,15S,18S,23aS,29S,32R,35S,37aS)-35-benzyl-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-isopropyl-5,6,11,12,16,19,32,33,36-nonamethyl-15-(piperidine-1-carbonyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1725) (9′S,12′S,16′S,19′S,24a′S,30′S,32a′R,38′S,40a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-38′-(4-fluorobenzyl)-19′-isopropyl-712′,13′,17′,20′,39′-hexamethyl-16′-(piperidine-1-carbonyl)hexacosahydro-5′H-spiro[cyclopentane-1,22′-tripyrrolo[2,1-i:2″,1′-o:2″,1″u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,37′,40′(15′H,23′H)-undecaone,
• (1726) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1727) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1728) (5S,8S,11S,15S,18S,2 3aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]-pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1729) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-N,N,7,10,13,16,2?,26,29-nonamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-carboxamide,
• (1730) (9′S,12′S,16′R,19′S,24a′S,30′S,32a′R,38′S,40a′S)-38′-benzyl-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-isopropyl-7′,12′,13′,16′,20′,39′-hexamethylhexacosahydro-5′H-spiro[cyclopentane-1,22′-tripyrrolo[2,1-i:2′,1′-o:2″,1″-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,37′,40′(15′11,23′H4)-undecaone,
• (1731) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopropoxymethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1732) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(4-fluorobenzyl)-19′-isopropyl-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29,32′,35′,38′(15′H,23′H)-undecaone,
• (1733) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1734) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-2,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1735) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-pentyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1736) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)-18-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1737) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18,35-diisopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1738) (5S,8S,11S,15S,18,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclopropoxymethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1739) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclopentylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,221-H)-undecaone,
• (1740) (3S,9S,18S,21S,25S,28S,34S)-21-butyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1741) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-ethyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1742) (9′S,12′S,16R,19′S,24a′S,30′S,33′R,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(4-fluorobenzyl)-19′-isopropyl-7′,12′,13, 6′,20′,33′,34′,37-octamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′11,23′1)-undecaone,
• (1743) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-ethyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1744) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,2,26,29-heptamethyl-25-(piperidine-1-carbonyl)-18-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1745) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(.morpholine-4-carbonyl)-8-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1746) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-(cyclobutylmethyl)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1747) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-11-isobutyl-5,6,12,15,19,33,36-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1748) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-36-ethoxy-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1749) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1750) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1751) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,21,21,33,36-nonamethyl-15-(piperidine-1-carbonyl)tetracosahydro-²H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (1752) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-ethyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1753) (9′S,12′S,16′S,19′S,24a′S,30′S,36′S,38a′S)-36′-benzyl-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-isopropyl-7′,12′,13′,17′,20′,34′,37′-heptamethyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11,14′,18′,21′,24′,29′,32′,35′,38(15′1H,23′H)-undecaone,
• (1754) (5S,85,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8,11-diisobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1755) (3S,6R,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-[(4-fluorophenyl)methyl]-28-isopropyl-6,7,10,13,16,21,22,26,29-nonamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1756) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4-1-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1757) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,2,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1758) (8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-6,12,16,19,33,36-hexamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1759) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-(cyclobutylmethyl)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1760) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-ethyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1761) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1762) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-N,N,7,10,13,16,22,26,29-nonamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-25-carboxamide,
• (1763) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-11-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1764) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(cyclopropoxymethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1765) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1766) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-(cyclopropoxymethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1767) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11,18-diisopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1768) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-(hydroxymethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[21-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1769) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(3,3-difluoropropyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1770) (3S,9S,18S,21S,25S,28S,34S)-3-[2-13-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1771) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-28-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1772) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1773) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,15,16,19,32,33,36-decamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1774) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1775) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-ethyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-]-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1776) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopentyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1777) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1778) (9′S,12′S,16′R,19′S,24a′S,30′S,36′S,38a′S)-36′-benzyl-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-isopropyl-7′,12′,13′,16′,20′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-a][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′11,23′H)-undecaone,
• (1779) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-N,N,7,10,13,16,22,26,29-nonamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-carboxamide,
• (1780) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,8,12,16,19,33,36-octamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1781) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-l-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1782) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(3,3-difluoropropyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1783) (9′S,12′S,16′R,19′S,24a′S,30′S,33′R,36′S,38a′S)-36′-benzyl-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-isopropyl-7′,12′,13′,16′,20′,33′,34′,37′-octamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′, 11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1784) (9′S,12′S,16′R,19′S,24a′S,30′S,33′R,36′S,38a′S)-9′-((S)-sec-buty)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,16′,17′,20′,33′,34′,37′-nonamethyl tetracosahydro-5′-H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1785) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-36-ethoxy-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1786) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(cyclopropoxymethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1787) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1788) (9′S,12′S,16′S,19′S,24a′S,33′S,33R,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-19′-isopropyl-7′,12′,13′,17′,20′,33′,34′,37′-octamethyl-16′-(morpholine-4-carbonyl)tetracosahydro-5′H11-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1-u] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5,8′,1′14′,18,21′,24′,29′,32′,35′,38′(15′H,23′-1)-undecaone,
• (1789) (3S,9S,18S,21S,25R,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-36-ethoxy-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1790) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1791) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-8,18-diisopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1792) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,25,26,29-octamethyl-18,28-bis[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1793) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1794) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)₁-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1795) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1796) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-cyclopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1797) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(3,3-difluoropropyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1798) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1799) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-(hydroxymethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1800) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1801) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,15,19,33,36-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1802) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,18,22,26,29-octamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1803) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11,35-diisobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,I-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1804) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1805) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1806) (9′S,12′S,16′S,19′S,24a′S,30′S,33′R,36′S,38a′S)-36′-benzyl-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-isopropyl-7′,12′,13′,17′,20′,33′,34′,37′-octamethyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1807) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1808) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,25,26,29-nonamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1809) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,15,16,19,33,36-octamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1810) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16-cyclohexyl-31-(cyclohexylmethyl)-4,9,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-22-(3-pyridylmethyl)-13-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1811) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-8-(cyclopropoxymethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1812) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-N,N,7,10,13,16,22,26,29-nonamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-carboxamide,
• (1813) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-baty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,15,16,19,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1814) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1815) (3S,9S,18S,21S,25S,28S,34S)-28-butyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1816) (5S,8S,11S,15S,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(4-fluorobenzyl)-18-isopropyl-5,6,11,12,16,19,32,33,36-nonamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1817) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclobutylmethyl)-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1818) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-cyclopentyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1819) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)icosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-4,7,10,13,17,20,23,25,28,31,34,37(14H,22H,26H)-dodecaene,
• (1820) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-(cyclopentylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1821) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1822) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopropyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1823) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-butyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1824) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-cyclopentyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1825) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopentyl-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[21-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1826) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-8-pentyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1827) (5S,8S,11S,15S,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,11,12,16,19,32,33,36-nonamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1828) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1829) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-9-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1830) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-9-isopentyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1831) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-8-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1832) (3S,9S,18S,21S,25S,28S,34S)-9-butyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1833) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isopentyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1834) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(15)-1-methylpropyl]-8-(3-pyridylmethyl)-33-(pyrrolidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1835) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-cyclopentyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1836) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-N,N,7,10,13,16,22,26,29-nonamethyl-18,28-bis[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-carboxamide,
• (1837) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-(hydroxymethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1838) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1839) (9′S,12′S,16′S,19′S,24a′S,30′S,32a′R,38′S,40a′S)-38′-benzyl-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-19′-isopropyl-7′,12′,13′,17′,20′,39′-hexamethyl-16′-(piperidine-1-carbonyl)hexacosahydro-5′H-spiro[cyclopentane-1,22′-tripyrrolo[2,1-i:2′,1′-o:2″,1″-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,37′,40′(15′H,23′H)-undecaone,
• (1840) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(pyrrolidine-11-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1841) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1842) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1843) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1844) (3S,6R,9S,18S,21S,25S,28S,34S)-9-benzyl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-isopropyl-6,7,10,13,16,21,22,26,29-nonamethyl-18-[(1S)₁-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1845) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopropane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1846) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-pentyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1847) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1848) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25n-morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1849) (8S,11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,33,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-8-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1850) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1851) (3S,9S,18S,21S,25R,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-36-ethoxy-21,28-diisobutyl-7,10,13,16,22,25,26,29-octamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3 0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1852) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35(4-methylbenzyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1853) (9′S,12′S,16′S,19′S,24a′S,30′S,33′R,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(4-fluorobenzyl)-19′-isopropyl-7′,12′,13′,17′,20′,33′,34′,37′-octamethyl-16′-(piperidine-1-carbonyl)tetracosahydro-5′I-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′H)-undecaone,
• (1854) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-35-pentyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1855) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6, 12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-18-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,I-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1856) (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1857) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-28-(cyclopropoxymethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1858) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,1922,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1859) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-buty-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1860) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-(cyclobutylmethyl)-35-(cyclohexylacetyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1861) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isopentyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1862) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-18-cyclopropyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1863) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,11-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1864) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-8-(2,2,2-trifluoroethyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H1)-undecaone,
• (1865) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-N,N,7,10,13,16,22,26,29-nonamethyl-18,28-bis[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-carboxamide,
• (1866) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1867) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-28-isopropyl-N,N,7,10,13,16,22,26,29-nonamethyl-18-[1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-25-carboxamide,
• (1868) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(pyrrolidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undcaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1869) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1870) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1871) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-propyl-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1872) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1873) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(3-bromophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1874) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,19,33,36-hexamethyl-35-(4-methylbenzyl)-15-phenethyldocosahydro-2H-4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1875) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpoline-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1876) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1877) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1878) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3,4-difluorophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1879) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1880) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-22-(o-tolylmethyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,21,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1881) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethane)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-[2-(4-pyridyl)ethyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1882) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-[[4-(trifluoromethyl)phenyl]methyl] spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1883) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-15-allyl-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1884) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1885) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]-3,4,9,10,14,17,23,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1886) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-[2-(3-pyridyl)ethyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1887) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-3,4,9,10,14,17,23,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1888) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-12-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-iodophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1″-cyclopentane]-13-carboxamide,
• (1889) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1890) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1891) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11,15-diisobutyl-5,6,12,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1892) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-[2-(3-pyridyl)ethyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1893) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(4-boronophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,V-cyclopentane]-13-carboxamide,
• (1894) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1895) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20123,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1896) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1897) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(4-pyridylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (1898) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-(3,3-difluoropropyl)-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1899) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11,15-diisobutyl-5,6,12,19,33,36-hexamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1900) (3S,95,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1901) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1902) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-[[4-trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1903) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]-22-(4-methoxyphenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1904) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpoline-4-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1905) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1906) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1907) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-(3,3-difluoropropyl)-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1908) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1909) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S) 1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane] 13-carboxamide,
• (1910) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3-iodophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1911) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-22-[3-(methylamino)-3-oxo-propyl]-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1912) (5S,8S,11S,14aR,21S,26aS,32S,38S,40aS)-8,21-di((S)-sec-butyl)-32-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,22,36,39-hexamethyl-38-(4-methylbenzyl)hexacosahydro-2H-spiro[azeto[1,2-j]pyrido[1,2-di]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-24,1′-cyclopentan]-4,7,10,13,20,23,26,31,34,37,40(25H)-undecaone,
• (1913) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(4-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1914) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1915) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1916) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1917) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,19,23,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(4-pyridylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (1918) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11,15-diisobutyl-5,6,12,19,33,36-hexamethyl-35-(4-15-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,113,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1919) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,19,33,36-hexamethyl-35-(4-methylbenzyl)-15-(trifluoromethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1920) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-[[4-(trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1921) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-22-[3-(methylamino)-3-oxo-propyl]-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-indecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1922) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3-methoxyphenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-13-carboxamide,
• (1923) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1924) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-22-(o-tolylmethyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,V-cyclopentane]-13-carboxamide,
• (1925) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1926) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[[4-(difluoromethyl)phenyl]methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1927) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-cyanophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1928) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1929) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(propoxymethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1930) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[[4-(difluoromethyl)phenyl]methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1931) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1932) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1933) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1934) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpoline-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1935) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-22-[(4-methoxyphenyl)methyl]-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,8,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1936) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1937) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclopentylmethyl)-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(morpholine-4-carbonyl)-29-propyl-8-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7, 10,13,16,19,22,25,28,31,35,38-undecone,
• (1938) (3S,9S,18S,21S,25S,28S,34S)-3-[2-13-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1939) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1940) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1941) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21- isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1942) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,4,9,10,14,17,23,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1943) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3,4-difluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1944) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3-iodophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1945) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-[[3-(trifloromethoxy)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1946) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclopentylmethyl)-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-29-propyl-8-(3-pyridylmethyl)-33-(pyrrolidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (1947) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1948) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1949) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(propoxymethyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1950) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1951) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1952) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1953) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-iodophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-l-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[322.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1954) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1955) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(4,4-difluoro-1-piperidyl)-2- oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1956) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1957) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1958) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1959) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-cyanophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1960)N-(tert-butyl)-2-(((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,19,33,36-hexamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-15-yl)methoxy)acetamide,
• (1961) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclobutyl-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1962) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(4-pyridylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1963) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]=28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1964) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(4-bromophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1965) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexymethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyli-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1966) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1967) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,19,33,36-hexamethyl-35-(4-methylbenzyl)-15-(prop-2-yn-1-yl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1968) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1969) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1970) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-[[3-trifluoromethoxy)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1971) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)-21-propyl-spiro 1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1972) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1i-methylpropyl]-25-(morpholine-4-carbonyl)-21-propyl-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1973) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,19,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-(4-pyridylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (1974) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11,15-diisobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1975) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1976) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1977) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1978) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1979) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18,28-bis[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1980) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[2-(4,4-difluoro-1-piperidyl)-2-oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1981) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3-cyanophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1982) (3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-19-isopropyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,A27,30,33-undecaoxo-22-(4-pyridylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-13-carboxamide,
• (1983) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1984) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropy]-21-propyl-25-(pyrrolidine-1-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1985) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)-22-[2-(4-pyridyl)ethyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (1986) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1987) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(4-fluorophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1988) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1989) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1990) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1991) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-22-[(3-methoxyphenyl)methyl]—N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,8,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (1992) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-3,4,9,10,14,17,23,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1993) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1994) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-11-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1995) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-buty)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11,15-diisobutyl-5,6,12,19,33,36-hexamethyl-35-(4-methylbenzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (1996) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1997) (3S,6S,9S,13S,16S,22R,25S,31S,34S)-22-benzyl-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,4,9,10,14,17,23,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (1998) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32=undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (1999) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(morpholine-4-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2000) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(3-bromophenyl)methyl]-25-12-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2001) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2002) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-22-[(3-cyanophenyl)methyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6,16-bis[(1S)₁-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17120,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2003) (5S,8S,11S,14aR,20S,25aS,31S,37S,39aS)-8,20-di((S)-sec-butyl)-31-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,21,35,38-hexamethyl-37-(4-methylbenzyl)tetracosahydro-2H,4H-spiro[azeto[1,2-j]dipyrrolo[1,2-e1:1″,2′-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-23,1′-cyclopentan]-4,7,10,13,19,22,25,30,33,36,39(14H,24H)-undecaone,
• (2004) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-21-propyl-9-(p-tolylmethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2005) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(propoxymethyl)-21-propyl-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2006) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(propoxymethyl)-25-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2007) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-17-(p-tolylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2008) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(pyrrolidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2009) (5S,8S,12R,15S,20aS,26S,29R,32S,34aS,39aS)-5-((S)-sec-butyl)-26-(3-chloro-4-(trifluoromethyl)phenethyl)-32-(cyclohexylmethyl)-15-isopropyl-8,9,12,16,29,30,33-heptamethyltetracosahydrospiro[azeto[1,2-g]dipyrrolo[1,2-j:1′2′-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1′-cyclopentan]-4,7,10,14,17,20,25,28,31,34,39(21H,11H,19H)-undecaone,
• (2010) (5S,8S,12R,15S,20aS,26S,29R,32S,37′aS)-5-((S)-sec-butyl)-26-(3-chloro-4-(trifluoromethyl)phenethyl)-32-(cyclohexylmethyl)-15-isopropyl-8,9,12,16,29,30,33,36-octamethyldocosahydrospiro[azeto[1,2-g]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1′-cyclopentan]-4,7,10,14,17,20,25,28,31,34,37(21H,1114,191)-undecaone,
• (2011) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(2-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]—N,N,3,4,9,10,14,17,23,29,32-undecamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,270,3,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2012) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-ethyl-18-isopropyl-6,11,12,15,19,32,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2013) (5S,8S,12R,15S,20aS,26S,29R,32S,34aS,38aS)-5-((S)-sec-butyl)-26-(3-chloro-4-(trifluoromethyl)phenethyl)-32-(cyclohexylmethyl)-15-isopropyl-8,9,12,16,29,30,33-heptamethyldocosahydro-25H-spiro[bis(azeto)[1,2-g:1′,2′-j]pyrrolo[1,2-v][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-18,1′-cyclopentan]-4,7,10,14,17,20,25,28,31,34,38(2H,11H,19H,34aH)-undecaone,
• (2014) (9′S,12′S,16′R,19′S,24a′S,30′S,33′R,36′S,38a′S)-9′-((S)-sec-butyl)-30′-(3-chloro-4-(trifluoromethyl)phenethyl)-36′-(cyclohexylmethyl)-7′-ethyl-19′-isopropyl-12′,13′,16′,20′,33′,34′,37′-heptamethyltetracosahydro-5′H-spiro[cyclopentane-1,22′-dipyrrolo[2,1-i:2′,1′-u] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin]-5′,8′,11′,14′,18′,21′,24′,29′,32′,35′,38′(15′H,23′11)-undecaone,
• (2015) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-5,35-bis(cyclohexylmethyl)-18-isopropyl-6,11,12,15,19,32,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazayclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2016) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-6,11,12,15,19,32,33,36-octamethyl-5-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2017) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-5-butyl-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-6,11,12,15,19,32,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2018) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5-isobutyl-18-isopropyl-6,11,12,15,19,32,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2019) (5S,8S,11S,15R,18S,23aS,29S,32R,35S,37aS)-5-benzyl-8-((S)-sec-butyl)-29-(³-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-6,11,12,15,19,32,33,36-octamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2020) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-36-isopropyl-9,15,18,21,24,29,30,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-33-(morpholine-4-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2021) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-[3-(4,4-difluoro-1-piperidyl)propyl]-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2022) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-[2-(4,4-difluoro-1-piperidyl)ethyl]-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2023) (3S,6S,9S,13S,16S,25S,31S,34S)-25-[2-[3-choro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-23-[2-(2-hydroxy-2-methyl-propoxy)ethyl]-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2024) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-9-[2-(2,2,2-trifluoroethoxy)ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2025) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9-[2-(2-methoxyethoxy)ethyl]-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2026) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-9-(3-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2027) (3S,6S,9S,13R,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-23-[2-(2-hydroxy-2-methyl-propoxy)ethyl]-9-isobutyl-3,4,10,13,14,17,29,32-octamethyl-6,16-bis[(1S)-1-methylpropyl]-31-(propoxymethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2028) (3S,6S,9S,13S,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-23-[2-(2-hydroxy-2-methyl-propoxy)ethyl]-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2029) (1S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-9-[2-(4-pyridyl)ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2030) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-9-(2-oxaspiro[3.3]heptan-6-yl)-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2031) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-9-(oxetan-3-ylmethyl)-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2032) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-9-[2-(3-pyridyl)ethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2033) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-9-(4-pyridylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2034) (3S,6S,9S,13S,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-23-[2-(2-hydroxy-2-methyl-propoxy)ethyl]-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2035) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2,2-difluorospiro[3.3]heptan-6-yl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2036) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-[2-(2,2-difluoroethoxy)ethyl]-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2037) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-hydroxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2038) 2-[2-[(11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]ethoxy]—N,N-dimethyl-acetamide,
• (2039) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-(3,4-dichlorophenoxy)ethyl]-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2040) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenoxy)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2041) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-[4-(trifluoromethyl)phenoxy]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2042) (3S,9S,18S,21S,25S,28S,34S)-3-[(4-chlorophenoxy)methyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2043) (3S,9S,18S,21S,25S,28S,34S)-3-[(2-chlorophenyl)methoxymethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2044) (3S,9S,18S,21S,25S,28S,34S)-3-[(4-chlorophenyl)methoxymethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2045) (3S,9S,18S,21S,25S,28S,34S)-3-[(3-chlorophenyl)methoxymethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2046) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(5-hydroxypent-2-enyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2047) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(4-hydroxy-4-methyl-pent-2-enyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2048) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(2-tetrahydropyran-4-ylethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2049) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(5-hydroxypentyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2050) tert-butyl 3-[2-[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropy]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]ethylidene]azetidine-1-carboxylate,
• (2051) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9-[(E)-4-methoxybut-2-enyl]-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2052) 4-[(11S,17S,26S,29S,33S,36S)-11-[2-[3-chlor-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]—N,N-dimethyl-butanamide,
• (2053) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(2-tetrahydropyran-4-ylideneethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2054) 4-[(11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]—N,N-dimethyl-but-2-enamide,
• (2055) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[3-[4-(trifluoromethyl)phenyl]propyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2056) tert-butyl 3-[2-[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]ethyl]azetidine-1-carboxylate,
• (2057) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethoxy)phenethyl)-35-(cyclohexymethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2058) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-[2-(4-methylsulfonylphenyl)ethyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2059) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-(3,4,5-trichlorophenyl)ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2060) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(2-(6-(difluoromethyl)pyridin-3-yl)ethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2061) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-(3,4-dichloro-5-methoxy-phenyl)ethyl]-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2062) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-(3,4-dichloro-5-isopropoxy-phenyl)ethyl]-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2063) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-29-(2-(benzofuran-5-yl)ethyl)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2064) (5S,8S,11S,1S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-29-(2-(1-methyl-11-H-indol-5-yl)ethyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2065) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-29-(2-(1-methyl-1H-indol-6-yl)ethyl)-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2066) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(3-butoxy-4,5-dichloro-phenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7, 10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2067) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethoxy)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21, 1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2068) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-(3,4,5-trichlorophenyl)ethyl]spiro[1,4,7,10,13,16,19,22,2629,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2069) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-29-(2-(5-(trifluoromethyl)pyridin-2-yl)ethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2070) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-29-(2-(quinolin-6-yl)ethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2071) 2,3-dichloro-5-[2-[(3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-3-yl]ethyl]benzonitrile,
• (2072) 5-(2-((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxo-15-(piperidine-1-carbonyl)tetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-29-yl)ethyl)-2-(trifluoromethyl)benzonitrile,
• (2073) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(3-tert-butoxy-4,5-dichloro-phenyl)ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2074) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2075) 2,3-dichloro-5-[2-[(3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,27,30,33-undecaoxo-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-3-yl]ethyl]benzonitrile,
• (2076) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(4-(difluoromethoxy)-3-fluorophenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2077) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-29-(2-(quinolin-7-yl)ethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2078) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)-29-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2079) (3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-3-[2-(3,4-dichloro-5-isopropoxy-phenyl)ethyl]-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabiyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2080) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-29-(3-methoxy-4-(trifluoromethyl)phenethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiroazeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2081) (3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylacetyl)-3-[2-(3,4-dichloro-5-methoxy-phenyl)ethyl]-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2082) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(3-tert-butoxy-4,5-dichloro-phenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2083) (3S,9S,18S,21S,25S,28S,34S)-3-[2-(3-butoxy-4,5-dichloro-phenyl)ethyl]-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2084) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-29-(2-(6-methoxypyridin-3-yl)ethyl)-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2085) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(4-(difluoromethyl)-3-fluorophenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidine-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone,
• (2086) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-12-[2-(4-chloro-2-fluoro-phenyl)ethyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4, 7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2087) (35,6S,9S,12S,18S,27,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(S)-1-methylpropy]-12-[2-(2,4,5-trifluorophenyl)ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2088) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2089) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[2-(2,4-difluorophenyl)ethyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2090) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-(2,4,6-trifluorophenyl)ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2091) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-(2,3,4,5,6-pentafluorophenyl)ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2092) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-12-[2-(2-chloro-6-fluoro-phenyl)ethyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2093) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-12-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2094) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-12-[2-(5-chloro-2-fluoro-phenyl)ethyl]-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2095) (3S,6S,9S,12S,18S,27S,30S,34R)-6-benzyl-18-[(4-chlorophenyl)methyl]-3,9-diisobutyl-4,7,16,19,22,25,30,31,34-nonamethyl-27-[(1S)-1-methylpropyl]-12-[2-[3-(trifluoromethyl)phenyl]ethyl]-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2096) (3S,9S,18S,21S,25S,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-3-[2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl]-28-isobutyl-7,10,13,16,21,22,29,32-octamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2097) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-(2-oxo-2-pyrrolidin-1-yl-ethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2098) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[3-(3,3-difluoroazetidin-1-yl)-3-oxo-propyl]-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2099) (3S,9S,12S,18S,27S,30S,34S)-34-(3,3-difluoropiperidine-1-carbonyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2100) 3-[(3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-6-yl]—N,N-dimethyl-propanamide,
• (2101) (3S,9S,12S,18S,27S,30S,34S)-34-(4,4-difluoropiperidine-1-carbonyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-11-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23, 26,29,32-undecone,
• (2102) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[2-(azetidin-1-yl)-2-oxo-ethyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2103) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[3-(azetidin-1-yl)-3-oxo-propyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2104) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)-22-(3-oxo-3-pyrrolidin-1-yl-propyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5, 8,11,15,18,21,24,27,30,33-undecone,
• (2105) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-22-[2-oxo-2-(1-piperidyl)ethyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2106) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(dimethylamino)-2-oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-indecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (2107) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)-22-(3-morpholino-3-oxo-propyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2108) 3-[(3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6- (1S)₁-methylpropyl]-13-(morpholine-4-carbonyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-22-yl]—N,N-dimethyl-propanamide,
• (2109) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-22-(2-morpholino-2-oxo-ethyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-13-carboxamide,
• (2110) 3-[(3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-22-butyl-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,20,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontan-19-yl]—N,N-dimethyl-propanamide,
• (2111) 3-[(3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-22-yl]—N-methyl-propanamide,
• (2112) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)-22-[3-oxo-3-(1-piperidyl)propyl]spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2113) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(triazol-1-yl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2114) (6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-22-(phenoxymethyl)-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2115) (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(triazol-1-yl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2116) (3S,9S,18S,21S,25R,28S,34S,36R)-36-benzyloxy-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2117) (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2-hydroxyethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2118) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-36-ethoxy-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2119) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2,2-difluoroethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)₁-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2120) (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-l-methylpropyl]-25-(piperidine-1-carbonyl)-36-(3-pyridylmethoxy)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2121) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(3-pyridylmethoxy)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2122) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2-hydroxyethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2123) (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2,2-difluoroethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2124) (3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(3-thienylmethoxy)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2125) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,2 8-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-36-(m-tolylmethoxy)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2126) (3S,9S,18S,21S,25S,28S,34S,36S)-36-[(3-chlorophenyl)methoxy]-9-(cyclohexymethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2127) (3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-36-ethoxy-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2128) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-36-[[4-(difluoromethoxy)phenyl]methoxy]-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2129) (3S,9S,18S,21S,25S,28S,34S,36S)-36-[(4-chlorophenyl)methoxy]-9-(cyclohexymethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2130) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(p-tolylmethoxy)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2131) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-36-[(3-methoxyphenyl)methoxy]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2132) (3S,9S,18S,21S,25S,28S,34S,36S)-36-[(2-chlorophenyl)methoxy]-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2133) (3S,9S,18S,21S,25S,28S,34S,36R)-36-[(4-chlorophenyl)methoxy]-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2134) (3S,9S,18S,21S,25S,28S,34S,36R)-36-[(3-chlorophenyl)methoxy]-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2135) (3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-36-[[4-(difluoromethoxy)phenyl]methoxy]-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2136) (3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-36-[(3-methoxyphenyl)methoxy]-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2137) (3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-36-(o-tolylmethoxy)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2138) (3S,9S,18S,21S,25S,28S,34S,36R)-36-[(2-chlorophenyl)methoxy]-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2139) (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-36-(o-tolylmethoxy)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2140) (3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(p-tolylmethoxy)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2141) (3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-36-(n-tolylmethoxy)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone,
• (2142) (3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-ethynylphenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2143) (11S,17S,26S,29S,33R,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclobutyl-17-(cyclohexylmethyl)-15,18,21,24,29,30,33,34,37-nonamethyl-26-[(1S)-1-methylpropyl]-9-phenyl-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2144) (3S,6S,9S,13S,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,31-di(cyclobutyl)-3,4,9,10,14,17,19,19,20,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-23-phenyl-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2145) (3S,12S,18S,27S,30S,34R)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3-cyclobutyl-18-(cyclohexylmethyl)-1,4,6,6, 7,16,19,22,25,30,31,34-dodecamethyl-27-[(1S)-1-methylpropyl]-10-phenyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2146) (3S,6S,9S,13S,16S,25S,31S,34S)-23-(3-chlorophenyl)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,31-di(cyclobutyl)-3,4,9,10,14,17,19,19,20,29,32 undecamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2147) (3S,6S,9S,13S,16S,25S,31S,34S)-23-(4-chlorophenyl)-25-[2-3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,31-di(cyclobutyl)-3,4,9,10,14,17,19,19,20,29,32-undecamethyl-6-[(1S)-1-methylpropyl]-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2148) (3S,6S,9S,13R,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-16,31-di(cyclobutyl)-3,4, 9,10,13,14,17,19,19,20,29,32-dodecamethyl-6-[(1S)-1-methylpropyl]-23-phenyl-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone,
• (2149) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclobutyl-17-(cyclohexylmethyl)-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-9-(3-thienyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2150) (3S,12S,18S,27S,30S,34S)-12-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-3-cyclobutyl-18-(cyclohexylmethyl)-1,4,6,6,7,16,19,22,25,30,31-undecamethyl-27-[(1S)-1-methylpropyl]-10-phenyl-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone,
• (2151) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclobutyl-17-(cyclohexylmethyl)-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-9-phenyl-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2152) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-(cyclobutylmethyl)-35-(cyclohexylmethyl)-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (2153) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(141)-undecaone,
• (2154) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-ethyl-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (2155) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclohexyl-35-(cyclohexylmethyl)-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (2156) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-21-1-azeto[2,1-U]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (2157) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclobutyl-35-(cyclohexylmethyl)-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (2158) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-(cyclopentylmethyl)-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaene,
• (2159) (5S,8S,1,1S,5R,8S,23aS,29S,35S,37aS)-8,11-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,15,16,19,21,21,22,33,36-undecamethyltetracosahydro-21-azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-4,7,10,13,17,20,23,28,31,34,37(14H)-undecaone,
• (2160) (5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isobutyl-5,6,11,12,15,16,19,21,21,22,33,36-dodecamethyltetracosahydro-2H-azete[2,1-u]pyrrolo [2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratoriacontin-4,7,10,13,17,20,23,28,31,34,37(141)-undecaone,
• (2161) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-9-ethyl-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropy]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2162) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-9-ethyl-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(pyrolidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2163) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(2-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-23-ethyl-N,N,3,4,9,10,14,17,29,32-decamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2164) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-9-ethyl-36-isopropyl-N,N,15,18,21,24,29,30,34,37-decamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-33-carboxamide,
• (2165) (3S,6S,9S,13S,16S,22S,25S,31S,34S)-22-[(2-chlorophenyl)methyl]-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-23-ethyl-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2166) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-ethyl-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-17-(p-tolylmethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2167) (8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-9-ethyl-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(morpholine-4-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2168) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexymethyl)-29-isobutyl-8-(2-methoxyethyl)-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2169) 5-[[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]methyl]pyridine-2-carbonitrile,
• (2170) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-8-[(3-fluoro-4-hydroxy-phenyl)methyl]-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2171) (8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-=(cyclohexylmethyl)-29-isobutyl-8-[(4-methoxyphenyl)methyl]-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropy]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2172) (3S,9S,18S,24R,27S,33S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-27-cyclopentyl-N,N,7,10,13,16,25,28-octamethyl-2,5,8,11,14,17,20,26,29,32-decaoxospiro[22-thia-1,4,7,10,13,16,19,25,28,31-decazabicyclo[31.3.0]hexatriacontane-30,1-cyclopentane]-24-carboxamide,
• (2173) (3S,9S,18S,24R,27S,33S)-18,27-bis[(2S)-butan-2-y]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]—N,N,7,10,13,16,25,28-octamethyl-9-[(4-methylphenyl)methyl]-2,5,8,11,14,17,20,26,29,32-decaoxospiro[22-thia-1,4,7,10,13,16,19,25,28,31-decazabicyclo[31.3.0]hexatriacontane-30,1′-cyclopentane]-24-carboxamide,
• (2174) (3S,9S,12S,17S,20S,23S,29R,32S,38S)-20-[(2S)-butan-2-yl]-32-cyclopentyl-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]—N,N,7,10,17,18,24,30,33-nonamethyl-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,31,34,37-undecaoxo-9-(propoxymethyl)spiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36.3.0.012,15]hentetracontane-35,1′-cyclopentane]-29-carboxamide,
• (2175) (3S,9S,18S,21S,27R,30S,36S)-18-[(2S)-butan-2-yl]-3-2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-N,N,7,10,13,16,22,28,31-nonamethyl-21-(2-methylpropyl)-2,5,8,11,14,17,20,23,29,32,35-undecaoxospiro[25-thia-1,4,7,10,13,16,19,22,28,31,34-undecazabicyclo[34.3.0]nonatriacontane-33,1′-cyclopentane]-27-carboxamide,
• (2176) (3S,9S,12S,17S,20S,23S,29R,32S,38S,40R)-20-[(2S)-butan-2-yl]-9—(Cyclohexylmethyl)-32-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-40-ethoxy-N,N,7,10,17,18,24,30,33-nonamethyl-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,31,34,37-undecaoxospiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36.3.0.012,15]hentetracontane-35,1′-cyclopentane]-29-carboxamide,
• (2177) (3S,9S,12S,17S,20S,23S,29R,32S,38S)-20-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-32-cyclopentyl-N,N,7,10,17,18,24,30,33-nonamethyl-9-[(4-methylphenyl)methyl]-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,31,34,37-undecaoxospiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36.3.0.012,15]hentetracontane-35,1′-cyclopentane]-29-carboxamide,
• (2178) (3S,9S,18S,21S,27R,30S,36S)-18,30-bis[(2S)-butan-2-y]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]—N,N,7,10,13,16,22,28,31-nonamethyl-9-[(4-methylphenyl)methyl]-21-(2-methylpropyl)-2,5,8,11,14,17,20,23,29,32,35-undecaoxospiro[25-thia-1,4,7,10,13,16,19,22,28,31,34-undecazabicyclo[34.3.0]nonatriacontane-33,1′-cyclopentane]-27-carboxamide,
• (2179) (3S,9S,12S,17S,20S,23S,29R,32S,38S)-20-[(2S)-butan-2-yl]-9,32-dicyclopentyl-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]—N,N,7,10,17,18,24,30,33-nonamethyl-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,31,34,37-undecaoxospiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36.3.0.012,15]hentetracontane-35,1 cyclopentane]-29-carboxamide,
• (2180) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-9-[2-(4-methylpiperazin-1-yl)ethyl]-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2181) (3S,6S,9S,13S,16S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-23-[2-[2-(dimethylamino)ethoxy]ethyl]-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide,
• (2182) (3S,6S,9S,13S,16S,25S,31S,34S)-23-[2-(azetidin-3-yl)ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-25-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (2183) (3S,6S,9S,13S,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-23-[2-[2-(methylamino)ethoxy]ethyl]-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1 cyclopentane]-13-carboxamide,
• (2184) (11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-9-(2-piperazin-1-ylethyl)-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2185) (11S,17S,26S,29S,33S,36S)-9-[2-(2-aminoethoxy)ethyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone,
• (2186) (11S,17S,26S,29S,33S,36S)-9-(4-aminobutyl)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone.
• (2187) (6S,9S,15S,18S,21S,24S,27S,30R,34S)-15-benzyl-21-[(3-chlorophenyl)methyl]-9-[(4-chlorophenyl)methyl]-24,27-bis[(3-fluoro-4-hydroxy-phenyl)methyl]-10,16,30,31-tetramethyl-6-[(1S)-1-methylpropyl]-18-(2-methylsulfonylethyl)-34-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone, and
• (2188) (3S,6S,9S,12S,15S,18S,21S,24S,28S,31S)-18,21-dibutyl-12-[(2-chlorophenoxy)methyl]-6-[(5-fluoro-3-pyridyl)methoxymethyl]-4,10,24,25-tetramethyl-15-[(1S)-1-methylpropyl]-3,9-bis(3-pyridylmethyl)-28-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,29-decazabicyclo[29.3.0]tetratriacontane-2,5,8,11,14,17,20,23,26,30-decone.

(General Production Method)

General production methods for the cyclic peptide compound, and the non-natural amino acid for use in the production of the cyclic peptide compound disclosed herein will be described below.

Chemical Synthesis Methods for Peptide Compounds

Examples of chemical synthesis methods for the peptide compounds or the cyclic peptide compounds herein include a liquid-phase synthesis method, a solid-phase synthesis method using Fmoc synthesis, Boc synthesis, or the like, and a combination thereof. In Fmoc synthesis, a basic unit is an amino acid in which a main-chain amino group is protected with an Fmoc group, and a side-chain functional group is protected as necessary with piperidine or a protecting group that is not cleaved by a base, such as a t-Bu group, a THP group, or a Trt group, and a main-chain carboxylic acid is not protected. The basic unit is not particularly limited as long as it is a combination having an Fmoc-protected amino group and a carboxyl group. For example, dipeptide may be a basic unit. The basic unit disposed at the N terminus may be a unit other than the Fmoc amino acid. For example, it may be a Boc amino acid or a carboxylic acid analog which does not have an amino group. The main-chain carboxyl group, or a side-chain carboxyl group of an amino acid that has a carboxyl group in a side chain and in which the main-chain carboxyl group is protected with a suitable protecting group, is supported on a solid phase by a chemical reaction with the functional group of a solid-phase carrier. Subsequently, the Fmoc group is deprotected by a base such as piperidine or DBU, and a newly produced amino group and a subsequently added, basic-unit protected amino acid having a carboxyl group are subjected to a condensation reaction to produce a peptide bond. In the condensation reaction, various combinations such as a combination of DIC and HOBt, a combination of DIC and HOAt, and a combination of HATU and DIPEA are possible as activating agents for the carboxyl group. The desired peptide sequence can be produced by repeating the Fmoc group deprotection and the subsequent peptide bond forming reaction. After the desired sequence is obtained, cleavage from the solid phase and deprotection of the optionally introduced protecting group of the side-chain functional group are conducted. Further, conformational conversion and cyclization of the peptide can be performed before cleaving from the solid phase. Cleaving from the solid phase and deprotection may be performed under the same conditions, e.g., in 90:10 TFA/H₂O, or deprotection may be performed under different conditions as necessary. Cleaving from the solid phase may be achieved using a weak acid such as 1% TFA in some cases, and Pd or the like may be used as a protecting group to utilize the orthogonality of both chemical reactions. During or at the end of these steps, a step such as cyclization can also be performed. For example, a side-chain carboxylic acid and an N-terminal main-chain amino group can be condensed, and a side-chain amino group and a C-terminal main-chain carboxylic acid can be condensed. In this case, reaction orthogonality is required between the carboxylic acid on the C-terminal side and the side-chain carboxylic acid to be cyclized, or between the main-chain amino group or hydroxy group on the N-terminal side and the side-chain amino group to be cyclized. As described above, the protecting group is selected in consideration of the orthogonality of the protecting group. The reaction product thus obtained can be purified by a reverse-phase column, a molecular sieve column, or the like. Details of these procedures are described in, for example, the Solid-Phase Synthesis Handbook published by Merck on May 1, 2002. Commercially available resins for solid phase synthesis are usable, and examples include CTC resin, Wang resin, and SASRIN resin.

A general method for synthesizing an amino acid-supported resin for use in peptide synthesis by a peptide synthesizer will be described below.

An Fmoc amino acid can be supported on a resin by the method described in WO2013/100132 or WO2018/225864. Specifically, for example, 2-chlorotrityl chloride resin and a solvent (e.g., dehydrated dichloromethane) are introduced into a filter-equipped reaction vessel to swell the resin. Next, the solvent and the resin are separated, and then a mixture of the resin, a C-terminal free Fmoc amino acid dissolved in a solvent (e.g., dehydrated dichloromethane), a solvent (e.g., dehydrated methanol), and a base (e.g., diisopropylethylamine) is added to the reaction vessel and mixed to support the Fmoc amino acid on the resin. After the resin and the reaction solution are separated, the resin is mixed with a mixture of one or more solvents and a base (e.g., a mixture of dehydrated dichloromethane, dehydrated methanol, and diisopropylethylamine) to wash the resin. After the resin is washed with a solvent (e.g., dichloromethane) multiple times as necessary, the resin and the reaction solution are separated. By drying the resulting resin under reduced pressure overnight, an Fmoc amino acid-supported resin can be obtained.

(wherein n represents an integer of 1 to 11; P₁ to P₁₁, Q₁ to Q₁₁, and R₁ to R₁₁ mean P₁ to P₁₁, Q₁ to Q₁₁, and R₁ to R₁₁ as defined herein, respectively; L₁ and L₁₁ mean L₁ and L₁₁ as described herein, respectively; L₂ to L₁₀ are single bonds; and o (circle) means a resin portion.)

The above structure shows that in the Fmoc-amino acid, the 2-chlorotrityl group on the resin is bonded to the carboxylic acid of the Fmoc amino acid via an ester bond.

In the production of the compound described herein, when the defined group undergoes undesired chemical conversion under the conditions of the performed method, the compound can be produced by means of, for example, protection and deprotection of a finctional group. Selection and introduction/removal procedures of a protecting group can be performed according to, for example, the methods described in Greene's “Protective Groups in Organic Synthesis” (5th Ed., John Wiley & Sons, 2014), which may be suitably used depending on the reaction conditions. Further, the order of reaction steps such as introduction of a substituent can be changed as necessary. For example, the protecting group for an amino group is an Fmoc, Boc, Cbz, or Alloc group. These carbamate groups can be introduced by reacting an amino group with a carbamating agent in the presence of a basic catalyst. Examples of the carbamating agent include Boc₂O, BocOPh, FmocOSu, FmocCl, CbzCl, and AllocCl. Examples of the basic catalyst include lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, cesium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, and N,N-dimethylaminopyridine. A carbamate group which is a protecting group for an amino group can be removed under basic conditions, acidic conditions, hydrogenolysis reaction conditions, or the like.

(Cyclization Methods for Cyclic Peptide Compounds)

A method for transforming a linear peptide compound into a cyclic peptide compound can be performed by carrying out a bond forming reaction within the molecule according to, for example, the method described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition by R. C. Larock, or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition by M. B. March. After the bond forming reaction, further, a functional group transforming reaction can also be performed. Examples of the bond forming reaction include a C(O)—N bond formed from carboxylic acid and amine; a C—O—C bond, a C(O)—O bond, and a C(S)—O bond using an oxygen atom; a C(O)—S bond, a C(S)—S bond, a C—S—S—C bond, a C—S—C bond, a C—S(O)—C bond, and a C—S(O₂)—C bond using a sulfur atom; and a C—N—C bond, a C—N—C bond, an N—C(O)—N bond, an N—C(S)N bond, and a C(S)—N bond using a nitrogen atom. Furthermore, examples include C—C bond forming reactions catalyzed by a transition metal, such as Suzuki reaction, Heck reaction, and Sonogashira reaction. Examples of the functional group transforming reaction further performed after the bond forming reaction include an oxidation reaction and a reduction reaction. A specific example is a reaction for oxidizing a sulfur atom to transform it into a sulfoxide group or a sulfone group. Another example is a reduction reaction for reducing a triple bond or a double bond of carbon-carbon bonds to a double bond or a single bond. While a closed ring structure is formed by a peptide bond when two amino acids are bonded with the amino acid main chain, a covalent bond between two amino acids may be formed by bonding between side chains of two amino acids, bonding between a side chain and a main chain, or the like. A black circle or a black square below indicates an amino acid residue, and connected black circles or black squares represent a peptide chain connected by an amide bond. The number of amino acid residues constituting a peptide chain are not particularly limited, and the number of black circles or black squares below does not represent the number of amino acid residues.

Herein, a peptide compound having a cyclic moiety may be referred to as a “cyclic peptide compound”. Herein, the “cyclic moiety” of a peptide compound means a cyclic portion formed of two or more connected amino acid residues.

(General Preparation Method 1 for Cyclic Peptide Compounds)

Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by activating the N-terminal amino group and the C-terminal side chain carboxyl group (e.g., L=—CH₂— in the case of aspartic acid or its derivative, and L=—CH₂CH₂— in the case of glutamic acid or its derivative) with an activating reagent or converting them to active esters, and then condensing them in the molecule to form a C(O)—N bond.

(General-Operation Method 2 for Cyclic Peptide Compound

Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Tem can be cyclized by activating the N-terminal amino group and the C-terminal side chain carboxyl group (e.g., L=—CH₂— in the case of aspartic acid or its derivative, and L=—CH₂CH₂— in the case of glutamic acid or its derivative) with an activating reagent or converting them to active esters, and then condensing them in the molecule to form a C(O)—N bond.

(General Preparation Method 3 for Cyclic Peptide Compounds)

(Method of Cyclizing with Haloalkyl and SH Groups)

Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting the haloalkyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond. Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the haloalkyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond. Further, a C—S(O)—C or C—S(O)₂—C bond can also be formed by oxidizing and converting a sulfur atom to a sulfoxide or sulfone.

(Method of Cyclizing with Vinyl and SH Groups)

Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting the vinyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond. Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the vinyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond. Further, a C—S(O)—C or C—S(O)₂—C bond can also be formed by oxidizing and converting a sulfur atom to a sulfoxide or sulfone.

(Method of Cyclizing with Ethynyl and SH Groups)

Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting the ethynyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond. Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the ethynyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond. Further, a C—S(O)—C or C—S(O)₂—C bond can also be formed by oxidizing and converting a sulfur atom to a sulfoxide or sulfone. The double bond site can also be reduced and converted to a single bond.

(Method of Cyclizing with Vinyl and Vinyl Groups)

Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting different vinyl groups of amino acid residues with each other in the molecule to form a C—C bond. Cyclic peptide compound is described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting different vinyl groups of amino acid residues with each other in the molecule to form a C—C bond.

(Method of Cyclizing by Forming a Triazole Ring with Azido and Ethynyl Groups)

C-Term represents OH, an alkoxy group, or an optionally substituted amino group. Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting the azido group of an amino acid residue with the ethynyl group of an amino acid residue in the molecule to form a triazole ring. Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the azido group of an amino acid residue with the ethynyl group of an amino acid residue in the molecule to form a triazole ring.

General preparation methods for peptide compounds by peptide modification are to shown below. In the following schemes, P_n represents a substituent for a nitrogen atom, R_n and Q_n each represent an amino acid side chain, a black circle represents an amino acid residue, linked black circles represent a peptide chain linked by amide bonds, and m represents the number of amino acid residues and may be any integer of 1 or more.

(Method of Preparing Peptides Containing N-Alkylamino Acids)

Peptides containing N-alkylamino acids can be synthesized according to the general peptide synthesis method described in the present Examples using an Fmoc-protected N-alkylamino acid as a raw material, or alternatively can be prepared by alkylating the N-terminal nitrogen on a resin as illustrated below. Specifically, the target peptides having an N-alkylamino acid at the N-terminus can be prepared by reacting the nitrogen of the N-terminal Tfa amide (trifluoroacetamide) of a resin-loaded peptide with an alkyl halide under basic conditions, and then treating the peptide with a reducing agent by referring to Organic Letters, 2008, 10, 4815-4818 or the like. Further, cyclic peptide compounds can be prepared by elongating, cleaving from the resin, cyclizing, deprotecting, and purifying the peptide according to the general peptide synthesis method described in the present Examples.

The method described in Nature Protocols, 2012, 7, 432-444 which is shown below can also be used as another method of introducing P_n onto the N-terminal nitrogen. Specifically, the target peptides having P_n at the N-terminus can be obtained by converting the N-terminal amine of a resin-loaded peptide to an Ns-substituted form, introducing P_n by Mitsunobu reaction, and then deprotecting the Ns group. Further, cyclic peptide compounds can be prepared by elongating, cleaving from the resin, cyclizing, deprotecting, and purifying the peptide according to the general peptide synthesis method described in the present Examples.

Peptides containing glycine with P_n introduced onto the nitrogen atom can be synthesized according to the general peptide synthesis method described in the present Examples using glycine with P_n introduced onto the Fmoc-protected nitrogen atom as a raw material, or alternatively can be prepared by substitution reaction between the N-terminal halogenated carbon and an amine as illustrated below. Specifically, the target peptides having N-terminal glycine with P_n introduced onto the nitrogen atom can be obtained by reacting the N-terminal amine with iodoacetic acid and then reacting it with any primary amine by referring to Organic Letters, 2010, 12, 4928-4931 or the like. Further, cyclic peptide compounds can be prepared by elongating, cleaving from the resin, cyclizing, deprotecting, and purifying the peptide according to the general peptide synthesis method described in the present Examples.

(Method of Preparing Peptides Containing an Aryloxy or Heteroaryloxy Group on the Side Chain)

Peptides containing an aryloxy or heteroaryloxy group on the side chain can be prepared according to the general peptide synthesis method described in the present Examples using an Fmoc amino acid having the target aryloxy or heteroaryloxy group on the side chain as a raw material, or alternatively can be prepared using a peptide having an alcohol on the side chain as a precursor by referring to Organic Letters, 2014, 16, 4944-4947, Tetrahedron Letters, 2003, 44, 3863-3865, or the like, as illustrated below. Specifically, peptides having an aryloxy or heteroaryloxy group on the side chain can be prepared by reacting a peptide having an alcohol on the side chain with triarylboroxane-pyridine complex in the presence of copper(II) acetate. n below represents the number of methylene groups and may be any integer of 1 or more.

Peptides having an ether group excluding an aryloxy or heteroaryloxy group on the side chain can be prepared according to the general peptide synthesis method described in the present Examples using an Fmoc amino acid having the target ether group on the side chain as a raw material, or alternatively can be prepared using a peptide having an alcohol on the side chain as a precursor by referring to the method described in Journal of Medicinal Chemistry, 2011, 54, 4815-4830 or Journal of Medicinal Chemistry, 2014, 57, 159-170, as illustrated below. Specifically, the peptides having the target ether group on the side chain can be prepared by reacting a peptide having an alcohol with an etherification agent (such as an alkyl halide) in the presence of silver(I) oxide, or by reacting a peptide having an alcohol with an etherification agent (such as an alkyl halide) using an aqueous sodium hydroxide solution as a base in the presence of a phase transfer catalyst such as a tetraalkylammonium salt.

(Method of Preparing Peptides Containing an Aryl or Heteroaryl Group on the Side Chain)

Peptides having an aryl or heteroaryl group on the side chain can be prepared according to the general peptide synthesis method described in the present Examples using an Fmoc amino acid having the target aryl or heteroaryl group on the side chain as a raw material, or alternatively can be prepared using a peptide having a carboxylic acid on the side chain as a precursor by referring to the method described in J. Am. Chem. Soc., 2016, 138, 5016-5019 or the like, as illustrated below. Specifically, the peptides having the target aryl or heteroaryl group on the side chain can be prepared by activating a peptide having a carboxylic acid on the side chain with N-hydroxyphthalimide, and reacting it with any aryl halide or heteroaryl halide. n below represents the number of methylene groups and may be any integer of 1 or more.

Alternatively, peptides having an aryl or heteroaryl group on the side chain can also be synthesized by Suzuki coupling using a peptide having a boronic acid on the side chain as a precursor, as illustrated below. Specifically, the target peptides having an aromatic ring on the side chain can be prepared by synthesizing a precursor peptide using an Fnmoc amino acid having a boronic acid on the side chain as a raw material and reacting it with any aryl halide in the presence of a palladium catalyst.

(Method of Preparing Peptides Containing an Amido Group on the Side Chain)

Peptides having an amido group on the side chain can be synthesized using an Fmoc amino acid having the target amido group on the side chain as a raw material, or alternatively can be synthesized by amidation of a peptide having a carboxylic acid on the side chain as a precursor, as illustrated below. Specifically, the target peptides having an amido group on the side chain can be obtained by deprotecting a peptide having a protected carboxylic acid on the side chain to synthesize a precursor peptide having a carboxylic acid on the side chain, and condensing it with any amine using a condensing agent such as HATU. n below represents the number of methylene groups and may be any integer of 1 or more.

(Synthesis of Peptides Containing a Double Bond on the Side Chain)

Peptides having a double bond on the side chain can be synthesized using an Fmoc amino acid having the target double bond on the side chain as a raw material, or alternatively can be prepared by functionalization of a terminal olefin. Specifically, a peptide having a terminal olefin on the side chain can be synthesized according to the general peptide synthesis method described in the present Examples, and the side chain can be further converted to a side chain having a highly substituted olefin by coupling with a substrate having any terminal olefin by olefin metathesis reaction. Further, the side chain can be converted to a corresponding side chain by reducing the olefin by hydrogenation reaction, n below represents the number of methylene groups and may be any integer of 1 or more.

Peptide compounds with a peptide backbone crosslinked can also be prepared using a peptide having multiple double bonds on the side chain. Specifically, crosslinked compounds can be prepared by synthesizing a peptide having terminal olefins at two sites on the side chain according to the general peptide synthesis method described in the present Examples, and further crosslinking the two olefins by olefin metathesis reaction by referring to Nature Protocols, 2011, 6, 761-771. Further, compounds crosslinked with saturated alkylenes can be prepared by reducing the olefins by hydrogenation reaction. m and n below represent the number of methylene groups and may be independently any integer of 1 or more.

(Synthesis of Peptides Containing a Triazole on the Side Chain)

Peptides having a triazole on the side chain can be prepared by click reaction with an azido group. Specifically, peptide compounds having an azido group on the side chain can be prepared by synthesizing a peptide having an azido group on the side chain according to the general peptide synthesis method described in the present Examples, and coupling the peptide with any acetylene in the presence of copper(I) iodide by referring to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 4130-4133 or the like. n below represents the number of methylene groups and may be any integer of 1 or more.

(Synthesis of Peptides Containing an Aryl Group Substituted with an Alkynyl Group on the Side Chain)

Peptides containing an aryl group substituted with an alkynyl group on the side chain can be synthesized by Sonogashira coupling reaction with an aryl halide group. Specifically, the conversion to peptide compounds having an aryl group substituted with an alkynyl group on the side chain can be conducted by synthesizing a peptide having an aryl iodide group on the side chain according to the general peptide synthesis method described in the present Examples, and coupling the peptide with any acetylene in the presence of copper(I) iodide. n below represents the number of methylene groups and may be any integer of 1 or more.

(General Preparation Methods for Non-Natural Amino Acids)

General preparation methods for C-terminal-free non-natural amino acids where the nitrogen atoms of the amino acids are protected are shown below. In the following schemes, PG₁ and PG₁′ each represent a protecting group for a nitrogen atom, PG₂ and PG₂′ each represent a protecting group for an oxygen atom, PG₃ and PG₄ each represent a protecting group for an amino acid side chain, R_n and Q_n each represent an amino acid side chain, P_n represents a substituent for a nitrogen atom, P′ represents C₁-C₅ alkyl, and R, R′, R″, and R′″ each represent a substituent for a hydrogen or amino group. In the methods of preparing amino acids shown below, a functional group other than the target functional group may cause chemical reaction. In such a case, only the desired reaction can be allowed to proceed by introducing a protecting group onto a non-target functional group. Examples of such protecting group introduction and removal reactions include methods described in Greene's “Protective Groups in Organic Synthesis” (5th ed., John Wiley & Sons 2014). For conversion reactions of compound functional groups, one can refer to Larock's “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” (5th ed.) or Smith's “March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” (8th ed.).

Non-natural amino acids having a protecting group (PG₁) introduced onto the amino acid nitrogen atom can be prepared using the following method. The target C-terminal-free non-natural amino acids can be prepared by introducing a protecting group onto an N-terminal-free amino acid available from a commercial supplier and deprotecting it as necessary according to conventional methods.

Non-natural amino acids having a protecting group (PG₁′) introduced onto the amino acid nitrogen atom can be prepared using the following method. The target C-terminal-free non-natural amino acids can be prepared by deprotecting an amino acid that has a protecting group (PG₁) introduced onto the N-terminus which is available from a commercial supplier, and introducing a protecting group, according to conventional methods.

Non-natural amino acids having an aminoalkyl group introduced onto the substituent (P,) of the amino acid nitrogen atom can be prepared using the following method. A bromoacetic acid ester derivative available from a commercial supplier is reacted with an amino alcohol according to the method of King et al. (Tetrahedron Letters, 2002, 43(11), 1987-1990), and then a protecting group (PG1) is introduced onto the nitrogen atom. Next, the hydroxyl group is oxidized according to the method of Dess et a. (J. Org. Chem., 1983, 48(22), 4155-4156), and the aldehyde group is reductively aminated according to the method of Borch et al. (J. Org. Chem. 1972, 37(10), 1673-1674) to introduce an amino group. Next, the target C-terminal-free non-natural amino acid can be prepared by deprotecting the protecting group for the oxygen atom.

N-substituted amino acids can also be prepared by the following scheme of introducing a substituent (P_n) onto the amino acid nitrogen atom. A bromoacetic acid ester derivative available, from a commercial supplier is reacted with an amine (P_nNH₂) in the, presence of a base, and then a protecting group (PG₁′) is introduced onto the nitrogen atom. Next, the target C-terminal-free non-natural amino acid can be prepared by deprotecting the protecting group for the oxygen atom.

Non-natural amino acids having a —CH₂—P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. An oxazolidinone compound having an introduced cyclic protecting group can be obtained by allowing an aldehyde to act on a C-terminal-free amino acid available from a commercial supplier according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.

Non-natural amino acids having a P_n group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. The P_n group can be introduced onto a commercially available C-terminal-free amino acid by allowing an alkylating agent (P_n—X) to act on it in the presence of a base. Next, a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.

Non-natural amino acids having an amido group introduced onto the amino acid side chain can be prepared according to the following scheme. An amido group can be introduced onto the side chain by deprotecting a commercially available protected amino acid (n=1 or 2) and allowing an amine (R″R′″NH) to act on the resulting carboxylic acid. Next, a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.

Non-natural amino acids having an amido group introduced onto the amino acid side chain and a —CH₂—P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. An oxazolidinone compound having an introduced cyclic protecting group can be obtained by allowing an aldehyde to act on a commercially available protected amino acid (n=1 or 2) according to the method of Freidinger et al. (J. Org. Chen., 1983, 48(1), 77-81). Next, an amide compound can be obtained by deprotecting the side-chain protecting group and then allowing an amine (R″R′″NH) to act on it. Next, the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.

Non-natural amino acids having an amino group introduced onto the amino acid side chain can be prepared according to the following scheme. An amido group can be introduced onto the side chain by allowing an amine (R″R′″NH) to act on the carboxyl group of a commercially available protected amino acid (n=1 or 2). Next, a C-terminal-free non-natural amino acid can be prepared by conducting reduction reaction according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52) and then deprotecting the C-terminal protecting group.

Non-natural amino acids having an amino group introduced onto the amino acid side chain and a —CH₂—P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. An amido group can be introduced onto the side chain by allowing an amine (R″R′″NH) to act on the carboxyl group of an amino acid protected by a cyclic protecting group (n=1 or 2). Next, the target C-terminal-free non-natural amino acid can be prepared by conducting reduction reaction according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52) and then performing ring-opening reaction.

Non-natural amino acids having a fluoroalkyl group introduced onto the amino acid side chain can be prepared according to the following scheme. The carboxyl group of a commercially available protected amino acid (n=1 or 2) can be reduced and converted to an aldehyde group according to a conventional method, and the aldehyde group can be converted to a difluoromethyl group by introducing a fluorine atom according to a conventional method. Next, a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.

Non-natural amino acids having a fluoroalkyl group introduced onto the amino acid side chain and a —CH₂—P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. The carboxyl group of an amino acid protected by a cyclic protecting group (n=1 or 2) can be reduced and converted to an aldehyde group according to a conventional method, and the aldehyde group can be converted to a difluoromethyl group by introducing a fluorine atom according to a conventional method. Next, a C-terminal-free non-natural amino acid can be prepared by ring-opening of the C-terminal cyclic protecting group.

C-terminal-free non-natural amino acids having a fluoroalkyl group introduced onto the amino acid side chain and a —CH₂—P′ group introduced onto the amino acid nitrogen atom can also be prepared by the method shown below.

Non-natural amino acids having an aryl or heteroaryl group (such groups are referred to as “Ar” in the scheme) introduced onto the amino acid side chain can be prepared according to the following scheme. An N-hydroxyphthalimide (NHPI) group can be introduced onto the side chain by allowing NHPI to act on the carboxyl group of a protected amino acid (n=1 or 2). A non-natural amino acid having an aryl or heteroaryl group introduced and possessing an aralkyl or heteroaralkyl group on the side chain can be prepared by allowing an aryl halide or heteroaryl halide to react according to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019). Next, a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.

Non-natural amino acids having an aryl or heteroaryl group (such groups are referred to as “Ar” in the scheme) introduced onto the amino acid side chain and having a —CH₂—P group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. An N-hydroxyphthalimide (NHPI) group can be introduced onto the side chain by allowing NHPI to act on the carboxyl group of an amino acid protected by a cyclic protecting group (n=1 or 2). A non-natural amino acid which has an aryl or heteroaryl group introduced, and has an aralkyl or heteroarylalkyl group on the side chain, and is protected by a cyclic protecting group, can be prepared by allowing an aryl halide or heteroaryl halide to react according to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019). Next, the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.

Non-natural amino acids having an aryl or heteroaryl group (such groups are referred to as “Ar” in the scheme) introduced onto the amino acid side chain can be prepared according to the following scheme. A non-natural amino acid having an aryl or heteroaryl group introduced and possessing an aralkyl or heteroaralkyl group on the side chain can be prepared by introducing a protecting group onto a commercially available protected amino group (n=0 or 1) and then allowing an aryl halide or heteroaryl halide to react according to the method of He et al. (Org. Lett. 2014, 16(24), 6488-6491). Next, the target C-terminal-free non-natural amino acid can be prepared by deprotection reaction and protecting group introduction reaction.

Non-natural amino acids having a halogen atom introduced onto the aralkyl group on the amino acid side chain can be prepared according to the following scheme. A boronic acid ester can be introduced onto the aralkyl group (n=1 to 3) which may have a substituent (Ra) on the amino acid side chain according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). A halogen atom can be introduced onto the introduced boryl group using N-halosuccinimide according to the method of Lindner et al. (Chem. Eur. J., 2016, 22, 13218-13235). The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.

Non-natural amino acids having a halogen atom introduced onto the aralkyl group of the amino acid side chain and a —CH₂—P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. A boronic acid ester can be introduced onto the aryl group of the amino acid having an aralkyl group (n=1 to 3) which may have a substituent (R_a) on the amino acid side chain according to the method of Ishiyama et al. (. Am. Chem. Soc. 2002, 124(3), 390-391). A halogen atom can be introduced onto the introduced boryl group using N-halosuccinimide according to the method of Lindner et al. (Chem. Eur. J., 2016, 22, 13218-13235). The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.

Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (R_bO) group on the amino acid side chain can be prepared according to the following scheme. A cyclized compound can be obtained according to the method of Mitsunobu et al. (Synthesis, 1981, 1, 1-28) after introducing a nosyl (Ns) group onto a commercially available serine derivative according to a conventional method. A serine ether compound can be obtained by ring-opening of the cyclized compound with a suitable alcohol (R_bOH) in the presence of a Lewis acid such as BF₃·OEt₂. The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.

Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (R_bO) group on the amino acid side chain can be prepared according to the following scheme. A serine ether compound can be obtained by ring-opening of a commercially available cyclic compound with a suitable alcohol (R_bOH) in the presence of a Lewis acid such as BF₃·OEt₂ according to a conventional method. The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.

Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (—OR_b) group on the amino acid side chain can be prepared according to the following scheme. A serine ether compound can be obtained by allowing an alkylating agent (R_b—X) to act on a commercially available serine derivative (n=1 or 2) in the presence of a suitable base according to the method of Williamson et al. (Liebigs Ann. Chem. 1851, 77, 37-49). When R_b has a further convertible functional group, Rb can be converted to a target functional group by additional functional group conversion. Examples of such additional functional group conversion include multiple bond reduction reaction. Next, the target C-terminal-free non-natural amino acid can be prepared by deprotecting the obtained non-natural amino acid.

Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (—OR_b) group on the amino acid side chain and having a group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. An oxazolidinone compound having a cyclic protecting group introduced can be obtained by allowing an aldehyde to act on a commercially available serine derivative or a serine derivative prepared by the above-described method (n=1 or 2) according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.

Non-natural amino acids having a protected hydroxy group on the amino acid side chain can be prepared according to the following scheme. The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from a commercially available serine derivative or a serine derivative prepared by the above-described method (n=1 or 2).

Non-natural amino acids having a protected hydroxy group on the amino acid side chain and a —CH₂—P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. An oxazolidinone compound having a cyclic protecting group introduced can be obtained by allowing an aldehyde to act on a commercially available serine derivative or a serine derivative prepared by the above-described method (n=1 or 2) according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction and protecting group introduction reaction.

Cyclic non-natural amino acids having a substituent (R_c) introduced onto the hydroxyl group of the cyclic amino acid can be prepared according to the following scheme. The hydroxy group of a commercially available cyclic amino acid can be converted to the target —OR_c group by appropriately introducing a functional group. As a reaction of converting the functional group, an ether bond can be produced by allowing an alkylating agent (R_c—X) to react in the presence of a suitable base according to the method of Williamson et al. (Liebigs Ann. Chem. 1851, 77, 37-49). When R_c has a further convertible functional group, Rr can be converted to a target functional group by additional functional group conversion. Next, the target C-terminal-free non-natural amino acid can be prepared by deprotection reaction.

Cyclic non-natural amino acids having a protecting group (PC₃) introduced onto the hydroxyl group of the cyclic amino acid can be prepared according to the following scheme. The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from a commercially available cyclic amino acid.

Non-natural amino acids having a boronic acid introduced onto the amino acid side chain can be prepared according to the following scheme. A non-natural amino acid having a boronic acid ester introduced can be obtained by allowing an aldehyde to act on a commercially available glycine derivative according to the method of Lee et al. (Bioorg. Med. Chem. Lett., 2009, 19(17), 4887-5274). Next, the target C-terminal-free non-natural amino acid can be prepared by appropriately introducing or removing a protecting group.

(Synthesis 1 of Fmoc Non-Natural Amino Acids Having a Carboxyl Group on the Side Chain)

Fmoc non-natural amino acids having a carboxyl group on the side chain can be prepared according to the following scheme. The main chain carboxyl group of a starting material which is available from a commercial supplier and has a side chain carboxyl group protected by PG₃ (n=1 or 2) can be converted to an amido group by condensing it with an amine (R″R′″NH) in the presence of a condensing agent such as DIC. Next, the target Fmoc non-natural amino acid having a carboxyl group on the side chain can be prepared by deprotecting PG₃.

(Synthesis 2 of Fmoc Non-Natural Amino Acids Having a Carboxyl Group on the Side Chain)

Fmoc non-natural amino acids having a carboxyl group on the side chain and a —CH₂—P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. The main chain carboxyl group of a starting material which is available from a commercial supplier and has a side chain carboxyl group protected by PG₃ (n=1 or 2) can be converted to an amido group by condensing it with an amine (R″R′″NH) in the presence of a condensing agent such as DIC. Next, the target Fmoc non-natural amino acid having a carboxyl group on the side chain can be prepared by deprotecting PG₃.

Non-natural amino acids (n=1 or 2) containing a thioether group on the side chain can be produced according to the following scheme. An amino acid having a protected side chain thiol group was subjected to carboxylic acid amidation, and following deprotection of the thiol group, halogenated acetic acid having a protected carboxylic acid was allowed to react to form a thioether bond. Next, the amino acid having a thioether group on the side chain can be produced by deprotecting the side chain carboxylic acid.

Peptides containing a thioether group on the peptide main chain can be produced by using as a raw material the aforementioned amino acid having a thioether group on the side chain, but alternatively, they can also be produced by the method of Roberts et al. in which an N-terminal bromoacetamide is reacted with a cysteine side chain (Tetrahedron Letters, 1998, 39, 8357-8360), or the method of Robey et al. in which an N-terminal chloroacetamide is reacted with a cysteine side chain (Journal of Peptide Research, 2000, 56, 115-120).

The compounds disclosed herein and salts thereof, and solvates thereof include all stereoisomers (such as enantiomers and diastereomers (including cis and trans geometric isomers)) of the target compounds obtained through the above-described reaction steps, and racemates and other mixtures of such isomers. For example, the compounds disclosed herein may have one or more asymmetric points, and the present invention encompasses racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

When the compounds according to the present invention are obtained as free forms, they can be converted to salts that may be formed by such compounds, or hydrates or solvates thereof, according to conventional methods.

When the compounds according to the present invention are obtained as salts, hydrates, or solvates of such compounds, they can be converted to free forms of such compounds according to conventional methods.

(Pharmaceutical Compositions, Medicaments, Therapeutic Agents, or Preventive Agents)

The present invention provides pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents containing the cyclic peptide compounds disclosed herein, salts of the cyclic peptide compounds, or solvates thereof.

The pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention may contain any of the cyclic peptide compounds disclosed herein, salts of the cyclic peptide compounds, or solvates thereof.

In one aspect, the pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention contain a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof:

wherein,

• • L₁ is a single bond, or —CHM₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)₂(CH₂)_m—, wherein n and m are each independently 1 or 2,
  • R₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkynl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₁-C₁ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or
  • R₁ and P₁, together with the carbon atom to which R₁ is attached and the nitrogen atom to which P₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and Q₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁ and M₁, together with the carbon atom to which R₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁ and P₁ form a 4- to 7-membered saturated heterocyclic ring, P₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁ and Q₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁ is hydrogen or C₁-C₆ alkyl, and
  • except when R₁ and M₁ form a 3- to 8-membered alicyclic ring, M₁ is hydrogen,
  • R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, or C₃-C₈ cycloalkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C₁-C₆ alkylsulfonyl, or
  • R₂ and P₂, together with the carbon atom to which R₂ is attached and the nitrogen atom to which P₂ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₂ and Q₂, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₂ and P₂ form a 4- to 7-membered saturated heterocyclic ring, P₂ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₂ and Q₂ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₂ is hydrogen or C₁-C₆ alkyl,
  • R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), or
  • R₃ and P₃, together with the carbon atom to which R₃ is attached and the nitrogen atom to which P₃ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₃ and Q₃, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₃ and P₃ form a 4- to 7-membered saturated heterocyclic ring, P₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C₁-C₆ aminoalkyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino is optionally substituted with one or more halogens),
  • except when R₃ and Q₃ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₃ is hydrogen or C₁-C₆ alkyl,
  • R₄ is hydrogen or C₁-C₆ alkyl, or
  • R₄ and P₄, together with the carbon atom to which R₄ is attached and the nitrogen atom to which P₄ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₄ and Q₄, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when RA and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂ mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₄ and Q₄. form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₄ is hydrogen or C₁-C₆ alkyl,
  • R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, C₇-C₁₄ aralkyl, C₆-C₁₀ aryloxyC₁-C₆alkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, and C₁-C₆ alkylsulfonyl, or R₅ together with R₈ forms C₄-C₈ alkylene, or
  • R₅ and P₅, together with the carbon atom to which R₅ is attached and the nitrogen atom to which P₅ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₅ and Q₅, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₅ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₅ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₅ and Q₅ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₅ is hydrogen or C₁-C₆ alkyl,
  • R₆ is hydrogen or C₁-C₆ alkyl, or
  • R₆ and P₅, together with the carbon atom to which R₆ is attached and the nitrogen atom to which P₆ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₆ and Q₆, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₆ and P₆ form a 4- to 7-membered saturated heterocyclic ring, P₆ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₆ and Q₆ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₆ is hydrogen or C₁-C₆ alkyl,
  • R₇ is C₆-C₁₀ aryloxyC₁-C₆ alkyl, C₇-C₁, aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, C₁-C₆ alkylsulfonyl, and SF₅, or
  • R₇ and P₇, together with the carbon atom to which R; is attached and the nitrogen atom to which P₇ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₇ and Q₇, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₇ and P₇ form a 4- to 7-membered saturated heterocyclic ring, P₇ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₇ and Q₇ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₇ is hydrogen or C₁-C₆ alkyl,
  • R₈ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyloxycarbonylC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylC₁-C₆ alkyl, C₆-C₁c aryloxyC₁-C₆ alkyl, C₁-C₁₄ aralkyl, C₇-C₁₄ aralkoxyC₁-C₆ alkyl, 5- to 10-membered heteroarylC₁-C₆ alkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, cyano, amino (wherein the amino is —NH₂, protected amino, mono-C₁-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkylidene, protected 4- to 7-membered heterocycloalkylidene, 4- to 7-membered heterocyclyl, and protected 4- to 7-membered heterocyclyl, or R₅ together with R₅ forms C₄-C₈ alkylene, or
  • R₈ and P₈, together with the carbon atom to which R₈ is attached and the nitrogen atom to which P₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS₈, and S₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₇-C₁₄ aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy), or 5- to 10-membered heteroarylC₁-C₆ alkyl, or
  • R₈ and Q₈, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₅ and P₅ form a 4- to 7-membered saturated heterocyclic ring, P₅ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆alkoxyC₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC₁-C₆ alkyl, C₆-C₁₀ aryl, C₇-C₁₄ aralkyl, 5- to 1-membered heteroaryl, or 5- to 10-membered heteroarylC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen or C₁-C₆ alkyl), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆, alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₅ and Q₅ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₅ is hydrogen or C₁-C₆ alkyl,
  • R₉ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₇-C₁₄ aralkyl, or 5- to 10-membered heteroarylC₁-C₆ alkoxyC₁-C₆ alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, aminocarbonyl (wherein the amino is —NH—, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₀ alkylsulfonyl, or
  • R₉ and P₉, together with the carbon atom to which R₉ is attached and the nitrogen atom to which P₉ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₉ and P₉ form a 4- to 7-membered saturated heterocyclic ring, P₉ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₉ and Q₉ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₉ is hydrogen or C₁-C₆ alkyl,
  • R₁₀ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkoxyC₁-C₆ alkyl, or C₇-C₁₄ aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C₁-C₆alkylsulfonyl, or
  • R₁₀ and P₁₀, together with the carbon atom to which R₁₀ is attached and the nitrogen atom to which P₁₀ is attached, form a 4- to 7-membered saturated heterocyclic ring, or R₁₀ and Q₁₀, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • except when R₁₀ and P₁₀ form a 4- to 7-membered saturated heterocyclic ring, P₁₀ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₀ and Q₁₀ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₀ is hydrogen or C₁-C₆ alkyl, and
  • L₁₁ is a single bond, or —CHM₁₁-, —(CH₄)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)2(CH₂)_m—, wherein n and m are each independently 1 or 2,
  • R₁₁ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₇-C₄ aralkyl, or aminocarbonyl (wherein the amino is —NH₂, mono C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C₁-C₆ alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino), and C₁-C₆ alkylsulfonyl, or R₁₁ is a peptide chain containing 1 to 4 amino acid residues, or
  • R₁₁ and P₁₁, together with the carbon atom to which R₁ is attached and the nitrogen atom 5 to which P₁₁ is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and Q₁₁, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R₁₁ and M₁₁, together with the carbon atom to which R₁₁ is attached and the carbon atom to which M₁ is attached, form a 3- to 8-membered alicyclic ring,
  • except when R₁₁ and P₁₁ form a 4- to 7-membered saturated heterocyclic ring, P₁₁ is hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkoxy, amino (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or 4- to 8-membered cyclic amino),
  • except when R₁₁ and Q₁₁ form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q₁₁ is hydrogen or C₁-C₆ alkyl,
  • except when R₁₁ and M₁₁ form a 3- to 8-membered alicyclic ring, M₁₁ is hydrogen,
  • wherein, when L₁ is a single bond, L₁₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)2(CH₂)_m—, and when L₁ is —CHM₁₁-, —(CH₂)_nS(CH₂)_m—, —(CH₂)_nS(O)(CH₂)_m—, or —(CH₂)_nS(O)2(CH₂)_m—, L₁₁ is a single bond, and
  • at least three of P₁₁ to P₁₁ are not hydrogen.

In one aspect, the pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention contain a cyclic peptide compound or salt thereof, or solvate thereof, selected from the group consisting of cyclic peptide compounds set forth in Table 39.

In one aspect, the pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention contain a cyclic peptide compound represented by formula (2) below or a salt thereof, or a solvate thereof:

wherein,

• • R₁ is C₁-C₆ alkyl,
  • P₁ is C₁-C₆ alkyl,
  • R₂ is C₁-C₆ alkyl,
  • P₂ is hydrogen,
  • R₃ is hydrogen or C₁-C₆ alkyl,
  • P₃ is C₁-C₆ alkyl,
  • R₄ is hydrogen, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • except when R₄ and P₄ form a 4- to 7-membered saturated heterocyclic ring, P₄ is C₁-C₆ alkyl,
  • R₅ is C₃-C₈ cycloalkylC₁-C₆ alkyl or C₇-C₁₄ aralkyl optionally substituted with C₁-C₆ alkyl,
  • P₅ is C₁-C₆ alkyl,
  • R₆ is hydrogen,
  • P₆ is C₁-C₆ alkyl,
  • R₇ is C₇-C₁₄ aralkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and C₁-C₆ haloalkyl,
  • Q₇ is hydrogen,
  • P₇ is hydrogen,
  • R₈ and P₈, together with the nitrogen atom to which P₅ is attached and the carbon atom to which R₈ is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with C₁-C₆ alkoxy,
  • R₉ and Q₉, together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring,
  • P₉ is hydrogen,
  • R₁₀ is C₃-C₈ cycloalkyl,
  • P₁₀ is C₁-C₆ alkyl,
  • R₁₁ is di-C₁-C₆ alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl,
  • M₁₁ is hydrogen, and
  • P₁₁ is C₁-C₆ alkyl.

As for R₁ in formula (2), methyl, ethyl, i-propyl, n-propyl, 2-methylpropyl, 1-methylpropyl, n-butyl, n-hexyl, 3-methylbutyl, 2-methylbutyl, or n-pentyl is preferable, and 2-methylpropyl is more preferable.

As for P₁ in formula (2), hydrogen, methyl, ethyl, or n-propyl is preferable, and methyl is more preferable.

As for R₂ in formula (2), methyl, ethyl, i-propyl, n-propyl, 2-methylpropyl, 1-methylpropyl, n-butyl, n-hexyl, 3-methylbutyl, 2-methylbutyl, or n-pentyl is preferable, and 1-methylpropyl is more preferable.

As for R₃ in formula (2), hydrogen, methyl, ethyl, i-propyl, n-propyl, 2-methylpropyl, 1-methylpropyl, n-butyl, n-hexyl, 3-methylbutyl, 2-methylbutyl, or n-pentyl is preferable, and hydrogen or methyl is more preferable.

As for P₃ in formula (2), hydrogen, methyl, ethyl, or n-propyl is preferable, and methyl is more preferable.

In formula (2), it is preferable that R₄ be hydrogen and P₄ be hydrogen, methyl, ethyl, or n-propyl, and it is more preferable that R₁ be hydrogen and P₄ be methyl. Alternatively, in formula (2), it is preferable that R₄ and P₄., together with the nitrogen atom to which P₄ is attached and the carbon atom to which R₄ is attached, form an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring, and it is more preferable that they form an azetidine ring.

As for R_z in formula (2), C₃-C₆ cycloalkoxyC₁-C₂ alkyl, or benzyl or phenethyl optionally substituted with one or more halogens, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyano is preferable, and cyclohexylmethyl or 4-methylbenzyl is more preferable.

As for P₅ in formula (2), hydrogen, methyl, ethyl, or n-propyl is preferable, and methyl or ethyl is more preferable.

As for P₆ in formula (2), hydrogen, methyl, ethyl, or n-propyl is preferable, and methyl is more preferable.

As for R₂ in formula (2), phenethyl or benzyl substituted with one to three groups independently selected from the group consisting of fluorine, chlorine, iodine, and C₁-C₃ fluoroalkyl is preferable, and phenethyl substituted with one or two fluorines or one or two chlorines and one trifluoromethyl is more preferable. Also, when benzyl or phenethyl has a substituent, it is preferable that it have a substituent on its phenyl group.

In formula (2), it is preferable that R₅ and P₈, together with the nitrogen atom to which P₅ is attached and the carbon atom to which R₈ is attached, form an azetidine ring, a pyrrolidine ring, or a piperidine ring, and it is more preferable that they form a pyrrolidine ring. It is preferable that the pyrrolidine ring be either unsubstituted or substituted with C₁-C₃ alkoxy, and it is more preferable that the pyrrolidine ring be either unsubstituted or substituted with ethoxy.

In formula (2), it is preferable that R₉ and Q₅, together with the carbon atom to which they are attached, form a 3- to 6-membered alicyclic ring, and it is more preferable that they form a cyclopentane ring.

As for R₁₀ in formula (2), C₃-C₆ cycloalkyl is preferable, and cyclopentyl or cyclohexyl is more preferable.

As for P₁₀ in formula (2), methyl, ethyl, or n-propyl is preferable, and methyl is more preferable.

As for R₁₁ in formula (2), di-C₁-C₃ alkylaminocarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, or 4-morpholinylcarbonyl is preferable, and dimethylaminocarbonyl, piperidinylcarbonyl, or 4-morpholinylcarbonyl is more preferable.

As for P₁, in formula (2), methyl, ethyl, or n-propyl is preferable, and methyl is more preferable.

In one aspect, the pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention contain a cyclic peptide compound represented by formula below or a salt thereof, or a solvate thereof:

wherein,

• • R₃ is hydrogen or methyl,
  • R₄ is hydrogen and P₄ is methyl, or
  • R₄ and P₄, together with the nitrogen atom to which P₄ is attached and the carbon atom to which R_j is attached, form an azetidine ring,
  • R₅ is cyclohexylmethyl or 4-methylbenzyl,
  • P₅ is methyl or ethyl,
  • R_7A, R_7B, and R_7C are independently selected from the group consisting of hydrogen, fluorine, chlorine, and trifluoromethyl,
  • R_8A is hydrogen or ethoxy,
  • R₁₀ is cyclopentyl or cyclohexyl, and
  • R_11A and R_11B are both methyl, or R_11A and R_11B, together with the nitrogen atom to which they are attached, form a piperidine ring or a morpholine ring.

In one aspect, the pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention contain a cyclic peptide compound or salt thereof, or solvate thereof, selected from the group consisting of:

• (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-1l-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (1201) (5S,8S,11S,1S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexymethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,
• (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, and
• (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

The pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention can be formulated by introducing a pharmaceutically acceptable carrier, in addition to the cyclic peptide compound of the present invention, a salt of the cyclic peptide compound, or a solvate thereof by conventional methods. Commonly used excipients, binders, lubricants, colorants, correctives, and as necessary, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, and the like can be used for formulation, and they are blended with ingredients generally used as raw materials of pharmaceutical formulations, and formulated by conventional methods.

For example, oral formulations are prepared by adding the cyclic peptide compound disclosed herein or a salt thereof, and an excipient, and as necessary, a binder, a disintegrant, a lubricant, a colorant, a corrective, and the like, and then formulating them into powder, fine granules, granules, tablets, coated tablets, capsules, and the like by a conventional method.

The pharmaceutically acceptable carrier refers to an ingredient other than the active ingredient in the pharmaceutical composition that is non-toxic to the subject (preferred embodiments thereof include mammals, including humans). Examples of the pharmaceutically acceptable carrier include, but are not limited to, buffers, excipients, stabilizers, and/or preservatives.

Examples of these ingredients include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resin; silicone oil; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate, and aluminum silicate; and purified water.

Examples of the excipients include lactose, corn starch, white soft sugar, glucose, mannitol, sorbitol, microcrystalline cellulose, and silicon dioxide.

Examples of the binders include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer, and meglumine.

Examples of the disintegrants include starch, agar, gelatin powder, microcrystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium.

Examples of the lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.

For colorants, those approved as additives to pharmaceuticals are used. For correctives, cocoa powder, peppermint camphor, empasm, mentha oil, borneol, powdered cinnamon bark, and the like are used.

Obviously, these tablets and granules may be sugar-coated or otherwise coated appropriately as necessary. When liquid formulations such as syrups and injectable formulations are prepared, they are formulated by adding pH adjusters, solubilizers, tonicity adjusting agents, and the like, and as necessary, solubilizing agents, stabilizers, and the like to the compounds according to the present invention or pharmacologically acceptable salts thereof using conventional methods.

The compounds disclosed herein may be incorporated into microcapsules prepared, for example, by droplet formation (coacervation) methods or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin microcapsules, and poly(methyl methacrylate) microcapsules, respectively), may be incorporated into colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or may be incorporated into macroemulsions. Such methods are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

The compounds disclosed herein may be prepared as sustained release formulations. Suitable examples of the sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing the compounds disclosed herein, said matrices being in the form of a shaped article, such as a film or a microcapsule, for example.

The compound disclosed herein, for example, the pharmaceutical compositions can be parenterally used in the form of injectable sterile solutions or suspensions with water or other pharmaceutically acceptable liquids. For example, they would be formulated by appropriately combining with pharmacologically acceptable carriers or media, specifically, sterile water, saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, or binders, and blending in unit dosage forms required in generally approved formulation. Specifically, carriers may include light anhydrous silicic acid, lactose, microcrystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, white soft sugar, carboxymethylcellulose, corn starch, and inorganic salts. The amount of the active ingredient in such a formulation is designed to provide a suitable dose within an indicated range.

Sterile compositions for injection can be formulated in a conventional formulation manner using a vehicle such as distilled water for injection.

Aqueous solutions for injection include, for example, isotonic solutions containing saline, glucose, and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may be used in combination with appropriate solubilizers, for example, alcohols, specifically, ethanol, polyalcohols, e.g., propylene glycol or polyethylene glycol, and nonionic surfactants, e.g., polysorbate 80 (registered trademark) or HCO-50.

Oily liquids include sesame oil and soybean oil, and may be used in combination with benzyl benzoate and benzyl alcohol as solubilizers. They may also be blended with buffering agents such as phosphate buffer and sodium acetate buffer; analgesics such as procaine hydrochloride; stabilizers such as benzyl alcohol and phenol; and antioxidants. Prepared injections are usually packed in suitable ampoules.

The administration method is preferably oral administration, but is not limited thereto. Specific examples of parenteral administration include dosage forms of injection, nasal administration, pulmonary administration, and transdermal administration. Examples of injection dosage forms include systemic or local administration by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc.

The administration method can also be selected according to the age and symptom of the patient. The dosage of the pharmaceutical composition, medicament, therapeutic agent, or preventive agent containing the peptide compound prepared by the method of the present invention can be selected, for example, in the range of 0.001 mg to 100 mg per kg body weight per dose. Alternatively, the dosage can be selected, for example, in the range of 0.1 to 1000 mg/body per patient; however, it is not necessarily limited to such values. The dosage and the administration method vary according to the body weight, the age, the symptom, and the like of the patient, but can be appropriately selected by those skilled in the art.

In an embodiment, the compounds disclosed herein can be used for inhibiting binding between Ras and other signaling molecules (for example, binding between Ras and SOS), thereby inhibiting intracellular signaling. In this case, the compounds disclosed herein can be referred to as “Ras inhibitors”. Also, if Ras is Kras protein, the compounds disclosed herein can be referred to as “Kras inhibitors”; if Ras is Nras protein, the compounds disclosed herein can be referred to as “Nras inhibitors”; and if Ras is 1-ras protein, the compounds disclosed herein can be referred to as “Hras inhibitors”. In an embodiment, pharmaceutical compositions containing the compounds disclosed herein can be referred to as “Ras inhibitors”. In a further embodiment, the compounds disclosed herein can be referred to as “Kras inhibitors”, “Nras inhibitors”, or “Bras inhibitors”.

In an embodiment, the pharmaceutical compositions, medicaments, and therapeutic agents or preventive agents of the present invention can be used for treating or preventing cancer in the subject (preferred embodiments thereof include mammals, including humans).

As used herein, “treatment” (and its grammatical derivatives, such as “to treat” and “treating”) means a clinical intervention intended to alter the natural course of the subject to be treated and may be performed both for prevention and during the course of the clinical condition. Desired effects of treatment include, but are not limited to, prevention of disease occurrence or recurrence, relief of symptoms, attenuation of any direct or indirect pathological effects due to the disease, prevention of metastasis, reduction in the rate of disease progression, recovery or alleviation of disease status, and remission or improved prognosis. In some embodiments, the compounds disclosed herein are used to delay the onset of disease or slow the disease progression.

As used herein, “cancer” and “cancerous” refer to or describe physiological conditions in mammals that are typically characterized by unregulated cell growth/proliferation. Examples of the cancer include solid cancer and hematological cancer. Further examples of the cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias. More detailed examples of such cancer include lung cancer, esophageal cancer, thyroid cancer, gastric cancer, liver cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, kidney cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma. Further detailed examples of such cancer include brain tumor, squamous cell cancer, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cancer of the lung, cancer of the peritoneum, hepatocellular cancer, cancer of the gastrointestinal tract, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, endometrial cancer, uterine body cancer, cervical cancer, salivary gland cancer, renal cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymnphoma, non-Hodgkin lymphoma, and other lymphoproliferative disorders, as well as various types of head and neck cancer. In one embodiment, “cancer” may be any cancer except pancreatic cancer.

As used herein, “cell proliferative disorder” and “proliferative disorder” refer to a disorder associated with a certain degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer.

As used herein, “tumor” refers to all neoplastic cell growth and proliferation, and all precancerous and cancerous cells and tissues, whether malignant or benign. As used herein, the terms “cancer”, “cancerous”, “cell proliferative disorder”, “proliferative disorder”, and “tumor” are not mutually exclusive.

In one aspect, the cancer includes cancer associated with an abnormality of a Ras gene. The cancer associated with an abnormality of a Ras gene refers to cancer in which, for example, cancer cells have a mutation in the coding region of the Ras gene and/or an amplification of the copy number of the Ras gene, and increased Ras activity (including increased generation of a Ras protein) is observed. The mutation in the coding region of the Ras gene refers to, for example, one or more base deletions, additions, or substitutions in the Ras gene coding region. The amplification of the copy number of the Ras gene refers to the presence of a larger copy number of the Ras gene than the copy number of the Ras gene normally present on the chromosome. The larger copy number means a larger copy number compared to normal cells, and it can be said that the copy number is amplified if the copy number is four or more.

Whether or not cancer is cancer associated with an abnormality of a Ras gene can be determined by checking whether or not the subject suffering from the cancer has an abnormality of the Ras gene. For example, by identifying the presence of a mutation in the base sequence of the coding region of the Ras gene in a biological sample obtained from the subject suffering from cancer, and further checking that a mutated Ras protein is expressed, it is possible to determine that the cancer is cancer associated with an abnormality of the Ras gene.

Also, whether or not cancer is cancer associated with an abnormality of the Ras gene can be determined by checking whether or not the subject suffering from the cancer has an amplification of the copy number of the Ras gene. For example, by checking that the copy number of the Ras gene is amplified and/or generation of the Ras protein is increased in a biological sample obtained from the subject suffering from cancer, it is possible to determine that the cancer is cancer associated with an abnormality of the Ras gene. Increased generation of the Ras protein can also be referred to as overexpression of the Ras protein. Whether or not generation of the Ras protein is increased can be checked by, for example, comparing the expression level of the Ras protein in general with the expression level of the Ras protein in a subject not suffering from the cancer or the expression level of the Ras protein in the subject before he or she developed the cancer.

Furthermore, if there is a mutation in the base sequence of the coding region of the Ras gene in the subject suffering from cancer and the copy number of the Ras gene is amplified, it can also be said that the cancer is associated with an abnormality of the Ras gene.

Any method that can detect a mutation in the coding region of the Ras gene or an amplification of the copy number of the Ras gene in a biological sample of the subject suffering from cancer can be used, and it can be carried out as is customary by those skilled in the art. For example, the Ras gene may be isolated from a biological sample obtained from the subject suffering from cancer, amplified by PCR or other means, and its base sequence may be directly determined by a sequencer or other means. Alternatively, commercially available extracorporeal diagnostic drugs that can detect a mutation of the Ras gene may be used, for example.

Three isoforms of the Ras protein are known: Kras protein, Nras protein, and Hras protein.

In one aspect, the Ras gene is one or more Ras genes selected from the group consisting of Kras gene, Nras gene, and Hras gene. Preferably, the Ras gene is Kras gene.

In one aspect, the cancer includes cancer associated with generation of a mutant Ras protein and/or increased generation of a Ras protein. The generation of a mutant Ras protein and/or increased generation of a Ras protein is normally attributed to the abnormality of the Ras gene mentioned above.

In one aspect, the mutant Ras protein is one or more mutant Ras proteins selected from the group consisting of mutant Kras proteins, mutant Nras proteins, and mutant liras proteins. Preferably, the mutant Ras protein is a mutant Kras protein.

In one aspect, the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequence of human wild-type Kras (SEQ ID No: 6), the amino acid sequence of human wild-type Nras (SEQ ID No: 7), or the amino acid sequence of human wild-type Hras (SEQ ID No: 8). In any of the amino acid sequences of human wild-type Kras, Nras, and Hras, the 12th and 13th amino acids are glycine and the 61st amino acid is glutamine.

In one aspect, the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence of wild-type Kras set forth in SEQ ID No: 6.

In one aspect, the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L as compared to the amino acid sequence of wild-type Nras set forth in SEQ ID No: 7.

In one aspect, the mutant Ras protein is a mutant Hras protein and has an amino acid mutation of G13R as compared to the amino acid sequence of wild-type Bras set forth in SEQ ID No: 8.

As used herein, “subject”, “individual”, or “test object” includes mammals. Examples of the mammals include, but are not limited to, domestic animals (for example, cows, sheep, cats, dogs, and horses), primates (for example, humans, and non-human primates such as monkeys), rabbits, and rodents (for example, mice and rats). The mammals are preferably humans.

The term “package insert” is used to refer to the instructions for use that are normally included in the commercial packages of therapeutic products and include information on indications, directions for use, dosage, administration methods, combination therapy, contraindications, and/or warnings regarding the use of such therapeutic products.

(Use of Compounds for Therapeutic Agents, Inhibitors, Methods of Inhibition, Therapeutic Compounds, Methods of Treatment, and Production of Medicaments)

In one aspect, the compounds disclosed herein may be used in therapeutic or preventive methods.

In one aspect, the compounds disclosed herein can be used as therapeutic agents or preventive agents for a disease, preferably cancer, in a subject.

In a further aspect, the compounds disclosed herein are provided for use in treatment or prevention of a disease, preferably cancer.

In one aspect, the present invention provides methods for treating a disease, preferably cancer. In one embodiment, the methods include a step of administering to a subject having such a disease, preferably cancer, an effective amount of the compounds disclosed herein.

In one aspect, the present invention provides use of the compounds disclosed herein in the manufacture or preparation of medicaments. In one embodiment, the medicaments are for treatment or prevention of a disease, preferably cancer. In a further embodiment, the medicaments are for use in methods for treating or preventing a disease, preferably cancer, the methods including a step of administering to a subject having cancer, an effective amount of the compounds disclosed herein.

In one aspect, the present invention provides methods for treating a subject having a disease, preferably cancer, the methods including a step of administering to the subject an effective amount of the compounds disclosed herein.

In one aspect, the compounds disclosed herein are provided for use as medicaments. In a further aspect, the compounds disclosed herein are provided for use in treatment of a disease, preferably cancer.

In one aspect, the compounds disclosed herein can be used as inhibitors of Ras in a subject. In one embodiment, examples of inhibition of Ras include inhibiting binding between Ras and other signaling molecules (for example, binding between Ras and SOS), thereby inhibiting intracellular signaling.

In one aspect, the present invention provides methods for inhibiting Ras in a subject. In one embodiment, the methods include a step of administering to a subject an effective amount of the compounds disclosed herein, for inhibiting Ras. In one embodiment, examples of inhibition of Ras include inhibition of binding between Ras and SOS.

In a further embodiment, the present invention provides the compounds disclosed herein for use in inhibition of Ras. In a specific embodiment, the present invention provides the compounds disclosed herein for use in methods including, for inhibition of Ras in a subject, a step of administering to the subject an effective amount of the compounds disclosed herein. The “subject” according to any of the above embodiments is suitably a human. Examples of inhibition of Ras include inhibition of binding between Ras and SOS.

(Combination Agents and Combination Therapy)

The compounds disclosed herein may be used either alone or in combination with other agents. In one aspect, the above-mentioned embodiments of use and methods further include a step of administering to a subject an effective amount of at least one additional therapeutic agent. For example, the compounds disclosed herein may be administered simultaneously with at least one additional therapeutic agent.

The combination therapy as mentioned above encompass combined administration (two or more therapeutic agents are included in the same formulation or separate formulations) and individual administration, and in the case of individual administration, administration of the compounds disclosed herein may precede, coincide with, and/or follow administration of additional therapeutic agents. In one embodiment, administration of the compounds disclosed herein and administration of additional therapeutic agents are performed within about one month, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days, of each other. The compounds disclosed herein may also be used in combination with radiation therapy.

The compounds disclosed herein (and any additional therapeutic agents) may be administered by any suitable means, including parenteral administration, pulmonary administration, and transnasal administration, as well as intralesional administration if desired for topical treatments. The parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing may be made through any suitable route, such as by injection including intravenous injection or subcutaneous injection, depending in part on whether the administration is short-term or long-term. Various dosing schedules are within the consideration herein, including, but not limited to, single administration, or repeated administration, bolus administration, and pulse infusion over various time points.

The compounds disclosed herein are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered from this viewpoint include specific disorders being treated, specific mammals being treated, the clinical presentation of individual patients, the cause of disorders, sites to which the agent is delivered, administration methods, schedules of administration, and other factors known to medical practitioners. The compounds are optionally, though not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of the compounds present in the formulation, the type of disorder or treatment, and other factors discussed above. They are normally used at the same dosage and via the same administration route as mentioned herein, or at about 1 to 99% of the dosage mentioned herein, or at any dosage and via any route deemed empirically/clinically appropriate.

The “effective amount” of certain agents, the compounds disclosed herein, and the pharmaceutical products of the present invention refers to the amount, at the required dosage and over the required period of time, that is effective to achieve the desired therapeutic or preventive results.

(In Vitro and In Vivo Measurements of Inhibition of Cell Proliferation and Tumor Growth)

In a specific embodiment, the compounds disclosed herein are tested for their ability to inhibit cell growth or proliferation in vitro. Methods for measuring inhibition of cell growth or proliferation are well known in the art. The cell viability is measured by specific cell proliferation measurement methods, exemplified by the “cell killing” measurement methods described herein. One of such measurement methods is the CellTiter-Glo™ Luminescent Cell Viability Assay, commercially available from Promega Corporation (Madison, WI). Such a measurement method determines the number of viable cells in the culture based on the amount of ATP present, which is an indicator of metabolically active cells. See Crouch et al., (1993) J. Immunol. Meth. 160: 81-88, U.S. Pat. No. 6,602,677. The measurement method may be performed in 96- or 384-well format, which allows for automated high-throughput screening (ITS). See Cree et al., (1995) AntiCancer Drugs 6: 398-404. The assay procedures include adding a single reagent (CellTiter-Glo® reagent) directly to cultured cells. This lyses the cells, and the luciferase reaction produces luminescent signals. The luminescent signals are proportional to the amount of ATP present, which is directly proportional to the number of viable cells present in the culture. The data can be recorded by a luminometer or CCD camera imaging apparatus. The luminescence value is expressed in relative light units (RLU).

Another cell proliferation measurement method is the “MTT” assay, which is a colorimetric determination method that measures oxidation of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to formazan by mitochondrial reductase. Similar to the CellTiter-Glo™ assay, this measurement method indicates the number of metabolically active cells present in the cell culture. See, for example, Mosmann (1983) J. Immunol. Meth. 65: 55-63 and Zhang et al., (2005) Cancer Res. 65: 3877-3882.

In one aspect, the compounds disclosed herein are tested for their ability to induce cell death in vitro. Methods for measuring induction of cell death are well known in the art. In some embodiments, such measurement methods measure loss of membrane integrity, as indicated by, for example, uptake of propidium iodide (PI), trypan blue (see Moore et al., (1995) Cytotechnology, 17: 1-11), or 7AAD. In an exemplary PI uptake measurement method, cells are cultured in Dulbecco's modified Eagle medium (D-MEM):Ham's F-12 (50:50) supplemented with 10% heat-inactivated FBS (Hyclone) and 2 mM L-glutamine. Accordingly, the measurement method is carried out in the absence of complements and immune effector cells. The cells are seeded in 100×20 mm dishes at a density of 3×10⁶ cells per dish and allowed to adhere overnight. The culture medium is removed and replaced with a fresh culture medium alone or with a culture medium containing various concentrations of the compounds. The cells are incubated for three days. After the treatment, the monolayer is washed with PBS and peeled off by a trypsin treatment. Next, for removal of cell aggregates, the cells are centrifuged at 4° C., at 1200 rpm for 5 minutes, the pellets are resuspended in 3 ml of cold Ca²⁺ binding buffer (10 n M Hepes, pH 7.4, 140 mM NaCl, 2.5 mM CaCl₂), which is then divided into 12×75 mm test tubes with 35 mm strainer caps (1 ml per test tube, three test tubes per treatment group). Next, PI (10 μg/ml) is added to the test tubes. The samples are analyzed using the FACSCAN™ flow cytometer and the FACSCONVERT™ CellQuest software (Becton Dickinson). In this way, compounds that induce statistically significant levels of cell death, as determined by PI uptake, are identified.

In one aspect, the compounds disclosed herein are tested for their ability to induce apoptosis (programmed cell death) in vitro. An exemplary measurement method for compounds that induce apoptosis is an annexin binding assay. In an exemplary annexin binding assay, cells are cultured and seeded in dishes, as discussed in the previous paragraph. The culture medium is removed and replaced with a fresh culture medium alone or with a culture medium containing 0.001 to 10 μg/ml of the compounds. After an incubation period of three days, the monolayer is washed with PBS and peeled off by a trypsin treatment. Next, the cells are centrifuged as discussed in the previous paragraph, resuspended in Ca²⁺ binding buffer, and divided into test tubes. Next, labeled annexin (for example, annexin V-FITC) (1 μg/ml) is added to the test tubes. The samples are analyzed using the FACSCAN™ flow cytometer and the FACSCONVERT™ CellQuest software (Becton Dickinson). In this way, compounds that induce statistically significant levels of annexin binding relative to the control are identified. Another exemplary measurement method for compounds that induce apoptosis is a Histone DNA ELISA colorimetric assay that detects intranucleosomic degradation of genomic DNA. Such a measurement method can be performed using, for example, the Cell Death Detection ELISA Kit (Roche, Palo Alto, CA).

Cells used in any of the above in vitro measurement methods include cells or cell lines that naturally express Ras proteins or mutant Ras proteins or that have been engineered to express Ras proteins or mutant Ras proteins. Such cells include tumor cells that overexpress Ras proteins or mutant Ras proteins compared to normal cells of the same tissue origin. Such cells also include cell lines (including tumor cell lines) that express Ras proteins or mutant Ras proteins, and cell lines that do not normally express Ras proteins or mutant Ras proteins but have been transfected with nucleic acids encoding Ras proteins or mutant Ras proteins. Exemplary cell lines disclosed herein that can be used in any of the above in vitro measurement methods include A549, AGS, SNU-1, SK-COH, HCC-44, NCI-H2122, LS 180, NCI-H1792, AsPC-1, NCI-H441, MIA PaCa-2, NCI-H358, FAMPAC, UM-UC-3, HPAC, NCI-H1373, NCI-H2009, NCI-H1944, HLC-1, KP4, LS513, NCI-H23, NCI-H2030, SW403, NCI-H460, LS 174T, SW480, HCC-1171, DLD-1, RERF-LC-Ad2, LoVo, NOMOH, HCT116, NCI-H1385, CFPAC-1, SK-LU-1, Calu-6, HEC-50B, PANC-1, A4/Fuk, KE-39, KURAMOCHI, MKN-1, COR-L23, HuG1-N, T.T, DMS 53, KLE, TYK-nu, PA-1, HEC-151, KMM-1, NCI-H929, AML-193, IPC-298, SK-MEL-30, MOLT-4, and C-643. These cell lines can be purchased from commercial suppliers if one is skilled in the art, but the cells used are not limited to these cell lines. For example, cells to which mutant Ras has been artificially introduced or cells into which Ras has been amplified can be used.

In one aspect, the compounds disclosed herein are tested for their ability to inhibit cell growth or proliferation in vivo. In a specific embodiment, the compounds disclosed herein are tested for their ability to inhibit tumor growth in vivo. In vivo model systems, such as xenograft models, can be used for such a test. In an exemplary xenograft system, human tumor cells are introduced into non-human animals that have been appropriately rendered immunodeficient, such as athymic “nude” mice. The compounds disclosed herein are administered to these animals. The ability of the compounds to inhibit or reduce tumor growth is measured. In a specific embodiment of the xenograft system described above, the human tumor cells are tumor cells derived from human patients. Such xenograft models are commercially available from Oncotest GmbH (Frieberg, Germany). In a specific embodiment, the human tumor cells are cells derived from human tumor cell lines, such as A549, AGS, SNU-1, SK-COH, HCC-44, NCI-H2122, LS 180, NCI-H1792, AsPC-1, NCI-H441, MIA PaCa-2, NCI-H358, FAMPAC, UM-UC-3, HPAC, NCI-H1373, NCI-H2009, NCI-H1944, HLC-I, KP4, LS513, NCI-H23, NCI-H2030, SW403, NCI-H460, LS 174T, SW480, HCC-1171, DLD-1, RERF-LC-Ad2, LoVo, NOMOH, HCT116, NCI-H1385, CFPAC-1, SK-LU-1, Calu-6, HEC-50B, PAN-1, A4/Fuk, KE-39, KURAMOCHI, MKN-1, COR-L23, HuG1-N, T.T, DMS 53, KLE, TYK-nu, PA-1, HEC-151, KMM-1, NCI-H929, AML-193, IPC-298, SK-MEL-30, MOLT-4, and C-643. In a specific embodiment, the human tumor cells are introduced into non-human animals that have been appropriately rendered immunodeficient by subcutaneous injection or by grafting into an appropriate site, such as a breast fat pad.

“Inhibition of cell growth or proliferation” means reducing growth or proliferation of cells by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, and includes induction of cell death.

As used herein, the term “vector” refers to a nucleic acid molecule that can increase another nucleic acid to which it is linked. This term includes vectors as self-replicating nucleic acid structures and vectors that are incorporated into the genome of the host cell into which they are introduced. Certain vectors can result in expression of nucleic acids to which they themselves are operatively linked. Such vectors are also referred to herein as “expression vectors”.

(Cyclic Peptide Compounds that Interact with Amino Acid Residues of Ras Protein and Bind to Ras Protein)

In one aspect, the present invention relates to cyclic peptide compounds or salts thereof, or solvates thereof, comprising 8 or more and 15 or less amino acid residues that bind to a Ras protein containing the amino acid sequence set forth in SEQ ID No: 9, wherein the compounds comprise

• • i) at least three N-substituted amino acid residues,
  • ii) at least one non-N-substituted amino acid residue, and
  • iii) a cyclic moiety containing at least eight amino acid residues, andwherein
  • iv) the compounds interact with at least one amino acid selected from the group consisting of Val8, Gly10, Lys16, Glu37, Leu56, Gln70, Tyr71, and Glu98 of the Ras protein.

The compounds of the present disclosure bind to a Ras protein containing the amino acid sequence set forth in SEQ ID No: 9. The amino acid sequence set forth in SEQ ID No. 9 represents the consensus sequence of the sequence of amino acids from position 1 to 165 of each of the following amino acid sequences:

• • amino acid sequence of wild-type hKras (SEQ ID NO. 6);
  • amino acid sequence of wild-type hNras (SEQ ID NO. 7);
  • amino acid sequence of wild-type hHras (SEQ ID NO. 8);
  • amino acid sequence of mutant-type hKRas (G12D);
  • amino acid sequence of mutant-type hKRas (G12C);
  • amino acid sequence of mutant-type hKRas (G12S);
  • amino acid sequence of mutant-type hKRas (G12V);
  • amino acid sequence of mutant-type hKRas (G12A);
  • amino acid sequence of mutant-type hKRas (G13D);
  • amino acid sequence of mutant-type hKRas (Q61H);
  • amino acid sequence of mutant-type hKRas (Q61K);
  • amino acid sequence of mutant-type hNRas (G12D, Q61K);
  • amino acid sequence of mutant-type hNRas (G12D);
  • amino acid sequence of mutant-type hNRas (G12C);
  • amino acid sequence of mutant-type hNRas (G13D);
  • amino acid sequence of mutant-type hNRas (G13V);
  • amino acid sequence of mutant-type hNRas (Q61L);
  • amino acid sequence of mutant-type hNRas (Q61K); and
  • amino acid sequence of mutant-type hHRas (G13R).

The 12th, 13th, 61st, 87th, 91st, 94th, 95th, 107th, 121st, 122nd, 126th, 127th, 128th, 131st, 132nd, 135th, 141st, and 151st Xaa, counted from the N-terminus, are each any amino acid, but suitably an amino acid as shown below:

• • 12th Xaa: Gly, Asp, Cys, Ser, Val, or Ala;
  • 13th Xaa: Gly, Asp, Val, or Arg;
  • 61st Xaa: Gln, His, Lys, or Leu;
  • 87th Xaa: Thr or Ser;
  • 91st Xaa: Glu or Ala;
  • 94th Xaa: His or Asn;
  • 95th Xaa: His, Leu, or Gln;
  • 107th Xaa: Cu or Asp;
  • 121st Xaa: Pro or Ala;
  • 122nd Xaa: Ser, TIr, or Ala;
  • 126th Xaa: Asp or Glu;
  • 127th Xaa: Thr or Ser;
  • 128th Xaa: Lys or Arg;
  • 131st Xaa: Gln or His;
  • 132nd Xaa: Asp or Glu;
  • 135th Xaa: Arg or Lys;
  • 141st Xaa: Phe or Tyr; and
  • 151st Xaa: Arg or Gly.

Accordingly, the Ras protein containing the amino acid sequence set forth in SEQ ID No: 9 encompasses all of the wild-type and mutant-type Ras proteins mentioned above.

For example, it is believed that expression and accumulation of the above mutant-type Ras proteins in the body activates signaling pathways that constantly promote cell proliferation, leading to increased likelihood of cancer development and/or faster cancer growth. Therefore, compounds that bind to Ras with such mutations are expected to be useful candidate compounds in the treatment and/or prevention of cancer.

In the present disclosure, the origin of Ras protein is not particularly limited and can encompass Ras proteins derived from various animals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, goats, rhesus monkeys, crab-eating monkeys, chimpanzees, and chickens. However, it is preferable that the Ras protein in the present disclosure be a Ras protein derived from humans.

Also, Ras is know to be in an inactivated state bound to GDP and an activated state bound to GTP. The Ras in the present disclosure may be either in the GTP form or in the GDP form, but the GDP form is preferable.

In one non-limiting embodiment, the compounds disclosed herein have high binding activity to the Ras protein containing the amino acid sequence set forth in SEQ ID No: 9. “Binding activity” herein means, for example, an inherent binding affinity that reflects a 1:1 interaction between the compounds disclosed herein and the Ras protein.

There is no particular limitation on the methods for measuring binding affinity and dissociation constant (K_D), but a surface plasmon resonance method (such as BIACORE) can be used. The binding rate constant (kon) and dissociation rate constant (koff) can be calculated using the simple one-to-one Langmuir binding model by simultaneously fitting binding and dissociation sensorgrams (Biacore T200 Evaluation Software (GE Healthcare)). The equilibrium dissociation constant (K_D) is calculated as the koff/kon ratio.

The compounds disclosed herein have high binding activity to the Ras protein. Specifically, examples of the dissociation constant (K_D) of the compounds disclosed herein for the Ras protein include, but are not limited to, 10.0 nM or less, 9.0 nM or less, 8.0 nM or less, 7.0 nM or less, 6.0 nM or less, 5.0 nM or less, 4.0 nM or less, or 3.0 nM or less.

In some embodiments, the total number of amino acid residues contained in the cyclic peptide compounds disclosed herein is 8 or more and 15 or less, preferably 10 or 11.

In an embodiment, the cyclic peptide compounds in the present disclosure may have a total number of amino acids contained in the cyclic moiety of 8 or more and 12 or less, 5 or more and 15 or less, 7 or more and 12 or less, 10 or more and 13 or less, 9 or more and 11 or less, or 11.

In one non-limiting embodiment, the number of N-substituted amino acid residues contained in the cyclic peptide compounds disclosed herein is preferably at least 3, more preferably 4 or more, 5 or more, or 6 or more, even more preferably 7 or more, and particularly preferably 8 or more, and is also preferably 20 or less, 15 or less, 14 or less, 13 or less, 12 or less, 10 or less, or 9 or less, for example. Examples of the number of N-substituted amino acid residues contained in the peptide compounds in the present disclosure include 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, and 80% or more of the number of amino acid residues constituting the peptide compounds.

In one non-limiting embodiment, the number of amino acid residues other than the N-substituted amino acid residues contained in the cyclic peptide compounds disclosed herein, that is, non-N-substituted amino acid residues is preferably at least 1, more preferably 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more, even more preferably 7 or more, and particularly preferably 8 or more, and is also preferably 20 or less, 15 or less, 14 or less, 13 or less, 12 or less, 10 or less, or 9 or less, for example. Examples of the number of N-substituted amino acid residues contained in the peptide compounds in the present disclosure include 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, and 80% or more of the number of amino acid residues constituting the peptide compounds.

In one aspect, the compounds disclosed herein interact with an amino acid of the Ras protein containing the amino acid sequence set forth in SEQ ID No: 9. The amino acid with which the compounds disclosed herein interact is not particularly limited, but it is preferably at least one (1, 2, 3, 4, 5, 6, 7, or 8) amino acid or at least two (2, 3, 4, 5, 6, 7, or 8) amino acids selected from the group consisting of Val8, Gly11, Lys16, Glu37, Leu56, Gln70, Tyr71, and Glu98, even more preferably at least one (1, 2, 3, or 4) amino acid selected from the group consisting of Gly10, Leu56, Tyr7l, and Glu98, and more preferably at least two (2, 3, or 4) amino acids or at least three (3 or 4) amino acids selected from the group consisting of Gly10, Leu56, Tyr71, and Glu98. In one embodiment, these amino acids are Leu56, Tyr71, and Glu98.

An amino acid of the Ras protein with which the compounds disclosed herein further interact is not particularly limited, but examples thereof include at least one (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more) amino acid selected from the group consisting of Val7, Va19, Ala11, Xaa12, Thr58, Ala59, Gly60, Xaa61, Glu62, Glu63, Tyr64, Arg68, Asp69, Met72, Arg73, Phe78, Asp92, Xaa95, Tyr96, Gln99, Ile100, Arg102, and Val103. Here,

• • the Xaa12 is an amino acid selected from the group consisting of Gly, Asp, Cys, Ser, Val, Ala, and Arg,
  • the Xaa61 is an amino acid selected from the group consisting of Gin, His, Lys, and Leu, and/or
  • the Xaa95 is an amino acid selected from the group consisting of Gln, His, and Leu.

The amino acid of the Ras protein with which the compounds disclosed herein further interact is preferably at least one (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more), at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine amino acids selected from the group consisting of Va19, Thr58, Xaa61, Glu62, Tyr64, Arg68, Met72, Asp92, Xaa95, Tyr96, Gln99, Arg102, and Val103, more preferably at least one (1, 2, 3, 4, or 5) amino acids selected from the group consisting of Thr58, Xaa61, Arg68, Gln99, and Arg102, even more preferably at least two (2, 3, 4, or 5), at least three (3, 4, or 5), at least four (4 or 5), or five amino acids selected from the group consisting of Thr58, Xaa61, Arg68, Gln99, and Arg102, and still more preferably Val9, Thr58, Glu62, Tyr64, Arg68, Met72, Tyr96, Gln99, Arg102, and Val103.

Three isoforms of the Ras protein are known: Kras protein, Nras protein, and HRas protein. The Ras protein containing the amino acid sequence set forth in SEQ ID No: 9 is not particularly limited, but in one aspect, the Ras protein containing the amino acid sequence set forth in SEQ ID No: 9 may be any of Kras protein, Nras protein, or HRas protein. Preferably, the Ras protein is Kras protein. Even more preferably, the Ras protein is a mutant Kras protein, a mutant Nras protein, and a mutant Hras protein. More preferably, the Ras protein is a mutant Kras protein.

In one aspect, the mutant Ras protein has a mutation of at least one amino acid shown in the consensus amino acid sequence set forth in SEQ ID No: 9. Although not particularly limited, it preferably has a mutation at least one amino acid position selected from the group consisting of G12, G13, and Q61.

In one aspect, when the Ras protein is a mutant Kras protein,

• • Xaa12 is an amino acid selected from the group consisting of Asp, Cys, Ser, Val, and Ala, and/or
  • Xaa61 is an amino acid selected from His or Lys.

In one aspect, when the Ras protein is a mutant Nras protein,

• • Xaa12 is an amino acid selected from Asp or Cys, and/or
  • Xaa61 is an amino acid selected from Lys or Leu.

Examples of the interaction disclosed herein include, but are not limited to, attraction exerted between molecules of the target protein in vivo, preferably the Ras protein, and the cyclic peptide compounds disclosed herein. The interaction can be analyzed from the X-ray crystal structure acquired from the Protein date bank (PDB), with reference to the method of Freitas et al. (Med. Chem. Commun., 2017, 8, 1970-1981), and can be utilized for the structural optimization of the cyclic peptide compounds. For analysis of the X-ray crystal structure acquired from the Protein date bank (PDB) and for analysis of the interaction between the target protein and the cyclic peptide compounds, commercially available software such as WebLab Viewer Lite, PyMOL, and Discovery Studio can be used, and the structural optimization and interaction analysis of the target protein and/or the cyclic peptide compounds may be carried out according to the manuals of the respective software.

Although not particularly limited, examples of the attraction include non-covalent interactions exemplified by electrostatic interactions (including ionic bond, hydrogen bond, and dipole interactions), van der Waals interactions (including hydrophobic interactions), and the like. Examples of the non-covalent interactions include CH-π interactions, NH-π interactions, S-π interactions, cation-n interactions, or halogen-n interactions. Such interactions are also described in detail in The Practice of Medicinal Chemistry (authored by Wermuth, 4th ed., ch. 4, published by Academic press).

The interaction disclosed herein may be mediated by other molecules such as water molecules or may not be mediated by other molecules such as water molecules, but it is preferable that the interaction not be mediated by other molecules such as water molecules. The interaction between the target protein and compounds with pharmacological effects is also described in detail in Introduction to medicinal chemistry (Chapter 1, authored by Gringauz, published by Wiley-VCH).

In one embodiment disclosed herein, the hydrogen bond refers to attraction formed between a hydrogen atom with a weak positive charge (δ+) (hydrogen bond donor) and a heteroatom with a weak negative charge (δ−) (hydrogen bond acceptor).

In one embodiment disclosed herein, examples of the electrostatic interactions include attraction formed between a positively charged atom and a negatively charged atom.

Examples of the hydrophobic interactions disclosed herein include attraction exerted between one functional group and another functional group. The functional groups are not particularly limited, but examples of the hydrophobic interactions include interactions between lipophilic functional groups, alkyl groups (alkyl-alkyl interactions), alkyl group and functional group with a π-electron (alkyl-π interactions), and functional groups with π-electrons (π-π interactions).

Another embodiment of the interaction disclosed herein can be a halogen interaction, in which one halogen atom is attracted to another atom.

Examples of the halogen atom include fluorine, chlorine, bromine, and iodine. Examples of the halogen interaction include van der Waals force and interactions between halogen atoms and functional groups with a positive charge that can form halogen interactions.

One aspect disclosed herein can be interaction with functional groups having n-electrons, such as aromatic rings, double bonds, or triple bonds. Examples thereof include interactions between functional groups with π-electrons (π-π interactions) and interactions between functional groups with π-electrons and CH groups (CH-π interactions), as well as cation-, interactions (Shinji Yamada, Journal of synthetic organic chemistry, Japan, 63(4), 339-350, 2005; S. Yamada, Coord. Chem. Rev., 2020, 415, 213301).

For example, in the case of Discovery studio 2020 Client, by using the Show types function of Display receptor-ligand interactions, it is possible to acquire information on the distances between atoms with which the receptor and ligand, herein Ras protein and cyclic peptide compounds may interact, as well as on the types of interactions. Examples of the distances between atoms include distances between the atomic centers of heavy atoms other than hydrogen.

In one aspect, the compounds disclosed herein interact with an amino acid of the Ras protein containing the amino acid sequence set forth in SEQ ID No: 9. The closer the distance between an atom involved in the interaction of the compounds disclosed herein and an atom constituting the amino acid of the Ras protein, the stronger the interaction may be. For example, the distance can be, but is not limited to, 6.0 Å or less, 5.9 Å or less, 5.8 Å or less, 5.7 Å or less, 5.6 Å or less, 5.5 Å or less, 5.4 Å or less, 5.3 Å or less, 5.2 Å or less, 5.1 Å or less, 5.0 Å or less, 4.9 Å or less, 4.8 Å or less, 4.7 Å or less, 4.6 Å or less, 4.5 Å or less, 4.4 Å or less, 4.3 Å or less, 4.2 Å or less, 4.1 Å or less, 4.0 Å or less, 3.9 Å or less, 3.8 Å or less, 3.7 Å or less, 3.6 Å or less, 3.5 Å or less, 3.4 Å or less, 3.3 Å or less, 3.2 Å or less, 3.1 Å or less, 3.0 Å or less, 2.9 Å or less, 2.8 Å or less, 2.7 Å or less, 2.6 Å or less, 2.5 Å or less, 2.4 Å or less, 2.3 Å or less, 2.2 Å or less, 2.1 Å or less, or 2.0 Å or less.

In addition, the distance between an atom involved in the interaction of the compounds disclosed herein and an atom constituting the amino acid of the Ras protein is preferably, but is not limited to, farther than 2.0 Å and 2.5 Å, 3.0 k, 3.5 Å, 4.0 Å, 4.5 Å, 5.0 Å, 5.5 Å, or 6.0 Å or less, farther than 2.5 Å and 3.0 Å, 3.5 Å, 4.0 Å, 4.5 Å, 5.0 Å, 5.5 Å, or 6.0 Å or less, farther than 3.0 Å and 3.5 Å, 4.0 Å, 4.5 Å, 5.0 Å, 5.5 Å, or 6.0 Å or less, farther than 3.5 Å and 4.0 Å, 4.5 Å, 5.0 Å, 5.5 Å, or 6.0 Å or less, farther than 4.0 Å and 4.5 Å, 5.0 Å, 5.5 Å, or 6.0 Å or less, farther than 4.5 Å and 5.0 Å, 5.5 Å, or 6.0 Å or less, farther than 5.0 Å and 5.5 Å or 6.0 Å or less, or farther than 5.5 Å and 6.0 Å or less, for example.

In the present disclosure, the interatomic distance can be measured through, for example, analysis of the three-dimensional structure of a complex of the Ras protein containing the amino acid sequence set forth in SEQ ID No: 9 and the compounds disclosed herein. Specifically, crystals of the complex of the Ras protein and the compounds disclosed herein are prepared by the sitting drop vapor diffusion method or other methods. X-ray diffraction of the crystals is carried out, and X-ray diffraction intensity data for the space group, unit cell, and others are acquired by processing with the AutoPROC (Global Phasing Ltd.) program or other programs. By applying the acquired X-ray diffraction intensity data to programs and software for determining initial structure or refined structure well known to those skilled in the art, such as the Phaser (J. Appl. Cryst. 40: 658-674 (2007)) program, Phenix (Acta Cryst. (2019). D75, 861-877), Coot (Acta Cryst. D66: 486-501 (2010)), Refmac5 (Acta Cryst. D67: 355-467 (2011)) programs, and PyMOL Version 2.3 (Schrodinger, LLC.) software, the three-dimensional structure of a complex of the Ras protein and the compounds disclosed herein can be determined.

When the three-dimensional structure of a complex of the Ras protein and the compounds disclosed herein can be determined, it is possible to measure the interatomic distance by methods well known to those skilled in the art. As an example, when the structural information of a complex of the Ras protein and the compounds disclosed herein is loaded into a software program used for molecular modeling or molecular simulation, such as Discovery studio 2020 Client and PyMOL, and the function incorporated in the software program (for example, in the case of Discovery studio 2020 Client, the Show distances function of Display receptor-ligand interactions) is used, it is possible to measure the interatomic distance. The structural information can also be viewed in PyMOL.

Crystals of the complex of the Ras protein and the compounds disclosed herein can also be acquired by methods well known to those skilled in the art. For example, a solution containing the compounds disclosed herein is mixed with a solution containing the Ras protein to acquire a complex of the Ras protein and the compounds disclosed herein. The resulting complex can be subjected to crystallization methods well known to those skilled in the art, such as vapor diffusion, batch (bulk batch, microbatch), dialysis, and counter diffusion methods, thereby preparing crystals of the complex of the Ras protein and the compounds disclosed herein. As the vapor diffusion method, the sitting drop method, hanging drop method, and sandwich drop method are known.

Note that the desired Ras protein can also be acquired by methods known to those skilled in the art. For example, the Ras protein can be prepared utilizing, but not limited to, recombinant polypeptide expression methods using cells. In one embodiment, a nucleic acid encoding the Ras protein in the present disclosure is inserted into an appropriate expression vector, the vector is introduced into appropriate cells, and the transformed cells are cultured, and the expressed modified protein is isolated, purified, and cultured. Such a protein can also be expressed as a fusion protein with other proteins for the purpose of facilitating purification or for other purposes. For example, the following methods can be utilized: a method of preparation as a fusion protein with a maltose-binding protein using E. coli as a host (the vector pMAL series available from New England BioLabs, USA); a method of preparation as a fusion protein with glutathione-S-transferase (GST) (the vector pGEX series available from Amersham Pharmacia Biotech); a method of preparation by adding a histidine tag (the pET series available from Novagen); a method of preparation by adding a HAT tag; and other methods. The host cell is not particularly limited as long as it is a cell suited for expression of the recombinant protein, and it is possible to use, for example, yeast, various animal and plant cells, insect cells, and others, in addition to the above-described E. coli. Various methods known to those skilled in the art can be used for the introduction of the vector into the host cell. For example, for the introduction into E. coli, introduction methods utilizing calcium ions (Mandel, M., Higa, A. (1970) Journal of Molecular Biology, 53, 158-162; Hanahan, D. (1983) Journal of Molecular Biology, 166, 557-580) can be used. The protein expressed in the host cell can be purified and recovered from the host cell or its cell culture or culture supernatant by methods known to those skilled in the art. When the protein is expressed as a fusion protein with a maltose-binding protein, HAT tag, or the like as described above, affinity purification or gel filtration chromatography (size exclusion chromatography, SEC) purification can be easily carried out. For the affinity chromatography purification and SEC purification, the AKTAxpress™ apparatus (GE Healthcare), the NGC™ chromatography system (Bio-Rad), the BioLogic DuoFlow™ chromatography system (Bio-Rad), or the like can be used.

In one aspect, the cyclic peptide compounds disclosed herein that interact with amino acids of the Ras protein and bind to the Ras protein are composed of eight to fifteen (preferably eleven) amino acid residues,

• • at least one of the amino acid residues is an amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group, wherein the amino acid residue is optionally N-substituted and is linked to the adjacent amino acid residue on the C-terminal side via the carbonyl group,
  • an amino acid residue located four amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group is a N-substituted amino acid residue, and
  • an amino acid residue located seven amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of a main chain amino group contains —(CH₂)_x—O_y—(CH₂)_z1—C₆-C₁₀ aryl or —(CH₂)_x—Oγ—(CH₂)_z2-5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C₁-C₄ alkyl, C₂-C₄ alkynyl, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, C₁-C₄ alkoxy, —CN, C₁-C₃ alkylsulfonyl, hydroxy, and SF₅, wherein
  • x is 1, 2, or 3,
  • y is 0 or 1,
  • z1 is 0, 1, 2, or 3, and
  • z2 is 1, 2, or 3,
  • provided that the sum of x, y, and z1 or z2 is 1 to 4.

As for the —(CH₂)_x—O_y—(CH₂)_z1—C₆-C₁₀ aryl or —(CH₂)_x—O_y—(CH₂)_z2-5- to 10-membered heteroaryl, phenethyl is preferable. It is preferable that the phenyl group of the phenethyl be substituted with one or two halogens (preferably fluorine or chlorine) and one C₁-C₃ haloalkyl (preferably trifluoromethyl). It is also preferable that the phenethyl have halogen at the position 3 or positions 3 and 5 of the phenyl group, and C₁-C₃ haloalkyl at the position 4 of the phenyl group.

In one aspect, as for the cyclic peptide compounds disclosed herein that interact with amino acids of the Ras protein and bind to the Ras protein, the amino acid residue located seven amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of the main chain amino group is Hph(4-CF3-3-Cl) or Hph(4-CF3-35-F2).

In one aspect, as for the cyclic peptide compounds disclosed herein that interact with amino acids of the Ras protein and bind to the Ras protein, the amino acid residue located four amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of the main chain amino group is MeGly or Aze(2).

In one aspect, as for the cyclic peptide compounds disclosed herein that interact with amino acids of the Ras protein and bind to the Ras protein, the amino acid residue located seven amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of the main chain amino group interacts with one or more selected from Tyr71, Leu56, and Glu37 of the Ras protein.

In one aspect, as for the cyclic peptide compounds disclosed herein that interact with amino acids of the Ras protein and bind to the Ras protein, the amino acid residue located four amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the β carbon of the main chain amino group interacts with Glu98 of the Ras protein.

In one aspect, as for the cyclic peptide compounds disclosed herein that interact with amino acids of the Ras protein and bind to the Ras protein, the amino acid residues located seven amino acid residues ahead and the amino acid residues located eight amino acid residues ahead on the C-terminal side of the amino acid residue having a carbonyl group attached to the carbon of a main chain amino group each interact with one or more selected from Tyr71, Leu56, Glu37, Lys16, and Gly10 of the Ras protein.

All prior art documents cited in the present specification are incorporated herein by reference.

EXAMPLE

The content of the present invention will be further described with reference to Examples and Reference Examples below, but it is not to be construed as being limited thereto. All starting materials and reagents were obtained from commercial suppliers or synthesized by known methods. The LC/MS analysis conditions are described in Table 1.

TABLE 1
		Column
Analysis		(I.D. × Length)
condition	Device	(mm)	Mobile phase
SQDAA05	Acquity UPLC/SQD	Ascentis Express C18	A) 10 mM AcONH4, water
	or	(2.1 × 50)	B) methanol
	Acquity UPLC/SQD2
SQDFA05	Acquity UPLC/SQD	Ascentis Express C18	A) 0.1% FA, water
	or	(2.1 × 50)	B) 0.1% FA, acetonitrile
	Acquity UPLC/SQD2
SQDAA50	Acquity UPLC/SQD	Ascentis Express C18	A) 10 mM AcONH4, water
	or	(2.1 × 50)	B) methanol
	Acquity UPLC/SQD2
SQDFA50	Acquity UPLC/SQD	Ascentis Express C18	A) 0.1% FA, water
	or	(2.1 × 50)	B) 0.1% FA, acetonitrile
	Acquity UPLC/SQD2
SQDFA05long	Acquity UPLC/SQD2	Ascentis Express C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SQDFA3080	Acquity UPLC/SQD2	Ascentis Express C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SQDFA30long50deg	Acquity UPLC/SQD2	Ascentis Express C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SMDmethod_01	Shimadzu	Kinetex EVO C18	A) 6.5 mM NH4HCO3 water
	LCMS-2020	(2.1 × 50)	(pH = 10)
			B) acetonitrile
SMDmethod_02	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_03	Nexera/2020	Ascentis Express C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SMDmethod_04	Nexera/2020	Ascentis Express C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SMDmethod_05	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0x50)	B) 0.05% TFA, acetonitrile
SMDmethod_06	Nexera/2020	Speed Core C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SMDmethod_07	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_08	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2010EV	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_09	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2010EV	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_10	Shimadzu	Gemini-NX 3u C18	A) 6.5 mM NH4HCO3 water
	LCMS-2020	110A	(pH = 10)
		(3.0 × 50)	B) acetonitrile
SMDmethod_11	Shimadzu	Phenomenex kinetex	A) 0.1% FA, water
	LCMS-2020	C18	B) 0.1% FA, acetonitrile
		(3.0 × 50)
SMDmethod_12	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_13	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_14	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_15	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_16	Shimadzu	Accucore C18	A) 0.1% FA, water
	LCMS-2020	(2.1 × 50)	B) 0.1% FA, acetonitrile
SMDmethod_17	Shimadzu	Ascentis Express	A) 0.05% TFA, water
	LCMS-2020	C18	B) 0.05% TFA, acetonitrile
		(3.0 × 50)
SMDmethod_18	Shimadzu	CORTECS C18	A) 0.1% FA, water
	LCMS-2020	(2.1 × 50)	B) 0.1% FA, acetonitrile
SMDmethod_19	Shimadzu	ACQUITY BEH C18	A) 0.15% FA, water
	LCMS-2020	(2.1 × 50)	B) 0.15% FA, acetonitrile
SMDmethod_20	Shimadzu	Ascentis Express	A) 0.05% TFA, water
	LCMS-2020	C18	B) 0.05% TFA, acetonitrile
		(3.0 × 50)
SMDmethod_21	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2010EV	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SMDmethod_22	Shimadzu	ACQUITY BEH C18	A) 0.1% FA, water
	LCMS-2020	(2.1 × 50)	B) 0.05% FA, acetonitrile
SMDmethod_23	Shimadzu	Shim-Pack XR-ODS	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 50)	B) 0.05% TFA, acetonitrile
SSC-AA-20	Nexera UC/2020	Ascentis Express	A) 10 mM AcONH4, water
		C18	B) methanol/1M AcONH4,
		(2.1 × 50)	water = 100/1
SSC-AF-00	Nexera UC/2020	Ascentis Express	A) 10 mM NH4HCO2
		C18	water
		(2.1 × 50)	B) methanol
SSC-FA-03	Nexera UC/2020	XSelect CSH C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SSC-TFA-07	Nexera/2020	Ascentis Express	A) 0.05% TFA, water
		C18	B) 0.05% TFA, acetonitrile
		(2.1 × 50)
SSC-A-AF-01	Nexera UC/2020	Ascentis Express	A) 10 mM NH4HCO2
		C18	water
		(2.1 × 50)	B) methanol
SSC-A-AF-02	Nexera UC/2020	Ascentis Express	A) 10 mM NH4HCO2
		C18	water
		(2.1 × 50)	B) methanol
SSC-A-FA-01	Nexera UC/2020	XSelect CSH C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SSC-A-FA-02	Nexera UC/2020	XSelect CSH C18	A) 0.1% FA, water
		(2.1 × 50)	B) 0.1% FA, acetonitrile
SQDFA05long	Acquity UPLC/SQD2	Ascentis Express	A) 0.1% FA, water
		C18	B) 0.1% FA, acetonitrile
		(2.1 × 50)
SMDmethod_30	Shimadzu	Halo C18	A) 0.05% TFA, water
	LCMS-2020	(3.0 × 30)	B) 0.05% TFA, acetonitrile
SMDmethod_31	Shimadzu	Ascentis Express	A) 0.05% TFA, water
	LCMS-2020	C18	B) 0.05% TFA, acetonitrile
		(3.0 × 50)
SMDAM05	Nexera/2020	Ascentis Express	A) 0.1% FA, water
		RP-amide	B) 0.1% FA, acetonitrile
		(2.1 × 50)
SMDFA05	Nexera/2020	Ascentis Express	A) 0.1% FA, water
		C18	B) 0.1% FA, acetonitrile
		(2.1 × 50)
SMDFA05long	Nexera/2020	Ascentis Express	A) 0.1% FA, water
		C18	B) 0.1% FA, acetonitrile
		(2.1 × 50)
		Flow	Column
Analysis		rate	temperature
condition	Gradient (A/B)	(mL/min)	(° C.)	Wavelength	Remarks
SQDAA05	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.0 min) =>			PDA total
	0/100 (0.4 mins)
SQDFA05	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.0 min) =>			PDA total
	0/100 (0.4 mins)
SQDAA50	50/50 (initial) =>	1.0	35	210-400 nm
	0/100 (0.7 mins) =>			PDA total
	0/100 (0.7 mins)
SQDFA50	50/50 (initial) =>	1.0	35	210-400 nm
	0/100 (0.7 mins) =>			PDA total
	0/100 (0.7 mins)
SQDFA05long	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (4.5 mins) =>			PDA total
	0/100 (0.5 mins)
SQDFA3080	70/30 (initial) =>	1.0 (initial-	35	210-400 nm
	20/80 (4.5 mins) =>	4.51 min)		PDA total
	0/100 (0.01 mins) =>	0.1 (4.51-
	0/100 (0.49 mins)	5.00 min)
SQDFA30long50deg	70/30 (initial) =>	0.5	50	210-400 nm
	0/100 (8.0 mins) =>			PDA total
	0/100 (2.0 mins)
SMDmethod_01	90/10 (initial) =>	1.0	35	190-400 nm
	50/50 (3.8 mins) =>			PDA total
	5/95 (0.4 mins) =>
	5/95 (0.4 mins)
SMDmethod 02	60/40 (initial) =>	1.2	40	190-400 nm
	5/95 (3.0 mins) =>			PDA total
	5/95 (0.7 mins)
SMDmethod_03	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (4.5 mins) =>			PDA total
	0/100 (0.5 mins)
SMDmethod_04	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.5 mins) =>			PDA total
	0/100 (0.5 mins)
SMDmethod_05	95/5 (initial) =>	1.2	40	190-400 nm
	5/95 (2.0 mins) =>			PDA total
	5/95 (0.7 mins)
SMDmethod_06	95/5 (initial) =>	1.0	35	210-400 nm
	0/100(1.5 mins) =>			PDA total
	0/100(0.5 mins)
SMDmethod_07	50/50 (initial) =>	1.2	40	190-400 nm
	5/95 (3.8 mins) =>			PDA total
	5/95 (0.8 mins)
SMDmethod_08	50/50 (initial) =>	1.2	40	190-400 nm
	5/95 (2.0 mins) =>			PDA total
	5/95 (0.7 mins)
SMDmethod_09	50/50 (initial) =>	1.2	40	190-400 nm
	5/95 (4.1 mins) =>			PDA total
	5/95 (0.9 mins)
SMDmethod_10	70/30 (initial) =>	1.2	45	190-400 nm
	20/80 (4.0 mins) =>			PDA total
	5/95 (0.5 mins) =>
	5/95 (0.5 mins)
SMDmethod_11	90/10 (initial) =>	1.5	40	190-400 nm
	5/95 (2.0 mins) =>			PDA total
	5/95 (0.7 mins)
SMDmethod_12	95/5 (initial) =>	1.2	40	190-400 nm
	5/95 (3.0 mins) =>			PDA total
	5/95 (0.7 mins)
SMDmethod_13	50/50 (initial) =>	1.2	40	190-400 nm
	5/95 (2.0 mins) =>			PDA total
	5/95 (0.7 mins)
SMDmethod_14	70/30 (initial) =>	1.2	40	190-400nm
	20/80 (3.8 mins) =>			PDA total
	0/100 (0.3 mins) =>
	0/100 (0.5 mins)
SMDmethod_15	95/5 (initial) =>	1.2	40	190-400 nm
	0/100 (1.1 mins) =>			PDA total
	0/100 (0.6 mins)
SMDmethod_16	90/10 (initial) =>	1.0	40	190-400 nm
	0/100 (1.1 mins) =>			PDA total
	0/100 (0.5 mins)
SMDmethod_17	95/5 (initial) =>	1.0	40	190-400 nm
	5/95 (2.7 mins) =>			PDA total
	5/95 (1.0 min)
SMDmethod_18	95/5 (initial) =>	1.0	40	190-400 nm
	0/100 (1.0 min) =>			PDA total
	0/100 (0.5 mins)
SMDmethod_19	90/10 (initial) =>	0.7	45	190-600 nm
	30/70 (3.6 mins) =>			PDA total
	30/70 (1.0 min)
SMDmethod_20	95/5 (initial) =>	1.0	40	190-400 nm
	5/95 (1.1 mins) =>			PDA total
	5/95 (0.5 mins)
SMDmethod_21	95/5 (initial) =>	1.2	40	190-400 nm
	5/95 (2.0 mins) =>			PDA total
	5/95 (0.7 mins)
SMDmethod_22	95/6 (initial) =>	0.7	45	190-800 nm
	20/80 (4 mins) =>			PDA total
	20/80 (1.2 mins)
SMDmethod_23	95/5 (initial) =>	1.0	40	190-400 nm
	0/100 (1.2 mins) =>			PDA total
	0/100 (1 min)
SSC-AA-20	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.75 mins) =>			PDA total
	0/100 (1.25 mins)
SSC-AF-00	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.75 mins) =>			PDA total
	0/100 (1.25 mins)
SSC-FA-03	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.75 mins) =>			PDA total
	0/100 (1.25 mins)
SSC-TFA-07	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.5 mins) =>			PDA total
	0/100 (0.5 mins)
SSC-A-AF-01	70/30 (initial) =>	0.5	50	210-400 nm	Loop
	0/100 (8.75 mins) =>			PDA total	injection
	0/100 (1.25 mins)
SSC-A-AF-02	70/30 (initial) =>	0.5	50	210-400 nm	Total
	0/100 (8.75 mins) =>			PDA total	volume
	0/100 (1.25 mins)				injection
SSC-A-FA-01	70/30 (initial) =>	0.5	50	210-400 nm	Loop
	10/90 (7.5 mins) =>			PDA total	injection
	0/100 (0.01 mins) =>
	0/100 (2.49 mins)
SSC-A-FA-02	70/30 (initial) =>	0.5	50	210-400 nm	Total
	10/90 (7.5 mins) =>			PDA total	volume
	0/100 (0.01 mins) =>				injection
	0/100 (2.49 mins)
SQDFA05long	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (4.5 mins) =>			PDA total
	0/100 (0. 5 mins)
SMDmethod_30	95/5 (initial) =>	1.2	45	190-400 nm
	0/100 (0.7 mins) =>			PDA total
	0/100 (0.4 mins)
SMDmethod_31	95/5 (initial) =>	1.5	40	190-400 nm
	0/100 (2.0 mins) =>			PDA total
	0/100 (0.7 mins)
SMDAM05	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.5 mins) =>			PDA total
	0/100 (0.5 mins)
SMDFA05	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (1.5 mins) =>			PDA total
	0/100 (0.5 mins)
SMDFA05long	95/5 (initial) =>	1.0	35	210-400 nm
	0/100 (4.5 mins) =>			PDA total
	0/100 (0.5 mins)

Example 1

Solid-Phase Synthesis of Peptide Compounds

Peptides were elongated by the following basic route (also called the basic peptide synthesis method) according to the peptide synthesis method by Fmoc methods described in WO 2013/100132 or WO 2018/225864, specifically, by the following five steps:

• • 1) elongation reaction of the peptide by the Fmoc method from the N-terminal amino acid of Asp side chain carboxylic acid or peptide main chain carboxylic acid loaded onto 2-chlorotrityl resin;
  • 2) cleavage of the peptide from the 2-chlorotrityl resin;
  • 3) amide cyclization by condensation between the Asp side chain carboxylic acid or peptide main chain carboxylic acid released from the 2-chlorotrityl resin by the cleavage and the amino group of the peptide chain N-terminus (triangle unit);
  • 4) deprotection of the protecting group of a side chain functional group contained in the peptide chain, as necessary; and
  • 5) purification of the compound by preparative HPLC. In the present Examples, unless otherwise stated, peptide compounds were synthesized based on this basic route. 1-1. Fmoc amino acids used in peptide synthesis by a peptide synthesizer Fmoc amino acids described in Tables 2 to 5 were used in peptide syntheses described herein using a peptide synthesizer.

Fmoc amino acids described in Table 2 were synthesized according to the methods described in WO 2013/100132 or WO 2018/225864.

Fmoc amino acids described in Table 3 were purchased from commercial suppliers or synthesized according to the methods described in WO 2018/225864,

Fmoc amino acids described in Table 4 were purchased from commercial suppliers.

Fmoc amino acids describe in Table 5 were synthesized according to the schemes provided below.

TABLE 2
Abbreviation	Structural formula	Name
Fmoc-MeAla(4-Thz)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 3-(1,3-thiazol-4-yl)propanoic acid
Fmoc-MePhe(3-Cl)—OH		(2S)-3-(3-chlorophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
Fmoc-nPrGly—OH		2-[9H-fluoren-9-ylmethoxycarbonyl (propyl)amino]acetic acid
Fmoc-Hyp(Et)—OH		(2S,4R)-4-ethoxy-1-(9H-fluoren-9- ylmethoxycarbonyl)pyrrolidin-2- carboxylic acid
Fmoc-(EtOEt)NGly—OH		2-[2-ethoxyethyl(9H-fluoren-9- ylmethoxycarbonyl)aminolacetic acid
Fmoc-cisPro(pip-4-F2)—OH		(2S,4S)-4-(4,4-difluoropiperidin-1- yl)-1-(9H-fluoren-9- ylmethoxycarbonyl)pyrrolidin-2- carboxylic acid
Fmoc-Hnl(7-F2)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-7,7- difluoroheptanoic acid
Fmoc-iPenGly—OH		2-[9H-fluoren-9- ylmethoxycarbonyl(3- methylbutyl)amino]acetic acid
Fmoc-MsAbu(pip-3-F2)—OH		(2S)-4-(3,3-difluoropiperidin-1-yl)- 2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino] butanoic acid
Fmoc-MeGln(Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 5-(methylamino)-5-oxopentanoic acid
Fmoc-MeGln(Me2)—OH		(2S)-5-(dimethylamino)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)aminoj-5-oxopentanoic acid
Fmoc-MaHnl(7-F2)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 7,7-difluoroheptanoic acid
Fmoc-MaHph—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 4-phenylbutanoic acid
Fmcc-MePhe(4-Cl)—OH		(2S)-3-(4-chlorophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
Fmoc-MeSer(THP)—OH		(2S)-2-19H-fluoren-9- ylmethoxycarbonyl(methyl)amino- 3-(oxan-2-yloxy)propanoic acid
Fmoc-MeSer (3-F-5-Ma-Pyr)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 3-[(5-fluoropyridin-3-yl) methoxy]propanoic acid
Fmoc-MeSer(iPen)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 3-(3-methylbutoxy)propanoic acid
Fmoc-MeSer(nPr)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 3-propoxypropanoic acid
Fmoc-MaSer(NtBu-Aca)—OH		(2S)-3-[2-(tert-butylamino)-2- oxocthoxy]-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino] propanoic acid
Fmoc-MeSer(Ph-2-Cl)—OH		(2S)-3-(2-chiorophenoxy)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
Fmoc-MeSer(tBuOTHP)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl)amino]- 3-[2-methyl-2-(oxan-2- yloxy)propoxy]propanoic acid
Fmoc-nBuGly—OH		2-[butyl(9H-fluoren-9- ylmethoxycarbonyl)aminoJacetic acid
Fmoc-Pro(4-pip-4-F2)—OH		(2S.4R)-4-(4,4-difluoropiperidin-1- yl)-1-(9H-fluoren-9- ylmethoxycarbonyl)pyrrolidin-2- carboxylic acid
Fmoc-Ser(3-F-5-Ma-Pyr)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-[(5- fluoropyridin-3- yl)methoxy]propanoic acid
Fmoc-Ser(iPen)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(3- methylbutoxy)propanoic acid
Fmoc-Ser(nPr)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3- propoxypropanoic acid
Fmoc-Ser(NtBu-Aca)—OH		(2S)-3-[2-(tert-butylamino)-2- oxoethoxy]-2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
Fmoc-Ser(tBuOTHP)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-12- methyl-2-(oxan-2- yloxy)propoxy]propanoic acid
Fmoc-Thr(THP)—OH		(2S,3R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(oxan- 2-yloxy)butanoic acid
Fmoc-Ser(THP)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(oxan- 2-yloxy)propanoic acid
Fmoc-Tyr(3-F.tBu)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-[3- fluoro-4-[(2-methylpropan-2- yl)oxy]phenyl]propanoic acid

TABLE 3
Abbreviation	Structural formula	Name
Fmoc-Hph(3-Cl)—OH		(2S)-4-(3-chlorophenyl)-2- (9H-fluoren-9- ylmethoxycarbonylamino) butanoic acid
Fmoc-Hph(4-Cl)—OH		(2S)-4-(4-chlorophenyl)-2- (9H-fluoren-9- ylmethoxycarbonylamino) butanoic acid

TABLE 4
Abbreviation	Structural formula	Name	CAS No.
Fmoc-Phe(4-CHF2)—OH		(2S)-3-[4- (difluoromethyl)phenyl]- 2-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	1808268-08-7
Fmoc-Phe(2-F-3-Br)—OH		(2S)-3-(3-bromo-2- fluorophenyl)-2-(9H- fluoren-9-yl methoxycarbonylamino) propanoic acid	2018410-80-5
Fmoc-Phe(2-F-5-Br)—OH		(2S)-3-(5-bromo-2- fluorophenyl)-2-(9H- fluoren-9-yl methoxycarbonylamino) propanoic acid	1998646-62-0
Fmoc-Phe(3-Br)—OH		(2S)-3-(3-bromophenyl)- 2-(9H-fluoren-9-y] methoxycarbonylamino) propanoic acid	220497-48-3
Fmoc-Phe(3- Br-5-F)—OH		(2S)-3-(3-bromo-5- fluorophenyl)-2-(9H- fluoren-9-yl methoxycarbonylamino) propanoic acid	1998639-82-9
Fmoc-Phe(3- Cl-5-F)—OH		(2S)-3-(3-chloro-5- fluorophenyl)-2-(9H- fluoren-9-yl methoxycarbonylamino) propanoic acid	1998650-51-3
Fmoc-Phe(3-CN)—OH		(2S)-3-(3-cyanophenyl)- 2-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	205526-36-9
Fmoc-Phe(4-Cl)—OH		(2S)-3-(4-chlorophenyl)- 2-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	175453-08-4
Fmoc-(Me)Abu—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 2-methylbutanoic acid	857478-30-9
Fmoc-(Me)Algly—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 2-methylpent-4-enoic acid	288617-71-0
Fmoc-(Me)Leu—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 2,4-dimethylpentanoic acid	312624-65-0
Fmoc-(Ms)Phe—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 2-methyl-3- phenylpropanoic acid	135944-05-7
Fmoc-1-ACPrC—OH		1-(9H-fluoren-9-yl methoxycarbonylamino) cyclopropan-1- carboxylic acid	126705-22-4
Fmoc-Abu—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) butanoic acid	135112-27-5
Fmoc-Abu(4-F3)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4,4,4-trifluorobutanoic acid	181128-48-3
Fmoc-Ahp(2)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) heptanoic acid	1197020-22-6
Fmoc-Ahpe(2)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) hept-6-enoic acid	856412-22-1
Fmoc-Aib—OH		2-(9H-fluoren-9-yl methoxycarbonylamino)- 2-methylpropanoic acid	94744-50-0
Fmoc-Ala—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	35661-39-3
Fmoc-Ala(cBu)—OH		(2S)-3-cyclobutyl-2-(9H- fluoren-9-ylmethoxy carbonylamino) propanoic acid	478183-62-9
Fmoc-Ala(ON)—OH		(2S)-3-cyano-2-(9H- fluoren-9-ylmethoxy carbonylamino) propanoic acid	127273-06-7
Fmoc-Ala(cPent)—OH		(2S)-3-cyclopentyl-2- (9H-fluoren-9-ylmethoxy carbonylamino) propanoic acid	371770-32-0
Fmoc-Ala(cPr)—OH		(2S)-3-cyclopropyl-2- (9H-fluoren-9-ylmethoxy carbonylamino) propanoic acid	214750-76-2
Fmoc-Algly—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) pent-4-enoic acid	146549-21-5
Fmoc-AllylGly—OH		2-[9H-fluoren-9-yl methoxycarbonyl(prop- 2-enyl)amino]acetic acid	222725-35-1
Fmoc-Athpc—OH		4-(9H-fluoren-9-yl methoxycarbonylamino) oxan-4-carboxylic acid	285996-72-7
Fmoc-Aze(2)—OH		(2S)-1-(9H-fluoren-9- ylmethoxycarbonyl) azetidin-2-carboxylic acid	136552-06-2
Fmoc-bAla—OH		3-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	35737-10-1
Fmoc-bMeAla—OH		3-[9H-fluoren-9- lylmethoxycarbonyl (methyl)amino] propanoic acid	172965-84-3
Fmoc-BnGly—OH		2-[benzyl(9H-fluoren-9- ylmethoxycarbonyl) amino]acetic acid	141743-13-7
Fmoc-Cha—OH		(2S)-3-cyclohexyi-2- (9H-fluoren-9-ylmethoxy carbonylamino) propanoic acid	135873-97-1
Fmoc-cHex—OH		1-(9H-fluoren-9-yl methoxycarbonylamino) cyclohexan-1-carboxylic acid	162648-54-6
Fmoc-Chg—OH		(2S)-2-cyclohexyl-2- (9H-fluoren-9-yl methoxycarbonylamino) acetic acid	161321-36-4
Fmoc-cLeu—OH		1-(9H-fluoren-9-yl methoxycarbonylamino) cyclopentan-1- carboxylic acid	117322-30-2
Fmoc-cVal—OH		1-(9H-fluoren-9-yl methoxycarbonylamino) cyclobutan-1-carboxylic acid	885951-77-8
Fmoc-D-(Me)Abu—OH		(2R)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 2-methylbutanoic acid	1231709-22-0
Fmoc-D-(Me)Algly—OH		(2R)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 2-methylpent-4-enoic acid	288617-76-5
Fmoc-D-Ala—OH		(2R)-2-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	79990-15-1
Fmoc-D-Algly—OH		(2R)-2-(9H-fluoren-9-yl methoxycarbonylamino) pent-4-enoic acid	170642-28-1
Fmoc-D-MeAbu—OH		(2R)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]butanoic acid	1210830-60-6
Fmoc-D-MeAls—OH		(2R)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino] propanoic acid	138774-92-2
Fmoc-D-MePhe—OH		(2R)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3- phenylpropanoic acid	138775-05-0
Fmoc-D-Mor(3)—OH		(3R)-4-(9H-fluoren-9- ylmethoxycarbonyl) morpholin-3-carboxylic acid	942153-03-9
Fmoc-D-Plc(2)—OH		(2R)-1-(9H-fluoren-9- ylmethoxycarbonyl) piperidin-2-carboxylic acid	101555-63-9
Fmoc-D-Pro—OH		(2R)-1-(9H-fluoren-9- ylmethoxycarbonyl) pyrrolidin-2-carboxylic acid	101555-62-8
Fmoo-D-Val—OH		(2R)-2-(9H-fluoren-9-y] methoxycarbonylamino)- 3-methylbutanoic acid	84624-17-9
Fmoc-EtGly—OH		2-[ethyl(9H-fluoren-9- ylmethoxycarbonyl) amino]acetic acid	162545-29-1
Fmoc-Glu(OAl)—OH		(2S)-2-(9H-fluoren-9-yl- methoxycarbonylamino) 5-oxo-5-prop-2- enoxypentanoic acid	133464-46-7
Fmoc-Gly—OH		2-(9H-fluoren-9-yl methoxycarbonylamino) acetic acid	29022-11-5
Fmoc-Gly(cBu)—OH		(2S)-2-cyclobutyl-2-(9H- fluoren-9-ylmethoxy carbonylamino)acetic acid	1391830-31-1
Fmoc-Gly(cPent)—OH		(2S)-2-cyclopentyl-2- (9H-fluoren-9-ylmethoxy carbonylamino)acetic acid	220497-61-0
Fmoc-Gly(cPr)—OH		(2S)-2-cyclopropyl-2- (9H-fluoren-9-ylmethoxy carbonylamino)acetic acid	1212257-18-5
Fmoc-Hle—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 5-methylhexanoic acid	180414-94-2
Fmoc-Hph—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-phenylbutanoic acid	132684-59-4
Fmoc-Hph(34-Cl2)—OH		(2S)-4-(3,4- dichlorophenyl)-2-(9H- fluoren-9-ylmethoxy carbonylamino) butanoic acid	1260616-12-3
Fmoc-Hph(3-F)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-(3-fluorophenyl) butanoic acid	1260594-44-2
Fmoc-Hph(4-CF3)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-[4-(trifluoromethyl) phenyl]butanoic acid	1260591-49-8
Fmoc-Hph(4-F)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-(4-fluorophenyl) butanoic acid	1260608-85-2
Fmoc-Hph(4-Me)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-(4-methylphenyl) butanoic acid	1260587-57-2
Fmoc-Hse(Me)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-methoxybutanoic acid	173212-86-7
Fmoc-iBuGly—OH		2-[9H-fluoren-9- ylmethoxycarbonyl(2- methylpropyl)amino] acetic acid	141743-14-8
Fmoc-IDC—OH		(2S)-1-(9H-fluoren-9- ylmethoxycarbonyl)-2,3- dihydroindol-2- carboxylic acid	198660-38-2
Fmoc-Ile—OH		(2S,3S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 3-methylpentanoic acid	71989-23-6
Fmoc-Leu—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-methylpentanoic acid	35661-60-0
Fmoc-Lys(Alloc)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 6-(prop-2- enoxycarbonylamino) hexanoic acid	146982-27-6
Fmoc-MeAbu—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]butanoic acid	1310575-53-1
Fmoc-MeAlb—OH		2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-2- methylpropanoic acid	400779-65-9
Fmoc-MeAla—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino] propanoic acid	84000-07-7
Fmoc-MeCha—OH		(2S)-3-cyclohexyl-2- [9H-fluoren-9- ylmethoxycarbonyl (methyl)amino] propanoic acid	148983-03-3
Fmoc-MaCha—OH		(2S)-2-cyclohexyl-2- [9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]acetic acid	925240-97-7
Fmoc-MeGly—OH		2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]acetic acid	77128-70-2
Fmoc-Melle—OH		(2S,3S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3- methylpentanoic acid	138775-22-1
Fmoc-MeLeu—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-4- methylpentanoic acid	103478-62-2
Fmoc-MeNle—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]hexanoic acid	112883-42-8
Fmoc-MaNva—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino] pentanoic acid	252049-05-1
Fmoc-MePhe—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3- phenylpropanoic acid	77128-73-5
Fmoc-MePhe(3-Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3-(3- methylphenyl)propanoic acid	absent
Fmoc-Met(O2)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4- methylsulfonylbutanoic acid	183437-14-7
Fmoc-Methagly—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 4-methylpent-4-enoic acid	87720-55-6
Fmoc-MeThr—OH		(2S,3R)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3- hydroxybutanoic acid	252049-06-2
Fmoc-MeThr(Bn)—OH		(2S,3R)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3- phenylmethoxybutanoic acid	198561-81-8
Fmoc-MaTyr(Ma)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3-(4- methoxyphenyl) propanoic acid	1260595-45-6
Fmoc-MeVal—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3- methylbutanoic acid	84000-11-3
Fmoc-Mor(3)—OH		(3S)-4-(9H-fluoren-9- ylmethoxycarbonyl) morpholin-3-carboxylic acid	281655-37-6
Fmoc-Nle—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) hexanoic acid	77284-32-3
Fmoc-Nva—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) pentanoic acid	135112-28-6
Fmoc-Nva(3-Et)—OH		(2S)-3-ethyl-2-(9H- fluoren-9-ylmethoxy carbonylamino) pentanoic acid	1310680-47-7
Fmoc-Oic—OH		(2S,3aS,7aS)-1-(9H- fluoren-9- ylmethoxycarbonyl)- 2,3,3a,4,5,6,7,7a- octahydroindol-2- carboxylic acid	130309-37-4
Fmoc-Phe—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-phenylpropanoic acid	35661-40-6
Fmoc-Phe(23-F2)—OH		(2S)-3-(2,3- difluorophenyl)-2-(9H- fluoren-9-ylmethoxy carbonylamino) propanoic acid	1260605-30-8
Fmoc-Phe(2-CF3)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-[2-(trifluoromethyl) phenyl)propanoic acid	352523-16-1
Fmoc-Phe(2-Cl)—OH		(2S)-3-(2-chlorophenyl)- 2-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	198560-41-7
Fmoc-Phe(2-F)—OH		(2S)-2-(9H-fluoren-9-yl- methoxycarbonylamino) 3-(2-fluorophenyl) propanoic acid	205526-26-7
Fmoc-Phe(2-Me)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(2-methylphenyl) propanoic acid	211687-75-1
Fmoc-Phe(2-OCF3)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-[2-(trifluoromethoxy) phenyl]propanoic acid	1260593-24-5
Fmoc-Phe(2-OMe)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(2-methoxyphenyl) propanoic acid	206080-41-5
Fmoc-Phe(36-F2)—OH		(2S)-3-(3,5- difluorophenyl)-2-(9H- fluoren-9-ylmethoxy carbonylamino) propanoic acid	205626-24-5
Fmoc-Phe(3-CF3)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-[3-(trifluoromethyl) phenyl]propanoic acid	205526-27-8
Fmoc-Phe(3-Cl)—OH		(2S)-3-(3-chiorophenyl)- 2-(9H-fluoren-9-yl methoxycarbonylamino) propanoic acid	198560-44-0
Fmoc-Phe(3-F)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(3-fluorophenyl) propanoic acid	198580-68-8
Fmoc-Phe(3-I)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(3-lodophenyl) propanoic acid	210282-31-8
Fmoc-Phe(3-Me)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(3-methylphenyl) propanoic acid	211637-74-0
Fmoc-Phe(3-OCF3)—OH		(2S)-2-(9H-fluoren-9-y] methoxycarbonylamino)- 3-[3-(trifluoromethoxy) phenyl)propanoic acid	1280592-32-2
Fmoc-Phe(3-OMe)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(3-methoxyphenyl) propanoic acid	206060-40-4
Fmoc-Phe(4-CF3)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-[4-(trifluoromethyl) phenyl]propanoic acid	247113-86-6
Fmoc-Phe(4-F)-OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(4-fluorophenyl) propanoic acid	189243-86-1
Fmoc-Phe(4-Me)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(4-methylphenyl) propanoic acid	199006-54-7
Fmoc-Phe3—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 5-phenylpentanoic acid	959678-11-1
Fmoc-Pic(2)—OH		(2S)-1-(9H-fluoren-9- ylmethoxycarbonyl) piperidin-2-carboxylic acid	86069-86-5
Fmoc-Pic(2)(4-Oxc)—OH		(2S)-1-(9H-fluoren-9- ylmethoxycarbonyl)-4- oxopiperidin-2- carboxylic acid	1221793-43-6
Fmoc-PRA—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino) pent-4-ynoic acid	198661-07-8
Fmoc-Pregly—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 5-methylhex-4-enoic acid	914486-08-1
Fmoc-Pro—OH		(2S)-1-(9H-fluoren-9- ylmethoxycarbonyl) pyrrolidin-2-carboxylic acid	71989-31-6
Fmoc-Pro(4-F2)—OH		(2S)-1-(9H-fluoren-9- ylmethoxycarbonyl)-4,4- difluoropyrrolidin-2- carboxylic acid	203866-21-1
Fmoc-Pro(4-kato)—OH		(2S)-1-(9H-fluoren-9- ylmethoxycarbonyl)-4- oxopyrrolidin-2- carboxylic acid	223681-83-7
Fmoc-Pro(4R-Ph)—OH		(2S,4R)-1-(9H-fluoren- 9-ylmethoxycarbonyl)-4- phenylpyrrolidin-2- carboxylic acid	1093651-96-7
Fmoc-Pro(4S-Ph)—OH		(2S,4S)-1-(9H-fluoren-9- ylmethoxycarbonyl)-4- phenylpyrrolidin-2- carboxylic acid	269078-71-9
Fmoc-Ser(Me)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-methoxypropanoic acid	159610-93-2
Fmoc-Thiopro—OH		(4R)-3-(9H-fluoren-9- ylmethoxycarbonyl)-1,3- thiazolidin-4-carboxylic acid	133054-21-4
Fmoc-Thr(Me)—OH		(2S,3R)-2-(9H-fluoren- 9-ylmethoxy carbonylamino)-3- methoxybutanoic acid	928063-81-4
Fmoc-Tle—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3,3-dimethylbutanoic acid	132684-60-7
Fmoc-Tyr(Me)—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-(4-methoxyphenyl) propanoic acid	77128-72-4
Fmoc-Val—OH		(2S)-2-(9H-fluoren-9-yl methoxycarbonylamino)- 3-methylbutanoic acid	68858-20-8
Fmoc-MePhe(3- OMe)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]-3-(3- methoxyphenyl) propanoic acid	absent
Fmoc-Phe(2-Cl- 5-Br)—OH		(2S)-3-(5-bromo-2- chlorophenyl)-2-(9H- fluoren-9-ylmethoxy carbonylamino) propanoic acid	2002401-84-3

TABLE 5
Compound
No.	Abbreviation	Structural formula	Name
aa001	Fmoc-(pip(4-F2)nPr)Gly-OH		2-[3-(4,4-difluoropiperidin-1- yl)propyl-(9H-fluoren-9- ylmethoxycarbonyl)amino] acetic acid
aa002	Fmoc-2-(pip-4-F2)-EtGly-OH		2-[2-(4,4-difluoropiperidin-1- yl)ethyl-(9H-fluoren-9- ylmethoxycarbonyl)amino] acetic acid
aa003	Fmoc-cPrGly-OH		2-[cyclopropyl(9H-fluoren-9- ylmethoxycarbonyl)amino] acetic acid
aa004	Fmoc-iPrGly-OH		2-[9H-fluoren-9- ylmethoxycarbonyl(propan-2- yl)amino]acetic acid
aa033	Fmoc-MeAla(3-Pyr-4-CF3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-[6- (trifluoromethyl)pyridin-3- yl]propanoic acid
aa034	Fmoc-MeAla(3-Pyr-5-OMe)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(5-methoxypyridin-3- yl)propanoic acid
aa035	Fmoc-MeAla(3-Pyr-5-Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(5-methylpyridin-3- yl)propanoic acid
aa036	Fmoc-MeAla(3-Pyr-4-OMe)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(6-methoxypyridin-3- yl)propanoic acid
aa037	Fmoc-MeAla(3-Pyr-4-Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(6-methylpyridin-3- yl)propanoic acid
aa038	Fmoc-Ala(3-Pyr-5-Br)—OH		(2S)-3-(5-bromopyridin-3-yl)-2- [9H-fluoren-9- ylmethoxycarbonylamino] propanoic acid
aa039	Fmoc-MeAbu(3-Pyr)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-pyridin-3-ylbutanoic acid
aa040	Fmoc-MeAbu(4-Pyr)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-pyridin-4-ylbutanoic acid
aa041	Fmoc-Ser(cPr)—OH		(2S)-3-cyclopropyloxy-2-(9H- fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa042	Fmoc-MeSer(cBu)—OH		(2S)-3-cyclobutyloxy-2-19H- fluoren-9- ylmethoxycarbonyl(methyl) amino]propanoic acid
aa043	Fmoc-Ser(cBu)—OH		(2S)-3-cyclobutyloxy-2-(9H- fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa044	Fmoc-Ser(Tfe)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3- (2,2,2-trifluoroethoxy) propanoic acid
aa045	Fmoc-MeSer(Tfe)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(2,2,2- trifluoroethoxy)propanoic acid
aa047	Fmoc-MeAbu(Aze-3-F2)—OH		(2S)-4-(3,3-difluoroazetidin-1- yl)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]butanoic acid
aa048	Fmoc-MeAlgly—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]pent-4-enoic acid
aa049	Fmoc-Hph(4-SF5)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-4- [4-(pentafluoro-)6-sulfanyl) phenylbutanoic acid
aa050	Fmoc-nPrAla-OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(propyl) amino]propanoic acid
aa053	Fmoc-Ala(B(OH)2)—OH		(2S)-3-borono-2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa054	Fmoc-D-MeSer(THP)-OH		(2R)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(oxan-2-yloxy) propanoic acid
aa055	Fmoc-O-MeSer( Pen)-OH		(2R)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(3-methylbutoxy) propanoic acid
aa060	Fmoc-MePhe(3-CN)—OH		(2S)-3-(3-cyanophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa061	Fmoc-MePhe(4-CN)—OH		(2S)-3-(4-cyanophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa062	Fmoc-MeSer(Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-methoxypropanoic acid
aa063	Fmoc-MePhe(2-CF3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-[2-(trifluoromethyl) phenyl]propanoic acid
aa064	Fmoc-MePhe(2-CN)—OH		(2S)-3-(2-cyanophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa065	Fmoc-MeAla(4-Pyr)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-pyridin-4-ylpropanoic acid
aa066	Fmoc-MsPhe(4-CHF2)—OH		(2S)-3-[4-(difluoromethyl) phenyl]-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]propanoic acid
aa067	Fmoc-MePhe(2-OMe)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(2-methoxyphenyl) propanoic acid
aa068	Fmoc-MeAla(3-Pyr)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-pyridin-3-ylpropanoic acid
aa069	Fmoc-MeSer(cPr)—OH		(2S)-3-cyclopropyloxy-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa070	Fmoc-MeAla(cPr)—OH		(2S)-3-cyclopropyl-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa071	Fmoc-MeAla(cPent)—OH		(2S)-3-cyclopentyl-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa072	Fmoc-MeAla(cBu)—OH		(2S)-3-cyclobutyl-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa073	Fmoc-MePhe(3-CF3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-[3-(trifluoromethyl) phenyl]propanoic acid
aa074	Fmoc-MePhe(2-OCF3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-[2-(trifluoromethoxy) phenyl]propanoic acid
aa075	Fmoc-MeGly(cBu)—OH		(2S)-2-cyclobutyl-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]acetic acid
aa076	Fmoc-MeAhxy(2)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]hex-5-ynoic acid
aa077	Fmoc-MePhe(2-Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(2-methylphenyl) propanoic acid
aa078	Fmoc-MeHse(Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-methoxybutanoic acid
aa079	Fmoc-MeGly(cPent)—OH		(2S)-2-cyclopentyl-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]acetic acid
aa080	Fmoc-MePhe(3-F)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(3-fluorophenyl) propanoic acid
aa081	Fmoc-MePhe(4-OCF3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-[4-(trifluoromethoxy) phenyl]propanoic acid
aa082	Fmoc-MePhe(4-F)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(4-fluorophenyl) propanoic acid
aa083	Fmoc-MePRA—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]pent-4-ynoic acid
aa084	Fmoc-MeHn —OH		(2S)-2-[9H-fuoren-9- ylmethoxycarbonyl(methyl) amino]heptanoic acid
aa085	Fmoc-MePhe(4-Me)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(4-methylphenyl) propanoic acid
aa086	Fmoc-MePhe(4-Br)—OH		(2S)-3-(4-bromophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa087	Fmoc-MePhe(3-OCF3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-[3-(trifluoromethoxy) phenyl]propanoic acid
aa088	Fmoc-MecLeu-OH		1-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]cyclopentan-1- carboxylic acid
aa089	Fmoc-MeGly(cPr)—OH		(2S)-2-cyclopropyl-2-[9H- fluoren-9- ylmethoxycarbonyl(methyl) amino]acetic acid
aa090	Fmoc-MePhe(4-CF3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-[4-(trifluoromethyl) phenyl]propanoic acid
aa091	Fmoc-MeAbu(4-F3)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4,4,4-trifluorobutanoic acid
aa092	Fmoc-MeMet(O2)—OH		(2S)-2-[9H-fuoren-9- ylmethoxycarbonyl(methyl) amino]-4- methylsulfonylbutanoic acid
aa093	Fmoc-MeThr(Me)—OH		(2S,3R)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-methoxybutanoic acid
aa094	Fmoc-MePhe(2-Cl)—OH		(2S)-3-(2-chiorophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa095	Fmoc-MePhe(2-F)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(2-fluorophenyl) propanoic acid
aa096	Fmoc-MePhe(4-I)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(4-iodophenyl) propanoic acid
aa097	Fmoc-MePhe(3-Br)—OH		(2S)-3-(3-bromophenyl)-2-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoic acid
aa098	Fmoc-Me(Me)Phe—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-2-methyl-3- phenylpropanoic acid
aa033-b	Fmoc-MeAsp(OAl)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxo-4-prop-2- enoxybutanoic acid
aa101	Fmoc-cisHyp(THP)-OH		(2S,4S)-1-(9H-fluoren-9- ylmethoxycarbonyl)-4-(oxan-2- yloxy)pyrrolidin-2-carboxylic acid
aa102	Fmoc-Hyp(TMP)-OH		(2S,4R)-1-(9H-fluoren-9- ylmethoxycarbonyl)-4-(oxan-2- yloxy)pyrrolidin-2-carboxylic acid
aa104	Fmoc-Phe(3-I-5-Cl)—OH		(2S)-3-(3-chloro-5- iodophenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa105	Fmoc-Phe(2-F-3-I)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3- (2-fluoro-3-iodophenyl) propanoic acid
aa106	Fmoc-Phe(3-I-5-F)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3- (3-fluoro-5-iodophenyl) propanoic acid
aa109	Fmoc-EtAla—OH		(2S)-2-[ethyl(9H-fluoren-9- ylmethoxycarbonyl)amino] propanoic acid
aa110	Fmoc-EtPhe(4-Cl)—OH		(2S)-3-(4-chlorophenyl)-2- [ethyl(9H-fluoren-9- ylmethoxycarbonyl)amino] propanoic acid
aa111	Fmoc-EtLeu—OH		(2S)-2-[ethyl(9H-fluoren-9- ylmethoxycarbonyl)amino]-4- methylpentanoic acid
aa112	Fmoc-EtCh —OH		(2S)-3-cyclohexyl-2-[ethyl(9H- fluoren-9-ylmethoxycarbonyl) amino]propanoic acid
aa113	Fmoc-EtPhe(4-Me)—OH		(2S)-2-[ethyl(9H-fluoren-9- ylmethoxycarbonyl)amino]-3- (4-methylphenyl)propanoic acid
aa114	Fmoc-EtPhe(4-CF3)—OH		(2S)-2-[ethyl(9H-fluoren-9- ylmethoxycarbonyl)amino]-3- [4-(trifluoromethyl)phenyl] propanoic acid
aa116	Fmoc-Phe(26-F2)—OH		(2S)-3-(2,6-difluorophenyl)-2- (9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa118	Fmoc-Phe(26-F2)—OH		(2S)-3-(2,5-difluorophenyl)-2- (9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa119	Fmoc-(Me)Phe(3-I)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3- (3-iodophenyl)-2- methylpropanoic acid
aa120	Fmoc-Phe(35-Cl2)—OH		(2S)-3-(3,5-dichlorophenyl)-2- (9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa121	Fmoc-Phe(2-F-5-I)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3- (2-fluoro-5-iodophenyl) propanoic acid
aa122	Fmoc-Phe(2-Cl-5-I)—OH		(2S)-3-(2-chloro-5- iodophenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa124	Fmoc-Ala(2-Th -5-Cl)—OH		(2S)-3-(5-chiorothiophen-2-yl)- 2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa125	Fmoc-Ala(2-Th -5-Br)—OH		(2S)-3-(5-bromothiophen-2-yl)- 2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa126	Fmoc-Phe(2-Br-5-I)—OH		(2S)-3-(2-bromo-5- iodophenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa127	Fmoc-Phe(2-Me-5-I)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3- (5-iodo-2-methylphenyl) propanoic acid
aa128	Fmoc-Phe(2-Me-5-Br)—OH		(2S)-3-(5-bromo-2- methylphenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino) propanoic acid
aa130	Fmoc-MeAOC(2)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]octanoic acid
aa131	Fmoc-MeHle-OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-5-methylhexanoic acid
aa132	Fmoc-Hph(4-CF3-3-Cl)—OH		(2S)-4-[3-chloro-4- (trifluoromethyl)phenyl]-2-(9H- fluoren-9- ylmethoxycarbonylamino) butanoic acid
aa133	Fmoc -Hph(4-CF3-3-F)—OH		(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-4- [3-fluoro-4-(trifluoromethyl) phenyl]butanoic acid
aa134	Fmoc-Hph(4-CF3-35-F2)—OH		(2S)-4-[3,5-difluoro-4- (trifluoromethyl)phenyl]-2-(9H- fluoren-9- ylmethoxycarbonylamino) butanoic acid
aa150	Fmoc-MeNva(5-F2)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-5,5-difluoropentanoic acid
aa151	Fmoc-MePhe(34-F2)—OH		(2S)-3-(3,4-difluorophenyl)-2- [9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]propanoic acid
aa152	Fmoc-MeAsn(pip-4-F2)—OH		(2S)-4-(4,4-difluoropiperidin-1- yl)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxobutanoic acid
aa153	Fmoc-MeAsn(Aze-3-F2)—OH		(2S)-4-(3,3-difluoroazetidin-1- yl)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxobutanoic acid
aa154	Fmoc-MePhe(3-I)—OH		(2S)-2-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-(3-iodophenyl) propanoic acid
aa156	Fmoc-(4-Me-piz-Et)Gly—OH		2-[9H-fluoren-9- ylmethoxycarbonyl-[2-(4- methylpiperazin-1- ylethyl]amino]acetic acid
aa157	Fmoc-(Aze(3)Et)Gly—OH		2-[2-(azetidin-3-yl)ethyl-(9H- fluoren-9-ylmethoxycarbonyl) amino]acetic acid
aa158	Fmoc-(H2NEtOEt)Gly—OH		2-[2-(2-aminoethoxy)ethyl-(9H- fluoren-9-ylmethoxycarbonyl) amino]acetic acid
aa159	Fmoc-(H2NnBu)Gly—OH		2-[4-aminobutyl(9H-fluoren-9- ylmethoxycarbonyl)amino] acetic acid
aa160	Fmoc-(Me2NEtOEt)Gly—OH		2-[2-[2-(dimethylamino)ethoxy] ethyl-(9H-fluoren-9- ylmethoxycarbonyl)amino] acetic acid
aa161	Fmoc-(MeNEtOEt)Gly—OH		2-[9H-fluoren-9- ylmethoxycarbonyl-[2-12- (methylamino)ethoxy]ethyl] amino]acetic acid
aa162	Fmoc-(piz-Et)Gly—OH		2-[9H-fluoren-9- ylmethoxycarbonyl(2- piperazin-1-ylethyl)amino] acetic acid
indicates data missing or illegible when filed

Synthesis of Fmoc Amino Acid

Synthesis of Compound aa01, 2-[3-(4,4-difluoropiperidin-1-yl)propyl-(9H-fluoren-6-ylmethoxycarbonyl)amino]acetic acid (Fmoc-(4-F2)nPr)Gly-OH)

3-Amino-1-propanol (3.85 g, 51.3 mmol) was dissolved in anhydrous tetrahydrofuran (51.2 ml) under a nitrogen atmosphere and cooled to 0° C., after which a solution of Compound aa001-a (tert-butyl bromoacetate) (5.0 g, 25.6 mmol) in anhydrous tetrahydrofuran (33.3 ml) was added dropwise. The mixture was stirred at 0° C. for 10 min and then stirred at room temperature for one hour. After cooling again to 0° C., water (81.9 ml), sodium bicarbonate (4.74 g, 56.4 mmol), and N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (17.29 g, 51.3 mmol) were sequentially added and the mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and then extracted with ethyl acetate (500 ml) and a saturated aqueous ammonium chloride solution (500 ml). The organic layer was washed with water (500 ml) and brine (500 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting concentrate was purified by normal phase chromatography (n-hexane/ethyl acetate) to give Compound aa001-b (7.37 g, 70%).

LCMS (ESI) m/z=434 (M+Na)+

Retention time: 0.88 min (analysis condition SQDFA05)

Compound aa001-b (6.37 g, 15.5 mmol) was dissolved in anhydrous dichloromethane (51.6 ml), Dess-Martin periodinane (7.22 g, 17.0 mmol) was added at 0° C., and the mixture was stirred for 10 minutes and then warmed to room temperature. After one hour, the mixture was cooled to 0° C. and extracted with ethyl acetate (500 nil) and an aqueous sodium bicarbonate solution (500 ml). The organic layer was washed with an aqueous sodium thiosulfate solution (500 ml) and brine (500 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting concentrate was purified by normal phase chromatography (n-hexane/ethyl acetate) to give Compound aa001-c (5.58 g, 88%).

LCMS (ESI) m/z=410 (M+H)+

Retention time: 0.96 min (analysis condition SQDFA05)

Compound aa001-c (0.97 g, 2.37 mmol) and 4,4-difluoropiperidine hydrochloride (0.44 g, 2.77 mmol) were dissolved in N,N-dimethylformamide (7.9 ml), sodium triacetoxyborohydride (0.75 g, 3.55 mmol) was added, and the mixture was stirred for 30 minutes. The reaction solution was purified by reverse phase chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa001-d (0.65 g, 49%).

LCMS (ESI) m/z=515.5 (M+H)+

Retention time: 0.68 min (analysis condition SQDFA05)

Compound aa001-d (0.64 g, 1.14 mmol) was dissolved in 2,2,2-trifluoroethanol (5.7 ml), and trimethylsilyl chloride (TMSCl) (0.43 ml, 3.42 mmol) was added thereto. The mixture was stirred at room temperature for one hour, and the solvent was then evaporated under reduced pressure to give Compound aa001 (2-[3-(4,4-difluoropiperidin-1-yl)propyl-(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic acid, Fmoc-(pip(4-F2)nPr)Gly-OH) (0.52 g, 99%).

LCMS (ESI) m/z=459 (M+H)+

Retention time: 0.54 min (analysis condition SQDFA05)

Synthesis of Compound aa002, 2-[2-(4,4-difluoropiperidin-1-yl)ethyl-(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic acid (Fmoc-(pip(4-F2)Et)Gly-OH)

Compound aa002-a (8.59 g, 84%) was obtained by the same method as in the synthesis of Compound aa001-b using Compound aa001-a (tert-butyl bromoacetate) (5.00 g, 25.6 mmol) as a starting material and using 2-aminoethanol instead of 3-amino-1-propanol.

LCMS (ESI) m/z=420 (M+Na)+

Retention time: 0.88 min (analysis condition SQDFA05)

Compound aa002-b was obtained as a crude product (5.58 g) under the same reaction conditions as in the synthesis of Compound aa001-c using the obtained Compound aa002-a (2.35 g, 5.91 mmol). The next reaction was performed without further purification.

LCMS (ESI) m/z=396 (M+H)+

Retention time: 0.96 min (analysis condition SQDFA05)

Compound aa002-c (1.33 g, 82%) was obtained under the same reaction conditions as in the synthesis of Compound aa001-d using Compound aa002-b (2.79 g, 2.955 mmol equivalents) obtained in the above reaction.

LCMS (ESI) m/z=501.5 (M+H)+

Retention time: 0.67 min (analysis condition SQDFA05)

Compound aa002 (2-[2-(4,4-difluoropiperidin-1-yl)ethyl-(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic acid, Fmoc-(pip(4-F2)Et)Gly-OH) (1.08 g, 99%) was obtained under the same reaction conditions as in the synthesis of Compound aa001 using the obtained Compound aa002-c (1.33 g, 2.433 mmol).

LCMS (ESI) m/z=445 (M+H)+

Retention time: 0.58 min (analysis condition SQDFA05)

Synthesis of Compound aa003, 2-[cyclopropyl(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic

Cyclopropylamine (1.756 g, 30.8 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml) under a nitrogen atmosphere and cooled to 0° C., after which a solution of Compound aa001-a (tert-butyl bromoacetate) (3.0 g, 15.38 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) was added dropwise. The mixture was then stirred at room temperature overnight. Water (30 mL), diisopropylethylamine (DIPEA) (5.96 g, 46.1 mmol), and N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (10.38 g, 30.8 mmol) were sequentially added and the mixture was stirred at room temperature for one hour. Dimethyl sulfoxide and a 20% aqueous formic acid solution were added to the reaction solution, and the tetrahydrofuran was then evaporated under reduced pressure. The resulting concentrate was purified by reverse phase chromatography (acetonitrile with 0.1% formic acid/0.1% aqueous formic acid solution) to give Compound aa003-a (2.72 g, 45%).

LCMS (ESI) m/z=394 (M+H)+

Retention time: 1.06 min (analysis condition SQDFA05)

Compound aa003-a (2.72 g, 6.91 mmol) was dissolved in 2,2,2-trifluoroethanol (TFE) (34.6 mL), and trimethylsilyl chloride (TMSCl) (2.63 ml, 20.74 mmol) was added. The mixture was stirred at room temperature for 40 minutes, and the solvent was then evaporated under reduced pressure. The resulting concentrate was purified by reverse phase chromatography (acetonitrile with 0.1% formic acid/0.1% aqueous formic acid solution) to give Compound aa003 (2-[cyclopropyl(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic acid, Fmoc-cPrGly-OH) (1.74 g, 75%).

LCMS (ESI) m/z=338 (M+H)+

Retention time: 0.79 min (analysis condition SQDFA05)

Synthesis of Compound aa004, 2-[9H-fluoren-9-ylmethoxycarbonyl(propan-2-yl)amino]acetic acid (Fmoc-iPrGly-OH)

Compound aa004 (2-[9H-fluoren-9-ylmethoxycarbonyl(propan-2-yl)amino]acetic acid, Fmoc-iPrGly-OH) (7.0 g, 48% through three steps) was obtained by the same method as in the synthesis of Compound aa003 using Compound aa001-a (tert-butyl bromoacetate) (6.6 g, 33.8 mmol) as a starting material and using sodium carbonate instead of DIPEA as a base for Fmoc addition in the second step.

LCMS (ESI) m/z=340 (M+H)+

Retention time: 0.80 min (analysis condition SQDFA05)

Synthesis of Compound aa033, (2s)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[6-(trifluoromethyl)pyridin-3-yl]propanoic acid (Fmoc-MeAla(3-Pyr-4-CF3)-OH)

Fmoc-Asp(OA1)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (200 g, 506 mmol), p-toluenesulfonic acid (5.7 g, 0.05 equivalents), and paraformaldehyde (45.6 g, 3 equivalents) were mixed with toluene and the mixture was stirred at 110° C. for 16 hours. The solvent was evaporated from the reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution twice. The organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether, 0/100 to 30/70) to give Compound aa033-a (9H-fluoren-9-ylmethyl (4S)-5-oxo-4-(2-oxo-2-prop-2-enoxyethyl)-1,3-oxazolidine-3-carboxylate) (175 g, 85%). This was mixed with another batch synthesized in the same manner and was used for the next reaction.

LCMS (ESI) nm/z=408 (M+H)+

Retention time: 1.407 min (analysis condition SMDmethod_20)

A mixed solution of Compound aa033-a (100 g, 245 mmol), zinc bromide (ZnBr₂) (110 g, 496 mmol), and triethylsilane (TES) (56 g, 481.6 mmol) in dichloromethane (DCM) (1 L) was stirred at room temperature for 48 hours under a nitrogen atmosphere. Four batches of the reaction solution on the same scale were mixed and the solvent was evaporated under reduced pressure. The residue was dissolved in TBME and extracted with 0.5 M phosphate buffer (pH=approximately 7.5) ten times. The aqueous layers were combined, adjusted to pH 2 with 5 M aqueous hydrochloric acid, and extracted with isopropyl acetate (IPAC) twice. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. To remove the IPAC, TBME was added to the resulting residue and the solvent was evaporated under reduced pressure. This operation was repeated six times to give Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (270 g, 54%).

LCMS (ESI) m/z=410 (M+H)+

Retention time: 1.956 min (analysis condition SMDmethod_05)

Under a nitrogen atmosphere, a solution of tert-butyl 2,2,2-trichloroacetimidate (106.73 g, 488.5 mmol) in cyclohexane (480 mL) and boron trifluoride-diethyl ether complex (BF₃·OEt₂) (346.6 mg, 2.442 mmol) were added to a solution of Compound aa033-b (100 g, 244 mmol) in DCM (240 mL) at 0° C., and the mixture was warmed to room temperature and stirred for one hour. The reaction was quenched by adding pyridine to the reaction solution, and the solid was removed by filtration. TBME was added to the filtrate and the resulting solution was sequentially washed with saturated aqueous sodium bicarbonate and brine. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa033-c as a crude product (102 g, 90%).

LCMS (ESI) m/z=488 (M+Na)+

Retention time: 1.574 min (analysis condition SMDmethod_15)

Under a nitrogen atmosphere, phenylsilane (2.01 g, 18.6 mmol) was added dropwise to a mixture of Compound aa033-c (12 g, 26.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.797 mmol) in DCM (110 mL) at room temperature and the mixture was stirred for 40 minutes. The solvent was evaporated from the reaction solution under reduced pressure, and the resulting residue was dissolved in TBME and extracted with saturated aqueous sodium carbonate. The aqueous layer was adjusted to pH=2 with phosphoric acid and extracted with TBME. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether, 0/100 to 40/60) to give Compound aa033-d (10.2 g, 93%). This was mixed with another batch synthesized in the same manner and was used for the next reaction.

LCMS (ESI) m/z=448 (M+Na)+

Retention time: 2.042 min (analysis condition SMDmethod_05)

Compound aa033-d (200 g, 470 mmol), DCC (96.99 g, 470 mmol), and N-hydroxyphthalimide (84.35 g, 517.062 mmol) were dissolved in THF (2 L), and the mixture was stirred at room temperature for one hour. The solid in the reaction solution was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether, 0/100 to 40/60) to give Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (200 g, 73%).

LCMS (ESI) m/z=593 (M+Na)+

Retention time: 2.706 min (analysis condition SMDmethod_07)

1H-NMR (400 MHz, DMSO-d6) δ 8.04-7.84 (m, 6H), 7.69-7.59 (m, 21), 7.44-7.28 (m, 4H), 4.91-4.65 (m, 1H), 4.63-4.14 (m, 3H), 3.31-3.09 (m, 1H), 3.07 (s, 2H), 2.81 (s, 31H), 1.38 (s, 9H), 1.10 (s, 4H).

Under a nitrogen atmosphere, nickel bromide trihydrate (NiBr₂·3H₂O) (0.287 g, 1.052 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (0.282 g, 1.052 mmol) were dissolved in DMA (16 mL) to prepare a Ni solution.

Under a nitrogen atmosphere. DMA (16 mL) was added to Compound aa033-e (2.0 g, 3.51 mmol), zinc powder (1.146 g, 17.53 mmol), and 5-bromo-2-(trifluoromethyl)pyridine (2.376 g, 10.52 mmol), after which the previously prepared Ni solution was added and the mixture was stirred at room temperature for 14 hours. The reaction solution was then diluted with TBME (250 mL), and the solid component was removed by filtration. The resulting TBME/DMA solution was washed with an aqueous EDTA solution (1 g dissolved in 100 mL of water) twice, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid), and the fractions were lyophilized to give Compound aa033-f (1.15 g, 62.3%).

LCMS (ESI) m/z=527 (M+H)+

Retention time: 1.08 min (analysis condition SQDFA05)

The obtained Compound aa033-f (1.15 g, 2.184 mmol) was dissolved in a 4N hydrochloric acid/1,4-dioxane solution (10.92 mL, 43.7 mmol), and the mixture was stirred at room temperature for 19 hours and then the reaction solution was concentrated under reduced pressure to give Compound aa033 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[6-(trifluoromethyl)pyridin-3-yl]propanoic acid, Fmoc-MeAla(3-Pyr-4-CF3)-OH) (1.20 g, quant.).

LCMS (ESI) m/z=471 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Herein, conversion of NI amino acid protected by Fmoc group to N-methylamino acid was carried out according to the basic two-step synthesis route provided below. Examples of synthesis by N-methylation reaction will be described herein for each amino acid, but any methods described in different parts of the present specification may be used.

Synthesis of Compound aa034: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]3-(5-methoxypyridin-3-yl)propanoic acid (Fmoc-MeAla(3-Pyr-5-OMe)-OH)

Compound aa034-a (0.72 g, 42%) was obtained by the same method as in the synthesis of Compound aa033-f using Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (2 g, 3.51 mmol) and 3-bromo-5-methoxypyridine as raw materials.

LCMS (ESI) m/z=489 (M+H)+

Retention time: 0.89 min (analysis condition SQDFA05)

Compound aa034 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(5-methoxypyridin-3-yl)propanoic acid, Fmoc-MeAla(3-Pyr-5-OMe)-OH) (807.4 mg, quant.) was obtained by the same method as in the synthesis of Compound aa033 using Compound aa034-a (0.72 g, 1.474 mmol) as a raw material.

LCMS (ESI) m/z=433 (M+H)+

Retention time: 0.63 min (analysis condition SQDFA05)

Synthesis of Compound aa035, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(5-methylpyridin-3-yl)propanoic acid (Fmoc-MeAla(3-Pyr-5-Me)-OH)

Compound aa035-a (0.49 g, 29.6%) was obtained by the same method as in the synthesis of Compound aa033-f using Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (2.0 g, 3.51 mmol) and 3-bromo-5-methylpyridine as raw materials.

LCMS (ESI) m/z=473 (M+H)+

Retention time: 0.78 min (analysis condition SQDFA05)

Compound aa035 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(5-methylpyridin-3-yl)propanoic acid, Fmoc-MeAla(3-Pyr-5-Me)-OH.) (1.14 g, quant.) was obtained by the same method as in the synthesis of Compound aa033 using Compound aa035-a (1.03 g, 2.18 mmol) as a raw material.

LCMS (ESI) m/z=417 (M+H)+

Retention time: 0.60 min (analysis condition SQDFA05)

Synthesis of Compound aa036, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(6-methoxypyridin-3-yl)propanoic acid Fmoc-MeAla(3-Pyr-4-OMe)-OH

Compound aa036-a (752 mg, 43.9%) was obtained by the same method as in the synthesis of Compound aa033-fusing Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (2 g, 3.51 mmol) and 5-bromo-2-methoxypyridine as raw materials.

LCMS (ESI) m/z=489 (M+H)+

Retention time: 1.08 min (analysis condition SQDFA05)

Compound aa036 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(6-methoxypyridin-3-yl)propanoic acid, Fmoc-MeAla(3-Pyr-4-OMe)-OH) (715 mg, 99%) was obtained by the same method as in the synthesis of Compound aa033 using Compound aa036-a (752 mg, 1.539 mmol) as a raw material.

LCMS (ESI) m/z=433 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Synthesis of Compound aa037 (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methy)amino]-3-(6-methylpyridin-3-yl)propanoic acid (Fmoc-MeAla(3-Pyr-4-Me)-OH

A crude product obtained by the same method as in the synthesis of Compound aa033-f using Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (2 g, 3.51 mmol) and 5-bromo-2-methylpyridine as raw materials was purified by silica gel column chromatography (hexane/ethyl acetate) to give Compound aa037-a (780 mg, 47.1%).

LCMS (ESI) m/z=473 (M+H)+

Retention time: 0.73 min (analysis condition SQDFA05)

Compound aa037 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(6-methylpyridin-3-yl)propanoic acid, Fmoc-MeAla(3-Pyr-4-Me)-OH) (686 mg, 92%) was obtained by the same method as in the synthesis of Compound aa033 using Compound aa037-a (780 mg, 1.65 mmol) as a raw material.

LCMS (ESI) m/z=417 (M+H)+

Retention time: 0.56 min (analysis condition SQDFA05)

Synthesis of Compound aa038, (2S)-3-(5-bromopyridin-3-yl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid (Fmoc-Ala(5-Pyr-5-Br)—OH)

Fmoc-Asp-OtBu ((3S)-3-[9H-fluoren-9-ylmethoxycarbonylamino]-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid, CAS No. 129460-09-9) (300 g, 729 mmol) and N-hydroxyphthalimide (130.8 g, 801.8 mmol) were added to THF (3 L), DCC (181.8 g, 1.1 mmol) was further added thereto, and the mixture was stirred at room temperature for three hours. The solvent was evaporated from the reaction solution under reduced pressure. Toluene was added to the residue, and the solid was removed by filtration. The solvent was evaporated from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give Compound aa038-a (272 g, 67%).

LCMS (ESI) m/z=578.7 (M+Na)+

Retention time: 1.728 min (analysis condition SMDmethod_08)

Compound aa038-b (722 mg, 30%) was obtained by the same method as in the synthesis of Compound aa033-f using Compound aa038-a (2.6 g, 4.67 mmol) and 3,5-dibromopyridine as raw materials.

LCMS (ESI) m/z=523 (M+H)+

Retention time: 1.08 min (analysis condition SQDFA05)

A concentrate of Compound aa038 was obtained by the same method as in the synthesis of Compound aa033 using Compound aa038-b (722 mg, 1.379 mmol). The resulting concentrate was purified by reverse phase chromatography (acetonitrile/distilled water) to give Compound aa038 ((2S)-3-(5-bromopyridin-3-yl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(3-Pyr-5-Br)—OH) (300 mg, 40%).

LCMS (ESI) m/z=467 (M+H)+

Retention time: 0.77 min (analysis condition SQDFA05)

Synthesis of Compound aa039, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-pyridin-3-ylbutanoic acid (Fmoc-MeAbu(3-Pyr)-OH)

Fmoc-Glu-OtBu ((4S)4-9H-fluoren-9-ylmethoxycarbonylamino)-5[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid, CAS No. 84793-07-7) (175 g, 411 mmol), N-hydroxyphthalimide (67.1 g, 411 mmol), WSCI·HCl (78.85 g, 411 mmol), and DMAP (2.51 g, 20.6 mmol) were added to DMF (2 L), and the mixture was stirred at room temperature for 16 hours. 1 mmol/L aqueous hydrochloric acid was added to the reaction solution, followed by extraction with TBME. The organic layers were combined, sequentially washed with water, saturated aqueous sodium bicarbonate/water (1/1), and brine, and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether, 0/100 to 30/70) to give Compound aa039-a (1-O-tert-butyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanedioate) (105 g, 45%).

LCMS (ESI) m/z=593.5 (M+Na)+

Retention time: 2.374 min (analysis condition SMDmethod_09)

1H-NMR (300 MHz, DMSO-d6) δ 8.00-7.91 (m, 4H), 7.85 (dd, J=23.0, 7.6 Hz, 3H), 7.75 (d, J=7.4 Hz, 2H), 7.75-7.32 (m, 4H), 4.60-4.31 (m 2H), 4.30-4.02 (m, 2H), 3.01-2.74 (m, 2H), 2.26-1.86 (m, 2H), 1.41 (s, 9H).

Under a nitrogen atmosphere, nickel bromide (NiBr₂·3H₂O) (_0.716 g, 2.63 mmol) and 4,4-di-tert-butyl-2,2-bipyridyl (0.706 g, 2.63 mmol) were dissolved in DMA (40 mL) to prepare a Ni solution.

Under a nitrogen atmosphere, DMA (40 mL) was added to Compound aa039-a (5.0 g, 8.76 mmol), zinc powder (2.86 g, 43.8 mmol), and 3-bromopyridine (2.55 mL, 26.3 mmol), after which the previously prepared Ni solution was added and the mixture was stirred at room temperature for 14 hours. The reaction solution was then diluted with TBME (150 mL), after which the resulting TB ME/DMA solution was washed with an aqueous EDTA solution (16 g dissolved in 250 mL of water) and then washed with saturated aqueous sodium carbonate/water (1/1, 80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid), and the fractions were lyophilized to give Compound aa039-b (2.5 g, 62.2%).

LCMS (ESI) m/z=459 (M+H)+

Retention time: 0.69 min (analysis condition SQDFA05)

The obtained Compound aa039-b (2.5 g, 5.45 mmol) was dissolved in TFE (27.3 mL), and TMSCl (2.1 mL, 16.4 mmol) was added. The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure. The resulting residue was dissolved in TBME (1 mL) and concentrated. This operation was performed three times to give the target Compound aa039-c as a crude product (2.38 g, 99%).

LCMS (ESI) m/z=403.2 (M+H)+

Retention time: 0.51 min (analysis condition SQDFA05)

The obtained Compound aa039-c (2.38 g, 5.42 mmol) and paraformaldehyde (0.488 g, 16.3 mmol) were dissolved in toluene (6.57 mL), TFA (3.76 mL, 48.8 mmol) was added, and the mixture was warmed to 40° C. The reaction solution was stirred at 40° C. for five hours and cooled to room temperature. The reaction solution was concentrated under reduced pressure to give a residue, which was then dissolved in ethyl acetate (20 mL), washed with a saturated aqueous sodium carbonate solution (20 mL), and then washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by normal phase column chromatography (hexane/ethyl acetate), and the resulting fractions were concentrated to give the target Compound aa039-d (1.33 g, 59%).

LCMS (ESI) m/z=415(M+H)+

Retention time: 0.58 min (analysis condition SQDFA05)

The obtained Compound aa039-d (1.33 g, 3.21 mmol) was dissolved in dichloroethane (DCE) (6.7 ml) and HCl/1,4-dioxane (4N, 6.9 mL), triethylsilane (4.58 mL, 28.9 mmol) was added, and TFA (6.68 mL, 87 mmol) was then added. The reaction solution was warmed to 70° C. and stirred for two hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile with 0.05% TFA/distilled water with 0.05% TFA), and the fractions were lyophilized. The resulting TFA salt was desalted through purification by reverse phase column chromatography (acetonitrile/distilled water) to give Compound aa039 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-pyridin-3-ylbutanoic acid, Fmoc-MeAbu(3-Pyr)-OH) (1.01 g, 69.5%).

LCMS (ESI) m/z=417 (M+H)+

Retention time: 0.52 min (analysis condition SQDFA05)

Synthesis of Compound aa040, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-pyridin-4-ylbutanoic acid (Fmoc-MeAbu(4-Pyr)-OH)

Under a nitrogen atmosphere, nickel bromide (NiBr₂·3H₂O) (0.615 g, 2.26 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (0.605 g, 2.26 mmol) were dissolved in DMA (37 mL) to prepare a Ni solution.

4-Bromopyridine hydrochloride (4.39 g, 22.6 mmol) was desalted by dissolving it in toluene (10 mL), a 5N aqueous sodium hydroxide solution (5 mL), and water (5 mL) and an organic layer was prepared as a 4-bromopyridine solution.

Under a nitrogen atmosphere, Compound aa039-a (1-O-tert-butyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanedioate) (4.3 g, 7.52 mmol) and zinc powder (2.46 g, 37.6 mmol) were added to DMA (37 mL), followed by stirring. The previously prepared 4-bromopyridine solution (10 mL, 22.6 mmol) was added, the previously prepared Ni solution was then added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was then diluted with TBME (150 mL), after which the resulting TBME/DMA. solution was washed with an aqueous EDTA-2Na solution (16 g dissolved in 250 mL of water) and then washed with saturated aqueous sodium carbonate/water (1/1, 80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the fractions were concentrated under reduced pressure to give Compound aa040-a (2.7 g, 78%).

LCMS (ESI) m/z=459 (M+H)+

Retention time: 0.65 min (analysis condition SQDFA05)

Compound aa040-b (2.7 g, quant.) was obtained by the same method as in the synthesis of Compound aa039-c using Compound aa040-a (2.7 g, 5.89 mmol) as a raw material.

LCMS (ESI) m/z=401 (M−H)−

Retention time: 0.55 min (analysis condition SQDFA05)

Compound aa040-c (1.8 g, 75%) was obtained by the same method as in the synthesis of Compound aa039-d using Compound aa040-b (2.55 g, 5.81 mmol) as a raw material.

LCMS (ESI) m/z=415 (M+H)+

Retention time: 0.55 min (analysis condition SQDFA05)

Compound aa040 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-pyridin-4-ylbutanoic acid, Fmoc-MeAbu(4-Pyr)-OH) (860 mg, 47%) was obtained by the same method as in the synthesis of Compound aa039 using Compound aa040-c (1.81 g, 4.37 mmol) as a raw material.

LCMS (ESI) m/z=417 (M-IT)+

Retention time: 0.51 min (analysis condition SQDFA05)

Synthesis of Compound aa041, (2S)-3-cyclopropyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Ser(cPr)—OH)

Methyl (S)—N-tritylaziridine-2-carboxylate (CAS No. 75154-68-6) (50 g, 146 mmol) was added to a mixed solution of chloroform (145 mL) and methanol (145 mL), trifluoroacetic acid (TFA) (33 mL, 3 equivalents) was added dropwise at 0° C. under a nitrogen atmosphere, and the mixture was stirred for seven hours. DIPEA (127 mL, 5 equivalents) was added to the reaction solution at 0° C., a solution of fluorenylmethyloxycarbonyl chloride (Fmoc-Cl) (36 g, 139 mmol) in 1,4-dioxane (145 mL) was further added dropwise, and the mixture was stirred at 0° C. for 90 minutes under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, dilated with ethyl acetate, and then sequentially washed with water, an aqueous ammonium chloride solution, an aqueous sodium bicarbonate solution, and brine. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether, 0/100 to 10/90) to give Compound aa041-a (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (40 g, 85%).

LCMS (ESI) m/z=323.9 (M+H)+

Retention time: 2.631 min (analysis condition SMDmethod_10)

Compound aa041-a (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (5 g, 15.46 mmol) was dissolved in DCM (30.9 mL) under a nitrogen atmosphere, cyclopropanol (1.665 mL, 26.3 mmol) was added, and then boron trifluoride-diethyl ether complex (BF₃·OEt₂) (0.291 mL, 2.319 mmol) was added with ice-cooling. The reaction solution was reacted for two hours on ice and then the reaction was quenched with water and a saturated aqueous sodium bicarbonate solution. The aqueous layer was removed by a phase separator, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by column chromatography (n-hexane/ethyl acetate=4/1) to give Compound aa041-b (4.6 g, 78%).

LCMS (ESI) m/z=382 (M+H)+

Retention time: 0.89 min (analysis condition SQDFA05)

Calcium chloride (20.08 g, 181 mmol) was dissolved in water (50.2 mL), lithium hydroxide monohydrate (2.024 g, 48.2 mmol) was added thereto, and the mixture was stirred at room temperature for five minutes to prepare an aqueous solution A. Compound aa041-b (4.6 g, 12.06 mmol) was dissolved in isopropanol (201 mL) and THF (50.2 mL), the previously prepared aqueous solution A was added, and the mixture was stirred at room temperature for five hours. 1 mol/L aqueous hydrochloric acid (36.2 mL) was then added to the reaction solution, after which isopropanol and THF were removed by concentration under reduced pressure. The resulting aqueous layer was diluted with water (50.2 mL) and extracted with ethyl acetate three times (total volume: 100 mL). The organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was then concentrated under reduced pressure. The resulting residue was washed with ethyl acetate/n-hexane (1/2, 20 v/w) to give the titled Compound aa041 ((2S)-3-cyclopropyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ser(cPr)—OH) (3.5 g, 79%).

LCMS (ESI) m/z=368 (M+H)+

Retention time: 0.78 min (analysis condition SQDFA05)

Synthesis of Compound aa042, (2S)-3-cyclobutyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid Fmoc-MeSer(cBu)-OH)

Compound aa042-a was obtained as a crude product by the same method as in the synthesis of Compound aa069-b using Compound aa043 ((2S)-3-cyclobutyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid) (10.61 g, 27.8 mmol) as a starting material.

LCMS (ESI) m/z=394.5 (M+H)+

Retention time: 1.01 min (analysis condition SQDFA05)

Compound aa042 ((2S)-3-cyclobutyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MeSer(cBu)-OH) (10.6 g, 96% through two steps) was obtained by the same method as in the synthesis of Compound aa069 using the total amount of Compound aa042-a obtained above.

LCMS (ESI) m/z=396 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Synthesis of Compound aa043, (2S)-3-cyclobutyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc Ser(cBu)-OH)

Compound aa043-a (4.54 g, 74.2%) was obtained by the same method as in the synthesis of Compound aa041-b using Compound aa041-a (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (5 g, 15.46 mmol) and cyclobutanol as raw materials.

LCMS (ESI) m/z=396 (M+H)+

Retention time: 0.94 min (analysis condition SQDFA05)

Compound aa043 ((2S)-3-cyclobutyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ser(cBu)-OH) (3.78 g, 86%) was obtained by the same method as in the synthesis of Compound aa041 using Compound aa043-a (4.54 g, 11.48 mmol) as a raw material.

LCMS (ESI) m/z=382 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Synthesis of Compound aa044, (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino) 3-(2,2,2-trifluoroethoxy)propanoic acid (Fmoc-Ser(Tfe)-OH)

2-Nitrobenzenesulfonyl chloride (NsCl) (32.37 g, 146 mmol) and L-serine methyl ester hydrochloride (25 g, 161 mmol, CAS No. 5680-80-8) were dissolved in DCM (874 mL), and DIPEA (51 mL, 292 mmol) was added at 5° C. After stirring at room temperature for one hour, the reaction solution was washed with water (440 mL) twice, washed with brine/water (1/1, 440 mL) once, and then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give Compound aa044-a (39.4 g, 89%) as a crude product.

LCMS (ESI) m/z=302.9 (M−H)−

Retention time: 0.729 min (analysis condition SMDmethod_06)

Compound aa044-a (23 g, 75.6 mmol) was dissolved in DCM (598 mL), and triphenylphosphine (31.7 g, 121 mmol) was added at room temperature. After cooling to −14° C., DEAD (55.0 mL, 121 mmol) was added over 10 minutes, and the mixture was then stirred at −5° C. for 50 minutes, n-Hexane (300 mL) was added and the precipitate was filtered off The filtrate was purified by silica gel column chromatography (n-hexane/DCM=50:50 to 0:100) to give Compound aa044-b (13.3 g, 62%),

LCMS (ESI) m/z=287 (M+H)+

Retention time: 0.872 min (analysis condition SMDmethod_06)

Compound aa044-b (10.7 g, 37.3 mmol) was dissolved in TFE (75 mL), boron trifluoride-diethyl ether complex (BF₃·OEt₂) (0.469 mL, 3.73 mmol) was added, and the mixture was then stirred at 70° C. for 30 minutes. TFE was evaporated under reduced pressure, and the resulting crude product was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa044-c (12.3 g, 85%).

LCMS (ESI) m/z=387 (M+H)+

Retention time: 0.72 min (analysis condition SQDFA05)

Compound aa044-c (12 g, 31.1 mmol) was dissolved in methanol (47 mL), and a solution of lithium hydroxide monohydrate (5.21 g, 124 mmol) in water (31 mL) was added. The reaction solution was stirred at room temperature for 90 minutes, followed by addition of formic acid (11.7 mL, 311 mmol). The reaction solution was diluted with water (30 mL) and then purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa044-d (7.90 g, 68%).

LCMS (ESI) m/z=373 (M+H)+

Retention time: 0.63 min (analysis condition SQDFA05)

Compound aa044-d (7.72 g, 20.7 mmol) was dissolved in acetonitrile (104 mL), potassium carbonate (7.17 g, 51.8 mmol) and dodecanethiol (7.44 mL, 31.1 mmol) were added, and the mixture was then stirred at room temperature for 74 hours. This was diluted with water (100 mL) and washed with TBME (200 mL) twice. A solution of Fmoc-OSu (3.5 g) in 1,4-dioxane (150 mL) was added to the resulting aqueous solution, and the mixture was stirred for 25 minutes. A solution of Fmoc-OSu (700 mg) in 1,4-dioxane (10 mL) was further added, and the mixture was stirred for five minutes. A solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was further added, and the mixture was stirred for five minutes. A solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was further added, and the mixture was stirred for five minutes, after which formic acid (3.9 mL) was added and the solvent was evaporated under reduced pressure. The resulting crude product was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa044 ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)propanoic acid, Fmoc-Ser(Tfe)-OH) (5.67 g, 67%).

LCMS (ESI) m/z=410 (M+H)+

Retention time: 2.35 min (analysis condition SQDFA05long)

Synthesis of Compound aa045, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-2,2,2-trifluoroethoxy)propanoic acid (Fmoc-MeSer(Tfe)-OH)

Compound aa045-a was obtained as a crude product by the same method as in the synthesis of Compound aa069-b using Compound aa044 (2.00 g, 4.89 mmol) as a starting material. In addition, Compound aa045 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-2,2,2-trifluoroethoxy)propanoic acid, Fmoc-MeSer(Tfe)-OH) (1.80 g, 87% through two steps) was obtained by the same method as in the synthesis of Compound aa069.

LCMS (ESI) m/z=424 (M+H)+

Retention time: 0.84 min (analysis condition SQDFA05)

Synthesis of Compound aa047 (2S)-4-(3,3-difluoroazetidin-1-yl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanoic acid (Fmoc-MeAbu(Aze-3-F2)-OH)

DMF (14 mL) was added to WSCI·HCl (1.65 g, 8.59 mmol) at room temperature under a nitrogen atmosphere., and the mixture was stirred and cooled in an ice bath. HOAt (1.07 g, 7.88 mmol) and Compound aa047-a ((S)-(+)-3-(benzyloxycarbonyl)-5-oxo-4-oxazolidine acetic acid) (2 g, 7.16 mmol) were added, and the mixture was stirred at the same temperature for 20 minutes. 3,3-Difluoroazetidine hydrochloride (1.02 g, 7.88 mmol) and DIPEA (1.25 mL, 7.16 mmol) were added and the mixture was stirred at the same temperature for six hours. Hexane/ethyl acetate (1/1, 20 mL) and potassium hydrogen sulfate (0.5 M aqueous solution, 30 mL) were added to the reaction mixture. The mixture was extracted with ethyl acetate twice, and the organic layers were washed with water (40 mL), saturated aqueous sodium bicarbonate/water (1/1.40 mL), and brine/water (1/1.40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give Compound aa047-b (2.52 g, 99%). The crude product, Compound aa047-b, was used for the next reaction without purification.

LCMS (ESI) m/z=355 (M+H)+

Retention time: 0.66 min (analysis condition SQDFA05)

Compound aa047-b (2.5 g, 7.06 mmol) was dissolved in DCM (15 mL) at room temperature under a nitrogen atmosphere, triethylsilane (TES) (3.38 ml., 21.17 mmol) and water (127 μL, 7.06 mmol) were added, and boron trifluoride-diethyl ether complex (BF₃·OEt₂) (1.79 mL, 14.11 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and 45 minutes, followed by addition of saturated aqueous ammonium chloride/water (1/1, 6 mL). The mixture was stirred for 10 minutes and then extracted with DCM. and the organic layer was washed with saturated aqueous ammonium chloride/water (1/1, 8 mL) and brine/water (1/1, 8 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was dissolved in acetonitrile and washed with hexane (5 mL) twice. The acetonitrile layer was concentrated under reduced pressure, and the resulting crude product was reverse-phase purified (eluent: water containing 0.1% formic acid-acetonitrile) to give Compound aa047-c ((2S)-4-(3,3-difluoroazetidin-1-yl)-2-[methyl(phenylmethoxycarbonyl)amino]-4-oxobutanoic acid) (2.20 g, 88%).

LCMS (ESI) m/z=357 (M+H)+

Retention time: 0.58 min (analysis condition SQDFA05)

1,1,3,3-Tetramethyldisiloxane (10.27 mL, 58.1 mmol) was added to a solution of Compound aa047-c (1.38 g, 3.87 mmol) and triruthenium dodecacarbonyl (Ru₃(CO)₁₂) (0.248 g, 0.387 mmol) in THF (15 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at a temperature between 35′C and 40° C. for 2 hours and 45 minutes. The reaction solution was left to cool at room temperature and was added dropwise to 2 mol/L aqueous hydrochloric acid (5 mL) cooled and stirred in an ice bath. The mixture was stirred at the same temperature for 25 minutes and then concentrated under reduced pressure. The crude product was purified by a reverse-phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa047-d (365.2 mg, 28%).

LCMS (ESI) m/z=341 (M−H)−

Retention time: 0.39 min (analysis condition SQDFA05)

A suspension of Compound aa047-d (360 mg, 1.05 mmol) and 10% palladium on carbon (50 w/w % water) (72 mg) in ethanol was stirred at room temperature for 3 hours and 45 minutes under a hydrogen atmosphere, after which 10% palladium on carbon (50 w/w % water) (72 mg) was added and the mixture was stirred at room temperature for 15 hours and 15 minutes under a hydrogen atmosphere. 10% palladium on carbon (50 w/w % water) (72 mg) was further added and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and washed with ethanol. The resulting filtrate was concentrated under reduced pressure to give Compound aa047-e (208.7 mg, 95%). The crude product, Compound aa047-e, was used for the next reaction without purification.

LCMS (ESI) m/z=207 (M−H)−

(Analysis condition SQDFA05)

Water (3 mL), DIPEA (0.69 mL, 3.94 mmol), and 1,4-dioxane (3 mL) were added to Compound aa047-e (205 mg, 0.985 mmol), and the mixture was stirred at room temperature. Fmoc-OSu (332 ng, 0.985 mmol) was added and the reaction mixture was stirred for about 40 minutes. Formic acid (1 mL) was added to the reaction mixture, and the mixture was purified by a reverse-phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa047 ((2S)-4-(3,3-difluoroazetidin-1-yl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanoic acid, Fmoc-MeAbu(Aze-3-F2)-OH) (352.7 mg, 83%).

LCMS (ESI) m/z=431 (M+H)+

Retention time: 0.54 min (analysis condition SQDFA05)

Synthesis of Compound aa048, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pent-4-enoic acid (Fmoc-MeAlgly-OH)

4N Hydrochloric acid-1,4-dioxane (8.23 ml, 32.9 mmol) was added to a solution of Compound aa048-a ((2S)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pent-4-enoic acid and Boc-MeAlgly-OH) (1.51 g, 6.59 mmol) in dichloromethane (6 ml), and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated to give Compound aa048-b as a crude product (1.55 g). The next reaction was performed without further purification.

LCMS (ESI) m/z=130 (M+H)+

Retention time: 0.14 min (analysis condition SQDFA05)

Compound aa048-b (6.59 mmol) was dissolved in water (9 ml), DIPEA (5.17 nil, 29.7 mmol), 1,4-dioxane (12 ml), and Fmoc-OSu (2.223 g, 6.59 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Water (25 ml) and diethyl ether/n-hexane (1/3, 18 ml) were added to the reaction solution, and the aqueous layer was washed with diethyl ether/n-hexane (1/3, 20 ml) twice. The aqueous layer was adjusted to pH 1.4 by adding potassium hydrogen sulfate (KHSO₄) and extracted with ethyl acetate. The organic layer was washed with brine/water (1/1) twice and dried over sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting crude product was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa048 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pent-4-enoic acid, Fmoc-MeAlgly-)-1) (2.62 g, 85%)

LCMS (ESI) m/z=352 (M+H)+

Retention time: 0.84 min (analysis condition SQDFA05)

Synthesis of Compound aa049, (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(pentafluoro-)λ6-sulfanyl)phenyl]butanoic acid (Fmoc-Hph(4-SF5)-OH)

DIPEA (161.5 mL, 3.00 equivalents) was added dropwise to a mixture of L-2-aminobutyric acid methyl ester hydrochloride (CAS No. 56545-22-3) (50 g, 325.51 mmol), pyridine-2-carboxylic acid (44.2 g, 359.03 mmol, 1.10 equivalents), and HATU (136.5 g, 358.99 mmol, 10.10 equivalents) in DCM (1 L) at room temperature, and the mixture was stirred for 16 hours. Water was added to the reaction solution, and the mixture was extracted with DCM three times. The organic layers were combined, sequentially washed with water and brine, and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether, 0/100 to 15/85) to give Compound aa049-a (209 g).

LCMS (ESI) m/z=223 (M+H)+

Retention time: 1.011 min (analysis condition SMDmethod_11)

1H-NMR (400 MHz, DMSO-d6): 8.87 (d, J=6.0 Hz, 1-1), 8.70-8.68 (m, 1H), 8.06-8.00 (n, 2H), 7.66-7.63 (m, 1H), 4.49-4.44 (q, 1H), 3.67 (s, 3H), 1.99-1.83 (m, 2H), 0.90 (t, J=5.7 Hz, 3H)

Compound aa049-a (1.35 g, 6.07 mmol), palladium(II) acetate (Pd (OAc)2, 0.273 g, 1.215 mmol), silver(I) carbonate (1.675 g, 6.07 mmol), dibenzyl phosphate (0.676 g, 2.43 mmol), 4-iodophenylsulfur pentafluoride (CAS No. 286947-68-0) (5.01 g, 15.2 mmol), and 2-methyl-2-butanol (35 mL) were mixed at room temperature, and the mixture was stirred at 115° C. for 5 hours and 15 minutes. The reaction solution was left to cool to room temperature, ethyl acetate was added, and the mixture was filtered through celite. The solvent was evaporated from the filtrate under reduced pressure to give Compound aa049-b (5.55 g) as a crude product.

LCMS (ESI) m/z=425 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Methanesulfonic acid (6.92 g, 72 mmol) and water (8.11 mL) were sequentially added to a mixture of Compound aa049-b (2.55 g, 6 mmol equivalents) in acetic acid (8.59 mL) at room temperature, and the mixture was stirred at a temperature between 110° C. and 115° C. for 24 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa049-c (1.13 g, 62%).

LCMS (ESI) m/z=306 (M+)+

Retention time: 0.47 min (analysis condition SQDFA05)

DIPEA (0.572 mL, 3.28 mmol), 1,4-dioxane (4 mL), and Fmoc-OSu (0.442 g, 1.31 mmol) were sequentially added to a solution of Compound aa049-c (0.4 g, 1.31 mmol) in water (3 mL) at room temperature, and the mixture was stirred for one hour. Formic acid was added to the reaction solution, and the reaction solution was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa049 ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(pentafluoro-λ6-sulfanyl)phenyl]butanoic acid) (0.564 g, 82%).

LCMS (ESI) m/z=528 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Synthesis of Compound aa050, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]propanoic acid (Fmoc-nPrAla-OH)

Allyl bromide (4.74 ml, 56.0 mmol) was added to a solution of Compound aa050-a (N-carbobenzoxy-L-alanine, Z-Ala-OH, CAS No. 1142-20-7) (5 g, 22.40 mmol) in tetrahydrofuran (74.7 ml) at room temperature, after which sodium hydride (2.69 g, 67.2 mmol) was added at 10° C. or below for 15 minutes or longer. The reaction solution was stirred at 10° C. or below for one hour, after which tetrahydrofuran (THF) (74.7 ml) was added and the mixture was stirred at room temperature for 65 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the mixture was then extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa050-b (3.91 g, 66%).

LCMS (ESI) m/z=264 (M+H)+

Retention time: 0.68 min (analysis condition SQDFA05)

A suspension of Compound aa050-b (3.81 g, 14.47 mmol) and 10 wt % palladium on carbon (0.41 g) in methanol (45 ml) was stirred at room temperature for two hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give Compound aa050-c (1.72 g, 91%).

LCMS (ESI) m/z=132 (M+H)+

Retention time: 0.13 min (analysis condition SQDFA05)

Compound aa050-c (1.72 g, 13.11 mmol) was suspended in water (45 ml), DIPEA (10.28 ml, 59.0 mmol), 1,4-dioxane (60 ml), and N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (4.42 g, 13.11 mmol) were added to the suspension, and then the mixture was stirred at room temperature for 30 minutes. Distilled water with 20% formic acid was added to the reaction solution, the mixture was then concentrated under reduced pressure, 1,4-dioxane was evaporated, and the resultant was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa050 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]propanoic acid, Fmoc-nPrAla-OH) (3.94 g, 85%).

LCMS (ESI) m/z=354 (M+H)+

Retention time: 0.86 min (analysis condition SQDFA05)

Synthesis of Compound aa053, (2S)-3-borono-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Ala(B(OH)2)-OH

A 1 M solution of lithium bis(trimethylsilyl)amide (LHMDS) in THF (78 ml, 78 mmol) was added to a solution of N-(diphenylmethylene)glycine tert-butyl (CAS No. 81477-94-3) (21 g, 71.1 mmol) in THF (237 mL) at −78° C. over 10 minutes under a nitrogen atmosphere, and the mixture was then stirred for 10 minutes. 2-(Iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22.9 g, 85 mmol) was added over 10 minutes, and the mixture was stirred for a further one hour. The reaction was quenched by adding water (300 mL), after which the reaction solution was warmed to room temperature and extracted with ethyl acetate (200 mL). The resulting organic layer was washed with brine/water (1/1, 50 mL) and dried over magnesium sulfate, and the solvent was then evaporated under reduced pressure. The resulting crude product containing Compound aa053-a was used for the next experiment without purification.

6 mol/L Aqueous hydrochloric acid (71 mL) was added to the crude product containing Compound aa053-a, which was then heated to 70° C., stirred for five hours. The reaction solution was cooled to room temperature and the reaction solution was then washed with dichloromethane (155 mL) twice. The resulting aqueous layer containing Compound aa053-b was used as it is for the next reaction without purification.

The aqueous layer containing Compound aa053-b was neutralized by adding a 6 mol/L aqueous sodium hydroxide solution at 0° C., after which dioxane (142 mL), DIPEA (37.2 mL, 214 mmol), and Fmoc-OSu (24 g, 71 mmol) were added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, then diluted with a water/acetonitrile/formic acid (25/75/0.1) solution and DMSO. The solution was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid), after which the acetonitrile was evaporated under reduced pressure and then lyophilized to give Compound aa053-c (24.8 g, 98% through three steps).

LCMS (ESI) m/z=354 (M−H)−

Retention time: 0.83 min (analysis condition SQDAA05)

Concentrated sulfuric acid (5.40 ml, 101 mmol) was added to a solution of Compound aa053-c (18 g, 50.7 mmol) in methanol (169 mL), and the mixture was stirred at 70° C. for 30 minutes. The reaction solution was cooled to 10° C., and water (255 mL) was then added over 30 minutes. The resulting precipitate was collected by filtration and then washed with water

• (54 ml) three times. The precipitate was dried to give Compound aa053-d (17.75 g, 95%). This was mixed with another lot synthesized in the same manner, and purified by following chiral column chromatography.

LCMS (ESI) m/z=392 (M+Na)+

Retention time: 0.95 min (analysis condition SQDAA05)

Compound aa053-d (20.8 g) was preparatively purified by chiral column chromatography (SFC CHIRALPAK AD-H (20 mm×250 mm), CO₂/MeOH=75/25, 15 mL/min; or LC CHIRALPAK OJ-RH (20 mm×250 mm), water/acetonitrile=55/45, 20 mL/min) to give Compound aa053-e (13.8 g).

Lithium hydroxide (2.41 g, 57.4 mmol) was added to a 3 mol/L aqueous calcium chloride solution (71.8 ml), and the mixture was stirred at room temperature for five minutes. Isopropyl alcohol (240 mL) and a solution of Compound aa053-f (5.30 g, 14.7 mmol) in THF (60 mL) were sequentially added to the resulting solution, and the mixture was stirred for one hour. The reaction was quenched with 5 M hydrochloric acid, the reaction solution was extracted with isopropyl acetate twice, and the resulting organic layers were dried over magnesium sulfate. The solution was filtered, and the solvent was then evaporated under reduced pressure to give Compound aa053 ((2S)-3-borono-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ala(B(OH)2)-OH) (5.6 g, quant.).

LCMS (ESI) m/z=354 (M−H)−

Retention time: 0.80 min (analysis condition SQDAA05)

Synthesis of Compound aa054, (2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(oxan-2-yloxy)propanoic acid (Fmoc-D-MeSer(THP)—OH)

Toluene (4 L), paraformaldehyde (293 g, 9.77 mol), and CSA (12.1 g, 52.1 mmol) were added to Compound aa054-a ((2R)-2-(9H-fluoren-9-“ylmethoxycarbonylamino)”-3- [(2-methylpropan-2-yl)oxy]propanoic acid, Fmoc-D-Ser(tBu)-OH, 400 g, 1.04 mol), and the mixture was stirred at 110° C. for four hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was sequentially washed with an aqueous sodium bicarbonate solution and brine, and dried over sodium sulfate, after which the solvent was evaporated under reduced pressure to give Compound aa054-b as a crude product (395 g).

LCMS (ESI) m/z=396 (M+H)+

Retention time: 2.935 min (analysis condition SMDmethod_12)

Compound aa054-b (100 g, 253 mmol) was dissolved in DCM/TFA (1/1, 2 L), triethylsilane (264 g, 2.27 mol) was added, and the mixture was stirred at 50° C. for four hours. The solvent was evaporated under reduced pressure to give Compound aa054-c as a crude product (96 g). This was mixed with another lot synthesized separately and was used for the next reaction.

LCMS (ESI) m/z=364 (M+Na)+

Retention time: 2.024 min (analysis condition SMDmethod_12)

3,4-Dihydro-2H-pyran (310 mL, 7 equivalents) and PPTS (6.6 g, 26.4 mmol) were added to a solution of Compound aa054-c (180 g, 527 mmol) in THF (1.08 L), and the mixture was stirred at 50° C. for four hours. Water was added to the reaction solution, and the organic layer was obtained by extraction with ethyl acetate, washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give Compound aa054 as a mixture with a THP-protected carboxylic acid (327 g). This was mixed with another lot synthesized separately and was used for the next reaction.

Phosphate buffer (pH=8, 3 L) was added to a solution of the above mixture (490 g) in THF (3 L), and the mixture was stirred at 50° C. for four hours. The reaction solution was extracted with ethyl acetate, and the resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from ether/heptane to give Compound aa054 sodium salt (500 g). TBME (8 L) and an aqueous phosphoric acid solution (110 g/22.5 L) were added thereto and the mixture was stirred at room temperature for 20 minutes. The reaction solution was extracted with TBME, and the resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa054 ((2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(oxan-2-yloxy)propanoic acid, Fmoc-D-MeSer(THP)—OH) as a white solid (366 g, 77%).

LCMS (ESI) m/z=448 (M+Na)+

Retention time: 2.095 min (analysis condition SMDmethod_01)

Synthesis of Compound aa055 (2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-methylbutoxy)propanoic acid (Fmoc-D-MeSer(iPen)-OH)

Sodium hydride (NaH) (120 g, 2.2 equivalents) was added to a solution of Compound aa055-a ((2R)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid, Boc-D-Ser-OH) (466 g, 2.27 mol) in DMF (1.5 L) at 0° C. under a nitrogen atmosphere, and the mixture was stirred for two hours. 1-Bromo-3-methyl-2-butene (372 g, 2.5 mmol) was added dropwise to the reaction solution at 0° C., and the mixture was stirred at room temperature for 16 hours. Ice water was added to the reaction solution, and the mixture was adjusted to pH=2 with concentrated hydrochloric acid. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water and dried over sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound aa055-b as a red oiled substance (530 g, 85%).

LCMS (ESI) m/z=296 (M+Na)+

Retention time: 1.259 min (analysis condition SMDmethod_15)

Compound aa055-b (420 g, 1.54 mol) was dissolved in methanol (3 L), ammonia (2 M methanol solution, 1.2 L, 67.7 mmol) and palladium on carbon (85 g, 0.52 equivalents) were added, and the mixture was stirred for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the solvent was evaporated from the filtrate under reduced pressure to give Compound aa055-c as a colorless oiled substance (360 g). The resulting crude product was used for the next experiment without purification. This was mixed with another lot synthesized separately and was used for the next reaction.

Concentrated hydrochloric acid (1.6 L, 52.7 mol) was added to a solution of Compound aa055-c (670 g, 2.43 mol) in 1,4-dioxane (3 L), and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated to give Compound aa055-d as an aqueous solution. This was adjusted to pH=7 with potassium carbonate, and diluted with 1,4-dioxane (3 L) and water (2 L). Fmoc-OSu (738 g, 2.2 mol) and potassium carbonate (677 g, 4.86 mol) were added thereto, and the mixture was stirred at room temperature for 16 hours. TBME/n-hexane (1/3, 2 L) was added to the reaction solution, and the precipitated solid was removed by filtration. The filtrate was adjusted to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure to give Compound aa055-e as a white solid (450 g). The resulting crude product was used for the next experiment without purification.

Toluene (1.5 L), paraformaldehyde (30 g, 1.15 mol), and p-toluenesulfonic acid (4.5 g, 26 mmol) were added to Compound aa055-e (150 g, 377 mmol) under a nitrogen atmosphere, and the mixture was stirred at 110° C. for 16 hours. The reaction solution was cooled to room temperature, followed by addition of ethyl acetate. The mixture was washed with an aqueous sodium bicarbonate solution and dried over sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound aa055-f as a white solid (110 g, 65%).

LCMS (ESI) m/z=410 (M+H)+

Retention time: 1.556 min (analysis condition SMDmethod_15)

Triethylsilane (102 g, 876 mmol) was added to a solution of Compound aa055-f (120 g, 293 mmol) in DCM/TFA (1/1, 2.4 L) at room temperature under a nitrogen atmosphere, the mixture was stirred for 48 hours, and the solvent was then evaporated under reduced pressure. The resulting residue was adjusted to pH=10 by adding an aqueous potassium carbonate solution. The solution was washed with n-hexane and then adjusted to pH 1 with concentrated hydrochloric acid. The residue was dissolved in acetonitrile and washed with n-heptane. The solvent was evaporated from the resulting acetonitrile layer under reduced pressure to give Compound aa055 ((2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-methylbutoxy)propanoic acid, Fmoc-D-MeSer(iPen)-OH) as a yellow oiled substance (120 g, 98%).

LCMS (ESI) m/z=412 (M+H)+

Retention time: 2.259 min (analysis condition SMDmethod_02)

Synthesis of Compound aa060, (2S)-3-(3-cyanophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid Fmoc-MePhe(3-CN)—OH)

Paraformaldehyde (172 mg, 5.74 mmol) and trifluoroacetic acid (TFA) (1.326 mL, 17.22 mmol) were added to a solution of commercially available (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-cyanophenyl)propanoic acid (Fmoc-Phe(3-CN)—OH) (789 mg 1.913 mmol) in toluene (5.7 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and diluted with dichloromethane (DCM). After the solution was washed with a saturated aqueous sodium bicarbonate solution, it was dried over anhydrous magnesium sulfate, and then filtered. The resulting solution was concentrated under reduced pressure to give a crude product, Compound aa060-b (859 mg). This was used for the next reaction without further purification.

Triethylsilane (TES) (2.75 mL, 17.22 mmol) and trifluoroacetic acid (TFA) (3.98 ml., 51.7 mmol) were added to a solution of the above crude product, Compound aa060-b (853 mg), in dichloroethane (DCE) (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at 60° C. for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. t-Butyl methyl ether/n-hexane=1/1 was added to the resulting crude product, and the mixture was extracted with a saturated aqueous sodium bicarbonate solution five times. The resulting aqueous layer was adjusted to an acidic pH with concentrated hydrochloric acid and then extracted with ethyl acetate three times. The organic layers were washed with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure to give Compound aa060 ((2S)-3-(3-cyanophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(3-CN)—OH) (811 mg, 99% through two steps). The obtained Compound aa060 was used for peptide synthesis without further purification.

LCMS (ESI) m/z=427 (M+H)+

Retention time: 0.83 min (analysis condition SQDFA05)

Synthesis of Compound aa061, (2S)-3-(4-cyanophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MePhe(4-CN)—OH)

Compound aa061 ((2S)-3-(4-cyanophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(4-CN)—OH) was obtained as a crude product (1.14 g, 108% through two steps) by the same method as in the synthesis of Compound aa060 using Compound aa061-a ((2S)-3-(4-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(4-CN)—OH) (1 g, 2.425 mmol) as a starting material. The obtained Compound aa061 was used for peptide synthesis without further purification.

LCMS (ESI) m/z=427 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Synthesis of Compound aa062, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methoxypropanoic acid (Fmoc-MeSer(Me)-OH)

Commercially available O-methyl-L-serine (H-Ser(Me)-OH) (498 mg, 4.18 mmol) and sodium carbonate (1.329 g, 12.54 mmol) were dissolved in water (8 mL), after which a solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (1.41 g, 4.18 mmol) in 1,4-dioxane (12 mL) was added at room temperature and the mixture was stirred overnight. Water was added to the reaction solution, and the mixture was washed with t-butyl methyl ether/n-hexane=1/10. IN Aqueous hydrochloric acid was added to the resulting aqueous layer until the pH was acidic, and the mixture was extracted with ethyl acetate twice. The resulting organic layers were washed with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure to give Compound aa062-a (Fmoc-Ser(Me)-OH) (1.46 g) as a crude product. The obtained Compound aa062-a was used for the next reaction without further purification.

Trifluoroacetic acid (TFA) (2.90 mL, 37.6 mmol) was added to a solution of the above crude product, Compound aa062-a (1.46 g), and paraformaldehyde (377 mg, 12.54 mmol) in toluene (12 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, after which ethyl acetate was added. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and then washed with brine. The resulting organic layer was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated from the resulting filtrate under reduced pressure to give a crude product, Compound aa062-b (2.13 g). The obtained Compound aa062-b was used for the next reaction without further purification.

Triethylsilane (TES) (6.02 mL, 37.7 mmol) and trifluoroacetic acid (TFA) (8.72 mL, 113 mmol) were added to a solution of the above crude product, Compound aa062-b (2.13 g), in dichloroethane (DCE) (15 mL) at room temperature, and the mixture was stirred at 60° C. for three hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. t-Butyl methyl ether/n-hexane=1/4 was added to the resulting crude product, and a saturated aqueous sodium bicarbonate solution was added, resulting in formation of a white solid. The organic solvent was evaporated under reduced pressure, and dimethyl sulfoxide was added to the aqueous layer. The resulting solution was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa062 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methoxypropanoic acid, Fmoc-MeSer(Me)-OH) (782 mg, 53% through three steps).

LCMS (ESI) m/z=356 (M+H)+

Retention time: 0.76 min (analysis condition SQDFA05)

Synthesis of Compound aa063, (2S))-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[2-(trifluoromethyl)phenyl]propanoic acid (Fmoc-MePhe(2-CF3)-OH)

Compound aa063-b was obtained as a crude product by the same method as in the synthesis of Compound aa060-b using Compound aa063-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[2-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(2-CF3)-OH) (1 g, 2.196 mmol) as a starting material. A crude product obtained by the same method as in the synthesis of Compound aa060 using the obtained Compound aa063-b was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa063 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[2-(trifluoromethyl)phenyl]propanoic acid, Fmoc-MePhe(2-CF3)-OH) (841 mg, 82% through two steps).

LCMS (ESI) m/z=470 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA05)

Synthesis of Compound aa064, (2S)-3-(2-cyanophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MePhe(2-CN)—OH)

Compound aa064-b was obtained as a crude product by the same method as in the synthesis of Compound aa060 using Compound aa064-a ((2S)-3-(2-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(2-CN)—OH) (1 g, 2.425 mmol) as a starting material. A crude product obtained by the same method as in the synthesis of Compound aa060 using the obtained Compound aa064-b was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa064 ((2S)-3-(2-cyanophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(2-CN)—OH) (529 mg, 51% through two steps).

LCMS (ESI) m/z=427 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA05)

Synthesis of Compound aa065, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-pyridin-4-ylpropanoic acid (Fmoc-MeAla(4-Pyr)-OH)

Compound aa065-b was obtained as a crude product by the same method as in the synthesis of Compound aa060-b using Compound aa065-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-pyridin-4-ylpropanoic acid, Fmoc-Ala(4-Pyr)-OH) (1.5 g, 3.86 mmol) as a starting material.

LCMS (ESI) m/z=401 (M+H)+

Retention time: 0.60 min (analysis condition SQDFA05)

A crude product obtained by the same method as in the synthesis of Compound aa060 using the total amount of Compound aa065-b obtained above was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0,1% formic acid-acetonitrile solution) to give Compound aa065 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-pyridin-4-ylpropanoic acid, Fmoc-MeAla(4-Pyr)-OH) (1.54 g, 91% through two steps).

LCMS (ESI) m/z=403 (M+H)+

Retention time: 0.51 min (analysis condition SQDFA05)

Synthesis of Compound aa066, (2S)-3-[4-(difluoromethyl)phenyl]-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MePhe(4-CHF2)-OH)

Compound aa066-b was obtained as a crude product by the same method as in the synthesis of Compound aa0160-b using Compound aa066-a ((2S)-3-[4-(difluoromethyl)phenyl]-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanaoic acid, Fmoc-Phe(4-CHF2)-OH) (2 g, 4.57 mmol) as a starting material. A crude product obtained by the same method as in the synthesis of Compound aa060 using the obtained Compound aa066-b was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa066 ((2S)-3-[4-(difluoromethyl)phenyl]-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(4-CHF2)-OH) (138 g, 67% through two steps).

LCMS (ESI) m/z=452 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

Synthesis of Compound aa067, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(2-methoxyphenyl)propanoic acid (Fmoc-MePhe(2-OMe)-OH

A crude product obtained by the same method as in the synthesis of Compound aa060-b using Compound aa06 7-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2-methoxyphenyl)propanoic: acid, Fmoc-Phe(2-OMe)-OH) (1.39 g, 3.33 mmol) as a starting material was purified by silica gel column chromatography (ethyl acetate/hexane) to give Compound aa067-b as a mixture with a diner.

As crude product obtained by the same method as in the synthesis of Compound aa060 using the obtained Compound aa067-b was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa067 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(2-methoxyphenyl)propanoic acid, Fmoc-MePhe(2-OMe)-OH) (456 mg, 34% through two steps).

LCMS (ESI) m/z=432 (M+H)+

Retention time: 0.90 min (analysis condition SQDFA05)

Synthesis of Compound aa068, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-pyridin-3-ylpropanoic acid Fmoc-MeAla(3-Pyr)—OH)

Compound aa068-b (2.95 g, 95%) was obtained by the same method as in the synthesis of Compound aa060-b using Compound aa068-a ((2S)-2-[0.9H-fluoren-9-ylmethoxycarbonylamino]-3-pyridin-3-ylpropanoic acid, Fmoc-Ala(3-Pyr)-OH) (3 g, 7.72 mmol) as a starting material.

Retention time: 0.64 min (analysis condition SQDFA05)

A crude product obtained by the same method as in the synthesis of Compound aa060 using the obtained Compound aa068-b (2.95 g) was suspended in DCM (50 mL), a 3 mol/L aqueous sodium dihydrogenphosphate solution (45 mL, containing 1.5 mol/L sodium chloride) was added, and the mixture was stirred. After removing the aqueous layer, the organic layer was washed with a 3 mol/L aqueous sodium dihydrogenphosphate solution (45 ml, containing 1.5 mol/L sodium chloride) twice. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (water/% acetonitrile) to give Compound aa0168 ((2S)-2-[9H-fluor-en-9-ylmethoxycarbonyl(methyl)amino]-3-pyridin-3-ylpropanoic acid, Fmoc-MeAla(3-Pyr)-OH) (2.67 g, 90%).

LCMS (ESI) m/z=403 (M+H)+

Retention time: 0.53 min (analysis condition SQDFA05)

Synthesis of Compound aa069, (2S)-3-cyclopropyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MeSer(cPr)—OH)

Paraformaldehyde (1.815 g, 60.5 mmol), magnesium sulfate (2.36 g, 19.63 mmol), and boron trifluoride-diethyl ether complex (BF₃·OEt₂) (1.184 mL, 9.42 mmol) were added to a solution of Compound aa041 ((2S)-3-cyclopropyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ser(cPr)—OH) (2.89 g, 7.85 mmol) in DCM (87 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for two hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to separate the organic layer from the aqueous layer. The aqueous layer was extracted with DCM twice, the combined organic layers were washed with brine and dried over sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa069-b as a crude product (3.1 g, quant.).

LCMS (ESI) m/z=380 (M+H)+

Retention time: 0.93 min (analysis condition SQDFA05)

Triethylsilane (3.13 mL, 19.64 mmol), water (0.141 mL, 7.85 mmol), and boron trifluoride-diethyl ether complex (BF₃·OEt₂) (2.49 mL, 19.6 mmol) were added to a solution of the obtained Compound aa069-b (2.98 g, 7.85 mmol) in DCM (26.2 mL) on ice under a nitrogen atmosphere, and the mixture was stirred for two hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous ammonium chloride solution, then washed with brine, and concentrated under reduced pressure to give a crude product. The resulting crude product was dissolved in acetonitrile and washed with n-hexane, and the acetonitrile layer was then concentrated under reduced pressure to give Compound aa069 ((2S)-3-cyclopropyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MeSer(cPr)—OH) (2.71 g, 90%).

LCMS (ESI) m/z=382 (M+H)+

Retention time: 0.83 min (analysis condition SQDFA05)

Synthesis of Compound aa070, (2S)-3-cyclopropyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MeAla(cPr-OH)

Compound aa070-b was obtained as a crude product (10.5 g) by the same method as in the synthesis of Compound aa069-b using Compound aa070-a ((2S)-3-cyclopropyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-A1a(cPr)—OH) (10 g, 28.5 mmol) as a starting material.

LCMS (ESI) m/z=364 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA05)

A crude product obtained after reaction by the same method as in the synthesis of Compound aa069 using the obtained Compound aa070-b (10.5 g) was purified by reverse phase column chromatography (0.1% formic acid-water/0.1% formic acid-acetonitrile) to give Compound aa070 ((2S)-3-cyclopropyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MeAla(cPr)—OH) (7.82 g, 75% through two steps).

LCMS (ESI) m/z=366 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Synthesis of Compound aa071, (2S)-3-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MeAla(cPent)-OH

Compound aa071-b was obtained as a crude product (10.5 g) by the same method as in the synthesis of Compound aa069-b using Compound aa071-a ((2S)-3-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(cPent)-OH) (10 g, 26.4 mmol) as a starting material.

LCMS (ESI) m/z=392 (M+H)+

Retention time: 1.05 min (analysis condition SQDFA05)

A crude product obtained after reaction by the same method as in the synthesis of Compound aa069 using the obtained Compound aa071-b (10.5 g) was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa071 ((2S)-3-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MeAla(cPent)-OH) (10.11 g, 96% through two steps).

LCMS (ESI) m/z=394 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Synthesis of Compound aa072, (2S)-3-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid Fmoc-MeAla(cBu)-OH

Compound aa072-b was obtained as a crude product (3.63 g) by the same method as in the synthesis of Compound aa069-b using Compound aa072-a ((2S)-3-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(cBu)-OH) (3.36 g, 9.19 mmol) as a starting material.

LCMS (ESI) m/z=378 (M+H)+

Retention time: 1.01 min (analysis condition SQDFA05)

A crude product obtained after reaction by the same method as in the synthesis of Compound aa069 using the obtained Compound aa072-b (3.63 g) was purified by reverse phase column chromatography (0.1% formic acid-water/0.1% formic acid-acetonitrile) to give Compound aa072 ((2S)-3-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MeAla(cBu)-OH) (3.18 g, 91% through two steps).

LCMS (ESI) m/z=380 (M+H)+

Retention time: 0.94 min (analysis condition SQDFA05)

Synthesis of Compound aa073,(2S)-2-f9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[3-trifluoromethyl)phenyl]propanoic acid Fmoc-MePhe(3-CF3)-OH

Compound aa073-b was obtained by the same method as in the synthesis of Compound aa069-b using Compound aa073-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[3-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(3-CF3)-OH) (2 g, 4.39 mmol) as a starting material. The obtained Compound aa073-b was reacted by the same method as in the synthesis of Compound aa069 and then purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa073 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoic acid, Fmoc-MePhe(3-CF3)-OH) (1.69 g, 82%).

LCMS (ESI) m/z=470 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA05)

Synthesis of Compound aa074, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[2-(trifluoromethoxy)phenyl]propanoic acid (Fmoc-MePhe(2-OCF3)-OH)

Compound aa074-b was obtained as a crude product by the same method as in the synthesis of Compound aa069-b using Compound aa074-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[2-(trifluoromethoxy)phenyl]propanoic acid, Fmoc-Phe(2-OCF3)-OH) (5 g, 10.61 mmol) as a starting material.

LCMS (ESI) m/z=484 (M+H)+

Retention time: 1.04 min (analysis condition SQDFA05)

Compound aa074 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[2-(trifluoromethoxy)phenyl]propanoic acid, Fmoc-MePhe(2-OCF3)-OH) (4.77 g, 93% through two steps) was obtained by the same method as in the synthesis of Compound aa069 using the total amount of Compound aa074-b obtained above.

LCMS (ESI) m/z=486 (M+H)+

Retention time: 0.96 min (analysis condition SQDFA05)

Synthesis of compound aa075, (2S)-2-cyclobutyl-2-[9Y-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid (Fmoc-MeGly(cBu)-OH)

Compound aa075-b was obtained as a crude product by the same method as in the synthesis of Compound aa069-b using Compound aa075-a ((2S)-2-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]acetic acid, Fmoc-Gly(cBu)-OH) (2.5 g, 7.11 mmol) as a starting material.

LCMS (ESI) m/z=364 (M+H)+

Retention time: 0.97 min (analysis condition SQDFA05)

A crude product obtained after reaction by the same method as in the synthesis of Compound aa069 using the total amount of Compound aa075-b obtained above was purified by reverse phase column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to give Compound aa075 ((2S)-2-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid, Fmoc-MeGly(cBu)-OH) (2.32 g, 89% through two steps).

LCMS (ESI) m/z=366 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

Synthesis of Compound aa076, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]hex-5-ynoic acid (Fmoc-MeAhxy(2)-OH)

Compound aa076-b was obtained as a crude product by the same method as in the synthesis of Compound aa069-b using Compound aa076-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]hex-5-ynoic acid, Fmoc-Ahxy(2)-OH) (989 mg, 2.83 mmol) as a starting material. Compound aa076 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(ethyl)amino]hex-5-ynoic acid, Fmoc-MeAhxy(2)-OH) (809 mg, 79% through two steps) was obtained by the same method as in the synthesis of Compound aa069 using the obtained Compound aa076-b.

LCMS (ESI) m/z=364 (M+H)+

Retention time: 0.81 min (analysis condition SQDFA05)

Synthesis of Compound aa077, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(2-methylphenyl)propanoic acid (Fmoc-MePhe(2-Me)-OH

Compound aa077-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(2-methylphenyl)propanoic acid, Fmoc-Phe(2-Me)-OH) (2 g, 4.98 mmol) was used as a starting material and a reaction solution was obtained by the same method as in the synthesis of Compound aa069-b. To the resulting reaction solution was added a saturated aqueous sodium bicarbonate solution. A silica gel column (2 v/w) was charged with the reaction solution, which was then eluted with DCM to give Compound aa077-b as a crude product (1.45 g). Compound aa077 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(2-methylphenyl)propanoic acid, Fmoc-MePhe(2-Me)-OH) (1.21 g, 58% through two steps) was obtained by the same method as in the synthesis of Compound aa069 using the obtained Compound aa077-b.

LCMS (ESI) m/z=416 (M+H)+

Retention time: 0.94 min (analysis condition SQDFA05)

Synthesis of Compound aa078, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methoxybutanoic acid (Fmoc-MeHse(Me)-OH)

Compound aa078-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-4-methoxybutanoic acid, Fmoc-Hse(Me)-OH) (5.0 g, 14.07 mmol), paraformaldehyde (1.27 g, 42.2 mmol), and CSA (0.163 g, 0.70 mmol) were suspended in toluene (82 mL) and stirred at 80° C. for 14 hours. The reaction solution was cooled to room temperature, after which the filtrate was diluted with ethyl acetate (100 mL) and then washed with saturated aqueous sodium bicarbonate/water (1/1) and brine/water (/1). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give Compound aa078-b as a crude product (5.1 g, 99%).

LCMS (ESI) m/z=368 (M+H)+

Retention time: 0.84 min (analysis condition SQDFA05)

To a solution of the obtained Compound aa078-b (5.12 g, 13.94 mmol) in DCM (46.5 mL) were added triethylsilane (6.68 mL, 41.8 mmol), water (0.251 mL, 13.94 mmol), and boron trifluoride-diethyl ether complex (BF₃·OEt₂) (3.53 mL, 27.9 mmol) under ice-cooling under a nitrogen atmosphere, and the mixture was stirred for two hours. To the reaction solution were added saturated aqueous ammonium chloride/water (1/1) and water (5 mL), and the organic layer was separated. The aqueous layer was extracted with DCM and the organic layer was washed with brine/water (1/1). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting compound was dissolved in acetonitrile, washed with n-hexane, and concentrated under reduced pressure to yield Compound aa078 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methoxybutanoic acid, Fmoc-MeHse(Me)-OH) (4.9 g, 95%).

LCMS (ESI) m/z=370 (M+H)+

Retention time: 0.76 min (analysis condition SQDFA05)

Synthesis of Compound aa079, (2S-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino acetic acid (Fmoc-MeGly(cPent)-OH

To a mixture of Compound aa079-a ((2S)-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]acetic acid, Fmoc-Gly(cPent)-OH) (30.0 g, 82 mmol), paraformaldehyde (7.39 g, 246 mmol), and CSA (0.954 g, 4.10 mmol) in toluene (160 mL) was added trifluoroacetic acid (TFA) (9.0 mL), and the mixture was then stirred at 60° C. for four hours, The reaction solution was cooled to room temperature, and the solid was then removed by filtration. The filtrate was concentrated under reduced pressure, diluted with ethyl acetate (220 mL), and then sequentially washed with a saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give Compound aa079-b as a crude product. The next reaction was performed without further purification.

LCMS (ESI) m/z=378 (M+H)+

Retention time: 1.01 min (analysis condition SQDFA05)

To a mixture of the total amount of Compound aa079-b obtained above and triethylsilane (TES) (65.5 mL, 410 mmol) in dichloroethane (DCE) (90 mL) was added trifluoroacetic acid (TFA) (76 mL, 984 mmol), and the mixture was stirred at 60° C. for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the resulting solid was washed with n-hexane/ethyl acetate (95/5) and dried under reduced pressure to give Compound aa079 ((2S)-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid, Fmoc-MeGly(cPent)-OH) (29.1 g, 93% through two steps).

LCMS (ESI) m/z=380 (M+H)+

Retention time: 0.92 min (analysis condition SQDFA05)

Synthesis of Compound aa080, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-fluorophenyl)propanoic acid (Fmoc-MePhe(3-F)—OH)

Compound aa080-b was obtained as a crude product (3.78 g, quant.) by the same method as in the synthesis of Compound aa078-b using Compound aa080-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3-fluorophenyl)propanoic acid, Fmoc-Phe(3-F)—OH) (3.38 g, 8.34 mmol) as a starting material.

LCMS (ESI) m/z=418 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Compound aa080 ((2S)-2-[9I-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-fluorophenyl)propanoic acid, Fmoc-MePhe(3-F)—OH) (3.52 g, quant.) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa080-b (3.6 g, 8.62 mmol).

LCMS (ESI) m/z=420 (M+H)+

Retention time: 0.89 min (analysis condition SQDFA05)

Synthesis of Compound aa081, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[4-(trifluoromethoxy)phen ylpropanoic acid (Fmoc-MePhe(4-OCF3)-OH)

Compound aa081-b was obtained as a crude product (516 mg) by the same method as in the synthesis of Compound aa078-b using Compound aa081-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[4-(trifluoromethoxy)phenyl]propanoic acid, Fmoc-Phe(4-OCF3)-OH) (0.5 g, 1.061 mmol) as a starting material. Compound aa81 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[4-(trifluoromethoxy)phenyl]propanoic acid, Fmoc-MePhe(4-OCF3)-OH) (462 mg, 90% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa081-b (516 mg).

LCMS (ESI) m/z=486 (M+H)+

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound aa082, (2S)-2-9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(4-fluorophenyl)propanoic acid (Fmoc-MePhe(4-F)—OH)

Compound aa082-b was obtained as a crude product (8.55 g) by the same method as in the synthesis of Compound aa078-b using Compound aa082-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(4-fluorophenyl)propanoic acid, Fmoc-Phe(4-F)—OH) (10.0 g, 24.67 m mol) as a starting material.

LCMS (ESI) m/z=418 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Compound aa082 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(4-fluorophenyl)propanoic acid, Fmoc-MePhe(4-F)—OH) (7.28 g, 70% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa082-b (8.55 g).

LCMS (ESI) m/z=420 (M+H)+

Retention time: 0.90 min (analysis condition SQDFA05)

Synthesis of Compound aa083, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pent-4-ynoic acid (Fmoc-MePRA-OH)

Compound aa083-b (2.71 g, 87%) was obtained by the same method as in the synthesis of Compound aa078-b using Compound aa083-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]pent-4-ynoic acid, Fmoc-PRA-OH) (3 g 8.95 mmol) as a starting material.

LC MS (ESI) m/z=348 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Compound aa083 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)aminopent-4-ynoic acid, Fmoc-MePRA-OH) (986 mg, 99%) was obtained by the same method as in the synthesis of Compound aa07 8 using the obtained Compound aa83-b (989 mg, 2.85 mmol).

LCMS (ESI) m/z=350 (M+H)+:

Retention time: 0.79 min (analysis condition SQDFA05)

Synthesis of Compound aa084, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]heptanoic acid (Fmoc-MeHnl-OH)

Compound aa084-b was obtained as a crude product (5.58 g) by the same method as in the synthesis of Compound aa078-b using Compound aa084-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]heptanoic acid, Fmoc-Hnl-OH) (5 g, 13.61 mmol) as a starting material.

LCMS (ESI) m/z=380 (M+H)+

Retention time: 1.05 min (analysis condition SQDFA05)

Compound aa084 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]heptanoic acid, Fmoc-MeHnl-OH) (4.869 g, 94%) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa084-b (5.16 g, 12.58 mmol).

LCMS (ESI) m/z=382 (M+H14)+

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound aa085, (2S-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-4-methylphenyl)propanoic acid (Fmoc-MePhe(4-Me)-OH)

Compound aa085-b was obtained as a crude product (22.66 g) by the same method as in the synthesis of Compound aa07 8-b using Compound aa085-a ((2S)-2-[9H1-fluoren-9-ylmethoxycarbonylamino]-3-(4-methylphenyl)propanoic acid, Fmoc-Phe(4-Me)-OH) (20 g, 49.8 mmol) as a starting material.

LCMS (ESI) m/z=414 (M+H)+

Retention time: 1.04 min (analysis condition SQDFA05)

A crude product obtained after reaction by the same method as in the synthesis of Compound aa0 78 using the obtained Compound aa085-b (22.66 g) was purified by reverse phase. column chromatography (0.1% formic acid-water/0.1′% formic acid-acetonitrile) to give Compound aa085 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(4-methylphenyl)propanoic acid, Fmoc-MePhe(4-Me)—OH) (17.3 g, 83.5% through two steps).

LCMS (ESI) m/z=416 (M+H)+

Retention time: 2.41 min (analysis condition SQDFA3080)

Synthesis of Compound aa086, (2S)-4-bromophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MePhe(4-Br)—OH)

A crude product obtained by the same method as in the synthesis of Compound aa078-b using Compound aa086-a ((2S)-3-(4-bromophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Phe(4-Br)—OH) (6 g, 12.87 mmol) as a starting material was purified by reverse phase column chromatography (0.1% aqueous formic acid/0.1% formic acid-acetonitrile) to give Compound aa086-b (3.57 g, 58%).

LCMS (ESI) ma/z=478 (M+H)+

Retention time: 1.05 min (analysis condition SQDFA05)

A crude product obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa086-b (3.57 g, 7.46 mmol) was washed with acetonitrile/hexane (1/1) to give Compound aa086 ((2S)-3-(4-bromophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(4-Br)—OH) (3.40 g, 95%).

LCMS (ESI) ma/z=480 (M+H)+

Retention time: 0.96 min (analysis condition SQDFA05)

Synthesis of Compound aa087, 2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[3-(trifluoromethoxy)phenyl]propanoic acid Fmoc-MePhe(3-OCF3)-OH)

Compound aa087-b was obtained as a crude product (5.84 g) by the same method as in the synthesis of Compound aa078-b using Compound aa087-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[3-(trifluoromethoxy)phenyl]propanoic acid, Fmoc-Phe(3-OCF3)-OH) (6.07 g, 12.87 mmol) as a starting material.

LCMS (ESI) m/z=484 (M+H)+

Retention time: 1.05 min (analysis condition SQDFA05)

Compound aa087 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[3-(trifluoromethoxy)pheny]propanoic acid, Fmoc-MePhe(3-OCF3)-OH) (5.66 g, 91% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa087-b (5.84 g).

LCMS (ESI) m/z=486 (M+H)+

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound aa088, 1-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]cyclopentane-1-carboxylic acid (Fmoc-MecLeu-OH)

Compound aa088-b was obtained as a crude product by the same method as in the synthesis of Compound aa078-b using Compound aa088-a (1-[9H-fluoren-9-ylmethoxycarbonylamino]cyclopentane-1-carboxylic acid, Fmoc-cLeu-OH) (10 g, 28.5 mmol) as a starting material. A crude product was obtained by the same method as in the synthesis of Compound aa078 using Compound aa088-b. The resulting crude product was purified by trituration (hexane/TBME) to give Compound aa088 (1-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]cyclopentane-1-carboxylic acid, Fmoc-MecLeu-OIH) (6.82 g, 66% through two steps).

LCMS (ESI) m/z=366 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Synthesis of Compound aa089, (2S)-2-cyclopropyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid (Fmoc-MeGly(cPr)—OH

Compound aa089-b was obtained as a crude product by the same method as in the synthesis of Compound aa078-b using Compound aa089-a ((2S)-2-cyclopropyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]acetic acid, Fmoc-Gly(cPr)—OH) (5 g, 14.82 mmol) as a starting material.

LCMS (ESI) m/z=350 (M+H)+

Retention time: 0.89 min (analysis condition SQDFA05)

Compound aa089 ((2S)-2-cyclopropyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid, Fmoc-MeGly(cPr)—OH) (5.18 g, 99% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the total amount of Compound aa089-b obtained above.

LCMS (ESI) m/z=352 (M+H)+

Retention time: 0.80 min (analysis condition SQDFA05)

Synthesis of Compound aa090, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid (Fmoc-MePhe(4-CF3)-OH)

Compound aa090-b was obtained as a crude product (206.8 g) by the same method as in the synthesis of Compound aa078-b using Compound aa090-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(4-CF3)-OH) (200 g, 439 mmol) as a starting material.

LCMS (ESI) m/z=468.5 (M+H)+

Retention time: 3.30 min (analysis condition SMDmethod_03)

Compound aa090 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-MePhe(4-CF3)-OH) (195 g, 95% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa090-b (205 g).

LCMS (ESI) m/z=469.95 (M+H)+

Retention time: 2.96 min (analysis condition SMDMethod_03)

Synthesis of Compound aa091, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4,4,4-trifluorobutanoic acid (Fmoc-MeAbu(4-F3)-OH)

Compound aa091-b was obtained as a crude product by the same method as in the synthesis of Compound aa078-b using Compound aa091-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-4,4,4-trifluorobutanoic acid, Fmoc-Abu(4-F3)-OH) (0.994 g, 2.62 mmol) as a starting material. A crude product obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa091-b (4.78 g), was washed with acetonitrile and filtered to collect a solid, which was then combined with a solid obtained by washing the filtrate with hexane and then evaporating the solvent from the filtrate under reduced pressure to give Compound aa091 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4,4,4-trifluorobutanoic acid, Fmoc-MeAbu(4-F3)-OH) (961 mg, 93% through two steps).

LCMS (ESI) m/z=394 (M+H)+

Retention time: 0.83 min (analysis condition SQDFA05)

Synthesis of Compound aa092, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methylsulfonylbutanoic acid (Fmoc-MeMet(O2)-OH)

Compound aa092-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-4-methylsulfonylbutanoic acid, Fmoc-Met(O2)-OH) (5.0 g, 12.39 mmol), paraformaldehyde (1.12 g, 37.2 mmol), and CSA (0.144 g, 0.62 mmol) were suspended in toluene (83 mL), and the mixture was stirred at 95° C. for four hours. The reaction solution was cooled to room temperature, after which the filtrate was diluted with ethyl acetate (100 mL) and then washed with saturated aqueous sodium bicarbonate/water (1/1) and brine/water (1/1). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give Compound aa092-b (4.2 g) as a crude product.

LCMS (ESI) m/z=416 (M-+)+

Retention time: 0.77 min (analysis condition SQDFA05)

To a solution of the obtained Compound aa092-b (4.20 g, 10.11 mmol) in DCM (33.7 mL) were added triethylsilane (4.84 nL, 30.3 mmol), water (0.182 mL, 10.11 mmol), and boron trifluoride-diethyl ether complex (BF₃·OEt₂) (2.56 mL, 20.22 mmol) under ice-cooling under a nitrogen atmosphere., and the mixture was stirred for two hours. To the reaction solution were added saturated aqueous ammonium chloride/water (1/1) and water (3 ml), and the organic layer was separated. The aqueous layer was extracted with DC M and the organic layer was washed with brine, resulting in precipitation of a solid. The precipitated compound was washed with hexane to give Compound aa092 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methylsulfonylbutanoic acid, Fmoc-MeMet(O2)-OH) (3.64 g, 86%).

LCMS (ESI) m/z=418 (M+H)+

Retention time: 0.68 min (analysis condition SQDFA05)

Synthesis of Compound aa093, (2S,3R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methoxybutanoic acid (Fmoc-MeThr(Me)-OH)

Compound aa093-b was obtained as a crude product by the same method as in the synthesis of Compound aa078-b using Compound aa093-a ((2S,3R)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-methoxybutanoic acid, Fmoc-Thr(Me)-OH) (3 g, 8.44 mmol) as a starting material.

LCMS (ESI) m/z=368 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

Compound aa093 ((2S,3R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methoxybutanoic acid, Fmoc-MeThr(Me)—OH) (2.79 g, 89% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the total amount of Compound aa093-b obtained above.

LCMS (ESI) m/z=370 (M+H)+

Retention time: 0.81 min (analysis condition SQDFA05)

Synthesis of Compound aa094, (2S)-3-(2-chlorophenyl)-2-[9-fluoren-9-ylmethoxycarbonyl(methylamino]propanoic acid (Fmoc-MePhe(2-Cl)—OH)

Compound aa094-b (4.2 g, 82%) was obtained by the same method as in the synthesis of Compound aa078-b using Compound aa094-a ((2S)-3-(2-chlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Phe(2-Cl)—OH) (5 g, 11.85 mmol) as a starting material.

LCMS (ESI) m/z=434 (M+H)+

Retention time: 1.01 min (analysis condition SQDFA05)

Compound aa094 ((2S)-3-(2-chlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(2-Cl)—OH) (3.32 g, 79%) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa094-b (4.2 g).

LCMS (ESI) m/z=436 (M+H)+

Retention time: 0.94 min (analysis condition SQDFA05)

Synthesis of Compound aa095, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(2-fluorophenyl)propanoic acid (Fmoc-MePhe(2-F)—OH)

Compound aa095-b (3.21 g, quant.) was obtained by the same method as in the synthesis of Compound aa079-b using Compound aa095-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(2-fluorophenyl)propanoic acid, Fmoc-Phe(2-F)—OH) (3 g, 7.4 mmol) as a starting material.

LCMS (ESI) m/z=418 (M+H)+

Retention time: 0.97 min (analysis condition SQDFA05)

Compound aa095 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(2-fluorophenyl)propanoic acid, Fmoc-MePhe(2-F)—OH) (2.89 g. 96%) was obtained by the same method as in the synthesis of Compound aa079 using the obtained Compound aa095-b (3 g, 7.19 mmol).

LCMS (ESI) m/z=420 (M+H)+

Retention time: 0.90 min (analysis condition SQDFA05)

Synthesis of Compound aa096, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(4-iodophenyl)propanoic acid (Fmoc-MePhe(4-I)—OH)

Compound aa096-b was obtained as a crude product (2.62 g) by the same method as in the synthesis of Compound aa078-b using Compound aa096-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(4-iodophenyl)propanoic acid, Fmoc-Phe(4-I)—OH) (2.36 g, 4.6 mmol) as a starting material.

LCMS (ESI) m/z=526 (M+H)+

Retention time: 1.07 min (analysis condition SQDFA05)

Compound aa096 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(4-iodophenyl)propanoic acid, Fmoc-MePhe(4-I)—OH) (2.36 g, 97%) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa096-b (2.62 g).

LCMS (ESI) m/z=528 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Synthesis of Compound aa097, (2S)-3-3-bromophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-MePhe(3-Br)—OH)

Compound aa097-b was obtained as a crude product (2.98 g) by the same method as in the synthesis of Compound aa078-b using Compound aa097-a ((2S)-3-(3-bromophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Phe(3-Br)—OH) (3 g, 6.43 mmol) as a starting material.

LCMS (ESI) m/z=478 (M+H)+

Retention time: 1.05 min (analysis condition SQDFA05)

Compound aa097 ((2S)-3-(3-bromophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(3-Br)—OH) (2.87 g, 92% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa097-b (2.98 g).

LCMS (ESI) m/z=480 (M+H)+

Retention time: 0.96 min (analysis condition SQDFA05)

Synthesis of Compound aa098, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-2-methyl-3-phenylpropanoic acid (Fmoc-Me(Me)Phe-OH)

Compound aa098-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-2-methyl-3-phenylpropanoic acid (Fmoc-(Me)Phe-OH)) (2 g, 4.98 mmol) was suspended in toluene (16.61 mL), paraformaldehyde (0.449 g, 14.95 mmol) and (1S)-(+)-10-camphorsulfonic acid (0.058 g, 0.249 mmol) were added thereto, and the mixture was then stirred at 85° C. for four hours, The reaction solution was cooled to room temperature and then diluted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium carbonate solution and an 18% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give Compound aa098-b (2.07 g, 100%).

LCMS (ESI) m/z=414 (M+H)+

Retention time: 1.01 min (analysis condition SQDFA05)

Compound aa098-b (520 mg, 1.258 mmol) was dissolved in dichloromethane (6.3 mL), triethylsilane (1.202 mL, 7.55 mmol) and a 1 M solution of titanium tetrachloride in dichloromethane (2.515 mL) were added, after which the mixture was stirred at 0° C. for one hour and then stirred at room temperature for one hour. To the reaction solution was added water, the mixture was filtered by a phase separator, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (0.1% formic acid-water/0.1% formic acid-acetonitrile) to give Compound aa098 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-2-methyl-3-phenylpropanoic acid, Fmoc-Me(Me)Phe-OH) (357 mg, 68%).

LCMS (ESI) m/z=416 (M+H)+

Retention time: 0.91 min (analysis condition SQDFA05)

Synthesis of Compound aa101, (2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-(oxan-2-yloxy)pyrrolidine-2-carboxylic acid (Fmoc-cisHyp(THP)—OH)

To a solution of Compound aa101-a ((2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid, Fmoc-cisHyp-OH) (4.18 g, 11.83 mmol) in dichloromethane (42 mL) were added 3,4-dihydropyran (2.24 g, 2.25 equivalents) and PPTS (0.3 g, 0.1 equivalents), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. The resulting organic layer was washed with water and brine. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in THF (35 mL), after which 1.0 M phosphate buffer (pH=8.0, 35 mL) was added and the mixture was stirred at 50° C. for 4 hours and 30 minutes. To the reaction solution was added ethyl acetate (35 mL), after which the organic layer and the aqueous layer were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered, and the solvent was then evaporated under reduced pressure. The resulting residue was dissolved in diethyl ether (50 mL), heptane (50 mL) was added, and the diethyl ether was evaporated under reduced pressure. The resulting solid was filtered to give Compound aa101 sodium salt (4.97 g). The obtained Compound aa101 sodium salt was dissolved in ethyl acetate (90 mL), a 0.05 M aqueous phosphoric acid solution (pH 2.1, 150 mL) was then added, and the mixture was stirred at room temperature for five minutes. The organic layer and the aqueous layer were separated, the aqueous layer was then extracted with ethyl acetate (90 mL), and the combined organic layers were washed with brine twice and dried over sodium sulfate. The resulting organic layer was filtered, and the solvent was then evaporated under reduced pressure to give Compound aa101 ((2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-(oxan-2-yloxy)pyrrolidine-2-carboxylic acid, Fmoc-cisHyp(THP)—OH) (4.57 g, yield: 80%).

LCMS (ESI) m/z=460 (M+Na)+

Retention time: 0.81 min (analysis condition SQDFA05)

Synthesis of Compound aa102,(2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-4-(oxan-2-yloxy)pyrrolidine-2-carboxylic acid (Fmoc-Hyp(THP)—OH

Compound aa102 ((2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-(oxan-2-yloxy)pyrrolidine-2-carboxylic acid, Fmoc-Hyp(THP)—OH) (5.15 g, 83%) was obtained by the same method as in the synthesis of Compound aa101 using Compound aa102-a ((2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid, Fmoc-Hyp-OH) (5 g, 14.15 mmol) as a starting material.

LCMS (ESI) m/z=438 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA05)

Synthesis of Compound aa104, (2S)-3-(3-chloro-5-iodophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Phe(3-1-5-Cl)—OH)

Compound aa104-a (methyl (2S)-3-(3-chlorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate) (1.05 g, 3.35 mmol) was dissolved in tert-butyl methyl ether (16.73 ml), bis(pinacolato)diboron (2.55 g, 10.04 mmol), (1,5-cyclooctadiene)(methoxy)iridium(1) dimer (0.111 g, 0.167 mmol), and 4,4′-di-tert-butyl-2,2′-bipyridine (0.090 g, 0.335 mmol) were added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction solution under reduced pressure, and the resulting residue was purified by reverse phase chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa104-b (0.920 g, 63%).

Retention time: 1.06 min (analysis condition SQDFA05)

¹H-NMR (varian ascend 400, 400 MHz, CDCl₃) δ 7.65-7.61 (m, 1H), 7.43 (bs, 1H), 7.21-7.20 (m, 1H), 5.01-4.98 (m, 1H), 4.55-4.54 (m, 1H), 3.74-3.73 (m, 3H), 3.14-3.10 (m, 1H), 3.02-2.97 (m, 1H), 1.43-1.41 (m, 12H), 1.34 (s, 9H)

Compound aa104-b (0.900 g, 2.047 mmol) was dissolved in a mixed solution of methanol (18.61 ml) and water (1.861 ml), copper(1) iodide (0.585 g, 3.07 mmol) and N-iodosuccinimide (0.691 g, 3.07 mmol) were added, and the mixture was stirred at 80° C. for two hours. The reaction solution was cooled to room temperature and then filtered through celite, and the solvent was evaporated from the resulting filtrate under reduced pressure. The concentrated residue was purified by reverse phase chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa104-c (0.703 g, 78%).

LCMS (ESI) m/z=439.9 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Calcium chloride (2.65 g, 23.88 mmol) was suspended in water (6.63 ml), lithium hydroxide monohydrate (0.267 g, 6.37 mmol) was added, and the mixture was stirred for five minutes. Isopropanol (26.5 ml), and a solution of Compound aa104-c (0.700 g, 1.592 mmol) in tetrahydrofuran (6.63 ml) were sequentially added, and the mixture was stirred at room temperature for four hours. A 20% aqueous formic acid solution was added until the pH of the reaction solution became about 3, and the reaction solution was extracted with tert-butyl methyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa104-d (679 mg, 1.595 mmol). This was mixed with another lot synthesized in the same manner, and the next reaction was performed.

LCMS (ESI) m/z=424 (M−H)−

Retention time: 0.86 min (analysis condition SQDFA05)

Compound aa104-d (1.09 g, 2.56 mmol) was dissolved in TFE (12.8 mL), TMSCl (0.485 mL, 3.84 mmol) was added, and the mixture was stirred at room temperature for one hour. The solvent was evaporated from the reaction solution under reduced pressure to give Compound aa104-e as a crude product (997 mg).

LCMS (ES) m/z=326 (M+H)+

Retention time: 0.43 min (analysis condition SQDFA05)

Compound aa104-e (925 mg, 2.56 mmol) was suspended in water (10 ml), after which diisopropylethylamine (2.003 ml, 11.50 mmol), 1,4-dioxane (13.33 ml), and N-(9-fluorenylmethoxycarbonyloxy)succinimide (862 mg, 2.56 mmol) were sequentially added and the mixture was stirred at room temperature for one hour. To the reaction solution was added a 20% aqueous formic acid solution, and the 1,4-dioxane was evaporated under reduced pressure. Ethyl acetate was added to the concentrate, and the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was suspended in tert-butyl methyl ether/n-hexane (1/1) and separated by filtration to give Compound aa104 ((2S)-3-(3-chloro-5-iodophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(3-1-5-Cl)—OH) (970 mg, 69%).

LCMS (ESI) m/z=570 (M+Na)+

Retention time: 0.99 min (analysis condition SQDFA05)

Synthesis of Compound aa105, (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2-fluoro-3-iodophenyl)propanoic acid (Fmoc-Phe(2-F-3-I)—OH)

Compound aa105-a ((2S)-3-(3-bromo-2-fluorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(2-F-3-Br)—OH) (0.7 g, 1.445 mmol) was dissolved in 1,4-dioxane (14.5 mL), bis(pinacolato)diboron (1.468 g, 5.78 mmol), potassium acetate (0.397 g, 4.015 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.212 g, 0.289 mmol) were added at room temperature, and the mixture was stirred at 80° C. for 5.5 hours. After 5.5 hours, bis(pinacolato)diboron (0.147 g, 0.578 mmol), potassium acetate (0.040 g, 0.405 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.021 g, 0.029 mmol) were further added at room temperature, and the mixture was stirred at 80° C. for 1.5 hours. The reaction solution was filtered through celite, after which the mother liquor was concentrated under reduced pressure and the 1,4-dioxane was evaporated to give Compound aa105-b as a crude product. This was mixed with two lots synthesized in the same manner and was used for the next reaction.

The obtained Compound aa105-b (1.15 g, 2.171 mmol) was dissolved in a mixed solvent of methanol (9.75 ml,) and water (1.08 mL), potassium acetate (0.425 g, 4.34 mmol), copper(I) iodide (1.16 g, 6.07 mmol), and N-iodosuccinimide (3.41 g, 15.17 mmol) were added at 0° C., and the mixture was stirred at 80° C. for two hours. Another reaction on the same scale was performed, two batches of the reaction solution were mixed and concentrated under reduced pressure to evaporate the methanol. The resulting residue was dissolved in ethyl acetate (80 mL), washed with a 7.7 to 8.3% aqueous ammonia solution (401 mL) three times, washed with a 1 M aqueous phosphoric acid solution (40 mL), and washed with a saturated sodium chloride aqueous solution (40 ml,). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa105 ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2-fluoro-3-iodophenyl)propanoic acid, Fmoc-Phe(2-F-3-I)—OH) (1.55 g, 88%).

LCMS (ESI) m/z=530 (M−H)−

Retention time: 0.90 min (analysis condition SQDFA05)

Synthesis of Compound aa106, (2S)-2-(H1-fluoren-9-ylmethoxycarbonylamino)-3-(3-fluoro-5-iodophenyl)propanoic acid (Fmoc-Phe(3-1-5-F)—OH)

Compound aa106-b was obtained as a crude product by the same method as in the synthesis of Compound aa105-b using Compound aa106-a ((2S)-3-(3-bromo-5-fluorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(3-Br-5-F)—OH) (2.1 g, 4.335 mmol) as a starting material.

Compound aa106 ((2S)-2-(91-1-fluoren-9-ylmethoxycarbonylamino)-3-(3-fluoro-5-iodophenyl)propanoic acid, Fmoc-Phe(3-1-5-F)—OH) (1.54 g, 67%) was obtained by the same method as in the synthesis of Compound aa105 using Compound aa106-b (1.152 g 2.17 mmol).

LCMS (ESI) m/z=530 (M−H)−

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound aa109, (2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid (Fmoc-EtAla-OH)

Compound aa109-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ala-OH) (30 g, 96 mmol) was dissolved in toluene (321 mL), paraldehyde (19.10 mL, 145 mmol) and CSA (2.24 gr, 9.64 mmol) were added, and the mixture was stirred at 80° C. for three hours. The reaction solution was cooled to room temperature, n-hexane (300 mL) and ethyl acetate (600 mL) were added, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The resulting concentrate was dissolved in 20% ethyl acetate-hexane (400 mal) again, washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa109-b (22.07 g, 68%) as a crude product.

LCMS (ESI) m/z=338 (M+H)+

Retention time: 0.90 min (analysis condition SQDFA05)

The obtained Compound aa1109-b (22.04 g, 65.3 mmol) was dissolved in DCM (218 mL), TFA (150 mL, 1960 mmol) and triethylsilane (104 mL, 653 mmol) were added, and the mixture was stirred at room temperature for two hours. After concentration under reduced pressure, the concentrate was dissolved in DCM. The solution was concentrated under reduced pressure to a volume of about 200 mL, hexane (500 mL) was added, resulting in precipitation of the target compound. The target compound was collected by filtration to give Compound aa109 ((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid, Fmoc-EtAla-OH) (13.41 g, 61%).

LCMS (ESI) m/z=340 (M+H)+

Retention time: 0.81 min (analysis condition SQDFA05)

Synthesis of Compound aa110, (2S)-3-4-chlorophenethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid (Fmoc-EtPhe(4-Cl)—OH

Compound aa110-a ((2S)-3-(4-chlorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(4-Cl)—OH) (3.00 g, 7.11 ml mol) was dissolved in toluene (17.8 mL), paraldehyde (0.940 mL, 7.11 mmol) and CSA (0.165 g, 0.711 mmol) were added, and the mixture was stirred at 80° C.: overnight. The reaction solution was cooled to room temperature, dissolved in 20% ethyl acetate-hexane (300 mL), washed twice with a saturated aqueous sodium bicarbonate solution and once with brine, and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa110-b (2.63 g, 83%) as a crude product.

LCMS (ESI) m/z=448 (M+H)+

Retention time: 1.06 min (analysis condition SQDFA05)

The obtained Compound aa110-b (2.6 g, 5.8 mmol) was dissolved in DCE (19.35 mL), TFA (13.33 mL, 174 mmol) and triethylsilane (9.25 mL, 58.0 mmol) were added, and the mixture was stirred at 60° C. for six hours and then stirred at room temperature overnight. The crude product obtained by concentration under reduced pressure was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa110 ((2S)-3-(4-chlorophenyl)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid, Fmoc-EtPhe(4-Cl)—OH) (1.46 g, 56%).

LCMS (ESI) m/z=450 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Synthesis of Compound aa111, (2S)-2-[ethyl(19H-fluoren-9-ylmethoxycarbonyl)amino-4-methylpentanoic acid (Fmoc-EtLeu-OH)

Compound aa111-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid, Fmoc-Leu-OH) (4.95 g, 14.0 mmol, CAS No. 35661-60-0) was suspended in DCE (17.5 mL) under a nitrogen atmosphere, paraldehyde (5.61 mL, 42.0 mmol) and TFA (9.65 mL, 126 mmol) were added, and the mixture was stirred at 50° C. for six hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was then dissolved in ethyl acetate (40 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa111-b as a crude product.

LCMS (ESI) m/z=380 (M+H)+

Retention time: 1.02 min (analysis condition SQDFA05)

The total amount of Compound aa111-b obtained above was dissolved in DCE (35 mL), TFA (28.9 mL, 378 mmol) and triethylsilane (20.1 mL, 126 mmol) were added, and the mixture was stirred at 60° C. for 90 minutes. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then azeotropically distilled with toluene three times. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa111 ((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-4-methylpentanoic acid, Fmoc-EtLeu-OH) (3.15 g, 59% through two steps).

LCMS (ESI) m/z=382 (M+H)+

Retention time: 0.94 min (analysis condition SQDFA05)

Synthesis of Compound aa112, (2S)-3-cyclohexyl-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl) aminopropanoic acid (Fmoc-EtCha-OH)

Compound aa112-b was obtained as a crude product by the same method as in the synthesis of Compound aa111-b using Compound aa112-a ((2S)-3-cyclohexyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Cha-OIH) (5.51 g, 14.0 mmol, CAS No. 135673-97-1) as a starting material.

LCMS (ESI) m/z=420 (M+H)+

Retention time: 1.12 min (analysis condition SQDFA05)

Compound aa112, ((2S)-3-cyclohexyl-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid, Fmoc-EtCha-OH) (4.78 g, 81% through two steps) was obtained by the same method as in the synthesis of Compound aa111 using the total amount of Compound aa112-b obtained above.

LCMS (ESI) m/z=422 (M+H)+

Retention time: 1.04 min (analysis condition SQDFA05)

Synthesis of Compound aa113, (2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(4-methylphenyl)propanoic acid (Fmoc-EtPhe(4-Me)-OH

Compound aa113-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-methylphenyl)propanoic acid, Fmoc-Phe(4-Me)-OH) (5.62 g, 14.0 mmol, CAS No. 199006-54-7) was suspended in dichloroethane (DCE) (17.5 mL) under a nitrogen atmosphere, paraldehyde (5.61 mL, 42.0 mmol) and trifluoroacetic acid (TFA) (9.65 mL, 126 mmol) were added, and the mixture was stirred at 60° C. for six hours. The resulting reaction solution containing Compound aa113-b was used as such for the next step.

LCMS (ESI) m/z=428 (M+H)+

Retention time: 1.03 min (analysis condition SQDFA05)

To the resulting reaction solution of Compound aa113-b were added dichloroethane (DCE) (17.5 mL), trifluoroacetic acid (TFA) (19.3 mL, 252 mmol), and triethylsilane (TES) (20.1 mL, 126 mmol), and the mixture was stirred at 60° C. for 17 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was then dissolved in ethyl acetate (40 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL) and washed with hexane (15 mL) twice, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa113 ((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(4-methylphenyl)propanoic acid, Fmoc-EtPhe(4-Me)-OH) (4.4 g, 73% through two steps).

LCMS (ESI) m/z=430 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA05)

Synthesis of Compound aa114, 2S-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-4-(trifluoromethyl)phenyl]propanoic acid (Fmoc-EtPhe(4-CF3)-OH)

Compound aa114-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(4-CF3)-OH) (4.04 g, 8.87 mmol, CAS No. 247113-86-6) was suspended in DCE (11.1 mL) under a nitrogen atmosphere, anhydrous magnesium sulfate (4.27 g, 35.4 mmol), paraldehyde (3.55 mL, 26.6 mmol), and trifluoroacetic acid (TFA) (6.11 mL, 80 mmol) were added, and the mixture was stirred at 60° C. for three hours. Anhydrous magnesium sulfate (2.14 g, 17.7 mmol) was further added and the mixture was stirred at 60° C. for one hour. The resulting reaction solution containing Compound aa114-b was used as such for the next reaction.

LCMS (ESI) m/z=482 (M+H)+

Retention time: 1.04 min (analysis condition SQDFA05)

To the resulting reaction solution containing Compound aa114-b were added DCE (11.1 mL), TFA (12.2 mL, 159 mmol), and triethylsilane (12.7 mL, 80 mmol), and the mixture was stirred at 60° C. for 10 hours. The reaction solution was cooled to room temperature, the magnesium sulfate was filtered off, and the filtrate was then concentrated under reduced pressure. Because the intended reaction was not completed, the resulting residue was dissolved in DCE (22.2 mL), TFA (18.3 mL, 239 mmol) and triethylsilane (12.7 mL, 80 mmol) were added, and the mixture was stirred at 60° C. for eight hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was then dissolved in ethyl acetate (40 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL) and washed with hexane (15 mL) twice, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (water-acetonitrile, containing 0.1% formic acid) to give Compound aa114 ((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-EtPhe(4-CF3)-OH) (1.90 g, 44% through two steps).

LCMS (ESI) m/z=484 (M+H)+

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound aa116, (2S)-3-(2,6-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Phe(26-F2)-OH)

Compound aa116-a ((2S)-2-amino-3-(2,6-difluorophenyl)propanoic acid, H-Phe(26-F2)-OH) (1.00 g, 4.97 mmol) was dissolved in a mixed solvent of 1,4-dioxane (12 mL) and distilled water (9 mL), diisopropylethylamine (DIPEA) (3.03 ml, 17.4 mmol) and N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (1.761 g, 5.22 mmol) were added, and the mixture was stirred at room temperature for one hour. To the reaction solution were added a 20% aqueous formic acid solution and dimethyl sulfoxide, after which the mixture was concentrated under reduced pressure and the 1,4-dioxane was evaporated. The resulting concentrate was purified by reverse phase chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa116 ((2S)-3-(2,6-difluorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(26-F2)-OH) (1.81 g, 86%).

LCMS (ESI) m/z=445.9 (M+Na)+

Retention time: 1.202 min (analysis condition SMDmethod_04)

Synthesis of Compound aa118, (2S)-3-(2,5-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Phe(25-F2)-OH)

Compound aa118 ((2S)-3-(2,5-difluorophenyl)-2-(91H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(25-F2)-OH) (2.43 g, 58%) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa118-a ((2S)-2-amino-3-(2,5-difluorophenyl) propanoic acid, H-Phe(25-F2)-OH)(2 g, 9.94 mmol) as a starting material.

LCMS (ESI) m/z=424 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA05)

Synthesis of Compound aa119, (2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(3-iodophenyl)-2-methylpropanoic acid (Fmoc-(Me)Phe(3-I)—OH)

Compound aa119 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(3-iodophenyl)-2-methylpropanoic acid, Fmoc-(Me)Phe(3-I)—OH) (1.1 g, 64%) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa119-a ((2S)-2-amino-3-(3-iodophenyl)-2-methylpropanoic acid, H—(Me)Phe(3-I)—OH) (1 g, 3.28 mmol) as a starting material.

LCMS (ESI) m/z=528 (M+H)+

Retention time: 0.98 minute (analysis condition SQDFA05)

Synthesis of Compound aa120, (2S)-3-(3,5-dichlorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Phe(35-Cl2)-OH)

Compound aa120 ((2S)-3-(3,5-dichlorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(35-Cl2)-OH) (1.2 g, 8%) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa119aa120-a ((2S)-2-amino-3-(3,5-dichlorophenyl)propanoic acid, H-Phe(35-Cl2)-OH) (4 g, 17.09 mol) as a starting material and using sodium carbonate instead of DIPEA.

LCMS (ESI) m/z=456 (M+H)+

Retention time: 0.94 min (analysis condition SQDFA05)

Synthesis of Compound aa121, (2S)-2-[9H-fluoren-9- ylmethoxycarbonylamino-3-2-fluoro-5-iodophenyl)propanoic acid (Fmoc-Phe(2-F-5-I)—OH)

Compound aa121 ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2-fluoro-5-iodophenyl)propanoic acid, Fmoc-Phe(2-F-5-I)—OH) (1.6 g, 92%) by the same method as in the synthesis of Compound aa116 using Compound aa121-a ((2S)-2-amino-3-(2-fluoro-5-iodophenyl)propanoic acid, H-Phe(2-F-5-I)—OH) (1 g, 3.24 mmol) as a starting material.

LCMS (ESI) m/z=52 (M+H)+

Retention time: 0.94 min (analysis condition SQDFA05)

System of Compound aa122, (2S)-3(2-chloro-5-iodophenyl)2-9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Phe(2-Cl-5-I)—OH)

Compound aa122 ((2S)-3-(2-chloro-5-iodophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(2-Cl-5-I)—OH) (0.93 g, 55%) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa122-a ((2S)-2-amino-3-(2-chloro-5-iodophenyl)propanoic acid, H-Phe(2-Cl-5-I)—OH) (1 g, 3.07 mmol) as a starting material.

LCMS (ESI) m/z=546 (M−H)−

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound aa124, (2S)-3-(5-chlorothiophen-2-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Ala(2-Thie-5-Cl)—OH)

Compound aa124 ((2S)-3-(5-chlorothiophen-2-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ala(2-Thie-5-Cl)—OH) (0.87 g, 84%) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa124-a ((2S)-2-amino-3-(5-chlorothiophen-2-yl)propanoic acid, H-Ala(2-Thie-5-Cl)—OH) (0.5 g, 2.431 mmol) as a starting material.

LCMS (ESI) m/z=426 (M−H)−

Retention time: 0.91 min (analysis condition SQDFA05)

Synthesis of Compound aa125, (2S)-3-(5-bromothiophen-2-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Ala(2-Thie-5-Br)—OH)

Compound aa125 ((2S)-3-(5-bromothiophen-2-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ala (2-Thie-5-Br)—OH) (0.80 g, 85%) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa125-a ((2S)-2-amino-3-(5-bromothiophen-2-yl)propanoic acid, H-Ala(2-Thie-5-Br)—OH) (0.5 g, 2 mmol) as a starting material.

LCMS (ESI) m/z=470 (M−H)−

Retention time: 0.91 min (analysis condition SQDFA05)

Synthesis of Compound aa126 (2S)-3-(2-bromo-5-iodophenyl)2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Phe(2-Br-5-I)—OH)

Compound aa126 ((2S)-3-(2-bromo-5-iodophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(2-Br-5-I)—OH) (0.80 g, 25%) was obtained by the same method as in the synthesis of Compound aa1116 using Compound aa126-a ((2S)-2-amino-3-(2-bromo-5-iodophenyl)propanoic acid, H-Phe(2-Br-5-I)—OH) (2 g, 5.41 mmol) as a starting material.

LCMS (ESI) m/z=590 (M−H)−

Retention time: 0.96 min (analysis condition SQDFA05)

Synthesis of Compound aa127, (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(5-iodo-2-methylphenyl)propanoic acid (Fmoc-Phe(2-Me-5-I)—OH

Compound aa127 ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(5-iodo-2-methylphenyl)propanoic acid, Fmoc-Phe(2-Me-5-I)—OH) (2.87 g, quant.) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa127-a ((2S)-2-amino-3-(5-iodo-2-methylphenyl)propanoic acid, H-Phe(2-Me-5-I)—OH) (1,651 g, 5.41 mmol) as a starting material.

LCMS (ESI) m/z=526 (M−H)−

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound aa128, (2S)-3-5-bromo-2-methylphenyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-Phe(2-Me-5-Br)—OH)

Compound aa128 ((2S)-3-(5-bromo-2-methylphenyl)-2-(9I-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(2-Me-5-Br)—OH) (2.91 g, quant.) was obtained by the same method as in the synthesis of Compound aa116 using Compound aa128-a ((2S)-2-amino-3-(5-bromo-2-methylphenyl)propanoic acid, H-Phe(2-Me-5-Br)—OH) (1.396 g, 5.41 mmol) as a starting material.

LCMS (ESI) m/z=478 (M−H)−

Retention time: 0.96 min (analysis condition SQDFA05)

Synthesis of Compound aa130, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino octanoic acid (Fmoc-MeAOC(2)-OH)

Compound aa130-b was obtained as a crude product by the same method as in the synthesis of Compound aa069-b using Compound aa130-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]octanoic acid, Fmoc-AOC(2)-OH) (6.15 g, 16.12 mmol) as a starting material. Further, Compound aa130 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]octanoic acid, Fmoc-MeAOC(2)-OH) (6.4 g, 100% through two steps) was obtained by the same method as in the synthesis of Compound aa069 using Compound aa130-b.

LCMS (ESI) m/z=396.3 (M+H)+

Retention time: 1.00 min (analysis condition SQDFA05)

Synthesis of Compound aa132, (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5-methylhexanoic acid Fmoc-Melle-OH)

Compound aa131-b was obtained as a crude product by the same method as in the synthesis of Compound aa078-b using Compound aa131-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-5-methylhexanoic acid, Fmoc-Hle-OH) (20 g, 54.4 mmol) as a starting material. Further, Compound aa131 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5-methylhexanoic acid, Fmoc-MeHle-OH) (21.5 g, quant.) was obtained by the same method as in the synthesis of Compound aa078 using Compound aa131-b,

LCMS (ESI) m/z=382 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA05)

Synthesis of Compound aa132, (2S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-[9H-fluoren-9-ylmethoxycarbonylamino) butanoic acid, Fmoc-Hph(4-CF3-3-Cl)—OH

To a solution of (4S)-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid (Boc-Glu-OBn, CAS No. 30924-93-7) (200 g, 592.82 mmol), N-hydroxyphthalimide (106 g, 649.78 mmol, 1.10 equivalents), and DMAP (3.6 g, 29.47 mmol, 0.05 equivalents) in THF (2 L) was added dropwise DIC (138 mL, 1.54 equivalents) at 0° C. under a nitrogen atmosphere. The reaction solution was stirred at 25° C. for 16 hours, the solid was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure. The residue was diluted with toluene, the resulting solid was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by recrystallization (acetone/heptane) to give Compound aa132-a (1-O-benzyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate) (230 g, 80%).

LCMS (ESI) m/z=505.2 (M-fNa)+

Retention time: 0.992 min (analysis condition SMDmethod_16)

Nickel bromide trihydrate (NiBr₂·3H₂O) (4 g, 0.07 equivalents) and 4,4′-di-tert-butyl-2,2′-bipyridyl (dtbbpy, CAS No. 72914-19-3) (3.9 g, 14.55 mmol, 0.07 equivalents) were added to DMA (500 mL), and the mixture was stirred at 50° C. for two hours under a nitrogen atmosphere to prepare a Ni solution.

To a mixture of Compound aa132-a (100 g, 207.3 mmol), zinc powder (70 g, 5 equivalents), and 4-bromo-2-chloro-1-(trifluoromethyl)benzene (CAS No. 467435-07-0, 160 g, 617 mmol, 3 equivalents) in DMA (500 mL) was added the Ni solution prepared above, and the mixture was stirred at 25° C. for 16 hours. To the reaction solution was added an aqueous EDTA-2Na solution (10%), and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound aa132-b (75 g, 77%).

LCMS (ESI) m/z=494 (M+Na)+

Retention time: 2.863 min (analysis condition SMDmethod_17)

A solution of Compound aa132-b (75 g, 158.93 mmol) in toluene (900 mL) was cooled to 0° C., and trifluoromethanesulfonic acid (TfOH) (42 mL, 3.00 equivalents) was added dropwise. After stirring at room temperature for one hour, water (75 mL) was added. The mixture was extracted with water, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. To the residue was added acetonitrile/water (900/900 mL), and the pH was adjusted to 7 with an aqueous sodium hydroxide solution (48%). To this solution was added Fmoc-OSu (51.2 g, 151.93 mmol, 0.95 equivalents), and the mixture was stirred at room temperature for 16 hours while maintaining the pH at 7.8-8.0. The reaction solution was filtered and the filtrate was adjusted to pH 2 with 6 mol/L aqueous hydrochloric acid. The precipitated solid was collected and dried at 50° C. to give Compound aa132 ((2S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, Fmoc-Hph(4-CF3-3-Cl)—OH) (70 g, 87%).

LCMS (ESI) m/z=525.8 (M+Na)+

Retention time: 2.180 min (analysis condition SMDmethod_21)

¹H-NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 7.91 (d, J=7.5 Hz, 2H), 7.79-7.59 (m, 5H), 7.45-7.28 (m, 5H), 4.40-4.19 (m, 3H), 3.96-3.88 (m, 1H), 2.82-2.60 (m, 2H), 2.11-1.77 (m, 2H)

Synthesis of Compound aa133, (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-fluoro-4-(trifluoromethyl)phenyl]butanoic acid (Fmoc-Hph(4-CF3-3-F)—OH)

Nickel bromide trihydrate (NiBr₂·3H₂O) (71.5 g, 263 mmol, 0.3 equivalents) and 4,4′-di-tert-butyl-2,2′bipyridyl (dtbbpy, CAS No. 72914-19-3) (70.56 g, 263 mmol, 0.3 equivalents) were added to DMA (2 L), and the mixture was stirred at 50° C. for three hours under a nitrogen atmosphere to prepare a Ni solution.

A mixture of Compound aa039-a (1-O-tert-butyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanedioate) (500 g, 876 mmol), which was synthesized according to the method described in this example using compound Fmoc-Glu-OtBu ((4S)-4-(9H-fluorene-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid, CAS No. 84793-07-7) as a raw material, zinc powder (287 g, 4.38 mol, 5 equivalents), and 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (CAS No. 142808-15-9, 425.87 g, 1.753 mol, 2 equivalents) in DMA (2 L) was stirred at room temperature for 1 hour under a nitrogen atmosphere. To this mixture was added the Ni solution prepared above, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added an aqueous EDTA-2Na solution (4 L, 10%), and the solid was removed by filtration while washing with ethyl acetate. The filtrate was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound aa133-a (230 g, 43%).

LCMS (ESI) m/z=566.2 (M+Na)+

Retention time: 1,317 min (analysis condition SMDmethod_18)

A mixture of the obtained Compound aa133-a (230 g, 423 mmol) and chlorotrimethylsilane (TMSCl) (137.9 g, 1.269 mol) in trifluoroethanol (TFE) (2.3 L) was stirred at room temperature for one hour, and the precipitated solid was collected by filtration. The resulting solid was dissolved in TBME and the solvent was evaporated under reduced pressure. This operation was repeated several times to give the target Compound aa133 ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-fluoro-4-(trifluoromethyl)phenyl]butanoic acid, Fimoc-Hph(4-CF3-3-F)—OH) (190 g, 90%).

LCMS (ESI) m/z=510.2 (M+Na)+

Retention time: 1.585 min (analysis condition SMDmethod_13)

¹H-NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.81-7.66 (m, 4H), 7.47-7.37 (m, 3H), 7.37-7.29 (m, 2H), 7.25 (d, J=8.1 Hz, 1H), 4.44-4.14 (i, 3H), 3.97-3.84 (m, 1H), 2.80-2.63 (m, 2H), 2.12-1.81 (m, 2H).

Synthesis of Compound aa134, (2S)-4-3,5-difluoro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, Fmoc-Hph(4-CF3-35-F2)-OH

Nickel bromide trihydrate (NiBr₂·3H₂O) (13.5 g, 49.7 mmol, 0.3 equivalents) and 4,4′-di-tert-butyl-2,2′-bipyridyl (dtbbpy, CAS No. 72914-19-3) (13.3 g, 49.7 mmol, 0.3 equivalents) were added to DMA (400 mL), and the mixture was stirred at 50° C. for three hours under a nitrogen atmosphere to prepare a Ni solution.

A mixture of Compound aa132-a (1-O-benzyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate) (80 g, 166 mmol), zinc powder (54.2 g, 829 mmol, 5 equivalents), and 4-bromo-1,3-difluoro-2-(trifluoromethyl)benzene (CAS No. 156243-64-0, 86.6 g, 332 mmol, 2 equivalents) in DMA (400 mL) was stirred at room temperature for one hour under a nitrogen atmosphere. The above-prepared Ni solution was added, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added an aqueous EDTA-2Na solution (800 mL, 10%), and the solid was removed by filtration. The filtrate was extracted with ethyl acetate, the combined organic layers were washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound aa134-a (57.2 g, 69%).

LCMS (ESI) m/z=496 (M+Na)+

Retention time: 1.544 min (analysis condition SMDmethod_15)

A mixture of Compound aa134-a (57.2 g, 121 mmol) in toluene (690 mL) was cooled to 0° C., and trifluoromethanesulfonic acid (TfOH) (54.4 g, 362 mmol, 3 equivalents) was added dropwise. After stirring at room temperature for one hour, water (58 mL) was added. The mixture was extracted with water, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give 60 g of a residue. To the residue was added acetonitrile/water (400/400 mL), and the pH was adjusted to 7 with an aqueous sodium hydroxide solution (48%). To the solution was added Fmoc-OSu (36.6 g, 108.6 mmol, 0.9 equivalents), the pH was adjusted to 8.0 with an aqueous sodium hydroxide solution (48%), and the mixture was then stirred at room temperature for 16 hours. The reaction solution was filtered while washing with acetonitrile/water (1/1) to remove the solid component. The filtrate was diluted with acetonitrile and acidified with 6 mol/L aqueous hydrochloric acid, and the precipitated solid was collected by filtration to give Compound aa134 ((2S)-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, Fmoc-41ph(4-CF3-35-F2)-OH) (52 g, 83%).

LCMS (ESI) m/z=528.45 (M+Na)+

Retention time: 3.538 min (analysis condition SMDmethod_14)

¹H-NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.78-7.54 (m, 31H), 7.48-7.20 (m, 6H), 4.33 (d, J=6.3 Hz, 2H), 4.24 (t, J=6.9 Hz, 1H), 3.97-3.84 (m, 1H), 2.79-2.65 (m, 2H), 2.15-2.00 (m, 1H), 2.00-1.83 (m, 1H)

Synthesis of Compound aa150 ((2S)-2-9H-fluoren-9-ylmethoxycarbonyl(methyl)amino-5,5,5-trifluoropentanoic acid, Fmoc-MeNva(5-F2)-OH)

A mixture of Compound aa1150-a ((2S)-2-(phenylmethoxycarbonylamino)pentanedioic acid) (50 g, 177.8 mmol), paraformaldehyde (11.87 g), and p-toluenesulfonic acid (1.84 g, 10.69 mmol) in toluene (500 mL) was stirred at 120° C. for 16 hours. The reaction solution was left to cool to room temperature, diluted with ethyl acetate, washed with brine, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa150-b as a crude product (52 g, 96%). The crude product was used for the next reaction without purification.

A solution of Compound aa150-b (4 g, 13.64 mmol) in thionyl chloride (50 mL) was stirred at 85° C. for one hour, and the solvent was then evaporated under reduced pressure. The residue was dissolved in THF (20 mL) and cooled to −78° C. under a nitrogen atmosphere. A solution of lithium tri-tert-butoxyaluminum hydride (2.76 g, 10.87 mmol) in THF (20 mL) was added thereto dropwise over 2.5 hours. After stirring at −78° C. for three hours, water was added to the reaction solution, and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the organic layer was washed with brine, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound aa150-c (2 g).

¹H-NMR (400 MHz, CDCl₃) δ 7.41-7.32 (m, 5H), 5.49 (br.s, 1H), 5.27-5.11 (m, 3H), 4.38-4.33 (m, 1H.), 2.58-2.19 (m, 4H)

To a solution of Compound aa150-c (450 mg, 1.62 mmol) in DCM (20 mL) was added N,N-diethylaminosulfur trifluoride (DAST) (780 mg, 4.84 mmol) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. After adding water, the reaction solution was diluted with DCM and sequentially washed with an aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound aa150-d (0.35 g, 72%). This was mixed with another lot synthesized in the same manner, and the next reaction was performed.

¹H-NMR (400 MHz, CDCl₃) δ 7.42-7.35 (m, 5H4), 5.97-5.58 (m, 2H), 5.25-5.16 (m, 3H), 4.50-4.35 (m, 1H), 2.14-1.68 (m, 4H)

¹⁹F-NMR (400 MHz, CDCl₃) δ−116.562

Compound aa150-d (1 g, 3.34 mmol) and TES (12.63 g, 109 mmol) were dissolved in TFA/DCM (10/10 mL), the mixture was stirred at room temperature for four days, and the solvent was then evaporated under reduced pressure. The residue was diluted with an aqueous sodium bicarbonate solution, washed with ether, and then adjusted to pH 3 with 2 N aqueous hydrochloric acid. The organic layer was extracted with DCM, washed with brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa150-e (0.6 g) as a crude product. The crude product was used for the next reaction without purification.

A mixture of Compound aa150-e (0.6 g) and palladium on carbon (10%, 60 mg) in methanol (10 mL) was stirred for 16 hours under a hydrogen atmosphere at about 3 atm. The palladium on carbon was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to give Compound aa150-f (0.23 g) as a crude product. The crude product was used for the next reaction without purification. This was mixed with another lot synthesized in the same manner, and the next reaction was performed.

To a mixture of Compound aa150-f (0.3 g, 1.79 mmol) and potassium carbonate (745 mg, 5.4 mmol) in 1,4-dioxane/water (5/5 mL) was added Fmoc-OSu (0.9 g, 1.5 equivalents), and the mixture was stirred for two hours. The reaction solution was diluted with water, washed with diethyl ether, and then adjusted to pH 3 with 2 N aqueous hydrochloric acid. The organic layers were extracted with ethyl acetate three times, combined, washed with brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.05% TFA/distilled water with 0.05% TFA) to give Compound aa150 ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5,5,5-trifluoropentanoic acid, Fmoc-MeNva(5-F2)-OH) (0.2 g, 29%). Another lot synthesized in the same manner was also used for peptide synthesis in the present Examples.

Retention time: 3.153 min (analysis condition SMDmethod_19)

¹H-NMR (300 MHz, DMSO-d6) δ 12.94 (br.s, 11H), 7.92-7.88 (d, J=7.2 Hz, 2H), 7.66-7.61 (m, 2H), 7.44-7.31 (m, 4H), 6.35-5.75 (m, 1H), 4.49-4.26 (m, 4H), 2.72 (s, 3H), 1.78-1.65 (m, 41-1)

¹⁹F-NMR (300 MHz, DMSO-d6) δ−115.730

Synthesis of Compound aa151 (2S)-3-(3 4-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino)propanoic acid Fmoc-MePhe(34-F2)-OH)

Compound aa151-b was obtained as a crude product by the same method as in the synthesis of Compound aa078-b using Compound aa151-a ((2S)-3-(3,4-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-Phe(34-F2)-OH) (105 mg, 0.247 mmol) as a starting material. Further, Compound aa151 ((2S)-3-(3,4-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-MePhe(34-F2)-OH) (74.4 mg, 69% through two steps) was obtained by the same method as in the synthesis of Compound aa060 using aa151-b.

LCMS (ESI) m/z=438 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

Synthesis of Compound aa152 ((2S)-4-(4,4-difluoropiperidin-1-yl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsn(pip-4-F2)-OH)

To a mixture of Compound aa033-a (9H-fluoren-9-ylmethyl (4S)-5-oxo-4-(2-oxo-2-prop-2-enoxyethyl)-1,3-oxazolidine-3-carboxylate) (10.3 g, 25.3 mmol) in DCM (25.3 mL) were added phenylsilane (2.176 ml, 17.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (146 mg, 0.126 mmol), and the mixture was stirred at room temperature for 50 minutes. The reaction solution was diluted with TBME (10 v/w) and washed with a 5% aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH 4 with phosphoric acid and extracted with TBME. The resulting organic layer was washed with brine/water (1/1) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa152-c (9.12 g, 98%).

LCMS (ESI) m/z=368 (M+H)+

Retention time: 0.72 min (analysis condition SQDFA05)

Compound aa152-c (9.1 g, 24.77 mmol) and HOBt (3.68 g, 27.2 mmol) were added to a suspension of WSCI·HCl (5.7 g, 29.7 mmol) in DMF (70.8 mL) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. 4,4-Difluoropiperidine hydrochloride (4.29 g, 27.2 mmol) and DIPEA (4.39 mL, 24.77 mL) were added thereto, and the mixture was stirred at 0° C. for one hour. The reaction solution was diluted with ethyl acetate and sequentially washed with 0.5 mol/L aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate/water (I/1), and brine/water (1/1). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure to give Compound aa152-d (10.87 g, 93%).

LCMS (ESI) m/z=471 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA05)

The obtained Compound aa152-d (10.87 g) was reacted by the same method as in the synthesis of Compound aa069 and then purified by reverse phase column chromatography (0.1% aqueous formic acid/0.1% formic acid-acetonitrile) to give Compound aa152, (2S)-4-(4,4-difluoropiperidin-1-yl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid (Fmoc-MeAsn(pip-4-F2)-OH) (10.6 g, 91%).

LCMS (ESI) m/z=473 (M+H)+

Retention time: 0.78 ruin (analysis condition SQDFA05)

Synthesis of Compound aa153 ((2S)-4-(3,3-difluoroazetidin-1-Yl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsn(Aze-3-F2)-OH)

A suspension of Compound aa047-c ((2S)-4-(3,3-difluoroazetidin-1-yl)-2-[methyl(phenylmethoxycarbonyl)amino]-4-oxobutanoic acid) (500 mg, 1.403 mmol) and 10% palladium on carbon (50 w/w % water, 100 mg) in ethanol (15 mL) was stirred at room temperature for 13 hours and 15 minutes under a hydrogen atmosphere, after which the reaction mixture was filtered through celite, and the resulting filtrate was concentrated under reduced pressure to yield Compound aa153-a as a crude product (324 mg).

Compound aa153-a (324 mg) was dissolved in distilled water (5 ml), 1,4-dioxane (5 ml), diisopropylethylamine (DIPEA) (1.019 ml, 5.83 mmol), and N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (492 mg, 1.458 mmol) were added, and the mixture was stirred at room temperature for 30 minutes, To the reaction solution were added water (5 mL) and hexane/cyclopentyl methyl ether (3/1, 5 mL), and the mixture was washed with hexane/ether (3/1). To the resulting aqueous layer were added potassium hydrogen sulfate (0.79 g), ethyl acetate, and saturated aqueous potassium hydrogen sulfate (1 mL), and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine/water (1/1) and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa153, (2S)-4-(3,3-difluoroazetidin-1-yl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid (Fmoc-MeAsn(Aze-3-F2)-OH) (660 mg, quant.).

LCMS (ESI) m/z=445 (M+H)+

Retention time: 0.72 min (analysis condition SQDFA05)

Synthesis of Compound aa154, ((2S)-2-9H-fluoren-9-ylmethoxycarbonyl(methyl)amino)-3-3-iodophenyl)propanoic acid, Fmoc-MePhe(3-I)—OH)

Compound aa154-b (3.11 g) was obtained as a crude product by the same method as in the synthesis of Compound aa078-b using Compound aa154-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3-iodophenyl)propanoic acid, Fmoc-Phe(3-I)—OH) (containing one molecule of THF per molecule of amino acid, 3.29 g, 5.62 mmol) as a starting material.

LCMS (ESI) m/z=526 (M+H)+

Retention time: 1.07 min (analysis condition SQDFA05)

Compound aa154 ((2S)-2-(9H-fluoren-9-ylmethoxycarbonyl(methyl)amino)-3-(3-iodopentyl)propanoic acid (Fmoc-MePhe(3-I)—OH)) (2.924 g, 99% through two steps) was obtained by the same method as in the synthesis of Compound aa078 using the obtained Compound aa154-b.

LCMS (ESI) m/z=526 (M+H)+

Retention time: 098 min (analysis condition SQDFA05)

The amino acid to be loaded on the resin was synthesized according to the following scheme.

Synthesis of Compound aa155-c, (2R)-3-(tert-butyldisulfanyl)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid

A mixture of (2R)-3-(tert-butyldisulfanyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid (20.0 g, 46.3 mmol), (+)-camphorsulfonic acid (752.6 mg, 3.2 mmol 0.07 equivalents), and paraformaldehyde (13.9 g, 463.4 mmol, 10.0 equivalents) in toluene (200 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution three times, and then washed with brine. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give Compound aa155-b (9H-fluoren-9-ylmethyl(4R)-4-[(tert-butyldisulfanyl)methyl]-5-oxo-1,3-oxazolidine-3-carboxylate, 23 g) as a crude product.

LCMS (ESI) m/z=466.1 (M+Na)+

Retention time: 1.560 min (analysis condition SMDmethod_20)

To a mixture of Compound aa155-b (9H-fluoren-9-ylmethyl(4R)-4-[(tert-butyldisulfanyl)methyl]-5-oxo-1,3-oxazolidine-3-carboxylate, 23 g) obtained above and triethylsilane (60.2 g, 518 mmol) in dichloromethane (120 mL) was added trifluoroacetic acid (120 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 40 hours. The solvent was evaporated from the reaction solution under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (C18, acetonitrile/water) to give Compound aa155-c, (2R)-3-(tert-butyldisulfanyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino] propanoic acid (13 g, 63% through two steps).

LCMS (ESI) m/z=446.1 (M+H)+

Retention time: 0.852 min (analysis condition SMDmethod_30)

Synthesis of Compound aa155-d, 9H-fluoren-9-ylmethyl N-[(2R)-3-(tert-butyldisulfanyl)-1-(dimethylamino)-1-oxopropan-2-yl]-N-methylcarbamate

Under a nitrogen atmosphere, Compound aa155-c ((2R)-3-(tert-butyldisulfanyl)-2-[9-1-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, 13.0 g, 29.2 mmol), WSCI·HCl (6.49 g, 33.84 mmol, 1.2 equivalents), and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt) (5.23 g, 32.09 mmol, 1.1 equivalents) were added to a mixture of DMF (26 mL) and DCM (90 mL) at room temperature, and the mixture was stirred for five minutes. The obtained reaction solution was cooled to 0° C., and dimethylamine (a solution of 2 mol/L in THF, 15.60 mL, 31.2 mmol, 1.07 equivalents) was added dropwise, and the reaction solution was stirred at 0° C. for one hour. The reaction solution was diluted with ethyl acetate, washed with hydrochloric acid (1 mol/L, 130 mL) twice, then washed with water (130 mL) once, washed with an aqueous sodium bicarbonate solution (130 mL) twice, and washed with brine (130 mL) once. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by normal phase chromatography (petroleum ether/ethyl acetate) to give Compound aa155-d (91-1-fluoren-9-ylmethyl N-[(2R)-3-(tert-butyldisulfanyl)-1-(dimethylamino)-1-oxopropan-2-yl]-N-methylcarbamate, 12.1 g, 88%).

LCMS (ESI) m/z=495.2 (M+Na)+

Retention time: 1.546 min (analysis condition SMDmethod_20)

Synthesis of Compound aa155-e 9H-fluoren-9-ylmethyl N-[(2R)-1-(dimethylamino)-1-oxo-3-sulfanylpropan-2-yl]-N-methylcarbamate

Under a nitrogen atmosphere, to a mixture of Compound aa155-d (91-1-fluoren-9-ylmethyl N-[(2R)-3-(tert-butyldisulfanyl)-1-(dimethylamino)-1-oxopropan-2-yl]-N-methylcarbamate, 11.7 g, 24.7 mmol) in ethanol (100 mL), DCM (150 mL), and water (25 mL), tri-n-butylphosphine (6.0 g, 29.7 mmol, 1.2 equivalents) was added dropwise at room temperature, and the mixture was stirred for three hours at room temperature. The reaction solution was extracted with dichloromethane (DCM), and the resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was purified by normal phase chromatography (petroleum ether/ethyl acetate), and the resulting mixture was purified by reverse phase column chromatography (C18, acetonitrile/water) to give Compound aa155-e (9H-fluoren-9-ylmethyl N-[(2R)-1-(dimethylamino)-1-oxo-3-sulfanylpropan-2-yl]-N-methylcarbamate, 3.03 g, 32%).

LCMS (ESI) m/z=407.2 (M+Na)+

Retention time: 1.326 min (analysis condition SMDmethod_20)

Synthesis of Compound aa155, 2-(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid

A mixture of Compound aa155-e (9H-fluoren-9-ylmethyl N-[(2R)-1-(dimethylamino)-1-oxo-3-sulfanylpropan-2-yl]-N-methylcarbamate, 2.80 g, 7.29 mmol) and tert-butyl bromoacetic acid (2.10 g, 10.77 mmol, 1.5 equivalents) in DMF (40 mL) was stirred at room temperature for five minutes, cesium carbonate (2.80 g, 8.59 mmol, 1.2 equivalents) was added thereto, and the mixture was stirred for one hour. The reaction solution was diluted with ethyl acetate and washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa155-f (tert-butyl 2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanyl acetate, 3.1 g) as a crude product. The obtained crude product was used for the next reaction without further purification.

LCMS (ESI) m/z=499.3 (M+H)+

Retention time: 1.467 min (analysis condition SMDmethod_20)

Compound aa155-f (tert-butyl 2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanyl acetate, 3.1 g) obtained above was dissolved in a mixture of trifluoroacetic acid (TFA) (30 mL) and dichloromethane (DCM) (30 mL), and the mixture was stirred for two hours at room temperature under a nitrogen atmosphere. The solvent was evaporated from the reaction solution under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (C18, acetonitrile/water). The obtained mixture was further purified by reverse phase high-performance column chromatography (acetonitrile/water, containing TFA), and the resulting eluate was extracted with DCM. The obtained organic layer was sequentially washed with water and hydrochloric acid (1 mol/L), and the solvent was evaporated under reduced pressure to give Compound aa155 (2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid, 1.79 g, 55% through two steps).

LCMS (ESI) m/z=443.2 (M+H)+

Retention time: 1.383 min (analysis condition SMDmethod_31)

1-2. Synthesis of Amino Acid-Loaded Resins Used for Solid-Phase Peptide Synthesis by an Automated Synthesizer

Amino acids listed in Table 6 were synthesized by the methods provided below, and were loaded on resins and used for peptide synthesis using a peptide synthesizer. Amino acids listed in Table 7 were purchased from commercial suppliers, and were loaded on resins and used for peptide synthesis using a peptide synthesizer. Fmoc amino acids were loaded on resins according to the method described in WO 2013/100132 or WO 2018/225864. 2-Chlorotrityl chloride resin (100-200 mesh, 1% DVB) was purchased from Watanabe Chemical Industries, Ltd. and Chem-Impex.

TABLE 6
Compound
No.	Abbreviation	Structural formula	Name
aa006	Fmoc-MeAsp-pip		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxo-4-piperidin-1- ylbutanoic acid
aa007	Fmoc-MeAsp-mor		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-morpholin-4-yl-4- oxobutanoic acid
aa008	Fmoc-MeAsp-pyrro(3-Me2)		(3S)-4-(3,3- dimethylpyrrolidin-1-y!)-3- [9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxobutanoic acid
aa009	Fmoc-MeAsp-plz(oxe)		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-[4-(oxetan-3- yl)piperazin-1-yl]-4- oxobutanoic acid
aa010	Fmoc-MeAsp-mor(26-bicyc)		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)- 4-oxobutanoic acid
aa011	Fmoc-MEAsp-NMe2		(3S)-4-(dimethylamino)-3- [9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxobutanoic acid
aa012	Fmoc-MeAsp-aze		(3S)-4-(azetidin-1-yl)-3-[9H- fluoren-9-ylmethoxycarbonyl (methyl)amino]-4- oxobutanoic acid
aa013	Fmoc-MeAsp-pyrro		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxo-4-pyrrolidin-1- ylbutanoic acid
aa014	Fmoc-MeAsp-pip(4-Me)		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-(4-methylpiperidin- 1-yl)-4-oxobutanoic acid
aa015	Fmoc-MeAsp-mor(SO2)		(3S)-4-(1,1-dioxo-1,4- thiazinan-4-yl)-3-19H-fluoren- 9-ylmethoxycarbonyl(methyl) amino]-4-oxobutanoic acid
aa016	Fmoc-Asp-plz(oxe)		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- [4-(oxetan-3-yl)piperazin-1- yl]-4-oxobutanoic acid
aa017	Fmoc-Asp-mor(26-bicye)		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- (3-oxa-8-azabicyclo[3.2.1] octan-8-yl)-4-oxobutanoic acid
aa018	Fmoc-Asp-pyrro		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- oxo-4-pyrrolidin-1-ylbutanoic acid
aa019	Fmoc-ASp-NMe2		(3S)-4-(dimethylamino)-3- (9H-fluoren-9- ylmethoxycarbonylamino)-4- oxobutanoic acid
aa020	Fmoc-Asp-pip-tBu		(3S)-4-(4-tert-butylpiperidin- 1-yl)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- oxobutanoic acid
aa021	Fmoc-Asp-mor(SO2)		(3S)-4-(1,1-dioxo-1,4- thiazinan-4-yl)-3-(9H-fluoren- 9-ylmethoxycarbonylamino)- 4-oxobutanoic acid
aa022	Fmoc-Asp-mor		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- morpholin-4-yl-4-oxobutanoic acid
aa023	Fmoc-Asp-pip(4-Me)		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- (4-methylpiperidin-1-yl)-4- oxobutanoic acid
aa024	Fmoc-Asp-pyrro(3-Me2)		(3S)-4-(3,3- dimethylpyrrolidin-1-y!)-3- (9H-fluoren-9- ylmethoxycarbonylamino)-4- oxobutanoic acid
aa025	Fmoc-MeAsp-pip(346-F8)		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-(3,3,4,4,5,5- hexafluoropiperidin-1-y1)-4- oxobutanoic acid
aa026	Fmoc-Asp-pip(345-F )		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- (3,3,4,4,5,5- hexafluoropiperidin-1-yl)-4- oxobutanoic acid
aa027	Fmoc-Asp-pyrro(34-F4)		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- oxo-4-(3,3,4,4- tetrafluoropyrrolidin-1- yl)butanoic acid
aa028	Fmoc-MeAsp-pyrro(34-F4)		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxo-4-(3,3,4,4- tetrafluoropyrrolidin-1- yl)butanoic acid
aa029	Fmoc-Asp-oxz		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- (1,3-oxazolidin-3-y!)-4- oxobutanoic acid
aa030	Fmoc-MeAsp-oxz		(3S)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-(1,3-oxazolidin-3- yl)-4-oxobutanoic acid
aa031	Fmoc-D-MeAsp-pyrro		(3R)-3-[9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-4-oxo-4-pyrrolidin-1- ylbutanoic acid
aa032	Fmoc-EtAsp-pip		(3S)-3-[ethyl(9H-fluoren-9- ylmethoxycarbonyl)amino]-4- oxo-4-piperidin-1-ylbutanoic acid
aa051	D-MeLeu-(C#CH2)—OH		(3R)-5-methyl-3- (methylamino)hexanoic acid
aa052	nPrAsp-pip		(3S)-4-oxo-4-piperidin-1-y1- 3-(propylamino)butanoic acid
aa107	Fmoc-D-Ser(NtBu-Aca)-(C#CH2)—OH		(3S)-4-[2-(tert-butylamino)-2- oxoethoxy]-3-(9H-fluoren-9- ylmethoxycarbonylamino) butanoic acid
aa108	Fmoc-D-Ser(Pen)-(C#CH2)—OH		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- (3-methylbutoxy)butanoic acid
aa149	Fmoc-Asp-pip		(3S)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4- oxo-4-piperidin-1-ylbutanoic acid
aa141	Fmoc-D-Leu-(C#CH2)—OH		(3R)-3-(9H-fluoren-9- ylmethoxycarbonylamino)-5- methylhexanoic acid
aa155	Fmoc-MeCys(AcOH)—NMe2		2-[(2R)-3-(dimethylamino)-2- [9H-fluoren-9- ylmethoxycarbonyl(methyl) amino]-3-oxo- propylsulfanylacetic acid
indicates data missing or illegible when filed

TABLE 7
Compound
No.	Abbreviation	Structural formula	Name	CAS No.
aa135	Fmoc-2-ACHxC—OH		(1R,2R)-2-(9H-fluoren-9- ylmethoxycarbonyl amino)cyclohexane-1- carboxylic acid	389057-34-5
aa136	Fmoc-2-ACPnC—OH		(1R,2R)-2-(9H-fluoren-9- ylmethoxycarbonyl amino)cyclopentane-1- carboxylic acid	358588-69-9
aa137	Fmoc-D-(Propargyl)Gly-(C#CH2)—OH		(3R)-3-(9H-fluoren-9- ylmethoxycarbonyl amino)hex-5-ynoic acid	3320 4-94-5
aa138	Fmoc-D-3-ABu—OH		(3R)-3-(9H-fluoren-9- ylmethoxycarbonyl amino)butanoic acid	201884-71-3
aa139	Fmoc-D-3-MeAbu—OH		(3R)-3-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]butanoic acid	146030 -60-8
aa140	Frioc-D-Gly(Ally)-(C#CH2)—OH		(3R)-3-(9H-fluoren-9- ylmethoxycarbonyl amino)hex-5-enoic acid	269726-95-6
aa143	Fmoc-D-Pic(2)-(CC#CH2)—OH		(R)-2-[1-(9H-fluoren-9- ylmethoxycarbonyl) piperidin-2-yl]acetic acid	193693-63-9
aa144	Fmoc-D-Pro-(C#CH2)—OH		2-[(2R)-1-(9H-fluoren-9- ylmethoxycarbonyl) pyrrolidin-2-yl]acetic acid	1938 -61-7
aa145	Fmoc-bMeAla—OH		3-[9H-fluoren-9- ylmethoxycarbonyl (methyl)amino]propanoic acid	172965-84-3
aa146	Fmoc-bAle-OH		3-(9H-fluoren-9- ylmethoxycarbonyl amino)propanoic acid	5737-10-1
aa147	Fmoc-D-Hph-(C#CH2)—OH		(3R)-3-(9H-fluoren-9- ylmethoxycarbonyl amino)-5- phenylpentanoic acid	2693 8-87-0
aa148	Fmoc-3-CF3-bAla-OH		(38)-3-(9H-fluoren-9- ylmethoxycarbonyl amino)-4,4,4- trifluorobutanoic acid	1310680-31-9
indicates data missing or illegible when filed

Synthesis of Compound as006-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip)

Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) was synthesized by the method described in WO 2018/225864.

In the present specification, when a resin is attached to a compound, the, resin portion may be indicated as “o.” In order to specify the point of reaction in the resin portion, the chemical structure of the reaction site may be indicated as a structure connected to “o” The above structure shows that the 2-chlorotrityl group on the resin is attached to the side chain carboxylic acid of MeAsp through an ester bond in Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip (Compound aa006-resin).

Synthesis of Compound aa007-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-morpholin-4-yl-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-mor)

WSCI·HCl (0.506 g, 2.64 mmol) was dissolved in DMF (4.4 mL), HOBt (0.356 g, 2.64 mmol) and Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid, Fmoc-MeAsp(OA1)-OH) (0.9 g, 2.2 mmol) were added, and the mixture was stirred at 0° C. for 10 minutes. To the reaction solution was added morpholine (0.23 mL, 2.64 mmol) dropwise, and the mixture was stirred at 0° C. for one hour. Ethyl acetate (9 mL) was added to the reaction solution, which was washed with 0.5 N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate/water (1/1), and brine/water (1/1) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to give Compound aa007-a as a crude product (522 mg, 50%).

LCMS (ESI) m/z=479 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

To a solution of Compound aa007-a (446 mg, 0.932 mmol) in DCM (1.86 mL) was added tetrakis(triphenylphosphine)palladium (0) (10.8 mg, 0.0093 mmol), and phenylsilane (0.081 mL, 0.653 mmol) was further added dropwise, then the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with TBME and a 5% aqueous sodium bicarbonate solution was added. The organic layer was removed, phosphoric acid (548 mg) was added to the aqueous layer, which was extracted with TBME. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa007 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-morpholin-4-yl-4-oxobutanoic acid, Fmoc-MeAsp-mor) (321 mg, 79%).

LCMS(ESI) m/z=439 (M-+H)+

Retention time: 0.69 min (analysis condition SQDFA05)

Fmoc amino acids were loaded on resins according to the method described in WO 2013/100132 or WO 2018/225864. In a reaction vessel equipped with a filter were placed 2-chlorotrityl chloride resin (1.60 mmol/g, 100-200 mesh, 1% DVB, 1 g, 1.6 mmol) and dehydrated dichloromethane (13.3 mL), and the vessel was shaken at room temperature for 10 minutes. The dichloromethane was removed by applying nitrogen pressure, after which dehydrated methanol (0.259 mL, 6.4 mmol) and diisopropylethylamine (DIPEA) (0.671 mL, 3.84 mmol) were added to a solution of Compound aa007 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-morpholin-4-yl-4-oxobutanoic acid, Fmoc-MeAsp-mor) (317 mg, 0.723 mmol) in dehydrated dichloromethane (13.3 mL), the resulting mixture was added to the reaction vessel, and the vessel was shaken for 30 minutes. The reaction solution was removed by applying nitrogen pressure, after which dehydrated methanol (1.99 mL) and diisopropylethylamine (DIPEA) (0.671 mL) were added to dehydrated dichloromethane (13.3 mL), the resulting mixture was added to the reaction vessel, and the vessel was shaken for 1 hour and 30 minutes. The reaction solution was removed by applying nitrogen pressure, after which dichloromethane was added to the reaction vessel, After shaking for 5 minutes, the reaction solution was removed by applying nitrogen pressure. This operation of washing the resin with dichloromethane was further repeated twice, and the resulting resin was dried under reduced pressure overnight to give Compound aa007-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-morpholin-4-yl-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-mor) (1.22 g, 0.37 mmol/g).

The amount of the amino acid loaded on the resin was calculated as follows. The obtained Compound aa007-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-morpholin-4-yl-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-mor) (10.4 mg) was placed in a reaction vessel, DMF (2 mL) was added, and the vessel was shaken at room temperature for one hour. DBU (40 μL) was then added and the mixture was shaken at 30° C. for 30 minutes. DMF (8 mL) was then added to the reaction mixture, and 1 mL of the solution was diluted with DMF (11.5 mL). The absorbance (294 nm) of the resulting diluted solution was measured (using Shimadzu, UV-1600PC (cell length: 1.0 cm)), and the loading amount of Compound aa007-resin was calculated to be 0.370 mmol/g.

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis.

Synthesis of Compound aa008-resin, (3S)-4-3,3-dimethylpyrrolidin-1-yl)-3-91H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-pyrro(3-Me2))

Compound aa008-a (359.6 mg, 60%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (0.5 g, 1.221 mmol) as a starting material and using 3,3-dimethylpyrrolidine instead of morpholine.

LCMS (ESI) m/z=491 (M+H)+

Retention time: 0.98 min (analysis condition SQDFA05)

Compound aa008 ((3S)-4-(3,3-dimethylpyrrolidin-1-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-pyrro(3-Me2)) (226.2 ng, 73%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa008-a (338 mg, 0.689 mmol).

LCMS (ESI) m/z=451 (M+H)+

Retention time: 0.84 min (analysis condition SQDFA05)

Compound aa008-resin ((3S)-4-(3,3-dimethylpyrrolidin-1-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pyrro(3-M e2)) (731 mg, loading amount 0.455 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa008 ((3S)-4-(3,3-dimethylpyrrolidin-1-yl)3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-pyrro(3-Me2)) (226 mg, 0.502 mmol).

Synthesis of Compound aa009-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-piz(oxe))

Compound aa009-a (466 mg, 89%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (0.4 g, 0.977 mmol) as a starting material and using 1-(oxetan-3-yl)piperazine instead of morpholine.

LCMS (ESI) m/z=534 (M+H)+

Retention time: 0.64 min (analysis condition SQDFA05)

A crude product obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa009-a (466 mg, 0.873 mmol) was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa009 ((3S)-3-[9I-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-[4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid, Fmoc-MeAsp-piz(oxe)) (385 mg, 89%).

LCMS (ESI) m/z=494 (M+H)+

Retention time: 0.50 min (analysis condition SQDFA05)

Compound aa009-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-[4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-piz(oxe)) (1.49 g, loading amount 0.266 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa009 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-[4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid, Fmoc-MeAsp-piz(oxe)) (385 mg, 0.78 mmol).

Synthesis of Compound aa010-resin, (3S)-3-9F-fluoren-9-ylmethoxycarbonyl(methyl)aminol-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid-2-chlorotrityl resin Fmoc-MeAsp(O-Trt(2-Cl)resin)-Mor(26-bicyc))

Compound aa010-a (5.8 g, 94%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (5 g, 12.21 mmol) as a starting material and using (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and one equivalent of DIPEA relative to amine, instead of morpholine.

LCMS (ESI) m/z=505 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Compound aa010 ((3S)-3-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid, Fmoc-MeAsp-Mor(26-bicyc)) (5.1 g, 96%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa10-a (5.8 g, 11.49 mmol).

LCMS (ESI) m/z=465 (M+H)+

Retention time: 0.69 (analysis condition SQDFA05)

Compound aa010-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(0-Trt(2-Cl)resin)-Mor(26-bicyc)) (18.3 g, loading amount 0.419 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa010 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid, Fmoc-MeAsp-Mor(26-bicyc)) (5.1 g, 10.98 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa011-resin, (3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-NMe2)

Compound aa011-a (1.47 g, 92%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (1.5 g, 3.66 mmol) as a starting material and using a solution of dimethylamine in THE (2 mol/L) instead of morpholine.

LCMS (ESI) m/z=437 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

Compound aa011 ((3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-NMe2) (1.30 g, quant.) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa011-a (1.4 g, 3.21 mmol).

LCMS (ESI) m/z=397 (M+H)+

Retention time: 0.70 min (analysis condition SQDFA05)

Compound aa011-resin ((3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-NMe2) (4.45 g, loading amount 0.318 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa011 ((3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-NMe2) (1.21 g, 3.05 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa012-resin, (3S)-4-(azetidin-1-yl)-3-9H-fluoren-9-ylmethoxycarbonyl(methylamino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-aze)

Compound aa012-a (1.41 g, 86%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (1.5 g, 3.66 mmol) as a starting material and using azetidine instead of morpholine.

LCMS (ESI) m/z=449 (M+H)+

Retention time: 0.86 min (analysis condition SQDFA05)

Compound aa012 ((3S)-4-(azetidin-1-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-aze) (1.14 g, 89%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa012-a (1.4 g, 3.12 mmol).

LCMS (ESI) m/z=409 (M+H)+

Retention time: 0.69 min (analysis condition SQDFA05)

Compound aa012-resin ((3S)-4-(azetidin-1-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-aze) (3.64 g, loading amount 0.2984 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa012 ((3S)-4-(azetidin-1-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-aze) (1.05 g, 2.57 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa013-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-MeAsn(O-Trt(2-Cl)resin)-pyo)

Compound aa013-a (30.7 g, 91%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (30 g, 73.3 mmol) as a starting material and using pyrrolidine instead of morpholine.

LCMS (ESI) m/z=463 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

Compound aa013 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid, Fmoc-MeAsp-pyrro) (26.2 g, 93%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa013-a (30.7 g, 66.4 mmol),

LCMS (ESI) m/z=423 (M+H)+

Retention time: 0.71 min (analysis condition SQDFA05)

Compound aa013-resin (9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pyrro) (84.1 g loading amount 0.5216 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa013 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid, Fmoc-MeAsp-pyrro) (24.6 g, 58.2 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa014-resin, (3S)-3-9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(4-methylpiperidin-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip(4-Me))

A crude product of Compound aa014-a was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (0.9 g, 2.198 mmol) as a starting material and using 4-methylpiperidine instead of morpholine. The resulting crude product was purified by reverse phase column chromatography (water-acetonitrile, containing 0.1% formic acid), further dissolved in 20% ethyl acetate-hexane, then washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, the solvent was then evaporated under reduced pressure to give Compound aa014-a (0.587 g, 54%).

LCMS (ESI) m/z=491 (M+H)+

Retention time: 1.02 min (analysis condition SQDFA05)

Compound aa014 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)imino]-4-(4-methylpiperidin-1-yl)-4-oxobutanoic acid, Fmoc-MeAsp-pip(4-Me)) (376.6 mg, 77%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa014-a (535 mg, 1.09 mmol).

LCMS (ESI) m/z=451 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA05)

Compound aa014-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(4-methylpiperidin-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip(4-Me)) (1.2 g, loading amount 0.403 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa014 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(4-methylpiperidin-1-yl)-4-oxobutanoic acid, Fmoc-MeAsp-pip(4-Me)) (364 mg, 0.808 mmol).

Synthesis of Compound aa015-resin, (3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-mor(SO2))

Compound aa015-a (796.2 mg, 69%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (0.9 g, 2.198 mmol) as a starting material and using 1,1-dioxido-thiomorpholine instead of morpholine.

LCMS (ESI) m/z=527 (M+H)+

Retention time: 0.84 min (analysis condition SQDFA05)

Compound aa015 ((3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-mor(SO2)) (624.2 mg, 91%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa015-a (743 mg, 1.41 mmol).

LCMS (ESI) m/z=487 (M+H)+

Retention time: 0.68 min (analysis condition SQDFA05)

Compound aa015-resin ((3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-mor(SO2)) (1.85 g, loading amount 0.424 mol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa015 ((3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid, Fmoc-MeAsp-mor(SO2)) (606.7 mg, 1.247 mmol).

Synthesis of Compound aa016-resin, (3S-3-9H-fluoren-9-ylmethoxycarbonylamino)4-[4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin-piz(oxe))

Compound aa016-a (499 mg, 95%) was obtained by the same method as in the synthesis of Compound aa007-a using Fmoc-Asp(OA1)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (0.4 g, 1.012 mmol) as a starting material and using 1-(oxetan-3-yl)piperazine instead of morpholine.

LCMS (ESI) m/z=520 (M+H)+

Retention time: 0.60 min (analysis condition SQDFA05)

Compound aa016 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid (Fmoc-Asp-piz(oxe)) (415 mg, 90%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa016-a (499 mg, 0.960 mmol).

LCMS (ESI) m/z=480 (M+H)+

Retention time: 0.49 min (analysis condition SQDFA05)

Compound aa016-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-piz(oxe)) (463 mg, loading amount 0.329 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa016 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(oxetan-3-yl)piperazin-1-yl]-4-oxobutanoic acid (Fmoc-Asp-piz(oxe)) (123 mg, 0.256 mmol).

Synthesis of Compound aa017-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-Mor 26-bicyc)

Compound aa017-a (706 mg, 95%) was obtained by the same method as in the synthesis of Compound aa007-a using Fmoc-Asp(OA)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (0.6 g, 1.517 mmol) as a starting material and using (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and one equivalent of DIPEA relative to amine, instead of morpholine.

LCMS (ESI) m/z=491 (M+H)+

Retention time: 0.82 (analysis condition SQDFA05)

Compound aa017 ((3S)-3-(9H1-fluoren-9-ylmethoxycarbonylamino)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid, Fmoc-Asp-Mor(26-bicyc)) (564.5 mg, 87%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa017-a (705 mg, 1.437 mmol).

LCMS (ESI) m/z=451 (M+H)+

Retention time: 0.66 min (analysis condition SQDFA05)

Compound aa017-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-Mor(26-bicyc)) (464 mg, loading amount 0.340 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa017 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid, Fmoc-Asp-Mor(26-bicyc)) (115 mg, 0.256 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa018-resin, (3S)-3-91H-fluoren-9- ylmethoxycarbonylamino)-4-oxo-4-pyrrolidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)-resin)-pyrro)

To DMF (600 mL) were sequentially added WSCI·HCl (67.1 g, 350 mmol), HOBt (43.4 g, 321 mmol), and Fmoc-Asp(OtBu)-OH (120 g, 292 mmol) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at 0° C. for one hour. To this reaction solution was slowly added pyrrolidine (26.3 mL, 321 mmol), and the mixture was stirred at 0° C. for 1.5 hours. To the reaction solution were added Ethyl acetate (10 v) and 0.5 mol/L aqueous hydrochloric acid (2 v) at 0° C., and the organic layer was separated. The resulting organic layer was sequentially washed with 0.5 mol/L aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate/water (1/1), and brine/water (1/1) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa018-a as a crude product (137.1 g, quant.).

LCMS (ESI) m/z=465 (M+H)+

Retention time: 1.05 min (analysis condition SQDAA05)

To a solution of Compound aa018-a (137 g, 395 mmol) in DCM (137 mL) was slowly added TFA (271 mL) under ice-cooling such that the internal temperature did not exceed 10° C. After stirring at room temperature for one hour, diisopropyl ether (3.4 L) were added in four portions, and the precipitated solid was collected by filtration and dried to give Compound aa018 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-pyrrolidin-1-ylbutanoic acid, Fmoc-Asp-pyrro) (108.4 g, 90%).

LCMS(ESI) m/z=409 (M+H)+

Retention time: 0.83 min (analysis condition SQDAA05)

Compound aa017-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-pyrrolidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)-resin)-pyrro)) (59.79 g, loading amount 0.464 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using Compound aa018 ((3S)-3-(91H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-pyrrolidin-1-ylbutanoic acid, Fmoc-Asp-pyrro) (15.91 g, 30 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa019-resin, (3S)-4-(dimethylamino)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-NMe2)

To a solution of Fmoc-Asp(OtBu)-OH (4-tert-butyl N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate, CAS No. 71989-14-5) (5 g, 12.15 mmol) and HOBt monohydrate (2.047 g, 13.37 mmol) in DMF (24.3 mL) were sequentially added dimethylamine hydrochloride (0.991 g, 12.15 mmol), WSCI·HCl (2.8 g, 14.58 mmol), and DIPEA (2.117 mL, 12.15 mmol) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at 0° C. for 50 minutes. To the reaction solution were added ethyl acetate/hexane (1/1, 100 mL) and brine/water (1/1, 50 mL), and the organic layer was separated. The resulting organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, water, and brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give Compound aa019-a (5.02 g, 94%).

LCMS (ESI) m/z=439 (M+H)+

Retention time: 1.03 min (analysis condition SQDAA05)

To Compound aa019-a (5 g, 11.4 mmol) was added toluene (150 mL) and the solvent was evaporated under reduced pressure. This operation was performed three times. The residue was dissolved in DCM (5.06 mL), TFA (10.13 mL, 137 mmol) was added dropwise at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for one hour. The reaction solution was cooled at 0° C., diethyl ether (10.1 mL) was added, and a 8 mol/L aqueous sodium hydroxide solution (17.1 mL) was added dropwise. A saturated aqueous sodium dihydrogenphosphate solution (7.6 mL) and water (5 mL) were further added. The solution was extracted with ethyl acetate, and the resulting organic layer was washed with saturated aqueous sodium dihydrogenphosphate/water (1/1) and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure to give Compound aa019 ((3S)-4-(dimethylamino)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-NMe2) (2.63 g, 60%), which was used for the next reaction without further purification.

LCMS (ESI) m/z=383 (M+H)+

Retention time: 0.80 min (analysis condition SQD compound AA05)

Compound aa019-resin ((3S)-4-(dimethylamino)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-NMe2) (9.07 g, loading amount 0.399 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa019 ((3S)-4-(dimethylamino)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-NMe2) (2.367 g, 6.19 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa020-resin, (3S-4-4-tert-butylpiperidin-1-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-pip-tBu)

Compound aa020-a (11.5 g, 93%) was obtained by the same method as in the synthesis of Compound aa019-a using Fmoc-Asp(OtBu)-OH (4-tert-butyl N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate, CAS No. 71989-14-5) (10 g, 24.3 mmol) as a starting material, using 4-(tert-butyl)piperidine hydrochloride instead of dimethylamine hydrochloride, and using 1.0 equivalent of 4-methylmorpholine relative to amine, instead of DIPEA.

LCMS (ESI) m/z=535.4 (M+H)+

Retention time: 1.19 min (analysis condition SQDAA05)

To Compound aa020-a (2 g, 3.74 mmol) was added toluene (150 mL) and the solvent was evaporated under reduced pressure. This operation was performed three times. The residue was dissolved in DCM (1.66 mL), TFA (1.66 mL, 22.44 mmol) was added dropwise at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 4 h. The reaction solution was cooled to 0° C. and triethylamine (3.13 mL, 22.4 mmol) was added dropwise. This solution was diluted with DCM (30 mL) and washed with an aqueous sodium dihydrogenphosphate solution (5%) nine times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa020 ((3S)-4-(4-tert-butylpiperidin-1-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-pip-tBu) (1.73 g, 96%).

LCMS (ESI) m/z=479.4 (M+H)+

Retention time: 1.02 min (analysis condition SQDAA05)

Compound aa020-resin ((3S)-4-(4-tert-butylpiperidin-1-yl)-3-(9I-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-pip-tBa) (5.23 g, loading amount 0.356 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa020 ((3S)-4-(4-tert-butylpiperidin-1-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-pip-tBu) (1.73 g, 3.61 mmol).

Synthesis of Compound aa021-resin, (3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-mor(SO2))

Compound aa021-a (492 mg, 38%) was obtained by the same method as in the synthesis of Compound aa019-a using Fmoc-Asp(OtBu)-OH (4-tert-butyl N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate, CAS No. 71989-14-5) (1 g, 2.43 mmol) as a starting material and using 1,1-dioxido-thiomorpholine instead of dimethylamine hydrochloride and DIPEA.

LCMS (ESI) m/z=551 (M+Na)+

Retention time: 0.86 min (analysis condition SQDFA05)

Compound aa021 ((3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-mor(SO2)) (356.4 mg, 95%) was obtained by the same method as in the synthesis of Compound aa020 using the obtained Compound aa021-a (420 mg, 0.795 mmol).

LCMS (ESI) m/z=473 (M+H)+

Retention time: 0.67 min (analysis condition SQDFA05)

Compound aa021-resin ((3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-mor(SO2)) (1.16 g, loading amount 0.371 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa021 ((3S)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-mor(SO2)) (346 mg, 0.773 mmol).

Synthesis of Compound aa022-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-morpholin-4-yl-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-mor)

Compound aa022-a (713 mg, 61%) was obtained by the same method as in the synthesis of Compound aa019-a using Fmoc-Asp(OtBu)-OH (4-tert-butyl N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate, CAS No. 71989-14-5) (1 g, 2.43 mmol) as a starting material and using morpholine instead of dimethylamine hydrochloride and DIPEA.

LCMS (ESI) m/z=481 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

Compound aa022 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-morpholin-4-yl-4-oxobutanoic acid, Fmoc-Asp-mor) (353.4 mg, 100%) was obtained by the same method as in the synthesis of Compound aa020 using the obtained Compound aa022-a (400 mg, 0.832 mmol).

LCMS (ESI) m/z=425 (M+H)+

Retention time: 0.66 min (analysis condition SQDFA05)

Compound aa022-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-morpholin-4-yl-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-mor) (1.21 g, loading amount 0.415 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa022 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-morpholin-4-yl-4-oxobutanoic acid, Fmoc-Asp-mor) (326 mg, 0.768 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa023-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(4-methylpyridin-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-pip(4-Me))

A crude product of Compound aa023-a was obtained by the same method as in the synthesis of Compound aa019-a using Fmoc-Asp(OtBu)-OH (4-tert-butyl N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate, CAS No. 71989-14-5) (1 g, 2.43 mmol) as a starting material and using 4-methylpiperidine instead of dimethylamine hydrochloride and DIPEA. The resulting crude product was dissolved in 20% ethyl acetate-hexane, washed three times with a saturated aqueous sodium bicarbonate solution and once with brine, and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure to give Compound aa023-a (430 mg, 36%).

LCMS (ESI) m/z=493 (M+H)+

Retention time: 0.74 min (analysis condition SQDAA50)

Compound aa023 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(4-methylpiperidin-1-yl)-4-oxobutanoic acid, Fmoc-Asp-pip(4-Me)) (326.5 mg, quant.) was obtained by the same method as in the synthesis of Compound aa020 using the obtained Compound aa023-a (359 mg, 0.728 mmol).

LCMS (ESI) m/z=437 (M+H)+

Retention time: 0.80 min (analysis condition SQDFA05)

Compound aa023-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(4-methylpiperidin-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-pip(4-Me)) (1.07 g, loading amount 0.363 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa023 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(4-methylpiperidin-1-yl)-4-oxobutanoic acid, Fmoc-Asp-pip(4-Me)) (315 mg, 0.722 mmol).

Synthesis of Compound aa024-resin, (3S)-4-3,3-dimethylpyrrolidin-1-yl-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-pyrro(3-Me2))

Compound aa024-a (1.36 g, 56%) was obtained by the same method as in the synthesis of Compound aa007-a using Fmoc-Asp(OA1)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (2 g, 5.06 mmol) as a starting material and using 3,3-dimethylpyrrolidine instead of morpholine.

LCMS (ESI) a/z=477 (M+H)+

Retention time: 1.322 min (analysis condition SMDmethod_04)

Compound aa024 ((3S)-4-(3,3-dimethylpyrrolidin-1-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-pyrro(3-Me2)) (1.041 g, 90%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa024-a (1.269 g, 2.66 mmol).

LCMS (ESI) m/z=437 (M+H)+

Retention time: 0.81 min (analysis condition SQDFA05)

Compound aa024-resin ((3S)-4-(3,3-dimethylpyrrolidin-1-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-pyrro(3-Me2)) (4.16 g, loading amount 0.569 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa024 ((3S)-4-(3,3-dimethylpyrrolidin-1-yl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid, Fmoc-Asp-pyrro(3-Me2)) (1.903 g, 5.81 mmol).

Synthesis of Compound aa025-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3,3,4,4,5,5-hexafluoropiperidine-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip(345-F6))

To a suspension of Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (0.62 g, 1.57 mmol) in DCM (7.8 mL, 0.2 M) were added thionyl chloride (0.136 mL, 1.88 mmol, 1.2 equivalents) and DMF (0.00607 mL, 0.078 mmol, 5 mol %) at room temperature, and the mixture was stirred for four hours. The reaction solution was concentrated, after which the resulting solution of the crude product in DCM (3 mL) was added to a mixed suspension composed of a solution of 3,3,4,4,5,5-hexafluoropiperidine hydrochloride (300 mug, 1.31 mmol) in DCM (10 mL) and a 1 mol/L aqueous sodium hydroxide solution (13 mL) at room temperature, and the mixture was stirred for 1.5 hours. The reaction solution was extracted with TBME twice, and the resulting organic layers were washed with water, dried over sodium sulfate, and then concentrated under reduced pressure to give a crude product. The resulting crude product was purified by medium pressure reverse phase column chromatography to give Compound aa025-a (587 mg, 77%).

LCMS (ESI) m/z=585 (M+H)+

Retention time: 1.03 min (analysis condition SQDFA05)

Compound aa025 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)-4-oxobutanoic acid, Fmoc-MeAsp-pip(345-F6)) (413 mg, 81%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa025-a (550 mg, 0.941 mmol).

LCMS (ESI) m/z=545 (M+H)+

Retention time: 0.89 min (analysis condition SQDFA05)

Compound aa025-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip(345-F6)) (1.17 g, loading amount 0.315 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa025 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)-4-oxobutanoic acid, Fmoc-MeAsp-pip(345-F6)) (327 mg, 0.6 mmol).

Synthesis of Compound aa026-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O: Trt(2-Cl)resin)-pip(345-F6))

Compound aa026-a (552 mg, 74%) was obtained by the same method as in the synthesis of Compound aa025-a using Fmoc-Asp(OA1)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (649 mg, 1.568 mmol) as a starting material.

LCMS (ESI) m/z=571 (M+H)+

Retention time: 0.97 min (analysis condition SQDFA05)

Compound aa026 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)-4-oxobutanoic acid, Fmoc-Asp-pip(345-F6)) (462 mg, 90%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa026-a (552 mg, 0.968 mmol).

LCMS (ESI) m/z=531 (M+H)+

Retention time: 0.84 mini (analysis condition SQDFA05)

Compound aa026-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-pip(345-F6)) (1.64 g, loading amount 0.309 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa026 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)-4-oxobutanoic acid, Fmoc-Asp-pip(345-F6)) (446 mg, 0.84 mmol).

Synthesis of Compound aa027-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(3,34,4-tetrafluoropyrrolidin-1-yl)butanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-pyrro(34-F4)

Compound aa027-a (478 mg, 91%) was obtained by the same method as in the synthesis of Compound aa025-a using Fmoc-Asp(OA1)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (0.62 g, 1.568 mmol) as a starting material and using 3,3,4,4-tetrafluoropyrrolidine hydrochloride instead of 3,3,4,4,5,5-hexafluoropiperidine hydrochloride.

LCMS (ESI) m/z=521 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA05)

Compound aa027 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)butanoic acid, Fmoc-Asp-pyrro(34-F4)) (388 mg, quant.) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa027-a (416 mg, 0.799 mmol).

LCMS (ESI) m/z=481 (M+H)+

Retention time: 0.81 min (analysis condition SQDFA05)

Compound aa027-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)butanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-pyrro(34-F4)) (1,74 g, loading amount 0.343 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa027 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)butanoic acid, Fmoc-Asp-pyrro(34-F4)) (0.388 g, 0.808 mmol).

Synthesis of Compound aa028-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)butanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-pyrro(34-F4))

Compound aa028-a (490 mg, 90%) was obtained by the same method as in the synthesis of Compound aa025-a using Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (0.416 mg, 1,208 mmol) as a starting material and using 3,3,4,4-tetrafluoropyrrolidine hydrochloride instead of 3,3,4,4,5,5-hexafluoropiperidine hydrochloride.

LCMS (ESI) m/z=535 (M+H)+

Retention time: 0.99 min (analysis condition SQDFA05)

Compound aa028 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)butanoic acid, Fmoc-MeAsp-pyrro(34-F4)) (388 mg, 97%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa028-a (450 mg, 0.842 mmol).

LCMS (ESI) m/z=495 (M+H)+

Retention time: 0.83 min (analysis condition SQDFA05)

Compound aa028-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)butanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-C)resin)-pyrro(34-F4)) (1.88 g, loading amount 0.355 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa028 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-(3,3,4,4-tetrafluoropyrrolidine-1-yl)butanoic acid, Fmoc-MeAsp-pyrro(34-F4)) (388 mg, 0.785 mmol).

Synthesis of Compound aa029-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,3-oxazolidin-3-yl)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-oxz)

To a solution of Fmoc-Asp(OA1)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (700 mg, 1.77 mmol) and HATU (740 mg, 1.1 equivalents) in DMF (3.5 mL, 0.5 M) was added DIPEA (229 mg, 1 equivalent), and the mixture was stirred at room temperature for 5 minutes, after which oxazolidine (155 mg, 1.2 equivalents) was added and the mixture was stirred for 15 minutes. Water was added to the reaction solution, which was then extracted with TBME and DCM. The solvent was evaporated from the resulting organic layer under reduced pressure. The resulting crude product was purified by medium pressure reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa029-a (456.7 mg, 57%).

LCMS (ESI) m/z=451 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Compound aa029 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,3-oxazolidin-3-yl)-4-oxobutanoic acid, Fmoc-Asp-oxz) (426 mg, quant.) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa029-a (444 mg, 0.985 mmol).

LCMS (ESI) m/z=411 (M+H)+

Retention time: 0.67 min (analysis condition SQDFA05)

Compound aa029-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,3-oxazolidin-3-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-Asp(O-Trt(2-Cl)resin)-oxz) (1.99 g, loading amount 0.285 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa029 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,3-oxazolidin-3-yl)-4-oxobutanoic acid, Fmoc-Asp-oxz) (425 mg, 1.036 mmol).

Synthesis of Compound aa030-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-1,3-oxazolidin-3-yl)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-oxz)

Compound aa030-a (164 mg, 20%) was obtained by the same method as in the synthesis of Compound aa029-a using Compound aa033-b ((2S)-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid) (725 mg, 1.77 mmol) as a starting material.

LCMS (ESI) m/z=465 (M+H)+

Retention time: 0.86 min (analysis condition SQDFA05)

Compound aa030 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(1,3-oxazolidin-3-yl)-4-oxobutanoic acid, Fmoc-MeAsp-oxz) (111 mg, 83%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa030-a (146.4 mg, 0.315 mmol). Another lot synthesized in the same manner was added thereto, and the next reaction was performed.

LCMS (ESI) ma/z=425 (M+H)+

Retention time: 0.69 min (analysis condition SQDFA05)

Compound aa030-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(1,3-oxazolidin-3-yl)-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-oxz) (1.06 g, loading amount 0.283 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa030 ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(1,3-oxazolidin-3-yl)-4-oxobutanoic acid, Fmoc-MeAsp-oxz) (0.25 g, 0.589 mmol).

Synthesis of Compound aa031-resin (3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-D-MeAsp(O-Trt(2-Cl)resin)-pyrro)

Fmoc-D-Asp(OA1)-OH ((2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid) (780 mg, 1.97 mmol) was suspended in toluene (10 ml), paraformaldehyde (178 mg, 5.92 mmol) and CSA (22.9 mg, 0.10 mmol) were added. and the mixture was stirred at 85° C. for two hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine/water (1/1) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa031-a as a crude product. The next reaction was performed without further purification.

Compound aa031-a was dissolved dichloromethane (10 mL), boron trifluoride-diethyl ether complex (0.50 mL, 3.95 mmol) and triethylsilane (0.63 mL, 3.95 mmol) were added, and the mixture was stirred at room temperature for three hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting concentrate was dissolved in acetonitrile and washed with hexane. The solvent was evaporated from the acetonitrile layer under reduced pressure to give Compound aa031-b (530 mg) as a crude product. The next reaction was performed without further purification.

Compound aa031-b (530 mg, 1.29 mmol) was dissolved in DMF (5 mL), HOBt-monohydrate (218 mg, 1.42 mmol) and WSCI·HCl (298 mg, 1.55 mmol) were added, and the mixture was stirred at 0° C. for 30 minutes. To the reaction solution was added pyrrolidine (0.11 ml, 1.29 mmol), and the mixture was further stirred at room temperature for 30 minutes. To the reaction solution was added a 0.5 N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa031-c (550 mg, 60% over three steps).

LCMS (ESI) m/z=463 (M+H)+

Retention time: 0.89 min (analysis condition SQDFA05)

Compound aa031-c (crude, 550 mg, 1.19 mmol) was dissolved in dichloromethane (10 ml), phenylsilane (0.10 ml, 0.83 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.7 mg, 0.012 mmol) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with TBME. and a 5% aqueous sodium bicarbonate solution (40 ml) was added. The organic layer was removed, phosphoric acid (699 mg) was added to the aqueous layer, which was extracted with TBME. The organic layer was washed with brine/water (1/1, 40 mL) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound aa031 ((3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid, Fmoc-D-MeAsp-pyrro) (334 mg, 67%).

LCMS (ESI) m/z=423 (M+H)+

Retention time: 0.71 min (analysis condition SQDFA05)

Compound aa031-resin ((3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-D-MeAsp(O-Trt(2-Cl)resin)-pyrro) (loading amount 0,423 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa031 ((3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-pyrrolidin-1-ylbutanoic acid, Fmoc-D-MeAsp-pyrro) (330 mg, 0.781 mmol).

Synthesis of Compound aa032-resin, (3S)-3-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-EtAsp(O-Trt(2-Cl)resin)-pip)

Fmoc-Asp(OA1)-OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (5 g, 12.65 mmol, CAS No. 146982-24-3) was suspended in toluene (15.2 mL) under a nitrogen atmosphere, anhydrous magnesium sulfate (4.57 g, 37.9 mmol), paraldehyde (2.53 mL, 19.0 mmol), and TFA (194 mL, 25.3 mmol) were added, and the mixture was stirred at 70° C. for five hours. The reaction solution was left to cool to room temperature, washed twice with a mixture of water (10 v), 1 M aqueous dipotassium hydrogenphosphate (K₂HPO₄) solution (3 v), 3.5% aqueous potassium bicarbonate (KHCO₃) solution (4 v), and acetonitrile (2 v), and washed with brine/water (1/1, 5 v), and the organic layer was dried over magnesium sulfate. The resulting organic layer was filtered and then concentrated under reduced pressure to give a crude product of aa032-a, which was used for the next reaction without further purification.

LCMS (ESI) m/z=422 (M+H)+

Retention time: 0.92 min (analysis condition SQDFA05)

To a solution of the crude product containing Compound aa032-a in toluene (16 mL) were added triethylsilane (4.04 mL, 25.3 mmol) and a 1 M solution of titanium tetrachloride (TiCl₄) in toluene (25.3 mL, 25.3 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 50 minutes. The reaction solution was washed with water (5 v) twice and washed with a 1 M aqueous dipotassium hydrogenphosphate (K₂HPO₄) solution (5 v). Hexane (9 v) was added to the resulting organic layer, which was extracted twice with a mixture of 3.5% aqueous potassium bicarbonate (KHCO₃) solution (4 v) and acetonitrile (2 v). The resulting aqueous layer was washed with hexane (8 v). The resulting aqueous layer was adjusted to pH 3 or lower with a 85% aqueous phosphoric acid solution and then extracted with TBME (5 v), and the resulting organic layer was washed with brine and then dried over magnesium sulfate. The resulting organic layer was filtered and then concentrated under reduced pressure to give Compound aa032-b (4.85 g, 91% through two steps).

LCMS (ESI) m/z=424 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA05)

Compound aa032-c (530 mg, 89%) was obtained by the same method as in the synthesis of Compound aa007-a using Compound aa032-b (512 mg, 1.21 mmol) as a starting material and using piperidine instead of morpholine.

LCMS (ESI) m/z=491 (M+H)+

Retention time: 0.99 min (analysis condition SQDFA05)

Compound aa032 ((3S)-3-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid, Fmoc-EtAsp-pip) (334 mg, 73%) was obtained by the same method as in the synthesis of Compound aa007 using the obtained Compound aa032-c (495 mg, 1.01 mmol).

LCMS (ESI) m/z=451 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Compound aa032-resin ((3S)-3-[ethyl(9I-fluoren-9-ylmethoxycarbonyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-EtAsp(O-Trt(2-Cl)resin)-pip) (18.3 g, loading amount 0.350 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound aa032 ((3S)-3-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid, Fmoc-EtAsp-pip) (0.33 g, 0.732 mmol).

Synthesis of Compound aa051 ((3R)-5-methyl-3-(methylamino)hexanoic acid-2-chlorotrityl resin, H-D-MeLeu-C#CH2)-O-Trt(2-Cl)resin)

To a reaction vessel equipped with a filter were added Compound aa141-resin (100 mg, 0.0499 mmol, 0.499 mmol/g) and dehydrated DCM (1.0 mL), and the resin was swollen. The DCM was removed, and the resin was then washed with dehydrated DMF (0.7 mL) twice. An Fmoc deprotection solution (a solution (2% v/v) of diazabicycloundecene (DBU) in DMF, 0.7 mL) was added, the vessel was shaken at room temperature for 10 minutes, and the reaction solution was then removed. The resin was washed with dehydrated THF (0.7 mL) four times to give resin-loaded Compound aa051-b.

To this were added a nosyl chloride/dehydrated THF solution (using 0.35 mL out of the solution prepared at 0.88 g/7 mL; 0.20 mmol) and a collidine/THF solution (using 0.35 mL out of the solution prepared by diluting collidine (1.35 mL) to 7 mL with THF; 0.50 mmol), and the vessel was shaken at 40° C. for two hours. Next, the reaction solution was removed, and the resin was washed with dehydrated THF (0.7 mL) four times and then washed with dehydrated DCM (0.7 mL) four times to give resin-loaded Compound aa051-c.

This was swollen with dehydrated DCM (1.0 mL) and washed with dehydrated THF (0.7 mL) four times, after which a triphenylphosphine/dehydrated THF solution (66.0 mg/0.7 mL, 0.25 mmol), methanol (0.020 mL, 0.50 mmol), and diisopropyl azodicarboxylate (DIAD) (0.05 mL, 0.25 mmol) were added, and the vessel was stirred at 40° C. for 30 minutes. Next, the reaction solution was removed, and the resin was washed with dehydrated THF (0.7 mL) four times and then washed with dehydrated DCM (0.7 mL) four times to give resin-loaded Compound aa051-d.

This was swollen with dehydrated DCM (1.0 mL) and washed with dehydrated NMP (0.7 mL) four times, after which a DBU/NMP solution (using 0.35 mL out of the solution prepared by dilating DBU (0.4 mL) to 3.5 mL with dehydrated NMP) and a 1-dodecanethiol/NMP solution (using 0.35 mL out of the solution prepared by diluting 1-dodecanethiol (1.2 mL) to 3.5 mL with dehydrated NMP) were added and the vessel was shaken at 40° C. for one hour. Next, the reaction solution was removed, and the resin was washed with dehydrated NMP (0.7 mL) four times and then washed with dehydrated DCM (0.7 mL) four times to give resin-loaded Compound aa051.

A small amount of the resin-loaded Compound aa051 was cleaved from the resin with TFE/DCM (1/1), and the structure of the amino acid was confirmed by LC/MS.

LCMS (ESI) m/z=160 (M+H)+

Retention time: 0.30 min (analysis condition SQDAA05)

Synthesis of Compound aa052 ((3S)4-oxo-4-piperidin-1-yl-3-(propylamino)butanoic acid-2-chlorotrityl resin H-nPrAsp-O-Trt(2-Cl)resin)

Into a reaction vessel equipped with a filter were placed Compound aa149-resin (3 g, 1.36 mmol, 0.452 mmol/g) and dehydrated DCM (30 mL), and the vessel was shaken at room temperature for 15 minutes. The DCM was removed by applying nitrogen pressure, after which dehydrated DMF (30 mL) was added and the DMF was removed by applying nitrogen pressure. This operation was performed four times. A 2% solution of DBU in DMF (18 mL) was added, the vessel was shaken at room temperature for 15 minutes, and the reaction solution was removed by applying nitrogen pressure. Dehydrated NMP (30 mL) was added and the NMP was removed by applying nitrogen pressure. This operation was performed six times to give resin-loaded Compound aa052-b.

Dehydrated NMP (30 mL) was added thereto and the NMP was removed by applying nitrogen pressure. This operation was performed six times. A solution of NsCl (1.20 g, 5.42 mmol) in dehydrated NMP (30 mL, and collidine (1.8 mL, 13.6 mmol) were added and the vessel was shaken at 40° C. for one hour, after which the reaction solution was removed by applying nitrogen pressure. Dehydrated NMP (30 mL) was added and the NMP was removed by applying nitrogen pressure. This operation was performed six times to give resin-loaded Compound aa052-c.

Dehydrated DCM (30 mL) was placed thereinto and the vessel was shaken at room temperature for 15 minutes. The DCM was removed by applying nitrogen pressure, after which dehydrated DCM (25 mL) was added and the DCM was removed by applying nitrogen pressure. This operation was performed twice. Dehydrated THF (25 mL) was added and the THF was removed by applying nitrogen pressure. This operation was performed four times. A solution of triphenylphosphine (1.78 g, 6.78 mmol), DIAD (1.34 mL, 6.78 mmol), and 1-propanol (1.02 mL, 13.6 mmol) in THF (30 mL) was added, the vessel was shaken at 40° C. for 30 minutes, and the reaction solution was removed by applying nitrogen pressure. Dehydrated THF (25 mL) was added and the THF was removed by applying nitrogen pressure. This operation was performed four times. Dehydrated DCM (25 mL) was added and the DC M was removed by applying nitrogen pressure. This operation was performed four times to give resin-loaded Compound aa052-d.

Into a reaction vessel equipped with a filter were placed resin-loaded Compound aa052-d (600 mug, 0.271 mol, 0.452 mmol/g) and dehydrated DCM (6 mL), and the vessel was shaken at room temperature for 15 minutes. The DCM was removed by applying nitrogen pressure, after which dehydrated NMP (6 mL) was added and the NMP was removed by applying nitrogen pressure. This operation was performed four times. A mixture of dehydrated NMP and DBU (9/1, 2.4 mL) and a mixture of dehydrated NMP and dodecanethiol (3/1, 3 mL) were added, the vessel was shaken at room temperature for 1.5 hours, and the reaction solution was removed by applying nitrogen pressure. Dehydrated NMP (6 mL) was added and the NMP was removed by applying nitrogen pressure. This operation was performed four times. Dehydrated DCM (6 mL) was added and the DCM was removed by applying nitrogen pressure. This operation was performed four times to give resin-loaded Compound aa052.

A small amount of the resin-loaded Compound aa052 was cleaved from the resin with TFE/DCM (1/1), and the structure of the amino acid was confirmed by LC/MS.

LCMS (ESI) m/z=243 (M+H)+

Retention time: 0.30 min (analysis condition SQDFA05)

Synthesis of Compo und aa135-resin ((1R,2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)cyclohexane-1-carboxylic acid-2-chlorotrityl resin, Fmoc-2-ACHxC-O-Trt(2-Cl)resin)

Compound aa135-resin ((1R,2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)cyclohexane-1-carboxylic acid-2-chlorotrityl resin, Fmoc-2-ACHxC-O-Trt(2-Cl)resin) (4.38 g, loading amount 0.411 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (1 R,2R)-2-(91H-fluoren-9-ylmethoxycarbonylamino)cyclohexane-1-carboxylic acid (Fmoc-2-ACHxC-OH) purchased from a commercial supplier (1.12 g, 3.07 mmol) and 2-chlorotrityl chloride resin (1.60 mmol/g, 100-200 mesh, 1% DVB, 3.84 g, 6.14 mmol).

Synthesis of Compound aa136-resin ((1R,2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)cyclopentane-1-carboxylic acid-2-chlorotrityl resin (Fmoc-2-ACPnC-O-Trt(2-Cl)resin))

Compound aa136-resin ((1R,2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)cyclopentane-1-carboxylic acid-2-chlorotrityl resin, Fmoc-2-ACPnC-O-Trt(2-Cl)resin) (1.65 g, loading amount 0.520 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (1R,2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)cyclopentane-1-carboxylic acid (Fmoc-2-ACPnC-OH) purchased from a commercial supplier (0.411 g, 1.17 mmol) and 2-chlorotrityl chloride resin (1.60 mmol/g, 100-200 mesh, 1% DVB, 1.46 g, 2.34 mmol).

Synthesis of Compound aa137-resin, (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)hex-5-ynoic acid-2-chlorotrityl resin (Fmoc-D-(Propargyl)Gly-(C#CH2)-O-Trt(2-Cl)resin)

Compound aa137-resin ((3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)hex-5-ynoic acid-2-chlorotrityl resin, Fmoc-D-(Propargyl)Gly-(C#CH2)-O-Trt(2-Cl)resin) (4.18 g, loading amount 0.432 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (3R)-3-(91H-fluoren-9-ylmethoxycarbonylamino)hex-5-ynoic acid (Fmoc-D-(Propargyl)Gly-(C#CH2)-OH) purchased from a commercial supplier (0.994 g, 2.85 mmol) and 2-chlorotrityl chloride resin (1.59 mmol/g, 100-200 mesh, 1% DVB, 3.58 g, 5.69 mmol).

Synthesis of Compound aa138-resin, (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid-2-chlorotrityl resin (Fmoc-D-3-Abu-O-Trt)2-Cl)resin)

Compound aa138-resin, (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid-2-chlorotrityl resin (Fmoc-D-3-Abu-O-Trt(2-Cl)resin) (33.44 g, loading amount 0.598 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid (Fmoc-D-3-Abu-OH) purchased from a commercial supplier (7.1 g, 21.82 mmol) and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 27.25 g, 43.6 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa139-resin, (3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methy)amino]butanoic acid-2-chlorotrityl resin (Fmoc-D-3-MeAbu-O-Trt(2-Cl)resin)

Compound aa139-resin, (3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanoic acid-2-chlorotrityl resin (Fmoc-D-3-MeAbu-O-Trt(2-Cl)resin) (58.95 g, loading amount 0.536 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanoic acid (Fmoc-D-3-MeAbu-OH) purchased from a commercial supplier (11.5 g, 33.9 mmol) and 2-chlorotrityl chloride resin (1.69 mmol/g, 100-200 mesh, 1% DVB, 50 g, 84.5 mmol).

Another lot synthesized in the same manner with a different loading amount was also used for peptide synthesis in the present Examples.

Synthesis of Compound aa140-resin, (3R)-3-(9H-fluoren-9- ylmethoxycarbonylamino)hex-5-enoic acid-2-chlorotrityl resin (Fmoc-D-Gly(Allyl)-(C#CH2)-O-Trt(2-Cl)resin)

Compound aa140-resin ((3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)hex-5-enoic acid-2-chlorotrityl resin, Fmoc-D-Gly(Allyl)-(C#CH2)-O-Trt(2-Cl)resin) (4.15 g, loading amount 0.420 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)hex-5-enoic acid (Fmoc-D-Gly(Allyl)-(C#CH2)-OH) purchased from a commercial supplier (1 g, 2.85 mmol) and 2-chlorotrityl chloride resin (1.59 mmol/g, 100-200 mesh, 1% DVB, 3.58 g, 5.69 mmol).

Synthesis of Compound aa141-resin, (3R)-3-91-1-fluoren-9-ylmethoxycarbonylamino)-5-methylhexanoic acid-2-chlorotrityl resin (Fmoc-D-Leu-(C#CH2)-O-Trt(2-Cl)resin)

To a mixture of diethyl ether (30 mL) and aqueous potassium hydroxide (50%, 12 mL) was added N-methyl-N-nitrosoacetamide (CAS No. 7417-67-6) (3.5 g, 29.5 mmol) at 0° C., and the mixture was stirred for 30 minutes. The diethyl ether layer was separated, and potassium hydroxide pellets were added to prepare a diazomethane solution. Two batches of the diazomethane solution on the same scale were further prepared and used for the next reaction.

Fmoc-D-Leu-OH (N-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-leucine) (5 g, 14.15 mmol) was dissolved in toluene and the solvent was evaporated under reduced pressure. This operation was performed three times. The residue was dissolved in THE (40.4 mL) and cooled in a salt ice bath. N-Methylmorpholine (2.022 mL, 18.39 mmol) and ethyl chloroformate (1.766 mL, 18.39 mmol) were added dropwise thereto, respectively. After stirring in the salt ice bath for 20 minutes, the prepared diazomethane solution (28.3 mmol) was added at room temperature three times at 30-minutes intervals. The progress of the reaction was confirmed by LC/MS. The reaction solution was cooled to 0° C. and diluted with diethyl ether, after which a 10% aqueous citric acid solution was added and the mixture was extracted with diethyl ether. The organic layer was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give aa14i-a (5 g, 13.24 mmol).

LCMS (ESI) m/z=378.3 (M+H)+

Retention time: 0.89 min (analysis condition SQDFA05)

A solution of aa141-a (4 g, 10.59 mmol) in THF (42.4 mL) was cooled to 0° C., water (4.24 mL), silver trifluoroacetate (0.257 g, 1.165 mmol), and N-methylmorpholine (2.91 mL, 26.5 mmol) were added, and the mixture was stirred at room temperature. After confirming the completion of the reaction by LC/MS, the reaction solution was cooled to 0° C. and diluted with diethyl ether (40 mL). An aqueous citric acid solution (10%) was added to the mixture, which was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was triturated with hexane/ethyl acetate, and the solid was collected by filtration to give the target compound, aa141 ((3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-5-methylhexanoic acid, Fmoc-D-Leu-(C#CH2)-OH.) (4 g, 82%).

LCMS (ESI) m/z=368.3 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA05)

Compound aa141-resin ((3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-5-methylhexanoic acid-2-chlorotrityl resin, Fmoc-D-Leu-(C#C-12)-O-Trt(2-Cl)resin) (4.1 g, loading amount 0.349 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using aa141 ((3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-5-methylhexanoic acid, Fmoc-D-Leu-(C#CH2)-01-I) (1.045 g, 2.85 mmol) and 2-chlorotrityl chloride resin (1.59 mmol/g, 100-200 mesh, 1% DVB, 3.58 g, 5.69 mmol).

Synthesis of Compound aa143-resin R)-2-1-9H-fluoren-9-ylmethoxycarbonyl)piperidin-2-yl]acetic acid-2-chlorotrityl resin (Fmoc-D-Pic(2)-(C#CH2)-O-Trt(2-Cl)resin)

Compound aa143-resin, (R)-2-[1-(9H)-fluoren-9-ylmethoxycarbonyl)piperidin-2-yl]acetic acid-2-chlorotrityl resin (Fmoc-D-Pic(2)-(C#CH2)-O-Trt(2-Cl)resin) (4.27 g, loading amount 0.347 mmol/g) was obtained by the same method as in the synthesis of Compound aa07-resin using (R)-2-[1-(9H-fluoren-9-ylmethoxycarbonyl,)piperidin-2-yl]acetic acid (Fmoc-D-Pic(2)-(C#CH2)-OH) (1.01 g, 2.76 mmol) purchased from a commercial supplier and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 3.84 g& 6.14 mmol).

Synthesis of Compound aa144-resin, 2-[(2R)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidin-2-yl]acetic acid-2-chlorotrityl resin (Fmoc-D-Pro-C#CH2)-O-Trt(2-Cl)resin)

Compound aa144-resin (2-[(2R)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidin-2-yl]acetic acid-2-chlorotrityl resin, Fmoc-D-Pro-(C#CH2)-O-Trt(2-Cl)resin) (7.19 g, loading amount 0.377 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using 2-[(2R)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidin-2-yl]acetic acid (Fmoc-D-Pro-(C#CH2)-OH) (1 g, 2.85 mmol) purchased from a commercial supplier and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 7 g, 21.39 mmol).

Synthesis of Compound aa107-resin, (3S)-4-[2-(tert-butylamino)-2-oxoethoxy]-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid-2-chlorotrityl resin (Fmoc-D-Ser(NtBu-Aca)-(C#CH2)-O-Trt(2-Cl)resin)

To Compound aa107-a ((S)-β-(carbobenzoxyamino)-γ-butyrolactone) (15 g, 63.8 mmol) and palladium on carbon (5 g, 30 wt %) was added DMF (180 mL) under a nitrogen atmosphere, and the atmosphere was replaced with a hydrogen atmosphere. The reaction solution was stirred at room temperature for seven hours and filtered through celite. The celite was washed with DMF (25 mL) twice and the resulting residue was concentrated to give Compound aa107-b as a crude product (6.0 g, 93%). This was used for the next reaction without further purification.

The obtained Compound aa107-b (6.0 g, 59.3 mmol) was dissolved in DMF (170 mL) and cooled to 0° C. To the reaction solution was added triethylamine (24.8 mL, 178 mmol), after which a solution of trityl chloride (TrCl) (18.2 g, 65.3 mmol) in DMF (130 mL) was slowly added dropwise over 20 minutes. The reaction solution was warned to room temperature and stirred at room temperature for 13 h. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give Compound aa107-c (17 g, 83%).

LCMS (ESI) m/z=366 (M+Na)+

Retention time: 0.65 min (analysis condition SQDAA50)

The obtained Compound aa107-c (20.8 g, 60.6 mmol) and sodium hydroxide (2.66 g, 66.6 mmol) were dissolved in a water/ethanol/THF solution (1.14 L, 1/5/5), the mixture was stirred at room temperature for one hour, and the reaction solution was concentrated under reduced pressure to give Compound aa107-d (23.9 g, quant.).

LCMS (ESI) m/z=384 (M+Na)+

Retention time: 0.47 min (analysis condition SQDAA50)

The obtained Compound aa107-d (6 g, 15.7 mmol) was dissolved in DMF (50 mL) and cooled to 0° C. A solution of sodium tert-pentoxide (46.9 mmol) in toluene (14.8 mL) was added thereto, and the mixture was warmed to room temperature and stirred for 30 minutes. Next, a solution of 2-bromo-N-(tert-butyl)acetamide (CAS No. 57120-58-8) (4.56 g, 23.5 mmol) in DMF (15 mL) was added at 0° C. The reaction solution was warmed to room temperature and stirred for five hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (10 mM aqueous ammonium acetate (AA)/methanol) to give Compound aa107-e (5.9 g, 79%).

LCMS (ESI) m/z=497 (M+Na)+

Retention time: 0.60 min (analysis condition SQDAA50)

The obtained Compound aa107-e (5.0 g, 10.5 mmol) was dissolved in DCM/water (140 mL, 5/2), and 4 N aqueous hydrochloric acid/1,4-dioxane (42.1 mL, 169 mmol) was added. The reaction solution was stirred at room temperature for one hour, water (40 mL) was then added, and the mixture was washed with n-hexane (100 mL) twice. The resulting aqueous solution containing Compound aa107-f was used as such for the next reaction.

LCMS (ESI) m/z=233 (M+H)+

Retention time: 0.27 min (analysis condition SQDFA05)

To the above aqueous solution of Compound aa107-f (ca. 90 mL) were added sodium carbonate (27.8 g, 263 mmol) and a solution of Fmoc-OSu (4.25 g, 12.6 mmol) in 1,4-dioxane (75 mL). The reaction solution was stirred at room temperature for two hours, after which TBME (300 mL) and 2 N aqueous hydrochloric acid (150 mL) were added. The organic layer was concentrated under reduced pressure, and the resulting residue was then purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa107 ((3S)-4-[2-(tert-butylamino)-2-oxoethoxy]-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, Fmoc-D-Ser(NtBu-Aca)-(C#CH2)-OH) (2.3 g, 48.2% through two steps).

LCMS (ESI) m/z=455 (M+H)+

Retention time: 0.75 min (analysis condition SQDFA05)

Compound aa107-resin ((3S)-4-[2-(tert-butylamino)-2-oxoethoxy]-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid-2-chlorotrityl resin, Fmoc-D-Ser(NtBu-Aca)-(C#CH2)-O-Trt(2-Cl)resin) (4 g, loading amount 0.279 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using Compound aa107 ((3S)-4-[2-(tert-butylamino)-2-oxoethoxy]-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, Fmoc-D-Ser(NtBu-Aca)-(C#CH2)-OH) (1 g, 2.2 mmol) and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 3.43 g, 5.5 mmol).

Synthesis of Compound aa108-resin, (3S)-3-(9H-fluoren-9ylmethoxycarbonylamino)-4-(3-methylbutoxy)butanoic acid-2-chlorotrityl resin Fmoc-D-Ser(iPen)-C#CH2)-O-Trt(2-Cl) resin

Compound aa107-d (6 g, 15.7 mmol) was dissolved in D MF (103 mL) and cooled to 0° C. To the reaction solution was added a solution of sodium tert-pentoxide (46.9 mmol) in toluene (14.1 mL), and the mixture was warmed to room temperature and stirred for 30 minutes. Next, 1-bromo-3-methyl-2-butene (2.71 mL, 23.5 mmol) was added at 0° C. The reaction solution was warmed to room temperature and stirred for four hours. 1-Bromo-3-methyl-2-butene (0.9 mL, 7.8 mmol) was further added and the mixture was stirred for four hours. Thereafter, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (10 mM aqueous ammonium acetate/methanol) to give Compound aa108-a (3.4 g, 50.6%).

LCMS (ESI) m/z=428 (M−H)−

Retention time: 0.59 min (analysis condition SQDFA50)

Compound aa108-a (3.6 g, 8.38 mmol) and palladium on carbon (360 mg, 10 wt %) were mixed in methanol (41.9 mL), and then the mixture was stirred at room temperature for 20 hours under hydrogen atmosphere. To the reaction solution were added formic acid and DMSO, and the mixture was decanted with hexane (100 mL) and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound aa108-b (600 mg, 38%).

LCMS (ESI) m/z=190 (M+H)+

Retention time: 0.15 min (analysis condition SQDFA50)

The obtained Compound aa108-b (600 mg, 3.17 mmol) was dissolved in water (3.6 mL), DIPEA (2.49 mL, 14.3 mmol) was added, and Fmoc-OSu (1.07 g, 3.17 mmol) was added as a solution in 1,4-dioxane (4.75 mL). The reaction solution was stirred at room temperature for 30 minutes, water (4 mL) was then added, and the mixture was extracted with hexane/ether (3 mL, 3/i) twice. Potassium hydrogen sulfate (KHSO₄) (1.62 g, 14.3 mmol) was added to the aqueous layer, which was extracted with ethyl acetate (20 mL) twice. The combined organic layers were washed with brine/water (1/1, 15 mL) twice, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to give Compound aa108 ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3-methylbutoxy)butanoic acid, Fmoc-D-Ser(iPen)-(C#CH2)-OH) (1.2 g, 92%).

LCMS (ESI) m/z=412 (M+H)+

Retention time: 0.91 min (analysis condition SQDFA05)

Compound aa108-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(3-methylbutoxy)butanoic acid-2-chlorotrityl resin, Fmoc-D-Ser(iPen)-(C#CH2)-O-Trt(2-Cl)resin) (434 mg, loading amount 0.415 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using Compound aa108 ((3S)-3-(91H-fluoren-9-ylmethoxycarbonylamino)-4-(3-methylbutoxy)butanoic acid, Fmoc-D-Ser(iPen)-(C#CH2)-OH) (0.1 g, 0.243 mmol) and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 0.380 g, 0.61 mmol).

Synthesis of Compound aa145-resin, 3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid-2-chlorotrityl resin (Fmoc-bMeAla-O-Trt(2-Cl)resin)

Compound aa145-resin (3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid-2-chlorotrityl resin, Fmoc-bMeAla-O-Trt(2-Cl)resin) (4.34 g, loading amount 0.449 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using 3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid (Fmoc-bMeAla-OH) (1 g, 3.07 mmol) purchased from a commercial supplier and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 3.84 g, 6.15 mmol).

Synthesis of Compound aa146-resin, 3-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid-2-chlorotrityl resin (Fmoc-bAla-O-Trt(2-Cl)resin)

Compound aa146-resin (3-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid-2-chlorotrityl resin, Fmoc-bAla-O-Trt(2-Cl)resin) (37.86 g, loading amount 0.528 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using 3-(91H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (Fmoc-bAla-OH) (8 g, 25.7 mmol) purchased from a commercial supplier and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 32.1 g, 51.4 mmol).

Synthesis of Compound aa147-resin, (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-5-phenylpentanoic acid-2-chlorotrityl resin Fmoc-D-Hph-(C#CH2)-O-Trt(2-Cl)resin

Compound aa147-resin ((3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-5-phenylpentanoic acid-2-chlorotrityl resin, Fmoc-D-Hph-(C#CH2)-O-Trt(2-Cl)resin) (3.61 g, loading amount 0.415 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-5-phenylpentanoic acid (Fmoc-D-Hph-(C#CH2)-OH) (1 g, 2.41 mmol) purchased from a commercial supplier and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 3.03 g, 4.82 mmol).

Synthesis of Compound aa148-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4,4,4-trifluorobutanoic acid-2-chlorotrityl resin (Fmoc-3-CF3-bAla-(C#CH2)-O-Trt(2-Cl)resin

Compound aa148-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4,4,4-trifluorobutanoic acid-2-chlorotrityl resin (Fmoc-3-CF3-bAla-(C#CH2)-O-Trt(2-Cl)resin) (2.19 g, loading amount 0.399 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using (3S)-3-(91I-fluoren-9-ylmethoxycarbonylamino)-4,4,4-trifluorobutanoic acid (Fmoc-3-CF3-bAla-(C#CH2)-OH) (0,569 mg, 1.5 mmol) purchased from a commercial supplier and 2-chlorotrityl chloride resin (1.59 mmol/g, 100-200 mesh, 1% DVB, 1.89 g, 3 mmol).

Synthesis of Compound aa149-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-pip)

Compound aa149-resin, (3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)resin)-pip) was synthesized by the method described in WO 2013/100132 or WO 2018/225864.

Synthesis of Compound aa155-resin, 2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid-2-chlorotrityl resin

The amino acid was loaded onto the resin according to the following scheme.

Compound aa155-resin, 2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid-2-chlorotrityl resin (1.54 g, loading amount 0.336 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using Compound aa155 (2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid) (0.46 g, 1.04 mmol) and 2-chlorotrityl chloride resin (1.6 mmol/g, 100-200 mesh, 1% DVB, 1.3 g, 2.08 mmol).

1-3. Peptide Solid-Phase Synthesis by an Automated Synthesizer

Cyclic peptide compounds (Compounds 1-762, 764-845, 847-1027, 1029-1146, 1148-1410, 1412-2020, 2111, 2143-2151, and 2172-2179, 2187, 2188) (Table 39) were synthesized by the method described in WO 2013/100132 or WO 2018/225864. Peptides were synthesized by the Fmoc method detailed below using a peptide synthesizer (Multipep RS; manufactured by Intavis). The detailed operational procedure was according to the manual appended to the synthesizer. The relationship between formal names, structures, and abbreviations of the respective amino acid residues constituting cyclic peptides described in Table 39 will be understood from Tables 2 to 7 above and Table 8 below.

TABLE 8
Abbreviation	Amino acid structural formula	Name
MeGln(Aze-3-F2)		(2S)-5-(3,3-difluoroazetidin-1-yl)-2- (methylamino)-5-oxo-pentanoic acid
(MeOMeallyl)Gly		2-[[(E)-4-methoxybut-2-enyl]amino] acetic acid
(DMAOEt)Gly		2-[2-[2-(dimethylamino)-2-oxo-ethoxy] ethylamino]acetic acid
(HOtBuOEt)Gly		2-[2-(2-hydroxy-2-methyl-propoxy) ethylamino]acetic acid
(HOtBuallyl)Gly		2-[[(E)-5-hydroxy-5-methyl-hex-2- enyl]amino]acetic acid
(Me2NCOnPr)Gly		2-[[4-(dimethylamino)-4-oxo-butyl]amino] acetic acid
5-OH-nPent)Gly		2-(5-hydroxypentylamino)acetic acid
(HOEtallyl)Gly		2-[[(E)-5-hydroxypent-2-enyl]amino] acetic acid
(DMFallyl)Gly		2-[[(E)-4-(dimethylamino)-4-oxo-but-2- enyl]amino]acetic acid
HOiPrallyl)Gly		2-[[(E)-4-hydroxy-4-methyl-pent-2-enyl] amino]acetic acid
Hph(24-F2)		(2S)-2-amino-4-(2,4-difluorophenyl) butanoic acid
(HOEt)Gly		2-(2-hydroxyethylamino)acetic acid
(3-pyr-Me)Gly		2-(3-pyridylmethylamino)acetic acid
(4-pyr-Me)Gly		2-(4-pyridylmethylamino)acetic acid
(3-pyr-Et)Gly		2-[2-(3-pyridyl)ethylamino]acetic acid
(4-pyr-Et)Gly		2-[2-(4-pyridyl)ethylamino]acetic acid
(Et(2-F3)OEt)Gly		2-[2-(2,2,2-trifluoroethoxy)ethylamino] acetic acid
(MeOEtOEt)Gly		2-[2-(2-methoxyethoxy)ethylamino] acetic acid
(Et(2-F2)OEt)Gly		2-[2-(2,2-difluoroethoxy)ethylamino] acetic acid
(pip(4-F2)Et)Gly		2-[2-(4,4-difluoro-1-piperidyl)ethylamino] acetic acid
MeAbu(BocAze)		(2S)-4-(1-tert-butoxycarbonylazetidin-3- yl)-2-(methylamino)butanoic acid
Hph(2-F-4-Cl)		(2S)-2-amino-4-(4-chloro-2-fluoro- phenyl)butanoic acid
MeAbu(BocAzedene)		(2S)-4-(1-tert-butoxycarbonylazetidin-3- ylidene)-2-(methylamino)butanoic acid
MeAbu(THP)		(2S)-2-(methylamino)-4-tetrahydropyran- 4-yl-butanoic acid
MeAbu(THPdene)		(2S)-2-(methylamino)-4-tetrahydropyran- 4-ylidene-butanoic acid
(OxecBu)Gly		2-(2-oxaspio[3.3]heptan-6-ylamino) acetic acid
(OxeMe)Gly		2-(oxetan-3-ylmethylamino)acetic acid
(F2cBucBu)Gly		2-[(2,2-difluorospiro[3.3]heptan-6- yl)amino]acetic acid
(Ph-4-Cl)Gly		2-(4-chloroanilino)acetic acid
(Ph-3-Cl)Gly		2-(3-chloroanilino)acetic acid
(3-Thienyl)Gly		2-(3-thienylamino)acetic acid
Hyp(2-EtOH)		(2S,4R)-4-(2-hydroxyethoxy)pyrrolidine- 2-carboxylic acid
cisHyp(2-EtOH)		(2S,4S)-4-(2-hydroxyethoxy)pyrrolidine- 2-carboxylic acid
Hph(2-F-5-Cl)		(2S)-2-amino-4-(5-chloro-2-fluorophenyl) butanoic acid
PhGly		2-annilinoacetic acid
Hyp(3-thie-Me)		(2S,4R)-4-(3-thienylmethoxy)pyrrolidine- 2-carboxylic acid
Ser(Ph)		(2S)-2-amino-3-phenoxy-propanoic acid
Pro(4S-Tri)		(2S,4S)-4-(triazol-1-yl)pyrrolidine-2- carboxylic acid
Pro(4R-Tn)		(2S,4R)-4-(triazol-1-yl)pyrrolidine-2- carboxylic acid
cisPro(4-pip-4-F2)		(2S,4S)-4-(4,4-difluoro-1-piperidyl) pyrrolidine-2-carboxylic acid
Hyp(Et(2-F2))		(2S,4R)-4-(2,2-difluoroethoxy) pyrrolidine-2-carboxylic acid
cisHyp(Et(2-F2))		(2S,4S)-4-(2,2-difluoroethoxy) pyrrolidine-2-carboxylic acid
cisHyp(3-Me—Pyr)		(2S,4S)-4-(3-pyridylmethoxy)pyrrolidine- 2-carboxylic acid
Hyp(3-Me—Pyr)		(2S,4R)-4-(3-pyridylmethoxy)pyrrolidine- 2-carboxylic acid
MeAla(3-Pyr-4-CN)		(2S)-3-(6-cyano-3-pyridyl)-2- (methylamino)propanoic acid
MeTyr(3-F)		(2S)-3-(3-fluoro-4-hydroxy-phenyl)-2- (methylamino)propanoic acid
cisHyp(Bzl(4-OCHF2))		(2S,4S)-4-[[4-(difluoromethoxy)phenyl] methoxy]pyrrolidine-2-carboxylic acid
cisHyp(Bzl(4-Me))		(2S,4S)-4-(p-tolylmethoxy)pyrrolidine-2- carboxylic acid
cisHyp(Bzl(3-OMe))		(2S,4S)-4-[(3-methoxyphenyl)methoxy] pyrrolidine-2-carboxylic acid
cisHyp(Bzl(3-Me))		(2S,4S)-4-(m-tolylmethoxy)pyrolidine-2- carboxylic acid
cisHyp(Bzl(2-Me))		(2S,4S)-4-(o-tolylmethoxy)pyrrolidine-2- carboxylic acid
Hyp(Bzl(4-OCHF2))		(2S,4R)-4-[[4-(difluoromethoxy)phenyl] methoxy]pyrrolidine-2-carboxylic acid
Hyp(Bzl(4-Me))		(2S,4R)-4-(p-tolylmethoxy)pyrrolidine-2- carboxylic acid
Hph(245-F3)		(2S)-2-amino-4-(2,4,5-trifluorophenyl) butanoic acid
Hyp(Bzl(3-OMe))		(2S,4R)-4-[(3-methoxyphenyl)methoxy] pyrrolidine-2-carboxylic acid
Hyp(Bzl(3-Me))		(2S,4R)-4-(m-tolylmethoxy)pyrrolidine-2- carboxylic acid
Hyp(Bzl(2-Me))		(2S,4R)-4-(o-tolylmethoxy)pyrrolidine-2- carboxylic acid
Hyp(Bzl(4-Cl))		(2S,4R)-4-[(4-chlorophenyl)methoxy] pyrrolidine-2-carboxylic acid
Hyp(Bzl(3-Cl))		(2S,4R)-4-[(3-chlorophenyl)methoxy] pyrrolidine-2-carboxylic acid
cisHyp(Bzl(4-Cl))		(2S,4S)-4-[(4-chlorophenyl)methoxy] pyrrolidine-2-carboxylic acid
cisHyp(Bzl(3-Cl))		(2S,4S)-4-[(3-chlorophenyl)methoxy] pyrrolidine-2-carboxylic acid
cisHyp(Bzl(2-Cl))		(2S,4S)-4-[(2-chlorophenyl)methoxy] pyrrolidine-2-carboxylic acid
Hyp(Bzl(2-Cl))		(2S,4R)-4-[(2-chlorophenyl)methoxy] pyrrolidine-2-carboxylic acid
cisHyp(Et)		(2S,4S)-4-ethoxypyrrolidine-2-carboxylic acid
Hph(F6)		(2S)-2-amino-4-(2,3,4,5,6- pentafluorophenyl)butanoic acid
Hyp(Bzl)		(2S,4R)-4-benzyloxypyrrolidine-2- carboxylic acid
cisHyp		(2S,4S)-4-hydroxypyrrolidine-2- carboxylic acid
Hyp		(2S,4R)-4-hydroxypyrrolidine-2- carboxylic acid
Ser(tBuOH)		(2S)-2-amino-3-(2-hydroxy-2-methyl- propoxy)propanoic acid
Ser(Bn-2-Cl)		(2S)-2-amino-3-[(2-chlorophenyl) methoxy]propanoic acid
Ser(Bn-3-Cl)		(2S)-2-amino-3-[(3-chlorophenyl) methoxy)propanoic acid
Ser(Ph-4-Cl)		(2S)-2-amino-3-(4-chlorophenoxy) propanoic acid
Hse(Ph-4-CF3)		(2S)-2-amino-4-[4-(trifluoromethyl) phenoxy]butanoic acid
Hse(Ph-34-Cl2)		(2S)-2-amino-4-(3,4-dichlorophenoxy) butanoic acid
Hse(Ph-4-Cl)		(2S)-2-amino-4-(4-chlorophenoxy) butanoic acid
Hph(4-CF3-2-F)		(2S)-2-amino-4-[2-fluoro-4- (trifluoromethyl)phenyl]butanoic acid
Ser(Bn-4-Cl)		(2S)-2-amino-3-[(4-chlorophenyl) methoxy]propanoic acid
Phe3(4-CF3)		(2S)-2-amino-5-[4-(trifluoromethyl) phenyl]pentanoic acid
Hph(34-Cl2-5-OtBu)		(2S)-2-amino-4-(3-tert-butoxy-4,5- dichloro-phenyl)butanoic acid
Hph(34-Cl2-5-OnBu)		(2S)-2-amino-4-(3-butoxy-4,5-dichloro- phenyl)butanoic acid
Hph(34-Cl2-5-OiPr)		(2S)-2-amino-4-(3,4-dichloro-5- isopropoxy-phenyl)butanoic acid
Hph(34-Cl2-5-CN)		(2S)-2-amino-4-(3,4-dichloro-5-cyano- phenyl)butanoic acid
Hph(34-Cl2-5-OMe)		(2S)-2-amino-4-(3,4-dichloro-5-methoxy- phenyl)butanoic acid
Hph(345-Cl3)		(2S)-2-amino-4-(3,4,5- trichlorophenyl)butanoic acid
Abu(7-Quino)		(2S)-2-amino-4-(7-quinolyl)butanoic acid
Hph(3-F-4-CHF2)		(2S)-2-amino-4-[4-(difluoromethyl)-3- fluoro-phenyl]butanoic acid
MeAsp-pip(4-F2)		(3S)-4-(4,4-difluoro-1-piperidyl)-3- (methylamino)-4-oxo-butanoic acid
Hph(4-SO2Me)		(2S)-2-amino-4-(4-methylsulfonylphenyl) butanoic acid
Abu(2-Pyr-4-CF3)		(2S)-2-amino-4-[5-(trifluoromethyl)-2- pyridyl]butanoic acid
Abu(3-Pyr-4-CHF2)		(2S)-2-amino-4-[6-(difluoromethyl)-3- pyridyl]butanoic acid
Abu(5-Bzfr)		(2S)-2-amino-4-(benzofuran-5-yl) butanoic acid
Abu(3-Pyr-4-OMe)		(2S)-2-amino-4-(6-methoxy-3-pyridyl) butanoic acid
Abu(1-Me-5-Indo)		(2S)-2-amino-4-(1-methylindol-5-yl) butanoic acid
Abu(1-Me-6-Indo)		(2S)-2-amino-4-(1-methylindol-6-yl) butanoic acid
Abu(6-Quino)		(2S)-2-amino-4-(6-quinolyl)butanoic acid
Hph(3-F-4-OCF3)		(2S)-2-amino-4-[3-fluoro-4- (trifluoromethoxy)phenyl]butanoic acid
Hph(3-Cl-4-OCF3)		(2S)-2-amino-4-[3-chloro-4- (trifluoromethoxy)phenyl]butanoic acid
MeAsp-pip(3-F2)		(3S)-4-(3,3-difluoro-1-piperidyl)-3- (methylamino)-4-oxo-butanoic acid
Abu(34-Cate(CF2))		(2S)-2-amino-4-(2,2-difluoro-1,3- benzodioxol-5-yl)butanoic acid
Abu(3-Pyr-4-CF3)		(2S)-2-amino-4-[6-(trifluoromethyl)-3- pyridyl]butanoic acid
Hph(3-OMe-4-CF3)		(2S)-2-amino-4-[3-methoxy-4- (trifluoromethyl)phenyl]butanoic acid
Hph(3-CN-4-CF3)		(2S)-2-amino-4-[3-cyano-4- (trifluoromethyl)phenyl]butanoic acid
Hph(3-F-4-OCHF2)		(2S)-2-amino-4-[4-(difluoromethoxy)-3- fluoro-phenyl]butanoic acid
Phe(3-C#C)		(2S)-2-amino-3-(3-ethynylphenyl) propanoic acid
Phe(3-Cl-4-F)		(2S)-2-amino-3-(3-chloro-4-fluoro- phenyl)propanoic acid
Hph(3-CF3)		(2S)-2-amino-4-[3-(trifluoromethyl) phenyl]butanoic acid
1-ACPrC		1-aminocyclopropanecarboxylic acid
cHex		1-aminocyclohexanecarboxylic acid
Hph(246-F3)		(2S)-2-amino-4-(2,4,6-trifluorophenyl) butanoic acid
EtPhet(2-Cl)		(2S)-3-(2-chlorophenyl)-2-(ethylamino) propanoic acid
MeAsn(mor)		(2S)-2-(methylamino)-4-morpholino-4- oxo-butanoic acid
MeAsn(pyrro)		(2S)-2-(methylamino)-4-oxo-4-pyrrolidin- 1-yl-butanoic acid
MeAsn(pip)		(2S)-2-(methylamino)-4-oxo-4-(1- piperidyl)butanoic acid
MeAsn(Aze)		(2S)-4-(azetidin-1-yl)-2-(methylamino)-4- oxo-butanoic acid
MeAsn(Me2)		(2S)-4-(dimethyalmino)-2- (methylamino)-4-oxo-butanoic acid
MeGln(mor)		(2S)-2-(methyalmino)-5-morpholino-5- oxo-pentanoic acid
MeGln(pyrro)		(2S)-2-(methylamino)-5-oxo-5-pyrrolidin- 1-yl-pentanoic acid
MeGln(pip)		(2S)-2-(methylamino)-5-oxo-5-(1- piperidyl)pentanoic acid
MeGln(Aze)		(2S)-5-(azetidin-1-yl)-2-(methylamino)-5- oxo-pentanoic acid
Hph(2-F-6-Cl)		(2S)-2-amino-4-(2-chloro-6-fluoro- phenyl)butanoic acid
MeSer(tBuOH)		(2S)-3-(2-hydroxy-2-methyl-propoxy)-2- (methylamino)propanoic acid

The peptide synthesis method by the Fmoc method (the basic peptide synthesis method) is described in detail in the following 1-3-1 to 1-3-5.

1-3-1. Peptide Elongation Reaction by the Fmoc Method from the N-Terminus of an Amino Acid

Peptide compounds were synthesized by a solid-phase synthesis method using Fmoc-protected amino acids on a peptide synthesizer (Multipep RS or Multipep RSi) manufactured by Intavis. Specific procedures for the operation were performed according to the instructions attached to the synthesizer.

Fmoc-protected amino acids (0.3-0.6 mol/L) constituting the target peptide, and HOAt, oxyma, or HOOBt (0.375 mol/L) serving as a carboxyl group activator were dissolved in NMP or NMP/DMF (1/1) to prepare Solution 1. When the Fmoc-protected amino acids were poorly soluble in the above-mentioned solvents, DMSO was added at 20% to 30% (v/v) to prepare Solution 1. When using, for example, Fmoc-MeSer(tBuOTHP)—OH, Fmoc-Ser(tBuOTHP)—OH, Fmoc-MeSer(THP)—OH, Fmoc-Thr(THP)—OH, Fmoc-Ser(THP)—OH, Fmoc-cisHyp(THP)—OH (Compound aa101), or Fmoc-Hyp(THP)—OH (Compound aa102) as an Fmoc-protected amino acid having a THP protecting group on the side chain, oxyma was used as the carboxyl group activator to prepare Solution 1, and Molecular Sieves 4A 1/8 (Wako Pure Chemical Industries) or Molecular Sieves 4A 1/16 (Wako Pure Chemical Industries) were added thereto, and the solution was used for peptide synthesis. N,N′-Diisopropylcarbodiimide (DIC) (10% v/v) and N,N-dimethylformamide (DMF) were mixed to prepare Solution 2.

2-Chlorotritylresin (100 mg) to which was attached the carboxylic acid at the side chain of an aspartic acid with the N-terminus protected by Fmoc group or the main chain carboxylic acid site of an amino acid with the N-terminus protected by Fmoc group was added to a solid-phase reaction vessel and the vessel was placed into the peptide synthesizer. Dichloromethane (DCM) (0.8 mL) was added to this resin (100 mg), and the resin was swollen by allowing to stand for one hour. Subsequently, the solution was removed from the frit. Solution 1 and Solution 2 were placed in the peptide synthesizer, and automated synthesis by the peptide synthesizer was started.

A solution of diazabicycloundecene (DBU) in DMF (2% v/v, 0.7 mL) was added to a resin-containing solid-phase reaction vessel to deprotect the N-terminal Fmoc group at room temperature. For deprotection of the first residue, the reaction was carried out for 4.5 minutes, and for deprotection of the second or subsequent residue, the reaction was carried out for 10 minutes, after which the solution was removed from the frit. DMF (0.7 mL) was added thereto, and after allowing to stand for 5 minutes, the solution was removed from the frit. Repeating this resin washing step three more times gave the resin onto which was attached the amino acid or peptide having an amino group at the N-terminus by removing the Fmoc group.

Next, Solution 1 (0.3 mL) and Solution 2 (0.36 mL) were mixed in a mixing vial of the synthesizer, and then added to the above-mentioned deprotected resin, and the solid-phase reaction vessel was warmed to 40° C. For sequences that elongated poorly, and such, the vessel was warmed to reach 60° C. as necessary. Condensation reaction between the amino group on the resin and the Fmoc-protected amino acid was carried out for 2.5 hours. For sequences that elongated poorly, and such, the reaction was carried out for 20 hours. After the reaction, the solution was removed from the frit. When the elongation efficiency was low, this condensation reaction with the Fmoc-protected amino acid was further repeated once or twice. Next, the resin was washed three times with DMF (0.7 mL). This Fmoc amino acid condensation reaction following the Fmoc deprotection reaction was defined as one cycle, and by repeating this cycle, the peptide was elongated on the resin surface. After completion of the peptide elongation, a solution of diazabicycloundecene (DBU) in DMF (2% v/v, 0.7 mL) was added to the resin, this was allowed to react for 15 minutes to carry out the Fmoc deprotection reaction, and then the solution was removed from the frit. The resulting resin was washed four times with DMF (0.7 mL), and four times with DCM (0.7 mL).

1-3-2. Cleavage of the Elongated Peptide from the Resin

To the resin obtained by methods described in WO2013/100132 and WO2018/225864, or by the above-mentioned method, 2,2,2-trifluoroethanol (TFE)/DCM (1/1, v/v, 2 mL) containing 0.75% (v/v) DIPEA was added, followed by the reaction at room temperature for two hours. Then, the reaction to cleave the peptide chain from the resin was carried out. After the reaction, the solution in the tube was recovered from the frit. The operation of adding 2,2,2-trifluoroethanol (TFE)/DCM (1/1, v/v, 1 mL) to the remaining resin and recovering the solution from the frit was performed twice. All the resulting cleavage solutions were combined, DMF (4 mL) or 1,2-dichloroethane (4 mL) were mixed therein, and then the solvent was evaporated under reduced pressure by a high throughput centrifugal evaporator (HT-12) manufactured by Genevac.

1-3-3. Method of Cyclizing the Cleaved Peptide

The residue obtained by the above-mentioned method was dissolved in a mixture of DMF (4 mL) and DCM (4 mL). To the mixture were added a solution of (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-mopholino-carbeniunhexatluorophosphate (COMU) in DMF (0.5 M, 1.5 equivalents) or a solution of O-(7-aza-1H-benzotriazol-1-yl)-N,N,N,N,-tetramethyluroniumhexafluorophosphate (HATU) in DMF (0.5 M, 1.5 equivalents), and DIPEA (1.8 equivalents), and by stirring this mixture at room temperature for two hours, a cyclocondensation reaction between the N-terminal amino group and the C-terminal carboxyl group was carried out. The number of equivalents was calculated based on the value obtained by multiplying the amount of resin used (normally 100 mg) to the amino acid loading rate (mmol/g) of the resin used as a raw material. After confirming the production of the target cyclic peptide by LC/MS measurement (SQ Detector 2, manufactured by Waters), the solvent was evaporated from the reaction solution under reduced pressure by a high throughput centrifugal evaporator (HT-12) manufactured by Genevac.

1-3-4. Deprotection of the Protecting Group for the Side Chain Functional Group Possessed by the Cyclic Peptide

For the sequences synthesized using an Fmoc-protected amino acid having a THP-protected hydroxyl group on the side chain, for example, Fmoc-MeSer(tBuOTHP)—OH, Fmoc-Ser(tBuOTHP)—OH, Fmoc-MeSer(THP)—OH, Fmoc-Thr(THP)—OH, Fmoc-Ser(THP)—OH, Fmoc-D-MeSer(THP)—OH (Compound aa054), Fmoc-cisHyp(THP)—OH (Compound aa101), or Fmoc-Hyp(THP)—OH (Compound aa102), 4 mL of a solution of tetramethylammonium hydrogensulfate (0.05 M) in 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP) (containing 2% (v/v) triisopropylsilane (TIPS) and 1% (v/v) 1,2-dichloroethane) was added to the above-obtained residue, and the residue was dissolved, after which the THP protecting group was deprotected by allowing to stand at room temperature for four hours. After confirming the completion of the reaction by LC/MS (SQ Detector 2 manufactured by Waters), diisopropylethylamine (DIPEA) (70 μL) was added and the solvent was evaporated under reduced pressure by a high throughput centrifugal evaporator (HIT-12) manufactured by Genevac. In this deprotection reaction, another fluoroalcohol such as 2,2,2-trifluoroethanol (TFE) may also be used instead of HFIP.

For the sequences synthesized using Fmoc-MeAsp(OA1)-OH, cyclic peptides were dissolved in DMF (0.5 M), tetrakis(triphenylphosphine)palladium (0) (0.01-0.05 equivalents relative to the peptide) and phenylsilane (0.7 equivalents relative to the peptide) were added at room temperature under a nitrogen atmosphere, and the allyl group was deprotected by stirring for 30 minutes. Production of the target cyclic peptide was confirmed by LC/MS measurements (SQ Detector 2 manufactured by Waters), and then the solvent was evaporated from the reaction solution under reduced pressure by a high throughput centrifugal evaporator (HT-12) manufactured by Genevac.

1-3-5. Method of Purifying the Cyclic Peptides

DMF or DMSO was added to the residue obtained by the above-mentioned method, insoluble substances were removed by filtration, and then purification by preparative HPLC was carried out to give the target cyclic peptide. Waters Auto Purification System was used for the purification instrument, YMC-Actus Triart C18 (internal diameter of 20 mm, length of 100 nm) or YMC-Actus Triart Phenyl (internal diameter of 20 mm, length of 100 mm) was used as the column, and methanol-aqueous ammonium acetate solution (50 mmol/L) or acetonitrile-water containing 0.1% formic acid was used as the mobile phase.

Synthesis of Compound 1

The target Compound 1 (16.6 mg, 23%) was obtained using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.478 mmol/g, 100 mg, 0.0478 mmol) as a raw material, and using Fmoc-MeChg-OH, Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hph(4-CF3-3-Cl)—OH, Fmoc-MeGly-OH, Fmoc-MeCha-OH. Fmoc-MeGly-OH, Fmoc-MeGly-OH, Fmoc-Cha-OH, and Fmoc-MeLeu-OH, by performing the above-described peptide elongation reaction by the Fmoc method, cleavage of the elongated peptide from the resin, cyclization of the cleaved peptide (using O-(7-aza-1-benzotriazol-1-yl)-N,N,N,N,-tetramethyluroniumhexafluorophosphate (HATU) as the cyclizing agent), and purification of the cyclic peptide.

Compound 1 ((3S,9,S18S,21S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9,18-bis(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo 32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

LCMS (ESI) m/z=1480.1 (M−H)−

Retention time: 2.155 min (analysis condition SSC-FA-03)

Compounds 2 to 762, Compounds 764 to 845, Compounds 847 to 1027, Compounds 1029 to 1135, Compounds 2007 to 2020, and Compound 2111 were produced based on the method for producing Compound 1. Compounds 1373 to 1376 were produced by performing an additional deprotection reaction to the cyclic peptide compounds produced based on the method for producing Compound 1. Compounds 1450 to 1460 were produced by a method based on the method for producing Compound 1 which additionally includes repeating the step of condensing an αα-disubstituted amino acid with an N-alkyl amino acid multiple times.

Synthesis of Compound 1355

The target Compound 1355 (9.75 mg, 24%) was obtained using Compound aa010-resin, (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-Mor(26-bicyc)) (0.279 mmol/g, 100 mg, 0.0279 mmol) as a raw material, and using Fmoc-MeGly(cPent)-OH, Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hph(4-CF3-35-F2)-OH, Fmoc-MeGly-OH, Fmoc-MeSer(nPr)—OH, Fmoc-Aze(2)-OH, Fmoc-MeAla-OH, Fmoc-Ile-OH, and Fmoc-MeLeu-OH, by performing the above-described peptide elongation reaction by the Fmoc method, cleavage of the elongated peptide from the resin, cyclization of the cleaved peptide (using (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-mopholino-carbeniumhexatluorophosphate (COMU) as the cyclizing agent), and purification of the cyclic peptide.

Compound 1355 ((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone)

LCMS (ESI) m/z=1457.9 (M−H)−

Retention time: 7.425 min (analysis condition SSC-A-AF-01)

Compounds 1136 to 1146, Compounds 1148 to 1354, and Compounds 1356 to 1372 were produced based on the method for producing Compound 1355. Compounds 1869 to 2006 were produced by a method based on the method for producing Compound 1355 which additionally includes the step of condensing a sequence comprising an αα-disubstituted amino acid and/or N-alkyl amino acid by heating at 40° C. to 60° C.

Synthesis of Compound 1471

The target Compound 1471 (12.68 mg, 19%) was obtained using Compound aa138-resin, (3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid-2-chlorotrityl resin (Fmoc-D-3-Abu-O-Trt(2-Cl)resin) (0.494 mmol/g, 100 mg, 0.0494 mmol) as a raw material, and using Fmoc-MeGly(cPent)-OH, Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-1Hph(4-CF3-3-Cl)—OH. Fmoc-MeGly-OH, Fmoc-MePhe(4-Me)-OH, Fmoc-MeGly-OH, Fmoc-MeGly-OH, Fmoc-Ile-OH, and Fmoc-MeLeu-OH, by performing the above-described peptide elongation reaction by the Fmoc method (for the elongation with Fmoc-cLeu-OH, Oxyma was used as the condensing agent, and after the reaction, disposal of the solution from the frit was followed by further condensation reaction with Fmoc-cLeu-OH which was repeated twice. Furthermore, the unreacted amino groups were capped using Z-Gly-OH (CAS No. 1138-80-3), HOAt and DIC as condensing agents, and DMF as solvent. The treatment step for unreacted amino groups is also called a removal step by glycine capping), cleavage of the elongated peptide from the resin, cyclization of the cleaved peptide (using O-(7-aza-11-benzotriazol-1-yl)-N,N,N,N,-tetramethyluroniumhexafluorophosphate (HATU) as the cyclizing agent), and purification of the cyclic peptide.

Compound 1471 (3S,9S,18S,21S,25R,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclopentyl-21-isobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.01heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone

LCMS (ESI) m/z=1322.9 (M—H)—

Retention time: 2.149 min (analysis condition SSC-AF-00)

Based on the method for producing Compound 1471, Compounds 1377 to 1410, Compounds 1412 to 1449, Compounds 1461 to 1470, and Compounds 1472 to 1643 were produced by a method based on the method for producing Compound 1471 which additionally includes performing the step of condensing a sequence comprising an αα-disubstituted amino acid and/or N-alkyl amino acid by repeating the step multiple times or by heating at 40° C. to 60° C., or by combining the repetition and heating.

Synthesis of Compound 1805

The target Compound 1805 (25.53 mg, 38%) was obtained by using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.478 mmol/g, 100 mg, 0.0478 mmol) as a raw material, and using Fmoc-MeChg-OH, Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hph(4-CF3-3-Cl)—OH, Fmoc-MeGly-OH, Fmoc-MeSer(nPr)—OH, Fmoc-MeGly-OH, Fmoc-MeGly-OH, Fmoc-Ile-OH, and Fmoc-MeLeu-OH, by performing the above-described peptide elongation reaction by the Fmoc method (Fmoc-MeChg-OH was subjected to a condensation reaction using Oxyma as the condensing agent at 50° C. for ten hours, and Fmoc-cLeu-OH was subjected to a condensation reaction using Oxyma as the condensing agent at 60° C. for 16 hours), cleavage of the elongated peptide from the resin, cyclization of the cleaved peptide (using (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU) as the cyclizing agent), and purification of the cyclic peptide.

Compound 1805 ((3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-9-(propoxymethyl)spiro[1,4,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,8,11,14,17,20,23,27,30,33-undecone)

LCMS (ESI) m/z=1415.9 (M−H)−

Retention time: 1.923 min (analysis condition SSC-FA-03)

Synthesis of Compound 2172 and Compound 21-73

Compound 2172 and Compound 2173 were synthesized using Compound aa155-resin (2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid-2-chlorotrityl resin, Fmoc-MeGly(cPent)-OH), Fmoc-Melle-OH, Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hph(4-CF3-3-Cl)—OH, Fmoc-MeGly-OH, Fmoc-MeCha-OH, Fmoc-MePhe(4-Me)-OH, and Fmoc-Ile-OH as raw materials, and using, by a method similar to the synthesis of any one of Compounds 1 to 762, Compounds 764 to 1027, Compounds 1029 to 1410, Compounds 1412 to 2020, and Compound 2111, and the target Compound 2172 (1.31 mg, 3%) and Compound 2173 (1.42 mg, 3%) were obtained.

Compound 2172((3S,9S,18S,24R,27S,33S)-18-[(2S)-butan-2yl]-3-[2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]=9-(cyclohexylmethyl)-27-cyclopentyl-N,N,7,10,13,16,25,28-octamethyl-2,5,8,11,14,17,20,26,29,32-decaoxospiro[22-thia-1,4,7,10,13,16,19,25,28,31-decazabicyclo 31.3 0]hexatriacontane-30,1′-cyclopentane]-24-carboxamide)

LCMS (ESI) m/z=1307.1 (M+H)+

Retention time: 1.48 min (analysis condition SQDFA05long)

Compound 2173((3S,9S,18S,24R,27S,33S)-18,27-bis[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-N,N,7,10,13,16,25,28-octamethyl-9-[(4-methylphenylmethyl]-2,5,8,11,14,17,20,26,29,32-decaoxospiro[22-thia-1,4,7,10,13,16,19,25,28,31-diazabicyclo[31.3.0]hexatriacontane-30,1′-cyclopentane]-24-carboxamide)

LCMS (ESI) m/z=1303.1 (M+H)+

Retention time: 1.16 min (analysis condition SQDFA05long)

Synthesis of Compound 2174 ((3S,9S,12S,17S,20S,23S,29R,32S,38S)-20-[(2S)-butan-2-yl]-32-cyclopentyl-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-N,N,7,10,17,18,24,30,33-nonamethyl-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,31,34,37-undecaoxo-9-(propoxymethyl)spiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36.3.0.012,15]hentetracontane-35,1′-cyclopentane)-29-carboxamide)

The peptide chain was elongated by the common peptide elongation method described herein, using Compound aa155-resin (2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid-2-chlorotrityl resin) as a raw material, and using Fmoc-MeGly(cPent)-OH, Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hph(4-CF3-3-F)—OH, Fmoc-MeGly-OH, Fmoc-MeSer(nPr)—OH, Fmoc-Aze(2)-OH, Fmoc-MeAla-OH, and Fmoc-Ile-OH in that order. The following operation was carried out while leaving the Fmoc group at the N terminus.

The resin was sequentially washed with DMF (four times with 0.7 mL), DCM (twice with 0.7 mL), and toluene (twice with 0.7 mL). A solution of diazabicycloundecene (DBU) in toluene (2% v/v, 0.7 mL) was added thereto, the solution was allowed to react for ten minutes, and then Fmoc group deprotection was performed. After removing the solution from the frit, the resin was sequentially washed with toluene (twice with 0.7 ml) and DCM (twice with 0.7 mL)

To the above-obtained resin was added a solution of Fmoc-MeLeu-OH (49 mg, 0.134 mmol, 4 equivalents), [ethylcyano(hydroxyimino)acetate-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphoric acid (PyOxym) (70.6 mg, 0.134 mmol, 4 equivalents), and DIPEA (0.035 mL, 0.2 mmol, 6 equivalents) in DCM (0.7 mL), and this was allowed to stand at room temperature for three hours. After removing the solution from the frit, the resin was washed with DCM (three times with 0.7 mL), and further washed with DMF (three times with 0.7 mL). To the obtained resin was added a solution of diazabicycloundecene (DBU) in DMF (2% v/v, 0.7 mL), this was allowed to react for 15 minutes to deprotect Fmoc group, and then the solution was removed from the frit. The obtained resin was washed with DMF (four times with 0.7 ml), and then with DCM (four times with 1.25 mL).

On the resin obtained by the above-mentioned method, 2,2,2-trifluoroethanol (TFE)/DCM (1/1, v/v, 2 mL) containing 0.75% DIPEA was added, and this was shaken at room temperature for two hours to carry out the reaction to cleave the peptide chain from the resin. After the reaction, the solution in the tube was recovered from the frit. The operation of adding 2,2,2-trifluoroethanol (TFE)/DCM (1/1, v/v, 1 mL) to the remaining resin and recovering the solution from the frit was performed twice. All the obtained cleavage solutions were combined, DMF (4 mL) was added, and the solvent was evaporated under reduced pressure by a high throughput centrifugal evaporator (HIT-12) manufactured by Genevac.

The residue obtained by the above-mentioned method was dissolved in a mixture of DMF (4 mL) and DCM (4 mL), a solution of (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-mopholino-carbeniumhexafluorophosphate (COMU) in DMF (0.5 M, 0.1 mL, and DIPEA (0.015 mL) were added thereto, and a cyclocondensation reaction between the N-terminal amino group and the side chain carboxylic acid was carried out by stirring at room temperature for two hours. After confirming the production of the target cyclic peptide by LC/MS measurement (SQ Detector 2, manufactured by Waters), the solvent was evaporated from the reaction solution under reduced pressure by a high throughput centrifugal evaporator (HT-12) manufactured by Genevac.

DMF was added to the residue obtained by the above-mentioned method, insoluble substances were removed by filtration, and then purification by preparative-HPLC (on a Waters Auto Purification System, YMC-Actus Triart Phenyl (internal diameter of 20 mm, length of 100 mm) was used as the column, and methanol-aqueous ammonium acetate solution (50 mmol/L) was used as the mobile phase) gave the target Compound 2174 (5.55 mg, 12%).

LCMS (ESI) m/z=1420.3 (M+H)+

Retention time: 1.10 min (analysis condition SQDFA05long)

Synthesis of Compounds 2175 to 2179

Compounds 2175 to 2179 were synthesized by a method similar to the synthesis of Compound 2174, using Compound aa155-resin (2-[(2R)-3-(dimethylamino)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-oxopropyl]sulfanylacetic acid-2-chlorotrityl resin) as a raw material, and using Fmoc-MeGly(cPent)-OH, Fmoc-Melle-OH, Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hyp(Et)-OH, Fmoc-Hph(4-CF3-3-Cl)—OH, Fmoc-Hph(4-CF3-3-F)—OH, Fmoc-Hph(4-CF3-35-F2)-OH, Fmoc-MeGly-OH, Fmoc-MeCha-OH, Fmoc-MePhe(4-Me)-OH, Fmoc-Aze(2)-OH, Fmoc-MeAla-OH, Fmoc-Ile-OIH, and Fmoc-MeLeu-OH as Fmoc amino acids.

Compound 2175 ((3S,9S,8S,21S,27R,30S,36S)-18-[(2S)-butan-2-yl]-3-[2-3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-N,N,7,10,13,16,22,28,31-nonamethyl-21-(2-methylpropyl)-2,5,8,11,14,17,20,23,29,32,35-undecaoxospiro[25-thia-1,4,7,10,13,16,19,22,28,31,34-undecazabicyclo[34.3.1]nonatriacontane-33,1-cyclopentane]-27-carboxamide)

LCMS (ESI) m/z=1434.3 (M+H)+

Retention time: 1.64 min (analysis condition SQDFA05long)

Compound 2176 ((3S,9S,12S,17S,20S,23S,29R,32S,38S,40R)-20-[(2S)-butan-2-yl]-9-(cyclohexylmethyl)-32-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-40-ethoxy-N,N,7,10,17,18,24,30,33-nonamethyl-23(2-methylpropyl)-2,5,8,11,16,19,22,25,31,34,37-undecaoxospiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36.3.0.012,15]hentetracontane-35,1′-cyclopentane]-29-carboxamide)

LCMS (ESI) m/z=1506.4 (M+H)+

Retention time: 1.88 min (analysis condition SQDFA05long)

Compound 2177 ((3S,9S,12S,17S,20S,23S,29R,32S,38S)-20-[(2S)-butan-2-yl-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-32-cyclopentyl-N,N,7,10,17,18,24,30,33-nonamethyl-9-[(4-methylphenyl)methyl]-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,31,34,37-undecaoxospiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36,3,0,012,15]hentetracontane-35,1′-cyclopentane]-29-carboxamide)

LCMS (ESI m/z=1468.3 (M+H)+

Retention time: 1.55 min (analysis condition SQDFA05long)

Compound 2178 ((3S,9S,18S,21S,27R,30S,36S)-18,30-bis[(2S)-butan-2-yl]-3-[2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]-N,N,7,10,13,16,22,28,31-nonamethyl-9-[(4-methylphenyl)methyl]-21-(2-methylpropyl)-2,5,8,11,14,17,20,23,29,32,35-undecaoxospiro[25-thia-1,4,7,10,13,16,19,22,28,31,34-undecazabicyclo[34.3.0]nonatriacontane-33,1′-cyclopentane]-27-carboxamide)

LCMS (ESI) m/z=1430.3 (M+H)+

Retention time: 1.43 min (analysis condition SQDFA05long)

Compound 2179 ((3S,9S,12S,17S,20S,23S,29R,32S,38S)-20-[(2S)-butan-2-yl-9,32-dicyclopentyl-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-N,N,7,10,17,18,24,30,33-nonamethyl-23-(2-methylpropyl)-2,5 8,11,16,19,22,25,31,34 37-undecaoxospiro[27-thia-1,4,7,10,15,18,21,24,30,33,36-undecazatricyclo[36.3.0.012,15]hentetracontane-35,1′-cyclopentane]-29-carboxamide)

LCMS (ESI) m/z=1416.3 (M+H)+

Retention time: 1.17 min (analysis condition SQDFA05long)

The mass spectral values and the liquid chromatography retention times of cyclic peptide compounds described in Examples are described in Table 22.

1-4 Cyclic Peptide Synthesis by Peptide Modification

1-4-1. Peptide Synthesis Through N-methylation of TFA Amides on Resins

Synthesis of Compound 2159 ((5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,11-di((S-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-isopropyl-5,6,12,15,16,19,21,21,22,33,36-undecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo(2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontyne-4,7,10,13,17,20,23,28,31,34,37(14H)-undecone)

Compound 2159 was synthesized according to the following scheme.

To a solution of 2-amino-2-methylpropanoic acid (H-Aib-OH, CAS No. 62-57-7) (2.5 g, 24.24 mmol) and DIPEA. (4.66 mL, 26.7 mmol) in methanol (12.12 mL) was added ethyl trifluoroacetate (3.76 a, 31.5 mmol), and the mixture was stirred at 60° C. for 20 hours the reaction solution was cooled to room temperature, and the, solvent was evaporated under reduced pressure. To the resulting residue was added 1 mol/L aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic: acid/distilled water with 0.1% formic: acid) to give 2-methyl-2-(2,2,2-trifluoroacetamido)propanoic acid (TFA-Aib-OH) (2.2 g, 46%)).

LCMS (ESI) m/z=198 (M−H)−

Retention time: 0.40 min (analysis condition SQDFA05)

Compound 2159-a-resin was obtained by elongating Fmoc-MeVal-OH using the basic peptide elongation method described in the present Examples in a reaction vessel equipped with a filter, and then elongating TFA-Aib-OH (2-methyl-2-(2,2,2-trifluoroacetamido)propanoic acid) obtained by the above formulation, with Compound aa139-resin ((3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanoic acid-2-chlorotrityl resin, Fmoc-D-3-MeAbu-O-Trt(2-Cl)resin) (100 mg, 0.343 mmol/g, 0.0343 mmol) used as a raw material.

The obtained Compound 2159-a-resin was swollen with DCM (1 mL) and then washed with DMF (1 mL) four times. A solution of phosphazene base P1-tBu (38 μL, 0.150 mmol) in DMF (180 PL) and a solution of methyl iodide (62 μL, 1 mmol) in DMF (180 μL) were added, and the vessel was shaken at 40° C. for 30 minutes under sealed conditions. After removing the reaction solution, the resin was washed with DMF (1 mL) four times and further washed with DCM (1 mL) four times to give Compound 2159-b-resin. The obtained resin was partially cleaved with TFE/DCM (1/1) and analyzed by LC/MS to confirm the progress of the reaction,

LCMS (ESI) m/z=424 (M−H)−

Retention time: 0.57 min (analysis condition SQDFA05)

Sodium borohydride (NaBH₄) (758 mg, 20 mmol) was placed in a flask, pumped up, and then, under a nitrogen atmosphere, dissolved in triglyme (10 mL) to provide Solution A. The above-obtained Compound 2159-b-resin was swollen with DCM (1 mL) and then washed with THF (0.7 mL) four times. To the resin were added THF (0.5 mL), methanol (0.25 mL), and Solution A (0.25 mL), and the flask was shaken at room temperature for 40 minutes in an open system. After removing the reaction solution, methanol (0.7 mL) was added, and after one minute, the solution was discarded. This resin-washing operation was repeated four times. Further, the resin was similarly washed with DCM (0.7 mL) four times to give Compound 2159-c-resin. The obtained resin was partially cleaved with TFE/DCM (1/1) and analyzed by LC/MS to confirm the progress of the reaction.

LCMS (ESI) m/z=330 (M+H)+

Retention time: 0.33 min (analysis condition SQDFA05)

Subsequent peptide elongation, cyclization, and purification steps were conducted according to the basic route to give Compound 2159 ((5S,8S,11S,15R,18S,23aS,29S,35S,37aS)-8,11-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cylohexylmethyl)-18-isopropyl-5,6,12,15,16,19,21,21,22,33,36-undecamethyltetracosahydro-2H-azeto[2,1-u]pyrrolo[2,1-i] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontyne-4,7,10,13,17,20,23,28,31,34,37(14H)-undecone) (4.1 mg, 9%). The LC/MS data are as described in Table 22.

Compounds 2152-2158 and Compound 2160 were synthesized by the same method as in the synthesis of Compound 2159. The LC/MS data are as described in Table 22.

1-4-2. Peptide Modification by Alkylation of OH

Synthesis of Compound 2116 ((3S,9S,18S,21S,25R,28S,34S,36R)-36-benzyloxy-9-(cylohexylmethyl-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22 25 29-heptamethyl-18- [(1S)-1-methylpropyl]spiro[1,47,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

In a glass screw cap vial were mixed Compound 1483 ((3S,9S,18S,21S,25R,28S,34S,36R)-9-(cylohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-36-hydroxy-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) synthesized by the basic peptide synthesis described in the present Examples (5 mg, 3.83 μmol), silver(I) oxide (26.6 mg, 0.115 mmol), and benzyl bromide (19.7 mg, 0.115 mmol), 1,4-dioxane (0.05 mol/L, 77 μL) was added, the vial was capped, and reaction was performed at 60° C. overnight. The reaction solution was filtered, and the filtrate was then purified by reverse phase medium pressure column chromatography (acetonitrile/water, containing 0.3% formic acid) to give Compound 2116 ((3S,9S,18S,21S,25R,28S,34S,36R)-36-benzyloxy-9-(cylohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,25,29-heptamethyl-18-[(1S)-1-methylpropyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (3.7 mg, 70%). The LC/MS data are as described in Table 22.

Synthesis of Compounds 2118, 2125, 2128, 2130,2131, 2133, 2134, 2138, and 2139

Compounds 2118, 2125, 2128, 2130, 2131, 2133, 2134, 2138, and 2139 were synthesized by the same method as in the synthesis of Compound 2116 using Compound 875 ((3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-36-hydroxy-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) synthesized by the basic peptide elongation method described in the present Examples, as a raw material, and using alkylating agents provided in the following table. Purification was conducted by reverse phase medium pressure column chromatography or preparative HPLC. The following table describes target compound peptides, alkylating agents used for reactions, amounts (mg) of Compound 875 used as a raw material, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 9
		Raw	Target
Target	Alkylating	material	compound	Yield
compound	agent	mg	mg	%
Compound 2138	2-chlorobenzyl bromide	5.4	3	50
Compound 2118	ethyl iodide	10.8	7	63
Compound 2134	3-chlorobenzyl bromide	5.4	2	35
Compound 2133	4-chlorobenzyl bromide	5.4	1.9	32
Compound 2139	2-methylbenzyl bromide	5.4	3.1	54
Compound 2125	3-methylbenzyl bromide	5.4	2.3	39
Compound 2131	3-methoxybenzyl bromide	5.4	2	34
Compound 2130	4-methylbenzyl bromide	5.4	2.9	50
Compound 2128	4-(difluoromethoxy)benzyl	5.4	2.3	38
	bromide

Synthesis of Compounds 2132, 2126, 2129, 2127, 2137, 2141, 2136, 2140, and 2135

Compounds 2132, 2126, 2129, 2127, 2137, 2141, 2136, 2140, and 2135 were synthesized by the same method as in the synthesis of Compound 2116 using Compound 544 ((3S,9S,18S,21S,25S,28S,34S,36S)-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-36-hydroxy-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1 cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) synthesized by the basic peptide elongation method described in the present Examples, as a raw material, and using alkylating agents provided in the following table. Purification was conducted by reverse phase medium pressure column chromatography or preparative HPLC. The following table describes target compound peptides, alkylating agents used for reactions, amounts (mg) of Compound 544 used as a raw material, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 10
		Raw	Target
Target	Alkylating	material	compound	Yield
compound	agent	mg	mg	%
Compound 2132	2-chlorobenzyl bromide	5.4	0.7	11
Compound 2126	3-chlorobenzyl bromide	5.4	0.3	6
Compound 2129	4-chlorobenzyl bromide	5.4	0.7	11
Compound 2127	ethyl iodide	10.8	2.6	23
Compound 2137	2-methylbenzyl bromide	5.4	2.4	41
Compound 2141	3-methylbenzyl bromide	5.4	2.5	42
Compound 2136	3-methoxybenzyl bromide	5.4	1.7	29
Compound 2140	4-methylbenzyl bromide	5.4	1.7	29
Compound 2135	4-(difluoromethoxy)benzyl	5.4	2	32
	bromide

Synthesis of Compounds 2043, 2044, and 2045

A precursor peptide shown below (Compound 2044-a) (230 mg, 0.188 mmol, 39%) was synthesized by the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.3 mmol/g, 1.6 g, 0.48 mmol) as a raw material.

LCMS (ESI) m/z=1224 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Compounds 2043, 2044, and 2045 were synthesized by the same method as in the synthesis of Compound 2116 using Compound 2044-a as a raw material, and using alkylating agents provided in the following table. Purification was conducted by reverse phase medium pressure column chromatography or preparative HPLC. The following table describes target compound peptides, alkylating agents used for reactions, amounts (mg) of raw material Compound 2044-a, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 11
		Raw	Target
Target	Alkylating	material	compound	Yield
compound	agent	mg	mg	%
Compound 2044	4-chlorobenzyl bromide	20	8.2	37
Compound 2045	3-chlorobenzyl bromide	9.9	6	55
Compound 2043	2-chlorobenzyl bromide	9.9	1	9

Synthesis of Compound 2117 (3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2-hydroxyethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro(1,4,7,10,13,16,19,22,6,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

To Compound 1374 ((3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-hydroxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (5 mg, 3.43 μmol) as a raw material were added 2-(2-bromoethoxy)tetrahydro-2H-pyran (14.3 mg, 0.0686 mmol) and tetrabutylammonium bromide (3.32 mg, 10.29 μmol), after which dichloromethane (0.04 mol/L, 86 μL) and a 5 mol/L aqueous sodium hydroxide solution (27.4 μL) were added and the mixture was reacted at room temperature for five days. The reaction solution was purified by reverse phase medium pressure column chromatography (acetonitrile/water, containing 0.3% formic acid) to give Compound 2117-a (3.3 mg, 61%).

LCMS (ESI) m/z=1586 (M+H)+

Retention time: 0.85 min (analysis condition SQDFA50)

Compound 2117-a (3.3 mg, 2.08 μmol) was subjected to deprotection of the THP protecting group according to the basic peptide elongation method described in the present Examples, and was then purified to give Compound 2117 ((3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2-hydroxyethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (1.59 mg, 54%). The LC/MS data are as described in Table 22.

Synthesis of Compound 2122 (3S,9S,18S,21S,25S,28S,34S,36)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2-hydroxyethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatricontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,3-undecone)

Compound 2122-a (3.1 mg, 57%) was obtained by the same method as in the synthesis of Compound 1374-a using Compound 1376 ((3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-hydroxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (5 mg, 3.43 μmol) as a raw material.

LCMS (ESI) m/z=1585.9 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA50)

Compound 2122-a (3.1 mg) was subjected to deprotection of the THP protecting group according to the basic peptide elongation method described in the present Examples, and was then purified to give Compound 2122 ((3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-(2-hydroxyethoxy)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (1.3 mg, 44%). The LC/MS data are as described in Table 22.

Synthesis of Compounds 2121, 2119, 2124, 2120, and 2123

Compounds 2121, 2119, and 2124 were synthesized by the same method as in the synthesis of Compound 2117-a using Compound 1376 ((3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-hydroxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) as a raw material. Purification was conducted by reverse phase medium pressure column chromatography or preparative HPLC. The following table describes target compound peptides, alkylating agents used for reactions, amounts (mg) of Compound 1376 used as a raw material, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 12
		Raw	Target
Target	Alkylating	material	compound	Yield
compound	agent	mg	mg	%
Compound 2124	3-bromomethylthiophene	5	2.1	39
Compound 2121	3-(chloromethyl)pyridine	15	0.67	4
Compound 2119	2,2-difluoroethyl	5	4.27	82
	triflate

Compounds 2120 and 2123 were synthesized by the same method as in the synthesis of Compound 2117-a using Compound 1374 ((3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-hydroxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,V-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) as a raw material. Purification was conducted by reverse phase medium pressure column chromatography or preparative 1-PLC. The following table describes target compound peptides, alkylating agents used for reactions, amounts (mg) of Compound 1374 used as a raw material, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 13
		Raw	Target
Target	Alkylating	material	compound	Yield
compound	agent	mg	mg	%
Compound 2120	3-(chloromethyl)pyridine	15	1.3	8
Compound 2123	2,2-difluoroethyl	5	5	96
	triflate

1-4-3. Peptide Modification by Reductive Coupling Reaction

Synthesis of Compound 2085 ((5S,8S,11S,15S,18S,23S,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(4-(difluoromethyl)-3-fluorophenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidin-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecazacyclotetratriacontyne-21,1′-cyclopentane]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecone

Compound 2085 was synthesized according to the following scheme.

Compound 2085-a (772 mg, 0.531 mmol, 77%) was obtained by the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.531 mmol/g, 1.3 g, 0.69 mmol) as a raw material.

LCMS (ESI) m/z=1360 (M+H)+

Retention time: 1.01 min (analysis condition SQDFA05)

Compound 2085-a (772 mg, 0.568 mmol) and tetrakis(triphenylphosphine)palladium(0) (6.56 mg, 5.68 μmol) were mixed, DCM (1.2 ml) and phenylsilane (49 μl, 0.398 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound 2085-b (255 mg, 34%).

LCMS (ESI) m/z=1320 (M+H)+

Retention time: 0.87 min (analysis condition SQDFA05)

Compound 2085-b (255 mg, 0.193 mmol), N-hydroxyphthalimide (40.9 mg, 0.25 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI·HCl) (74.1 mg, 0.386 mmol) were dissolved in DCM (2 ml), and the reaction solution was stirred at room temperature for 2 hours and 15 minutes. The reaction mixture was diluted with DCM and washed with water twice. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give Compound 2085-c as a crude product (299 mg, quant.).

LCMS (ESI) m/z=1465 (M+H)+

Retention time: 1.00 min (analysis condition SQDFA05)

Nickel bromide trihydrate (NiBr₂·3H₂O) (2.79 mg, 10.24 μmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (2.75 mg, 1.052 μmol) were dissolved in DMA (60 μL) under a nitrogen atmosphere to prepare a Ni solution.

To a mixture of Compound 2085-c (15.0 mg, 10.24 μmol), zine powder (10 mg, 0.154 mmol), and 4-bromo-1-(difluoromethyl)-2-fluorobenzene (12.0 mg, 51.2 μmol) was added DMA (60 μL) under a nitrogen atmosphere, after which the above-prepared Ni solution was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was then purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid), and the fractions were lyophilized to give Compound 2085 ((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-buty)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(4-(difluoromethyl)-3-fluorophenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(piperidin-1-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecazacyclotetratriacontyne-21,1′-cyclopentane]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecone) (6.2 mg, 42.7%). The LC/MS data are as described in Table 22.

Synthesis of Compounds 2077, 2076, 2072, 2080, 2078, 2074, 2057, 2067, 2070, 2065, 2064, 2084, 2063, 2060, and 2069

Compounds 2077, 2076, 2072, 2080, 2078, 2074, 2057, 2067, 2070, 2065, 2064, 2084, 2063, 2060, and 2069 were obtained by the same synthesis method as in Compound 2085 using Compound 2085-c (15 mg) and using aryl bromides provided below (5 equivalents relative to the raw material peptide). The following table describes target compound peptides, aryl bromides used for reactions, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 14
		Target
Target		compound	Yield
compound	Aryl bromide	mg	%
Compound 2077	7-bromoquinoline	7.6	53
Compound 2076	4-bromo-1-(difluoromethoxy)-2-	6.3	43
	fluorobenzene
Compound 2072	5-bromo-2-(trifluoromethyl)	4.6	31
	benzonitrile
Compound 2080	4-bromo-2-methoxy-1-	5.2	35
	(trifluoromethyl)benzene
Compound 2078	5-bromo-2-(trifluoromethyl)	3.8	26
	pyridine
Compound 2074	5-bromo-2,2-difluoro-1,3-	5.8	40
	benzodioxole
Compound 2057	4-bromo-2-chloro-1-	1.4	9
	(trifluoromethoxy)benzene
Compound 2067	4-bromo-2-fluoro-1-	4.7	31
	(trifluoromethoxy)benzene
Compound 2070	6-bromoquinoline	6	42
Compound 2065	6-bromo-1-methyl-1H-indole	4.6	32
Compound 2064	5-bromo-1-methyl-1H-indole	4.4	30
Compound 2084	5-bromo-2-methoxypyridine	5.8	41
Compound 2063	5-bromobenzofuran	3.8	27
Compound 2060	5-bromo-2-(difluoromethyl)	5.5	38
	pyridine
Compound 2069	2-bromo-5-(trifluoromethyl)	3.8	26
	pyridine

Synthesis of Compound 2058 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-[2-(4-methylsulfonyl)phenyl)ethyl]-25-(piperidine-1-carbonyl)spiro(1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

Compound 2058 was synthesized according to the following scheme.

Compound 2058-a was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) as a raw material. Further, Compound 2058-b was obtained by the same method as in the synthesis of Compound 2085-b. Further, Compound 2058-c (299 mg, 0.206 mmol) was obtained by the same method as in the synthesis of Compound 2085-c.

LCMS (ESI) m/z=1453 (M+H)+

Retention time: 1.03 min (analysis condition SQDFA05)

Compound 2058 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-3-[2-(4-methylsulfonylphenyl)ethyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (4.1 mg, 28%) was obtained by the same method as in the synthesis of Compound 2085 using Compound 2058-c (15 mg, 10.32 mol) as a raw material and using 1-bromo-4-(methylsulfonyl)benzene (5 equivalents relative to the peptide) as an aryl halide. The LC/MS data are as described in Table 22.

Synthesis of Compound 2059 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-(3,4,5-trichlorophenyl)ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone

Compound 2059 was synthesized according to the following scheme.

Compound 2059-a was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.437 mmol/g, 3 g, 1.311 mmol) as a raw material. Further, Compound 2059-b was obtained by the same method as in the synthesis of Compound 2085-b. Further, Compound 2059-c (388 mg, 0.275 mmol, 21%) was obtained by the same method as in the synthesis of Compound 2085-c.

LCMS (ESI) m/z=1411 (M+H)+

Retention time: 0.95 min (analysis condition SQDFA05)

Compound 2059 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(] S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-(3,4,5-trichlorophenyl)ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (6.6 mg, 47%) was obtained by the same method as in the synthesis of Compound 2085 using Compound 2059-c (15 mg) as a raw material and using 5-bromo-1,2,3-trichlorobenzene (10 equivalents relative to the peptide) as an aryl halide. The LC/MS data are as described in Table 22.

Synthesis of Compounds 2081, 2075, 2062, 2066, and 2082

Compounds 2081, 2075, 2062, 2066, and 2082 were obtained by the same synthesis method as in Compound 2059 using Compound 2059-c (15 mg) as a raw material and using aryl halides provided below (10 equivalents relative to the raw material peptide). The following table describes target compound peptides, aryl halides used for reactions, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 15
Target		Yield	Yield
compound	Aryl halide	mg	%
Compound 2081		6.9	47
Compound 2081-a
Compound 2075		0.7	5
	Compound 2075-a
Compound 2062		9.4	60
	Compound 2062-a
Compound 2066		3.3	21
	Compound 2066-a
Compound 2082		8.3	53
	Compound 2082-a

Synthesis of Compound 2068 ((3S,9S,18S,21S,25S,28S,34S)-9 (cyclohexymethyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)3-[2-(3,4,5-trichlorophenyl)ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

Compound 2068 was synthesized according to the following scheme.

Compound 2068-a was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.437 mmol/g, 4.1 g, 1.79 mmol) as a raw material. Further, Compound 2068-b was obtained by the same method as in the synthesis of Compound 2085-b. Further, Compound 2068-c (553 mg, 0.403 mmol, 23%) was obtained by the same method as in the synthesis of Compound 2085-c.

LCMS (ESI) m/z=1371 (M+H)+

Retention time: 0.86 min (analysis condition SQDFA05)

Nickel bromide trihydrate (5.97 mg, 0.022 mmol) and 4,4′-ditert-butyl-2,2′-bipyridyl (5.87 mg, 0.022 mmol) were dissolved in DMA (110 μL) under a nitrogen atmosphere to prepare a Ni solution.

To Compound 2068-c (15.0 mg, 10.94 μmol), zinc powder (10.7 mg, 0.164 mmol), and 5-bromo-1,2,3-trichlorobenzene (28.5 mg, 109 μmol) was added DMA (55 μL) under a nitrogen atmosphere, after which the above-prepared Ni solution was added and the mixture was stirred at room temperature for five hours. The precipitate was filtered oft; and the solvent was then evaporated under reduced pressure. n-Hexane/TFE/water=1/1/1 was added and the precipitate was filtered off, after which the n-hexane layer was removed and the solvent was evaporated under reduced pressure. The reaction solution was then purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid distilled water with 0.1% formic acid) to give Compound 2068 ((3S,9S,18S,21S,25S,28S,34S)-9-(cyclohexylmethyl)-28-isopropyl-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-(3,4,5-trichlorophenyl)ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cylopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (5.0 mg, 33%). The LC/MS data are as described in Table 22.

Synthesis of Compounds 2061, 2071, 2079, 2083, and 2073

Compounds 2061, 2071, 2079, 2083, and 2073 were obtained by the same synthesis method as in Compound 2068 using Compound 2068-c (15 mg) as a raw material and using aryl halides provided below (10 equivalents relative to the raw material peptide). The following table describes target compound peptides, aryl halides used for reactions, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 16
Target		Yield	Yield
compound	Aryl halide	mg	%
Compound 2061		6.8	46
	Compound 2081-a
Compound 2071		2.5	17
	Compound 2075-a
Compound 2079		1.1	7
	Compound 2062-a
Compound 2083		7.2	47
	Compound 2066-a
Compound 2073		9.2	60
	Compound 2082-a

Aryl halides used for synthesizing Compounds 2081, 2075, 2062, 2066, 2082, 2061, 2071, 2079, 2083, and 2073 were synthesized as follows.

Synthesis of Compound 2081-a (1,2-dichloro-5-iodo-3-methoxybenzene)

To a solution of 2,3-dichloroanisole (1.0 g, 5.65 mmol) in TBME (28.2 mL) were added bis(pinacolato)diboron (B₂pin₂) (2.15 g, 8.48 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) (dimer) ([Ir(COD)(OMe)]₂) (0.187 g, 0.282 mmol), and the mixture was stirred at room temperature for two hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, DMF (50 mL) was added, copper(I) iodide (CuI) (1.61 g, 8.47 mmol) was further added, and the mixture was stirred at 80° C. for four hours in air. After cooling to room temperature, n-hexane/ethyl acetate=1/1 (100 mL) was added and the mixture was sequentially washed with 100 mL each of a saturated aqueous ammonium chloride solution, a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and 50% saline. This was dried over anhydrous sodium sulfate and filtered off, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid). The fractions were collected, concentrated, then dissolved in n-hexane/ethyl acetate=1/1, and washed with a saturated aqueous sodium bicarbonate solution. This was dried over anhydrous sodium sulfate and filtered off, after which the solvent was evaporated under reduced pressure to give Compound 2081-a (1,2-dichloro-5-iodo-3-methoxybenzene) (514 mg, 30%).

Retention time: 1.01 min (analysis condition SQDFA05)

¹H-NMR (DMSO-D₆) δ: 7.60 (1H, d, J=1.9 Hz), 7.45 (1H, d, J=1.9 Hz), 3.90 (3H, s).

Synthesis of Compound 2075-a (2,3-dichloro-5-iodobenzonitrile)

To a solution of 2, 3-dichlorobenzonitrile (500 mg, 2.91 mmol) in THF (14.5 mL) were added bis(pinacolato)diboron (B₂pin₂) (1.11 g, 4.36 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) (dimer) ([Ir(COD)(OMe)]₂) (96 mg, 0.145 mmol), and the mixture was stirred at 60° C. for one hour under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, DMF (30 mL) was added, copper(I) iodide (CuI) (830 mg, 4.36 mmol) and N-iodosuccinimide (NIS) (981 mg, 4.36 mmol) were further added, and the mixture was stirred at 80° C. for six hours in air. After cooling to room temperature, n-hexane/ethyl acetate=1/1 (30 mL) was added and the mixture was sequentially washed with 60 mL each of a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and 50% saline. This was dried over anhydrous sodium sulfate and filtered off, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid). The fractions were collected, concentrated, then dissolved in n-hexane/ethyl acetate=1/1, and washed with a saturated aqueous sodium bicarbonate solution. This was dried over anhydrous sodium sulfate and filtered off, after which the solvent was evaporated under reduced pressure to give Compound 2075-a (2,3-dichloro-5-iodobenzonitrile) (535 mg, 62%).

Retention time: 0.91 min (analysis condition SQDFA05)

¹H-NMR (DMSO-D₆) δ: 8.42 (1H d, J=1.9 Hz), 8.39 (1H, d, J=1.9 Hz).

Synthesis of Compound 2062-a (5-bromo-1,2-dichloro-3-propan-2-yloxybenzene)

A solution of 5-bromo-1,2-dichloro-3-fluorobenzene (200 mg, 0.820 mmol) and 2-propanol (246 mg, 4.10 mmol) in DMF (1.0 mL) was cooled to 0° C. under ice-cooling, and sodium hydride (NaH) (60%. oil, 65.6 mg, 1.64 mmol) was added. The mixture was stirred at 60° C. for one hour and then cooled to 0° C., and sodium hydride (NaH) (60%, oil, 10.0 ng, 0.250 mmol) was added. The mixture was stirred at 60° C. for 30 minutes and then cooled to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate/n-hexane=1/1. This was dried over anhydrous sodium sulfate and filtered off, and the solvent was evaporated under reduced pressure to give Compound 2062-a (5-bromo-1,2-dichloro-3-propan-2-yloxybenzene) (211 mg, 91%).

Retention time: 1.11 min (analysis condition SQDFA05)

¹H-NMR (CDCl₃) δ: 7.22 (1H d, J=2.1 Hz), 6.97 (1H, dd, J=2.1, 0.5 Hz), 4.58-4.51 (1H, m), 1.39 (6H, d, J=6.2 Hz).

Synthesis of Compound 2066-a (5-bromo-1-butoxy-2,3-dichlorobenzene)

Compound 2066-a (5-bromo-1-butoxy-2,3-dichlorobenzene) (211 mg, 86%) was obtained by the same synthesis method as in Compound 2062-a using 5-bromo-1,2-dichloro-3-fluorobenzene and n-butanol.

Retention time: 1.19 min (analysis condition SQDFA05)

¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J=2.1 Hz), 6.95 (1H, d, J=2.1 Hz), 4.01 (2H, t, J=6.4 Hz), 1.86-1.79 (21H, m), 1.57-1.48 (2H, m), 0.99 (3H, t, J=7.4 Hz).

Synthesis of Compound 2082-a (5-bromo-1,2-dichloro-3-[(2-methylpropan-2yl)oxy]benzene)

A solution of 5-bromo-1,2-dichloro-3-fluorobenzene (200 mg, 0.820 mmol) and tert-butanol (304 mg, 4.10 mmol) in DMF (1.0 mL) was cooled to 0° C. under ice-cooling, and sodium hydride (NaH) (60%, oil, 49.2 mug, 1.23 mmol) was added. The mixture was stirred at 60° C. for 1.5 hours and then cooled to 0° C. under ice-cooling, and sodium hydride (NaH) (60%, oil, 49.2 mg, 1.23 mmol) was added. The mixture was stirred at 60° C. for 30 minutes and then cooled to room temperature, and water (100 μL) was added. The reaction solution was then purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid), and the fractions were lyophilized to give Compound 2082-a (5-bromo-1,2-dichloro-3-[(2-methylpropan-2-yl)oxy]benzene) (127 mg, 52%).

Retention time: 1.15 min (analysis condition SQDFA05)

¹H-NMR (CDCl₃) δ: 7.34 (1H, d, J=2.1 Hz), 7.18 (1H, d, J=2.1 Hz), 1.44 (9H, s).

1-4-4. Peptide Modification by Sonogashira Coupling Reaction

Synthesis of Compound 2142 ((3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-ethynylphenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

Compound 2142-a (123.7 mg, 49%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino)]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (400 mg, 0.436 mmol/g, 0.1744 mmol) as a raw material.

LCMS (ESI) m/z=1443.6 (M+H)+

Retention time: 1.06 min (analysis condition SQDFA05)

To a mixture of Compound 2142-a (30 mg, 0.021 mmol), bis(triphenylphosphine)palladium(IT) dichloride (7.3 mg, 0.5 equivalents), and copper(I) iodide (4 mg, 1 equivalent) in DMF (208 μl) were added triethylamine (0.145 mL, 50 equivalents) and trimethylsilylacetylene (35.2 μL, 12 equivalents), and the mixture was stirred at room temperature for 30 minutes. Half of the reaction solution was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid). To the resulting fractions were, added potassium carbonate (6 equivalents relative to the raw material peptide) and water (6 equivalents relative to the raw material peptide), and the mixture was concentrated under reduced pressure. To the residue were added methanol (500 μL) and water (50 μL). After confirming that the trimethylsilyl group was deprotected, the resulting reaction solution was concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL) and then purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid), and the fractions containing the target compound were lyophilized. The residue was dissolved in DMSO (1 ml) and then concentrated under reduced pressure again to give Compound 2142 ((3S,9S,12S,18S,27S,30S,34S)-9-butyl-18-[(4-chlorophenyl)methyl]-12-[(3-ethinylphenyl)methyl]-3,30-diisobutyl-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-34-(piperidine-1-carbonyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone) (1.6 mg, 6%). The LC/MS data are as described in Table 22.

1-4-5. Peptide Modification by Click Chemistry

Synthesis of Compound 2113 ((3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(triazol-1-yl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone

Compound 2113-a (5.4 mg, 10%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (100 mg, 0.37 mmol/g, 0.037 mmol) as a raw material and using (2S,4R)-4-azido-1-Fmoc-pyrrolidine-2-carboxylic acid (Fmoc-L-Pro(4-N3)-OH(2S,4R), CAS No. 702679-55-8) as an Fmoc amino acid.

LCMS (ESI) m/z=1428.97 (M+H)+

Retention time: 1.05 min (analysis condition SQDFA05)

To Compound 2113-a (5.4 mg, 3.8 μmol) were added copper(1) iodide (3 mg, 15.75 μmol), acetonitrile (0.5 mL), DIPEA (50 μL, 286 μmol), and trimethylsilylacetylene (50 μL, 0.361 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, washed with acetonitrile, and then concentrated under reduced pressure. The resulting crude product was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound 2113-b (6.4 mg, quant.).

LCMS (ESI) m/z=1527.06 (M+H)+

Retention time: 1.10 min (analysis condition SQDFA05)

Compound 2113-b (6.4 mg) was dissolved in 1,4-dioxane (1 mL), and a solution of tetrabutylammonium fluoride (TBAF) in THF (1 M, 0.5 mL, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 162 hours and then concentrated under reduced pressure. The resulting crude product was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound 2113 ((3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(triazol-1-yl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31, 1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (4.6 mg, 84% through two steps). The LC/MS data are as described in Table 22.

Synthesis of Compound 2115 ((3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-trifluormethyl)phenyl]ethyl]-9 (cyclopentylmethyl-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl-25-(piperidine-1-carbonyl-36-(triazol-1-yl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane:2,5,8,11,14,17,20,23,27,33-undecone)

Compound 2115 ((3S,9S,18S,21S,25S,28S,34S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclopentylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-36-(triazol-1-yl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (8.0 mg) was obtained by the same method as in the synthesis of Compound 2113 using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) as a starting material for peptide synthesis according to the basic peptide synthesis method described in the present Examples, and using (2S,4S)-4-azido-1-Fmoc-pyrrolidine-2-carboxylic acid (Fmoc-L-Pro(4-N3)-OH(2S,4S), CAS No. 263847-08-1) as an Fmoc amino acid. The LC/MS data are as described in Table 22.

1-4-6. Peptide Modification by Suzuki Coupling

Synthesis of Compound 2096 ((3S,9S,18S,21S,25S,28S,31S,34S)-31-benzyl-9-4-chlorophenyl)methyl]-3-[2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl]-28-isobutyl-7,10,13,16,21,22,29,32-octamethyl-18-[1S)-1-methylpropyl]-25-(pyrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone)

Compound 2096-a (157 mg) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa018-resin ((3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-pyrrolidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)-resin)-pyrro)) as a raw material.

LCMS (ESI) m/z=1273.3 (M−H)−

Retention time: 0.74 min (analysis condition SQDFA05)

To a mixed solution of Compound 2096-a (15 mg, 0.012 mmol), thallium carbonate (55.1 mg, 0.118 mmol), and RuPhos Pd G4 (CAS No. 1599466-85-9, 30 mg, 0.035 mmol) in water/THF (1/10, 0.235 mL) was added 1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (24.2 mg, 0.094 mmol) under a nitrogen atmosphere, and the mixture was then stirred at 70° C. for 18 hours. The reaction solution was filtered through celite and then purified by reverse phase column chromatography (C₁₈, methanol/10 mM aqueous ammonium acetate and 0.3% formic acid/acetonitrile/water) to give Compound 2096 ((3S,9S,18S,21S,25S,28S,31S,34S)-31-benzyl-9-[(4-chlorophenyl)methyl]-3-[2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl]-28-isobutyl-7,10,13,16,21,22,29,32-octamethyl-18-[(1S)-1-methylpropyl]-25-(pyrrolidine-1-carbonyl)-1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-2,5,8,11,14,17,20,23,27,30,33-undecone) (14.1 mg, 71%). The LC/MS data are as described in Table 22.

Synthesis of Compounds 2093, 2091, 2087, 2094, 2086, 2089, 2092, 2090, 2088, and 2095

Compound 2093-a (312 mg) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa138-resin ((3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid-2-chlorotrityl resin, Fmoc-D-3-Abu-O-Trt(2-Cl)resin) as a raw material.

LCMS (ESI) m/z=1188.4 (M−H)—(detected as dehydrated form)

Retention time: 2.84 min (analysis condition SQDFA30long50deg)

Compound 2093, 2091, 2087, 2094, 2086, 2089, 2092, 2090, 2088, and 2095 were obtained by the same synthesis method as in Compound 2096 using Compound 2093-a as a raw material and using a benzyl bromide provided below (8 equivalents relative to the raw material peptide). The following table describes target compound peptides, benzyl bromides used for reactions, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 17
Target		Yield	Yield
compound	Benzyl bromide	mg	%
Compound 2093	1-(bromomethyl)-3-fluoro-4-	5.6	34
	(trifluoromethyl)benzene
Compound 2091	1-(bromomethyl)-2,3,4,5,6-	9	54
	pentafluorobenzene
Compound 2087	1-(bromomethyl)-2,4,5-trifluorobenzene	5.3	33
Compound 2094	2-(bromomethyl)-4-chloro-1-	5.8	35
	fluorobenzene
Compound 2086	1-(bromomethyl)-4-chloro-2-	2.6	16
	fluorobenzene
Compound 2089	1-(bromomethyl)-2,4-difluorobenzene	1.7	11
Compound 2092	2-(bromomethyl)-1-chloro-3-	0.7	4.6
	fluorobenzene
Compound 2090	2-(bromomethyl)-1,3,5-trifluorobenzene	7	43
Compound 2088	4-(bromomethyl)-2-chloro-1-	3.8	22
	(trifluoromethyl)benzene
Compound 2095	1-(bromomethyl)-3-	1.4	8.8
	(trifluoromethyl)benzene

1-4-6. Peptide modification by Chan-Lam-Evans coupling The following table shows structural formulas of 2,4,6-triarylboroxane-pyridine complexes used for reactions corresponding to target compounds. These 2,4,6-triarylboroxane-pyridine complexes were synthesized with reference to J. Org. Chem. 2004, 69, 5087-5092.

TABLE 18
Target compound 2,4,6-triarylboroxan-pyridine complex
Compound 2040 Compound 2042
Compound 2039
Compound 2041
Compound 2114

Synthesis of Compound 2040 ((3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenoxy)ethyl]-28-cyclohexyl-9-cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonylspiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

To a mixture of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-hydroxybutanoic acid (Fmoc-Hse-OH) (2.56 g, 7.5 mmol) in THF (15 mL) were added PPTS (94 mg, 0.375 mmol) and 3,4-dihydropyran (4.75 mL, 52.5 mmol), and the mixture was stirred at 50° C.; for 16 hours. Ethyl acetate was added to the reaction solution, which was washed with brine three times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give a mixture of Compound 2040-a with a compound having a carboxylic acid converted to THP. The resulting crude product was used for the next reaction without further purification.

The total amount of the crude product obtained above was dissolved in THF (30 mL), an aqueous disodium hydrogenphosphate solution (1 M, 30 mL) was added, and the mixture was stirred at 50° C. for four hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound 2040-a (3.6 g, quant.). The resulting crude product was used for the next reaction without further purification.

LCMS (ESI) m/z=448 (M+Na)+

Retention time: 0.82 min (analysis condition SQDFA05)

Compound 2040-b (410 mg) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (1.6 g) as a raw material and using the above-obtained Compound 2040-a as an Fmoc amino acid.

LCMS (ESI) m/z=1238.1 (M−H)−

Retention time: 0.81 min (analysis condition SQDFA05)

To a solution of Compound 2040-b (15 mg, 0.012 mmol) in 1,2-dichloroethane (225 μL, 0.05 mol/L) were added DIPEA (8 equivalents), copper(II) acetate (4 equivalents), 2,4,6-triarylboroxane-pyridine complex (1.7 equivalents), and molecular sieves 4A (3.3 w/w), and the mixture was then reacted at room temperature overnight under an oxygen atmosphere. The reaction solution was concentrated and then partially purified by reverse phase column chromatography (C₁₈, methanol/10 mM aqueous ammonium acetate solution). The resulting residue was purified by preparative HPLC to give Compound 2040 ((3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenoxy)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (3.3 mg, 22%). The LC//MS data are as described in Table 22.

Synthesis of Compound 2039 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-(3,4-dichlorophenoxy)ethyl]-7,10,13,1621,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

Compound 2039 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-(3,4-dichlorophenoxy)ethyl]-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (1.3 mg, 7.5%) was obtained by the same method as in the synthesis of Compound 2040 using Compound 2040-b (15 mg, 0.012 mmol) as a raw material. The LC/MS data are as described in Table 22.

Synthesis of Compound 2041 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-[4-(trifluoromethyl)phenoxy]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

Compound 2041 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[2-[4-(trifluoromethyl)phenoxy]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (2.1 mg, 13%) was obtained by the same method as in the synthesis of Compound 2040 using Compound 2040-b (15 mg, 0.012 mmol) as a raw material. The LC/MS data are as described in Table 22.

Synthesis of Compound 2042 ((3S,9S,18S,21S,25S,28S,34S)-3-[(4-chlorophenoxy)methyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31.1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

Compound 2042-a (230 mg) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (1.6 g) as a raw material.

LCMS (ESI) 2m/z=1224.1 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Compound 2042 ((3S,9S,18S,21S,25S,28S,34S)-3-[(4-chlorophenoxy)methyl]-28-cyclohexyl-9-(cyclohexymethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (2.56 mg, 16%) was obtained by the same method as in the synthesis of Compound 2040 using Compound 2042-a (15 mg, 12 μmol) as a raw material. The LC/MS data are as described in Table22

Synthesis of Compound 2114 ((6S,9S,13S,16S,22S,25S,31S,34S)-25-[3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-22-(phenoxymethyl)-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone)

Compound 2114-a (60 mg, 36%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.4 g, 0.3 mmol/g, 0.12 mmol) as a raw material.

LCMS (ESI) m/z=1409.6 (M+H)+

Retention time: 0.92 min (analysis condition SQDFA05)

Compound 2114 ((6S,9S,13S,16S,22S,25S,31S,34S)-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-4,10,14,19,19,20,29,32-octamethyl-6-[(1S)-1-methylpropyl]-22-(phenoxymethyl)-13-(piperidine-1-carbonyl)-31-(p-tolylmethyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-2,5,8,11,15,18,21,24,27,30,33-undecone) (1.53 mg, 29%) was obtained by the same method as in the synthesis of Compound 2040 using Compound 2114-a (5 mg, 3.55 μmol) as a raw material. The LC/MS data are as described in Table 22.

1-4-7. Peptide Synthesis Through N-Alkylation by Mitsunobu Reaction on Resins

Synthesis of Compound 2161 ((8S,11S,17S,26S,29S,33S,36S)-8-[2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-9-ethyl-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Compound 2161 was synthesized according to the following route.

Compound 2161-a-resin was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (100 mg, 0.462 mmol/g, 0.0462 mmol) as a raw material.

To the above-obtained Compound 2161-a-resin were added a nosyl chloride/THF solution (0.2 mmol, 0.35 mL) and a collidine/THF solution (0.5 mmol, 0.35 mL), and the mixture was shaken at 40° C. for two hours. Thereafter, the resin was washed with TI- F (0.7 mL) four times and then washed with DCM (0.7 mL) four times to give Compound 2161-b-resin. The obtained resin was partially cleaved with TFE/DCM (1/1) and analyzed by LC/MS to confirm the progress of the reaction.

LCMS (ESI) m/z=805 (M+H)+

Retention time: 0.79 min (analysis condition SQDFA05)

The above-obtained Compound 2161-b-resin was swollen with DCM (1.0 mL) and washed with THF (0.7 mL) four times, after which a triphenylphosphine/TH-F solution (66.0 mg/0.7 mL, 0.25 mmol), ethanol (0.024 mL, 0.41 mmol), and diisopropyl azodicarboxylate (DIAD) (0.05 mL, 0.26 mmol) were added and the mixture was shaken at 40° C. for 30 minutes. Thereafter, the resin was washed with THF (0.7 mL) four times and then washed with DCM (0.7 mL) four times to give Compound 2161-c-resin. The obtained resin was partially cleaved with TFE/DCM (1/1) and analyzed by LC/MS to confirm the progress of the reaction.

LCMS (ESI) m/z=833 (M+H)+

Retention time: 0.88 min (analysis condition SQDFA05)

The above-obtained Compound 2161-c-resin was swollen with DCM (1.0 mL) and washed with NMP (0.7 mL) four times, after which a DBU/NMP solution (36 μL/314 μL) and a 1-dodecanethiol/NMP solution (89 μL/261 μL) were added and the mixture was shaken at 40° C. for one hour. Thereafter, the resin was washed with NMP (0.7 mL) four times and then washed with DCM (0.7 mL) four times to give Compound 2161-d-resin. The obtained resin was partially cleaved with TFE/DCM (1/1) and analyzed by LC/MS to confirm the progress of the reaction.

LCMS (ESI) m/z=648 (M+H)+

Retention time: 0.51 min (analysis condition SQDFA05)

Peptide chain elongation and cyclic peptide synthesis were conducted according to the basic route using the above-obtained Compound 2161-d-resin to give Compound 2161 ((8S,11S,17S,26S,29S,33S,36S)-8-[(2-chlorophenyl)methyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-17-(cyclohexylmethyl)-9-ethyl-36-isopropyl-15,18,21,24,29,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (5.5 mg, 8%). The LC/MS data are as described in Table 22.

Synthesis of Compounds 2162-2167

Compounds 2162-2167 were synthesized in the same manner as in the synthesis of Compound 2161. The LC/MS data are as described in Table 22.

Synthesis of Compound 2118-2111

Compounds 2168-2171 were synthesized according to the basic scheme provided below in the same manner as in the synthesis of Compound 2161 using methanol (0.019 mL, 0.47 mmol) instead of ethanol in Mitsunobu reaction.

The Fmoc amino acid having a pyridine ring on the side chain, as used for synthesizing Compound 2169, was synthesized according to the following scheme.

A mixture of Compound 2169-a synthesized according to the method described in WO 2018/225864 (5 g, 13.47 mmol), zinc powder (2.63 g, 40.46 mmol), and iodine (515 mg, 2.03 mmol) in DMF (15 mL) was stirred at room temperature for two hours under a nitrogen atmosphere. To the solution were added 5-bromopyridine-2-carbonitrile (3.19 g, 17.43 mmol), tris(dibenzylideneacetone)(chloroform)dipalladium (0), (350 mg, 0.34 mmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (321 mg, 0.67 mmol) were added, and the mixture was stirred at 50° C. for three hours. The reaction solution was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give Compound 2169-b (2.5 g, 53%). This was mixed with another lot synthesized in the same manner and was used for the next reaction.

LCMS (ESI) m/z=348 (M+H)+

Retention time: 1.508 min (analysis condition SMDmethod23)

A solution of Compound 2169-b (12 g, 34.54 mmol) in dichloromethane (100 mL) was stirred at 25° C. for two hours while bubbling with hydrochloric acid gas. The precipitated solid was collected by filtration to give Compound 2169-c as a crude product (7.83 g, 100%). This was used for the next reaction without farther purification.

To a solution of Compound 2169-c (2.4 g, 10.54 mmol) and potassium carbonate (3.77 g, 27.28 mmol) in water (34 mL) was added a solution of Fmoc-OSu (3.06 g, 10.54 mmol) in 1,4-dioxane (34 mL), and the mixture was stirred at 0° C. for one hour. The reaction solution was diluted with water and washed with diethyl ether three times. The resulting aqueous layer was adjusted to a pH range of 5 to 6 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol) to give Compound 2169-d (1 g, 23%).

LCMS (ESI) m/z=414.2 (M+H)+

Retention time: 2.737 min (analysis condition SMDmethod_22)

Compound 2170 was synthesized using, as an Fmoc amino acid, 9H-fluoren-9-ylmethoxycarbonylamino-3-[3-fluoro-4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid (Fmoc-Tyr(3-F,tBu)-OH) synthesized as described in WO 2018/225864. The phenol tBu group was deprotected by adding 2 mL of a 0.1 M tetramethylammonium bisulfate/1,1,1,33,3-hexafluoroisopropyl alcohol (HFIP) solution containing 2% triisopropylsilane (TIPS) to the residue after cyclization reaction, and allowing to stand at room temperature for 24 hours.

1-4-8. Peptides Synthesis Through Amination on Resins

Synthesis of Compound 2035 ((11S,17S,26S,29S,33S,36S)-11-2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2,2-difluorospiro[3.3]heptan-6-yl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Fmoc-MeChg-OH and then Fmoc-cLeu-OH were elongated and the Fmoc group was deprotected by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin(3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (100 mg, 0.437 mmol/g, 0.0437 mmol) as a raw material, after which Compound 2035-a-resin with the peptide N-terminus iodinated on the resin was obtained using a mixture composed of a solution of iodoacetic acid (0.6 mol/L, 0.3 mL) in NMP/DMF (1/1) and a solution of diisopropylcarbodiimide (DIC) in N,N-dimethylformamide (DMF) (10% v/v, 0.36 mL). Further, this was reacted with 6,6-difluorospiro[3.3]heptan-2-amine hydrochloride in the presence of DIPEA to give Compound 2035-b-resin. Subsequent peptide chain elongation and cyclic peptide synthesis were conducted according to the basic route to give Compound 2035 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2,2-difluorospiro[3.3]heptan-6-yl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine,-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (4.12 mg, 6%). The LC/MS data are as described in Table 22.

Synthesis of Compounds 2031, 2030, 2022, 2021 2036, 2025, 2024, 2029, 2032 2033, 2026, 2023, 2028 2027, and 2034

Tripeptide-loaded resins were synthesized by the same method as in the synthesis of Compound 2035, iodoacetic acids were then condensed and aminated, and peptide chain elongation and cyclic peptide synthesis were further conducted according to the basic route to synthesize Compounds 2031, 2030, 2022, 2021, 2036, 2025, 2024, 2029, 2032, 2033, 2026, 2023, 2028, 2027, and 2034. The following table describes target compound peptides, amines used for reactions, and yield amounts (mg) of the target compounds. The LC/MS data are as described in Table 22.

TABLE 19
Peptide	Amine	Yield mg
Compound 2031		5.09
Compound 2030		2.76
Compound 2022		10.32
Compound 2021		8.99
Compound 2036		5.06
Compound 2025		8.11
Compound 2024		2.99
Compound 2029		18.06
Compound 2032		16.68
Compound 2033		9.24
Compound 2026		14.51
Compound 2023		3.39
Compound 2028		4.78
Compound 2027		5.34
Compound 2034		4.99

Synthesis of Compound-2037 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-hydroxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) and Compound 2038 (2-[2-[(11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]ethoxy]-N,N-dimethyl-acetamide

Compound 2037 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(2-hydroxyethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) was obtained by the same method as in the synthesis of Compound 2035 using Compound 2035-a-resin and using 2-(2-aminoethoxy)oxane as an amine, and by conducting peptide chain elongation, and cyclic peptide synthesis including THP deprotection, according to the basic route. The LC/MS data are described in Table 22.

Compound 2038 (2-[2-[(11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(Trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]ethoxy]-N,N-dimethyl-acetamide) (4.7 mg, 89%) was obtained by the same method as in the synthesis of Compound 2116 using Compound 2037 (5 mg, 3.46 mol), silver oxide (24.0 mg, 0.104 mml), and 2-bromo-N,N-dimethylacetamide (17.2 mg, 0.104 mmol). The LC/MS data are described in Table 22.

1-4-9. Peptide Modification by Amidation of Carboxylic Acids

Synthesis of Compound 2108 (3-(3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexymethyl)-16-cyclopentyl-19-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-22-yl]-N,N-dimethyl-propanamide)

Compound 2108-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5-oxo-5-prop-2-enoxypentanoic acid) was obtained as a crude product (2.179 g, 96%) by the same method as in the synthesis of Compound aba078-b using (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-prop-2-enoxypentanoic acid (Fmoc-Glu(OA1)-OH) (2.197 g, 5.37 mmol) as a starting material.

LCMS (ESI) m/z=424 (M+H)+:

Retention time: 0.84 min (analysis condition SQDFA05)

Compound 2108-b was obtained as a crude product by peptide synthesis according to the basic peptide synthesis method described in the present. Examples, using Compound aa007-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-morpholin-4-yl-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-mor) (0.424 mmol/g, 600 mg, 0.254 mmol) as a starting material and using Compound 2108-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5-oxo-5-prop-2-enoxypentanoic acid) as a reagent.

The total amount of Compound 2108-b obtained above (0.254 mmol) was dissolved in dichloromethane (2.5 mL), tetrakistriphenylphosphinepalladium (14.7 mg, 0.05 equiv.) and phenylsilane (22 μL, 0.7 equiv.) were added, and the mixture was stirred at room temperature for 75 minutes. Tetrakistriphenylphosphinepalladium (14.7 mg, 0.05 equiv.) and phenylsilane (22 μL, 0.7 equiv.) were added to the reaction solution, and the mixture was stirred for 90 minutes to give a reaction solution containing Compound 2108-c. A solution of HATU (193 mg, 2 equiv.) in dimethylformamide (2.5 mL), and diisopropylethylamine (0.11 mL, 2.4 equiv.) were added thereto, and the mixture was stirred for 15 minutes. This reaction solution (Reaction Solution A) was divided into six portions, one of which was used for the subsequent reaction.

Dimethylamine (0.11 mL, 5 equiv., 2.0 M tetrahydrofuran solution) was added to Reaction Solution A (0.0424 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give Compound 2108 (3-[(3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-3,4,10,14,17,23,29,32-octamethyl-6-[(1S)-1-methylpropyl]-13-(morpholine-4-carbonyl)-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-22-yl]-N,N-dimethyl-propanamide) (3.6 mg, 5.6%). The LC/MS data are described in Table 22.

Synthesis of Compounds 2098, 2103, 2112, 2104, and 2107

Compound 2098, 2103, 2112, 2104, or 2107 was obtained by adding an amine (5 equiv. relative to the peptide) shown in the following table instead of dimethylamine to one of the six divided portions of Reaction Solution A as obtained in the synthesis of Compound 2108, by the same method as in the synthesis of Compound 2108. The following table describes target compound peptides, amines used for reactions, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are described in Table 22.

TABLE 20
		Yield	Yield
Peptide	Amine	mg	%
Compound 2098	3,3-difluoroazetidine-hydrochloride	2.7	4
Compound 2103	azetidine	3.6	5.5
Compound 2112	piperidine	3.8	5.7
Compound 2104	pyrrolidine	2.5	3.8
Compound 2107	morpholine	4.5	6.8

Synthesis of Compound 2106 ((3S,6S,9S,13S,22S,25S31S,34S)2-[2-[3-chlor-4-trifluoromethyl)phenyl]ethyl]-31-cyclohexylmethyl)-16-cyclopentyl-22-[2-dimethylamino)-2-oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane-1-13-carboxamide)

Compound 2106-a was obtained as a crude product by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa011-resin ((3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-NMe2) (600 ng, 0.371 mmol/g, 0.223 mmol) as a starting material and using Compound 2108-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5-oxo-5-prop-2-enoxypentanoic acid) as a reagent.

The total amount of Compound 2106-a obtained above (0.223 mmol) was dissolved in dichloromethane (2.5 mL), tetrakis(triphenylphosphine)palladium(0) (14.7 mg, 0.05 equiv.) and phenylsilane (22 μL, 0.7 equiv.) were added thereto, and the mixture was stirred at room temperature for one hour. Tetrakis(triphenylphosphine)palladium (0) (14.7 mg, 0.05 equiv.) and phenylsilane (22 μL, 0.7 equiv.) were added to the reaction solution, and the mixture was stirred for two hours to give a reaction solution containing Compound 2106-b. A solution of HAT U (193 mg, 2 equiv.) in dimethylformamide (2.5 mL) and diisopropylethylamine (0.11 mL, 2.4 equiv.) were added to the reaction solution, and the mixture was stirred for 15 minutes. This reaction solution (Reaction Solution B) was divided into six portions, one of which was used for the subsequent reaction.

Dimethylamine (0.11 mL, 5 equiv., 2.0 M tetrahydrofuran solution) was added to Reaction Solution B (0.037 mmol), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give Compound 2106 ((3S,6S,9S,13S,16S,22S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-22-[2-(dimethylamino)-2-oxo-ethyl]-9-isobutyl-N,N,3,4,10,14,17,23,29,32-decamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1-cyclopentane]-13-carboxamide) (6.6 mg, 12%). The LC/MS data are described in Table 22.

Synthesis of Compounds 2102, 2105, 2097, and 2109

Compound 2102, 2105, 2097, or 2109 was obtained by adding an amine (5 equiv. relative to the peptide) shown in the following table instead of dimethylamine to one of the six divided portions of Reaction Solution B as obtained in the synthesis of Compound 2106, by the same method as in the synthesis of Compound 2106. The following table describes target compound peptides, amines used for reactions, and yield amounts (mg) and yield percentages (%) of the target compounds. The LC/MS data are described in Table 22.

TABLE 21
Target		Yield	Yield
compound	Amine	mg	%
Compound 2102	Azetidine	6.3	11
Compound 2105	piperidine	5.6	10
Compound 2097	pyrrolidine	4.4	8
Compound 2109	morpholine	9.2	16

Synthesis of Compound 2110 (3-[(3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-22-butyl-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,20,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo 32.2.0]hexatriacontan-19-yl]-N,N-dimethyl-propanamide)

A solution of Compound 2108-a (10.34 g, 24.42 mmol), WSCI·HCl (6.09 g, 31.7 mmol), and HOAt (4.32 g, 31.7 mmol) in DCM (116 ml,) was stirred at room temperature for 15 minutes, methanol (1.038 ml, 25.6 mmol) and DIPEA (5.53 mL, 31.7 mmol) were added thereto, and the mixture was stirred for 90 minutes. The reaction solution was diluted with dichloromethane and sequentially washed with saturated aqueous ammonium chloride/water (1/1) and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound 2110-a as a crude product (10.93 g). This was mixed with another lot synthesized by the sane method and was used for the next reaction.

LCMS (ESI) m/z=438 (M+H)+

Retention time: 1.338 min (analysis condition SMDmethod_04)

Tetrakis(triphenylphosphine)palladium(0) (0.19 g, 0.164 mmol) and phenylsilane (2.359 mL, 19.18 mmol) were added to a solution of Compound 2110-a (11.99 g, 27.4 mmol) in DCM (54.8 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with TBME and washed with a 5% aqueous sodium carbonate solution and water. The aqueous layer was acidified with phosphoric acid (11.25 mL, 164 mmol) and extracted with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give Compound 2110-b (9.56 g, 95%).

LCMS (ESI) m/z=420 (M+Na)+

Retention time: 1.069 min (analysis condition SMDmethod_04)

A solution of 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (13.5 g, 48.1 mmol) in DCM/cyclohexane (1/1, 32.8 mL) was added to a solution of Compound 2110-b (9.56 g, 24.05 mmol) in DCM (16.04 mL) at room temperature, and the mixture was stirred overnight. The reaction solution was filtered through celite, and the solvent was evaporated from the filtrate under reduced pressure to give Compound 2110-c as a crude product (17.29 g). This was used for the next reaction without further purification.

A solution of Compound 2110-c (17.29 g) in THF (100 mL) and 2-propanol (401 mL) was added to a suspension of calcium chloride (40 g, 361 mmol) and lithium hydroxide monohydrate (4.04 g, 96 mmol) in water (100 mL) at room temperature, and the mixture was stirred overnight. The solid in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a 0.1 M aqueous phosphoric acid solution and brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was diluted with TB ME/hexane (1/1) and extracted with 5% aqueous sodium carbonate/water/methanol (15/12/4). The resulting aqueous layer was washed with TBME/hexane (1/1) and extracted with ethyl acetate. The resulting organic layer was sequentially washed with a 0.2 M aqueous phosphoric acid solution and brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound 2110-d (9.68 g, 80%).

LCMS (ESI) m/z=524 (M+Na)+

Retention time: 1.365 min (analysis condition SMDmethod_04)

Compound 2110-e (25 mg, 40%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (100 mg, 0.411 mmol/g, 0.0411 mmol) as a raw material and using the above-obtained Compound 2110-d as a reagent. The Pis group was deprotected under the same conditions as in the deprotection of the THP group.

LCMS (ESI) m/z=1510 (M+H)+

Retention time: 0.71 min (analysis condition SQDAA50)

Compound 2110-e (15 mg, 0.0099 mmol) was dissolved in tetrahydrofuran (0.2 ml). Sodium bicarbonate (4.17 mg, 0.050 mmol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (14.87 mg, 0.050 mmol), and Dimethylamine (2 mol/L, a THF solution, 0.025 ml, 0.050 mmol) were added, and the mixture was then stirred at room temperature for four hours. The reaction solution was concentrated, and the resulting residue was then purified by preparative HPLC to give Compound 2110 (3-[(3S,6S,9S,13S,16S,19S,22S,25S,31S,34S)-22-butyl-25-[(3-iodophenyl)methyl]-9,16-diisobutyl-31-[(4-methoxyphenyl)methyl]-3,4,10,14,20,29,32-heptamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-13-(piperidine-1-carbonyl)-1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontan-19-yl]-N,N-dimethyl-propanamide) (5.07 mg, 33%). The LC/MS data are described in Table 22.

Synthesis of Compound 2100 (3-[(3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-12-3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,18,22,25,28,31-undecazacyclotetatriacont-6-yl]-N,N-dimethyl-propanamide)

Compound 2100-a (27.5 mg, 46%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present. Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (100 mag, 0.411 mmol/g, 0.0411 mmol) as a raw material and using Compound 2110-d as a reagent. The Pis group was deprotected under the same conditions as in the deprotection of the THP group.

LCMS (ESI) m/z=1468 (M+H)+

Retention time: 0.73 min (analysis condition SQDAA50)

Compound 2100 (3-[(3S,6S,9S,12S,18S,27S,30S,34S)-9-butyl-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-1,7,16,19,22,25,31-heptamethyl-27-[(1S)-1-methylpropyl]-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-34-(piperidine-1-carbonyl)-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacont-6-yl]-N,N-dim-ethyl-propanamide) (6.441 mg, 43%) was obtained by the same method as in the synthesis of Compound 2110 using Compound 2100-a. The LC/MS data are described in Table 22.

Synthesis of Compound 2101 ((3S,9s,12s,18s,27s,30S,34S)-34-(4,4-difluoropiperidine-1-carbonyl)-12-[3-iodophenyl)methyl]-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-18- (p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone)

2-Phenylpropan-2-yl 2,2,2-trichloroacetimidate (2.74 g, 9.77 mmol) was added as a DCM solution to a solution of aa033-b (2 g, 4.88 mmol) in DCM (15 mL), and the mixture was stirred at room temperature for two hours. The solvent was evaporated from the reaction solution under reduced pressure, and the resulting residue was purified by reverse phase column chromatography to give Compound 2101-a (2.10 g, 81%).

LCMS (ESI) m/z=550.3 (M+Na)+

Retention time: 0.76 min (analysis condition SQDAA50)

Tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04 mmol) and phenylsilane (0.343 mL, 2.79 mmol) were added to a solution of Compound 2101-a (2.1 g, 3.98 mmol) in DCM (15 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for one hour. The reaction solution was diluted with MT BE and a 5% aqueous sodium bicarbonate solution, the solvent was evaporated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography to give Compound 2101-b (1.67 g, 86%).

LCMS (ESI) m/z=510 (M+Na)+

Retention time: 0.94 min (analysis condition SQDFA05)

Compound 2101-b-resin (3.6 g, 0.377 mmol/g) was obtained by the same method as in the synthesis of Compound aa007-resin using the obtained Compound 2101-b (1.17 g, 2.4 mmol).

Compound 2101-c (38 mg, 24%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound 2101-b-resin (300 mg, 0.377 mmol/g, 0.1131 mmol) as a raw material. The Pis group was deprotected under the same conditions as in the deprotection of the THP group.

LCMS (ESI) m/z=1421 (M+H)+

Retention time: 0.64 min (analysis condition SQDAA50)

Compound 2101 ((3S,9S,12S,18S,27S,30S,34S)-34-(4,4-difluoropiperidine-1-carbonyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone) (6.77 mg, 42%) was obtained by the same method as in the synthesis of Compound 2110 using Compound 2101-c (15 mg, 10.56 μmol) and using 4,4-difluoropiperidine hydrochloride instead of dimethylamine. The LC/MS data are described in Table 22.

Synthesis of Compound 2099 ((3S,9S,12S,18S,27S,30S,34S)-34-(3,3-difluoropiperidine-1-cabonyl)-12[(3-iodophenyl)methyl-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone)

Compound 2099 ((3S,9S,12S,18S,27S,30S,34S)-34-(3,3-difluoropiperidine-1-carbonyl)-12-[(3-iodophenyl)methyl]-3,30-diisobutyl-9-[(4-methoxyphenyl)methyl]-1,6,6,7,16,19,22,25,31-nonamethyl-27-[(1S)-1-methylpropyl]-18-(p-tolylmethyl) 1,4,7,10,13,16,19,22,25,28,31-undecazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone) (5.24 mg, 33%) was obtained by the same method as in the synthesis of Compound 2110 using Compound 2101-c (15 mg, 10.56 mmol) and using 3,3-difluoropiperidine hydrochloride instead of dimethylamine. The LC/MS data are described in Table 22.

1-4-10. Peptide Modification by Olefin Metathesis Reaction

Synthesis of Compound 2053 ((8S,11S,17S,26S,29S,33S,36S))-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl-8-(2-tetrahydropyran-4-ylideneethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

A solution of Compound 1449 (9 mg, 6.18 μmol), Grubbs catalyst 2nd generation (2.6 mg), and 4-methylenetetrahydro-2H-pyran (20 μL) in 1,2-dichloroethane (1 mL) was stirred at 60° C. for six hours under a nitrogen atmosphere. 4-Methylenetetrahydro-2H-pyran (50 μL) was further added and the mixture was stirred at the same temperature for 2 hours and 45 minutes. Grubbs catalyst 2nd generation (2.6 mg) was further added and the mixture was stirred at the same temperature for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound 2053 ((8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(2-tetrahydropyran-4-ylideneethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (5.0 mg, 60%). The LC/MS data are described in Table 22.

Synthesis of Compound 2048 ((8S,11S,17S,26S,29S,33S,365S)-11-(2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(2-tetrahydropyran-4-ylethyl]-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38 undecone)

A mixture of Compound 2053 (7.8 mg, 5.11 μmol) and platinum(IV) oxide (1.2 mg, 5.11 μmol) in ethanol (1 mL) was stirred at room temperature for 10 hours under a hydrogen atmosphere, after which platinum(IV) oxide (1.2 mg, 5.11 μmol) was further added and the mixture was stirred at the, same temperature for about 17 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (10 mM aqueous ammonium acetate solution/methanol) to give Compound 2048 ((8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-8-(2-tetrahydropyran-4-ylethyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (7.8 mug, 99%). The LC/MS data are described in Table 22.

Synthesis of Compound 2050 (tert-butyl 3-[2-(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]ethylidene]azetidine-1-carboxylate)

Under a nitrogen atmosphere, a solution of Compound 1449 (9 mg, 6.18 μmol), Hoveyda-Grubbs catalyst 2nd generation (3.9 mg), and 1-tert-butoxycarbonyl-3-methyleneazetidine (20 μL) in dichloroethane (1 mL) was stirred at 60° C. for 2 hours and 30 minutes and then stirred at 75° C. Hoveyda-Grubbs catalyst 2nd generation (3.9 mg) and 1-tert-butoxycarbonyl-3-methylene-azetidine (20 μL) were further added and the mixture was stirred at 80° C. for 14 hours, after which Hoveyda-Grubbs catalyst 2nd generation (3.9 mg) was further added and the mixture was stirred at the same temperature for about 10 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by preparative 1-PLC to give Compound 2050 (tert-butyl 3-[2-[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]ethylidene]azetidine-1-carboxylate) (0.65 mg, 6.6%). The LC/MS data are described in Table 22.

Synthesis of Compound 2056 tert-butyl 3-[2-8S,11S,17S,26S,29S,33S,36S)-11-2-3-chloro-4-(trifluoromethyl phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-8-yl]ethyl]azetidine-1-carboxylate)

A mixture of Compound 2050 (1.6 mg, 1 μmol) and platinum(IV) oxide (1 mg, 4.4 μmol) in ethanol (1 mL) was stirred at room temperature for- three hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (10 mM aqueous ammonium acetate solution/methanol) to give Compound 2056 (tert-butyl 3-[2-[(8S,11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9,15,18,21,24,30,34,37-octamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.3 3]octatriacontan-8-yl] ethyl]azetidine-1-carboxylate) (1.2 mg, 75%). The LC/MS data are described in Table 22.

Synthesis of Compound 2046 ((11S,17S,26S,29S,33S,36S)-11-(2-[3-chloro-4-(trifluormethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(5-hydroxypent-2-enyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone

Compound 899 (40 mg, 0.028 μmol) was dissolved in 1,2-dichloroethane (0.66 mL), Stewart-Grubbs catalyst (CAS No. 927429-61-6, 24 mg, 0.042 mmol) and homoallyl alcohol (20 μL, 8 equiv.) were added, and the mixture was stirred at room temperature for 16 hours. Homoallyl alcohol (20 μL, 8 equiv.) was further added and the mixture was stirred for two hours, after which Stewart-Grubbs catalyst (CAS No. 927429-61-6, 12 mg, 0.021 mmol) was added and the mixture was further stirred for two hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound 2046 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(5-hydroxypent-2-enyl)-29-isobutyl-15,18,21,24,30,34,37-heptaethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (12.3 mg, 30%). The LC/MS data are described in Table 22.

Synthesis of Compound 2049 ((11S,17S,26S,29S,33S,36S,)-11-[2-[3-chloro-4-trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-5-hydroxypentyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Platinum(IV) oxide (3.7 mg, 16 μmol) was added to a solution of Compound 2046 (3.0 mg, 2.02 μmol) in ethanol (1.0 mL), the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography to give Compound 2049 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(5-hydroxypentyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (2.6 mg, 87%). The LC/MS data are described in Table 22.

Synthesis of Compound 2047 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(4-hydroxy-4-methyl-pent-2-enyl-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Compound 899 (20 mg, 14 μmol) was dissolved in dichloroethane (0.33 mL), Stewart-Grubbs catalyst (CAS No. 927429-61-6, 12 mg, 21 μmol) and 2-methyl-3-buten-2-ol (12 μL, 8 equiv.) were added, and the mixture was stirred at room temperature for 16 hours. 2-Methyl-3-buten-2-ol (12 μL, 8 equiv.) was further added and the mixture was stirred for 45 minutes, after which Stewart-Grubbs catalyst (CAS No. 927429-61-6, 6.0 mg, 0.8 equiv.) was added and the mixture was stirred for three hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give a crude product. The crude product was purified by preparative HPLC to give Compound 2047 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-9-(4-hydroxy-4-methyl-pent-2-enyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (1.4 mg, 7%). The LC/MS data are described in Table 22.

Synthesis of Compound 2054 (4-[11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]-N,N-dimethyl-but-2-enamide)

Compound 2054 (4-[(11S,17S,26S,29S,3S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]-N,N-dimethyl-but-2-enamide) (1.4 mg, 6%) was obtained by the same synthesis method as in the synthesis of Compound 2047 using Compound 899 (20 mg, 14 μmol) as a starting material and using N,N-dimethylacrylamide (16 equiv.) instead of 2-methyl-3-buten-2-ol. The LC/MS data are described in Table 22.

Synthesis of Compound 2052 (4-[(11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]-N,N-dimethyl-butanamide)

Platinum(IV) oxide (4.7 mg, 10 equiv.) was added to a solution of Compound 2054 (3.1 mg, 2.08 μmol) in ethanol (1.0 mL), the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography and then further purified by preparative HPLC to give Compound 2052 (4-[(1S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-7,10,13,16,19,22,25,28,31,35,38-undecaoxo-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontan-9-yl]-N,N-dimethyl-butanamide) (1.4 mg, 45%). The LC/MS data are described in Table 22.

Synthesis of Compound 2051 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-chloro(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9-[(E)-4-methoxybut-2-enyl]-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)j

Compound 899 (50 mg, 35 μmol) was dissolved 1,2-dichloroethane (0.69 mL), Stewart-Grubbs catalyst (CAS No. 927429-61-6, 29.7 mg, 1.5 equiv.) and allyl methyl ether (52 μL, 16 equiv.) were added, and the mixture was stirred at room temperature for two hours. Stewart-Grubbs catalyst (CAS No. 927429-61-6, 29.7 mg, 1.5 equiv.) and allyl methyl ether (52 μL, 16 equiv.) were further added, the mixture was stirred for two hours, and the reaction solution was then concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography and then further purified by preparative HPLC to give Compound 2051 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-9-[(E)-4-methoxybut-2-enyl]-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (7.4 mg, 14%). The LC/MS data are described in Table 22.

Synthesis of Compound 2055 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[3-[4-(trifluoromethyl)phenyl]propyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone)

Compound 2055-a (490 mg, 83%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluor-en-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (1.6 g, 0.3 mmol/g, 0.48 mmol) as a raw material.

LCMS (ESI) m/z=1234 (M+H)+

Retention time: 0.93 min (analysis condition SQDFA05)

Compound 2055-b was obtained as a crude product by the same method as in Compound 2046 using Compound 2055-a (20 mg, 16 μmol) as a raw material and using 1-(trifluoromethyl)-4-vinylbenzene instead of homoallyl alcohol. The obtained compound 2055-b was dissolved in methanol (3 mL), palladium on carbon (10%) (60 mg) was added, and the mixture was then stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was concentrated, and the resulting residue was purified by reverse phase column chromatography (10 mM aqueous ammonium acetate solution/water) and then further purified by preparative HPLC to give Compound 2055 ((3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)-3-[3-[4-(trifluoromethyl)phenyl]propyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone) (1.92 mg, 8.6%). The LC/MS data are described in Table 22.

Synthesis of Compound 1411 ((1S,7S,10S,14S,17S,26S,32S)-32-[(3-iodophenyl)methyl]-7,14-diisobutyl-3,4,4,9,13,19,22,25,28-nonamethyl-17-[(S1)1-methylpropyl]-10-(piperidine-1-carbonyl-3,6,9,13,16,19,22,25,28,31,34-undecazabicyclo[24.8.6]tetracontane-2,5,8,12,15,18,21,24,27,30,33-undecone)

Compound 1411-a (56.1 mg, 31%) was obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp (O-Trt(2-Cl)resin)-pip) (0.3 g, 0.436 mmol/g, 0.131 mmol) as a raw material.

LCMS (ESI) m/z=1372 (M+H)+

Retention time: 0.97 min (analysis condition SQDFA05)

Stewart-Grubbs catalyst (CAS No. 927429-61-6, 3.6 mg, 6.3 μmol) was added to a solution of Compound 1411-a (28.7 mg, 21 μmol) in 1,2-dichloroethane (3 mL), and the mixture was stirred at a temperature between 45° C. and 50° C. for five hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography to give Compound 1411-b (23 mg, 82%).

LCMS (ESI) m/z=1344 (M+H)+

Retention time: 0.90 min (analysis condition SQDFA05)

Platinum(IV) oxide (4 mg, 18 μmol) was added to a solution of Compound 1411-b (20.2 mg, 15 μmol) in ethanol (1.5 mL). the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography to give Compound 1411 ((1S,7S,10S,14S,17S,26S,32S)-32-[(3-iodophenyl)methyl]-7,14-diisobutyl-3,4,4,9,13,19,22,25,28-nonamethyl-17-[(1S)-1-methylpropyl]-10-(piperidine-1-carbonyl)-3,6,9,13,16,19,22,25,28,31,34-undecazabicyclo[24.8.6]tetracontane-2,5,8,12,15,18,21,24,27,30,33-undecone) (14 mg, 69%). The LC/MS data are described in Table 22.

1-5. Cyclic Peptide Synthesis Using Fmoc-Protected Dipeptides as Reagents

Synthesis of Compound 2144-b (2-(N-[(2S)-4-3-chloro-4-(trifluoromethyl)phenyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoyl]anilino)acetic acid)

Thionyl chloride (4.32 mL, 59.5 mmol) and DMF (154 μL, 1,985 mmol) were added to a solution of Compound aa132 (10 g, 19.85 mmol) in DCM (397 mL), and the mixture was stirred at room temperature for four days. The solvent was evaporated from the reaction solution under reduced pressure to give an acid chloride (10.95 g), which was used as it is for the next reaction.

A solution of tert-butyl 2-anilinoacetate (1.8 g, 8.68 mmol) in DCM (25 mL) was added to a solution of the above-obtained acid chloride (4.76 g, 9.12 mmol) in DCM (65 mL) at 0° C., and the mixture was stirred at room temperature for four hours. Methanol (1.8 mL) and a saturated aqueous ammonium chloride solution were added, and the mixture was extracted with DCM. The resulting organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound 2144-a (4.27 g, 71%).

LCMS (ESI) m/z=693.2 (M+H)+

Retention time: 1.18 min (analysis condition SQDFA05)

TMSCl (2.307 mL, 18.18 mmol) was added to a solution of Compound 2144-a (4.2 g, 6.06 mmol) in TFE. (30.3 ml) at room temperature, and the mixture was stirred. After confirming by LC/MS that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (acetonitrile with 0.1% formic acid/distilled water with 0.1% formic acid) to give Compound 2144-b (2-(N-[(2S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoyl]anilino)acetic acid) (3.795 g, 98%).

LCMS (ESI) m/z=637.2 (M+H)+

Retention time: 1.01 min (analysis condition SQDFA05)

Synthesis of Compound 2146-b 2-3-chloro-N-2S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoyl]anilino)acetic acid)

Compound 2146-b (2-(3-chloro-N-[(2S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoyl]anilino)acetic acid) (3.9 g, 97%) was obtained in the same manner as in the synthesis of Compound 2144-b using tert-butyl 243-chloroanilino)acetate instead of N-phenylglycine tert-butyl 2-anilinoacetate.

LCMS (ESI) m/z=671.2 (M+H)+

Retention time: 1.05 min (analysis condition SQDFA05)

Synthesis of Compound 2147-b (2- (4-chloro-N-2S)-4-3-chloro-4- (trifluoromethylphenyl-2-(9H-fluoren 9-ylmethoxycarbonylamino)butanoyl]anilino)acetic acid)

Compound 2147-b (2-(4-chloro-N-[(2S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoyl]anilino)acetic acid) (3.21 g, 94%) was obtained in the same manner as in the synthesis of Compound 2144-b using tert-butyl 2-(4-chloroanilino)acetate instead of N-phenylglycine tert-butyl 2-anilinoacetate.

LCMS (ESI) m/z=671 (M+H)+

Retention time: 1.06 min (analysis condition SQDFA05)

Synthesis of Compound 2149-b (2-[[(2S)-4-[3-chloro-4- trifluoromethyl)phenyl]-2-9H-fluoren-9-ylmethoxycarbonylamino)butanoyl]-thiophen-3-ylamino]acetic acid)

Compound 2149-b (2-[[(2S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoyl]-thiophen-3-ylamino]acetic acid) (4.3 g, quant.) was obtained in the same manner as in the synthesis of Compound 2144-b using tert-butyl 2-(thiophen-3-ylamino)acetate instead of N-phenylglycine tert-butyl 2-anilinoacetate.

LCMS (ESI) m/z=643 (M+H)+

Retention time: 1.00 min (analysis condition SQDFA05)

Synthesis of Compounds 2143-2151

Compounds 2143-2151 were obtained by peptide synthesis according to the basic peptide synthesis method described in the present Examples, using Compound 2144-b, 2146-b, 2147-b, and 2149-b as reagents. The LC/MS data are described in Table 22.

Synthesis of Compound 2180 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-9-[2-(4-methylpiperazin-1-yl)ethyl]-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Compound 2180 was synthesized according to the following scheme.

Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (100 mg, 0.411 mmol/g, 0.0411 mmol) was used as a raw material, and by subjecting the obtained Compound 2035-a-resin to reaction with 2-(4-methylpiperazin-1-yl)ethanamine hydrochloride (CAS: 401817-30-9) (0.45 mol/L solution in N-methylpyrrolidone, 0.3 mL) in the presence of DIPEA, iodine was substituted with an amino group to give Compound 2180-a-resin. Subsequent peptide chain elongation and cyclic peptide synthesis were performed according to the basic peptide synthesis method to obtain Compound 2180 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoro-ethyl)phenyl][ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-9-[2-(4-methylpiperazin-1-yl)ethyl]-26-[(1S)-1-methylpropyl]8-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)(6.4 mg, 9%).

LCMS (ESI) m/z=1528.3 (M+H)+

Retention time: 0.82 min (analysis condition SQDFA05)

Synthesis of Compound 2181 ((3S,6S,9S,13S,16S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-23-[2-[2-(dimethylamino)ethoxy]ethyl-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31- (p-tolylmethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane)-13-carboxamide)

Compound 2181 was synthesized according to the following scheme.

Peptide synthesis according to the basic peptide synthesis method described in the present Example was performed using Compound aa011-resin ((3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp (0-Trt(2-Cl)resin)-NMe2) (100 mg, 0.456 mmol/g, 0.0456 mmol) as a raw material. Elongation with Fmoc-MeIle-OH and then with Fmoc-cLeu-OH, and deprotection of the Fmoc group were followed by condensation between the amino groups on the resin and iodoacetic acid in a mixture of a solution of iodoacetic acid (0.6 mol/L, 0.3 mL) in NMP/DMF (1/1) and a solution of diisopropylcarbodiimide (DIC) in N,N-dimethylformamide (DMF) (10% v/v, 0.36 mL) to obtain Compound 2181-a-resin in which the N-terminus of the peptide on the resin was iodinated. By further allowing 2-(2-aminoethoxy)-N,N-dimethylethanamine (CAS: 85322-63-0) (0.45 mol/L solution in N-methylpyrrolidone, 0.3 mL) to react in the presence of DIPEA, iodine was substituted with an amino group to obtain Compound 2181-b-resin. Subsequent peptide chain elongation and cyclic peptide synthesis were performed according to the basic peptide synthesis method to give Compound 2181 ((3S,6S,9S,13S,16S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-23-[2-[2-(dimethylamino)ethoxy]ethyl]-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6,16-bis[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-31-(p-tolylethyl)spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide) (1.7 mg, 2.5%).

LCMS (ESI) m/z=1485.2 (M+H)+

Retention time: 0.77 min (analysis condition SQDFA05)

Synthesis of Compound 2182 ((3S,6S,9S,13S,16S,25S,31S,34S)-23-[2-(azetidin-3-yl)ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-25-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9isobutyl: N,N,3,4,10,14,17,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide)

Compound 2182 was synthesized according to the following scheme.

Peptide synthesis according to the basic peptide synthesis method described in the present Example was performed using Compound aa011-resin ((3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp (O-Trt(2-Cl)resin)-NMe2) (100 mg, 0.456 mmol/g, 0.0456 mmol) as a raw material. Elongation with Fmoc-MeGly(cPent)-OH (aa079) and then with fmoc-cLeu-OH, and deprotection of the Fmoc group were followed by condensation between the amino groups on the resin and iodoacetic acid in a mixture of a solution of iodoacetic acid (0.6 mob/L, 0.3 mL) in NMP/DMF (1/1) and a solution of diisopropylcarbodiimide (DIC) in N,N-dimethylformamide (DMF) (10%) v/v, 0.36 mL) to obtain Compound 2182-a-resin in which the N-terminus of the, peptide on the resin was iodinated. By further allowing 1-azetidine carboxylic acid, 3-(2-aminoethyl)-phenylmethylester (CAS: 1420898-03-8) (0.45 mol/L solution in N-methylpyrrolidone, 0.3 mL) to react in the presence of DIPEA, Compound 2182-b-resin was obtained. Subsequent peptide chain elongation and cyclic peptide synthesis were performed according to the basic peptide synthesis method to give Compound 2182-c (6 mg, 2.5%).

Compound 2182-c (6 mg) was dissolved in acetic acid (1 mL), and 10 wt % palladium-activated carbon (5.0 mg) was added thereto. Upon purging the reaction vessel with hydrogen, this mixture was stirred at room temperature for one hour. With additional 10 wt % palladium-activated carbon (5.0 mg), the mixture was stirred under a hydrogen atmosphere at room temperature for another two hours. The reaction solution was filtered through celite, the solids were washed with ethanol, and then the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by fractionation HPLC to obtain Compound 2182 ((3S,6S,9S,13S,16S,25S,31S,34S)-23-[2-(azetidin-3-yl)ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-25-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide) (1.25 mg, 23)

LCMS (ESI) m/z=1441.2 (M+H)+

Retention time: 2.42 min (analysis condition SQDFA05long)

Synthesis of Compound 2183 ((3S,6S,9S,13S,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethylphenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-23-[2-[2-(methylamino)ethoxy]ethyl]-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide)

Compound 2183 was synthesized according to the following scheme.

Carbamic acid, N-[2-[2-(methylamino)ethoxy]ethyl]-,1,1-dimethylethylester (CAS: 1185772-28-4) (2.00 g, 9.16 mmol) was dissolved in a mixture of THF (3 mL) and water (2 mL), and cooled to 0° C. Aqueous sodium carbonate solution (2 mol/L, 4.58 mL, 1 equivalent) and allyl chloroformate (Alloc-Cl) (0.883 g, 0.8 equivalents) were added thereto, and then aqueous sodium carbonate solution (2 mol/L, 2.29 mL, 0.5 equivalents) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was diluted with water, and extracted twice with MTBE. The organic phases were combined, the mixture was washed with brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain Compound 2183-a (1.79 g, 64.6%).

LCMS (ESI) m/z=303.18 (M+H)+(analysis condition SQDFA05)

¹H-NMR (DMSO-D₆) δ: 6.79-6.67 (1H, m), 6.00-5.83 (1H, m), 5.31-5.22 (1H, m), 5.20-5.13 (1H,m), 4.53-4.48 (1H, m), 3.49 (2H, t, J=5.6 Hz), 3.40-3.32 (4Hm), 3.05 (21H, q, J=5.8 Hz), 2.91-2.82 (31H, m), 1.37 (9H, s).

To the above-obtained Compound 2183-a (0.9 g, 2.98 mmol) was added a hydrogen chloride, 1,4-dioxane solution (4 mol/L, 6.61 mL, 8.5 equivalents), and the mixture was allowed to react at room temperature for six hours. The reaction solution was concentrated to obtain Compound 2183-b (1.08 g).

LCMS (ESI) m/z=203.06 (M+H)+(analysis condition SQDFA05)

¹H-NMR (DMSO-D₆) δ: 7.89 (3H, bs), 5.92 (1H, ddd, J=16.2, 10.7, 5.2 Hz), 5.31-5.23 (1H, m), 5.21-5.16 (1H, m), 4.53-4.49 (2H, m), 3.62-3.51 (4H, m), 3.44-3.37 (2H, m) 3.00-2.92 (2H, m), 2.92-2.84 (3H, m).

Compound 2182-a-resin was allowed to react with carbamic acid, N-[2-(2-aminoethoxy)ethyl]-N-methyl-,2-propan-1-ylester hydrochloride (Compound 2183-b) (0.45 mol/L solution in N-methyl pyrrolidone, 0.3 mL) in the presence of DIPEA to obtain Compound 2183-c-resin. Subsequent peptide chain elongation and cyclic peptide synthesis were carried out according to the basic peptide synthesis method to obtain Compound 2183-d (6.59 mg).

Compound 2183-d (6.59 mg) was dissolved in tetrahydrofuran (1 mL) under a nitrogen atmosphere, and a solution of zinc chloride in tetrahydrofuran (0.5 M, 84 μL), tetramethyldisiloxane (30 μL), and tetrakistriphenylphosphine palladium (2.4 mg) were added. The reaction vessel was shaken at room temperature for three hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by fractionation HPLC to obtain Compound 2183 ((3S,6S,9S,13S,16S,25S,31S,34S)-25-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-31-(cyclohexylmethyl)-16-cyclopentyl-9-isobutyl-N,N,3,4,10,14,17,29,32-nonamethyl-23-[2-[2-(methylamino)ethoxy]ethyl]-6-[(1S)-1-methylpropyl]-2,5,8,11,15,18,21,24,27,30,33-undecaoxo-spiro[1,4,7,10,14,17,20,23,26,29,32-undecazabicyclo[32.2.0]hexatriacontane-19,1′-cyclopentane]-13-carboxamide) (1.18 mg, 19%).

LCMS (ESI) m/z=1475.2 (M+H)+

Retention time: 2.55 min (analysis condition SQDFA05long)

Synthesis of Compound 2184 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-(1S)-1-methylpropyl-9-(2-piperazin-1-ylethyl)-33-(piperidine-1-carbon yl-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Compound 2184 was synthesized according to the following scheme.

Carbamic, acid, N-[2-(1-piperazinyl)ethyl]-,1,1-dimethylethylester (CAS: 140447-78-5) (4.84 g, 21.11 mmol) was dissolved in a mixture of THF (3 mil-) and water (2 mL), and cooled to 0° C. Aqueous sodium carbonate solution (2 mol/L, 10.55 mL, 1 equivalent) and allyl chloroformate (Alloc-Cl) (2.035 g, 0.8 equivalents) were, added thereto, and then aqueous sodium carbonate solution (2 mol/L, 5.28 mL, 0.5 equivalents) was added, and the mixture was stirred at room temperature for three hours. The reaction solution was diluted with water, and extracted twice with MTBE. The organic phases were combined, the mixture was washed with brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain Compound 2184-a (4.46 g, 84%).

LCMS (ESI) m/z=314.19 (M+H)+

Retention time: 0.85 min (analysis condition SQDAA05)

To the above-obtained Compound 2184-a (1 g, 3.19 mmol) was added a hydrogen chloride, 1,4-dioxane, solution (4 mmol/L, 6.78 mL, 8.5 equivalents), and the mixture was allowed to react at room temperature overnight. The reaction solution was concentrated to obtain Compound 2184-b (884.1 mg).

LCMS (ESI) m/z=214.10 (M+H)+(analysis condition SQDAA05)

¹H-NMR (DMSO-D₆) δ: 8.40 (3H, bs), 5.94 (1H, ddd, J:=17.2, 10.5, 5.3 Hz), 5.31 (1H, dq, J=17.2, 1.6 Hz), 5.22 (1H, dq, J=10.5, 1.4 Hz), 4.60-4.55 (21H, m), 4.20-3.00 (12H, m).

Compound 2035-a-resin (100 mg, 0.0462 mmol) was allowed to react with Compound 2184-b (0.45 mol/L solution in N-methyl pyrrolidone, 0.3 mL) in the presence of DIPEA to obtain Compound 2184-c-resin. Subsequent peptide chain elongation and cyclic peptide synthesis were carried out according to the basic peptide synthesis method to obtain Compound 2184-d as a crude product.

To Compound 2184-d in THF (0.25 mL), phenylsilane (3.5 mg, 0.32 mmol) and tetrakistriphenylphosphine palladium (14.5 mg, 0.013 mmol) were sequentially added, and the mixture was allowed to react at room temperature for 8 hours and 30 minutes. The obtained reaction solution was purified by reverse phase H1PLC to obtain Compound 2184 ((11S,17S,26S,29S,33S,36S)-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-9-(2-piperazin-1-ylethyl)-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7.10,13,16,19,22,25,28,31,35,38-undecone) (2.6 mg, 4.2%).

LCMS (ESI) m/z=1511.7 (M−H)−

Retention time: 0.80 min (analysis condition SQDAA05)

Synthesis of Compound 2185 ((11S,17S,26S,29S,33S,36S)-9-[2-(2-aminoethoxy)ethyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Compound 2185 was synthesized according to the following scheme.

Carbamic acid, N-[2-(2-aminoethoxy)ethyl]-,1,1-dimethylethylester (CAS: 127828-22-2) (2 g, 9.79 mmol) was dissolved in a mixture of THF (3 mL) and water (2 mL), and cooled to 0° C. Aqueous sodium carbonate solution (2 mol/L, 4.9 mL, 1 equivalent) and allyl chloroformate (Alloc-Cl) (0.828 mL, 7.83 mmol, 0.8 equivalents) were added thereto at 0° C., and then aqueous sodium carbonate solution (2 mol/L, 2.448 mL, 0.5 equivalents) was added, and the mixture was stirred at room temperature. 2.5 hours later, the reaction solution was diluted with water, and extracted twice with MTBE. The organic phases were combined, the mixture was washed with brine, and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain Compound 2185-a (1.5 g, 66%).

LCMS (ESI) m/z=289.13 (M+H)+

Retention time: 0.62 min (analysis condition SQDFA05)

To the above-obtained Compound 2185-a (1.5 g, 5.2 mmol) was added a hydrogen chloride, 1,4-dioxane solution (4 mmol/L, 11.05 mL, 8.5 equivalents), and the mixture was stirred at room temperature for six hours. The solvent was evaporated from the reaction solution under reduced pressure to obtain Compound 2185-b (1.35 g).

LCMS (ESI) m/z=189.03 (M+H)+(analysis condition SQDFA05)

¹H-NMR (DMSO-D₆) δ: 7.96 (3H, bs), 7.32-7.20 (1H, m), 5.91 (1H, ddd, J=17.2, 10.6, 5.3 Hz), 5.33-5.24 (1H, m), 5.20-5.15 (1H, m), 4.53-4.44 (2H, m), 3.65-3.52 (2H, m), 3.63 (2H, t, J=5.7 Hz), 3.19 (2H, q, J=5.7 Hz), 3.03-2.90 (2H, m).

Compound 2035-a-resin (100 mg, 0.0462 mmol) was allowed to react with Compound 2185-b (0.45 mol/L solution in N-methyl pyrrolidone, 0.3 mL) in the presence of DIPEA to obtain Compound 2185-c-resin. Subsequent peptide chain elongation and cyclic peptide synthesis were carried out according to the basic peptide synthesis method to obtain Compound 2185-d (6.66 mg).

Compound 2185-d (6.66 mg) was dissolved in tetrahydrofuran (1 mL) under a nitrogen atmosphere, and a solution of zinc chloride in tetrahydrofuran (0.5 mol/L, 84 μL), tetramethyldisiloxane (30 μL), and tetrakistriphenylphosphine palladium (2.4 mg) were added thereto, and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by fractionation HPLC to obtain Compound 2185 ((11S,17S,26S,29S,33S,36S)-9-[2-(2-aminoethoxy)ethyl]-11-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (1.51 mg, 24%).

LCMS (ESI) m/z=1489.2 (M+H)+

Retention time: 2.73 min (analysis condition SQDFA05long)

Synthesis of Compound 2186 ((11S,17S,26S,29S,33S,36S)-9-(4-aminobut 1-11-2-3-chloro-4-(trifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone)

Compound 2186 was synthesized according to the following scheme.

The target Compound 2186-a (1.282 g, 0.893 mmol, 52%) was obtained using Compound aa006-resin ((3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin, Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) (0.411 mmol/g, 4.2 g, 1.726 mmol) as a starting material, and using Fmoc-MeChg-OH, Fmoc-cLeu-OH, Fmoc-AllylGly-OH, Fmoc-Hph(4-CF3-3-Cl)—OH, Fmoc-MeGly-OH, Fmoc-MeCha-OH, Fmoc-MeGly-OH, Fmoc-MeGly-OH, Fmoc-Ile-OH, and Fmoc-MeLeu-OH by performing the above-described peptide elongation reaction by the Fmoc method, cleavage of the elongated peptide from the resin, cyclization of the cleaved peptide (using (1-cyano-2-ethoxy-2-oxoethbylideneam-inooxy)dimethylamino-m-iopholino-carbeiutmhexafluorophosphate (COM U) as the cyclizing agent), and purification of the cyclic peptide (reverse phase medium pressure column chromatography, C18, methanol/10 mM aqueous ammonium acetate solution)).

LCMS (ESI) m/z=1440.13 (M−H)−

Retention time: 0.88 min (analysis condition SQDAA50

Compound 2186-a (50.0 mg, 0.35 mmol) was dissolved in dichloroethane (0.659 mL), Stewart-Grubbs catalyst (29.7 mg, 1.5 equivalents) and N-allylphthalimide (51.9 mg, 8 equivalents.) were added thereto, and the mixture was stirred at room temperature for two hours. Stewart-Grubbs catalyst (30 mg, 1.5 equivalents) and N-allylphthalimide (104 mg, 16 equivalents) were further added and the mixture was stirred for three hours, then the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase medium pressure column chromatography (acetonitrile with 0.1% formic acid/water with 0.1% formic acid) to obtain Compound 2186-b (2.0 mg, 3.6%).

Compound 2186-b (2.0 mg, 1.249 μmol) was dissolved in ethanol (1.0 mL), and platinum (IV) oxide (3.9 mg, 14 equivalents) was added thereto. The reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 30 min. The reaction solution was filtered through celite, solids were washed with ethanol, and then the filtrate was concentrated under reduced pressure to obtain Compound 2186-c. The next reaction was carried out without further purification. The obtained Compound 2186-c was dissolved in ethanol (1.0 mL), hydrazine-hydrate (0.03 mL) was added, and the mixture was stirred at 80° C. for 24 hours. The solvent was evaporated from the reaction solution under reduced pressure to obtain Compound 2186 as a crude product. The crude product was mixed with the crude product of Compound 2186 obtained using Compound 2186-a (0.7 mg) by performing olefin metathesis reaction, reduction by platinum oxide, and further treatment with hydrazine-hydrate similarly, and reverse phase HPLC purification was performed to obtain Compound 2186 ((11S,17S,26S,29S,33S,36S)-9-(4-aminobutyl)-11-[2-[3-chloro-4-(triifluoromethyl)phenyl]ethyl]-36-cyclohexyl-17-(cyclohexylmethyl)-29-isobutyl-15,18,21,24,30,34,37-heptamethyl-26-[(1S)-1-methylpropyl]-33-(piperidine-1-carbonyl)-6,9,12,15,18,21,24,27,30,34,37-undecazaspiro[4.33]octatriacontane-7,10,13,16,19,22,25,28,31,35,38-undecone) (0.48 mg, 1%).

LCMS (ESI) m/z=1473.3 (M+H)+

Retention time: 2.77 min (analysis condition SQDFA05long)

TABLE 22
			MS Found
Compound No.	Analytical condition	Retention time (min)	(m/z)	MS polarity
1	SSC-FA-03	2.155	1480.1	(M − H)−
2	SSC-TFA-07	1.575	1318.8	(M + H)+
3	SSC-FA-03	1.948	1520.8	(M − H)−
4	SSC-FA-03	1.788	1383.9	(M − H)−
5	SSC-A-AF-01	7.456	1436.0	(M + H)+
6	SSC-AF-00	2.247	1584.9	(M − H)−
7	SSC-FA-03	1.823	1414.0	(M − H)−
8	SSC-AF-00	2.225	1341.0	(M − H)−
9	SSC-FA-03	1.688	1414.0	(M − H)−
10	SSC-FA-03	2.165	1572.8	(M − H)−
11	SSC-A-FA-01	5.059	1425.7	(M − H)−
12	SSC-TFA-07	1.416	1401.7	(M + H)+
13	SSC-AF-00	2.160	1470.0	(M − H)−
14	SSC-TFA-07	1.415	1288.7	(M + H)+
15	SSC-TFA-07	1.408	1441.7	(M + H)+
16	SSC-FA-03	1.708	1404.0	(M − H)−
17	SSC-FA-03	1.827	1427.8	(M − H)−
18	SSC-TFA-07	1.337	1238.7	(M + H)+
19	SSC-AF-00	2.084	1224.6	(M − H)−
20	SSC-FA-03	1.748	1429.9	(M − H)−
21	SSC-TFA-07	1.296	1379.6	(M + H)+
22	SSC-TFA-07	1.577	1332.7	(M + H)+
23	SSC-FA-03	2.037	1440.0	(M − H)−
24	SSC-AF-00	2.112	1373.9	(M − H)−
25	SSC-AA-20	2.107	1330.8	(M − H)−
26	SSC-A-FA-01	6.444	1574.7	(M + H)+
27	SSC-AF-00	2.209	1481.9	(M − H)−
28	SSC-TFA-07	1.295	1210.8	(M + H)+
29	SSC-AA-20	2.103	1389.7	(M − H)−
30	SSC-TFA-07	1.599	1441.8	(M + H)+
31	SSC-TFA-07	1.480	1258.9	(M + H)+
32	SSC-AF-00	2.060	1367.9	(M − H)−
33	SSC-A-FA-02	6.625	1412.7	(M + H)+
34	SSC-A-FA-02	6.601	1454.6	(M − H)−
35	SSC-AF-00	2.153	1411.9	(M − H)−
36	SSC-FA-03	1.727	1504.8	(M − H)−
37	SSC-TFA-07	1.615	1453.8	(M + H)+
38	SSC-TFA-07	1.627	1356.7	(M + H)+
39	SSC-A-FA-01	6.352	1434.6	(M + H)+
40	SSC-AF-00	2.156	1441.8	(M − H)−
41	SSC-A-AF-01	7.864	1536.8	(M − H)−
42	SSC-FA-03	1.881	1340.5	(M − H)−
43	SSC-FA-03	2.056	1494.0	(M − H)−
44	SSC-FA-03	1.749	1418.0	(M − H)−
45	SSC-FA-03	1.953	1453.9	(M − H)−
46	SSC-TFA-07	1.403	1372.0	(M + H)+
47	SSC-AF-00	2.053	1433.9	(M − H)−
48	SSC-A-AF-02	8.379	1475.8	(M − H)−
49	SSC-AF-00	2.168	1339.0	(M − H)−
50	SSC-TFA-07	1.404	1405.7	(M + H)+
51	SSC-TFA-07	1.475	1322.7	(M + H)+
52	SSC-AF-00	2.165	1490.0	(M − H)−
53	SSC-TFA-07	1.335	1444.9	(M + H)+
54	SSC-A-FA-01	5.477	1503.7	(M − H)−
55	SSC-A-AF-01	7.507	1448.1	(M − H)−
56	SSC-AF-00	2.199	1411.9	(M − H)−
57	SSC-TFA-07	1.532	1320.7	(M + H)+
58	SSC-AF-00	2.221	1452.0	(M − H)−
59	SSC-TFA-07	1.545	1316.7	(M + H)+
60	SSC-AF-00	2.204	1426.0	(M − H)−
61	SSC-TFA-07	1.528	1292.7	(M + H)+
62	SSC-A-AF-02	7.791	1414.6	(M + H)+
63	SSC-AF-00	2.223	1504.8	(M − H)−
64	SSC-AF-00	2.340	1383.0	(M − H)−
65	SSC-TFA-07	1.439	1366.5	(M + H)+
66	SSC-A-FA-02	6.275	1438.7	(M + H)+
67	SSC-FA-03	1.788	1381.8	(M − H)−
68	SSC-AF-00	2.223	1437.8	(M − H)−
69	SSC-AF-00	2.165	1421.9	(M − H)−
70	SSC-TFA-07	1.588	1445.7	(M + H)+
71	SSC-AF-00	2.083	1332.4	(M − H)−
72	SSC-FA-03	1.877	1363.7	(M − H)−
73	SSC-FA-03	1.884	1485.7	(M − H)−
74	SSC-A-FA-02	6.389	1376.8	(M + H)+
75	SSC-TFA-07	1.407	1262.6	(M + H)+
76	SSC-TFA-07	1.524	1316.7	(M + H)+
77	SSC-AF-00	2.164	1284.7	(M − H)−
78	SSC-FA-03	1.844	1435.9	(M − H)−
79	SSC-FA-03	1.909	1314.8	(M − H)−
80	SSC-AF-00	2.153	1427.9	(M − H)−
81	SSC-TFA-07	1.545	1318.7	(M + H)+
82	SSC-FA-03	1.899	1328.4	(M + H)+
83	SSC-TFA-07	1.453	1320.8	(M + H)+
84	SSC-AF-00	2.244	1451.8	(M − H)−
85	SSC-A-FA-02	6.600	1444.6	(M + H)+
86	SSC-AF-00	2.189	1514.1	(M − H)−
87	SSC-AF-00	2.276	1480.0	(M − H)−
88	SSC-TFA-07	1.463	1290.7	(M + H)+
89	SSC-AF-00	2.180	1581.9	(M − H)−
90	SSC-AF-00	2.292	1517.8	(M + H)+
91	SSC-FA-03	1.785	1413.9	(M − H)−
92	SSC-AF-00	2.203	1490.0	(M − H)−
93	SSC-AF-00	2.033	1234.7	(M − H)−
94	SSC-FA-03	1.928	1475.8	(M − H)−
95	SSC-FA-03	2.059	1493.8	(M − H)−
96	SSC-TFA-07	1.424	1389.8	(M + H)+
97	SSC-FA-03	1.833	1480.8	(M − H)−
98	SSC-FA-03	1.808	1272.9	(M − H)−
99	SSC-A-FA-02	6.297	1434.7	(M − H)−
100	SSC-TFA-07	1.465	1411.6	(M + H)+
101	SSC-TFA-07	1.407	1274.6	(M + H)+
102	SSC-AF-00	2.140	1388.0	(M − H)−
103	SSC-FA-03	1.939	1441.7	(M − H)−
104	SSC-A-FA-01	5.293	1532.7	(M − H)−
105	SSC-A-AF-01	8.051	1590.9	(M + H)+
106	SSC-TFA-07	1.577	1427.7	(M + H)+
107	SSC-A-FA-02	6.531	1366.6	(M + H)+
108	SSC-TFA-07	1.476	1367.7	(M + H)+
109	SSC-FA-03	1.756	1232.5	(M − H)−
110	SSC-FA-03	1.919	1458.5	(M − H)−
111	SSC-FA-03	2.101	1587.8	(M − H)−
112	SSC-TFA-07	1.459	1345.7	(M + H)+
113	SSC-TFA-07	1.616	1356.7	(M + H)+
114	SSC-AF-00	2.140	1274.7	(M − H)−
115	SSC-FA-03	1.868	1383.7	(M − H)−
116	SSC-TFA-07	1.589	1318.7	(M + H)+
117	SSC-FA-03	1.853	1320.9	(M − H)−
118	SSC-FA-03	2.035	1457.6	(M − H)−
119	SSC-TFA-07	1.549	1310.8	(M + H)+
120	SSC-FA-03	1.892	1479.7	(M − H)−
121	SSC-AF-00	2.120	1316.6	(M − H)−
122	SSC-TFA-07	1.547	1316.7	(M + H)+
123	SSC-TFA-07	1.645	1332.7	(M + H)+
124	SSC-TFA-07	1.589	1364.6	(M + H)+
125	SSC-AF-00	2.192	1513.9	(M − H)−
126	SSC-FA-03	1.788	1399.9	(M − H)−
127	SSC-AF-00	2.141	1409.8	(M − H)−
128	SSC-A-FA-01	5.245	1409.8	(M − H)−
129	SSC-A-FA-01	5.524	1483.0	(M − H)−
130	SSC-A-AF-01	7.763	1496.7	(M + H)+
131	SSC-TFA-07	1.492	1387.7	(M + H)+
132	SSC-A-FA-02	6.548	1464.6	(M + H)+
133	SSC-AF-00	2.127	1274.7	(M + H)+
134	SSC-FA-03	1.717	1367.6	(M − H)−
135	SSC-AF-00	2.163	1383.9	(M − H)−
136	SSC-TFA-07	1.515	1425.6	(M + H)+
137	SSC-FA-03	2.113	1454.0	(M − H)−
138	SSC-A-AF-02	8.124	1454.6	(M + H)+
139	SSC-TFA-07	1.481	1397.8	(M + H)+
140	SSC-AF-00	2.113	1441.8	(M − H)−
141	SSC-FA-03	1.843	1441.8	(M − H)−
142	SSC-TFA-07	1.533	1314.8	(M + H)+
143	SSC-FA-03	2.095	1587.9	(M − H)−
144	SSC-A-AF-01	7.877	1437.8	(M − H)−
145	SSC-FA-03	1.904	1475.7	(M − H)−
146	SSC-FA-03	1.795	1310.4	(M − H)−
147	SSC-AF-00	2.289	1530.0	(M + H)+
148	SSC-FA-03	1.949	1427.9	(M − H)−
149	SSC-TFA-07	1.455	1278.7	(M + H)+
150	SSC-FA-03	1.873	1412.0	(M − H)−
151	SSC-FA-03	1.889	1306.7	(M − H)−
152	SSC-AF-00	2.093	1403.8	(M − H)−
153	SSC-TFA-07	1.349	1226.7	(M + H)+
154	SSC-A-FA-01	4.451	1470.6	(M + H)+
155	SSC-A-FA-01	5.567	1423.8	(M − H)−
156	SSC-AF-00	2.148	1373.9	(M − H)−
157	SSC-AF-00	2.175	1424.0	(M − H)−
158	SSC-TFA-07	1.493	1360.6	(M + H)+
159	SSC-FA-03	1.847	1401.9	(M − H)−
160	SSC-AF-00	2.233	1429.5	(M + H)+
161	SSC-AF-00	2.171	1555.7	(M − H)−
162	SSC-AF-00	2.091	1463.9	(M − H)−
163	SSC-A-FA-01	5.444	1455.8	(M − H)−
164	SSC-AF-00	2.193	1424.0	(M − H)−
165	SSC-TFA-07	1.468	1320.8	(M + H)+
166	SSC-AF-00	2.211	1462.0	(M − H)−
167	SSC-TFA-07	1.425	1319.8	(M + H)+
168	SSC-FA-03	2.059	1537.6	(M − H)−
169	SSC-AF-00	2.184	1503.9	(M − H)−
170	SSC-AA-20	2.055	1244.6	(M − H)−
171	SSC-FA-03	1.953	1457.9	(M − H)−
172	SSC-FA-03	1.933	1437.9	(M − H)−
173	SSC-AF-00	2.108	1555.9	(M − H)−
174	SSC-FA-03	1.755	1475.9	(M − H)−
175	SSC-AF-00	2.077	1389.6	(M + H)+
176	SSC-AF-00	2.109	1455.8	(M − H)−
177	SSC-AF-00	2.179	1466.8	(M − H)−
178	SSC-TFA-07	1.497	1304.8	(M + H)+
179	SSC-FA-03	2.097	1509.9	(M − H)−
180	SSC-TFA-07	1.488	1498.8	(M + H)+
181	SSC-TFA-07	1.453	1314.7	(M + H)+
182	SSC-AF-00	2.161	1423.8	(M + H)+
183	SSC-TFA-07	1.489	1302.7	(M + H)+
184	SSC-TFA-07	1.269	1361.8	(M + H)+
185	SSC-TFA-07	1.525	1316.7	(M + H)+
186	SSC-FA-03	1.887	1328.4	(M + H)+
187	SSC-FA-03	1.911	1385.9	(M − H)−
188	SSC-FA-03	1.817	1497.8	(M − H)−
189	SSC-TFA-07	1.544	1354.7	(M + H)+
190	SSC-A-AF-01	7.563	1466.6	(M − H)−
191	SSC-AF-00	2.135	1386.0	(M − H)−
192	SSC-FA_03	1.991	1435.9	(M − H)−
193	SSC-A-FA-01	5.300	1367.9	(M − H)−
194	SSC-FA-03	1.837	1312.5	(M + H)+
195	SSC-FA-03	1.811	1383.9	(M − H)−
196	SSC-TFA-07	1.380	1262.7	(M + H)+
197	SSC-TFA-07	1.469	1399.8	(M + H)+
198	SSC-A-FA-02	6.440	1368.7	(M + H)+
199	SSC-TFA-07	1.440	1419.9	(M + H)+
200	SSC-FA-03	2.148	1467.6	(M − H)−
201	SSC-AF-00	2.105	1410.0	(M − H)−
202	SSC-AF-00	2.165	1367.7	(M − H)−
203	SSC-A-FA-02	6.648	1456.6	(M + H)+
204	SSC-TFA-07	1.532	1316.7	(M + H)+
205	SSC-FA-03	2.016	1413.9	(M − H)−
206	SSC-FA-03	1.836	1298.5	(M − H)−
207	SSC-TFA-07	1.403	1330.6	(M + H)+
208	SSC-AF-00	2.156	1469.7	(M − H)−
209	SSC-A-AF-01	7.703	1489.9	(M + H)+
210	SSC-TFA-07	1.543	1304.7	(M + H)+
211	SSC-TFA-07	1.445	1286.7	(M + H)+
212	SSC-TFA-07	1.432	1276.7	(M + H)+
213	SSC-TFA-07	1.604	1318.7	(M + H)+
214	SSC-TFA-07	1.453	1322.9	(M + H)+
215	SSC-A-FA-01	5.729	1410.0	(M − H)−
216	SSC-FA-03	1.985	1505.8	(M − H)−
217	SSC-TFA-07	1.632	1334.7	(M + H)+
218	SSC-FA-03	1.879	1494.9	(M − H)−
219	SSC-AF-00	2.105	1232.8	(M + H)+
220	SSC-TFA-07	1.487	1387.7	(M + H)+
221	SSC-TFA-07	1.505	1399.7	(M + H)+
222	SSC-A-FA-01	6.188	1548.7	(M + H)+
223	SSC-TFA-07	1.479	1292.7	(M + H)+
224	SSC-AA-20	2.103	1389.7	(M − H)−
225	SSC-AF-00	2.200	1438.0	(M − H)−
226	SSC-FA-03	2.073	1467.8	(M − H)−
227	SSC-TFA-07	1.397	1282.7	(M + H)+
228	SSC-AF-00	2.136	1427.8	(M − H)−
229	SSC-TFA-07	1.424	1413.7	(M + H)+
230	SSC-TFA-07	1.499	1302.6	(M + H)+
231	SSC-TFA-07	1.524	1302.8	(M + H)+
232	SSC-AF-00	2.144	1407.9	(M − H)−
233	SSC-TFA-07	1.353	1492.8	(M + H)+
234	SSC-AF-00	2.144	1937.6	(M − H)−
235	SSC-FA-03	1.708	1435.7	(M − H)−
236	SSC-AF-00	2.132	1400.0	(M − H)−
237	SSC-AF-00	2.264	1366.9	(M − H)−
238	SSC-TFA-07	1.399	1323.7	(M + H)+
239	SSC-FA-03	1.887	1527.8	(M − H)−
240	SSC-AF-00	2.152	1508.8	(M − H)−
241	SSC-A-FA-02	6.756	1364.7	(M − H)−
242	SSC-TFA-07	1.472	1290.7	(M + H)+
243	SSC-FA-03	1.543	1472.8	(M − H)−
244	SSC-FA-03	1.719	1360.7	(M − H)−
245	SSC-AF-00	2.096	1513.9	(M − H)−
246	SSC-FA-03	1.875	1383.8	(M − H)−
247	SSC-FA-03	1.857	1485.8	(M − H)−
248	SSC-TFA-07	1.439	1288.6	(M + H)+
249	SSC-FA-03	2.119	1465.9	(M − H)−
250	SSC-FA-03	2.155	1485.9	(M − H)−
251	SSC-AF-00	2.177	1523.0	(M + H)+
252	SSC-TFA-07	1.353	1362.7	(M + H)+
253	SSC-AF-00	2.163	1467.5	(M − H)−
254	SSC-AF-00	2.101	1441.9	(M − H)−
255	SSC-AF-00	2.345	1543.8	(M + H)+
256	SSC-FA-03	1.793	1399.7	(M + H)+
257	SSC-TFA-07	1.484	1334.8	(M + H)+
258	SSC-AF-00	2.124	1296.7	(M − H)−
259	SSC-AF-00	2.228	1533.9	(M − H)−
260	SSC-TFA-07	1.472	1346.8	(M + H )+
261	SSC-TFA-07	1.489	1302.8	(M + H)+
262	SSC-TFA-07	1.489	1274.8	(M + H)+
263	SSC-A-AF-01	7.788	1453.9	(M − H)−
264	SSC-TFA-07	1.405	1276.7	(M + H)+
265	SSC-TFA-07	1.405	1299.8	(M + H)+
266	SSC-TFA-07	1.377	1343.7	(M + H)+
267	SSC-FA-03	1.991	1299.0	(M − H)−
268	SSC-TFA-07	1.423	1276.7	(M + H)+
269	SSC-A-FA-02	6.321	1430.6	(M + H)+
270	SSC-AF-00	2.216	1449.8	(M − H)−
271	SSC-TFA-07	1.441	1322.8	(M + H)+
272	SSC-FA-03	1.839	1501.8	(M − H)−
273	SSC-TFA-07	1.471	1314.7	(M + H)+
274	SSC-AF-00	2.152	1399.5	(M − H)−
275	SSC-TFA-07	1.447	1278.7	(M + H)+
276	SSC-AF-00	2.097	1503.8	(M − H)−
277	SSC-FA-03	2.051	1413.8	(M − H)−
278	SSC-FA-03	1.804	1408.7	(M − H)−
279	SSC-A-FA-01	5.560	1434.0	(M − H)−
280	SSC-AF-00	2.143	1409.6	(M − H)−
281	SSC-TFA-07	1.575	1427.6	(M + H)+
282	SSC-FA-03	2.008	1456.0	(M − H)−
283	SSC-AF-00	2.156	1489.9	(M − H)−
284	SSC-AF-00	2.107	1395.9	(M − H)−
285	SSC-TFA-07	1.588	1330.6	(M + H)+
286	SSC-TFA-07	1.443	1286.9	(M + H)+
287	SSC-TFA-07	1.571	1401.7	(M + H)+
288	SSC-AF-00	2.097	1395.9	(M − H)−
289	SSC-FA-03	1.705	1372.0	(M − H)−
290	SSC-TFA-07	1.503	1302.6	(M + H)+
291	SSC-FA-03	1.815	1302.5	(M + H)+
292	SSC-FA-03	1.871	1329.6	(M − H)−
293	SSC-AF-00	2.171	1409.9	(M − H)−
294	SSC-AF-00	2.229	1428.0	(M − H)−
295	SSC-TFA-07	1.471	1443.7	(M + H)+
296	SSC-A-FA-02	7.016	1474.9	(M − H)−
297	SSC-AF-00	2.301	1493.7	(M − H)−
298	SSC-TFA-07	1.512	1385.8	(M + H)+
299	SSC-TFA-07	1.471	1320.8	(M + H)+
300	SSC-FA-03	1.885	1444.3	(M − H)−
301	SSC-A-FA-01	6.227	1450.6	(M + H)+
302	SSC-AF-00	2.095	1425.9	(M − H)−
303	SSC-A-FA-01	5.293	1419.8	(M − H)−
304	SSC-AF-00	2.164	1481.7	(M − H)−
305	SSC-TFA-07	1.571	1318.8	(M + H)+
306	SSC-TFA-07	1.373	1461.7	(M + H)+
307	SSC-AF-00	2.171	1397.5	(M − H)−
308	SSC-A-FA-01	5.464	1407.8	(M − H)−
309	SSC-FA-03	1.932	1427.5	(M − H)−
310	SSC-AF-00	2.147	1342.4	(M − H)−
311	SSC-TFA-07	1.592	1415.8	(M + H)+
312	SSC-TFA-07	1.445	1375.7	(M + H)+
313	SSC-FA-03	1.773	1381.6	(M − H)−
314	SSC-FA-03	1.821	1371.9	(M − H)−
315	SSC-TFA-07	1.449	1302.9	(M + H)+
316	SSC-AF-00	2.040	1359.9	(M − H)−
317	SSC-FA-03	1.871	1415.5	(M − H)−
318	SSC-TFA-07	1.479	1425.7	(M + H)+
319	SSC-A-FA-01	6.677	1468.6	(M + H)+
320	SSC-AF-00	2.177	1478.0	(M − H)−
321	SSC-TFA-07	1.633	1441.7	(M + H)+
322	SSC-TFA-07	1.444	1350.8	(M + H)+
323	SSC-TFA-07	1.339	1260.7	(M + H)+
324	SSC-TFA-07	1.636	1407.7	(M + H)+
325	SSC-TFA-07	1.404	1359.7	(M + H)+
326	SSC-FA-03	1.867	1437.7	(M + H)+
327	SSC-AF-00	2.136	1409.9	(M − H)−
328	SSC-AF-00	2.139	1439.8	(M − H)−
329	SSC-TFA-07	1.587	1348.7	(M + H)+
330	SSC-FA-03	1.999	1481.4	(M − H)−
331	SSC-A-FA-01	4.375	1452.6	(M − H)−
332	SSC-TFA-07	1.465	1320.8	(M + H)+
333	SSC-AF-00	2.171	1300.5	(M − H)−
334	SSC-FA-03	1.825	1396.0	(M − H)−
335	SSC-FA-03	1.884	1481.9	(M − H)−
336	SSC-AF-00	2.215	1516.0	(M − H)−
337	SSC-TFA-07	1.457	1288.7	(M + H)+
338	SSC-AF-00	2.279	1545.1	(M − H)−
339	SSC-FA-03	1.848	1431.8	(M − H)−
340	SSC-FA-03	2.008	1486.0	(M − H)−
341	SSC-FA-03	1.747	1274.9	(M − H)−
342	SSC-A-AF-01	7.544	1407.8	(M − H)−
343	SSC-A-FA-01	5.341	1440.0	(M − H)−
344	SSC-A-FA-01	6.165	1464.6	(M + H)+
345	SSC-A-FA-02	7.005	1466.7	(M − H)−
346	SSC-FA-03	1.988	1435.8	(M − H)−
347	SSC-TFA-07	1.476	1316.6	(M + H)+
348	SSC-A-AF-01	7.915	1430.6	(M − H)−
349	SSC-AF-00	2.224	1424.0	(M − H)−
350	SSC-AF-00	2.160	1437.8	(M − H)−
351	SSC-TFA-07	1.415	1308.6	(M + H)+
352	SSC-FA-03	1.889	1427.7	(M − H)−
353	SSC-FA-03	1.852	1473.9	(M − H)−
354	SSC-FA-03	1.845	1322.9	(M − H)−
355	SSC-AF-00	2.135	1470.8	(M − H)−
356	SSC-AF-00	2.203	1425.8	(M − H)−
357	SSC-TFA-07	1.399	1323.6	(M + H)+
358	SSC-AF-00	2.173	1423.8	(M − H)−
359	SSC-A-FA-02	6.141	1358.7	(M − H)−
360	SSC-TFA-07	1.421	1359.6	(M + H)+
361	SSC-FA-03	1.651	1204.8	(M − H)−
362	SSC-A-FA-01	6.135	1452.6	(M + H)+
363	SSC-A-AF-01	7.219	1405.9	(M + H)+
364	SSC-TFA-07	1.505	1306.8	(M + H)+
365	SSC-A-AF-02	8.011	1464.7	(M + H)+
366	SSC-FA-03	1.927	1331.0	(M − H)−
367	SSC-FA-03	1.817	1453.5	(M − H)−
368	SSC-FA-03	1.896	1411.6	(M − H)−
369	SSC-FA-03	1.691	1258.5	(M − H)−
370	SSC-FA-03	1.915	1514.0	(M − H)−
371	SSC-A-FA-01	6.021	1420.6	(M + H)+
372	SSC-TFA-07	1.364	1391.9	(M + H)+
373	SSC-TFA-07	1.281	1348.8	(M + H)+
374	SSC-A-FA-02	6.708	1464.6	(M + H)+
375	SSC-A-AF-02	7.887	1374.6	(M − H)−
376	SSC-AF-00	2.172	1523.8	(M − H)−
377	SSC-A-FA-02	6.900	1468.7	(M − H)−
378	SSC-FA-03	1.827	1395.9	(M − H)−
379	SSC-AF-00	2.132	1516.9	(M − H)−
380	SSC-AF-00	2.172	1371.8	(M − H)−
381	SSC-AF-00	2.092	1413.9	(M − H)−
382	SSC-AF-00	2.049	1341.6	(M − H)−
383	SSC-TFA-07	1.499	1312.7	(M + H)+
384	SSC-AF-00	2.155	1482.8	(M − H)−
385	SSC-FA-03	1.955	1489.8	(M − H)−
386	SSC-FA-03	1.863	1310.6	(M − H)−
387	SSC-FA-03	1.912	1481.9	(M − H)−
388	SSC-AF-00	2.147	1463.9	(M − H)−
389	SSC-FA-03	1.560	1520.9	(M − H)−
390	SSC-FA-03	1.808	1438.1	(M − H)−
391	SSC-AF-00	2.205	1438.0	(M − H)−
392	SSC-AF-00	2.283	1482.0	(M − H)−
393	SSC-AF-00	2.169	1411.9	(M − H)−
394	SSC-AF-00	2.156	1414.0	(M + H)+
395	SSC-TFA-07	1.523	1304.7	(M + H)+
396	SSC-FA-03	1.647	1230.4	(M − H)−
397	SSC-AF-00	2.140	1427.9	(M − H)−
398	SSC-AA-20	2.108	1349.8	(M − H )−
399	SSC-TFA-07	1.568	1439.7	(M + H)+
400	SSC-A-FA-01	5.539	1433.8	(M − H)−
401	SSC-A-AF-02	8.128	1462.6	(M + H)+
402	SSC-TFA-07	1.484	1288.7	(M + H)+
403	SSC-AF-00	2.113	1443.8	(M − H)−
404	SSC-FA-03	1.856	1335.0	(M − H)−
405	SSC-TFA-07	1.563	1318.7	(M + H)+
406	SSC-TFA-07	1.393	1322.8	(M + H)+
407	SSC-TFA-07	1.401	1318.8	(M + H)+
408	SSC-FA-03	1.739	1428.0	(M − H)−
409	SSC-AF-00	2.196	1424.1	(M − H)−
410	SSC-FA-03	1.805	1447.9	(M − H)−
411	SSC-AF-00	2.215	1437.9	(M − H)−
412	SSC-AF-00	2.128	1272.9	(M − H)−
413	SSC-FA-03	1.704	1218.8	(M − H)−
414	SSC-TFA-07	1.475	1270.8	(M + H)+
415	SSC-FA-03	1.919	1427.9	(M − H)−
416	SSC-AF-00	2.208	1340.4	(M − H)−
417	SSC-AF-00	2.160	1385.9	(M − H)−
418	SSC-TFA-07	1.449	1344.6	(M + H)+
419	SSC-FA-03	1.777	1475.8	(M − H)−
420	SSC-AF-00	2.168	1328.5	(M − H)−
421	SSC-TFA-07	1.497	1399.8	(M + H)+
422	SSC-AF-00	2.120	1541.8	(M − H)−
423	SSC-TFA-07	1.504	1457.7	(M + H)+
424	SSC-A-FA-02	6.431	1379.1	(M − H)−
425	SSC-FA-03	2.051	1489.8	(M − H)−
426	SSC-FA-03	1.853	1415.7	(M − H)−
427	SSC-FA-03	1.811	1387.9	(M − H)−
428	SSC-AF-00	2.296	1516.1	(M − H)−
429	SSC-AF-00	2.112	1260.5	(M + H)+
430	SSC-A-FA-02	6.889	1476.6	(M − H)−
431	SSC-AF-00	2.217	1383.7	(M − H)−
432	SSC-A-AF-02	8.151	1422.8	(M − H )−
433	SSC-AF-00	2.205	1489.0	(M − H)−
434	SSC-FA-03	1.833	1425.9	(M − H)−
435	SSC-TFA-07	1.851	1514.0	(M + H)+
436	SSC-AF-00	2.161	1300.8	(M − H)−
437	SSC-FA-03	1.891	1411.9	(M − H)−
438	SSC-TFA-07	1.529	1401.8	(M + H)+
439	SSC-TFA-07	1.525	1304.7	(M + H)+
440	SSC-FA-03	1.947	1422.7	(M − H)−
441	SSC-FA-03	1.827	1478.5	(M − H)−
442	SSC-AF-00	2.140	1481.9	(M − H)−
443	SSC-FA-03	2.117	1442.0	(M + H)+
444	SSC-AF-00	2.141	1494.8	(M − H)−
445	SSC-FA-03	1.740	1445.4	(M + H)+
446	SSC-AF-00	2.113	1383.9	(M − H)−
447	SSC-AF-00	2.152	1397.6	(M + H)+
448	SSC-TFA-07	1.373	1349.7	(M + H)+
449	SSC-FA-03	2.101	1490.0	(M − H)−
450	SSC-AF-00	2.127	1413.5	(M − H)−
451	SSC-AF-00	2.171	1411.9	(M − H)−
452	SSC-FA-03	1.911	1423.9	(M − H)−
453	SSC-AF-00	2.163	1411.9	(M − H)−
454	SSC-FA-03	1.801	1288.7	(M − H)−
455	SSC-TFA-07	1.540	1328.7	(M + H)+
456	SSC-TFA-07	1.485	1316.7	(M + H)+
457	SSC-TFA-07	1.401	1415.6	(M + H)+
458	SSC-AF-00	2.079	1350.0	(M − H)−
459	SSC-FA-03	1.852	1497.8	(M − H)−
460	SSC-FA-03	1.583	1476.9	(M − H)−
461	SSC-AF-00	2.160	1452.0	(M − H)−
462	SSC-A-AF-02	7.828	1428.6	(M + H)+
463	SSC-FA-03	1.939	1509.0	(M − H)−
464	SSC-AF-00	2.159	1340.7	(M − H)−
465	SSC-TFA-07	1.485	1314.6	(M + H)+
466	SSC-A-FA-02	6.693	1478.6	(M + H)+
467	SSC-TFA-07	1.298	1357.6	(M + H)+
468	SSC-TFA-07	1.452	1373.7	(M + H)+
469	SSC-FA-03	1.913	1457.6	(M − H)−
470	SSC-AF-00	2.191	1430.0	(M − H)−
471	SSC-TFA-07	1.477	1354.7	(M + H)+
472	SSC-FA-03	2.063	1488.1	(M − H)−
473	SSC-AA-20	2.161	1419.7	(M − H)−
474	SSC-TFA-07	1.496	1314.7	(M + H)+
475	SSC-A-FA-02	6.823	1416.7	(M + H)+
476	SSC-TFA-07	1.559	1427.8	(M + H)+
477	SSC-FA-03	1.681	1532.8	(M + H)+
478	SSC-FA-03	2.093	1468.1	(M − H)−
479	SSC-FA-03	2.249	1061.0	(M + H)+
480	SSC-AF-00	2.193	1517.1	(M − H)−
481	SSC-FA-03	1.877	1346.9	(M − H)−
482	SSC-FA-03	1.833	1280.9	(M − H)−
483	SSC-AF-00	2.197	1521.8	(M − H)−
484	SSC-AF-00	2.145	1427.8	(M − H)−
485	SSC-FA-03	2.045	1470.1	(M − H)−
486	SSC-A-FA-01	6.473	1478.7	(M + H)+
487	SSC-AF-00	2.092	1373.9	(M − H)−
488	SSC-TFA-07	1.521	1316.8	(M + H)+
489	SSC-AF-00	2.043	1295.5	(M + H)+
490	SSC-TFA-07	1.429	1300.6	(M + H)+
491	SSC-FA-03	1.884	1382.1	(M − H)−
492	SSC-AF-00	2.172	1439.9	(M − H)−
493	SSC-FA-03	1.889	1495.0	(M − H)−
494	SSC-A-FA-02	6.515	1376.6	(M − H)−
495	SSC-FA-03	2.001	1425.8	(M − H)−
496	SSC-AF-00	2.163	1455.9	(M − H)−
497	SSC-AF-00	2.144	1427.9	(M − H)−
498	SSC-FA-03	2.076	1571.7	(M − H)−
499	SSC-TFA-07	1.321	1343.7	(M + H)+
500	SSC-AF-00	2.239	1510.8	(M − H)−
501	SSC-AF-00	2.197	1328.5	(M − H)−
502	SSC-TFA-07	1.307	1451.8	(M + H)+
503	SSC-A-FA-02	6.264	1418.6	(M + H)+
504	SSC-TFA-07	1.521	1304.8	(M + H)+
505	SSC-A-AF-02	8.020	1452.6	(M − H)−
506	SSC-A-FA-01	5.477	1447.7	(M + H)+
507	SSC-AF-00	2.048	1345.5	(M − H)−
508	SSC-TFA-07	1.421	1373.6	(M + H)+
509	SSC-A-FA-01	5.879	1501.7	(M − H)−
510	SSC-A-FA-02	6.465	1373.1	(M − H)−
511	SSC-TFA-07	1.356	1248.7	(M + H)+
512	SSC-TFA-07	1.531	1362.6	(M + H)+
513	SSC-AA-20	2.085	1488.7	(M + H)+
514	SSC-FA-03	2.116	1487.9	(M − H)−
515	SSC-FA-03	1.853	1423.9	(M − H)−
516	SSC-FA-03	2.004	1286.9	(M − H)−
517	SSC-TFA-07	1.279	1454.7	(M + H)+
518	SSC-AF-00	2.212	1496.0	M( − H)−
519	SSC-FA-03	1.549	1422.8	(M − H)−
520	SSC-TFA-07	1.459	1276.6	(M + H)+
521	SSC-TFA-07	1.375	1284.7	(M + H)+
522	SSC-TFA-07	1.420	1359.7	(M + H)+
523	SSC-FA-03	2.113	1491.9	(M − H)−
524	SSC-FA-03	1.993	1437.9	(M − H)−
525	SSC-A-AF-02	8.091	1406.6	(M − H)−
526	SSC-AF-00	2.159	1411.8	(M − H)−
527	SSC-FA-03	2.204	1515.9	(M − H)−
528	SSC-FA-03	2.001	1366.9	(M − H)−
529	SSC-AF-00	2.140	1318.5	(M − H)−
530	SSC-TFA-07	1.513	1359.7	(M + H)+
531	SSC-AF-00	2.164	1362.9	(M − H)−
532	SSC-AF-00	2.167	1397.9	(M − H)−
533	SSC-TFA-07	1.463	1385.6	(M + H)+
534	SSC-FA-03	1.917	1411.7	(M − H)−
535	SSC-AF-00	2.195	1441.9	(M − H)−
536	SSC-TFA-07	1.500	1411.8	(M + H)+
537	SSC-AF-00	2.209	1329.0	(M − H)−
538	SSC-AF-00	2.113	1324.9	(M − H)−
539	SSC-FA-03	1.895	1314.5	(M − H)−
540	SSC-TFA-07	1.427	1256.7	(M + H)+
541	SSC-A-FA-02	6.353	1434.7	(M − H)−
542	SSC-TFA-07	1.555	1316.7	(M + H)+
543	SSC-FA-03	2.103	1453.9	(M − H)−
544	SSC-TFA-07	1.445	1415.7	(M + H)+
545	SSC-FA-03	1.812	1529.9	(M − H)−
546	SSC-TFA-07	1.501	1336.9	(M + H)+
547	SSC-A-FA-02	6.729	1448.7	(M − H)−
548	SSC-AF-00	2.153	1399.6	(M − H)−
549	SSC-AF-00	2.147	1326.7	(M − H)−
550	SSC-TFA-07	1.451	1288.7	(M + H)+
551	SSC-FA-03	1.984	1422.0	(M − H)−
552	SSC-AF-00	2.256	1466.0	(M − H)−
553	SSC-AF-00	2.183	1409.9	(M − H)−
554	SSC-FA-03	1.869	1381.9	(M − H)−
555	SSC-AF-00	2.052	1356.0	(M − H)−
556	SSC-AF-00	2.143	1473.5	(M − H)−
557	SSC-FA-03	1.496	1432.8	(M − H)−
558	SSC-TFA-07	1.637	1441.8	(M + H)+
559	SSC-FA-03	1.859	1407.9	(M − H)−
560	SSC-TFA-07	1.336	1258.7	(M + H)+
561	SSC-TFA-07	1.504	1399.7	(M + H)+
562	SSC-FA-03	2.024	1437.9	(M − H)−
563	SSC-AF-00	2.192	1435.6	(M − H)−
564	SSC-TFA-07	1.365	1309.6	(M + H)+
565	SSC-TFA-07	1.412	1300.7	(M + H)+
566	SSC-AF-00	2.193	1396.7	(M − H)−
567	SSC-FA-03	1.800	1402.0	(M − H)−
568	SSC-FA-03	1.837	1385.9	(M − H)−
569	SSC-TFA-07	1.509	1316.6	(M + H)+
570	SSC-TFA-07	1.520	1328.5	(M + H)+
571	SSc-A-FA-01	5.515	1425.7	(M + H)+
572	SSC-AF-00	2.261	1465.6	(M − H)−
573	SSC-A-FA-02	6.337	1396.6	(M + H)+
574	SSC-A-FA-02	6.388	1452.6	(M + H)+
575	SSC-FA-03	1.847	1385.9	(M − H)−
576	SSC-AF-00	2.116	1220.5	(M − H)−
577	SSC-TFA-07	1.644	1455.8	(M + H)+
578	SSC-TFA-07	1.540	1338.8	(M + H)+
579	SSC-A-FA-02	6.495	1430.6	(M + H)+
580	SSC-TFA-07	1.491	1314.7	(M + H)+
581	SSC-TFA-07	1.439	1274.6	(M + H)+
582	SSC-TFA-07	1.307	1417.8	(M + H)+
583	SSC-TFA-07	1.664	1368.8	(M + H)+
584	SSC-AF-00	2.133	1324.5	(M − H)−
585	SSC-AF-00	2.179	1441.9	(M − H)−
586	SSC-TFA-07	1.572	1318.7	(M + H)+
587	SSC-AF-00	2.147	1416.9	(M − H)−
588	SSC-TFA-07	1.496	1288.7	(M + H)+
589	SSC-FA-03	1.799	1499.9	(M − H)−
590	SSC-AF-00	2.229	1499.0	(M − H)−
591	SSC-FA-03	1.967	1399.9	(M − H)−
592	SSC-FA-03	2.153	1534.9	(M − H)−
593	SSC-TFA-07	1.581	1330.7	(M + H)+
594	SSC-A-FA-02	6.632	1461.0	(M − H)−
595	SSC-AF-00	2.205	1342.7	(M + H)+
596	SSC-AF-00	2.173	1259.9	(M − H)−
597	SSC-FA-03	1.824	1328.5	(M − H)−
598	SSC-AF-00	2.181	1336.9	(M − H)−
599	SSC-TFA-07	1.440	1397.8	(M + H)+
600	SSC-TFA-07	1.587	1415.8	(M + H)+
601	SSC-AF-00	2.179	1272.5	(M − H)−
602	SSC-AF-00	2.152	1302.7	(M + H)+
603	SSC-FA-03	1.940	1427.9	(M − H)−
604	SSC-FA-03	1.655	1427.7	(M − H)−
605	SSC-FA-03	1.852	1360.9	(M − H)−
606	SSC-A-AF-01	7.861	1470.7	(M + H)+
607	SSC-FA-03	1.825	1373.6	(M − H)−
608	SSC-TFA-07	1.503	1304.7	(M + H)+
609	SSC-AA-20	2.107	1389.5	(M − H)−
610	SSC-TFA-07	1.485	1411.7	(M + H)+
611	SSC-A-FA-02	6.413	1428.6	(M + H)+
612	SSC-TFA-07	1.217	1301.6	(M + H)+
613	SSC-TFA-07	1.297	1324.0	(M + H)+
614	SSC-AF-00	2.267	1547.0	(M − H)−
615	SSC-TFA-07	1.597	1342.8	(M + H)+
616	SSC-FA-03	1.971	1489.8	(M − H)−
617	SSC-AF-00	2.172	1496.0	(M − H)−
618	SSC-FA-03	1.793	1313.6	(M − H)−
619	SSC-FA-03	1.884	1441.9	(M − H)−
620	SSC-TFA-07	1.511	1389.7	(M + H)+
621	SSC-AF-00	2.121	1246.8	(M − H)−
622	SSC-A-AF-01	7.701	1472.0	(M + H)+
623	SSC-FA-03	1.833	1387.9	(M − H)−
624	SSC-AF-00	2.131	1401.7	(M − H)−
625	SSC-AF-00	2.081	1315.6	(M − H)−
626	SSC-A-FA-02	6.673	1396.6	(M + H)+
627	SSC-AF-00	2.200	1425.9	(M − H)−
628	SSC-A-FA-02	6.727	1393.1	(M − H)−
629	SSC-TFA-07	1.608	1344.7	(M + H)+
630	SSC-AF-00	2.163	1501.8	(M − H)−
631	SSC-AF-00	2.148	1449.9	(M − H)−
632	SSC-AA-20	2.149	1332.7	(M + H)+
633	SSC-FA-03	1.873	1310.1	(M − H)−
634	SSC-AA-20	2.128	1475.6	(M − H)−
635	SSC-TFA-07	1.304	1423.7	(M + H)+
636	SSC-FA-03	1.824	1413.9	(M − H)−
637	SSC-TFA-07	1.479	1463.5	(M + H)+
638	SSC-FA-03	1.851	1486.0	(M − H)−
639	SSC-AF-00	2.179	1441.8	(M − H)−
640	SSC-A-FA-01	6.267	1462.6	(M + H)+
641	SSC-TFA-07	1.413	1264.7	(M + H)+
642	SSC-TFA-07	1.615	1453.7	(M + H)+
643	SSC-AF-00	2.321	1495.6	(M − H)−
644	SSC-TFA-07	1.489	1304.7	(M + H)+
645	SSC-TFA-07	1.440	1326.7	(M + H)+
646	SSC-TFA-07	1.329	1355.9	(M + H)+
647	SSC-FA-03	1.912	1451.9	(M − H)−
648	SSC-FA-03	1.832	1334.5	(M − H)−
649	SSC-TFA-07	1.460	1276.8	(M + H)+
650	SSC-AF-00	2.201	1441.9	(M − H)−
651	SSC-FA-03	1.701	1244.5	(M − H)−
652	SSC-A-FA-01	6.589	1476.6	(M + H)+
653	SSC-AF-00	2.151	1465.9	(M + H)+
654	SSC-TFA-07	1.339	1292.7	(M + H)+
655	SSC-A-FA-01	3.989	1442.7	(M + H)+
656	SSC-AF-00	2.253	1531.1	(M − H)−
657	SSC-TFA-07	1.404	1375.6	(M + H)+
658	SSC-TFA-07	1.424	1288.7	(M + H)+
659	SSC-AF-00	2.077	1295.8	(M − H)−
660	SSC-A-FA-01	4.956	1383.6	(M + H)+
661	SSC-AF-00	2.248	1470.0	(M − H)−
662	SSC-AF-00	2.225	1455.9	(M − H)−
663	SSC-TFA-07	1.483	1302.8	(M + H)+
664	SSC-TFA-07	1.243	1230.8	(M + H)+
665	SSC-AF-00	2.147	1288.7	(M − H)−
666	SSC-FA-03	1.857	1300.6	(M + H)+
667	SSC-FA-03	1.996	1439.8	(M − H)−
668	SSC-A-FA-01	6.295	1442.6	(M + H)+
669	SSC-TFA-07	1.495	1338.6	(M + H)+
670	SSC-TFA-07	1.437	1369.7	(M + H)+
671	SSC-FA-03	1.800	1308.5	(M + H)+
672	SSC-FA-03	1.963	1438.0	(M − H)−
673	SSC-A-AF-02	8.123	1450.7	(M + H)+
674	SSC-AF-00	2.135	1396.1	(M − H)−
675	SSC-TFA-07	1.479	1415.8	(M + H)+
676	SSC-TFA-07	1.665	1483.7	(M + H)+
677	SSC-FA-03	1.864	1398.0	(M − H)−
678	SSC-FA-03	1.865	1431.6	(M − H)−
679	SSC-A-FA-01	5.848	1494.7	(M + H)+
680	SSC-AF-00	2.124	1453.8	(M − H)−
681	SSC-FA-03	1.824	1422.0	(M − H)−
682	SSC-AF-00	2.171	1504.6	(M − H)−
683	SSC-FA-03	1.840	1501.9	(M − H)−
684	SSC-AF-00	2.069	1385.5	(M − H)−
685	SSC-FA-03	1.668	1299.6	(M − H)−
686	SSC-TFA-07	1.584	1318.8	(M + H)+
687	SSC-TFA-07	1.479	1338.8	(M + H)+
688	SSC-FA-03	2.045	1471.9	(M − H)−
689	SSC-FA-03	2.015	1437.8	(M − H)−
690	SSC-FA-03	1.925	1415.9	(M − H)−
691	SSC-FA-03	1.989	1415.8	(M − H)−
692	SSC-FA-03	2.217	1485.9	(M − H)−
693	SSC-AF-00	2.083	1419.5	(M + H)+
694	SSC-FA-03	1.933	1304.6	(M + H)+
695	SSC-A-FA-02	6.256	1422.7	(M − H)−
696	SSC-AF-00	2.247	1517.8	(M − H)−
697	SSC-TFA-07	1.360	1248.6	(M + H)+
698	SSC-A-FA-02	6.627	1461.0	(M − H)−
699	SSC-AF-00	2.255	1467.6	(M − H)−
700	SSC-FA-03	1.904	1423.6	(M − H)−
701	SSC-AF-00	2.187	1465.8	(M − H)−
702	SSC-FA-03	1.851	1401.7	(M − H)−
703	SSC-AF-00	2.180	1514.0	(M + H)+
704	SSC-A-FA-02	6.629	1400.7	(M − H)−
705	SSC-TFA-07	1.548	1306.7	(M + H)+
706	SSC-FA-03	1.911	1489.6	(M − H)−
707	SSC-TFA-07	1.483	1302.7	(M + H)+
708	SSC-TFA-07	1.520	1304.7	(M + H)+
709	SSC-TFA-07	1.531	1439.7	(M + H)+
710	SSC-TFA-07	1.411	1420.7	(M + H)+
711	SSC-AF-00	2.189	1466.0	(M − H)−
712	SSC-TFA-07	1.493	1387.7	(M + H)+
713	SSC-A-FA-02	6.597	1408.6	(M + H)+
714	SSC-TFA-07	1.375	1262.6	(M + H)+
715	SSC-AF-00	2.073	1355.6	(M − H)−
716	SSC-FA-03	1.964	1421.8	(M − H)−
717	SSC-AF-00	2.137	1404.9	(M − H)−
718	SSC-FA-03	1.995	1455.5	(M − H)−
719	SSC-A-AF-01	8.037	1558.9	(M − H)−
720	SSC-FA-03	1.865	1340.7	(M − H)−
721	SSC-FA-03	1.785	1451.9	(M − H)−
722	SSC-FA-03	2.163	1454.0	(M − H)−
723	SSC-TFA-07	1.544	1330.7	(M + H)+
724	SSC-A-FA-02	6.811	1424.7	(M + H)+
725	SSC-AF-00	2.211	1500.0	(M − H)−
726	SSC-A-FA-01	5.923	1437.9	(M − H)−
727	SSC-AF-00	2.275	1557.1	(M − H)−
728	SSC-FA-03	2.157	1453.9	(M − H)−
729	SSC-AF-00	2.211	1437.8	(M − H)−
730	SSC-FA-03	2.199	1469.9	(M − H)−
731	SSC-A-AF-02	8.049	1452.7	(M + H)+
732	SSC-FA-03	1.920	1455.7	(M − H)−
733	SSC-TFA-07	1.579	1439.6	(M + H)+
734	SSC-AF-00	2.152	1464.0	(M − H)−
735	SSC-AF-00	2.059	1427.7	(M − H)−
736	SSC-FA-03	1.765	1347.5	(M + H)+
737	SSC-AF-00	2.281	1442.0	(M − H)−
738	SSC-A-FA-02	6.660	1368.7	(M + H)+
739	SSC-TFA-07	1.388	1387.8	(M + H)+
740	SSC-TFA-07	1.484	1322.6	(M + H) +
741	SSC-AF-00	2.191	1414.0	(M − H)−
742	SSC-TFA-07	1.441	1334.7	(M + H)+
743	SSC-A-FA-02	6.651	1461.1	(M − H)−
744	SSC-FA-03	1.813	1416.0	(M − H)−
745	SSC-AF-00	2.161	1409.5	(M − H)−
746	SSC-AF-00	2.205	1286.9	(M − H)−
747	SSC-TFA-07	1.577	1330.6	(M + H)+
748	SSC-FA-03	1.943	1427.7	(M − H)−
749	SSC-FA-03	1.884	1360.5	(M − H)−
750	SSC-A-FA-02	6.584	1428.5	(M + H)+
751	SSC-TFA-07	1.404	1306.7	(M + H)+
752	SSC-TFA-07	1.501	1419.6	(M + H)+
753	SSC-FA-03	1.968	1348.5	(M − H)−
754	SSC-AF-00	2.191	1511.9	(M − H)−
755	SSC-FA-03	1.937	1453.8	(M − H)−
756	SSC-AF-00	2.179	1427.9	(M − H)−
757	SSC-FA-03	1.751	1517.0	(M − H)−
758	SSC-TFA-07	1.361	1357.6	(M + H)+
759	SSC-AF-00	2.140	1442.0	(M − H)−
760	SSC-AF-00	2.179	1399.9	(M − H)−
761	SSC-A-FA-01	6.021	1520.7	(M + H)+
762	SSC-TFA-07	1.592	1429.8	(M + H)+
764	SSC-TFA-07	1.415	1322.9	(M + H)+
765	SSC-AF-00	2.147	1441.6	(M − H)−
766	SSC-FA-03	1.865	1421.6	(M − H)−
767	SSC-TFA-07	1.375	1309.7	(M + H)+
768	SSC-A-AF-01	7.712	1423.8	(M − H)−
769	SSC-TFA-07	1.409	1397.7	(M + H)+
770	SSC-FA-03	1.877	1548.9	(M + H)+
771	SSC-TFA-07	1.473	1314.7	(M + H)+
772	SSC-TFA-07	1.515	1346.8	(M + H)+
773	SSC-AF-00	2.159	1260.9	(M − H)−
774	SSC-FA-03	1.872	1467.7	(M − H)−
775	SSC-A-FA-02	6.701	1420.7	(M − H)−
776	SSC-FA-03	1.868	1314.9	(M − H)−
777	SSC-A-FA-01	6.740	1491.9	(M + H)+
778	SSC-FA-03	2.020	1425.8	(M − H)−
779	SSC-TFA-07	1.401	1421.8	(M + H)+
780	SSC-A-FA-01	5.719	1638.9	(M + H)+
781	SSC-FA-03	1.888	1501.6	(M − H)−
782	SC-TFA-07	1.435	1352.6	(M + H)+
783	SSC-FA-03	2.005	1505.6	(M − H)−
784	SSC-FA-03	1.775	1395.8	(M − H )−
785	SSC-A-FA-02	6.371	1464.6	(M + H)+
786	SSC-AF-00	2.220	1531.0	(M − H)−
787	SSC-TFA-07	1.513	1413.7	(M + H)+
788	SSC-TFA-07	1.368	1260.7	(M + H)+
789	SSC-FA-03	2.068	1515.9	(M − H)−
790	SSC-FA-03	1.823	1426.0	(M − H)−
791	SSC-FA-03	1.924	1537.4	(M + H)+
792	SSC-AF-00	2.161	1429.9	(M − H)−
793	SSC-A-FA-01	5.032	1456.7	(M + H)+
794	SSC-FA-03	2.153	1483.9	(M − H)−
795	SSC-FA-03	1.815	1324.5	(M − H)−
796	SSC-FA-03	2.139	1520.1	(M − H)−
797	SSC-TFA-07	1.459	1320.7	(M + H)+
798	SSC-FA-03	2.189	1370.6	(M − H)−
799	SSC-AF-00	2.109	1397.8	(M − H)−
800	SSC-TFA-07	1.456	1320.8	(M + H)+
801	SSC-TFA-07	1.643	1346.7	(M + H)+
802	SSC-TFA-07	1.379	1266.6	(M + H)+
803	SSC-AF-00	2.211	1468.0	(M − H)−
804	SSC-TFA-07	1.395	1371.7	(M + H)+
805	SSC-FA-03	1.817	1442.8	(M − H)−
806	SSC-A-FA-01	5.865	1439.9	(M + H)+
807	SSC-AF-00	2.167	1412.0	(M − H)−
808	SSC-TFA-07	1.368	1391.8	(M + H)+
809	SSC-AF-00	2.281	1483.8	(M − H)−
810	SSC-AF-00	2.160	1385.5	(M − H)−
811	SSC-TFA-07	1.460	1288.7	(M + H)+
812	SSC-AF-00	2.272	1514.1	(M − H)−
813	SSC-FA-03	2.088	1571.7	(M − H)−
814	SSC-AF-00	2.091	1459.7	(M − H)−
815	SSC-TFA-07	1.455	1288.7	(M + H)+
816	SSC-A-FA-02	6.792	1476.6	(M + H)+
817	SSC-A-FA-01	4.897	1524.7	(M + H)+
818	SSC-AF-00	2.135	1528.9	(M − H)−
819	SSC-AF-00	2.233	1587.7	(M − H)−
820	SSC-AF-00	2.207	1441.8	(M − H)−
821	SSC-FA-03	1.945	1439.9	(M − H)−
822	SSC-AF-00	2.152	1445.9	(M − H)−
823	SSC-FA-03	1.961	1423.8	(M − H)−
824	SSC-TFA-07	1.455	1290.6	(M + H)+
825	SSC-FA-03	1.939	1363.6	(M − H)−
826	SSC-AF-00	2.136	1494.9	(M − H)−
827	SSC-AF-00	2.049	1401.6	(M − H)−
828	SSC-A-AF-01	7.365	1355.6	(M + H)+
829	SSC-FA-03	1.747	1367.9	(M − H)−
830	SSC-AF-00	2.133	1298.6	(M − H)−
831	SSC-FA-03	1.875	1286.5	(M − H)−
832	SSC-TFA-07	1.451	1278.7	(M + H)+
833	SSC-A-FA-02	6.701	1440.7	(M − H)−
834	SSC-FA-03	2.081	1312.9	(M − H)−
835	SSC-FA-03	1.935	1439.8	(M − H)−
836	SSC-FA-03	1.787	1413.7	(M − H)−
837	SSC-TFA-07	1.477	1290.6	(M + H)+
838	SSC-FA-03	2.008	1505.6	(M − H)−
839	SSC-AF-00	2.165	1274.8	(M + H)+
840	SSC-A-FA-01	5.016	1394.0	(M − H)−
841	SSC-TFA-07	1.419	1317.7	(M + H)+
842	SSC-TFA-07	1.396	1250.7	(M + H)+
843	SSC-TFA-07	1.555	1328.9	(M + H)+
844	SSC-AF-00	2.105	1272.7	(M − H)−
845	SSC-TFA-07	1.497	1316.7	(M + H)+
847	SSC-TFA-07	1.519	1312.9	(M + H)+
848	SSC-FA-03	2.136	1456.0	(M − H)−
849	SSC-FA-03	2.104	1466.1	(M − H)−
850	SSC-FA-03	1.809	1401.9	(M − H)−
851	SSC-TFA-07	1.501	1332.6	(M + H)+
852	SSC-TFA-07	1.645	1374.7	(M + H)+
853	SSC-AF-00	2.077	1415.7	(M − H)−
854	SSC-FA-03	2.063	1475.8	(M − H)−
855	SSC-FA-03	2.113	1515.6	(M + H)+
856	SSC-FA-03	1.736	1438.5	(M − H)−
857	SSC-TFA-07	1.469	1302.7	(M + H)+
858	SSC-TFA-07	1.527	1376.8	(M + H)+
859	SSC-AF-00	2.165	1326.6	(M − H)−
860	SSC-AF-00	2.033	1299.6	(M − H)−
861	SSC-AF-00	2.169	1451.7	(M − H)−
862	SSC-FA-03	1.715	1373.5	(M − H)−
863	SSC-A-FA-01	6.205	1444.7	(M + H)+
864	SSC-TFA-07	1.560	1348.7	(M + H)+
865	SSC-AA-20	2.064	1292.7	(M + H)+
866	SSC-A-AF-01	7.561	1421.8	(M − H)−
867	SSC-TFA-07	1.401	1420.7	(M + H)+
868	SSC-FA-03	1.880	1410.1	(M − H)−
869	SSC-A-FA-02	6.093	1348.6	(M + H)+
870	SSC-TFA-07	1.439	1342.8	(M + H)+
871	SSC-AF-00	2.053	1410.0	(M − H)−
872	SSC-FA-03	2.127	1472.0	(M − H)−
873	SSC-AF-00	2.195	1340.9	(M − H)−
874	SSC-TFA-07	1.431	1302.7	(M + H)+
875	SSC-TFA-07	1.425	1415.7	(M + H)+
876	SSC-FA-03	2.055	1517.7	(M − H)−
877	SSC-AF-00	2.195	1425.9	(M − H)−
878	SSC-TFA-07	1.443	1419.7	(M + H)+
879	SSC-TFA-07	1.400	1274.7	(M + H)+
880	SSC-FA-03	1.909	1413.8	(M − H)−
881	SSC-FA-03	1.924	1493.8	(M − H)−
882	SSC-FA-03	1.817	1487.9	(M − H)−
883	SSC-AF-00	2.151	1292.8	(M + H)+
884	SSC-AA-20	2.132	1449.6	(M + H)+
885	SSC-AF-00	2.172	1427.8	(M − H)−
886	SSC-TFA-07	1.627	1334.7	(M + H)+
887	SSC-AF-00	2.223	1535.0	(M − H)−
888	SSC-TFA-07	1.389	1323.7	(M + H)+
889	SSC-TFA-07	1.360	1458.8	(M + H)+
890	SSC-AF-00	2.153	1439.9	(M − H)−
891	SSC-A-FA-02	6.420	1338.6	(M − H)−
892	SSC-TFA-07	1.567	1320.8	(M + H)+
893	SSC-TFA-07	1.468	1333.8	(M + H)+
894	SSC-AF-00	2.211	1495.7	(M − H)−
895	SSC-AF-00	2.187	1445.8	(M − H)−
896	SSC-A-AF-01	7.573	1422.0	(M − H)−
897	SSC-AF-00	2.173	1346.7	(M + H)+
898	SSC-A-FA-02	6.677	1418.7	(M − H)−
899	SSC-A-FA-01	6.756	1439.9	(M − H)−
900	SSC-A-AF-01	7.679	1456.7	(M + H)+
901	SSC-TFA-07	1.540	1316.6	(M + H)+
902	SSC-TFA-07	1.388	1272.7	(M + H)+
903	SSC-FA-03	1.729	1315.6	(M − H)−
904	SSC-TFA-07	1.551	1318.7	(M + H)+
905	SSC-TFA-07	1.512	1304.8	(M + H)+
906	SSC-FA-03	1.861	1427.7	(M − H)−
907	SSC-A-AF-01	7.649	1408.6	(M + H)+
908	SSC-FA-03	2.101	1489.8	(M − H)−
909	SSC-AF-00	2.109	1298.6	(M − H)−
910	SSC-AF-00	2.200	1532.7	(M − H)−
911	SSC-TFA-07	1.551	1413.7	(M + H)+
912	SSC-FA-03	2.017	1487.5	(M + H)+
913	SSC-TFA-07	1.427	1334.6	(M + H)+
914	SSC-FA-03	1.588	1476.8	(M − H)−
915	SSC-AF-00	2.051	1369.7	(M − H)−
916	SSC-TFA-07	1.417	1345.8	(M + H)+
917	SSC-AF-00	2.200	1399.8	(M − H)−
918	SSC-AF-00	2.075	1394.1	(M − H)−
919	SSC-AF-00	2.048	1281.8	(M − H)−
920	SSC-AF-00	2.193	1494.1	(M − H)−
921	SSC-A-FA-01	5.544	1435.8	(M − H)−
922	SSC-AF-00	2.156	1324.7	(M − H)−
923	SSC-TFA-07	1.429	1300.7	(M + H)+
924	SSC-TFA-07	1.536	1316.6	(M + H)+
925	SSC-TFA-07	1.409	1395.7	(M + H)+
926	SSC-FA-03	1.856	1453.9	(M − H)−
927	SSC-TFA-07	1.493	1336.9	(M + H)+
928	SSC-A-FA-02	6.937	1421.0	(M − H)−
929	SSC-FA-03	1.856	1387.8	(M − H)−
930	SSC-AF-00	2.061	1262.5	(M + H)+
931	SSC-FA-03	1.951	1473.9	(M − H)−
932	SSC-A-FA-02	6.813	1464.7	(M + H)+
933	SSC-FA-03	1.905	1337.0	(M − H)−
934	SSC-FA-03	2.075	1537.7	(M − H)−
935	SSC-TFA-07	1.415	1420.6	(M + H)+
936	SSC-AF-00	2.148	1397.5	(M − H)−
937	SSC-TFA-07	1.540	1316.6	(M + H)+
938	SSC-FA-03	1.701	1446.0	(M − H)−
939	SSC-FA-03	1.949	1387.8	(M − H)−
940	SSC-AF-00	2.347	1514.1	(M − H)−
941	SSC-FA-03	1.963	1441.8	(M − H)−
942	SSC-FA-03	1.633	1474.8	(M − H)−
943	SSC-FA-03	1.785	1469.5	(M − H)−
944	SSC-TFA-07	1.467	1292.7	(M + H)+
945	SSC-AF-00	2.167	1439.7	(M − H)−
946	SSC-AF-00	2.124	1407.9	(M − H)−
947	SSC-A-FA-02	6.931	1414.7	(M + H)+
948	SSC-AF-00	2.152	1397.9	(M − H)−
949	SSC-A-FA-02	6.668	1454.5	(M + H)+
950	SSC-FA-03	2.104	1552.9	(M − H)−
951	SSC-A-FA-02	6.720	1408.7	(M − H)−
952	SSC-TFA-07	1.472	1300.7	(M + H)+
953	SSC-AF-00	2.175	1359.6	(M + H)+
954	SSC-FA-03	1.868	1329.6	(M − H)−
955	SSC-TFA-07	1.465	1419.7	(M + H)+
956	SSC-AF-00	2.105	1306.7	(M + H)+
957	SSC-FA-03	1.780	1381.9	(M − H)−
958	SSC-AF-00	2.161	1471.8	(M − H)−
959	SSC-FA-03	2.021	1438.0	(M − H)−
960	SSC-AF-00	2.283	1529.7	(M + H)+
961	SSC-AF-00	2.143	1484.6	(M − H)−
962	SSC-A-FA-02	6.436	1352.6	(M + H)+
963	SSC-FA-03	1.999	1455.7	(M − H)−
964	SSC-AF-00	2.195	1409.5	(M − H)−
965	SSC-A-FA-01	5.088	1422.0	(M − H)−
966	SSC-TFA-07	1.544	1328.7	(M + H)+
967	SSC-TFA-07	1.457	1278.8	(M + H)+
968	SSC-TFA-07	1.565	1427.7	(M + H)+
969	SSC-TFA-07	1.528	1389.8	(M + H)+
970	SSC-TFA-07	1.636	1332.7	(M + H)+
971	SSC-FA-03	1.881	1470.4	(M − H)−
972	SSC-AF-00	2.183	1362.9	(M − H)−
973	SSC-FA-03	1.899	1479.6	(M − H)−
974	SSC-FA-03	1.731	1429.8	(M − H)−
975	SSC-TFA-07	1.372	1309.6	(M + H)+
976	SSC-FA-03	1.711	1295.7	(M − H)−
977	SSC-FA-03	1.923	1423.6	(M − H)−
978	SSC-TFA-07	1.419	1294.8	(M + H)+
979	SSC-AF-00	2.108	1274.4	(M − H)−
980	SSC-TFA-07	1.449	1385.7	(M + H)+
981	SSC-FA-03	1.812	1529.7	(M − H)−
982	SSC-FA-03	1.784	1466.7	(M − H)−
983	SSC-FA-03	2.175	1480.0	(M − H)−
984	SSC-A-FA-01	6.952	1588.8	(M + H)+
985	SSC-TFA-07	1.441	1276.7	(M + H)+
986	SSC-AF-00	2.223	1440.0	(M − H)−
987	SSC-FA-03	1.745	1398.1	(M − H)−
988	SSC-TFA-07	1.581	1453.8	(M + H)+
989	SSC-TFA-07	1.329	1391.8	(M + H)+
990	SSC-FA-03	1.817	1326.4	(M + H)+
991	SSC-TFA-07	1.584	1344.7	(M + H)+
992	SSC-TFA-07	1.705	1376.7	(M + H)+
993	SSC-AF-00	2.117	1359.9	(M − H)−
994	SSC-TFA-07	1.476	1368.6	(M + H)+
995	SSC-AF-00	2.184	1425.6	(M − H)−
996	SSC-TFA-07	1.520	1340.7	(M + H)+
997	SSC-FA-03	2.023	1521.5	(M − H)−
998	SSC-TFA-07	1.653	1556.9	(M + H)+
999	SSC-FA-03	1.841	1383.6	(M − H)−
1000	SSC-AF-00	2.157	1489.8	(M − H)−
1001	SSC-FA-03	1.791	1475.9	(M − H)−
1002	SSC-FA-03	1.800	1439.6	(M − H)−
1003	SSC-A-FA-02	6.353	1416.6	(M + H)+
1004	SSC-FA-03	1.813	1292.9	(M − H)−
1005	SSC-FA-03	2.143	1455.9	(M − H)−
1006	SSC-A-FA-02	6.283	1446.6	(M − H)−
1007	SSC-AF-00	2.279	1348.6	(M − H)−
1008	SSC-AF-00	2.137	1444.0	(M − H)−
1009	SSC-FA-03	2.075	1509.8	(M − H)−
1010	SSC-FA-03	1.879	1399.8	(M − H)−
1011	SSC-AF-00	2.057	1307.9	(M − H)−
1012	SSC-AF-00	2.168	1463.0	(M − H)−
1013	SSC-TFA-07	1.363	1272.8	(M + H)+
1014	SSC-TFA-07	1.541	1348.6	(M + H)+
1015	SSC-AF-00	2.183	1481.9	(M − H)−
1016	SSC-FA-03	2.263	1541.8	(M − H)−
1017	SSC-FA-03	1.724	1391.9	(M − H)−
1018	SSC-TFA-07	1.432	1344.6	(M + H)+
1019	SSC-TFA-07	1.481	1316.7	(M + H)+
1020	SSC-TFA-07	1.491	1302.7	(M + H)+
1021	SSC-AF-00	2.156	1328.7	(M + H)+
1022	SSC-AF-00	2.220	1454.0	(M − H)−
1023	SSC-AF-00	2.195	1363.0	(M − H)−
1024	SSC-AF-00	2.075	1368.0	(M − H)−
1025	SSC-FA03	1.845	1492.9	(M − H)−
1026	SSC-FA-03	2.020	1443.8	(M − H)−
1027	SSC-FA-03	1.808	1372.0	(M − H)−
1029	SSC-AF-00	2.129	1412.1	(M − H)−
1030	SSC-AF-00	2.084	1440.1	(M − H)−
1031	SSC-TFA-07	1.439	1278.8	(M + H)+
1032	SSC-AF-00	2.245	1332.6	(M + H)+
1033	SSC-TFA-07	1.604	1332.7	(M + H)+
1034	SSC-FA-03	1.741	1371.9	(M − H)−
1035	SSC-AF-00	2.209	1521.6	(M − H)−
1036	SSC-AF-00	2.179	1423.9	(M − H)−
1037	SSC-FA-03	1.952	1427.8	(M − H)−
1038	SSC-TFA-07	1.517	1304.7	(M + H)+
1039	SSC-A-FA-01	6.327	1616.8	(M + H)+
1040	SSC-AF-00	2.161	1410.0	(M − H)−
1041	SSC-FA-03	1.801	1401.9	(M − H)−
1042	SSC-A-AF-01	7.533	1421.8	(M − H)−
1043	SSC-AF-00	2.117	1317.8	(M + H)+
1044	SSC-AF-00	2.231	1537.6	(M − H)−
1045	SSC-AF-00	2.260	1441.8	(M − H)−
1046	SSC-FA-03	1.916	1326.9	(M − H)−
1047	SSC-FA-03	1.904	1423.7	(M − H)−
1048	SSC-TFA-07	1.339	1389.9	(M + H)+
1049	SSC-A-AF-02	7.935	1456.6	(M + H)+
1050	SSC-TFA-07	1.536	1316.7	(M + H)+
1051	SSC-TFA-07	1.453	1373.7	(M + H)+
1052	SSC-FA-03	2.075	1571.8	(M − H)−
1053	SSC-FA-03	2.221	1542.0	(M − H)−
1054	SSC-AF-00	2.107	1306.7	(M + H)+
1055	SSC-AF-00	2.137	1309.7	(M − H)−
1056	SSC-AF-00	2.129	1272.9	(M − H)−
1057	SSC-FA-03	1.869	1479.9	(M − H)−
1058	SSC-AF-00	2.183	1525.5	(M − H)−
1059	SSC-A-FA-01	5.319	1419.7	(M − H)−
1060	SSC-FA-03	1.897	1451.9	(M − H)−
1061	SSC-TFA-07	1.459	1427.7	(M + H)+
1062	SSC-A-AF-01	7.752	1454.6	(M + H)+
1063	SSC-AF-00	2.229	1509.8	(M − H)−
1064	SSC-AF-00	2.169	1411.9	(M − H)−
1065	SSC-AF-00	2.176	1314.5	(M − H)−
1066	SSC-FA-03	1.765	1258.5	(M − H)−
1067	SSC-TFA-07	1.364	1270.8	(M + H)+
1068	SSC-TFA-07	1.563	1320.7	(M + H)+
1069	SSC-TFA-07	1.473	1334.6	(M + H)+
1070	SSC-A-AF-01	7.624	1425.9	(M − H)−
1071	SSC-FA-03	1.613	1476.8	(M − H)−
1072	SSC-AF-00	2.125	1401.7	(M − H)−
1073	SSC-AF-00	2.191	1425.9	(M − H)−
1074	SSC-A-FA-02	6.265	1402.6	(M + H)+
1075	SSC-AF-00	2.137	1316.9	(M − H)−
1076	SSC-TFA-07	1.536	1308.7	(M + H)+
1077	SSC-FA-03	1.847	1310.5	(M − H)−
1078	SSC-FA-03	1.923	1522.8	(M − H)−
1079	SSC-TFA-07	1.527	1356.6	(M + H)+
1080	SSC-A-AF-01	7.272	1410.0	(M − H)−
1081	SSC-FA-03	1.516	1492.6	(M − H)−
1082	SSC-TFA-07	1.555	1328.7	(M + H)+
1083	SSC-FA-03	1.875	1306.9	(M − H)−
1084	SSC-TFA-07	1.411	1306.7	(M + H)+
1085	SSC-TFA-07	1.391	1391.8	(M + H)+
1086	SSC-AA-20	2.083	1290.4	(M − H)−
1087	SSC-FA-03	1.739	1518.9	(M − H)−
1088	SSC-FA-03	1.880	1294.5	(M − H)−
1089	SSC-AF-00	2.185	1468.0	(M − H)−
1090	SSC-TFA-07	1.355	1228.8	(M + H)+
1091	SSC-FA-03	1.860	1422.1	(M − H)−
1092	SSC-TFA-07	1.373	1455.7	(M + H)+
1093	SSC-FA-03	2.097	1457.8	(M − H)−
1094	SSC-FA-03	1.800	1449.7	(M − H)−
1095	SSC-TFA-07	1.577	1318.8	(M + H)+
1096	SSC-AF-00	2.328	1544.0	(M + H)+
1097	SSC-TFA-07	1.429	1254.8	(M + H)+
1098	SSC-AF-00	2.060	1398.0	(M − H)−
1099	SSC-AF-00	2.131	1407.6	(M − H)−
1100	SSC-FA-03	1.883	1486.0	(M − H)−
1101	SSC-FA-03	1.879	1415.9	(M − H)−
1102	SSC-TFA-07	1.604	1372.7	(M + H)+
1103	SSC-FA-03	1.909	1397.9	(M − H)−
1104	SSC-A-AF-01	7.524	1480.6	(M + H)+
1105	SSC-TFA-07	1.485	1340.6	(M + H)+
1106	SSC-AF-00	2.171	1411.9	(M − H)−
1107	SSC-TFA-07	1.495	1314.7	(M + H)+
1108	SSC-A-FA-01	5.573	1510.7	(M + H)+
1109	SSC-AF-00	2.161	1399.9	(M − H)−
1110	SSC-TFA-07	1.527	1348.6	(M + H)+
1111	SSC-TFA-07	1.424	1262.7	(M + H)+
1112	SSC-AF-00	2.157	1454.1	(M + H)+
1113	SSC-AF-00	2.301	1481.8	(M − H)−
1114	SSC-AF-00	2.200	1437.9	(M − H)−
1115	SSC-AF-00	2.293	1485.8	(M + H)+
1116	SSC-FA-03	1.749	1515.8	(M − H)−
1117	SSC-A-FA-01	5.455	1397.6	(M + H)+
1118	SSC-FA-03	1.989	1397.5	(M − H)−
1119	SSC-TFA-07	1.463	1449.7	(M + H)+
1120	SSC-A-FA-01	5.471	1421.8	(M − H)−
1121	SSC-FA-03	1.825	1383.6	(M − H)−
1122	SSC-AF-00	2.193	1402.7	(M − H)−
1123	SSC-FA-03	1.929	1490.0	(M − H)−
1124	SSC-TFA-07	1.453	1373.7	(M + H)+
1125	SSC-AF-00	2.144	1407.9	(M − H)−
1126	SSC-TFA-07	1.539	1340.6	(M + H)+
1127	SSC-FA-03	1.940	1524.0	(M − H)−
1128	SSC-TFA-07	1.529	1413.7	(M + H)+
1129	SSC-FA-03	2.043	1565.5	(M − H)−
1130	SSC-AF-00	2.168	1387.9	(M − H)−
1131	SSC-A-AF-01	7.592	1395.7	(M − H)−
1132	SSC-FA-03	1.993	1425.8	(M − H)−
1133	SSC-AF-00	2.157	1346.7	(M + H)+
1134	SSC-AF-00	2.240	1452.0	(M − H)−
1135	SSC-FA-03	1.444	1488.8	(M − H)−
1136	SSC-FA-03	1.953	1483.9	(M − H)−
1137	SSC-A-FA-01	5.269	1439.6	(M − H)−
1138	SSC-FA-03	2.125	1427.9	(M − H)−
1139	SSC-A-AF-01	7.524	1557.7	(M − H)−
1140	SSC-A-FA-01	4.973	1427.7	(M + H)+
1141	SSC-A-FA-01	5.353	1419.7	(M − H)−
1142	SSC-A-FA-01	5.333	1439.8	(M − H)−
1143	SSC-A-FA-01	5.688	1470.1	(M − H)−
1144	SSC-A-FA-01	5.969	1470.1	(M − H)−
1145	SSC-A-AF-01	7.457	1437.8	(M − H)−
1146	SSC-A-FA-01	5.632	1487.8	(M − H)−
1148	SSC-A-AF-01	7.523	1433.8	(M − H)−
1149	SSC-A-FA-01	5.876	1499.6	(M + H)+
1150	SSC-FA-03	2.049	1454.0	(M − H)−
1151	SSC-A-FA-01	5.496	1517.8	(M − H)−
1152	SSC-A-AF-01	7.393	1417.6	(M − H)−
1153	SSC-FA-03	1.961	1336.5	(M − H)−
1154	SSC-A-AF-01	7.671	1469.9	(M − H)−
1155	SSC-AF-00	2.105	1513.4	(M − H)−
1156	SSC-FA-03	1.977	1471.7	(M + H)+
1157	SSC-FA-03	2.037	1428.0	(M − H)−
1158	SSC-A-AF-01	7.832	1467.9	(M − H)−
1159	SSC-A-AF-01	7.680	1501.7	(M − H)−
1160	SSC-A-FA-01	5.996	1450.0	(M − H)−
1161	SSC-FA-03	1.984	1425.9	(M − H)−
1162	SSC-A-FA-01	5.751	1458.1	(M − H)−
1163	SSC-A-AF-01	7.803	1447.9	(M − H)−
1164	SSC-A-AF-01	7.359	1382.0	(M − H)−
1165	SSC-A-FA-01	5.871	1413.9	(M − H)−
1166	SSC-A-FA-01	5.811	1450.0	(M − H)−
1167	SSC-A-FA-01	5.355	1455.8	(M − H)−
1168	SSC-FA-03	1.980	1457.9	(M − H)−
1169	SSC-AF-00	2.061	1419.9	(M − H)−
1170	SSC-A-FA-01	5.619	1414.0	(M − H)−
1171	SSC-A-AF-01	7.760	1453.8	(M − H)−
1172	SSC-FA-03	2.005	1413.7	(M − H)−
1173	SSC-A-AF-01	7.568	1453.7	(M + H)+
1174	SSC-AF-00	2.140	1386.0	(M − H)−
1175	SSC-A-AF-01	7.673	1504.0	(M − H)−
1176	SSC-A-AF-01	7.804	1465.8	(M − H)−
1177	SSC-AF-00	2.035	1405.5	(M − H)−
1178	SSC-FA-03	1.801	1427.9	(M − H)−
1179	SSC-A-FA-01	6.292	1505.6	(M + H)+
1180	SSC-FA-03	1.896	1427.9	(M − H)−
1181	SSC-AF-00	2.084	1483.0	(M − H)−
1182	SSC-A-FA-01	5.596	1565.7	(M − H)−
1183	SSC-A-AF-01	7.759	1515.6	(M + H)+
1184	SSC-FA-03	1.736	1389.8	(M − H)−
1185	SSC-FA-03	2.019	1354.6	(M − H)−
1186	SSC-AF-00	2.239	1453.9	(M − H)−
1187	SSC-FA-03	1.635	1345.7	(M − H)−
1188	SSC-FA-03	1.771	1399.8	(M − H)−
1189	SSC-A-AF-01	7.953	1455.8	(M − H)−
1190	SSC-A-AF-01	7.725	1501.8	(M − H)−
1191	SSC-AF-00	2.101	1456.9	(M − H)−
1192	SSC-A-FA-01	6.016	1450.0	(M − H)−
1193	SSC-A-AF-01	7.640	1469.8	(M − H)−
1194	SSC-A-FA-01	6.040	1477.9	(M − H)−
1195	SSC-FA-03	1.763	1401.5	(M − H)−
1196	SSC-A-FA-01	5.849	1549.9	(M − H)−
1197	SSC-A-FA-01	5.459	1422.0	(M − H)−
1198	SSC-A-AF-01	7.805	1437.8	(M − H)−
1199	SSC-A-FA-01	5.912	1449.8	(M − H)−
1200	SSC-FA-03	1.781	1415.5	(M + H)+
1201	SSC-A-FA-01	5.771	1458.1	(M − H)−
1202	SSC-AF-00	2.189	1455.6	(M − H)−
1203	SSC-FA-03	2.121	1454.0	(M − H)−
1204	SSC-A-FA-01	6.067	1467.9	(M − H)−
1205	SSC-A-FA-01	5.757	1410.1	(M − H)−
1206	SSC-A-AF-01	7.420	1573.7	(M − H)−
1207	SSC-FA-03	2.064	1497.9	(M − H)−
1208	SSC-A-AF-01	7.500	1439.6	(M − H)−
1209	SSC-A-FA-01	5.433	1466.1	(M − H)−
1210	SSC-A-AF-01	7.595	1534.0	(M − H)−
1211	SSC-FA-03	1.887	1385.9	(M − H)−
1212	SSC-FA-03	1.771	1423.5	(M + H)+
1213	SSC-AF-00	2.108	1335.0	(M − H)−
1214	SSC-FA-03	1.809	1439.8	(M − H)−
1215	SSC-A-FA-01	5.611	1504.1	(M − H)−
1216	SSC-FA-03	1.849	1399.4	(M − H)−
1217	SSC-A-AF-01	7.496	1437.7	(M + H)+
1218	SSC-FA-03	1.948	1362.6	(M − H)−
1219	SSC-AF-00	2.119	1473.8	(M − H)−
1220	SSC-A-FA-01	5.807	1469.6	(M + H)+
1221	SSC-AF-00	2.115	1308.5	(M − H)−
1222	SSC-AF-00	2.113	1308.7	(M − H)−
1223	SSC-A-AF-01	7.413	1425.8	(M − H)−
1224	SSC-A-FA-01	5.505	1466.0	(M − H)−
1225	SSC-FA-03	1.799	1306.9	(M − H)−
1226	SSC-FA-03	1.891	1455.9	(M + H)+
1227	SSC-FA-03	2.128	1454.0	(M − H)−
1228	SSC-A-AF-01	7.584	1454.0	(M − H)−
1229	SSC-FA-03	2.159	1547.8	(M − H)−
1230	SSC-AF-00	2.075	1433.8	(M − H)−
1231	SSC-A-FA-01	5.629	1441.7	(M + H)+
1232	SSC-A-AF-01	7.825	1448.0	(M − H)−
1233	SSC-A-AF-01	7.552	1503.7	(M − H)−
1234	SSC-A-FA-01	5.547	1517.8	(M − H)−
1235	SSC-AF-00	2.152	1453.9	(M − H)−
1236	SSC-A-FA-01	5.704	1501.8	(M − H)−
1237	SSC-A-AF-01	7.513	1440.0	(M − H)−
1238	SSC-FA-03	1.759	1475.7	(M − H)−
1239	SSC-FA-03	1.735	1294.6	(M − H)−
1240	SSC-FA-03	1.597	1388.6	(M − H)−
1241	SSC-A-AF-01	7.871	1455.6	(M − H)−
1242	SSC-A-FA-01	5.708	1523.7	(M − H)−
1243	SSC-FA-03	1.995	1413.9	(M − H)−
1244	SC-A-FA-01	5.623	1516.0	(M − H)−
1245	SSC-A-FA-01	5.728	1495.5	(M − H)−
1246	SSC-AF-00	2.047	1431.8	(M − H)−
1247	SSC-AF-00	2.125	1387.4	(M − H)−
1248	SSC-A-FA-01	5.768	1464.0	(M + H)+
1249	SSC-AF-00	2.044	1453.9	(M − H)−
1250	SSC-A-FA-01	5.671	1500.1	(M − H)−
1251	SSC-A-FA-01	5.504	1481.8	(M − H)−
1252	SSC-A-FA-01	5.383	1396.0	(M − H)−
1253	SSC-A-FA-01	5.845	1414.1	(M − H)−
1254	SSC-A-AF-01	7.511	1525.5	(M − H)−
1255	SSC-FA-03	2.147	1453.8	(M − H)−
1256	SSC-FA-03	1.660	1345.7	(M − H)−
1257	SSC-FA-03	1.857	1427.8	(M − H)−
1258	SSC-FA-03	1.849	1483.8	(M − H)−
1259	SSC-A-FA-01	5.759	1499.6	(M + H)+
1260	SSC-A-FA-01	5.477	1567.9	(M − H)−
1261	SSC-A-FA-01	5.271	1550.1	(M − H)−
1262	SSC-A-AF-01	7.683	1424.0	(M − H)−
1263	SSC-AF-00	2.123	1489.6	(M − H)−
1264	SSC-A-FA-01	5.695	1432.1	(M − H)−
1265	SSC-FA-03	2.044	1507.7	(M − H)−
1266	SSC-A-AF-01	7.741	1455.9	(M + H)+
1267	SSC-A-AF-01	7.871	1455.9	(M − H)−
1268	SSC-FA-03	1.655	1345.7	(M − H)−
1269	SSC-A-AF-01	7.455	1431.8	(M − H)−
1270	SSC-A-AF-01	7.739	1447.8	(M − H)−
1271	SSC-A-FA-01	5.608	1560.0	(M − H)−
1272	SSC-A-FA-01	5.901	1468.0	(M − H)−
1273	SSC-FA-03	1.960	1414.0	(M − H)−
1274	SSC-AF-00	2.204	1425.8	(M − H)−
1275	SSC-A-FA-01	5.880	1426.1	(M − H)−
1276	SSC-AF-00	2.192	1440.0	(M − H)−
1277	SSC-AF-00	2.135	1401.6	(M − H)−
1278	SSC-A-AF-01	7.327	1461.5	(M − H)−
1279	SSC-FA-03	1.817	1449.9	(M − H)−
1280	SSC-AF-00	2.203	1425.6	(M − H)−
1281	SSC-A-FA-01	6.031	1490.0	(M − H)−
1282	SSC-A-AF-01	7.433	1419.9	(M − H)−
1283	SSC-A-FA-01	5.857	1460.0	(M − H)−
1284	SSC-FA-03	1.616	1496.8	(M − H)−
1285	SSC-A-FA-01	5.607	1463.8	(M − H)−
1286	SSC-AF-00	2.145	1459.6	(M − H)−
1287	SSC-A-FA-01	5.337	1409.5	(M + H)+
1288	SSC-FA-03	1.876	1499.9	(M − H)−
1289	SSC-A-AF-01	7.719	1503.7	(M + H)+
1290	SSC-A-AF-01	7.801	1488.1	(M − H)−
1291	SSC-FA-03	2.011	1439.8	(M − H)−
1292	SSC-A-FA-01	5.412	1396.0	(M − H)−
1293	SSC-A-FA-01	5.055	1491.9	(M + H)+
1294	SSC-FA-03	1.456	1468.8	(M − H)−
1295	SSC-A-AF-01	7.777	1462.1	(M − H)−
1296	SSC-A-FA-01	5.695	1455.9	(M − H)−
1297	SSC-A-FA-01	5.351	1576.0	(M − H)−
1298	SSC-AF-00	2.095	1485.7	(M − H)−
1299	SSC-A-FA-01	5.024	1441.8	(M − H)−
1300	SSC-FA-03	1.745	1258.8	(M − H)−
1301	SSC-A-FA-01	5.500	1507.6	(M + H)+
1302	SSC-FA-03	2.048	1428.0	(M − H)−
1303	SSC-A-AF-01	7.389	1551.9	(M − H)−
1304	SSC-AF-00	2.033	1405.7	(M − H)−
1305	SSC-AF-00	2.088	1333.6	(M − H)−
1306	SSC-A-FA-01	5.596	1458.0	(M − H)−
1307	SSC-FA-03	1.875	1322.5	(M − H)−
1308	SSC-A-AF-01	7.648	1456.0	(M − H)−
1309	SSC-A-FA-01	4.709	1411.9	(M − H)−
1310	SSC-A-AF-01	7.676	1489.7	(M + H)+
1311	SSC-A-FA-01	5.421	1539.7	(M − H)−
1312	SSC-A-AF-01	7.629	1517.9	(M − H)−
1313	SSC-FA-03	1.787	1415.8	(M − H)−
1314	SSC-AF-00	2.147	1399.9	(M − H)−
1315	SSC-AF-00	2.208	1425.8	(M − H)−
1316	SSC-AF-00	2.163	1399.9	(M − H)−
1317	SSC-A-FA-01	5.619	1499.6	(M + H)+
1318	SSC-AF-00	2.124	1355.7	(M − H)−
1319	SSC-A-FA-01	5.979	1501.7	(M − H)−
1320	SSC-A-AF-01	7.676	1501.8	(M + H)+
1321	SSC-FA-03	1.956	1468.0	(M − H)−
1322	SSC-A-FA-01	5.521	1463.9	(M − H)−
1323	SSC-AF-00	2.195	1439.9	(M − H)−
1324	SSC-A-AF-01	7.652	1410.0	(M − H)−
1325	SSC-A-FA-01	5.819	1447.9	(M − H)−
1326	SSC-A-FA-01	5.428	1455.8	(M − H)−
1327	SSC-AF-00	2.064	1407.8	(M − H)−
1328	SSC-AF-00	2.117	1324.5	(M + H)+
1329	SSC-FA-03	1.792	1413.5	(M − H)−
1330	SSC-A-FA-01	5.368	1547.6	(M − H)−
1331	SSC-AF-00	2.116	1334.5	(M − H)−
1332	SSC-FA-03	1.908	1340.5	(M − H)−
1333	SSC-AF-00	2.163	1441.8	(M − H)−
1334	SSC-AF-00	2.147	1411.8	(M − H)−
1335	SSC-A-AF-01	7.671	1531.8	(M − H)−
1336	SSC-A-AF-01	7.255	1428.0	(M − H)−
1337	SSC-A-FA-02	6.216	1481.7	(M + H)+
1338	SSC-A-FA-01	5.437	1469.9	(M − H)−
1339	SSC-A-FA-01	5.604	1503.9	(M − H)−
1340	SSC-A-FA-01	5.424	1408.0	(M − H)−
1341	SSC-A-FA-01	6.053	1514.0	(M − H)−
1342	SSC-A-AF-01	7.621	1414.1	(M − H)−
1343	SSC-A-FA-01	5.456	1490.0	(M − H)−
1344	SSC-FA-03	1.691	1419.7	(M − H)−
1345	SSC-FA-03	2.153	1454.0	(M − H)−
1346	SSC-A-FA-01	5.835	1449.9	(M − H)−
1347	SSC-FA-03	2.111	1453.8	(M − H)−
1348	SSC-A-FA-01	5.337	1543.6	(M + H)+
1349	SSC-FA-03	1.755	1463.5	(M + H)+
1350	SSC-AF-00	2.072	1445.9	(M − H)−
1351	SSC-A-FA-01	5.725	1450.0	(M − H)−
1352	SSC-FA-03	1.920	1475.3	(M − H)−
1353	SSC-AF-00	2.163	1412.0	(M − H)−
1354	SSC-AF-00	2.216	1426.0	(M − H)−
1355	SSC-A-AF-01	7.425	1457.9	(M − H)−
1356	SSC-A-AF-01	7.568	1503.7	(M − H)−
1357	SSC-A-FA-01	6.156	1487.8	(M − H)−
1358	SSC-AF-00	2.095	1449.8	(M − H)−
1359	SSC-A-FA-01	5.357	1467.9	(M − H)−
1360	SSC-A-AF-01	7.449	1473.6	(M − H)−
1361	SSC-FA-03	1.813	1457.8	(M − H)−
1362	SSC-A-FA-01	5.183	1506.0	(M − H)−
1363	SSC-A-AF-01	7.851	1460.0	(M − H)−
1364	SSC-A-FA-01	5.587	1520.0	(M − H)−
1365	SSC-A-FA-01	5.475	1422.0	(M − H)−
1366	SSC-A-FA-02	6.213	1459.7	(M + H)+
1367	SSC-A-FA-01	5.889	1458.1	(M − H)−
1368	SSC-A-AF-01	7.532	1478.0	(M − H)−
1369	SSC-A-FA-01	5.992	1495.8	(M − H)−
1370	SSC-A-FA-01	5.833	1457.7	(M + H)+
1371	SSC-A-FA-01	5.392	1517.9	(M + H)+
1372	SSC-FA-03	1.871	1405.7	(M − H)−
1373	SSC-TFA-07	1.352	1322.8	(M + H)+
1374	SSC-A-AF-01	8.067	1457.7	(M + H)+
1375	SSC-TFA-07	1.348	1322.7	(M + H)+
1376	SSC-AF-00	2.192	1455.9	(M − H)−
1377	SSC-FA-03	1.755	1284.4	(M − H)−
1378	SSC-AF-00	2.161	1290.9	(M − H)−
1379	SSC-FA-03	2.015	1340.5	(M − H)−
1380	SSC-FA-03	1.821	1264.5	(M − H)−
1381	SSC-FA-03	1.829	1286.9	(M − H)−
1382	SSC-AF-00	2.132	1300.5	(M + H)+
1383	SSC-FA-03	1.863	1352.5	(M − H)−
1384	SSC-AF-00	2.185	1330.6	(M + H)+
1385	SSC-FA-03	1.845	1342.4	(M + H)+
1386	SSC-FA-03	1.875	1326.7	(M − H)−
1387	SSC-FA-03	1.816	1276.5	(M − H)−
1388	SSC-AF-00	2.144	1314.6	(M − H)−
1389	SSC-AF-00	2.217	1320.9	(M − H)−
1390	SSC-FA-03	1.905	1278.9	(M − H)−
1391	SSC-AF-00	2.160	1290.9	(M − H)−
1392	SSC-AF-00	2.072	1340.4	(M + H)+
1393	SSC-AF-00	2.173	1382.4	(M − H)−
1394	SSC-AF-00	2.188	1340.9	(M − H)−
1395	SSC-FA-03	1.969	1394.9	(M − H)−
1396	SSC-FA-03	1.905	1368.8	(M − H)−
1397	SSC-FA-03	1.792	1328.6	(M + H)+
1398	SSC-FA-03	1.763	1272.8	(M − H)−
1399	SSC-AF-00	2.120	1352.8	(M − H)−
1400	SSC-FA-03	2.071	1333.0	(M − H)−
1401	SSC-FA-03	2.001	1394.4	(M − H)−
1402	SSC-AF-00	2.124	1298.9	(M − H)−
1403	SSC-AF-00	2.133	1380.8	(M − H)−
1404	SSC-AF-00	2.133	1393.8	(M − H)−
1405	SSC-FA-03	1.904	1426.0	(M + H)+
1406	SSC-FA-03	1.787	1360.3	(M − H)−
1407	SSC-TFA-07	1.359	1337.8	(M + H)+
1408	SSC-FA-03	1.797	1368.8	(M − H)−
1409	SSC-TFA-07	1.376	1463.7	(M + H)+
1410	SSC-TFA-07	1.348	1415.7	(M + H)+
1411	SSC-FA-03	1.672	1345.6	(M + H)+
1412	SSC-TFA-07	1.304	1333.8	(M + H)+
1413	SSc-FA-03	1.903	1411.8	(M − H)−
1414	SSC-AF-00	2.113	1451.7	(M − H)−
1415	SSC-AF-00	2.143	1419.4	(M − H)−
1416	SSC-AF-00	2.180	1413.9	(M − H)−
1417	SSC-AF-00	2.168	1479.6	(M + H)+
1418	SSC-AF-00	2.137	1356.8	(M − H)−
1419	SSC-FA-03	1.985	1479.7	(M − H)−
1420	SSC-FA-03	1.904	1425.9	(M − H)−
1421	SSC-FA-03	1.847	1439.8	(M − H)−
1422	SSC-FA-03	1.889	1453.8	(M − H)−
1423	SSC-AF-00	2.152	1401.5	(M + H)+
1424	SSC-TFA-07	1.468	1411.7	(M + H)+
1425	SSC-FA-03	1.767	1469.9	(M − H)−
1426	SSC-FA-03	1.793	1423.3	(M − H)−
1427	SSC-FA-03	1.715	1372.3	(M − H)−
1428	SSC-AF-00	2.105	1449.8	(M − H)−
1429	SSC-AF-00	2.135	1465.8	(M − H)−
1430	SSC-TFA-07	1.425	1477.7	(M + H)+
1431	SSC-TFA-07	1.339	1413.6	(M + H)+
1432	SSC-TFA-07	1.572	1427.7	(M + H)+
1433	SSC-AF-00	2.176	1489.9	(M − H)−
1434	SSC-AF-00	2.301	1515.9	(M − H)−
1435	SSC-FA-03	2.109	1441.6	(M − H)−
1436	SSC-AF-00	2.333	1513.9	(M − H)−
1437	SSC-FA-03	2.192	1499.9	(M − H)−
1438	SSC-FA-03	2.000	1427.9	(M − H)−
1439	SSC-FA-03	2.059	1428.0	(M − H)−
1440	SSC-AF-00	2.315	1499.9	(M − H)−
1441	SSC-FA-03	2.076	1454.0	(M − H)−
1442	SSC-AF-00	2.263	1489.8	(M − H)−
1443	SSC-FA-03	2.272	1525.7	(M − H)−
1444	SSC-FA-03	1.881	1429.9	(M − H)−
1445	SSC-FA-03	2.032	1456.0	(M − H)−
1446	SSC-AF-00	2.268	1489.9	(M − H)−
1447	SSC-AF-00	2.217	1441.6	(M + H)+
1448	SSC-AF-00	2.189	1443.8	(M − H)−
1449	SSC-FA-03	2.140	1453.8	(M − H)−
1450	SSC-TFA-07	1.500	1487.9	(M + H)+
1451	SSC-AF-00	2.087	1318.7	(M + H)+
1452	SSC-TFA-07	1.479	1290.8	(M + H)+
1453	SSC-TFA-07	1.403	1411.8	(M + H)+
1454	SSC-TFA-07	1.481	1385.9	(M + H)+
1455	SSC-TFA-07	1.360	1385.8	(M + H)+
1456	SSC-TFA-07	1.447	1413.8	(M + H)+
1457	SSC-AF-00	2.148	1290.7	(M + H)+
1458	SSC-TFA-07	1.468	1385.9	(M + H)+
1459	SSC-TFA-07	1.521	1304.7	(M + H)+
1460	SSC-AF-00	2.088	1328.7	(M + H)+
1461	SSC-AF-00	2.176	1306.9	(M − H)−
1462	SSC-FA-03	1.760	1292.5	(M − H)−
1463	SSC-FA-03	1.788	1346.4	(M − H)−
1464	SSC-AF-00	2.151	1398.5	(M + H)+
1465	SSC-FA-03	1.892	1294.6	(M − H)−
1466	SSC-FA-03	1.741	1266.6	(M − H)−
1467	SSC-TFA-07	1.491	1399.8	(M + H)+
1468	SSC-AF-00	2.223	1402.9	(M − H)−
1469	SSC-TFA-07	1.399	1260.8	(M + H)+
1470	SSC-AF-00	2.144	1360.8	(M − H)−
1471	SSC-AF-00	2.149	1322.9	(M − H)−
1472	SSC-TFA-07	1.485	1384.7	(M + H)+
1473	SSC-AF-00	2.161	1384.9	(M − H)−
1474	SSC-TFA-07	1.453	1274.8	(M + H)+
1475	SSC-FA-03	1.916	1402.8	(M − H)−
1476	SSC-TFA-07	1.439	1372.7	(M + H)+
1477	SSC-FA-03	1.993	1340.9	(M − H)−
1478	SSC-AF-00	2.123	1272.5	(M − H)−
1479	SSC-FA-03	1.939	1310.5	(M − H)−
1480	SSC-TFA-07	1.536	1510.9	(M + H)+
1481	SSC-FA-03	1.839	1284.9	(M − H)−
1482	SSC-FA-03	2.025	1416.8	(M − H)−
1483	SSC-TFA-07	1.404	1304.9	(M + H)+
1484	SSC-TFA-07	1.471	1372.7	(M + H)+
1485	SSC-FA-03	1.763	1280.9	(M − H)−
1486	SSC-AF-00	2.081	1320.8	(M − H)−
1487	SSC-AF-00	2.183	1348.9	(M − H)−
1488	SSC-FA-03	1.899	1360.9	(M − H)−
1489	SSC-TFA-07	1.447	1371.8	(M + H)+
1490	SSC-TFA-07	1.484	1288.8	(M + H)+
1491	SSC-FA-03	1.851	1298.9	(M − H)−
1492	SSC-AF-00	2.172	1425.7	(M + H)+
1493	SSC-AF-00	2.115	1274.7	(M + H)+
1494	SSC-FA-03	1.885	1320.5	(M + H)+
1495	SSC-TFA-07	1.515	1413.8	(M + H)+
1496	SSC-FA-03	1.883	1388.4	(M − H)−
1497	SSC-FA-03	1.899	1374.4	(M − H)−
1498	SSC-FA-03	1.873	1308.5	(M − H)−
1499	SSC-AF-00	2.205	1326.9	(M − H)−
1500	SSC-FA-03	1.883	1334.9	(M − H)−
1501	SSC-AF-00	2.137	1398.0	(M − H)−
1502	SSC-TFA-07	1.491	1476.9	(M + H)+
1503	SSC-TFA-07	1.529	1304.8	(M + H)+
1504	SSC-FA-03	1.984	1362.6	(M − H)−
1505	SSC-TFA-7	1.560	1386.7	(M + H)+
1506	SSC-FA-03	1.796	1258.5	(M − H)−
1507	SSC-AF-00	2.183	1360.5	(M − H)−
1508	SSC-FA-03	1.895	1362.4	(M − H)−
1509	SSC-AF-00	2.140	1324.7	(M + H)+
1510	SSC-FA-03	1.955	1312.9	(M − H)−
1511	SSC-TFA-07	1.495	1278.8	(M + H)+
1512	SSC-FA-03	1.787	1360.3	(M − H)−
1513	SSC-TFA-07	1.537	1425.8	(M + H)+
1514	SSC-AF-00	2.109	1306.4	(M − H)−
1515	SSC-TFA-07	1.396	1298.8	(M + H)+
1516	SSC-AF-00	2.115	1370.9	(M − H)−
1517	SSC-AF-00	2.225	1348.9	(M − H)−
1518	SSC-AF-00	2.147	1288.8	(M + H)+
1519	SSC-TFA-07	1.475	1372.7	(M + H)+
1520	SSC-AF-00	2.172	1350.4	(M + H)+
1521	SSC-AF-00	2.223	1336.9	(M − H)−
1522	SSC-FA-03	1.936	1372.4	(M − H)−
1523	SSC-FA-03	1.784	1334.4	(M − H)−
1524	SSC-AF-00	2.149	1376.8	(M − H)−
1525	SSC-AF-00	2.136	1306.9	(M − H)−
1526	SSC-AF-00	2.067	1302.8	(M + H)+
1527	SSC-TFA-07	1.536	1314.8	(M + H)+
1528	SSC-TFA-07	1.464	1449.8	(M + H)+
1529	SSC-TFA-07	1.404	1304.8	(M + H)+
1530	SSC-AF-00	2.263	1329.0	(M − H)−
1531	SSC-FA-03	2.080	1340.5	(M − H)−
1532	SSC-AF-00	2.113	1451.9	(M − H)−
1533	SSC-AF-00	2.077	1270.7	(M + H)+
1534	SSC-AF-00	2.132	1274.7	(M + H)+
1535	SSC-F-00	2.199	1286.5	(M − H)−
1536	SSC-AF-00	2.164	1320.9	(M − H)−
1537	SSC-FA-03	1.907	1348.9	(M − H)−
1538	SSC-TFA-07	1.492	1407.8	(M + H)+
1539	SSC-FA-03	1.975	1299.0	(M − H)−
1540	SSC-FA-03	1.861	1332.5	(M − H)−
1541	SSC-TFA-07	1.477	1469.8	(M + H)+
1542	SSC-AF-00	2.224	1390.4	(M − H)−
1543	SSC-AF-00	2.176	1298.9	(M − H)−
1544	SSC-FA-03	1.931	1300.5	(M − H)−
1545	SSC-AF-00	2.128	1274.7	(M + H)+
1546	SSC-TFA-07	1.431	1358.7	(M + H)+
1547	SSC-TFA-07	1.428	1298.7	(M + H)+
1548	SSC-TFA-07	1.632	1358.7	(M + H)+
1549	SSC-TFA-07	1.444	1312.7	(M + H)+
1550	SSC-TFA-07	1.444	1312.6	(M + H)+
1551	SSC-AF-00	2.079	1326.4	(M − H)−
1552	SSC-TFA-07	1.727	1495.8	(M + H)+
1553	SSC-TFA-07	1.556	1453.8	(M + H)+
1554	SSC-TFA-07	1.699	1467.7	(M + H)+
1555	SSC-TFA-07	1.499	1463.7	(M + H)+
1556	SSC-TFA-07	1.405	1302.6	(M + H)+
1557	SSC-TFA-07	1.443	1413.7	(M + H)+
1558	SSC-TFA-07	1.657	1469.7	(M + H)+
1559	SSC-AF-00	2.203	1473.9	(M − H)−
1560	SSC-TFA-07	1.587	1344.7	(M + H)+
1561	SSC-TFA-07	1.689	1503.7	(M + H)+
1562	SSC-TFA-07	1.425	1385.6	(M + H)+
1563	SSC-TFA-07	1.493	1382.6	(M + H)+
1564	SSC-TFA-07	1.476	1302.7	(M + H)+
1565	SSC-AF-00	2.140	1366.8	(M − H)−
1566	SSC-AF-00	2.211	1451.8	(M − H)−
1567	SSC-TFA-07	1.473	1366.6	(M + H)+
1568	SSC-TFA-07	1.525	1316.7	(M + H)+
1569	SSC-AF-00	2.208	1440.0	(M − H)−
1570	SSC-AF-00	2.100	1310.5	(M − H)−
1571	SSC-TFA-07	1.417	1316.6	(M + H)+
1572	SSC-TFA-07	1.484	1366.6	(M + H)+
1573	SSC-TFA-07	1.480	1368.6	(M + H)+
1574	SSC-TFA-07	1.760	1509.8	(M + H)+
1575	SSC-TFA-07	1.461	1352.7	(M + H)+
1576	SSC-TFA-07	1.473	1473.6	(M + H)+
1577	SSC-AF-00	2.279	1482.0	(M − H)−
1578	SSC-TFA-07	1.391	1274.6	(M + H)+
1579	SSC-TFA-07	1.493	1463.7	(M + H)+
1580	SSC-TFA-07	1.624	1467.8	(M + H)+
1581	SSC-AF-00	2.301	1397.0	(M − H)−
1582	SSC-TFA-07	1.447	1334.5	(M + H)+
1583	SSC-TFA-07	1.445	1413.7	(M + H)+
1584	SSC-AF-00	2.131	1407.9	(M − H)−
1585	SSC-TFA-07	1.403	1302.6	(M + H)+
1586	SSC-AF-00	2.201	1340.4	(M − H)−
1587	SSC-TFA-07	1.452	1362.5	(M + H)+
1588	SSC-TFA-07	1.425	1425.7	(M + H)+
1589	SSC-TFA-07	1.472	1348.6	(M + H)+
1590	SSC-TFA-07	1.459	1376.5	(M + H)+
1591	SSC-TFA-07	1.424	1318.6	(M + H)+
1592	SSC-AF-00	2.233	1454.0	(M − H)−
1593	SSC-AF-00	2.204	1328.5	(M − H)−
1594	SSC-AF-00	2.124	1409.5	(M + H)+
1595	SSC-TFA-07	1.587	1441.7	(M + H)+
1596	SSC-AF-00	2.252	1468.0	(M − H)−
1597	SSC-TFA-07	1.473	1376.5	(M + H)+
1598	SSC-AF-00	2.101	1393.8	(M − H)−
1599	SSC-TFA-07	1.425	1316.7	(M + H)+
1600	SSC-TFA-07	1.740	1495.8	(M + H)+
1601	SSC-AF-00	2.221	1454.0	(M − H)−
1602	SSC-TFA-07	1.400	1302.6	(M + H)+
1603	SSC-AF-00	2.259	1480.1	(M − H)−
1604	SSC-TFA-07	1.416	1298.7	(M + H)+
1605	SSC-TFA-07	1.393	1314.6	(M + H)+
1606	SSC-TFA-07	1.395	1284.6	(M + H)+
1607	SSC-TFA-07	1.433	1288.6	(M + H)+
1608	SSC-AF-00	2.131	1407.5	(M − H)−
1609	SSC-TFA-07	1.491	1445.7	(M + H)+
1610	SSC-TFA-07	1.427	1316.7	(M + H)+
1611	SSC-AF-00	2.136	1427.7	(M − H)−
1612	SSC-TFA-07	1.609	1356.7	(M + H)+
1613	SSC-TFA-07	1.453	1352.6	(M + H)+
1614	SSC-TFA-07	1.416	1298.7	(M + H)+
1615	SSC-TFA-07	1.445	1332.5	(M + H)+
1616	SSC-TFA-07	1.557	1427.6	(M + H)+
1617	SSC-TFA-07	1.467	1366.5	(M + H)+
1618	SSC-AF-00	2.281	1382.9	(M − H)−
1619	SSC-TFA-07	1.617	1358.6	(M + H)+
1620	SSC-TFA-07	1.447	1352.6	(M + H)+
1621	SSC-TFA-07	1.463	1332.6	(M + H)+
1622	SSC-AF-00	2.221	1452.0	(M − H)−
1623	SSC-TFA-07	1.443	1318.6	(M + H)+
1624	SSC-TFA-07	1.700	1517.8	(M + H)+
1625	SSC-TFA-07	1.441	1362.5	(M + H)+
1626	SSC-AF-00	2.128	1407.9	(M − H)−
1627	SSC-TFA-07	1.431	1298.7	(M + H)+
1628	SSC-AF-00	2.244	1390.9	(M − H)−
1629	SSC-TFA-07	1.481	1463.8	(M + H)+
1630	SSC-AF-00	2.155	1477.7	(M − H)−
1631	SSC-AF-00	2.104	1411.8	(M − H)−
1632	SSC-TFA-07	1.428	1298.7	(M + H)+
1633	SSC-TFA-07	1.487	1382.6	(M + H)+
1634	SSC-AF-00	2.100	1310.5	(M − H)−
1635	SSC-TFA-07	1.469	1368.6	(M + H)+
1636	SSC-TFA-07	1.469	1429.6	(M + H)+
1637	SSC-TFA-07	1.500	1382.6	(M + H)+
1638	SSC-AF-00	2.143	1397.8	(M − H)−
1639	SSC-TFA-07	1.513	1413.7	(M + H)+
1640	SSC-TFA-07	1.519	1479.8	(M + H)+
1641	SSC-TFA-07	1.511	1479.7	(M + H)+
1642	SSC-TFA-07	1.663	1467.8	(M + H)+
1643	SSC-TFA-07	1.496	1473.7	(M + H)+
1644	SSC-FA-03	2.124	1454.0	(M − H)−
1645	SSC-AF-00	2.101	1433.8	(M − H)−
1646	SSC-FA-03	1.849	1401.5	(M − H)−
1647	SSC-AF-00	2.120	1421.9	(M − H)−
1648	SSC-AF-00	2.136	1315.0	(M − H)−
1649	SSC-AF-00	2.131	1421.9	(M − H)−
1650	SSC-AF-00	2.216	1440.0	(M − H)−
1651	SSC-FA-03	2.100	1453.8	(M − H)−
1652	SSC-FA-03	1.947	1399.8	(M − H)−
1653	SSC-AF-00	2.029	1393.8	(M − H)−
1654	SSC-AF-00	2.200	1328.7	(M − H)−
1655	SSC-FA-03	1.755	1272.8	(M − H)−
1656	SSC-AF-00	2.137	1411.9	(M − H)−
1657	SSC-FA-03	1.988	1439.9	(M − H)−
1658	SSC-AF-00	2.121	1433.5	(M − H)−
1659	SSC-FA-03	1.844	1385.8	(M − H)−
1660	SSC-AF-00	2.167	1461.8	(M − H)−
1661	SSC-AF-00	2.139	1336.5	(M − H)−
1662	SSC-FA-03	1.885	1400.0	(M − H)−
1663	SSC-FA-03	2.127	1465.9	(M − H)−
1664	SSC-FA-03	1.759	1399.8	(M − H)−
1665	SSC-FA-03	1.821	1411.7	(M − H)−
1666	SSC-AF-00	2.117	1383.9	(M − H)−
1667	SSC-AF-00	2.084	1312.4	(M + H)+
1668	SSC-AF-00	2.232	1455.8	(M − H)−
1669	SSC-FA-03	1.956	1411.9	(M − H)−
1670	SSC-AF-00	2.105	1397.8	(M − H)−
1671	SSC-AF-00	2.225	1439.8	(M − H)−
1672	SSC-FA-03	1.920	1412.0	(M − H)−
1673	SSC-FA-03	2.000	1376.9	(M − H)−
1674	SSC-FA-03	1.731	1343.6	(M − H)−
1675	SSC-FA-03	1.959	1425.8	(M − H)−
1676	SSC-AF-00	2.165	1408.0	(M − H)−
1677	SSC-AF-00	2.075	1369.9	(M − H)−
1678	SSC-AF-00	2.160	1411.9	(M − H)−
1679	SSC-AF-00	2.152	1437.8	(M − H)−
1680	SSC-FA-03	1.956	1413.9	(M − H)−
1681	SSC-AF-00	2.100	1357.9	(M − H)−
1682	SSC-FA-03	1.957	1350.9	(M − H)−
1683	SSC-FA-03	1.736	1280.9	(M − H)−
1684	SSC-FA-03	1.831	1385.8	(M − H)−
1685	SSC-FA-03	1.831	1433.8	(M − H)−
1686	SSC-AF-00	2.159	1399.9	(M − H)−
1687	SSC-FA-03	1.771	1373.9	(M − H)−
1688	SSC-FA-03	1.852	1287.0	(M − H)−
1689	SSC-AF-00	2.196	1425.9	(M − H)−
1690	SSC-AF-00	2.179	1454.0	(M − H)−
1691	SSC-FA-03	1.755	1254.4	(M − H)−
1692	SSC-FA-03	2.107	1454.0	(M − H)−
1693	SSC-AF-00	2.171	1490.8	(M − H)−
1694	SSC-FA-03	1.904	1336.9	(M − H)−
1695	SSC-FA-03	1.881	1397.8	(M − H)−
1696	SSC-FA-03	1.937	1399.5	(M + H)+
1697	SSC-FA-03	2.021	1440.0	(M − H)−
1698	SSC-FA-03	1.775	1395.7	(M − H)−
1699	SSC-AF-00	2.087	1371.9	(M − H)−
1700	SSC-AF-00	2.192	1461.6	(M − H)−
1701	SSC-AF-00	2.180	1465.9	(M − H)−
1702	SSC-AF-00	2.089	1298.4	(M − H)−
1703	SSC-FA-03	1.491	1476.8	(M − H)−
1704	SSC-FA-03	1.908	1451.8	(M − H)−
1705	SSC-FA-03	2.009	1439.9	(M − H)−
1706	SSC-FA-03	2.065	1354.8	(M − H)−
1707	SSC-FA-03	2.044	1453.8	(M − H)−
1708	SSC-AF-00	2.224	1439.8	(M − H)−
1709	SSC-AF-00	2.152	1399.6	(M − H)−
1710	SSC-FA-03	1.811	1411.8	(M − H)−
1711	SSC-AF-00	2.097	1386.0	(M − H)−
1712	SSC-FA-03	1.853	1385.9	(M − H)−
1713	SSC-AF-00	2.169	1413.9	(M − H)−
1714	SSC-AF-00	2.181	1362.6	(M − H)−
1715	SSC-AF-00	2.123	1383.9	(M − H)−
1716	SSC-AF-00	2.132	1397.7	(M − H)−
1717	SSC-AF-00	2.187	1354.8	(M − H)−
1718	SSC-AF-00	2.104	1465.0	(M − H)−
1719	SSC-AF-00	2.201	1427.9	(M − H)−
1720	SSC-FA-03	1.833	1383.7	(M − H)−
1721	SSC-FA-03	1.701	1359.5	(M − H)−
1722	SSC-AF-00	2.235	1440.0	(M − H)−
1723	SSC-AF-00	2.232	1440.0	(M − H)−
1724	SSC-FA-03	1.811	1391.9	(M − H)−
1725	SSC-AF-00	2.111	1421.8	(M − H)−
1726	SSC-FA-03	2.004	1452.0	(M − H)−
1727	SSC-AF-00	2.164	1447.7	(M − H)−
1728	SSC-FA-03	1.808	1385.9	(M − H)−
1729	SSC-AF-00	2.149	1399.9	(M − H)−
1730	SSC-AF-00	2.083	1292.5	(M − H)−
1731	SSC-AF-00	2.139	1413.9	(M − H)−
1732	SSC-FA-03	1.711	1284.4	(M − H)−
1733	SSC-FA-03	2.021	1342.7	(M − H)−
1734	SSC-FA-03	1.832	1487.5	(M − H)−
1735	SSC-AF-00	2.269	1454.0	(M − H)−
1736	SSC-FA-03	2.052	1455.8	(M − H)−
1737	SSC-AF-00	2.101	1371.8	(M − H)−
1738	SSC-AF-00	2.117	1399.8	(M − H)−
1739	SSC-FA-03	1.901	1412.0	(M − H)−
1740	SSC-AF-00	2.240	1439.9	(M − H)−
1741	SSC-AF-00	2.133	1385.9	(M − H)−
1742	SSC-AF-00	2.129	1298.9	(M − H)−
1743	SSC-FA-03	1.871	1371.6	(M − H)−
1744	SSC-FA-03	2.020	1465.9	(M − H)−
1745	SSC-AF-00	2.151	1507.0	(M − H)−
1746	SSC-FA-03	2.087	1451.8	(M − H)−
1747	SSC-FA-03	1.951	1362.9	(M − H)−
1748	SSC-FA-03	1.865	1444.0	(M − H)−
1749	SSC-FA-03	1.745	1393.8	(M − H)−
1750	SSC-AF-00	2.141	1362.6	(M − H)−
1751	SSC-FA-03	1.873	1401.5	(M + H)+
1752	SSC-FA-03	1.764	1357.8	(M − H)−
1753	SSC-FA-03	1.787	1377.6	(M − H)−
1754	SSC-FA-03	1.972	1425.9	(M − H)−
1755	SSC-AF-00	2.084	1383.9	(M − H)−
1756	SSC-AF-00	2.076	1419.9	(M − H)−
1757	SSC-FA-03	1.937	1425.8	(M − H)−
1758	SSC-FA-03	1.731	1413.9	(M − H)−
1759	SSC-FA-03	2.056	1452.0	(M − H)−
1760	SSC-AF-00	2.148	1397.9	(M − H)−
1761	SSC-AF-00	2.077	1419.9	(M − H)−
1762	SSC-AF-00	2.081	1407.7	(M − H)−
1763	SSC-FA-03	1.920	1441.5	(M − H)−
1764	SSC-FA-03	1.889	1439.9	(M − H)−
1765	SSC-AF-00	2.135	1499.7	(M − H)−
1766	SSC-AF-00	2.211	1453.9	(M − H)−
1767	SSC-AF-00	2.169	1412.0	(M − H)−
1768	SSC-FA-03	1.751	1399.8	(M − H)−
1769	SSC-AF-00	2.079	1407.8	(M − H)−
1770	SSC-AF-00	2.196	1411.9	(M − H)−
1771	SSC-FA-03	1.919	1429.8	(M − H)−
1772	SSC-AF-00	2.152	1459.6	(M − H)−
1773	SSC-AF-00	2.165	1300.5	(M − H)−
1774	SSC-AF-00	2.113	1310.9	(M − H)−
1775	SSC-AF-00	2.183	1412.0	(M − H)−
1776	SSC-FA-03	2.048	1453.8	(M − H)−
1777	SSC-AF-00	2.125	1411.8	(M − H)−
1778	SSC-FA-03	1.737	1268.4	(M + H)+
1779	SSC-FA-03	1.761	1393.8	(M − H)−
1780	SSC-FA-03	1.812	1383.9	(M − H)−
1781	SSC-FA-03	1.899	1425.8	(M − H)−
1782	SSC-AF-00	2.135	1436.0	(M − H)−
1783	SSC-AF-00	2.133	1282.5	(M + H)+
1784	SSC-FA-03	1.923	1300.6	(M − H)−
1785	SSC-AF-00	2.136	1459.8	(M − H)−
1786	SSC-FA-03	2.016	1453.9	(M − H)−
1787	SSC-FA-03	2.020	1451.8	(M − H)−
1788	SSC-FA-03	1.741	1399.5	(M − H)−
1789	SSC-AF-00	2.183	1346.9	(M − H)−
1790	SSC-FA-03	1.807	1407.8	(M − H)−
1791	SSC-AF-00	2.157	1411.9	(M − H)−
1792	SSC-AF-00	2.100	1324.5	(M − H)−
1793	SSC-FA-03	1.912	1350.6	(M − H)−
1794	SSC-FA-03	1.845	1411.9	(M − H)−
1795	SSC-AF-00	2.188	1474.0	(M − H)−
1796	SSC-FA-03	1.971	1423.9	(M − H)−
1797	SSC-AF-00	2.132	1447.7	(M − H)−
1798	SSC-FA-03	2.017	1425.9	(M − H)−
1799	SSC-AF-00	2.161	1413.9	(M − H)−
1800	SSC-AF-00	2.168	1328.5	(M − H)−
1801	SSC-FA-03	1.836	1322.9	(M − H)−
1802	SSC-FA-03	1.952	1397.6	(M − H)−
1803	SSC-AF-00	2.120	1385.9	(M − H)−
1804	SSC-AF-00	2.157	1447.9	(M − H)−
1805	SSC-FA-03	1.923	1415.9	(M − H)−
1806	SSC-FA-03	1.801	1391.8	(M − H)−
1807	SSC-FA-03	2.015	1425.9	(M − H)−
1808	SSC-FA-03	1.880	1301.0	(M − H)−
1809	SSC-FA-03	1.856	1336.9	(M − H)−
1810	SSC-AF-00	2.116	1460.8	(M − H)−
1811	SSC-AF-00	2.172	1439.8	(M − H)−
1812	SSC-AF-00	2.079	1359.5	(M − H)−
1813	SSC-AF-00	2.228	1368.9	(M − H)−
1814	SSC-AF-00	2.131	1399.9	(M − H)−
1815	SSC-FA-03	1.940	1413.8	(M − H)−
1816	SSC-AF-00	2.105	1409.7	(M − H)−
1817	SSC-AF-00	2.179	1411.7	(M − H)−
1818	SSC-AF-00	2.124	1411.8	(M − H)−
1819	SSC-FA-03	1.936	1439.7	(M − H)−
1820	SSC-AF-00	2.251	1465.8	(M − H)−
1821	SSC-AF-00	2.205	1425.9	(M − H)−
1822	SSC-FA-03	1.885	1424.0	(M − H)−
1823	SSC-FA-03	1.972	1426.0	(M − H)−
1824	SSC-FA-03	2.063	1451.9	(M − H)−
1825	SSC-FA-03	1.843	1397.5	(M − H)−
1826	SSC-AF-00	2.231	1439.8	(M − H)−
1827	SSC-FA-03	1.809	1383.9	(M − H)−
1828	SSC-AF-00	2.111	1434.0	(M − H)−
1829	SSC-FA-03	1.900	1385.9	(M − H)−
1830	SSC-FA-03	1.992	1414.0	(M − H)−
1831	SSC-FA-03	1.935	1441.9	(M − H)−
1832	SSC-FA-03	1.955	1399.9	(M − H)−
1833	SSC-AF-00	2.212	1439.9	(M − H)−
1834	SSC-FA-03	1.627	1448.8	(M − H)−
1835	SSC-AF-00	2.236	1451.9	(M − H)−
1836	SSC-FA-03	1.779	1381.6	(M − H)−
1837	SSC-FA-03	1.760	1399.5	(M − H)−
1838	SSC-FA-03	2.095	1465.6	(M − H)−
1839	SSC-AF-00	2.121	1403.9	(M − H)−
1840	SSC-AF-00	2.101	1445.9	(M − H)−
1841	SSC-AF-00	2.136	1425.8	(M − H)−
1842	SSC-AF-00	2.085	1407.9	(M − H)−
1843	SSC-AF-00	2.163	1425.9	(M − H)−
1844	SSC-AF-00	2.091	1365.9	(M − H)−
1845	SSC-AF-00	2.176	1411.9	(M − H)−
1846	SSC-AF-00	2.196	1413.6	(M − H)−
1847	SSC-FA-03	1.800	1399.8	(M − H)−
1848	SSC-AF-00	2.071	1387.9	(M − H)−
1849	SSC-AF-00	2.201	1407.8	(M − H)−
1850	SSC-FA-03	1.904	1433.7	(M − H)−
1851	SSC-FA-03	1.948	1360.9	(M − H)−
1852	SSC-AF-00	2.137	1460.0	(M − H)−
1853	SSC-AF-00	2.099	1409.5	(M − H)−
1854	SSC-FA-03	1.911	1399.5	(M − H)−
1855	SSC-FA-03	1.957	1455.8	(M − H)−
1856	SSC-AF-00	2.148	1336.6	(M − H)−
1857	SSC-FA-03	1.877	1429.7	(M + H)+
1858	SSC-AF-00	2.131	1399.9	(M − H)−
1859	SSC-FA-03	1.985	1439.8	(M − H)−
1860	SSC-AF-00	2.223	1451.8	(M − H)−
1861	SSC-AF-00	2.259	1454.0	(M − H)−
1862	SSC-FA-03	1.980	1424.0	(M − H)−
1863	SSC-FA-03	1.953	1425.8	(M − H)−
1864	SSC-AF-00	2.187	1451.5	(M − H)−
1865	SSC-AF-00	2.097	1373.9	(M − H)−
1866	SSC-FA-03	1.737	1420.0	(M − H)−
1867	SSC-AF-00	2.024	1367.8	(M − H)−
1868	SSC-AF-00	2.172	1437.8	(M − H)−
1869	SSC-FA-03	1.871	1475.8	(M − H)−
1870	SSC-AF-00	2.140	1410.0	(M − H)−
1871	SSC-AF-00	2.101	1435.7	(M − H)−
1872	SSC-FA-03	1.817	1449.6	(M − H)−
1873	SSC-FA-01	6.407	1549.7	(M − H)−
1874	SSC-A-AF-01	8.385	1427.0	(M − H)−
1875	SSC-AF-00	2.139	1428.0	(M − H)−
1876	SSC-A-FA-01	6.835	1531.7	(M + H)+
1877	SSC-FA-03	1.836	1425.6	(M − H)−
1878	SSC-A-FA-01	5.625	1467.7	(M + H)+
1879	SSC-FA-03	1.924	1465.6	(M − H)−
1880	SSC-AF-00	2.231	1490.0	(M − H)−
1881	SSC-FA-03	1.537	1491.0	(M − H)−
1882	SSC-A-AF-01	7.781	1546.1	(M + H)+
1883	SSC-A-FA-01	6.135	1364.6	(M + H)+
1884	SSC-AF-00	2.092	1475.7	(M − H)−
1885	SSC-A-AF-01	7.835	1487.7	(M − H)−
1886	SSC-FA-03	1.516	1486.8	(M − H)−
1887	SSC-A-FA-01	6.040	1473.7	(M + H)+
1888	SSC-A-FA-01	6.519	1598.0	(M − H)−
1889	SSC-A-FA-01	5.489	1431.6	(M + H)+
1890	SSC-AF-00	2.101	1459.7	(M − H)−
1891	SSC-A-AF-01	8.248	1380.6	(M − H)−
1892	SSC-AF-00	2.144	1490.8	(M − H)−
1893	SSC-A-FA-01	5.875	1509.7	(M + H)+
1894	SSC-FA-03	1.919	1411.8	(M − H)−
1895	SSC-A-FA-01	6.648	1513.8	(M − H)−
1896	SSC-AF-00	2.049	1389.9	(M − H)−
1897	SSC-AF-00	2.061	1460.8	(M − H)−
1898	SSC-FA-03	1.879	1459.8	(M − H)−
1899	SSC-A-AF-01	8.316	1432.5	(M − H)−
1900	SSC-FA-03	1.807	1443.6	(M − H)−
1901	SSC-AF-00	2.169	1440.0	(M − H)−
1902	SSC-A-FA-01	6.504	1555.9	(M − H)−
1903	SSC-A-FA-01	5.531	1461.6	(M + H)+
1904	SSC-AF-00	2.080	1421.7	(M − H)−
1905	SSC-FA-03	1.801	1405.8	(M − H)−
1906	SSC-AF-00	2.156	1439.8	(M − H)−
1907	SSC-FA-03	1.956	1463.9	(M − H)−
1908	SSC-FA-03	1.877	1427.8	(M − H)−
1909	SSC-A-AF-01	7.932	1471.6	(M − H)−
1910	SSSC-A-FA-01	6.503	1597.8	(M − H)−
1911	SSC-FA-03	1.779	1466.8	(M − H)−
1912	SSC-A-FA-01	6.449	1378.7	(M + H)+
1913	SSC-AF-00	2.131	1476.8	(M − H)−
1914	SSC-A-FA-01	5.473	1450.0	(M − H)−
1915	SSC-FA-03	1.841	1413.6	(M − H)−
1916	SSC-FA-03	1.868	1439.8	(M − H)−
1917	SSC-FA-03	1.500	1436.9	(M − H)−
1918	SSC-A-AF-01	8.237	1436.6	(M + H)+
1919	SSC-A-FA-01	6.120	1392.6	(M + H)+
1920	SSC-A-FA-01	5.977	1515.6	(M + H)+
1921	SSC-FA-03	1.852	1470.8	(M − H)−
1922	SSC-A-FA-01	5.559	1459.9	(M − H)−
1923	SSC-FA-03	1.849	1427.8	(M − H)−
1924	SSC-FA-03	1.965	1485.8	(M − H)−
1925	SSC-FA-03	1.912	1411.8	(M − H)−
1926	SSC-AF-00	2.191	1526.0	(M − H)−
1927	SSC-A-FA-01	5.764	1497.1	(M − H)−
1928	SSC-FA-03	1.923	1453.6	(M − H)−
1929	SSC-FA-03	1.745	1373.9	(M − H)−
1930	SSC-AF-00	2.139	1522.0	(M − H)−
1931	SSC-FA-03	1.831	1383.9	(M − H)−
1932	SSC-FA-03	1.904	1529.8	(M − H)−
1933	SSC-FA-03	1.924	1453.8	(M − H)−
1934	SSC-FA-03	1.796	1401.9	(M − H)−
1935	SSC-A-AF-01	7.776	1501.9	(M − H)−
1936	SSC-FA-03	1.913	1454.0	(M − H)−
1937	SSC-AF-00	2.104	1479.0	(M − H)−
1938	SSC-AF-00	2.169	1441.8	(M − H)−
1939	SSC-AF-00	2.141	1391.6	(M − H)−
1940	SSC-AF-00	2.163	1434.2	(M − H)−
1941	SSC-AF-00	2.135	1373.6	(M − H)−
1942	SSC-A-FA-01	6.349	1525.6	(M + H)+
1943	SSC-A-FA-01	6.147	1507.5	(M − H)−
1944	SSC-A-FA-01	5.992	1557.6	(M + H)+
1945	SSC-A-FA-01	6.043	1515.6	(M + H)+
1946	SSC-AF-00	2.117	1462.8	(M − H)−
1947	SSC-FA-03	1.851	1408.2	(M − H)−
1948	SSC-FA-03	1.847	1503.9	(M − H)−
1949	SSC-FA-03	1.733	1403.5	(M − H)−
1950	SSC-A-AF-02	7.981	1399.8	(M − H)−
1951	SSC-A-AF-01	7.521	1501.9	(M − H)−
1952	SSC-A-FA-01	6.000	1492.0	(M − H)−
1953	SSC-A-AF-01	7.695	1555.6	(M − H)−
1954	SSC-FA-03	1.836	1427.8	(M − H)−
1955	SSC-AF-00	2.204	1546.8	(M − H)−
1956	SSC-FA-03	1.741	1415.8	(M − H)−
1957	SSC-FA-03	1.908	1452.0	(M − H)−
1958	SSC-AF-00	2.145	1397.6	(M − H)−
1959	SSC-A-AF-01	7.092	1454.7	(M − H)−
1960	SSC-A-FA-01	5.577	1465.6	(M − H)−
1961	SSC-A-FA-01	4.977	1359.6	(M + H)+
1962	SSC-FA-03	1.501	1472.9	(M − H)−
1963	SSC-AF-00	2.123	1448.0	(M − H)−
1964	SSC-A-FA-01	6.416	1549.6	(M − H)−
1965	SSC-FA-03	1.860	1426.1	(M − H)−
1966	SSC-FA-03	1.760	1418.0	(M − H)−
1967	SSC-A-FA-01	5.724	1360.5	(M − H)−
1968	SSC-AF-00	2.148	1358.0	(M − H)−
1969	SSC-FA-03	1.895	1411.8	(M − H)−
1970	SSC-A-AF-01	8.021	1556.1	(M − H)−
1971	SSC-AF-00	2.109	1429.7	(M − H)−
1972	SSC-AF-00	2.107	1489.9	(M − H)−
1973	SSC-AF-00	2.045	1432.7	(M − H)−
1974	SSC-A-AF-01	8.269	1392.7	(M − H)−
1975	SSC-AF-00	2.128	1397.6	(M − H)−
1976	SSC-FA-03	1.905	1454.0	(M − H)−
1977	SSC-FA-03	1.941	1512.0	(M − H)−
1978	SSC-AF-00	2.131	1487.9	(M − H)−
1979	SSC-AF-00	2.131	1415.8	(M − H)−
1980	SSC-FA-03	1.871	1542.8	(M − H)−
1981	SSC-A-FA-01	5.297	1456.6	(M + H)+
1982	SSC-FA-03	1.548	1464.8	(M − H)−
1983	SSC-FA-03	1.873	1515.9	(M − H)−
1984	SSC-AF-00	2.116	1473.7	(M − H)−
1985	SSC-AF-00	2.085	1486.9	(M − H)−
1986	SSC-A-FA-01	5.824	1505.6	(M + H)+
1987	SSC-A-FA-01	6.361	1545.7	(M + H)+
1988	SSC-AF-00	2.160	1423.8	(M − H)−
1989	SSC-A-FA-01	6.744	1512.1	(M − H)−
1990	SSC-FA-03	1.896	1485.6	(M − H)−
1991	SSC-A-AF-01	7.800	1501.7	(M − H)−
1992	SSC-A-FA-01	6.268	1527.6	(M + H)+
1993	SSC-FA-03	1.841	1501.9	(M − H)−
1994	SSC-FA-03	1.840	1461.8	(M − H)−
1995	SSC-A-AF-01	8.312	1379.0	(M − H)−
1996	SSC-AF-00	2.148	1427.8	(M − H)−
1997	SSC-A-AF-01	7.956	1469.6	(M − H)−
1998	SSC-AF-00	2.115	1413.9	(M − H)−
1999	SSC-FA-03	1.789	1399.5	(M − H)−
2000	SSC-A-FA-01	5.895	1509.5	(M + H)+
2001	SSC-FA-03	1.908	1411.8	(M − H)−
2002	SSC-A-AF-01	7.488	1496.8	(M − H)−
2003	SSC-A-AF-01	7.715	1362.6	(M − H)−
2004	SSC-FA-03	1.835	1419.9	(M − H)−
2005	SSC-FA-03	1.775	1387.6	(M − H)−
2006	SSC-FA-03	1.808	1401.6	(M − H)−
2007	SSC-A-FA-02	6.119	1465.7	(M + H)+
2008	SSC-A-FA-02	5.992	1443.7	(M + H)+
2009	SSC-FA-03	1.867	1298.5	(M − H)−
2010	SSC-AF-00	2.117	1272.9	(M − H)−
2011	SSC-A-FA-02	5.859	1463.5	(M − H)−
2012	SSC-AF-00	2.199	1300.9	(M − H)−
2013	SSC-FA-03	1.796	1284.5	(M − H)−
2014	SSC-FA-03	2.105	1300.5	(M − H)−
2015	SSC-FA-03	2.127	1368.7	(M − H)−
2016	SSC-FA-03	2.021	1344.9	(M − H)−
2017	SSC-FA-03	2.012	1328.9	(M − H)−
2018	SSC-AF-00	2.241	1328.6	(M − H)−
2019	SSC-FA-03	2.019	1362.9	(M − H)−
2020	SSC-A-FA-02	5.791	1457.6	(M − H)−
2021	SSC-A-AF-01	8.403	1560.9	(M − H)−
2022	SSC-A-AF-01	8.377	1546.9	(M − H)−
2023	SSC-A-AF-01	.795	1487.9	(M − H)−
2024	SSC-A-FA-01	7.003	1526.0	(M − H)−
2025	SSC-A-FA-01	6.751	1501.8	(M − H)−
2026	SSC-A-AF-01	8.057	1491.0	(M − H)−
2027	SSC-A-FA-01	5.683	1396.6	(M + H)+
2028	SSC-A-FA-01	5.761	1477.8	(M + H)+
2029	SSC-A-AF-01	8.036	1504.9	(M − H)−
2030	SSC-AF-00	2.200	1495.9	(M − H)−
2031	SSC-FA-03	1.979	1469.8	(M − H)−
2032	SSC-A-AF-01	8.084	1504.9	(M − H)−
2033	SSC-A-AF-01	7.992	1491.0	(M − H)−
2034	SSC-A-FA-01	5.313	1485.8	(M + H)+
2035	SSC-FA-03	2.117	1529.9	(M − H)−
2036	SSC-A-FA-01	6.809	1508.0	(M − H)−
2037	SSC-A-FA-01	6.308	1443.9	(M − H)−
2038	SSC-A-FA-01	6.261	1528.8	(M − H)−
2039	SSC-A-AF-01	7.985	1381.7	(M + H)+
2040	SSC-A-AF-01	7.727	1345.6	(M − H)−
2041	SSC-A-AF-01	7.716	1381.8	(M + H)+
2042	SSC-A-AF-01	7.679	1333.7	(M + H)+
2043	SSC-A-AF-01	7.745	1347.7	(M + H)+
2044	SSC-A-AF-01	7.796	1347.7	(M + H)+
2045	SSC-A-FA-01	5.783	1347.7	(M + H)+
2046	SSC-A-FA-01	6.255	1483.8	(M − H)−
2047	SSC-A-AF-01	8.128	1499.8	(M + H)+
2048	SSC-AF-00	2.244	1525.9	(M − H)−
2049	SSC-A-FA-01	6.192	1486.1	(M − H)−
2050	SQDAA05	0.89	1595.3	(M − H)−
2051	SSC-A-AF-01	8.191	1485.7	(M + H)+
2052	SSC-A-FA-01	6.256	1514.7	(M + H)+
2053	SSC-AF-00	2.245	1524.1	(M − H)−
2054	SSC-A-AF-01	8.000	1511.1	(M − H)−
2055	SSC-A-AF-01	7.879	1379.8	(M + H)+
2056	SQDFA50	1.10	1597.5	(M − H)−
2057	SSC-AF-00	2.235	1467.7	(M − H)−
2058	SSC-AF-00	2.009	1416.1	(M − H)−
2059	SSC-AF-00	2.267	1397.7	(M − H)−
2060	SSC-FA-03	1.748	1401.0	(M − H)−
2061	SSC-AF-00	2.119	1353.6	(M − H)−
2062	SSC-FA-03	2.067	1421.6	(M − H)−
2063	SSC-AF-00	2.155	1389.6	(M − H)−
2064	SSC-FA-03	1.881	1403.1	(M − H)−
2065	SSC-FA-03	1.908	1403.2	(M − H)−
2066	SSC-FA-03	2.188	1435.6	(M − H)−
2067	SSC-FA-03	2.003	1451.7	(M − H)−
2068	SSC-FA-03	1.893	1357.7	(M − H)−
2069	SSC-AF-00	2.140	1419.0	(M − H)−
2070	SSC-AF-00	2.077	1401.2	(M − H)−
2071	SSC-FA-03	1.756	1350.5	(M + H)+
2072	SSC-AF-00	2.131	1443.0	(M − H)−
2073	SSC-FA-03	1.957	1395.7	(M − H)−
2074	SSC-FA-03	1.977	1430.0	(M − H)−
2075	SSC-FA-03	1.885	1388.8	(M − H)−
2076	SSC-FA-03	1.881	1434.0	(M − H)−
2077	SSC-AF-00	2.091	1403.1	(M + H)+
2079	SSC-FA-03	1.927	1381.8	(M − H)−
2080	SSC-AF-00	2.169	1448.0	(M − H)−
2081	SSC-AF-00	2.193	1393.8	(M − H)−
2082	SSC-AF-00	2.277	1437.6	(M + H)+
2083	SSC-FA-03	2.037	1395.8	(M − H)−
2084	SSC-FA-03	1.755	1381.0	(M − H)−
2085	SSC-AF-00	2.143	1419.7	(M + H)+
2086	SQDFA05	1.04	1306.7	(M + H)+
2087	SQDFA05	1.01	1308.7	(M + H)+
2088	SQDFA05	1.07	1356.7	(M + H)+
2089	SQDFA05	1.00	1290.7	(M + H)+
2090	SQDFA05	1.00	1308.7	(M + H)+
2091	SQDFA05	1.04	1344.7	(M + H)+
2092	SQDFA05	1.02	1306.7	(M + H)+
2093	SQDFA05	1.04	1340.6	(M + H)+
2094	SQDFA05	1.03	1306.7	(M + H)+
2095	SQDFA05	1.04	1322.7	(M + H)+
2096	SSC-TFA-07	1.363	1407.7	(M + H)+
2097	SSC-A-FA-01	5.915	1497.1	(M − H)−
2098	SSC-A-FA-01	5.805	1576.8	(M + H)+
2099	SSC-A-AF-01	7.441	1521.8	(M − H)−
2100	SSC-A-FA-01	5.575	1494.6	(M + H)+
2101	SSC-A-FA-01	5.523	1523.6	(M + H)+
2102	SSC-A-FA-01	5.717	1484.7	(M + H)+
2103	SSC-A-FA-01	5.472	1540.9	(M + H)+
2104	SSC-A-AF-01	7.816	1553.0	(M − H)−
2105	SSC-A-AF-01	8.048	1510.9	(M − H)−
2106	SSC-A-AF-01	7.720	1472.7	(M + H)+
2107	SSC-A-FA-01	5.476	1570.7	(M + H)+
2108	SSC-A-FA-01	5.508	1528.7	(M + H)+
2109	SSC-A-FA-01	5.720	1513.1	(M − H)−
2110	SSC-A-FA-01	5.288	1535.1	(M − H)−
2111	SSC-A-FA-01	5.409	1512.8	(M − H)−
2112	SSC-A-FA-01	5.979	1568.7	(M + H)+
2113	SSC-AF-00	2.089	1452.9	(M − H)−
2114	SSC-FA-03	1.861	1483.8	(M − H)−
2115	SSC-AF-00	2.080	1452.9	(M − H)−
2116	SSC-TFA-07	1.576	1394.8	(M + H)+
2117	SSC-FA-03	1.961	1500.0	(M − H)−
2118	SSC-TFA-07	1.527	1443.8	(M + H)+
2119	SSC-FA-03	2.023	1520.0	(M − H)−
2120	SSC-FA-03	1.819	1546.9	(M − H)−
2121	SSC-AF-00	2.199	1547.0	(M − H)−
2122	SSC-FA-03	1.927	1499.9	(M − H)−
2123	SSC-FA-03	2.116	1519.9	(M − H)−
2124	SSC-FA-03	2.105	1552.0	(M − H)−
2125	SSC-TFA-07	1.640	1519.8	(M − H)+
2126	SSC-TFA-07	1.704	1539.8	(M + H)+
2127	SSC-TFA-07	1.580	1443.8	(M + H)+
2128	SSC-TFA-07	1.581	1571.9	(M + H)+
2129	SSC-TFA-07	1.700	1539.9	(M + H)+
2130	SSC-TFA-07	1.640	1519.9	(M + H)+
2131	SSC-TFA-07	1.588	1535.9	(M + H)+
2132	SSC-TFA-07	1.696	1539.9	(M + H)+
2133	SSC-TFA-07	1.640	1540.0	(M + H)+
2134	SSC-TFA-07	1.640	1539.7	(M + H)+
2135	SSC-TFA-07	1.611	1571.9	(M + H)+
2136	SSC-TFA-07	1.637	1535.9	(M + H)+
2137	SSC-TFA-07	1.692	1519.8	(M + H)+
2138	SSC-TFA-07	1.635	1540.0	(M + H)+
2139	SSC-TFA-07	1.632	1519.9	(M + H)+
2140	SSC-TFA-07	1.700	1519.9	(M + H)+
2141	SSC-TFA-07	1.704	1519.9	(M + H)+
2142	SSC-AF-00	2.084	1339.6	(M − H)−
2143	SSC-AF-00	2.133	1308.4	(M − H)−
2144	SSC-AF-00	2.069	1379.5	(M + H)+
2145	SSC-FA-03	1.812	1296.5	(M − H)−
2146	SSC-FA-03	1.861	1411.5	(M − H)−
2147	SSC-FA-03	1.873	1411.5	(M − H)−
2148	SSC-FA-03	1.752	1280.5	(M − H)−
2149	SSC-FA-03	1.893	1411.7	(M − H)−
2150	SSC-FA-03	1.851	1395.5	(M + H)+
2151	SSC-FA-03	1.911	1405.9	(M − H)−
2152	SSC-A-FA-01	5.337	1302.6	(M + H)+
2153	SSC-A-AF-01	7.408	1288.7	(M − H)−
2154	SSC-A-FA-01	4.595	1262.5	(M + H)+
2155	SSC-A-AF-01	7.603	1314.9	(M − H)−
2156	SSC-A-FA-01	5.383	1300.7	(M − H)−
2157	SSC-A-AF-01	7.243	1286.9	(M − H)−
2158	SSC-A-FA-01	5.564	1316.6	(M + H)+
2159	SSC-A-AF-01	7.513	1318.6	(M + H)+
2160	SSC-A-FA-01	5.204	1290.6	(M + H)+
2161	SSC-A-FA-02	6.656	1469.9	(M − H)−
2162	SSC-A-FA-02	6.215	1455.6	(M − H)−
2163	SSC-A-AF-02	8.011	1477.9	(M − H)−
2164	SSC-A-FA-02	6.060	1429.8	(M − H)−
2165	SSC-A-AF-02	8.325	1519.9	(M − H)−
2166	SSC-A-FA-02	6.292	1479.6	(M + H)+
2167	SSC-A-FA-02	6.045	1471.8	(M − H)−
2168	SSC-AF-00	2.245	1471.9	(M − H)−
2169	SSC-FA-03	2.100	1529.6	(M − H)−
2170	SSC-AF-00	2.192	1537.9	(M − H)−
2171	SSC-AF-00	2.287	1533.7	(M − H)−
2172	SQDFA05long	1.480	1307.1	(M + H)+
2173	SQDFA05long	1.160	1303.1	(M + H)+
2174	SQDFA05long	1.100	1420.3	(M + H)+
2175	SQDFA05long	1.640	1434.3	(M + H)+
2176	SQDFA05long	1.880	1506.4	(M + H)+
2177	SQDFA0flong	1.550	1468.3	(M + H)+
2178	SQDFA05long	1.430	1430.3	(M + H)+
2179	SQDFA05long	1.170	1416.3	(M + H)+
2180	SQDFA05	0.820	1528.3	(M + H)+
2181	SQDFA05	0.770	1485.2	(M + H)+
2182	SQDFA05long	2.420	1441.2	(M + H)+
2183	SQDFA05long	2.550	1475.2	(M + H)+
2184	SQDAA50	0.800	1511.7	(M − H)−
2185	SQDFA05long	2.730	1489.2	(M + H)+
2186	SQDFA05long	2.770	1473.3	(M + H)+
2187	SQDFA05	0.790	1541.4	(M − H)−
2188	SQDFA05	0.600	1406.0	(M − H)−

Example 2 Synthesis of Compounds Used for Measurement of Cell Growth Inhibitory Activity and Measurement of In Vivo Antitumor Activity

Scale-up synthesis of the compounds used in Examples 4 and 5 was carried out.

Scale-up Synthesis of Compound 1217

Compound 1217 was synthesized according to the following scheme.

Synthesis of Compound aa011-a

Under a nitrogen atmosphere to a solution of WSCI·HCl (27.4 g, 143 mmol) in DMF (217 mL) was added HOB t (17.72 g, 131 mmol) under ice-cooling, and Compound aa033b (48.8 g, 119 mmol) was further added as a mixed solution in DCM (90 mL,) and DMF (90 mL). The mixture was stirred at 0° C. for 30 minutes. A solution of dimethylamine in THF (21 mol/1, 65.6 mL, 131 mmol) was added dropwise thereto, and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was diluted with ethyl acetate (488 mL), and the organic layer was washed with hydrochloric acid (1 mol/L, 390 mal.) twice, then washed with water, further washed with a mixed solution of a saturated aqueous sodium bicarbonate solution and water (1:1, 488 mL) twice, and further washed with a mixed solution of brine and water (1:1, 488 mL) once. Then, the resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound aa011-a (51.16 g, yield: 98%).

LCMS (ESI) m/z=437.0 (M+H)+

Retention time: 1.262 min (analysis condition SMDFA05)

Synthesis of Compound 1217-a

To a solution of Compound aa079 (42.2 g, 111 mmol), produced by the same method as the method described in the present Examples, and Oxyma (19.99 g, 141 mmol) in DMF (391 mL) was added WSCI—HCl (31.5 g, 164 mmol) at room temperature, and the mixture was stirred for 30 minutes to give Solution A.

Under a nitrogen atmosphere, DBU (17.49 mL, 117 mmol) was added dropwise to a solution of Compound aa011-a (51.16 g, 117 mmol) in DMF (391 ml) at room temperature, and the mixture was stirred for 5 minutes. Pyridine hydrochloride (14.9 g, 129 mmol) was added thereto, and the mixture was stirred for 10 minutes. To the resulting reaction solution were added Solution A and DIPEA (22.46 mL, 129 mmol), and under a nitrogen atmosphere, the mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with ethyl acetate (422 mL), washed with hydrochloric acid (I mol/L, 422 mL) twice, and the resulting aqueous layer was extracted with ethyl acetate (422 mL) twice. All organic layers were combined, and sequentially washed with water (422 mL), a mixed solution of a saturated aqueous sodium bicarbonate solution and water (1:1, 422 mL), and a mixed solution of brine and water (1:1, 422 mL). Then, the resulting organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. DCM (512 mL) was added to the resulting residue, and the mixture was stirred for 0.5 hours. Magnesium sulfate (30 g) was added thereto, the mixture was stirred for 30 minutes, and the solid was then removed by filtration. The resulting solution was purified by silica gel column chromatography (hexane/ethyl acetate) to give Compound 1217-a (55.55 g, yield: 87%).

LCMS (ESI) m/z=598.2 (M+Na)+

Retention time: 1.320 min (analysis condition SMDAM05)

Synthesis of Compound 1217-b

Under a nitrogen atmosphere, to a solution of Compound 1217-a (55.55 g, 96 mmol) in DCM (193 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.115 g, 0.965 mmol) at room temperature, and phenylsilane (8.31 ml, 67.5 mmol) was further added dropwise. The mixture was stirred for 30 minutes. The reaction solution was diluted with MTBE (556 ml) and extracted with a mixed solution of a saturated aqueous sodium bicarbonate solution and water (1:1, 556 mL). The resulting organic layer was extracted with water (278 ml). The aqueous layers were combined, and DCM (556 ml) was added. Phosphoric acid (56.7 g, 579 mmol) was added dropwise thereto and the pH was adjusted to 2 to 3. After separating the organic layer, the aqueous layer was extracted with DCM (556 ml). The resulting organic layers were combined, washed with a mixed solution of brine and water (1:1, 556 nil), and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound 1217-b (48.87 g, yield: 95%).

LCMS (ESI) m/z=536 (M+H)+

Retention time: 1.138 min (analysis condition SMDAM05)

Synthesis of Compound 1217-b-resin

In a reaction vessel equipped with a filter was set 2-chlorotrityl chloride resin (purchased from Sunresin New Materials Co., Ltd., 1.36 mmol/g, 114 g, 155 mmol), DCM (1140 mL) was added, the mixture was stirred at 25° C. for 45 minutes, and the solvent was then removed through the filter. A solution of Compound 1217-b (48.87 g, 91 mmol), methanol (29.6 mL, 730 mmol), and DIPEA (76 mL, 438 mmol) in DCM (798 mL) was added to the reaction vessel, the mixture was stirred at 25° C. for 60 minutes, and the solution was removed through the filter. Subsequently, a solution of methanol (111 mL, 2737 mmol) and DIPEA (76 mL, 438 mmol) in DCM (684 mL) was added to the reaction vessel, the mixture was stirred at 25° C. for 90 minutes, and the solution was removed through the filter. DCM (570 mL) was added to the reaction vessel, the mixture was stirred for 5 minutes, and the solution was removed through the filter. This operation of washing the resin was further repeated four times, and the resulting resin was dried under reduced pressure to give Compound 1217-b-resin (140.5 g). By quantifying the Fmoc group of the compound attached to the resin, the loading amount was calculated to be 0.482 mmol/g.

Synthesis of Compound 1217-c-resin

The resin (0.482 mmol/g, 60 g, 28.92 mmol) obtained as described above was set in a plastic solid-phase reaction vessel. DCM (600 mL) was added to this solid-phase reaction vessel at room temperature, and after shaking for 5 minutes, the solvent was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solvent was removed from the frit. This step of washing the resin was further repeated once. A solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added to this solid-phase reaction vessel to deprotect the Fmoc group. After shaking for 10 minutes, the solution was removed from the frit, DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.96 g, 57.8 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was removed from the frit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-cLeu-OH (40.7 g, 116 mmol) and Oxyma (10.3 g, 72.3 mmol) in DMF (180 mL) and a solution of N,N′-diisopropylcarbodiimide (DIC) in DMF (10%, 216 mL) were mixed, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 50° C. for 24 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. This step of washing the resin with DCM was further repeated five times. The resulting resin was dried under reduced pressure to give Compound 1217-c-resin (62.5 g).

Subsequent elongation of Fmoc-Pro-OH, Fmoc-Hph(4-CF3-35-F2)-OH (Compound aa134). Fmoc-MeGly-OH, Fmoc-EtPhe(4-Me)—OH (Compound aa113), Fmoc-Aze(2)-OH, Fmoc-MeAla-OH, and Fmoc-Ile-OH was carried out using a peptide synthesizer manufactured by Intavis (Multipep RSi), and the synthesis was performed by the Fmoc solid-phase synthesis method. Specific procedures for the operation were performed according to the instructions attached to the synthesizer.

Compound 1217-c-resin (200 mg per solid-phase reaction vessel) obtained as described above was added to thirty solid-phase reaction vessels and set in the peptide synthesizer. Dichloromethane (DCM) was added to all of these thirty solid-phase reaction vessels, and the resin was swollen by allowing to stand for 1 hour. Thereafter, the solvent was removed from the frit.

Elongation of Fmoc-Pro-OH

To all of the thirty solid-phase reaction vessels, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 1.4 mL per solid-phase reaction vessel) was added, heated to 30° C., and after 10 minutes, the solution was removed from the frit. To all of these thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin with DMF was further repeated three times. Subsequently, a solution of Fmoc-Pro-OH (CAS No. 71989-31-6) (0.6 mol/L) and HOAt (0.375 mol/L) in NMP (0.6 mL per solid-phase reaction vessel) and a solution of N,N′-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer, then added to all of the thirty solid-phase reaction vessels, and allowed to stand at 40° C. for 4 hours. Thereafter, the solution was removed from the frit. To all of the thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated twice.

Elongation of Fmoc-l h 4-CF3-35-F2-OH (Compound aa134 To all of the thirty resin-containing solid-phase reaction vessels obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %. 14 mL per solid-phase reaction vessel) was added, heated to 35° C., and after 10 minutes, the solution was removed from the frit. To all of these thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin with DMF was further repeated three times. Subsequently, a solution of Fmoc-Hph(4-CF3-35-F2)-OH (Compound aa134) (0.45 mol/L) and HOAt (0.375 mol/L) in NMP (0.6 mL per solid-phase reaction vessel) and a solution of N,N′-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer, then added to all of the thirty solid-phase reaction vessels, and allowed to stand at 40° C. for 2.5 hours. Thereafter, the solution was removed from the frit. To all of the thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated twice.

Elongation of Fmoc-MeGly-OH

To all of the thirty resin-containing solid-phase reaction vessels obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 1.4 mL per solid-phase reaction vessel) was added, heated to 35° C., and after 10 minutes, the solution was removed from the frit. To all of these thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin with DMF was further repeated three times. Subsequently, a solution of Fmoc-MeGly-OH (0.6 mol/L) and HOAt (0.375 mol/L) in NMP (0.6 mL per solid-phase reaction vessel) and a solution of N,N-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer, then added to all of the thirty solid-phase reaction vessels, and allowed to stand at 40° C. for 2.5 hours. Thereafter, the solution was removed from the frit. To all of the thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated twice.

Elongation of Fmoc-EtPhe(4-Me)-OH (Compound aa113)

To all of the thirty resin-containing solid-phase reaction vessels obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 1.4 mL per solid-phase reaction vessel) was added, heated to 35° C., and after 10 minutes, the solution was removed from the frit. To all of these thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin with DMF was further repeated three times. Subsequently, a solution of Fmoc-EtPhe(4-Me)-OH (0.6 mol/L), produced by the same method as the method described in the present Examples, and HOAt (0.375 mol/L) in NMP (0.6 mL per solid-phase reaction vessel) and a solution of N,N′-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer, then added to all of the thirty solid-phase reaction vessels, and allowed to stand at 40° C. for 2.5 hours. Thereafter, the solution was removed from the frit. To all of the thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated twice.

Elongation of Fmoc-Aze(2)-OH

To all of the thirty resin-containing solid-phase reaction vessels obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 1.4 mL per solid-phase reaction vessel) was added, heated to 35° C., and after 10 minutes, the solution was removed from the frit. To all of these thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin with DMF was further repeated three times. Subsequently, a mixed solution of Fmoc-Aze(2)-OH (0.6 mol/L) and HOOBt (0.375 mol/L) in NMP and DMSO (7:3) (0.6 mL per solid-phase reaction vessel) and a solution of N,N-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer, then added to all of the thirty solid-phase reaction vessels, and allowed to stand at 60′C for 5 hours. Thereafter, a solution of N,N-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) was added to all of the thirty solid-phase reaction vessels, and allowed to stand at 60° C. for 5 hours. Thereafter, the solution was removed from the frit. To all of the thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated twice.

Elongation of Fmoc-MeAla-OH

To all of the thirty resin-containing solid-phase reaction vessels obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 1.4 mL per solid-phase reaction vessel) was added, heated to 35′C, and after 10 minutes, the solution was removed from the frit. To all of these thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin with DMF was further repeated three times. Subsequently, a solution of Fmoc-MeAla-OH (0.6 mol/L) and HOAt (0.375 mol/L) in NMP (0.6 mL per solid-phase reaction vessel) and a solution of N,N′-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer, then added to all of the thirty solid-phase reaction vessels, and allowed to stand at 40° C. for 2.5 hours. Thereafter, the solution was removed from the frit. To all of the thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated twice.

Elongation of Fmoc-Ile-OH

To all of the thirty resin-containing solid-phase reaction vessels obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 1.4 mL per solid-phase reaction vessel) was added, heated to 35° C., and after 10 minutes, the solution was removed from the frit. To all of these thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin with DMF was further repeated three times. Subsequently, a solution of Fmoc-Ile-OH (0.6 mol/L) and HOAt (0.375 mol/L) in NMP (0.6 mL per solid-phase reaction vessel) and a solution of N,N-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer, then added to all of the thirty solid-phase reaction vessels, and allowed to stand at 40° C. for 10 hours. Thereafter, the solution was removed from the frit. To all of the thirty solid-phase reaction vessels, DMF (1.4 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated twice. Subsequently, to all of the thirty solid-phase reaction vessels, DCM (1.6 mL per solid-phase reaction vessel) was added, and the solvent was removed from the frit. This step of washing the resin was further repeated five times. The resin was recovered from all of the thirty solid-phase reaction vessels and mixed to perform the subsequent operation.

Elongation of Fmoc-MeLeu-OH

The resin obtained as described above was added to a 200 mL plastic solid-phase reaction vessel, DCM (60 mL) was added thereto, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. Toluene (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. This step of washing the resin with toluene was further repeated once. To this solid-phase reaction vessel, a solution of diazabicycloundecene (DBU) in toluene (2 v/v %, 45 mL) was added, and after shaking at 30° C. for 5 minutes, the solution was removed from the frit. Toluene (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. This step of washing the resin with toluene was further repeated once. DCM (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30′C for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated once. To this solid-phase reaction vessel was added a solution of Fmoc-MeLeu-OH (4.25 g, 11.57 mmol), [ethylcyano(hydroxyimino)acetate-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphoric acid (PyOxym) (6.10 g, 11.57 mmol), and DIPEA (3.03 mL, 17.35 mmol) in DCM (45 mL), and the vessel was shaken at 30° C. for 3 hours. Thereafter, the solution was removed from the frit. DMF (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the fit. This step of washing the resin with DMF was further repeated four times. DCM (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated three times. Thereafter, the resulting resin was dried under reduced pressure.

DCM (60 mL) was added to the above-described solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. DMF (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once. To this solid-phase reaction vessel, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 45 mL) was added, and after shaking at 30° C. for 15 minutes, the solution was removed from the frit. DMF (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (50 mL) was added to this solid-phase reaction vessel, and after shaking at 30° C. for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated four times to give Compound 1217-d-loaded resin.

Synthesis of Compound 1217-d (Cleavage of Peptide from Resin)

To the resin-containing solid-phase reaction vessel obtained as described above was added a mixed solution of 2,2,2-trifluoroethanol (TFE) (60 mL), DC M (60 mL), and DIPEA (0.909 mL), and the vessel was shaken at room temperature for 2 hours. Thereafter, the solution was recovered from the frit. To this solid-phase reaction vessel was added a mixed solution of 2,2,2-trifluoroethanol (TFE) (30 mL) and DCM (30 mL), the vessel was shaken at room temperature for 5 minutes, and the solution was then recovered from the frit. To this solid-phase reaction vessel was further added a mixed solution of 2,2,2-trifluoroethanol (TFE) (30 mL) and DC M (30 mL), the vessel was shaken at room temperature for 5 minutes, and the solution was then recovered from the frit. All recovered solutions were combined, and the solvent was evaporated under reduced pressure to give Compound 1217-d (3.85 g) as a crude product.

LCMS (ESI) m/z=1453.9 (M−H)−

Retention time: 0.67 min (analysis condition SQDAA50)

Synthesis of Compound 1217 (Cyclization and Purification of Peptide)

Compound 1217-d (3.85 g) obtained as described above was dissolved in a mixture of isopropyl acetate (529 mL) and DIPEA (0.915 mL, 5.24 mmol), HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, CAS No. 330645-87-9) (1.805 g, 4.36 mmol) was added, and the mixture was stirred at room temperature for 21 hours. Thereafter, the solvent was evaporated under reduced pressure until the solution volume was reduced to about half. To the resulting solution was added a mixed solution of a saturated aqueous ammonium chloride solution (40 mL) and water (40 mL), and the mixture was extracted with isopropyl acetate (350 mL). The resulting organic layer was sequentially washed with a mixed solution of a saturated aqueous sodium bicarbonate solution (40 mL) and water (40 mL) and a mixed solution of brine (40 mL) and water (40 mL), then dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 3.36 g of a residue. The resulting residue was purified by reverse phase silica gel column chromatography (Daisogel SP-120-40/60-ODS-RPS, acetonitrile (containing 0.1% formic acid)/water (containing 0.1% formic acid) was used as the eluting solution), and the eluate containing the target compound was lyophilized to give Compound 1217 (1.36 g, yield: 34%). The mass spectral value and the liquid chromatography retention time of the obtained Compound 1217 are described in Table 22.

Scale-Up Synthesis of Compound 1201

By the same method as in the synthesis of Compound 1217, Compound 1201 (3.05 g) was obtained by using Fmoc-Hyp(Et)-OH instead of Fmoc-Pro-OH and using Fmoc-MeCha-OH instead of Fmoc-EtPhe(4-Me)-OH. The mass spectral value and the liquid chromatography retention time of the obtained Compound 1201 are described in Table 22.

Scale-Up Synthesis of Compound 558

Using Compound aa006-resin (0.437 mmol/g, 14.4 g, 6.3 mmol) synthesized by the method described in WO 2018/225864 as a raw material, Compound 558 (2.54 g, 27/%) was obtained by the same method as in the synthesis of Compound 1217. The mass spectral value and the liquid chromatography retention time of the obtained Compound 558 are described in Table 22.

Scale-Up Synthesis of Compound 926

Compound 926 was synthesized according to the following scheme.

Synthesis of Compound aa007-a

Under a nitrogen atmosphere, to a solution of Compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid, Fmoc-MeAsp(OA1)-OH) (87.94 g, 215 mmol) in DMF (430 ml) were added HOBt (31.9 g, 236 mmol) and WSCI·HCl (49.4 g, 258 mmol), and the mixture was stirred for 30 minutes. Thereafter, the reaction solution was cooled to 0° C., morpholine (20.44 mL, 236 mmol) was added dropwise, and the, mixture was stirred at 0° C. for 45 minutes. Water (180 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water (180 mL) was further added, and the mixture was stirred at room temperature for 105 minutes. The precipitated solid was collected by filtration and dried under reduced pressure to give Compound aa007%-a. (86.83 g, 84%).

LCMS (ESI) m/z=479 (M+H)+

Retention time: 2.57 min (analysis condition SMDFA05long)

Synthesis of Compound 926-a

To a solution of Compound aa079 (22.6 g, 59.6 mmol), produced by the method described in the present Examples, and Oxyma (10.69 g, 75 mmol) in DMF (203 mL) was added WSCI·HCl (16.83 g, 88 mmol) at room temperature, and the mixture was stirred for 30 minutes to give Solution A.

Under a nitrogen atmosphere, DBU (9.45 mL, 62.7 mmol) was added dropwise to a solution of Compound aa007-a (30 g, 62.7 mmol) in DMF (203 mL) at room temperature, and the mixture was stirred for 5 minutes. Pyridine hydrochloride (7.97 g, 69 mmol) was added thereto, and the mixture was stirred for 5 minutes. To the resulting reaction solution were added Solution A and DIPEA (10.95 mL, 62.7 mmol), and under a nitrogen atmosphere, the mixture was stirred at room temperature for 2.5 hours. The reaction solution was diluted with ethyl acetate (300 mL), washed with hydrochloric acid (1 mol/L, 300 mL) twice, and the resulting aqueous layer was extracted with ethyl acetate (300 mL) twice. All organic layers were combined, and sequentially washed with water (300 mL), washed with a mixed solution of a saturated aqueous sodium bicarbonate solution and water (1:1, 300 mL) twice, and further washed with a mixed solution of brine and water (1:1, 300 mL). Then, the resulting organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. DCM (300 mL) was added to the resulting residue, and the solid was removed by filtration. From the resulting solution, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give Compound 926-a (23.8 g, yield: 61.5%).

LCMS (ESI) m/z=640.4 (M+Na)+

Retention time: 0.97 min (analysis condition SQDFA05)

Synthesis of Compound 926-b

Under a nitrogen atmosphere, to a solution of Compound 926-a (23.8 g, 38.5 mmol) in DCM (77 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.445 g, 0.385 mmol) at room temperature, and phenylsilane (3.32 mL, 27 mmol) was further added. The mixture was stirred for 30 minutes. The reaction solution was diluted with MTBE (240 mL) and extracted with a mixed solution of a saturated aqueous sodium bicarbonate solution and water (1:1, 240 mL). The resulting organic layer was extracted with water (50 mL). All aqueous layers were combined, and DCM (240 mL) was added. Phosphoric acid (13.44 ml, 231 mmol) was added dropwise thereto, and after separating the organic layer, the aqueous layer was extracted with DCM (240 mL). The resulting organic layers were combined, washed with a mixed solution of brine and water (1:1, 240 mL), and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Compound 926-b (21.35 g, yield: 96%).

LCMS (ESI) nm/z=578.4 (M+H)+

Retention time: 0.80 min (analysis condition SQDFA05)

Synthesis of Compound 926-b-resin

In a reaction vessel equipped with a filter was set 2-chlorotrityl chloride resin (1.36 mmol/g, 46.2 g, 62.8 mmol), DCM (462 mL) was added, the vessel was shaken at room temperature for 45 minutes, and the solvent was then removed through the filter, A solution of Compound 926-b (21.35 g, 37 mmol), methanol (11.96 mL, 296 mmol), and DIPEA (30.9 mL, 177 mmol) in DCM (323 mL) was added to the reaction vessel, the vessel was shaken at room temperature for 60 minutes, and the solution was removed through the filter. Subsequently, a solution of methanol (44.85 mL, 1.1 mol) and DIPEA (30.9 mL, 177 mmol) in DCM (323 mL) was added to the reaction vessel, the vessel was shaken at room temperature for 90 minutes, and the solution was removed through the filter. DCM (323 mL) was added to the reaction vessel, the vessel was shaken for 5 minutes, and the solution was removed through the filter. This operation of washing the resin was further repeated four times, and the resulting resin was dried under reduced pressure to give Compound 926-b-resin (59.1 g). By quantifying the Fmoc group of the compound attached to the resin, the loading amount was calculated to be 0.433 mmol/g.

Synthesis of Compound 926-c

Subsequent elongation of Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hph(4-CF3-3-Cl)—OH (Compound aa132), Fmoc-MeGly-OH, Fmoc-MeCha-OH, Fmoc-Aze(2)-OH, Fmoc-MeAla-OH, Fmoc-Ile-OH, and Fmoc-MeLeu-OH was carried out by the Fmoc solid-phase synthesis method.

Elongation of Fmoc-cLeu-OH

Compound 926-b-resin (0.433 mmol/g, 59 g, 25.5 mmol) was added to a reaction vessel equipped with a filter. DCM (600 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once. To this solid-phase reaction vessel, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the flit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-cLeu-OH (35.9 g, 102 mmol) and Oxyma (9.08 g, 63.9 mmol) in DMF (180 ml) and a solution of N,N′-diisopropylcarbodiimide (DIC) in DMF (10 v/v %, 216 mL) were mixed at room temperature, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 50° C. for 24 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times.

Elongation of Fmoc-Pro-OH

To the solid-phase reaction vessel obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-Pro-OH (17.24 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) and N,N′-diisopropylcarbodiimide (DIC) (11.54 mL, 74.1 mmol) were mixed at room temperature, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 30° C. for 17 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin was further repeated four times. The resulting resin was dried under reduced pressure to give 63.1 g of a resin.

Elongation of Fmoc-Hph(4-CF3-3-CD-OH (Compound aa132)

DCM (600 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. DMF (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once. A solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added thereto, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the fit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-Hph(4-CF3-3-Cl)—OH (Compound aa132) (25.7 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) and N,N′-diisopropylcarbodiimide (DIC) (11.54 mL, 74.1 mmol) were mixed at room temperature, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 30° C. for 21 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times.

Elongation of Fmoc-MeGly-OH

To the solid-phase reaction vessel obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylarsine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the fit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-MeGly-OH (15.91 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) and N,N′-diisopropylcarbodiimide (DIC) (11.54 mL, 74.1 mmol) were mixed at room temperature, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 30° C. for 32 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. This step of washing the resin with DMF was further repeated four times.

Elongation of Fmoc-MeCha-OH

To the solid-phase reaction vessel obtained as described above, a solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-MeCha-OH (20.82 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) and N,N-diisopropylcarbodiimide (DIC) (11.54 mL, 74.1 mmol) were mixed at room temperature, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 30° C. for 12 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated four times. The resulting resin was dried under reduced pressure to give 72.4 g of a resin.

Elongation of Fmoc-Aze(2)-OH

DCM (600 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. DMF (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once. A solution of diazabicycloundecene (DBU) in DMF (2 v/v % X, 420 mL) was added thereto, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-Aze(2)-OH (16.52 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) and N,N′-diisopropylcarbodiimide (DIC) (11.54 mL, 74.1 mmol) were mixed at room temperature, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 30° C. for 21 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated four times. The resulting resin was dried under reduced pressure to give 73.1 g of a resin.

Elongation of Fmoc-MeAla-OH

DCM (600 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. DMF (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once. A solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added thereto, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-MeAla-OH (16.63 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) and N,N′-diisopropylcarbodiimide (DIC) (11.54 mL, 74.1 mmol) were mixed, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. After shaking this solid-phase reaction vessel at 30° C. for 16 hours, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated four times. The resulting resin was dried under reduced pressure to give 76.4 g of a resin.

Elongation of Fmoc-Ile-OH

DCM (600 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. DMF (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once. A solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 420 mL) was added thereto, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. A solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DCM (420 ml) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once.

A solution of Fmoc-Ile-OH (36.1 g, 102 mmol) and HOAt (8.69 g, 63.9 mmol) in DMF (180 mL) and a solution of N,N′-diisopropylcarbodiimide (DIC) (10 v/v %) in DMF (216 mL) were mixed, and after 2 minutes, added to the solid-phase reaction vessel obtained as described above. This solid-phase reaction vessel was shaken at 40° C. for 8 hours, and then shaken at 30° C. for 14 hours. Thereafter, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the fit. This step of washing the resin with DMF was further repeated three times. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated once. Toluene (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the fit. This step of washing the resin with toluene was further repeated once.

Elongation of Fmoc-MeLeu-O

To the solid-phase reaction vessel obtained as described above, a solution of diazabicycloundecene (DBU) in toluene (2 v/v %, 420 mL) was added, and after shaking at room temperature for 10 minutes, the solution was removed from the frit.

Toluene (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with toluene was further repeated once. DCM (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated once. A solution of Fmoc-MeLeu-OH (37.6 g, 102 mmol), [ethylcyano(hydroxyimino)acetate-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphoric acid (PyOxym) (53.9 g, 102 mmol), and DIPEA (26.8 mL, 153 mmol) in DCM (300 mL) was added thereto, and the vessel was shaken at 30° C. for 2 hours. Thereafter, the solution was removed from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (420 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the fit. This step of washing the resin with DCM was further repeated four times. The resulting resin was dried under reduced pressure to give 80.9 g of a resin. 40.4 g of the obtained resin (equivalent to 13 mmol in terms of the amount of Compound 926-b-resin loaded) was transferred to another solid-phase reaction vessel equipped with a filter to carry out the next reaction.

Synthesis of Compound 926-c (Cleavage of Peptide from Resin)

To the solid-phase reaction vessel obtained as described above, containing 40.4 g of the resin (equivalent to 13 mmol in terms of the amount of Compound 926-b-resin loaded), was added DCM (300 mL), and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. DMF (210 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated once. A solution of diazabicycloundecene (DBU) in DMF (2 v/v %, 210 mL) was added thereto, and after shaking at room temperature for 10 minutes, the solution was removed from the frit. DMF (210 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DMF was further repeated four times. DCM (210 mL) was further added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was removed from the frit. This step of washing the resin with DCM was further repeated four times.

To the resin-containing solid-phase reaction vessel obtained as described above was added a mixed solution of 2,2,2-trifluoroethanol (TFE) (270 mL), DCM (270 mL), and DIPEA (4.01 mL, 23 mmol), and the vessel was shaken at room temperature for 2 hours. Thereafter, the solution was recovered from the frit. To this solid-phase reaction vessel was added a mixed solution of 2,2,2-trifluoroethanol (TFE) (150 mL) and DCM (150 mL), the vessel was shaken at room temperature for 20 minutes, and the solution was then recovered from the frit. To this solid-phase reaction vessel was further added a mixed solution of 2,2,2-trifluoroethanol (TFE) (150 mL) and DCM (150 mL), the vessel was shaken at room temperature for 20 minutes, and the solution was then recovered from the frit. All recovered solutions were combined, and the solvent was evaporated under reduced pressure to give Compound 926-c (18.9 g) as a crude product.

LCMS (ESI) m/z=1474.0 (M+H)+

Retention time: 0.69 min (analysis condition SQDFA05)

Synthesis of Compound 926 (cyclization and purification of peptide)

Compound 926-c (9.6 g) obtained as described above was dissolved in a mixture of isopropyl acetate (1246 mL) and DIPEA (1.959 mL, 11.21 mmol), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) (4 g, 9.35 mmol) was added, and the mixture was stirred at room temperature for 14 hours. Thereafter, the reaction solution was washed with a mixed solution of a saturated aqueous ammonium chloride solution (350 mL) and water (350 mL), and then further washed with brine (700 ml). The resulting organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give about 8 g of a residue. Furthermore, the same operation was also carried out on Compound 926-c (9.3 g), and all obtained residues were purified by reverse phase silica gel column chromatography (acetonitrile (containing 0.1% formic acid)/water (containing 0.1% formic acid) was used as the eluting solution) to give a crude product (8.1 g). 7.9 g of the resulting crude product was purified by silica gel column chromatography (DCM/methanol) to give Compound 926 (6.9 g, 37%). The mass spectral value and the liquid chromatography retention time of the obtained Compound 926 are described in Table 22.

Example 3: Pharmacological Test Example

Protein-Protein Interaction Inhibition Between Kras and SOS1 (KasG12D-SOS PPI) Using AlphaScreen

Protein-protein interaction inhibition (PPI) between Kras and SOS1 was measured by energy transfer from nickel-conjugated donor beads to streptavidin-conjugated acceptor beads using biotin-tagged human Kras expressed in E. coli and loaded with GDP after purification and His-tagged human SOS1 enzyme. This measurement utilizes the phenomenon in which donor beads are irradiated with light at 680 nm, such that energy is transferred to acceptor beads through singlet oxygen and light at 520-620 nm is detected from the acceptor beads. The 50% inhibitory concentration (IC50 value) was calculated from the inhibition rate relative to the test substance-free control group.

IC50 values of the test compounds are shown in the following table. The cyclic peptide compounds disclosed herein were shown to inhibit the protein-protein interaction between Kras and SOS1. Inhibition of binding between K-ras and SOS1 is known to inhibit signaling downstream of Kras. Accordingly, the compounds of the present invention are also suggested to have cell growth inhibitory activity.

TABLE 23
Compound KRAS G12D-SOS PPI
No.      IC50(μM)
1        0.0059
2        0.015
3        0.31
4        0.013
5        0.00099
6        0.013
7        0.018
8        0.075
9        0.0015
10       0.018
11       0.0015
12       0.24
13       0.038
14       0.11
15       0.0033
16       0.00070
17       0.030
18       0.23
19       0.050
20       0.00076
21       0.25
22       0.11
23       0.0027
24       0.025
25       0.15
26       0.0043
27       0.0033
28       0.16
29       0.32
30       0.0046
31       0.38
32       0.020
33       0.0069
34       0.074
35       0.0021
36       0.0047
37       0.017
38       0.16
39       0.011
40       0.00096
41       0.011
42       0.19
43       0.031
44       0.0011
45       0.084
46       0.12
47       0.0015
48       0.00097
49       0.012
50       0.028
51       0.090
52       0.00066
53       0.12
54       0.0019
55       0.00077
56       0.0023
57       0.016
58       0.028
59       0.036
60       0.0079
61       0.016
62       0.0038
63       0.0037
64       0.13
65       0.24
66       0.0036
67       0.0083
68       0.00058
69       0.0088
70       0.16
71       0.15
72       0.00047
73       0.00033
74       0.0072
75       0.094
76       0.19
77       0.10
78       0.0016
79       0.0093
80       0.0028
81       0.014
82       0.14
83       0.11
84       0.073
85       0.015
86       0.0090
87       0.045
88       0.018
89       0.0019
90       0.0050
91       0.0015
92       0.0055
93       0.0069
94       0.0033
95       0.011
96       0.22
97       0.040
98       0.068
99       0.0029
100      0.0074
101      0.16
102      0.011
103      0.022
104      0.028
105      0.0053
106      0.0089
107      0.0040
108      0.0050
109      0.040
110      0.0038
111      0.10
112      0.073
113      0.28
114      0.020
115      0.0060
116      0.14
117      0.021
118      0.0019
119      0.039
120      0.00055
121      0.0054
122      0.0086
123      0.17
124      0.14
125      0.0028
126      0.00050
127      0.00043
128      0.0016
129      0.011
130      0.010
131      0.0033
132      0.00096
133      0.023
134      0.00061
135      0.038
136      0.0077
137      0.00076
138      0.044
139      0.0084
140      0.00081
141      0.032
142      0.038
143      0.068
144      0.0011
145      0.025
146      0.0040
147      0.0067
148      0.0018
149      0.051
150      0.0013
151      0.0050
152      0.11
153      0.060
154      0.0048
155      0.0016
156      0.00098
157      0.0075
158      0.010
159      0.0024
160      0.0010
161      0.00082
162      0.23
163      0.0061
164      0.0022
165      0.041
166      0.021
167      0.058
168      0.029
169      0.016
170      0.35
171      0.014
172      0.0040
173      0.00056
174      0.057
175      0.012
176      0.0014
177      0.045
178      0.022
179      0.042
180      0.011
181      0.13
182      0.00098
183      0.026
184      0.32
185      0.17
186      0.048
187      0.0032
188      0.0061
189      0.11
190      0.15
191      0.0034
192      0.022
193      0.42
194      0.027
195      0.0095
196      0.013
197      0.0068
198      0.0085
199      0.036
200      0.013
201      0.00058
202      0.039
203      0.031
204      0.18
205      0.00049
206      0.11
207      0.0030
208      0.12
209      0.0016
210      0.080
211      0.043
212      0.042
213      0.048
214      0.28
215      0.029
216      0.0080
217      0.066
218      0.0019
219      0.073
220      0.0031
221      0.0028
222      0.020
223      0.018
224      0.23
225      0.015
226      0.0035
227      0.082
228      0.024
229      0.0067
230      0.039
231      0.12
232      0.020
233      0.066
234      0.0021
235      0.011
236      0.0085
237      0.042
238      0.012
239      0.00077
240      0.14
241      0.018
242      0.027
243      0.00043
244      0.14
245      0.00037
246      0.00030
247      0.0070
248      0.031
249      0.0016
250      0.0098
251      0.0038
252      0.055
253      0.00099
254      0.015
255      0.0078
256      0.00098
257      0.097
258      0.036
259      0.021
260      0.050
261      0.052
262      0.043
263      0.0029
264      0.0045
265      0.28
266      0.0046
267      0.13
268      0.018
269      0.0034
270      0.00067
271      0.065
272      0.00052
273      0.036
274      0.00082
275      0.046
276      0.00076
277      0.0051
278      0.025
279      0.00099
280      0.024
281      0.0078
282      0.094
283      0.0068
284      0.071
285      0.052
286      0.096
287      0.0051
288      0.0017
289      0.00030
290      0.16
291      0.055
292      0.00045
293      0.12
294      0.0014
295      0.068
296      0.055
297      0.049
298      0.021
299      0.13
300      0.0095
301      0.00074
302      0.00068
303      0.00068
304      0.087
305      0.17
306      0.044
307      0.0044
308      0.00093
309      0.00075
310      0.096
311      0.0059
312      0.0010
313      0.0042
314      0.0026
315      0.12
316      0.0033
317      0.030
318      0.019
319      0.0082
320      0.0099
321      0.011
322      0.031
323      0.14
324      0.38
325      0.014
326      0.00070
327      0.00047
328      0.094
329      0.040
330      0.080
331      0.030
332      0.21
333      0.11
334      0.00050
335      0.067
336      0.093
337      0.016
338      0.22
339      0.00038
340      0.0047
341      0.0029
342      0.00095
343      0.00087
344      0.00083
345      0.058
346      0.011
347      0.027
348      0.0060
349      0.19
350      0.064
351      0.28
352      0.0055
353      0.00069
354      0.0016
355      0.053
356      0.00092
357      0.022
358      0.033
359      0.0032
360      0.0028
361      0.34
362      0.00066
363      0.00065
364      0.0097
365      0.038
366      0.0040
367      0.00060
368      0.0027
369      0.35
370      0.00035
371      0.0013
372      0.13
373      0.33
374      0.0065
375      0.012
376      0.044
377      0.024
378      0.00068
379      0.013
380      0.0056
381      0.0016
382      0.035
383      0.26
384      0.0010
385      0.0047
386      0.010
387      0.0042
388      0.00050
389      0.045
390      0.00077
391      0.00040
392      0.012
393      0.0053
394      0.013
395      0.047
396      0.22
397      0.0023
398      0.12
399      0.0089
400      0.00085
401      0.0036
402      0.026
403      0.0011
404      0.0048
405      0.27
406      0.25
407      0.039
408      0.011
409      0.0024
410      0.00048
411      0.00062
412      0.12
413      0.050
414      0.11
415      0.0015
416      0.054
417      0.015
418      0.017
419      0.0024
420      0.0034
421      0.010
422      0.00087
423      0.064
424      0.011
425      0.00057
426      0.0087
427      0.00071
428      0.0091
429      0.099
430      0.039
431      0.25
432      0.0045
433      0.0022
434      0.00052
435      0.25
436      0.16
437      0.00047
438      0.0060
439      0.052
440      0.0029
441      0.00073
442      0.070
443      0.030
444      0.018
445      0.00067
446      0.0018
447      0.014
448      0.091
449      0.030
450      0.0066
451      0.010
452      0.080
453      0.017
454      0.0027
455      0.059
456      0.034
457      0.069
458      0.0059
459      0.0095
460      0.0010
461      0.0012
462      0.012
463      0.0044
464      0.13
465      0.055
466      0.0031
467      0.20
468      0.0025
469      0.0036
470      0.0022
471      0.058
472      0.14
473      0.41
474      0.28
475      0.051
476      0.0041
477      0.0043
478      0.0030
479      0.30
480      0.0014
481      0.0020
482      0.17
483      0.017
484      0.11
485      0.16
486      0.0048
487      0.0059
488      0.029
489      0.0081
490      0.24
491      0.00035
492      0.012
493      0.30
494      0.0086
495      0.0032
496      0.010
497      0.0043
498      0.049
499      0.085
500      0.0048
501      0.16
502      0.047
503      0.0071
504      0.053
505      0.086
506      0.00068
507      0.00048
508      0.012
509      0.0013
510      0.0040
511      0.090
512      0.15
513      0.046
514      0.014
515      0.00055
516      0.062
517      0.028
518      0.00067
519      0.0020
520      0.017
521      0.071
522      0.0053
523      0.0058
524      0.082
525      0.0023
526      0.0066
527      0.038
528      0.020
529      0.0082
530      0.14
531      0.0016
532      0.00048
533      0.0085
534      0.013
535      0.00065
536      0.23
537      0.082
538      0.11
539      0.19
540      0.15
541      0.0043
542      0.061
543      0.00056
544      0.0022
545      0.0011
546      0.13
547      0.0010
548      0.0016
549      0.0040
550      0.11
551      0.00052
552      0.00063
553      0.027
554      0.0053
555      0.0026
556      0.030
557      0.0044
558      0.0018
559      0.0017
560      0.11
561      0.0034
562      0.00056
563      0.0011
564      0.0096
565      0.055
566      0.16
567      0.0015
568      0.0080
569      0.073
570      0.027
571      0.00083
572      0.039
573      0.010
574      0.0086
575      0.00056
576      0.23
577      0.021
578      0.12
579      0.017
580      0.066
581      0.032
582      0.024
583      0.37
584      0.031
585      0.094
586      0.16
587      0.0012
588      0.36
589      0.00049
590      0.0014
591      0.0021
592      0.026
593      0.034
594      0.00054
595      0.29
596      0.034
597      0.011
598      0.30
599      0.012
600      0.0045
601      0.087
602      0.28
603      0.00089
604      0.016
605      0.0090
606      0.0083
607      0.22
608      0.0059
609      0.11
610      0.15
611      0.0033
612      0.12
613      0.50
614      0.024
615      0.22
616      0.0039
617      0.11
618      0.0024
619      0.019
620      0.011
621      0.059
622      0.0017
623      0.0018
624      0.16
625      0.070
626      0.0024
627      0.013
628      0.020
629      0.010
630      0.0017
631      0.0010
632      0.073
633      0.12
634      0.26
635      0.19
636      0.0011
637      0.026
638      0.045
639      0.014
640      0.00086
641      0.018
642      0.054
643      0.027
644      0.017
645      0.058
646      0.12
647      0.00058
648      0.0032
649      0.36
650      0.00060
651      0.086
652      0.0043
653      0.044
654      0.11
655      0.0049
656      0.017
657      0.31
658      0.15
659      0.13
660      0.21
661      0.013
662      0.0032
663      0.016
664      0.025
665      0.037
666      0.025
667      0.0051
668      0.0019
669      0.22
670      0.0051
671      0.052
672      0.0025
673      0.011
674      0.0056
675      0.059
676      0.031
677      0.0041
678      0.0017
679      0.037
680      0.0099
681      0.0059
682      0.020
683      0.00061
684      0.0019
685      0.13
686      0.17
687      0.016
688      0.0023
689      0.0021
690      0.0018
691      0.0071
692      0.0069
693      0.0016
694      0.014
695      0.0023
696      0.040
697      0.012
698      0.023
699      0.00083
700      0.0050
701      0.00069
702      0.13
703      0.0085
704      0.013
705      0.36
706      0.066
707      0.014
708      0.011
709      0.041
710      0.0044
711      0.035
712      0.0027
713      0.0040
714      0.0023
715      0.0061
716      0.0011
717      0.00086
718      0.039
719      0.0059
720      0.039
721      0.0015
722      0.42
723      0.017
724      0.024
725      0.0078
726      0.0013
727      0.0069
728      0.016
729      0.043
730      0.012
731      0.0035
732      0.0014
733      0.051
734      0.0022
735      0.00044
736      0.037
737      0.11
738      0.015
739      0.036
740      0.011
741      0.086
742      0.017
743      0.040
744      0.0075
745      0.029
746      0.13
747      0.011
748      0.13
749      0.0028
750      0.028
751      0.082
752      0.20
753      0.035
754      0.024
755      0.0056
756      0.00058
757      0.0037
758      0.14
759      0.16
760      0.0052
761      0.00057
762      0.0055
764      0.083
765      0.050
766      0.13
767      0.024
768      0.0011
769      0.052
770      0.020
771      0.025
772      0.15
773      0.14
774      0.00055
775      0.0046
776      0.0073
777      0.33
778      0.00070
779      0.16
780      0.021
781      0.060
782      0.021
783      0.0098
784      0.0040
785      0.0035
786      0.0060
787      0.0029
788      0.013
789      0.00061
790      0.0025
791      0.32
792      0.0035
793      0.024
794      0.011
795      0.072
796      0.0093
797      0.019
798      0.059
799      0.0014
800      0.086
801      0.45
802      0.39
803      0.30
804      0.00099
805      0.038
806      0.0011
807      0.00074
808      0.099
809      0.047
810      0.049
811      0.059
812      0.036
813      0.069
814      0.00041
815      0.026
816      0.0039
817      0.015
818      0.0012
819      0.053
820      0.00073
821      0.012
822      0.15
823      0.016
824      0.0056
825      0.00035
826      0.11
827      0.0028
828      0.040
829      0.0023
830      0.28
831      0.18
832      0.12
833      0.0091
834      0.057
835      0.00054
836      0.00066
837      0.0060
838      0.010
839      0.22
840      0.0012
841      0.024
842      0.043
843      0.049
844      0.028
845      0.0082
847      0.054
848      0.016
849      0.0019
850      0.024
851      0.027
852      0.19
853      0.00062
854      0.011
855      0.0084
856      0.014
857      0.017
858      0.33
859      0.064
860      0.21
861      0.0045
862      0.0027
863      0.0025
864      0.073
865      0.055
866      0.0012
867      0.0034
868      0.0029
869      0.0098
870      0.015
871      0.00078
872      0.0019
873      0.051
874      0.025
875      0.0031
876      0.018
877      0.0025
878      0.32
879      0.036
880      0.0029
881      0.00056
882      0.00047
883      0.049
884      0.063
885      0.0019
886      0.10
887      0.0062
888      0.0039
889      0.070
890      0.00047
891      0.0096
892      0.068
893      0.021
894      0.011
895      0.0084
896      0.0011
897      0.15
898      0.012
899      0.0019
900      0.00084
901      0.035
902      0.14
903      0.024
904      0.0073
905      0.18
906      0.0027
907      0.0014
908      0.039
909      0.020
910      0.0043
911      0.0045
912      0.012
913      0.053
914      0.0011
915      0.040
916      0.042
917      0.0020
918      0.00089
919      0.052
920      0.015
921      0.0011
922      0.23
923      0.23
924      0.13
925      0.36
926      0.00099
927      0.023
928      0.027
929      0.0041
930      0.039
931      0.27
932      0.0054
933      0.083
934      0.034
935      0.0060
936      0.0011
937      0.25
938      0.00069
939      0.0080
940      0.15
941      0.0033
942      0.0010
943      0.00083
944      0.018
945      0.0098
946      0.0075
947      0.075
948      0.0031
949      0.0013
950      0.0090
951      0.0079
952      0.12
953      0.18
954      0.0019
955      0.026
956      0.080
957      0.00044
958      0.0021
959      0.0014
960      0.0079
961      0.012
962      0.0078
963      0.013
964      0.011
965      0.00086
966      0.11
967      0.058
968      0.0031
969      0.0020
970      0.25
971      0.016
972      0.33
973      0.0028
974      0.00091
975      0.022
976      0.18
977      0.00033
978      0.17
979      0.037
980      0.0038
981      0.00037
982      0.048
983      0.0018
984      0.025
985      0.042
986      0.025
987      0.00096
988      0.012
989      0.034
990      0.083
991      0.076
992      0.18
993      0.016
994      0.011
995      0.0057
996      0.090
997      0.024
998      0.017
999      0.0017
1000     0.0026
1001     0.00044
1002     0.0021
1003     0.0084
1004     0.013
1005     0.0035
1006     0.0063
1007     0.013
1008     0.00076
1009     0.043
1010     0.0043
1011     0.038
1012     0.0012
1013     0.031
1014     0.013
1015     0.018
1016     0.024
1017     0.00088
1018     0.011
1019     0.014
1020     0.051
1021     0.24
1022     0.00042
1023     0.020
1024     0.0019
1025     0.0043
1026     0.00079
1027     0.0082
1029     0.0014
1030     0.0017
1031     0.32
1032     0.060
1033     0.36
1034     0.0017
1035     0.011
1036     0.0077
1037     0.00066
1038     0.018
1039     0.045
1040     0.014
1041     0.0016
1042     0.00072
1043     0.060
1044     0.055
1045     0.0067
1046     0.0046
1047     0.0063
1048     0.018
1049     0.0037
1050     0.049
1051     0.0029
1052     0.11
1053     0.0067
1054     0.12
1055     0.0022
1056     0.018
1057     0.0012
1058     0.014
1059     0.00064
1060     0.00065
1061     0.014
1062     0.00092
1063     0.043
1064     0.0043
1065     0.070
1066     0.024
1067     0.29
1068     0.12
1069     0.017
1070     0.00091
1071     0.0013
1072     0.0012
1073     0.0021
1074     0.011
1075     0.14
1076     0.019
1077     0.034
1078     0.19
1079     0.015
1080     0.0010
1081     0.025
1082     0.27
1083     0.019
1084     0.053
1085     0.050
1086     0.18
1087     0.015
1088     0.17
1089     0.0016
1090     0.088
1091     0.0010
1092     0.041
1093     0.00073
1094     0.0022
1095     0.046
1096     0.0026
1097     0.23
1098     0.0056
1099     0.00092
1100     0.0063
1101     0.0090
1102     0.16
1103     0.016
1104     0.011
1105     0.021
1106     0.035
1107     0.093
1108     0.011
1109     0.023
1110     0.13
1111     0.041
1112     0.0060
1113     0.41
1114     0.011
1115     0.0025
1116     0.00044
1117     0.0022
1118     0.20
1119     0.18
1120     0.0025
1121     0.0014
1122     0.067
1123     0.18
1124     0.0070
1125     0.0025
1126     0.25
1127     0.26
1128     0.0021
1129     0.15
1130     0.0044
1131     0.013
1132     0.0013
1133     0.056
1134     0.0060
1135     0.0058
1136     0.070
1137     0.0046
1138     0.067
1139     0.00059
1140     0.0020
1141     0.00097
1142     0.0065
1143     0.00073
1144     0.00049
1145     0.0011
1146     0.0019
1148     0.0012
1149     0.00062
1150     0.00052
1151     0.0052
1152     0.0012
1153     0.0025
1154     0.0024
1155     0.17
1156     0.14
1157     0.0016
1158     0.00052
1159     0.0028
1160     0.00042
1161     0.060
1162     0.00057
1163     0.00046
1164     0.0014
1165     0.00073
1166     0.00047
1167     0.0087
1168     0.10
1169     0.053
1170     0.00054
1171     0.00099
1172     0.0068
1173     0.00074
1174     0.062
1175     0.00079
1176     0.00080
1177     0.012
1178     0.0010
1179     0.00052
1180     0.00050
1181     0.0060
1182     0.00056
1183     0.00073
1184     0.13
1185     0.011
1186     0.0086
1187     0.099
1188     0.033
1189     0.00074
1190     0.00083
1191     0.0067
1192     0.00039
1193     0.0021
1194     0.00052
1195     0.038
1196     0.00048
1197     0.00060
1198     0.0012
1199     0.00070
1200     0.045
1201     0.00053
1202     0.24
1203     0.0021
1204     0.00044
1205     0.0028
1206     0.00057
1207     0.0027
1208     0.00069
1209     0.00085
1210     0.00074
1211     0.031
1212     0.12
1213     0.017
1214     0.077
1215     0.0018
1216     0.12
1217     0.0010
1218     0.0049
1219     0.016
1220     0.00064
1221     0.038
1222     0.025
1223     0.0012
1224     0.00067
1225     0.034
1226     0.015
1227     0.0013
1228     0.00059
1229     0.046
1230     0.098
1231     0.00059
1232     0.00047
1233     0.0025
1234     0.0045
1235     0.0055
1236     0.0073
1237     0.00086
1238     0.0099
1239     0.18
1240     0.29
1241     0.00050
1242     0.00052
1243     0.027
1244     0.00063
1245     0.00054
1246     0.055
1247     0.0048
1248     0.00067
1249     0.033
1250     0.00063
1251     0.0026
1252     0.0025
1253     0.00081
1254     0.00054
1255     0.0014
1256     0.0091
1257     0.0065
1258     0.026
1259     0.00049
1260     0.00054
1261     0.00065
1262     0.0013
1263     0.0027
1264     0.00054
1265     0.28
1266     0.0012
1267     0.00036
1268     0.019
1269     0.0010
1270     0.00061
1271     0.00049
1272     0.0020
1273     0.0072
1274     0.0038
1275     0.00065
1276     0.017
1277     0.0067
1278     0.00065
1279     0.016
1280     0.074
1281     0.00042
1282     0.00081
1283     0.00063
1284     0.00069
1285     0.00053
1286     0.024
1287     0.0011
1288     0.031
1289     0.00067
1290     0.00063
1291     0.0054
1292     0.0020
1293     0.00096
1294     0.050
1295     0.00050
1296     0.00059
1297     0.00051
1298     0.028
1299     0.0036
1300     0.094
1301     0.00067
1302     0.00075
1303     0.00072
1304     0.085
1305     0.24
1306     0.00050
1307     0.0027
1308     0.00065
1309     0.00085
1310     0.00087
1311     0.00051
1312     0.00074
1313     0.065
1314     0.090
1315     0.0010
1316     0.0032
1317     0.00057
1318     0.078
1319     0.00082
1320     0.0014
1321     0.00055
1322     0.00082
1323     0.0043
1324     0.0012
1325     0.00096
1326     0.0051
1327     0.072
1328     0.22
1329     0.0017
1330     0.00062
1331     0.0011
1332     0.023
1333     0.00048
1334     0.0030
1335     0.00049
1336     0.00066
1337     0.00055
1338     0.017
1339     0.00057
1340     0.0012
1341     0.00082
1342     0.00053
1343     0.00061
1344     0.19
1345     0.040
1346     0.00060
1347     0.0013
1348     0.00062
1349     0.15
1350     0.017
1351     0.00082
1352     0.11
1353     0.011
1354     0.0077
1355     0.0032
1356     0.0011
1357     0.00052
1358     0.019
1359     0.0062
1360     0.00097
1361     0.024
1362     0.00081
1363     0.00057
1364     0.0012
1365     0.0012
1366     0.00063
1367     0.00065
1368     0.00067
1369     0.00055
1370     0.00060
1371     0.0016
1372     0.017
1373     0.0077
1374     0.00054
1375     0.0093
1376     0.00071
1377     0.0058
1378     0.38
1379     0.064
1380     0.016
1381     0.15
1382     0.23
1383     0.13
1384     0.23
1385     0.20
1386     0.0100
1387     0.014
1388     0.010
1389     0.24
1390     0.28
1391     0.065
1392     0.028
1393     0.38
1394     0.13
1395     0.27
1396     0.016
1397     0.0064
1398     0.0066
1399     0.070
1400     0.21
1401     0.12
1402     0.057
1403     0.032
1404     0.017
1405     0.082
1406     0.16
1407     0.17
1408     0.16
1409     0.17
1410     0.27
1411     0.082
1412     0.31
1413     0.19
1414     0.038
1415     0.034
1416     0.097
1417     0.029
1418     0.11
1419     0.046
1420     0.089
1421     0.032
1422     0.016
1423     0.19
1424     0.20
1425     0.019
1426     0.048
1427     0.25
1428     0.042
1429     0.044
1430     0.40
1431     0.22
1432     0.26
1433     0.029
1434     0.15
1435     0.0074
1436     0.039
1437     0.081
1438     0.036
1439     0.0037
1440     0.016
1441     0.0064
1442     0.28
1443     0.023
1444     0.0088
1445     0.25
1446     0.15
1447     0.10
1448     0.0011
1449     0.014
1450     0.22
1451     0.020
1452     0.038
1453     0.11
1454     0.011
1455     0.030
1456     0.012
1457     0.011
1458     0.0072
1459     0.29
1460     0.13
1461     0.037
1462     0.00079
1463     0.00068
1464     0.19
1465     0.051
1466     0.0010
1467     0.12
1468     0.090
1469     0.23
1470     0.21
1471     0.0017
1472     0.067
1473     0.39
1474     0.24
1475     0.0027
1476     0.046
1477     0.028
1478     0.0030
1479     0.12
1480     0.0089
1481     0.0050
1482     0.088
1483     0.034
1484     0.19
1485     0.00084
1486     0.00050
1487     0.34
1488     0.26
1489     0.018
1490     0.32
1491     0.0037
1492     0.24
1493     0.10
1494     0.14
1495     0.12
1496     0.0020
1497     0.025
1498     0.0017
1499     0.019
1500     0.0039
1501     0.014
1502     0.024
1503     0.016
1504     0.057
1505     0.22
1506     0.0029
1507     0.024
1508     0.0013
1509     0.023
1510     0.11
1511     0.19
1512     0.0012
1513     0.27
1514     0.0010
1515     0.077
1516     0.34
1517     0.049
1518     0.37
1519     0.12
1520     0.059
1521     0.11
1522     0.090
1523     0.00075
1524     0.0019
1525     0.10
1526     0.10
1527     0.19
1528     0.041
1529     0.011
1530     0.13
1531     0.23
1532     0.0048
1533     0.068
1534     0.062
1535     0.041
1536     0.021
1537     0.0039
1538     0.11
1539     0.054
1540     0.23
1541     0.0040
1542     0.17
1543     0.16
1544     0.0056
1545     0.042
1546     0.040
1547     0.022
1548     0.14
1549     0.0036
1550     0.019
1551     0.0049
1552     0.061
1553     0.012
1554     0.20
1555     0.0061
1556     0.017
1557     0.0057
1558     0.071
1559     0.028
1560     0.16
1561     0.033
1562     0.0048
1563     0.0062
1564     0.038
1565     0.014
1566     0.020
1567     0.033
1568     0.094
1569     0.016
1570     0.0043
1571     0.0048
1572     0.0098
1573     0.057
1574     0.035
1575     0.045
1576     0.0051
1577     0.050
1578     0.028
1579     0.0082
1580     0.011
1581     0.23
1582     0.035
1583     0.012
1584     0.0095
1585     0.043
1586     0.059
1587     0.031
1588     0.0041
1589     0.039
1590     0.0032
1591     0.097
1592     0.21
1593     0.14
1594     0.0032
1595     0.015
1596     0.023
1597     0.011
1598     0.0092
1599     0.017
1600     0.31
1601     0.022
1602     0.0063
1603     0.094
1604     0.0058
1605     0.012
1606     0.015
1607     0.028
1608     0.0058
1609     0.0053
1610     0.0067
1611     0.0032
1612     0.39
1613     0.11
1614     0.051
1615     0.040
1616     0.012
1617     0.0027
1618     0.29
1619     0.36
1620     0.0054
1621     0.0072
1622     0.13
1623     0.054
1624     0.092
1625     0.0072
1626     0.0044
1627     0.015
1628     0.067
1629     0.0025
1630     0.0062
1631     0.0050
1632     0.0029
1633     0.050
1634     0.013
1635     0.14
1636     0.011
1637     0.017
1638     0.0073
1639     0.0058
1640     0.0066
1641     0.0083
1642     0.058
1643     0.0072
1644     0.0031
1645     0.0010
1646     0.0046
1647     0.0030
1648     0.010
1649     0.00042
1650     0.0026
1651     0.0049
1652     0.0031
1653     0.00089
1654     0.022
1655     0.085
1656     0.0014
1657     0.0028
1658     0.00055
1659     0.00038
1660     0.016
1661     0.0027
1662     0.00065
1663     0.0016
1664     0.0088
1665     0.019
1666     0.0011
1667     0.013
1668     0.00085
1669     0.0018
1670     0.0010
1671     0.0011
1672     0.0043
1673     0.0054
1674     0.058
1675     0.0012
1676     0.0016
1677     0.0086
1678     0.026
1679     0.00085
1680     0.00061
1681     0.0031
1682     0.0024
1683     0.052
1684     0.0043
1685     0.00060
1686     0.0015
1687     0.0042
1688     0.024
1689     0.0011
1690     0.097
1691     0.12
1692     0.0035
1693     0.0017
1694     0.00055
1695     0.0080
1696     0.00057
1697     0.11
1698     0.0012
1699     0.0011
1700     0.00066
1701     0.00075
1702     0.031
1703     0.00041
1704     0.0060
1705     0.0098
1706     0.14
1707     0.18
1708     0.010
1709     0.010
1710     0.33
1711     0.00078
1712     0.0098
1713     0.00049
1714     0.0023
1715     0.0024
1716     0.0079
1717     0.0033
1718     0.00080
1719     0.018
1720     0.00058
1721     0.022
1722     0.0028
1723     0.0036
1724     0.016
1725     0.023
1726     0.00068
1727     0.0012
1728     0.0012
1729     0.00044
1730     0.035
1731     0.0019
1732     0.0055
1733     0.13
1734     0.071
1735     0.0011
1736     0.0043
1737     0.0083
1738     0.011
1739     0.0047
1740     0.00079
1741     0.0038
1742     0.020
1743     0.0013
1744     0.0040
1745     0.0013
1746     0.00089
1747     0.016
1748     0.00061
1749     0.00074
1750     0.0013
1751     0.0073
1752     0.017
1753     0.0025
1754     0.067
1755     0.0079
1756     0.00054
1757     0.00043
1758     0.0012
1759     0.0027
1760     0.032
1761     0.00041
1762     0.00037
1763     0.0045
1764     0.0032
1765     0.074
1766     0.0036
1767     0.0072
1768     0.14
1769     0.011
1770     0.00071
1771     0.078
1772     0.00075
1773     0.051
1774     0.00084
1775     0.0040
1776     0.024
1777     0.00063
1778     0.0073
1779     0.00052
1780     0.12
1781     0.049
1782     0.0022
1783     0.052
1784     0.011
1785     0.00045
1786     0.00072
1787     0.0011
1788     0.0043
1789     0.0065
1790     0.00070
1791     0.0030
1792     0.00092
1793     0.0019
1794     0.040
1795     0.00099
1796     0.00076
1797     0.0037
1798     0.0010
1799     0.015
1800     0.011
1801     0.0029
1802     0.021
1803     0.0053
1804     0.00051
1805     0.00092
1806     0.014
1807     0.00089
1808     0.047
1809     0.0014
1810     0.00065
1811     0.056
1812     0.00056
1813     0.036
1814     0.17
1815     0.0025
1816     0.012
1817     0.0014
1818     0.00040
1819     0.0038
1820     0.014
1821     0.00099
1822     0.050
1823     0.059
1824     0.00075
1825     0.0034
1826     0.099
1827     0.0066
1828     0.0027
1829     0.0015
1830     0.0016
1831     0.071
1832     0.0010
1833     0.0075
1834     0.00081
1835     0.0011
1836     0.00047
1837     0.0020
1838     0.0026
1839     0.055
1840     0.0012
1841     0.0044
1842     0.00066
1843     0.00084
1844     0.017
1845     0.00084
1846     0.0011
1847     0.00063
1848     0.0014
1849     0.23
1850     0.00060
1851     0.0025
1852     0.00094
1853     0.0089
1854     0.0055
1855     0.34
1856     0.0054
1857     0.019
1858     0.0011
1859     0.015
1860     0.011
1861     0.0013
1862     0.0020
1863     0.010
1864     0.048
1865     0.00043
1866     0.0028
1867     0.00073
1868     0.10
1869     0.00076
1870     0.00074
1871     0.00048
1872     0.00065
1873     0.033
1874     0.40
1875     0.00042
1876     0.098
1877     0.00086
1878     0.0088
1879     0.00066
1880     0.013
1881     0.0014
1882     0.0097
1883     0.065
1884     0.00041
1885     0.032
1886     0.00093
1887     0.18
1888     0.053
1889     0.098
1890     0.00055
1891     0.23
1892     0.0015
1893     0.014
1894     0.00055
1895     0.36
1896     0.00049
1897     0.0099
1898     0.00093
1899     0.22
1900     0.00099
1901     0.00056
1902     0.054
1903     0.0040
1904     0.00057
1905     0.00033
1906     0.00055
1907     0.0013
1908     0.00065
1909     0.11
1910     0.060
1911     0.00067
1912     0.027
1913     0.0011
1914     0.0077
1915     0.00038
1916     0.00099
1917     0.028
1918     0.28
1919     0.21
1920     0.021
1921     0.00083
1922     0.0031
1923     0.00089
1924     0.0051
1925     0.00055
1926     0.021
1927     0.0033
1928     0.00050
1929     0.00061
1930     0.0036
1931     0.00056
1932     0.0011
1933     0.00059
1934     0.0010
1935     0.011
1936     0.00068
1937     0.0031
1938     0.00076
1939     0.00071
1940     0.0016
1941     0.0015
1942     0.29
1943     0.0080
1944     0.045
1945     0.018
1946     0.0015
1947     0.0012
1948     0.00054
1949     0.00060
1950     0.0028
1951     0.0099
1952     0.0081
1953     0.051
1954     0.0023
1955     0.0015
1956     0.00076
1957     0.0012
1958     0.00045
1959     0.0052
1960     0.056
1961     0.0018
1962     0.0014
1963     0.00063
1964     0.036
1965     0.00055
1966     0.00092
1967     0.077
1968     0.0012
1969     0.00061
1970     0.052
1971     0.0011
1972     0.00037
1973     0.0071
1974     0.045
1975     0.00051
1976     0.0015
1977     0.00047
1978     0.00051
1979     0.00064
1980     0.0015
1981     0.0051
1982     0.047
1983     0.00068
1984     0.00038
1985     0.00070
1986     0.011
1987     0.015
1988     0.00069
1989     0.46
1990     0.00043
1991     0.0092
1992     0.28
1993     0.00064
1994     0.00058
1995     0.34
1996     0.00064
1997     0.22
1998     0.00075
1999     0.00082
2000     0.015
2001     0.00048
2002     0.0030
2003     0.0086
2004     0.00033
2005     0.00064
2006     0.00062
2007     0.23
2008     0.14
2009     0.082
2010     0.22
2011     0.017
2012     0.20
2013     0.15
2014     0.34
2015     0.26
2016     0.27
2017     0.35
2018     0.32
2019     0.11
2020     0.27
2021     0.0028
2022     0.0038
2023     0.0017
2024     0.0043
2025     0.0014
2026     0.0013
2027     0.11
2028     0.011
2029     0.00083
2030     0.0023
2031     0.00082
2032     0.0012
2033     0.00065
2034     0.0020
2035     0.024
2036     0.0011
2037     0.00058
2038     0.0083
2039     0.018
2040     0.15
2041     0.11
2042     0.070
2043     0.012
2044     0.0079
2045     0.015
2046     0.0037
2047     0.0057
2048     0.0035
2049     0.0040
2050     0.051
2051     0.0025
2052     0.0049
2053     0.010
2054     0.0041
2055     0.027
2056     0.013
2057     0.0011
2058     0.38
2059     0.00096
2060     0.11
2061     0.021
2062     0.0069
2063     0.0088
2064     0.012
2065     0.016
2066     0.063
2067     0.00084
2068     0.0017
2069     0.078
2070     0.018
2071     0.0092
2072     0.00042
2073     0.012
2074     0.0027
2075     0.0011
2076     0.0025
2077     0.047
2078     0.011
2079     0.017
2080     0.00033
2081     0.0020
2082     0.041
2083     0.052
2084     0.13
2085     0.0029
2086     0.10
2087     0.13
2088     0.030
2089     0.30
2090     0.38
2091     0.27
2092     0.35
2093     0.037
2094     0.20
2095     0.24
2096     0.019
2097     0.00057
2098     0.0080
2099     0.025
2100     0.015
2101     0.053
2102     0.00092
2103     0.0083
2104     0.010
2105     0.0026
2106     0.0020
2107     0.0048
2108     0.0079
2109     0.0018
2110     0.0098
2111     0.0082
2112     0.011
2113     0.00047
2114     0.11
2115     0.0011
2116     0.11
2117     0.00041
2118     0.0032
2119     0.00039
2120     0.0010
2121     0.00056
2122     0.00046
2123     0.0015
2124     0.00091
2125     0.016
2126     0.037
2127     0.0045
2128     0.015
2129     0.046
2130     0.010
2131     0.0098
2132     0.091
2133     0.012
2134     0.0098
2135     0.088
2136     0.039
2137     0.069
2138     0.0086
2139     0.023
2140     0.032
2141     0.072
2142     0.044
2143     0.041
2144     0.0069
2145     0.022
2146     0.0051
2147     0.0080
2148     0.063
2149     0.0040
2150     0.0057
2151     0.0025
2152     0.071
2153     0.0069
2154     0.033
2155     0.028
2156     0.0045
2157     0.0069
2158     0.089
2159     0.0035
2160     0.0038
2161     0.48
2162     0.20
2163     0.073
2164     0.30
2165     0.22
2166     0.33
2167     0.38
2168     0.0013
2169     0.0061
2170     0.069
2171     0.12
2172     0.014
2173     0.0060
2174     0.87
2175     0.18
2176     0.12
2177     0.25
2178     0.16
2179     0.54
2180     0.00093
2181     0.0055
2182     0.0036
2183     0.0019
2184     0.0079
2185     0.0024
2186     0.0075

Measurement of AsPC-1 cell Growth Inhibition AsPC-1 CGI)

Test compounds were serially dilated with dimethyl sulfoxide, and 200 nL was then dispensed to a U-bottom 96-well plate using Labcyte Echo. Human pancreatic cancer cell line AsPC-1 (G12D mutation Kras) was suspended in RPMI-1640 medium supplemented with 15% fetal bovine serum to prepare a cell suspension at 1000 cells/100 μL. The cell suspension was dispensed to a. plate containing a test compound at 100 μL per well and incubated at 37° C. in a 5% carbon dioxide gas incubator. 96 hours later, 80 μL of CellTiter-Glo (Promega) was added to each well and fluorescence was measured. The cell growth inhibition (CGI) of the test compound was calculated as 50% growth inhibitory concentration (IC50 value) from the growth inhibition rate when the test compound was added relative to the test compound-free control. IC50 values (μM) of the test compounds were classified in that range and the results are shown below.

Cyclic peptide compounds of Compound Nos. 5, 9, 16, 20, 27, 33, 40, 47, 54, 55, 66, 120, 132, 134, 144, 150, 176, 209, 245, 253, 270, 276, 279, 289, 301, 302, 303, 308, 316, 334,342, 343, 344, 362, 363, 370, 371, 374, 378, 381, 390, 391, 400, 404, 415, 422, 432, 466, 481, 506, 509, 515, 529, 545, 547, 555, 567, 571, 574, 587, 589, 594, 626, 630, 640, 668, 678, 690, 693, 695, 713, 717, 721, 731, 734, 775, 799, 806, 816, 835, 836, 840, 863, 866, 871, 882, 896, 907, 926, 938, 965, 973, 974, 981, 987, 999, 1017, 1042, 1059, 1070, 1080, 1091, 1099, 1116, 1117, 1120, 1132, 1139, 1141, 1143, 1144,1148, 1149, 1151, 1152, 1158, 1160, 1162, 1163, 1165, 1166, 1170, 1173, 1175, 1179, 1182, 1183, 1190, 1192, 1194, 1196, 1199, 1201, 1204, 1205, 1206, 1208, 1209, 1210, 1215, 1217, 1220, 1224, 1231, 1232, 1234, 1237, 1241, 1242, 1244, 1245, 1248, 1250, 1259, 1260, 1261, 1264, 1267, 1269, 1270, 1271, 1272, 1281, 1282, 1283, 1285, 1289, 1290, 1293, 1295, 1296, 1297, 1301, 1303, 1306, 1308, 1310, 1311, 1312, 1317, 1319, 1320, 1322, 1324, 1325, 1330, 1333, 1335, 1336, 1337, 1339, 1341, 1342, 1343, 1346, 1348, 1351, 1356, 1357, 1360, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1645, 1649, 1659, 1661, 1662, 1750, 1756, 1772, 1777, 1779, 1787, 1792, 1793, 1809, 1818, 1836, 1842, 1843, 1858, 1865, 1875, 1886, 1894, 1898, 1962, 1977, 1979, 1985, 1990, 2001, and 2080 showed an IC50 value which is 0.02 (μM) or lower.

Cyclic peptide compounds of Compound Nos. 44, 48, 49, 56, 73, 79, 89, 127, 128, 155, 173, 182, 201, 236, 243, 263, 272, 311, 313, 339, 340, 366, 386, 388, 403, 410, 441, 469, 531, 558, 563, 622, 647, 684 694, 726, 768, 774, 776, 778, 790, 807, 814, 818, 827, 868, 885, 890, 900, 918, 921, 958, 959, 977, 1000, 1001, 1002, 1008, 1029, 1030, 1046, 1060, 1062, 1073, 1093, 1098, 1137, 1142, 1146, 1154, 1159, 1164, 1171, 1193, 1197, 1198, 1223, 1228, 1236, 1251, 1253, 1254, 1275, 1278, 1287, 1292, 1299, 1326, 1340, 1355, 1658, 1675, 1679, 1685, 1694, 1700, 1701, 1722, 1726, 1727, 1729, 1757, 1761, 1762, 1790, 1821, 1840, 1850, 1851, 1852, 1870, 1871, 1872, 1884, 1890, 1904, 1905, 1907, 1925, 1930, 1936, 1938, 1948, 1950, 1958, 1972, 1978, 1983, 1984, 1996, 2004, 2067, 2072, and 2119 showed an IC50 value which is higher than 0.02 (μM) and is 0.05 (μM) or lower.

Cyclic peptide compounds of Compound Nos. 11, 68, 88, 126, 137, 160, 161, 163, 239, 246, 274, 292, 326, 327, 353, 385, 408, 409, 411, 420, 425, 434, 437, 438, 453, 486, 518, 532, 535, 543, 551, 562, 608, 616, 650, 652, 662, 674, 677, 683, 699, 701, 708, 712, 735, 783, 820, 825, 837, 845, 859, 881, 904, 909, 912, 948, 1023, 1037, 1047, 1112, 1150, 1176, 1178,1180, 1189, 1233, 1309, 1321, 1331, 1338, 1359, 1374, 1463, 1475, 1496, 1512, 1524, 1537, 1549, 1550, 1551, 1563, 1570, 1571, 1572, 1590, 1597, 1604, 1610, 1617, 1620, 1621, 1629, 1634, 1637, 1653, 1654, 1668, 1671, 1680, 1689, 1696, 1714, 1717, 1720, 1728, 1735, 1740, 1746, 1748, 1770, 1784,1785, 1786, 1795, 1798, 1800, 1801, 1804, 1805, 1807, 1812, 1824, 1835, 1861, 1869, 1879, 1881, 1892, 1901, 1906, 1908, 1911, 1915, 1923, 1932, 1933, 1941, 1947, 1963, 1965, 1966, 1968, 1969, 1975, 1988, 1993, 1994, 2005, 2006, 2057, 2063, 2074, 2076, 2118, 2121, and 2122 showed an IC50 value which is higher than 0.05 (μM) and is 0.1 (μM) or lower.

Cyclic peptide compounds of Compound Nos. 2, 15, 23, 30, 35, 36, 37, 39, 52, 58, 60, 64, 72, 78, 80, 81, 86, 90, 94, 100, 106, 108, 110, 119, 121, 122, 131, 136, 140, 147, 157, 164, 168, 207, 211, 212, 216, 220, 221, 223, 225, 229, 238, 249, 250, 256, 264, 273, 285, 287, 288, 294, 300, 309, 319, 321, 328, 337, 341, 348, 354, 356, 360, 364, 367, 384, 387, 393, 395, 397, 399, 416, 428, 439, 445, 446, 449, 455, 456, 461, 470, 476, 478, 480, 488, 491, 496, 497, 520, 523, 526, 544, 548, 552, 559, 561, 568, 572, 575, 580, 599, 600, 606, 618, 620, 629, 631, 644, 663, 667, 672, 676, 680, 689, 700, 714, 732, 740, 747, 749, 755, 756, 757, 762, 771, 787, 789,798, 804, 809, 811, 815, 824, 838, 849, 853, 854, 872, 873, 877, 880, 888, 893, 901, 910, 911, 916, 920, 929, 930,943, 944, 957, 960, 961, 968, 971, 980, 983, 985, 988, 995, 997, 1005, 1012, 1014, 1018, 1019, 1022, 1026, 1035, 1036, 1038, 1040, 1051, 1055, 1057, 1064, 1066, 1069, 1071, 1072, 1109, 1114, 1115, 1124, 1128, 1130, 1140, 1145, 1153, 1167, 1172, 1181, 1203, 1207, 1213, 1218, 1227, 1235, 1252, 1255, 1262, 1266, 1273, 1284, 1291, 1302, 1315, 1323, 1329, 1332, 1334, 1347, 1353, 1376, 1439, 1454, 1457, 1458, 1462,1466, 1471, 1477, 1481, 1482, 1485, 1486, 1497, 1498, 1499, 1500, 1501, 1504, 1508, 1514,1523, 1544, 1555, 1557, 1561, 1564, 1565, 1567, 1569, 1576, 1579, 1583, 1584, 1588, 1589, 1594, 1596, 1598, 1599, 1601, 1602, 1605, 1607, 1608, 1609, 1611, 1615, 1616, 1625, 1626, 1630, 1631, 1632, 1633, 1636, 1638, 1639, 1640, 1641, 1643, 1646, 1648, 1650, 1652, 1656, 1657, 1663, 1669, 1670, 1672, 1673, 1682, 1684, 1686, 1693, 1699, 1704, 1705, 1709, 1711, 1712, 1713, 1716, 1731, 1737, 1738, 1739, 1744, 1749, 1751, 1758, 1763, 1764, 1766, 1767, 1773, 1774, 1789, 1791, 1796, 1797, 1803, 1817, 1825, 1828, 1829, 1830, 1832, 1833, 1838, 1845, 1846, 1847, 1854, 1859, 1860, 1863, 1866, 1867, 1877, 1896, 1900, 1913, 1916, 1921, 1924, 1926, 1928, 1929, 1931, 1934, 1939, 1940, 1949, 1954, 1955, 1956, 1957, 1971, 1976,1980, 1998, 1999, 2031, 2059, 2064, 2065, 2077, 2078, 2084, 2085, 2097, 2102, 2117, 2120, 2123, 2124, 2131, 2138, 2139, and 2168 showed an IC50 value which is higher than 0.1 (μM) and is 0.5 (μM) or lower.

Cyclic peptide compounds of Compound Nos. 1, 4, 6, 7, 10, 12, 13, 14,17, 22, 24, 32, 43 45, 57, 59, 61, 63, 67, 69, 71, 75, 76, 83, 87, 91, 92, 93, 95, 97, 102, 103, 109, 111, 114, 115, 116, 117, 118, 123, 124, 125, 133, 135, 139, 141, 142, 143, 145, 146, 148, 149, 151, 156, 158, 159, 162, 165, 166, 169, 171, 172, 174, 175, 177, 178, 179, 180, 183, 185, 186, 187, 188, 191, 192, 194, 195, 196, 197, 200, 202, 204, 205, 208, 210, 213, 217, 218, 226, 228, 230, 231, 232, 234, 235, 237, 247, 248, 251, 254, 255, 257, 259, 262, 265, 266, 268, 275, 277, 278, 280, 281, 283, 284, 295, 297, 298, 304, 305, 307, 312, 314, 317, 318, 320, 325, 329, 330, 332, 335, 336, 346, 347, 352, 357, 358, 368, 376, 379, 380, 382, 389, 392, 394, 402, 405, 407, 417, 418, 419, 421, 423, 426, 427, 433, 440, 442, 443, 444, 447, 450, 451, 454, 457, 458, 459, 460, 463, 468, 471, 477, 483, 484, 485, 487, 489, 492, 495, 498, 500, 501, 504, 507, 508, 511, 514, 516, 519, 522, 524, 527, 528, 533, 534, 538, 540, 542, 549, 553, 554, 556, 557, 564, 565, 569, 570, 577, 581, 584, 585, 586, 590, 591, 592, 593, 596, 597, 598, 603, 604, 605, 614, 619, 623, 627, 635, 636, 638, 641, 643, 645, 648, 653, 656, 661, 664, 665, 666, 670, 681, 682, 687, 688, 691, 692, 696, 697, 703, 705, 706, 707, 709, 710, 711, 715, 716, 718, 720, 722, 723, 725, 727, 728, 729, 730, 736, 741, 742, 744, 745, 753, 754, 760, 765, 766, 767, 769, 770, 772, 781, 782, 784, 786, 788, 792, 794, 796, 797, 800, 801, 803, 805, 810, 812, 813, 819, 821, 822, 823, 829, 841, 842, 844, 848, 850, 851, 855, 856, 857, 858, 861, 862, 864, 867, 874, 875, 876, 879, 883, 887, 892, 894, 895, 897, 903, 905, 906, 908,913, 914, 915, 917, 933, 934, 935, 936, 939, 940, 941, 942, 945, 946, 950, 954, 955 956, 963, 964, 967, 969, 970, 975, 979, 982, 986, 991, 993, 994, 998, 1004, 1007, 1009, 1010, 1011, 1015, 1016, 1020, 1021, 1024, 1025, 1027, 1033, 1034, 1041, 1043, 1044, 1045, 1050, 1053, 1054, 1056, 1058, 1061, 1063, 1068, 1076, 1077, 1079, 1081, 1083, 1084, 1087, 1089, 1094, 1095, 1096, 1100, 1101, 1103, 1105, 1106, 1110, 1111, 1121, 1123, 1125, 1129, 1133, 1134, 1135, 1138, 1157, 1169, 1174, 1177, 1185, 1186, 1187, 1188, 1191, 1195, 1200, 1202, 1211, 1214, 1216, 1219, 1221, 1222, 1225, 1226, 1229, 1230, 1238, 1239, 1243, 1246, 1247, 1249, 1256, 1257, 1258, 1263, 1268, 1274, 1276, 1277, 1279, 1286, 1288, 1294, 1298, 1300, 1304, 1305, 1307, 1313, 1314, 1316, 1318, 1327, 1328, 1345, 1350, 1354, 1358, 1361, 1372, 1377, 1380, 1386, 1387, 1388, 1392, 1396, 1397, 1398, 1403, 1404, 1411, 1414, 1415, 1417, 1419, 1421, 1422, 1424, 1425, 1426, 1428, 1429, 1432, 1433, 1435, 1436, 1438, 1440, 1441, 1443, 1444, 1448, 1449, 1451, 1452, 1453, 1455, 1456, 1459, 1460, 1461, 1465, 1467, 1469, 1472, 1474, 1476, 1478, 1480, 1483, 1484, 1489, 1490, 1491, 1493, 1495, 1502, 1503, 1506, 1507, 1509, 1511, 1515, 1517, 1518, 1519, 1520, 1526, 1527, 1528, 1529, 1532, 1533, 1534, 1535, 1536, 1539, 1541, 1545, 1546, 1547, 1553, 1556, 1559, 1562, 1566, 1573, 1574, 1575, 1578, 1580, 1582, 1585, 1587, 1591, 1595, 1606, 1613, 1614, 1623, 1627, 1635, 1644, 1647, 1651, 1660, 1664, 1665, 1666, 1667, 1674, 1676, 1677, 1678, 1681, 1687, 1688, 1690, 1692, 1695, 1697, 1698, 1702, 1703, 1706, 1707, 1708, 1715, 1718, 1719, 1721, 1723, 1724, 1725, 1730, 1732, 1733, 1736, 1741, 1742, 1743, 1745, 1747, 1752, 1753, 1754, 1755, 1759, 1760, 1768, 1769, 1771, 1775, 1776, 1778, 1780, 1782, 1788, 1799, 1802, 1806, 1808, 1810, 1811, 1813, 1815, 1816, 1819, 1820, 1822, 1823, 1826, 1827, 1831, 1834, 1837, 1841, 1844, 1848, 1849, 1853, 1855, 1856, 1857, 1862, 1864, 1880, 1897, 1917, 1937, 1946, 1973, 1982, 2030, 2035, 2058, 2060, 2061, 2062, 2066, 2068, 2069, 2070, 2071, 2073, 2075, 2079, 2081, 2082, 2083, 2113, 2115, 2116, 2125, 2127,2128, 2129, 2130, 2132, 2135, 2136, 2137, 2140, 2141, 2142, 2143, 2144, 2145, 2146, 2147, 2149, 2150, 2151, 2169, 2172, 2173, 2174, 2175, 2176, 2177, 2178, and 2179 showed an IC50 value which is higher than 0.5 (μM).

Example 4 Measurement of Cell Growth Inhibitory Activity

Various cancer cell lines used were purchased from commercial suppliers. The test compounds 1217, 1201, 926, and 558, which were scale-up synthesized in Example 2, were serially diluted with DMSO, and 40 nL (384 well plate) or 200 nL (96 well plate) was then dispensed to a U-bottom well plate using Labcyte Echo. The cell suspension and culture medium supplemented with serum were dispensed to a plate containing the test compounds at 40 μL (384 well plate) or 200 μL (96 well plate) per well and incubated in a carbon dioxide gas incubator. The culture medium (source of purchase) for various cancer cell lines, serum concentration, number of cells seeded, cultivation days, and carbon dioxide gas concentration during cultivation are shown in Table 24. Six days or seven days after the start of cultivation, 20 μL of CellTiter-Glo (Promega) was added to each well and fluorescence was measured. The 50% growth inhibitory concentration (IC50 value) of the test compounds was calculated from the growth inhibition rate when the test compounds were added relative to the test compound-free. The results for Compounds 1217, 1201, 926, and 558 are shown in Tables 25, 26, 27, and 28, respectively. In each table, “TISSUE” indicates the tissue from which each cancer cell line is derived, “CELL LINES” indicates the name of the cell line, “Mutation status” indicates the type of Ras and the status of Ras mutant protein, and “AA substitution” indicates the position of amino acid substitution in the Ras protein and the type of amino acid before and after substitution, etc. In addition, all Ras proteins are derived from humans. For example, when “KRAS” and “G12S” are described in “Mutation status”, it indicates that the 12th amino acid residue glycine of the amino acid sequence of the wild-type Kras (SEQ ID No: 6) is substituted with serine. “amp” indicates an amplification of the copy number of the Ras gene. “mut” indicates a mutant of the Ras protein. For example, the description “KRAS Amp(G12P)” indicates a mutant in which the copy number of the Ras gene is amplified by substituting the 12th amino acid residue glycine of the amino acid sequence of the wild-type Kras (SEQ ID No: 6) with proline.

All compounds tested were shown to have high cell growth inhibitory activity against all cancer cell lines.

TABLE 24
		Fetal bovine				Carbonioc
		serum	Horse serum	Number		acid gas
		concentration	concentration	of cells	Cultivation	concentration
Cell name	Culture medium (manufacturer)	(%)	(%)	seeded	days	(%)
A549	D-MEM (Sigma)	10	0	500	6	5
AGS	Ham's F-12K (Thermo Fisher)	10	0	250	6	5
SNU-1	RPMI-1640 (Sigma)	10	0	250	6	5
SK-CO-1	E-MEM (Sigma)	10	0	500	6	5
HCC-44	RPMI-1640 (Sigma)	10	0	250	6	5
NCI-H2122	RPMI-1640 (Sigma)	10	0	250	6	5
LS 180	E-MEM (Sigma)	10	0	500	6	5
NCI-H1792	RPMI-1640 (Sigma)	10	0	250	6	5
AsPC-1	RPMI-1640 (Sigma)	15	0	250	6	5
NCI-H441	RPMI-1640 (Sigma)	10	0	250	6	5
MIA PaCa-2	D-MEM (Sigma)	10	2.5	250	6	5
NCI-H358	RPMI-1640 (Sigma)	10	0	500	6	5
FAMPAC	RPMI-1640 (Sigma)	10	0	250	6	5
UM-UC-3	E-MEM (Sigma)	10	0	125	6	5
HPAC	DMEM/Ham's F-12 (Thermo Fisher)	5	0	250	6	5
NCI-H1373	RPMI-1640 (Sigma)	10	0	250	7	5
NCI-H2009	DMEM/Ham's F-12 (Thermo Fisher)	10	0	1000	6	5
NCI-H1944	RPMI-1640 (Sigma)	10	0	500	6	5
HLC-1	Ham's F-12 (Thermo Fisher)	10	0	250	6	5
KP4	DMEM/Ham's F-12 (Thermo Fisher)	10	0	500	7	5
LS513	RPMI-1640 (Sigma)	10	0	250	6	5
NCI-H23	RPMI-1640 (Sigma)	10	0	1000	6	5
NCI-H2030	RPMI-1640 (Sigma)	10	0	1000	6	5
SW403	Leibovitz's L-15 (Thermo Fisher)	10	0	500	6	0
NCI-H460	RPMI-1640 (Sigma)	10	0	250	6	5
LS 174T	E-MEM (Sigma)	10	0	250	6	5
SW480	Leibovitz's L-15 (Thermo Fisher)	10	0	250	6	5
HCC-1171	RPMI-1640 (Sigma)	10	0	1000	6	5
DLD-1	RPMI-1640 (Sigma)	10	0	500	6	5
RERF-LC-Ad2	RPMI-1640 (Sigma)	10	0	250	6	5
LoVo	Ham's F-12 (Thermo Fisher)	20	0	500	6	5
NOMO-1	RPMI-1640 (Sigma)	10	0	2500	6	5
HCT116	McCoy's 5A (Sigma)	10	0	250	6	5
NCI-H1385	RPMI-1640 (Sigma)	10	0	500	7	5
CFPAC-1	IMDM (Thermo Fisher)	10	0	250	6	5
SK-LU-1	E-MEM (Sigma)	10	0	1000	6	5
Calu-6	E-MEM (Sigma)	10	0	250	6	5
HEC-50B	E-MEM (Sigma)	15	0	250	6	5
PANC-1	D-MEM (Sigma)	10	0	250	6	5
A4/Fuk	RPMI-1640 (Sigma)	10	0	1000	6	5
KE-39	RPMI-1640 (Sigma)	10	0	250	6	5
KURAMOCHI	RPMI-1640 (Sigma)	10	0	1000	6	5
MKN-1	RPMI-1640 (Sigma)	10	0	250	6	5
COR-L23	RPMI-1640 (Sigma)	10	0	250	6	5
HuG1-N	RPMI-1640 (Sigma)	10	0	250	6	5
T.T	DMEM/Ham's F-12 (Thermo Fisher)	10	0	250	7	5
DMS 53	Waymouth's MB 752/1 (Thermo Fisher)	10	0	500	6	5
KLE	DMEM/Ham's F-12 (Thermo Fisher)	10	0	1000	6	5
TYK-nu	E-MEM (Sigma)	10	0	500	6	5
PA-1	E-MEM (Sigma)	10	0	500	6	5
HEC-151	E-MEM (Sigma)	15	0	500	6	5
KMM-1	RPMI-1640 (Sigma)	10	0	2000	6	5
NCI-H929	RPMI-1640 (Sigma)	10	0	750	6	5
AML-193	IMDM (Thermo Fisher)	10	0	1000	6	5
IPC-298	RPMI-1640 (Sigma)	10	0	250	6	5
SK-MEL-30	RPMI-1640 (Sigma)	10	0	250	6	5
MOLT-4	RPMI-1640 (Sigma)	10	0	1250	6	5
C-643	RPMI-1640 (Sigma)	10	0	500	6	5

TABLE 25
		Compound	Mutation status
		1217		AA sub-	Mutation
TISSUE	CELL_LINES	IC50 (nM)	RAS	stitution	status
NSCLC	A549	0.30	KRAS	G12S	KRAS
Stomach	AGS	0.32	KRAS	G12D	mut
Stomach	SNU-1	0.46	KRAS	G12D
Colon	SK-CO-1	0.49	KRAS	G12V
NSCLC	HCC-44	0.55	KRAS	G12C
NSCLC	NCI-H2122	0.80	KRAS	G12C
Colon	LS 180	0.83	KRAS	G12D
NSOLC	NCI-H1792	0.86	KRAS	G12C
Pancreas	AsPC-1	0.87	KRAS	G12D
NSCLC	NCI-H441	1.12	KRAS	G12V
Pancreas	MIA PaCa-2	1.45	KRAS	G12C
NSCLC	NCI-H358	1.55	KRAS	G12C
Pancreas	FAMPAC	2.09	KRAS	G12V
Bladder	UM-UC-3	2.11	KRAS	G12C
Pancreas	HPAC	2.19	KRAS	G12D
NSCLC	NCI-H1373	2.33	KRAS	G12C
NSCLC	NCI-H2009	2.35	KRAS	G12A
NSCLC	NCI-H1944	2.53	KRAS	G13D
NSCLC	HLG-1	3.29	KRAS	G12V
Pancreas	KP4	3.30	KRAS	G12D
Colon	LS513	3.69	KRAS	G12D
NSCLC	NCI-H23	3.92	KRAS	G12C
NSCLC	NCI-H2030	4.05	KRAS	G12C
Colon	SW403	4.10	KRAS	G12V
NSCLC	NCI-H460	4.20	KRAS	Q61H
Colon	LS 174T	4.31	KRAS	G12D
Colon	SW480	4.31	KRAS	G12V
NSCLC	HCC-1171	4.86	KRAS	G12C
Colon	DLD-1	5.08	KRAS	G13D
NSCLC	RERF-LC-Ad2	5.20	KRAS	G12V
Colon	LoVo	5.50	KRAS	G13D
AML	NOMO-1	6.50	KRAS	G13D
Colon	HCT-116	8.58	KRAS	G13D
NSCLC	NCI-H1385	14.30	KRAS	G12C
Pancreas	CFPAC-1	17.26	KRAS	G12V
NSCLC	SK-LU-1	25.98	KRAS	G12D
NSCLC	Calu-6	43.72	KRAS	Q61K
Endometrium	HEC-50B	43.78	KRAS	G12D
Pancreas	PANC-1	44.32	KRAS	G12D
Non-Hodgkin	|A4/Fuk	0.75	KRAS	Amp	KRAS
lymphoma					amp
Stomach	KE-39	0.80	KRAS	Amp
Ovary	KURAMOCHI	1.18	KRAS	Amp
Stomach	MKN-1	1.77	KRAS	Amp
NSCLC	COR-L23	2.85	KRAS	Amp
				(G12V)
Stomach	HuG1-N	3.74	KRAS	Amp
Esophageal	T.T	5.68	KRAS	Amp
SCLC	DMS 53	12.25	KRAS	Amp
Endometrium	KLE	169.63	KRAS	Amp
Ovary	TYK-nu	1.14	NRAS	G12D,	NRAS
				Q61K	mut
Ovary	PA-1	2.38	NRAS	G12D
Endometrium	HEC-151	2.42	NRAS	G12D
Myeloma	KMM-1	8.59	NRAS	G13D
Myeloma	NCI-H929	9.79	NRAS	G13D
AML	AML-193	11.83	NRAS	G13V
Skin	IPC-298	23.52	NRAS	Q61L
Skin	SK-MEL-30	91.61	NRAS	Q61K
ALL	MOLT-4	174.80	NRAS	G12C
Thyroid	C-643	3.24	HRAS	G13R	HRAS
					mut

TABLE 26
		Compound	Mutation status
		1201		AA sub-	Mutation
TISSUE	CELL_LINES	IC50 (nM)	RAS	stitution	status
NSCLC	A549	0.25	KRAS	G12S	KRAS
Stomach	AGS	0.48	KRAS	G12D	mut
Stomach	SNU-1	0.53	KRAS	G12D
Colon	LS 180	1.32	KRAS	G12D
Pancreas	AsPC-1	0.84	KRAS	G12D
NSCLC	NCI-H441	0.89	KRAS	G12V
Pancreas	MIA PaCa-2	1.81	KRAS	G12C
Colon	SW480	9.60	KRAS	G12V
AML	NOMO-1	4.90	KRAS	G13D
Non-Hodgkin	A4/Fuk	0.65	KRAS	Amp	KRAS
lymphoma					amp
Ovary	KURAMOCHI	2.63	KRAS	Amp
Ovary	PA-1	1.16	NRAS	G12D	NRAS
Endometrium	HEC-151	2.30	NRAS	G12D	mut
Myeloma	NCI-H929	4.62	NRAS	G13D	HRAS
					mut

TABLE 27
		Com-
		pound	Mutation status
		926		AA sub-	Mutation
TISSUE	CELL_LINES	IC50 (nM)	RAS	stitution	status
NSCLC	A549	1.09	KRAS	G12S	KRAS
Stomach	AGS	1.46	KRAS	G12D	mut
Stomach	SNU-1	2.74	KRAS	G12D
Colon	LS 180	5.39	KRAS	G12D
Pancreas	AsPC-1	3.33	KRAS	G12D
NSCLC	NCI-H441	2.87	KRAS	G12V
Pancreas	MIA PaCa-2	8.93	KRAS	G12C
Colon	SW480	56.68	KRAS	G12V
AML	NOMO-1	29.15	KRAS	G13D
Non-Hodgkin	A4/Fuk	1.28	KRAS	Amp	KRAS
lymphoma					mut
Ovary	KURAMOCHI	7.89	KRAS	Amp
Myeloma	NCI-H929	18.80	NRAS	G13D	NRAS
					mut

TABLE 28
		Compound	Mutation status
		558		AA sub-	Mutation
TISSUE	CELL_LINES	IC50 (nM)	RAS	stitution	status
NSCLC	A549	7.98	KRAS	G12S	KRAS
Stomach	SNU-1	29.81	KRAS	G12D	mut
Colon	LS 180	22.57	KRAS	G12D
NSCLC	NCI-H441	31.57	KRAS	G12V
Pancreas	MIA PaCa-2	18.74	KRAS	G12C
Colon	SW480	17.54	KRAS	G12V
Non-Hodgkin	A4/Fuk	5.83	KRAS	Amp	KRAS
lymphoma					amp
Ovary	KURAMOCHI	23.42	KRAS	Amp
Myeloma	NCI-H929	55.68	NRAS	G13D	NRAS
					mut

Example 5 Measurement of In Vivo Antitumor Activity

The in vivo antitumor activity of Compounds 1217, 1201, 926, and 558 was evaluated using mouse xenograft models into which the following six cell lines in total were grafted: non-small cell lung cancer cell line NC1-1441 with a KRAS mutation, large bowel carcinoma cell lines LS 180/LoVo, pancreatic cancer cell lines MIA PaCa-2/KP4, and gastric cancer cell line MKN-1 with an amplified copy number of the KRAS gene. Each type of cell line was subcutaneously grafted into nude mice, which were randomized after tumor size reached 200 to 300 mm³, and compound administration (once daily) was initiated (Day 0). The solvents used to dissolve the compounds were DMSO and Cremophor EL. The dosage of each compound, the composition of the solvent, the dosing period, the number of mice per group, and the number of grafted cells per mouse are shown in Table 29. From the tumor volume data on the last measurement day, the tumor growth inhibition rate (TGI %: Tumor Growth Inhibition %) was calculated using the following expressions.

Tumor growth inhibition rate (TGI %)=(1−TV/CV)×100

tumor volume (mm³):½×long diameter (mm)×short diameter (mm)×short diameter (mm)

amount of change in tumor volume (mm³)=tumor volume after Day 0−tumor volume at Day 0

• TV: average value of amount of change in tumor volume in administered group
• CV: average value of amount of change in tumor volume in non-administered group

TABLE 29
				Dosing	Number of	Number of
	Compound	Dosage	Composition of	period	mice per	grafted cells
Cell name	No.	(mg/kg)	solvent	(days)	group	per mouse
NCI-H441	1217	3, 5, 10	10% DMSO,	14	8	5 × 106
			5% Cremophor EL
LS 180	1217	3, 5, 10	10% DMSO,	7	8	5 × 106
			5% Cremophor EL
LoVo	1217	7, 5, 10	10% DMSO,	10	8	5 × 106
			5% Cremophor EL
MIA PaCa-2	1217	3, 5, 10	10% DMSO,	14	8	5 × 106
			5% Cremophor EL
KP4	1217	5, 10	10% DMSO,	10	5	5 × 106
			5% Cremophor EL
MKN1	1217	5, 10	10% DMSO,	10	8	5 × 106
			5% Cremophor EL
NCI-H441	1201	3, 6, 7, 5,	10% DMSO,	14	4	5 × 106
		10	5% Cremophor EL
LS 180	926	15, 30	10% DMSO,	7	4	5 × 106
			5% Cremophor EL
A549	558	10, 15, 30	10% DMSO,	10	4	5 × 106
			10% Cremophor EL

The test results are shown in Tables 30, 31, 32, and 33. Each table shows the test results for Compounds 1217, 1201, 926, and 558. All compounds tested were shown to have high antitumor activity against all cancer cell lines in vivo in a dose-dependent manner.

TABLE 30
Compound 1217	Dose (mg/kg)	TGI (%)
NCI-H441 (NSCLC)	3	59
	5	92
	10	110
LS 180 (Colon)	3	11
	5	38
	10	65
LoVo (Colon)	7.5	67
	10	85
MIA PaCa-2 (Pancreas)	3	16
	5	65
	10	149
KP4 (Pancreas)	5	65
	10	104
MKN1 (Stomach)	5	55
	10	205

TABLE 31
Compound 1201	Dose (mg/kg)	TGI (%)
NCI-H441 (NSCLC)	3	68
	6	92
	7.5	103
	10	104

TABLE 32
Compound 926	Dose (mg/kg)	TGI (%)
LS 180 (Colon)	15	29
	30	75

TABLE 33
Compound 558	Dose (mg/kg)	TGI (%)
A549 (NSCLC)	10	46
	15	57
	30	106

Example 6 Analysis of X-Ray Crystal Structure of Complex of hKras-G12D and Cyclic Peptide Compound

(Example 6-1) Preparation of Human Kras G12D Mutant Protein

A construct formed by adding a HAT tag (KDHLIHNVHKEEHAHAH, SEQ ID No: 4), a linker sequence, and a thrombin recognition sequence (LVPRGS, SEQ ID No: 5) to the N-terminus of an amino acid sequence in which the G12D mutation is introduced into Position 2-174 of human Kras Isoform 2B (UniprotKB identifier: P01116-2) was designed (hereinafter, also referred to as HAT_Linker_Thrombin_Linker_hKras-G12D. The base sequence is shown in SEQ ID No: 1 and the amino acid sequence is shown in SEQ ID No: 2.).

The synthesized HAT_Linker_Thrombin_Linker_hKras-G12D gene was subcloned into the pETBlue™-1 vector (Novagen) and transformed into E. coli strain Tuner™ (DE3) pLacI (Novagen). The transformed E. coli was cultured in a LB culture medium containing ampicillin at 37° C. with shaking until reaching OD₆₀₀=0.6. Subsequently, by adding isopropyl β-D-1-thiogalactopyranoside at a final concentration of 1 mM and shaking and culturing at 30° C. for 24 hours, expression of HAT_Linker_Thrombin_Linker_hKras-G12D was induced. The centrifuged bacterial cells were suspended in an extraction buffer (50 mM Tris hydrochloride (Tris-1-Cl) pH 8.0, 150 mM sodium chloride (NaCl), 1% (w/v) CHAPS, 5% (v/v) Glycerol, and cOmplete™ EDTA-Free Protease Inhibitor Cocktail (Roche)), 0.75 mg of lysozyme per g of wet bacterial cell weight was then added, and the cells were incubated at room temperature for 20 minutes. After the bacterial cells were disintegrated by the ultrasonic disintegration method, magnesium chloride (MgCl₂) at a final concentration of 2 mM and benzonase were added, and allowed to stand at room temperature for 20 minutes.

Subsequently, the centrifuged supernatant was purified by a gradient of 0 to 500 mM imidazole, using cOmplete™ His-Tag Purification Column 1 mL (Roche), equilibrated with a solvent consisting of 50 mM Tris-HCl, pH 8.0, 400 mM NaCl, 1% (w/v) CHAPS, 5% (v/v) Glycerol, and 1 mM dithiothreitol (DTT). After thrombin was added for cleavage of the HAT tag, the fraction containing HAT_Linker_Thrombin_Linker_hKras-G12D obtained by affinity purification was loaded into a dialysis cassette, and while dialysis was performed to remove imidazole in about 100-fold volume of external solution (50 mM Tris-HCL, pH 8.0, 400 mM NaCl, and 1 mM DTT) overnight, digestion with thrombin was carried out. Subsequently, thrombin was removed by passing through the Benzamidine Sepharose 4 Fast Flow (GE Healthcare) resin. Finally, gel filtration chromatography (hereinafter, also referred to as size exclusion chromatography, SEC) purification was carried out using HiLoad® 16/600 Superdex® 75 pg (GE Healthcare) equilibrated with a solvent consisting of 20 mM HEPES, pH 8.0, 100 mM NaCl, 1 mM DTT, and 5 mM MgCl₂. At this time, cOmplete™ His-Tag Purification Column 1 mL (Roche) was connected in tandem downstream of the column for SEC in order to remove any remaining HAT-tagged molecules. As a result of these purifications, a monomeric fraction of tag-cleaved human Kras G12D mutant protein (hereinafter, also referred to as Linker_hKras-G12D. SEQ ID No: 3) was obtained in high purity. In addition, for the above affinity chromatography purification and SEC purification, the AKTAxpress™ apparatus (GE Healthcare), the NGC™ chromatography system (Bio-Rad), or the BioLogic DuoFlow™ chromatography system (Bio-Rad) was used.

(Example 6-2) Analysis of X-Ray Crystal Structure of Complex of Linker_hKras-G12D and Cyclic Peptide Compound 488

For preparation of a complex sample for crystallization, 3 mg/mL Linker_hKras-G12D prepared by the same method as in Example 6-1 and a 100% dimethyl sulfoxide (DMSO) solution stock with 10 mM of Compound 488 were used. At first, 10 mM of Compound 488 was diluted to 1 mM with pure water, to which Linker_hKras-G12D was added at a molar concentration ratio of about 6:1. After allowing to stand at room temperature for 1 hour, the supernatant after centrifugation was passed through a 0.2 μm filter to remove precipitated Compound 488.

The prepared complex of Linker_hKras-G12D and Compound 488 was concentrated to 18 mg/mL using an ultrafiltration membrane and crystallized by the sitting drop vapor diffusion method at 21° C. One of the crystals obtained under the A9 condition (10% (w/v) polyethylene glycol 20000, 20% (v/v) polyethylene glycol monomethyl ether 550, 0.1 M bicine/Trizma base, pH 8.5, 30 mM magnesium chloride, and 30 mM calcium chloride) of a commercially available screening kit Morpheus® IT-96 (Molecular Dimensions) was frozen in liquid nitrogen using a solution with the same composition as the reservoir as a cryoprotectant.

The diffraction image was collected with the beamline BiL17A of a synchrotron radiation facility Photon Factory at a temperature of 95 K and a wavelength of 0.98 Å. Processing with the AutoPROC (Global Phasing Ltd.) program provided X-ray diffraction intensity data down to a resolution of 1.24 Å. Data collection statistics are shown in Table 34.

Using the X-ray diffraction intensity data obtained, molecular substitutions were performed by the Phaser (J. Appl. Cryst. 40: 658-674 (2007)) program to determine the initial structure. Thereafter, model construction and refinement were repeatedly performed using the Phenix (Acta Cryst. (2019). D75, 861-877), Coot (Acta Cryst. D66: 486-501 (2010)), and Refinac5 (Acta Cryst. D67: 355-467 (2011)) programs to obtain the final refined coordinates. The resolution was 1.43 Å. Refinement statistics are shown in Table 34. The overall structure is shown in FIG. 1. FIG. 1 was created using the PyMOL Version 2.3 (Schrodinger, LLC.) software.

TABLE 34
Data collection and refinement statistics
(Complex of Linker_hKras-G12D and Compound 488)
Data collection
Space group                      P1 21 1
Unit cell a, b, c (Å)            45.768, 41.168, 56.732
Unit cell α, β, γ (°)            90.00, 101.43, 90.00
Resolution (Å)                   44.860-1.238 (1.340-1.238)*
Rmerge, Rmeas, Rpim              0.081 (1.207)*, 0.088 (1.352)*,
                                 0.034 (0.589)*
CC(1/2)                          0.999 (0.433)*
mean I/σ(I)                      13.3 (1.3)*
Completeness, sphere (%)         77.8 (18.5)*
Completeness, ellipsoid (%)      92.3 (47.5)*
Total number of reflections      288789 (11410)*
Number of unique reflections     46057 (2305)*
Redundancy                       6.5 (5.0)*
Refinement
Resolution (Å)                   55.61-1.43
Number of reflections            36732
Rwork/Rfreea                     0.16931/0.19554
Root mean square deviation: bond 0.024
distance (Å)
Root mean square deviation:      2.347
bond angle (°)
*The values in parentheses are those for the outermost shell.
aRfree is calculated using 5% of randomly selected reflections.

FIG. 1 shows the overall X-ray crystal structure of a complex of the human Cras C12D mutant and cyclic peptide compound 488. FIG. 6 shows interaction sites between the Kras G12D mutant and cyclic peptide compound 488. The Aze(2) residue of Core 4 is positioned in the vicinity of Gu98 and the Hph(4-CF3-3-Cl) residue of Core 7 in the vicinity of Leu56 and Tyr71 (about 3.5 to 3.9 Å), suggesting that they interact with each other.

(Example 6-3) Analysis of X-Ray Crystal Structure of Complex of Linker_hKras-G12D and Cyclic Peptide Compound 872

For preparation of a complex sample for crystallization, 3 mg/mL Linker_hKras-G12D prepared by the same method as in Example 6-1 and a 100% DMSO solution stock with 10 mM of Compound 872 were used. Linker_hKras-G12D was diluted to 1 mg/mL with a solvent consisting of 20 mM HEPES, pH 7.1, 100 mM NaCl, 1 mM DTT, and 5 mM MgCl₂ (hereinafter, also referred to as Kras dilation solvent). 10 mM of Compound 872 was diluted to 1 nM with pure water, to which 1 mg/mL Linker_hKras-G12D was added at a molar concentration ratio of about 8:1. After allowing to stand at room temperature overnight, the supernatant after centrifugation was passed through a 0.2 μm filter to remove precipitated Compound 872.

The prepared complex of Linker_hKras-G12D and Compound 872 was concentrated to 18 mg/mL using an ultrafiltration membrane and crystallized by the sitting drop vapor diffusion method at 21° C. combined with microseeding. One of the crystals obtained under the C₁₁ condition (0.2 M sodium acetate trihydrate, 0.1 M MES monohydrate, pH 6.5, and 30.0% (w/v) polyethylene glycol 8,000) of a commercially available screening kit SG1™ HT-96 Eco Screen (Molecular Dimensions) was briefly immersed in a solution formed by adding glycerol at a final concentration of 20% (v/v) to the reservoir solution, and frozen in liquid nitrogen.

The diffraction image was collected with the beamline BL17A of a synchrotron radiation facility Photon Factory at a temperature of 95 K and a wavelength of 0.98 Å. Processing with the AutoPROC (Global Phasing Ltd.) program provided X-ray diffraction intensity data down to a resolution of 1.83 Å. Data collection statistics are shown in Table 35.

Using the X-ray diffraction intensity data obtained, molecular substitutions were performed by the Phaser (J. Appl. Cryst. 40: 658-674 (2007)) program to determine the initial structure. Thereafter, model construction and refinement were repeatedly performed using the Phenix (Acta Cryst. (2019). D75, 861-877), Coot (Acta Cryst. D66: 486-501 (2010)), and Buster (Global Phasing Ltd.) programs to obtain the final refined coordinates. The resolution was 1.82 Å. Refinement statistics are shown in Table 35. The overall structure is shown in FIG. 2. FIG. 2 was created using the PyMOL Version 2.3 (Schrodinger, LLC.) software.

TABLE 35
Data collection and refinement statistics
(Complex of Linker_hKras-G12D and Compound 872)
Data collection
Space group                      P 31 2 1
Unit cell a, b, c (Å)            64.702, 64.702, 86.715
Unit cell α, β, γ (°)            90.00, 90.00, 120.00
Resolution (Å)                   56.034-1.829 (1.937-1.829)*
Rmerge, Rmeas, Rpim              0.266 (1.753)*, 0.276 (1.946)*,
                                 0.070 (0.815)*
CC(1/2)                          0.988 (0.414)*
mean I/σ(I)                      10.9 (1.0)*
Completeness, sphere (%)         76.7 (24.9)*
Completeness, ellipsoid (%)      81.5 (36.3)*
Total number of reflections      215364 (3526)*
Number of unique reflections     14622 (733)*
Redundancy                       14.7(4.8)*
Refinement
Resolution (Å)                   56.03-1.82
Number of reflections            14655
Rwork/Rfreea                     0.170/0.227
Root mean square deviation: bond 0.01
distance (Å)
Root mean square deviation:      1.09
bond angle (°)
*The values in parentheses are those for the outermost shell.
aRfree is calculated using 5% of randomly selected reflections.

FIG. 2 shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 872. FIG. 7 shows interaction sites between the Kras G12D mutant and cyclic peptide compound 872. The MeGly residue of Core 4 is positioned in the vicinity of Glu98, and the Hph(4-CF3-3-Cl) residue of Core 7 and the (EtOEt)NGly residue of Core 8 are each positioned in the vicinity of Gly10, Lys16, Glu37, Leu56 and Tyr71 (about 3.2 to 4.5 Å), suggesting that they interact with each other.

(Example 6-4) Analysis of X-Ray Crystal Structure of Complex of Linker_hKras-G12D and Cyclic Peptide Compound 1201

For preparation of a complex sample for crystallization, Linker_hKras-G12D that was prepared by the same method as in Example 6-1 and then concentrated to 27 mg/mL and a 100% DMSO solution stock with 10 mM of Compound 1201 were used. Linker_hKras-G12D was dilated to 1 mg/mL with the Kras dilution solvent shown in Example 6-3. 10 mM of Compound 1201 was diluted to 1 mM with the Kras dilution solvent, to which 1 mg/mL Linker_hKras-G12D was added at a molar concentration ratio of about 7:1. After allowing to stand at 4° C. for 1 hour, the supernatant after centrifugation was passed through a 0.2 μm filter to remove precipitated Compound 1201.

The prepared complex of Linker_hKras-G12D and Compound 1201 was concentrated to 38 mg/mL using an ultrafiltration membrane and crystallized by the sitting drop vapor diffusion method at 21° C. One of the crystals obtained under the condition where G11 of a commercially available screening kit SG1™ HT-96 Eco Screen (Molecular Dimensions) was diluted by 0.8 times (0.16 M sodium chloride, 1.6 M ammonium sulfate, and 80 mM MES monohydrate, pH 6.5) was frozen in liquid nitrogen using a solution with the same composition as the reservoir as a cryoprotectant.

The diffraction image was collected with the beamline BL45XU of a synchrotron radiation facility SPring-8 at a temperature of 100 K and a wavelength of 1.00 Å. Processing with the AutoPROC (Global Phasing Ltd.) program provided X-ray diffraction intensity data down to a resolution of 1.65 Å. Data collection statistics are shown in Table 36.

Using the X-ray diffraction intensity data obtained, molecular substitutions were performed by the Dimple (Acta. Cryst. D67, 235-242 (2011)) program to determine the initial structure. Thereafter, model construction and refinement were repeatedly performed using the Phenix (Acta Cryst. (2019). D75, 861-877), Coot (Acta Cryst. D66: 486-501 (2010)), Refmac5 (Acta Cryst. D67: 355-467 (2011)), and Buster (Global Phasing Ltd.) programs to obtain the final refined coordinates. The resolution was 1.64 Å. Refinement statistics are shown in Table 36. The overall structure is shown in FIG. 3. FIG. 3 was created using the PyMOL Version 2.3 (Schrodinger, LLC.) software.

TABLE 36
Data collection and refinement statistics
(Complex of Linker_hKras-G12D and Compound 1201)
Data collection
Space group                      P1 21 1
Unit cell a, b, c (Å)            45.100, 39.566, 56.252
Unit cell α, β, γ (°)            90.00, 101.18, 90.00
Resolution (Å)                   54.204-1.645 (1.783-1.645)*
Rmerge, Rmeas, Rpim              0.062 (0.577) *, 0.075 (0.691)*,
                                 0.042 (0.375)*
CC(1/2)                          0.998 (0.766)*
mean I/σ(I)                      12.6 (1.6)*
Completeness, sphere (%)         66.6 (15.6)*
Completeness, ellipsoid (%)      83.3 (56.2)*
Total number of reflections      48576 (2535)*
Number of unique reflections     15623 (780)*
Redundancy                       3.1 (3.2)*
Refinement
Resolution (Å)                   44.24-1.64
Number of reflections            15440
Rwork/Rfreea                     0.206/0.271
Root mean square deviation: bond 0.01
distance (Å)
Root mean square deviation:      1.21
bond angle (°)
*The values in parentheses are those for the outermost shell.
aRfree is calculated using 5% of randomly selected reflections.

FIG. 3 shows the overall X-ray crystal structure of a complex of the human Kras C₁₂D mutant and cyclic peptide compound 1201. FIG. 8 shows interaction sites between the Kras G12D mutant and cyclic peptide compound 1201. The Aze(2) residue of Core 4 is positioned in the vicinity of Glu98 and the Hph(4-CF3-35-F) residue of Core 7 in the vicinity of Glu37. Leu56, and Tyr71 (about 3.3 to 4.3 Å), suggesting that they interact with each other.

(Example 6-5) Analysis of X-Ray Crystal Structure of Complex of Linker_hKras-G12D and Cyclic Peptide Compound 2187

For preparation of a complex sample for crystallization, 1.7 ng/mL Linker_hKras-G12D prepared by the same method as in Example 6-1 and a 100% DMSO solution stock with 10 mM of Compound 2187 were used. Linker_hKras-G12D was diluted to 1 mg/mL with the Kras dilution solvent shown in Example 6-3. Compound 2187 was diluted to 1 mM with the Kras dilation solvent, to which 1 mg/mL Linker_hKras-G12D was added at a molar concentration ratio of about 6:1. After allowing to stand on ice for 1 hour, the supernatant after centrifugation was passed through a 0.2 μm filter to remove precipitated Compound 2187.

The prepared complex of Linker_hKras-G12D and Compound 2187 was concentrated to 36 mg/mL using an ultrafiltration membrane and crystallized by the sitting drop vapor diffusion method at 21° C. One of the crystals obtained under the D8 condition (0.1 M Tris-HCl, pH 8.5, and 25% (w/v) polyethylene glycol 4,000) of a commercially available screening kit PEGs Suite (Qiagen) was briefly immersed in a solution formed by adding glycerol at a final concentration of 25% (v/v) to the reservoir solution, and frozen in liquid nitrogen.

The diffraction image was collected with the beamline X10SA of a synchrotron radiation facility Swiss Light Source at a temperature of 100 K and a wavelength of 1.0 Å. Processing with the AutoPROC (Global Phasing Ltd.) program provided X-ray diffraction intensity data down to a resolution of 1.50 Å. Data collection statistics are shown in Table 37.

Using the X-ray diffraction intensity data obtained, molecular substitutions were performed by the Phaser (J. Appl. Cryst. 40: 658-674 (2007)) program to determine the initial structure. Thereafter, model construction and refinement were repeatedly performed using the Phenix (Acta Cryst. (2019). D75, 861-877), Coot (Acta Cryst. D66: 486-501 (2010)), Refmac5 (Acta Cryst. D67: 355-467 (2011)), and Buster (Global Phasing Ltd.) programs to obtain the final refined coordinates. The resolution was 1.50 Å. Refinement statistics are shown in Table 37. As the overall structure is shown in FIG. 4-(1), the asymmetric unit of the resulting crystal structure contained complex molecule 1 and molecule 2. Molecules 1 and 2 have well matched steric structures (RMSD=0.852 Å for all atoms in Linker_hKRas-G12D), as can be seen from the superimposition results shown in FIG. 4-(2). Molecule 1 was used for description of the recognition sites by the compound below. FIG. 4 was created using the PyMOL Version 2.3 (Schrodinger, LLC.) software.

TABLE 37
Data collection and refinement statistics
(Complex of Linker_hKras-G12D and Compound 2187)
Data collection
Space group                      P1 21 1
Unit cell a, b, c (Å)            44.534, 71.269, 62.231
Unit cell α, β, γ (°)            90.00, 105.97, 90.00
Resolution (Å)                   40.486-1.500 (1.608-1.500)*
Rmerge, Rmeas, Rpim              0.059 (0.581)*, 0.070 (0.682)*,
                                 0.037 (0.354)*
CC(1/2)                          0.998 (0.681)*
mean I/σ(I)                      7.6 (1.7)*
Completeness, sphere (%)         43.4 (11.6)*
Completeness, ellipsoid (%)      80.1 (96.9)*
Total number of reflections      89837 (4769)*
Number of unique reflections     26966 (1299)*
Redundancy                       3.5 (3.7)*
Refinement
Resolution (Å)                   40.00-1.496
Number of reflections            25994
Rwork/Rfreea                     0.2140/0.2488
Root mean square deviation: bond 0.008
distance (Å)
Root mean square deviation:      0.900
bond angle (°)
*The values in parentheses are those for the outermost shell.
aRfree is calculated using 5% of randomly selected reflections.

FIG. 4 shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 2187. FIG. 9 shows interaction sites between the Kras G12D mutant and cyclic peptide compound 2187. The Tyr(3-F) residue of Core 2 is positioned in the vicinity of Val8, Gly10, and Lys16 and the Gly residue of Core 10 in the vicinity of Glu98 (about 3.3 to 4.5 Å), suggesting that they interact with each other.

(Example 6-6) Analysis of X-Ray Crystal Structure of Complex of Linker_hKras-G12D and Cyclic Peptide Compound 2188

For preparation of a complex sample for crystallization, 1.7 ng/mL Linker_hKras-G12D prepared by the same method as in Example 6-1 and a 100% DMSO solution stock with 10 mM of Compound 2188 were used. Linker_hKras-G12D was diluted to 1 mg/ml, with the Kras dilution solvent shown in Example 6-3. Compound 2188 was diluted to 1 mM with the Kras dilation solvent, to which 1 mg/mL Linker_hKras-G12D was added at a molar concentration ratio of about 6:1. After allowing to stand on ice for 1 hour, the supernatant after centrifugation was passed through a 0.2 μm filter to remove precipitated Compound 2188.

The prepared complex of Linker_hKras-G12D and Compound 2188 was concentrated to 32 mg/mL using an ultrafiltration membrane and crystallized by the sitting drop vapor diffusion method at 21° C. One of the crystals obtained under the A2 condition (2.0 M ammonium sulfate) of a commercially available screening kit SG1™ HT-96 Eco Screen (Molecular Dimensions) was briefly immersed in a solution formed by adding ethylene glycol at a final concentration of 25% (v/v) to the reservoir solution, and frozen in liquid nitrogen.

The diffraction image was collected with the beamline BL17A of a synchrotron radiation facility Photon Factory at a temperature of 95 K and a wavelength of 0.98 Å. Processing with the AutoPROC (Global Phasing Ltd.) program provided X-ray diffraction intensity data down to a resolution of 2.05 Å. Data collection statistics are shown in Table 38.

Using the X-ray diffraction intensity data obtained, molecular substitutions were performed by the Phaser (J. Appl. Cryst. 40: 658-674 (2007)) program to determine the initial structure. Thereafter, model construction and refinement were repeatedly performed using the Phenix (Acta Cryst. (2019). D75, 861-877) and Coot (Acta Cryst. D66: 486-501 (2010)) programs to obtain the final refined coordinates. The resolution was 2.05 Å. Refinement statistics are shown in Table 38. The overall structure is shown in FIG. 5. FIG. 5 was created using the PyMOL Version 2.3 (Schrodinger, LLC.) software.

TABLE 38
Data collection and refinement statistics
(Complex of Linker_hKras-G12D and Compound 2188)
Data collection
Space group                      P6
Unit cell a, b, c (Å)            107.537, 107.537, 36.615
Unit cell α, β, γ (°)            90.00, 90.00, 120.00
Resolution (Å)                   93.130-2.048 (2.187-2.048)*
Rmerge, Rmeas, Rpim              0.110 (2.237)*, 0.113 (2. 309)*,
                                 0.026 (0.564)*
CC(1/2)                          0.999 (0.660)*
mean I/σ(I)                      19.9 (1.4)*
Completeness, sphere (%)         63.1 (17.9)*
Completeness, ellipsoid (%)      90.2 (68.5)*
Total number of reflections      182657 (8042)*
Number of unique reflections     9812 (490)*
Redundancy                       19.6 (16.4)*
Refinement
Resolution (Å)                   93.13-2.05
Number of reflections            9797
Rwork/Rfreea                     0.2161/0.2509
Root mean square deviation: bond 0.009
distance (Å)
Root mean square deviation:      1.206
bond angle (°)
*The values in parentheses are those for the outermost shell.
aRfree is calculated using 5% of randomly selected reflections.

FIG. 5 shows the overall X-ray crystal structure of a complex of the human Kras G12D mutant and cyclic peptide compound 2188. FIG. 10 shows interaction sites between the Kras G12D mutant and cyclic peptide compound 2188. The Ser(Ph-2-Cl) residue of Core 5 is positioned in the vicinity of Gln70 (about 5), suggesting that they interact with each other.

These X-ray crystallographic results suggest for the first time that the cyclic peptide compounds of the present invention interact with at least one amino acid residue selected from the group consisting of Val8, Gly10, Lys16, Glu37, Leu56, Gln70, Tyr71, and Glu98 of the human Kras G12D mutant. It is suggested for the first time that the cyclic peptide compounds of the present invention can interact with at least one amino acid residue selected from the group consisting of Val8, Gly10, Lys16, Glu37, Leu56, Gln70, Tyr71, and Glu98 of the human Ras protein.

Lengthy table referenced here
US20240148821A1-20240509-T00001
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INDUSTRIAL APPLICABILITY

The present invention provides cyclic peptide compounds having a Ras inhibitory effect, and pharmaceutical compositions containing the cyclic peptide compounds or salts thereof, or solvates thereof.

SEQUENCE LISTING

LENGTHY TABLES
The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

Claims

1. A pharmaceutical composition containing a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof:

2. The pharmaceutical composition according to claim 1, wherein the cyclic peptide compound is represented by formula (2) below:

3. The pharmaceutical composition according to claim 2, wherein the cyclic peptide compound is represented by formula below:

4. The pharmaceutical composition according to claim 1, wherein the cyclic peptide compound is selected from the group consisting of: (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,(1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide,(558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone, and(926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

5. The pharmaceutical composition according to claim 1, wherein the cyclic peptide compound is: (1217) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i] [1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

6. The pharmaceutical composition according to claim 1, wherein the cyclic peptide compound is: (1201) (5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide.

7. The pharmaceutical composition according to claim 1, wherein the cyclic peptide compound is: (558) (3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone.

8. The pharmaceutical composition according to claim 1, wherein the cyclic peptide compound is: (926) (5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.

9. The pharmaceutical composition according to claim 1, wherein the cyclic peptide compound is a RAS inhibitor.

10. A method for treating or preventing cancer, comprising administering to a subject in need thereof the pharmaceutical composition according to claim 1.

11. The method according to claim 10, wherein the cancer is solid cancer or hematological cancer.

12. The method according to claim 10, wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, large bowel cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

13. The method according to claim 10, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine body cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

14. The method according to claim 10, wherein the cancer is associated with an abnormality of a Ras gene.

15. A method of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof:

16. The method according to claim 14, wherein the cancer is associated with generation of a mutant Ras protein.

17. The method according to claim 16, wherein the mutant Ras protein has a mutation in at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences set forth in SEQ ID Nos: 6, 7, or 8.

18. The method according to claim 16, wherein the mutant Ras protein is a mutant Kras protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence set forth in SEQ ID No: 6.

19. The method according to claim 16, wherein the mutant Ras protein is a mutant Nras protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L as compared to the amino acid sequence set forth in SEQ ID No: 7.

20. The method according to claim 16, wherein the mutant Ras protein is a mutant Hras protein and has an amino acid mutation of G13R as compared to the amino acid sequence set forth in SEQ ID No: 8.

21. The method according to claim 10, wherein the cyclic peptide compound is selected from the group consisting of cyclic peptide compounds set forth in Table 39.

22. The method according to claim 10, wherein the cyclic peptide compound or salt thereof, or solvate thereof is ((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof;(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof;(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof;(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide;(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or solvate thereof;(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or salt thereof, or hydrate thereof;(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide or hydrate thereof;(5S,8S,11S,15S,18S,23aS,25R,29S,35S,37aS)-8-((S)-sec-butyl)-35-(cyclohexylmethyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-25-ethoxy-11-isobutyl-N,N,5,6,12,16,19,33,36-nonamethyl-4,7,10,13,17,20,23,28,31,34,37-undecaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentane]-15-carboxamide;(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or solvate thereof;(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or salt thereof, or hydrate thereof;(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone or hydrate thereof;(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone;(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or solvate thereof;(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or salt thereof, or hydrate thereof;(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone or hydrate thereof; or(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-15-(morpholine-4-carbonyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1′-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone.