STAT5 and STAT6 Inhibitors and Uses Thereof

Abstract

Described herein are compounds of Formula I and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, as well as their uses as STAT5 and/or STAT6 inhibitors.

Description

BACKGROUND

The signal transducer and activator of transcription (STAT) proteins play important roles in biological processes. For example, the abnormal activation of STAT signaling pathways is implicated in cancer, autoimmune diseases, rheumatoid arthritis, asthma, diabetes, and other human diseases. See, e.g., Miklossy et al., Nat Rev Drug Discov 12:611-629 (2013).

The STAT protein family is composed of seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. Structurally, they share five domains: an amino-terminal domain, a coiled-coil domain, a DNA-binding domain, an SH2 domain, and a carboxy-terminal transactivation domain. The transactivation domain contains one or two amino acid residues that are crucial for the activity of the STAT protein. In particular, phosphorylation of a particular tyrosine residue promotes dimerization, whereas phosphorylation of a particular serine residue enhances transcriptional activation.

STAT proteins promote fundamental cellular processes, including cell growth and differentiation, development, apoptosis, immune responses, and inflammation. In particular, STAT5/STAT6 function may be abnormal in the context of cancer, and this abnormality represents an underlying mechanism of STAT5/STAT6 for promoting malignant transformation and progression. Constitutively active STAT5/STAT6 is detected in numerous malignancies, including breast, melanoma, prostate, head and neck squamous cell carcinoma (HNSCC), multiple myeloma, pancreatic, ovarian, and brain tumors. Aberrant STAT5/STAT6 signaling promotes tumorigenesis and tumor progression partly through dysregulating the expression of critical genes that control cell growth and survival, angiogenesis, migration, invasion, or metastasis. These genes include those that encode p21^WAF1/CIP2, cyclin D1, MYC, BCL-X, BCL-2, vascular endothelial growth factor (VEGF), matrix metalloproteinase 1 (MMP1), MMP7 and MMP9, and survivin. STAT5/STAT6 may also play a role in the suppression of tumor immune surveillance. Consequently, the genetic and pharmacological modulation of persistently active STAT5/STAT6 was shown to control the tumor phenotype and to lead to tumor regression in vivo.

There exists a need in the art for STAT5/STAT6 inhibitors and STAT5/STAT6 degraders having physical and pharmacological properties that allow them to be used in therapeutic applications for treating disease.

SUMMARY

In certain aspects, the present disclosure provides compounds of Formula I:

and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formula I, is described, embodied, and exemplified herein.

In certain aspects, the present disclosure provides methods of inhibiting a STAT5 and/or STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of inhibiting a STAT5 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of inhibiting a STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides methods of degrading a STAT5 and/or STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of degrading a STAT5 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of degrading a STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject, comprising administering a compound disclosed herein to the subject (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder.

In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder.

In certain aspects, the present disclosure provides methods of treating a disease or disorder in a patient, comprising administering a compound disclosed herein to the subject (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder.

In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder.

DETAILED DESCRIPTION

In certain aspect, the present disclosure provides compounds of Formula I:

and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein:

• • R^1a and R^1b are independently hydrogen or C_1-6 alkyl;
  • each R² is independently hydrogen or halogen; or
  • Ring A is C_6-10 aryl or 5- to 10-membered heteroaryl;
  • each R^A is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • m is an integer selected from 0 to 6;
  • Ring B is 3- to 12-membered heterocyclyl;
  • each R^B is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^B-1;
  • two vicinal R^B, together with atoms to which they are bonded, form C₆ aryl or 5- to 6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R^B-1;
  • each R^B-1 is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • n is an integer selected from 0 to 6;
  • X is —CR^X═CR^X— or absent;
  • each R^X is independently hydrogen, halogen, or C_1-6 alkyl;
  • R³ is hydrogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u;
  • each R⁴ independently is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^4a; or
  • R⁴ and R^B, together with the intervening atoms, form a 3- to 12-membered heterocyclyl optionally substituted with one or more R^4b; or
  • two R⁴, together with the carbon atom to which they are attached, form C_3-6 carbocyclyl or 3- to 6-membered heterocyclyl;
  • each R^4a is independently halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^CR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • each R^4b is independently oxo, halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;

is

• • R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), or —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c;
  • each R^5c is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), or —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • Ring D is 3- to 12-membered heterocyclyl;
  • Ring E is C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, or 3- to 12-membered heterocyclyl;
  • each R^5d and R^5e is independently oxo, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • p and q independently are integers selected from 0 to 6;
  • wherein:
  • each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^CR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, and 3- to 6-membered heterocyclyl; or
  • two R^u, together with the one or more intervening atoms, form C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^z;
  • each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl;
  • each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; and
  • R^c and R^d are independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R^Z,
  • wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and
  • each R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl.

In certain embodiments, the compound is a compound of Formula I-a or I-b:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, the compound is a compound of Formula I-a-i to I-b-iii

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, the compound is a compound of Formula I-a-i-1 or I-b-i-1

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein r is an integer from 0 to 10, as valency permits.

In certain embodiments, the compound is a compound of Formula I-a-i-2 or I-b-i-2

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, when one of R^5a and R^5b is hydrogen, then the other one of R^5a and R^5b is not:

wherein:

Y is —O—, —NH—, or —CH₂—; and

R^1′ is H or benzyl.

In certain embodiments, R^5a and R^5b is not:

wherein:

Y is —O—, —NH—, or —CH₂—; and

R^1′ is H or benzyl.

In certain embodiments, R^1a is hydrogen or C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)).

In certain embodiments, R^1b is hydrogen or C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)).

In certain embodiments, each R² is independently hydrogen or halogen (e.g., —F, —Cl, —Br, or —I).

In certain embodiments, two R², together with the carbon atom to which they are attached, form C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, Ring A is C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, each R^A is independently halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently halogen, —CN, —NO₂, —OH, —NH₂, C₁-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently halogen, —CN, —NO₂, —OH, —NH₂, C₁-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently halogen, —CN, —NO₂, —OH, —NH₂, C₁-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, m is an integer selected from 0 to 6. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.

In certain embodiments, Ring B is 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, each R^B is independently oxo, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^B is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^B is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^B is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^B is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, two vicinal R^B, together with atoms to which they are bonded, form C₆ aryl or 5- to 6-membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-5 heteroatoms selected from N, O, and S), wherein the aryl or heteroaryl is optionally substituted with one or more R^B1.

In certain embodiments, each R^B-1 is independently oxo, halogen (e.g., —F, —C₁, —Br, or —I), —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^B-1 is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^B-1 is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^B-1 is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^B-1 is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, n is an integer selected from 0 to 6. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.

In certain embodiments, X is —CR^X═CR^X— or absent.

In certain embodiments, each R^X is independently hydrogen, halogen (e.g., —F, —Cl, —Br, or —I), or C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)).

In certain embodiments, R³ is hydrogen, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, R³ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R⁴ is independently oxo, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^4a.

In certain embodiments, each R⁴ is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^4a.

In certain embodiments, each R⁴ is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^4a.

In certain embodiments, each R⁴ is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^4a.

In certain embodiments, each R⁴ is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^4a.

In certain embodiments, R⁴ and R^B, together with the intervening atoms, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S) optionally substituted with one or more R^4b.

In certain embodiments, two R⁴, together with the carbon atom to which they are attached, form C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen (e.g., —F, —C₁, —Br, or —I), —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), —NR^bC(═O)R^a, —OR^b, —C(═O)R^a, or —C(═O)NR^cR^d, wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4b is independently oxo, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4b is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4b is independently oox, halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4b is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^4b is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^4b is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, or —C(═O)R^a, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u.

In certain embodiments, r is an integer from 0 to 10, as valency permits. In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4. In certain embodiments, r is 5. In certain embodiments, r is 6. In certain embodiments, r is 7. In certain embodiments, r is 8. In certain embodiments, r is 9. In certain embodiments, r is 10.

In certain embodiments,

is

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —(C_1-6 alkyl)-(C_6-10 aryl), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), or —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^5c.

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^5c.

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^5c.

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c.

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c.

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-10 aryl), wherein the alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c.

In certain embodiments, each R^5c is independently halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —(C_1-6 alkyl)-(C_3-12 carbocyclyl), or —(C_1-6 alkyl)-(3- to 12-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5c is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5c is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5c is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R⁵, is independently halogen, —CN, —NO₂, —OH, —NH₂, —B(OH)₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^5c is independently halogen, C_1-6 alkyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C_1-6 alkyl)-(5- to 10-membered heteroaryl), —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, Ring D is 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, each R^5d is independently oxo, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5d is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5d is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5d is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^5d is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^5d is independently oxo, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C₆_o aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, —S(═O)₂R^a, —OR^b, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, carbocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, p is an integer selected from 0 to 6. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6.

In certain embodiments, Ring E is C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, each R^5e is independently oxo, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5e is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5e is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5e is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^5e is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^5e is independently halogen, C_1-6 alkyl, C_6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, q is an integer selected from 0 to 6. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6.

In certain aspects, the present disclosure provides compounds of Formula I:

• • and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein:
  • R^1a is hydrogen or C_1-6 alkyl;
  • R^1b is hydrogen or C_1-6 alkyl;
  • each R² is independently hydrogen or halogen; or
  • two R², together with the carbon atom to which they are attached, form a C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl;
  • Ring A is C_6-14 aryl or 5- to 14-membered heteroaryl;
  • Ring B is 3- to 10-membered heterocyclyl;
  • each R^A is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • each R^B is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^B-1;
  • each R^B-1 is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • m and n independently are integers selected from 0 to 6;
  • X is —CR^X═CR^X— or absent;
  • each R^X is independently hydrogen, halogen, or C_1-6 alkyl;
  • R³ is hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u;
  • each R⁴ independently is hydrogen, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^4a; or
  • R⁴ and R^B, together with the intervening atoms, form a 3- to 10-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R^4b; or two R⁴, together with the carbon atom to which they are attached, form C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl;
  • each R^4a is independently halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • each R^4b is independently halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;

is

• • R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), or —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c;
  • each R^5c is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), or —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • Ring D is 3- to 12-membered heterocyclyl;
  • Ring E is C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
  • each R^5d and R^5e is independently oxo, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • p and q independently are integers selected from 0 to 6;
  • wherein:
  • each R^u is independently oxo, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more oxo, halogen, —CN, —OH, —O(C_1-6 alkyl), —O(C═O)(C_1-6 alkyl), —NH₂, —NH(C_1-6 alkyl), —N(C_1-6 alkyl)₂, —NH(C═O)(C_1-6 alkyl), —N(C═O)(C_1-6 alkyl)₂, C_1-6 alkyl, C_1-6 haloalkyl, —C(═O)(C_1-6 alkyl), —C(═O)OH, —C(═O)O(C_1-6 alkyl), —C(═O)NH₂, —C(═O)NH(C_1-6 alkyl), or —C(═O)N(C_1-6 alkyl)₂; or
  • two R^u, together with the one or more intervening atoms, form a C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl;
  • each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl;
  • each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; and
  • each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 10-membered heterocyclyl,
  • wherein each of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and
  • each R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-10 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, when one of R^5a and R^5b is hydrogen, then the other one of R^5a and R^5b is not:

wherein:

Y is —O—, —NH—, or —CH₂—; and

R^1′ is H or benzyl.

In certain embodiments, R^1a and R^1b are both hydrogen. In certain embodiments, Ria and R^1b are both C_1-6 alkyl. In certain embodiments, one of R^1a and R^1b is hydrogen, and the other one of R^1a and R^1b is C_1-6 alkyl.

In certain embodiments, each R² is independently halogen. In certain embodiments, each R² is fluoride. In certain embodiments, each R² is hydrogen. In certain embodiments, one R² is halogen, and the other R² is hydrogen. In certain embodiments, one R² is fluoride, and the other R² is hydrogen.

In certain embodiments, Ring A is C_6-14 aryl. In certain embodiments, Ring A is 5- to 14-membered heteroaryl. In certain embodiments, Ring A is 5- to 10-membered heteroaryl. In certain embodiments, Ring A is 10-membered heteroaryl. In certain embodiments, Ring A is 9-membered heteroaryl. In certain embodiments, Ring A is 8-membered heteroaryl. In certain embodiments, Ring A is 7-membered heteroaryl. In certain embodiments, Ring A is 5- or 6-membered heteroaryl. In certain embodiments, Ring A is 5-membered heteroaryl. In certain embodiments, Ring A is 6-membered heteroaryl.

In certain embodiments, Ring A is

In certain embodiments, the compound is a compound of Formula I-a or I-b:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, each R^A is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_3-10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d.

In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain preferred embodiments, m is 0.

In certain embodiments, X is —CR^X═CR^X—. In certain embodiments, X is absent.

In certain embodiments, R³ is hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_3-10 carbocyclyl, or 3- to 10-membered heterocyclyl. In certain embodiments, R³ is hydrogen or C_1-6 alkyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R³ is C_1-6 alkyl.

In certain embodiments, Ring B is 5- to 8-membered heterocyclyl. In certain embodiments, Ring B is 5-membered heterocyclyl. In certain embodiments, Ring B is 6-membered heterocyclyl.

In certain embodiments, each R^B is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_3-10 carbocyclyl, or 3- to 10-membered heterocyclyl.

In certain embodiments, each R^B is independently —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d.

In certain embodiments, each R^B is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^B-1.

In certain embodiments, each R^B is independently halogen, —CN, —NO₂, 5- to 14-membered heteroaryl, —NR^cR^d, —OR^b, —C(═O)R^a, or —C(═O)OR^b, wherein the heteroaryl is optionally substituted with one or more R^B-1.

In certain embodiments, each R^B-1 is independently halogen, —CN, —NO₂, C_1-6 alkyl, C₁-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^B-1 is independently C_1-6 alkyl, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl is optionally substituted with one or more R^u.

In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain preferred embodiments, n is 0.

In certain embodiments, the compound is a compound of Formula I-a-i to I-b-iii

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, each R⁴ is independently hydrogen, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C₁-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^4a.

In certain embodiments, each R⁴ is independently hydrogen, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), or —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^4a.

In certain embodiments, each R⁴ is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_6-14 aryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), or —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, heterocyclyl, or aryl is optionally substituted with one or more R^4a.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C₁-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C₁-6 alkyl)-(3- to 10-membered heterocyclyl), —NR^bC(═O)R^a, —OR^b, —C(═O)R^a, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4a is independently halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —NR^bC(═O)R^a, —OR^b, —C(═O)R^a, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, one R⁴ and one R^B, together with the intervening atoms, form a 3- to 10-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R^4b.

In certain embodiments, the compound is a compound of Formula I-a-i-1 or I-b-i-1

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein r is an integer from 0 to 10, as valency permits.

In certain embodiments, the compound is a compound of Formula I-a-i-3 or I-b-i-4

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein r is an integer from 0 to 10, as valency permits.

In certain embodiments, each R^4b is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^4b is independently —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d.

In certain embodiments, at least one R^4b is acetyl.

In certain embodiments, two R⁴, together with the carbon atom to which they are attached, form C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl. In certain embodiments, two R⁴, together with the carbon atom to which they are attached, form C_3-10 carbocyclyl. In certain embodiments, two R⁴, together with the carbon atom to which they are attached, form 3- to 10-membered heterocyclyl.

In certain embodiments,

is

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), or —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c.

In certain embodiments, R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, or —(C_1-6 alkyl)-(C_6-14 aryl), wherein the alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c. In certain embodiments, each R⁵, is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), or —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R⁵, is independently halogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —C(═O)OR^b, or —C(═O)NR^CR^d, wherein the alkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, one of R^5a and R^5b is hydrogen, and the other one of R^5a and R^5b is 5- to 14-membered heteroaryl substituted with C_6-14 aryl, wherein the aryl is optionally substituted with one or more R^u.

In certain embodiments,

is

In certain embodiments,

is

In certain embodiments, Ring D is 3- to 12-membered heterocyclyl. In certain embodiments, Ring D is 5- or 6-membered heterocyclyl. In certain embodiments, Ring D is 5-membered heterocyclyl. In certain embodiments, Ring D is 6-membered heterocyclyl.

In certain embodiments, each R^5d is independently oxo, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5d is independently oxo, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, —S(═O)₂R^a, —OR^b, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, or aryl is optionally substituted with one or more R^u.

In certain embodiments, Ring E is C_6-14 aryl, 5- to 14-membered heteroaryl, or C_3-10 carbocyclyl.

In certain embodiments, Ring E is C_6-14 aryl or C_3-10 carbocyclyl.

In certain embodiments, each R^5e is independently halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^5e is independently halogen, C_1-6 alkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6.

In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6.

In certain embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring A is

• • Ring B is 5- or 6-membered heterocyclyl;
  • each R⁴ independently is C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_6-14 aryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, heterocyclyl, or aryl is optionally substituted with one or more R^4a; or, R⁴ and R^B, together the intervening atoms, form a 3- to 10-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R^4b; or
  • two R⁴, together with the carbon atom to which they are attached, form C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl;
  • each R^4a is independently halogen, —CN, —NO₂, —B(OH)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —NR^bC(═O)R^a, —OR^b, —C(═O)R^a, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • R^4b is —C(═O)R^a;

is

• • R^5a and R^5b are independently hydrogen, C_1-6 alkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), wherein the alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^5c;
  • each R^5c is independently halogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • Ring D is 3- to 12-membered heterocyclyl;
  • Ring E is C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
  • each R^5d is independently oxo, halogen, C_1-6 alkyl, C_1-6haloalkyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, —S(═O)₂R^a, —OR^b, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • each R^5e is independently halogen, —C_1-6 alkyl, C_6-14 aryl, or 5- to 14-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • p and q independently are integers selected from 0 to 6;
  • wherein:
  • each R^u is independently oxo, halogen, —CN, —NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, —(C_1-6 alkyl)-(C_6-14 aryl), —(C_1-6 alkyl)-(5- to 14-membered heteroaryl), —(C_1-6 alkyl)-(C_3-10 carbocyclyl), —(C_1-6 alkyl)-(3- to 10-membered heterocyclyl), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^CR^d, —NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more oxo, halogen, —CN, —OH, —O(C_1-6 alkyl), —O(C═O)(C_1-6 alkyl), —NH₂, —NH(C_1-6 alkyl), —N(C_1-6 alkyl)₂, —NH(C═O)(C_1-6 alkyl), —N(C═O)(C_1-6 alkyl)₂, C_1-6 alkyl, C_1-6haloalkyl, —C(═O)(C_1-6 alkyl), —C(═O)OH, —C(═O)O(C_1-6 alkyl), —C(═O)NH₂, —C(═O)NH(C_1-6 alkyl), or —C(═O)N(C_1-6 alkyl)₂; or
  • two R^u, together with the one or more intervening atoms, form a C_6-14 aryl, 5- to 14-membered heteroaryl, C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl;
  • each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl;
  • each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; and
  • each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 10-membered heterocyclyl,
  • wherein each of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and
  • each R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-10 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, when one of R^5a and R^5b is hydrogen, then the other one of R^5a and R^5b is not:

wherein:

Y is —O—, —NH—, or —CH₂—; and

R^1′ is H or benzyl.

In certain embodiments, each R^a is independently C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl.

In certain embodiments, each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, each R^a is independently C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C₂-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C₂-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C_2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^c and each R^d is independently hydrogen, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^c and each R^d is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more R^u.

In certain embodiments, R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more R^z.

In certain embodiments, R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z.

In certain embodiments, R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C₁-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, two R^u, together with the carbon atom(s) to which they are attached, form C_3-6 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C₆)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).

In certain embodiments, two geminal R^u, together with the carbon atom to which they are attached, form C_3-6 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C₆)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).

Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I and I′, as applicable, are described below. Any of the variables can be any moiety as described in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, is also contemplated.

Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “C_1-6 alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6 alkyl.

In certain embodiments, the compound is selected from compounds described in Table 1 and pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

TABLE 1
Listing of Compounds
Cpd.
No.	Structure	Name
1		(difluoro(4-((E)-3-(((S)-1-((S)-2- ((4- iodophenyl)(phenyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-3-oxoprop-1- en-1-yl)phenyl)methyl)phosphonic acid
2		(difluoro(2-(((S)-1-((S)-2-((4- iodophenyl)(phenyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)carbamoyl)-1H- indol-5-yl)methyl)phosphonic acid
3		((2-(((5S,8S,10aR)-3-acetyl-8- (benzhydrylcarbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
4		((3-(((5S,8S,10aR)-3-acetyl-8-((4- iodophenyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
5		((4-((E)-3-(((5S,8S,10aR)-3-acetyl- 8-(benzhydrylcarbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)amino)-3- oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
6		((4-((E)-3-(((5S,8S,10aR)-3-acetyl- 8-((4-iodophenyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)amino)-3- oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
7		((2-(((5S,8S,10aR)-3-acetyl-8- (benzhydryl(methyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
8		((4-((E)-3-(((S)-6-amino-1-oxo-1- ((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)hexan-2- yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
9		((2-(((S)-6-amino-1-oxo-1-((S)-2- (1,2,3,4-tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)hexan-2- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
10		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(((R)-1,2,3,4- tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
11		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(((S)-1,2,3,4- tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
12		((2-(((2S)-1-((2S)-2-((2,3-dihydro- 1H-inden-1- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
13		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(4-phenylpiperazine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
14		((2-(((S)-1-((S)-2- (benzhydrylcarbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
15		((2-(((S)-3,3-dimethyl-1-((S)-2- (naphthalen-2- ylcarbamoyl)pyrrolidin-1-yl)-1- oxobutan-2-yl)carbamoyl)-1H- indol-5- yl)difluoromethyl)phosphonic acid
16		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(((1R,2S)-2- phenylcyclopropyl)carbamoyl) pyrrolidin-1-yl)butan-2-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
17		((2-(((S)-1-((S)-2-(4-benzylthiazol- 2-yl)pyrrolidin-1-yl)-3,3-dimethyl- 1-oxobutan-2-yl)carbamoyl)-1H- indol-5- yl)difluoromethyl)phosphonic acid
18		((4-((E)-3-(((S)-1-((S)-2-(4- benzylthiazol-2-yl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
19		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(4-phenylthiazol-2-yl)pyrrolidin- 1-yl)butan-2-yl)carbamoyl)-1H- indol-5- yl)difluoromethyl)phosphonic acid
20		((4-((E)-3-(((S)-3,3-dimethyl-1-oxo- 1-((S)-2-(4-phenylthiazol-2- yl)pyrrolidin-1-yl)butan-2- yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
21		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(5-phenylthiazol-2-yl)pyrrolidin- 1-yl)butan-2-yl)carbamoyl)-1H- indol-5- yl)difluoromethyl)phosphonic acid
22		((4-((E)-3-(((S)-3,3-dimethyl-1-oxo- 1-((S)-2-(5-phenylthiazol-2- yl)pyrrolidin-1-yl)butan-2- yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
23		((2-(((S)-3-cyclohexyl-1-oxo-1-((S)- 2-(1,2,3,4-tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
24		((4-((E)-3-(((S)-3-cyclohexyl-1-oxo- 1-((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)propan-2- yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
25		((2-(((S)-1-((S)-2-(5-benzylthiazol- 2-yl)pyrrolidin-1-yl)-3,3-dimethyl- 1-oxobutan-2-yl)carbamoyl)-1H- indol-5- yl)difluoromethyl)phosphonic acid
26		((4-((E)-3-(((S)-1-((S)-2-(5- benzylthiazol-2-yl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid
27		(difluoro(2-(((S)-1-oxo-3-(pyridin- 4-yl)-1-((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)-1H-indol-5- yl)methyl)phosphonic acid
28		(difluoro(2-((2-oxo-1-(piperidin-4- yl)-2-((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1- yl)ethyl)carbamoyl)-1H-indol-5- yl)methyl)phosphonic acid
29		(difluoro(4-((E)-3-oxo-3-((2-oxo-1- (piperidin-4-yl)-2-((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1- yl)ethyl)amino)prop-1-en-1- yl)phenyl)methyl)phosphonic acid
30		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((4-phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
31		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
32		((2-(((S)-1-((S)-2- (benzhydryl(methyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)carbamoyl)-1H- indol-5- yl)difluoromethyl)phosphonic acid
33		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(5-phenyl-1H-imidazol-2- yl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
34		((2-((1-(1-acetylpiperidin-4-yl)-2- oxo-2-((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1- yl)ethyl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
35		((2-(((S)-3-(1-benzyl-1,2,3,6- tetrahydropyridin-4-yl)-1-oxo-1- ((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
36		(difluoro(2-(((S)-1-oxo-3-(piperidin- 4-yl)-1-((S)-2-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)-1H-indol-5- yl)methyl)phosphonic acid
37		((2-(((S)-1-((S)-2-((4- ((benzyloxy)carbonyl)phenyl)(4- iodophenyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
38		(difluoro(2-(((S)-1-((S)-2-((3- methoxy-3- oxopropyl)(phenyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
39		(difluoro(2-(((S)-1-((S)-2-((4- iodophenyl)(phenyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
40		((2-(((S)-1-((S)-2-((4- chlorophenyl)(cyclohexyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)carbamoyl)-1H- indol-5- yl)difluoromethyl)phosphonic acid
41		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(1,2,3,4-tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
42		(difluoro(2-(((S)-1-((S)-2-((4- iodophenyl)(4- (methylcarbamoyl)phenyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
43		N-((3R,6S,9S,12R)-6-ethyl-12- methyl-2,5,8,11-tetraoxo-3-phenyl- 9-((pyridin-2-ylamino)methyl)- 1,4,7,10-tetraazacyclotetradecan-12- yl)isobutyramide
44		((2-(((S)-1-((S)-2-((4- chlorophenyl)(4- (methylcarbamoyl)phenyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
45		((2-(((S)-1-((S)-2-((4- bromophenyl)(3-(methylamino)-3- oxopropyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
46		3-((S)-N-(4-bromophenyl)-1-((S)-2- (5- (difluoro(phosphono)methyl)benzo[b] thiophene-2-carboxamido)-3,3- dimethylbutanoyl)pyrrolidine-2- carboxamido)propanoic acid
47		3-((2S,4S)-N-(4-bromophenyl)-1- ((S)-2-(5- (difluoro(phosphono)methyl)benzo [b]thiophene-2-carboxamido)-3,3- dimethylbutanoyl)-4-(2-ethoxy-2- oxoethoxy)pyrrolidine-2- carboxamido)propanoic acid
48		3-((2S,4R)-N-(4-bromophenyl)-1- ((S)-2-(5- (difluoro(phosphono)methyl)benzo[b] thiophene-2-carboxamido)-3,3- dimethylbutanoyl)-4-(2-ethoxy-2- oxoethoxy)pyrrolidine-2- carboxamido)propanoic acid
49		3-((2S,4S)-N-(4-bromophenyl)-4- (carboxymethoxy)-1-((S)-2-(5- (difluoro(phosphono)methyl)benzo[b] thiophene-2-carboxamido)-3,3- dimethylbutanoyl)pyrrolidine-2- carboxamido)propanoic acid
50		3-((2S,4R)-N-(4-bromophenyl)-4- (carboxymethoxy)-1-((S)-2-(5- (difluoro(phosphono)methyl)benzo[b] thiophene-2-carboxamido)-3,3- dimethylbutanoyl)pyrrolidine-2- carboxamido)propanoic acid
51		((2-(((S)-1-((2S,4S)-2-((4- bromophenyl)(3-(methylamino)-3- oxopropyl)carbamoyl)-4-(2- (methylamino)-2- oxoethoxy)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
52		((2-(((S)-1-((2S,4R)-2-((4- bromophenyl)(3-(methylamino)-3- oxopropyl)carbamoyl)-4-(2- (methylamino)-2- oxoethoxy)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
53		((2-(((S)-1-((2S,4S)-4-(2-ethoxy-2- oxoethoxy)-2-((4- iodophenyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
54		((2-(((S)-1-((2S,4S)-2-((4- bromophenyl)(methyl)carbamoyl)- 4-(2-ethoxy-2- oxoethoxy)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
55		((2-(((S)-1-((2S,4S)-2-((4- bromophenyl)(propyl)carbamoyl)-4- (2-ethoxy-2-oxoethoxy)pyrrolidin- 1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
56		((2-(((S)-1-((2S,4S)-2-((4- bromophenyl)(3-(methylamino)-3- oxopropyl)carbamoyl)-4-(2-ethoxy- 2-oxoethoxy)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
57		((2-(((S)-1-((2S,4S)-2-((4- bromophenyl)(3-(dimethylamino)-3- oxopropyl)carbamoyl)-4-(2-ethoxy- 2-oxoethoxy)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
58		((2-(((S)-1-((S)-2-(1- azaspiro[4.4]nonane-1- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
59		((2-(((S)-1-((S)-2-(2- azaspiro[4.4]nonane-2- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
60		((2-(((S)-1-((S)-2-(1- azaspiro[4.5]decane-1- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
61		((2-(((S)-1-((S)-2-(2- azaspiro[4.5]decane-2- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
62		((2-(((S)-1-((S)-2-(2- azaspiro[4.6]undecane-2- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
63		((2-(((S)-1-((S)-2-(5- azaspiro[2.4]heptane-5- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
64		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((S)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
65		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((S)-3-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
66		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-3-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
67		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
68		((2-(((S)-1-((S)-2-(7-chloro-1,2,3,4- tetrahydroisoquinoline-2- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
69		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(2,3,4,5-tetrahydro-1H- benzo[d]azepine-3- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
70		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(2,3,4,5-tetrahydro-1H- benzo[c]azepine-2- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
71		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((1- phenylcyclopropyl)carbamoyl) pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
72		((2-(((S)-1-((S)-2- (benzyl(methyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
73		((2-(((S)-1-((S)-2-((4- chlorobenzyl)(methyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
74		((2-(((S)-1-((S)-2-((4- bromobenzyl)(methyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
75		((2-(((S)-1-((S)-2- (benzyl(cyclohexyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
76		((2-(((S)-1-((S)-2- (benzyl(tetrahydro-2H-pyran-4- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
77		((2-(((S)-1-((S)-2-(1,4-oxazepane-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
78		((2-(((S)-3,3-dimethyl-1-((S)-2- ((3aR,7aR)-octahydro-1H- pyrrolo[2,3-c]pyridine-6- carbonyl)pyrrolidin-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
79		((2-(((S)-3,3-dimethyl-1-((S)-2- ((3aR,6aR)-octahydropyrrolo[3,4- b]pyrrole-1-carbonyl)pyrrolidin-1- yl)-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
80		((2-(((S)-3,3-dimethyl-1-((S)-2- ((3aR,6aR)-octahydropyrrolo[3,4- b]pyrrole-5-carbonyl)pyrrolidin-1- yl)-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
81		((2-(((S)-1-((S)-2-((3aS,7aR)-1- acetyloctahydro-1H-pyrrolo[2,3- c]pyridine-6-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
82		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((3aS,7aR)-1-pentanoyloctahydro- 1H-pyrrolo[2,3-c]pyridine-6- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
83		(difluoro(2-(((S)-1-((S)-2- ((3aS,7aR)-1-(4- fluorobenzoyl)octahydro-1H- pyrrolo[2,3-c]pyridine-6- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
84		((2-(((S)-1-((S)-2-((3aR,6aR)-5- acetyloctahydropyrrolo[3,4- b]pyrrole-1-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
85		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((3aR,6aR)-5- pentanoyloctahydropyrrolo[3,4- b]pyrrole-1-carbonyl)pyrrolidin-1- yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
86		(difluoro(2-(((S)-1-((S)-2- ((3aR,6aR)-5-(4- fluorobenzoyl)octahydropyrrolo[3,4-b] pyrrole-1-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
87		((2-(((S)-1-((S)-2-((3aR,6aR)-1- acetyloctahydropyrrolo[3,4- b]pyrrole-5-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
88		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((3aR,6aR)-1- pentanoyloctahydropyrrolo[3,4- b]pyrrole-5-carbonyl)pyrrolidin-1- yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
89		(difluoro(2-(((S)-1-((S)-2- ((3aR,6aR)-1-(4- fluorobenzoyl)octahydropyrrolo[3,4- b]pyrrole-5-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
90		((2-(((S)-1-((S)-2-((3aS,7aR)-6- acetyloctahydro-1H-pyrrolo[2,3- c]pyridine-1-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
91		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((3aS,7aR)-6-pentanoyloctahydro- 1H-pyrrolo[2,3-c]pyridine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
92		((2-(((S)-1-((S)-2-((3aS,6aS)-5- acetyloctahydropyrrolo[3,4- b]pyrrole-1-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
93		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((3aS,6aS)-5- pentanoyloctahydropyrrolo[3,4- b]pyrrole-1-carbonyl)pyrrolidin-1- yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
94		(difluoro(2-(((S)-1-((S)-2- ((3aS,6aS)-5-(4- fluorobenzoyl)octahydropyrrolo[3,4-b] pyrrole-1-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
95		((2-(((S)-1-((S)-2-((3aS,6aS)-1- acetyloctahydropyrrolo[3,4- b]pyrrole-5-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
96		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((3aS,6aS)-1- pentanoyloctahydropyrrolo[3,4- b]pyrrole-5-carbonyl)pyrrolidin-1- yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
97		(difluoro(2-(((S)-1-((S)-2- ((3aS,6aS)-1-(4- fluorobenzoyl)octahydropyrrolo[3,4-b] pyrrole-5-carbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
98		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((S)-3-phenylpiperidine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
99		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-3-phenylpiperidine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
100		(difluoro(2-(((2S)-1-((2S)-2-(2-(4- fluorophenyl)-2-methylmorpholine- 4-carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
101		((2-(((2S)-1-((2S)-2-(2-(4- chlorophenyl)-2-methylmorpholine- 4-carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
102		(difluoro(2-(((2S)-1-((2S)-2-(2-(4- fluorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
103		((2-(((2S)-1-((2S)-2-(2-(3- chlorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
104		((2-(((2S)-1-((2S)-2-(2-(2,4- dichloro-5- fluorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
105		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(3-(o-tolyl)piperidine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
106		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-(o-tolyl)morpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
107		((2-(((2S)-1-((2S)-2-(2-(2,4- dimethylphenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
108		(difluoro(2-(((2S)-1-((2S)-2-(2-(4- fluoro-3-methylphenyl)morpholine- 4-carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
109		(difluoro(2-(((2S)-1-((2S)-2-(2-(2- fluorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
110		((2-(((2S)-1-((2S)-2-(2-(2,4- difluorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
111		((2-(((2S)-1-((2S)-2-(2-(3,4- difluorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
112		((2-(((2S)-1-((2S)-2-(2-(2- chlorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
113		((2-(((2S)-1-((2S)-2-(2-(3-chloro-4- fluorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
114		((2-(((2S)-1-((2S)-2-(2-(3,4- dichlorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
115		((2-(((2S)-1-((2S)-2-(4- (ethoxycarbonyl)-3- phenylpiperidine-1- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
116		(difluoro(2-(((S)-1-((2S,4S)-4- hydroxy-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
117		(difluoro(2-(((S)-1-((2S,4R)-4- hydroxy-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
118		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
119		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((S)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
120		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((S)-3-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
121		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((R)-3-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
122		((2-(((S)-3-acetamido-3-methyl-1- oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
123		1-(((S)-2-(5- (difluoro(phosphono)methyl)benzo [b]thiophene-2-carboxamido)-3,3- dimethylbutanoyl)-L-prolyl)-3- phenylpiperidine-4-carboxylic acid
124		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-phenyl-1,4-oxazepane-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
125		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(3-phenylazepane-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
126		((2-(((2S)-3,3-dimethyl-1-((2S)-2- (5-methyl-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
127		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-(thiophen-2- yl)morpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
128		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-(thiazol-2-yl)morpholine- 4-carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
129		((2-(((2S)-3,3-dimethyl-1-((2S)-2- (2-(naphthalen-1-yl)morpholine-4- carbonyl)pyrrolidin-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
130		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-(pyridin-3- yl)morpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
131		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-(pyridin-4- yl)morpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
132		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-phenylthiomorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
133		((2-(((2S)-1-((2S)-2-(2- benzylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
134		((2-(((2S)-1-((2S)-2-(2- cyclohexylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
135		((2-(((S)-1-((S)-2-((R)-1,1-dioxido- 2-phenylthiomorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
136		((2-(((S)-1-((S)-2-((S)-1,1-dioxido- 2-phenylthiomorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
137		(difluoro(2-(((2S)-1-((2S)-2-(4- hydroxy-3-phenylpiperidine-1- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
138		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-3-phenylpiperazine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
139		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((S)-3-phenylpiperazine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
140		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((2S)-2-(2-(pyridin-2- yl)morpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
141		((2-(((2S)-3,3-dimethyl-1-oxo-1-(1- ((R)-2-phenylmorpholine-4- carbonyl)isoindolin-2-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
142		((2-(((2S)-3,3-dimethyl-1-oxo-1-(1- ((S)-2-phenylmorpholine-4- carbonyl)isoindolin-2-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
143		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(((R)-2- phenylmorpholino)methyl)pyrrolidin- 1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
144		((2-(((S)-3-ethyl-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pentan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
145		((6-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid
146		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
147		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pent-4-yn- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
148		((2-(((S)-1-cyclopropyl-2-oxo-2- ((S)-2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1- yl)ethyl)carbamoyl)benzo[b]thiophen- 5-yl)difluoromethyl)phosphonic acid
149		(difluoro(2-(((S)-3-hydroxy-3- methyl-1-oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
150		((2-(((S)-3-ethyl-1-oxo-1-((S)-2- ((S)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pentan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
151		((6-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((S)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid
152		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((S)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pentan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
153		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((S)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pent-4-yn- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
154		((2-(((S)-1-cyclopropyl-2-oxo-2- ((S)-2-((S)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1- yl)ethyl)carbamoyl)benzo[b]thiophen- 5-yl)difluoromethyl)phosphonic acid
155		(difluoro(2-((1-((S)-2-((S)-2- phenylmorpholine-4- carbonyl)pyrrolidine-1- carbonyl)cyclobutyl)carbamoyl)benzo [b]thiophen-5- yl)methyl)phosphonic acid
156		(difluoro(2-(((S)-3-hydroxy-3- methyl-1-oxo-1-((S)-2-((S)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
157		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((S)-3-phenylpiperidine-1- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
158		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((R)-3-phenylpiperidine-1- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
159		((2-(((5S,8S,10aR)-3-acetyl-8-(2-(4- fluorophenyl)-2-methylmorpholine- 4-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
160		((2-(((5S,8S,10aR)-3-acetyl-8-(2-(4- chlorophenyl)-2-methylmorpholine- 4-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
161		((2-(((5S,8S,10aR)-3-acetyl-8-(2-(4- fluorophenyl)morpholine-4- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
162		((2-(((5S,8S,10aR)-3-acetyl-8-(2-(3- chlorophenyl)morpholine-4- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
163		((2-(((5S,8S,10aR)-3-acetyl-8-(2- (2,4-dichloro-5- fluorophenyl)morpholine-4- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
164		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(2-(o-tolyl)morpholine-4- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
165		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((5-phenylthiazol-2- yl)carbamoyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
166		((2-(((S)-1-((S)-2-((R)-4-acetyl-3- phenylpiperazine-1- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
167		((2-(((S)-1-((S)-2-((S)-4-acetyl-3- phenylpiperazine-1- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
168		((2-(((S)-3,3-dimethyl-1-((S)-2-((R)- 4-(methylsulfonyl)-3- phenylpiperazine-1- carbonyl)pyrrolidin-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
169		((2-(((S)-3,3-dimethyl-1-((S)-2-((S)- 4-(methylsulfonyl)-3- phenylpiperazine-1- carbonyl)pyrrolidin-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
170		((2-(((S)-1-((S)-4-acetyl-2-((R)-2- phenylmorpholine-4- carbonyl)piperazin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
171		((2-(((S)-1-((S)-4-acetyl-2-((S)-2- phenylmorpholine-4- carbonyl)piperazin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
172		((2-(((S)-1-((S)-4-acetyl-2-((S)-3- phenylpyrrolidine-1- carbonyl)piperazin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
173		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-3-phenylpyrrolidine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
174		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((S)-3-phenylpyrrolidine-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
175		((2-(((S)-1-((S)-4-acetyl-2-((R)-3- phenylpiperidine-1- carbonyl)piperazin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
176		((2-(((S)-1-((S)-4-acetyl-2-((R)-3- phenylpyrrolidine-1- carbonyl)piperazin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
177		((2-(((S)-1-((S)-4-acetyl-2-((S)-3- phenylpyrrolidine-1- carbonyl)piperazin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
178		((2-(((5S,8S,10aR)-3-acetyl-8-(1,1- dioxido-2-phenylthiomorpholine-4- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
179		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-2-phenylmorpholine-4- carbonyl)piperidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
180		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-3-phenylpiperidine-1- carbonyl)piperidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
181		(difluoro(2-(((S)-1-((S)-2- (isoindoline-2-carbonyl)piperidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
182		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-phenylthiazol-2- yl)carbamoyl)piperidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
183		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-2-phenylmorpholine-4- carbonyl)azepan-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
184		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-3-phenylpiperidine-1- carbonyl)azepan-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
185		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((R)-3-phenylpyrrolidine-1- carbonyl)azepan-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
186		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((S)-3-phenylpyrrolidine-1- carbonyl)azepan-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
187		(difluoro(2-(((S)-1-((S)-2- (isoindoline-2-carbonyl)azepan-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
188		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-phenylthiazol-2- yl)carbamoyl)azepan-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
189		((2-(((2S)-3,3-dimethyl-1-oxo-1-(3- ((R)-2-phenylmorpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
190		((2-(((2S)-3,3-dimethyl-1-oxo-1-(3- ((R)-3-phenylpiperidine-1- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
191		((2-(((2S)-3,3-dimethyl-1-oxo-1-(3- ((R)-3-phenylpyrrolidine-1- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
192		((2-(((2S)-3,3-dimethyl-1-oxo-1-(3- ((S)-3-phenylpyrrolidine-1- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
193		(difluoro(2-(((2S)-1-(3-(isoindoline- 2-carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
194		((2-(((2S)-3,3-dimethyl-1-oxo-1-(3- ((5-phenylthiazol-2-yl)carbamoyl)- 3,4-dihydroisoquinolin-2(1H)- yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
195		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 1-((R)-2-phenylmorpholine-4- carbonyl)isoindolin-2-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
196		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 1-((R)-3-phenylpiperidine-1- carbonyl)isoindolin-2-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
197		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 1-((R)-3-phenylpyrrolidine-1- carbonyl)isoindolin-2-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
198		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 1-((S)-3-phenylpyrrolidine-1- carbonyl)isoindolin-2-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
199		(difluoro(2-(((S)-1-((S)-1- (isoindoline-2-carbonyl)isoindolin- 2-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
200		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 1-((5-phenylthiazol-2- yl)carbamoyl)isoindolin-2-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
201		((2-(((S)-1-((S)-4- ((benzyloxy)carbonyl)-2-((5- phenylthiazol-2- yl)carbamoyl)piperazin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
202		((2-(((S)-1-((2S,4R)-4-(benzyloxy)- 2-(isoindoline-2- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
203		((2-(((S)-1-((2S,4R)-4-(benzyloxy)- 2-((5-phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
204		(difluoro(2-(((S)-1-((S)-2- (isoindoline-2-carbonyl)pyrrolidin- 1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
205		((2-(((S)-1-((2S,4S)-4-(2-ethoxy-2- oxoethoxy)-2-((5-phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
206		((2-(((S)-1-((2S,4R)-4-(2-ethoxy-2- oxoethoxy)-2-((5-phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
207		((2-(((S)-3,3-dimethyl-1-oxo-1- ((2S,4S)-4-phenoxy-2-((5- phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
208		((2-(((S)-3,3-dimethyl-1-oxo-1- ((2S,4R)-4-phenoxy-2-((5- phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
209		((2-(((S)-3,3-dimethyl-1-((2S,4S)-4- (naphthalen-2-yloxy)-2-((5- phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
210		((2-(((S)-3,3-dimethyl-1-((2S,4R)-4- (naphthalen-2-yloxy)-2-((5- phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
211		((2-(((S)-1-((S)-2-((5-benzylthiazol- 2-yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
212		((2-(((S)-1-((S)-2-((4-benzylthiazol- 2-yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
213		((2-(((S)-1-((S)-2-(benzo[d]thiazol- 2-ylcarbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
214		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(((S)-1,2,3,4- tetrahydronaphthalen-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
215		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(((R)-1,2,3,4- tetrahydronaphthalen-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
216		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(2-(pyridin-2- yl)morpholine-4-carbonyl)-3,4- dihydroisoquinolin-2(1H)-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
217		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(2-(pyridin-3- yl)morpholine-4-carbonyl)-3,4- dihydroisoquinolin-2(1H)-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
218		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(2-(pyridin-4- yl)morpholine-4-carbonyl)-3,4- dihydroisoquinolin-2(1H)-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
219		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(2-(thiazol-2-yl)morpholine- 4-carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
220		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(2-phenyl-1,4-oxazepane-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
221		((2-(((2S)-1-((3S)-3-(2- benzylmorpholine-4-carbonyl)-3,4- dihydroisoquinolin-2(1H)-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
222		((2-(((2S)-1-((3S)-3-(2- cyclohexylmorpholine-4-carbonyl)- 3,4-dihydroisoquinolin-2(1H)-yl)- 3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
223		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(2-phenylthiomorpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
224		((2-(((S)-1-((S)-3-((R)-1,1-dioxido- 2-phenylthiomorpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
225		((2-(((S)-1-((S)-3-((S)-1,1-dioxido- 2-phenylthiomorpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
226		((2-(((2S)-3,3-dimethyl-1-((3S)-3- (2-methyl-6-phenylmorpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
227		((2-(((2S)-3,3-dimethyl-1-((3S)-3- (2-(naphthalen-1-yl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
228		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(2-(o-tolyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
229		((2-(((2S)-1-((3S)-3-(2-(2,4- dimethylphenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
230		(difluoro(2-(((2S)-1-((3S)-3-(2-(2- fluorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
231		(difluoro(2-(((2S)-1-((3S)-3-(2-(4- fluorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
232		((2-(((2S)-1-((3S)-3-(2-(2- chlorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
233		((2-(((2S)-1-((3S)-3-(2-(3- chlorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
234		((2-(((2S)-1-((3S)-3-(2-(4- chlorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
235		((2-(((2S)-1-((3S)-3-(2-(4- chlorophenyl)-2-methylmorpholine- 4-carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
236		(difluoro(2-(((2S)-1-((3S)-3-(2-(4- fluorophenyl)-2-methylmorpholine- 4-carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
237		((2-(((2S)-1-((3S)-3-(2-(2,4- difluorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
238		((2-(((2S)-1-((3S)-3-(2-(3,4- difluorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
239		((2-(((2S)-1-((3S)-3-(2-(3-chloro-4- fluorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
240		((2-(((2S)-1-((3S)-3-(2-(3,4- dichlorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
241		(difluoro(2-(((2S)-1-((3S)-3-(2-(4- fluoro-3-methylphenyl)morpholine- 4-carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
242		((2-(((2S)-1-((3S)-3-(2-(3,5- dichlorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
243		((2-(((2S)-1-((3S)-3-(2-(2,4- dichloro-5- fluorophenyl)morpholine-4- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
244		((2-(((2S)-3,3-dimethyl-1-oxo-1- ((3S)-3-(3-phenylazepane-1- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
245		(difluoro(2-(((2S)-1-((3S)-3-(3-(3- fluorophenyl)piperidine-1- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
246		((2-(((2S)-1-((3S)-3-(3-(4- chlorophenyl)piperidine-1- carbonyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-1-oxobutan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
247		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(thiazol-2-ylcarbamoyl)pyrrolidin- 1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
248		(difluoro(2-(((S)-1-((S)-2-((5- (hydroxymethyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
249		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-(tetrahydro-2H-pyran-4- yl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
250		((2-(((S)-1-((S)-2-((5-(1H-indol-2- yl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
251		(difluoro(2-(((S)-1-((S)-2-((5- isopropylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
252		((2-(((S)-1-((S)-2-((5-(tert- butyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
253		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-propylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
254		((2-(((S)-1-((S)-2-((5- cyclohexylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
255		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
256		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-(o-tolyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
257		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-(m-tolyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
258		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-(p-tolyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
259		(difluoro(2-(((S)-1-((S)-2-((5-(2- fluorophenyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
260		(difluoro(2-(((S)-1-((S)-2-((5-(3- fluorophenyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
261		(difluoro(2-(((S)-1-((S)-2-((5-(4- fluorophenyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
262		((2-(((S)-1-((S)-2-((5-(3- chlorophenyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
263		((2-(((S)-1-((S)-2-((5-(4- chlorophenyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
264		((2-(((S)-1-((S)-2-((5-(4- bromophenyl)thiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
265		((2-(((2S)-1-((2S)-2-(2-(3,5- difluorophenyl)morpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
266		1-(((S)-2-(5- (difluoro(phosphono)methyl)benzo [b]thiophene-2-carboxamido)-3,3- dimethylbutanoyl)-L-prolyl)-5- phenylpiperidine-3-carboxylic acid
267		((2-(((S)-1-((2S,4S)-4-amino-2-((R)- 2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
268		((2-(((S)-1-((2S,4R)-4-amino-2-((5- phenylthiazol-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
269		(difluoro(2-(((S)-2-oxo-2-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-1- (piperidin-4- yl)ethyl)carbamoyl)benzo[b]thiophen- 5-yl)methyl)phosphonic acid
270		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3- (pyridin-4-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
271		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3- (pyridin-3-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
272		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)hexan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
273		((2-(((S)-3-(4-bromophenyl)-1-oxo- 1-((S)-2-((R)-2-phenylmorpholine- 4-carbonyl)pyrrolidin-1-yl)propan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
274		((2-(((S)-5-(dimethylamino)-1-oxo- 1-((S)-2-((R)-2-phenylmorpholine- 4-carbonyl)pyrrolidin-1-yl)pentan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
275		((2-(((S)-4-(dimethylamino)-1-oxo- 1-((S)-2-((R)-2-phenylmorpholine- 4-carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
276		((2-(((S)-5-amino-1,5-dioxo-1-((S)- 2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pentan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
277		((2-(((S)-3-(4-(tert-butyl)phenyl)-1- oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
278		((2-(((S)-3-(3,4-difluorophenyl)-1- oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
279		((2-(((S)-1-cyclohexyl-2-oxo-2-((S)- 2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1- yl)ethyl)carbamoyl)benzo[b]thiophen- 5-yl)difluoromethyl)phosphonic acid
280		((2-(((S)-5-amino-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pentan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
281		((2-(((S)-3-(3-cyanophenyl)-1-oxo- 1-((S)-2-((R)-2-phenylmorpholine- 4-carbonyl)pyrrolidin-1-yl)propan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
282		(difluoro(2-(((S)-3-(3-nitrophenyl)- 1-oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
283		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3-(m- tolyl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
284		(difluoro(2-(((S)-3-(4- methoxyphenyl)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
285		(difluoro(2-(((S)-3-(naphthalen-2- yl)-1-oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
286		((2-(((S)-3-(benzo[d]thiazol-2-yl)-1- oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
287		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3- (thiophen-2-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
288		(difluoro(2-(((S)-1-oxo-4-phenyl-1- ((S)-2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
289		(difluoro(2-(((S)-1-oxo-5-phenyl-1- ((S)-2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)pentan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
290		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3- (piperidin-4-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
291		(difluoro(2-(((S)-3-(1- methylpiperidin-4-yl)-1-oxo-1-((S)- 2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
292		((2-(((S)-3-(1-ethylpiperidin-4-yl)- 1-oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
293		(difluoro(2-(((S)-3-(1- isopentylpiperidin-4-yl)-1-oxo-1- ((S)-2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
294		((2-(((S)-3-(1- (cyclohexylmethyl)piperidin-4-yl)- 1-oxo-1-((S)-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
295		((2-(((S)-3-(1-(2- ethylbutyl)piperidin-4-yl)-1-oxo-1- ((S)-2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
296		(difluoro(2-(((S)-1-oxo-3-(1- phenethylpiperidin-4-yl)-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
297		(difluoro(2-(((S)-1-oxo-1-((S)-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3-(1-(3- phenylpropyl)piperidin-4-yl)propan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
298		((2-(((S)-3-(4-boronophenyl)-1-oxo- 1-((S)-2-((R)-2-phenylmorpholine- 4-carbonyl)pyrrolidin-1-yl)propan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
299		((2-(((S)-3,3-dimethyl-1-oxo-1- ((2S,4R)-4-phenoxy-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
300		((2-(((S)-1-((2S,4R)-4-(benzyloxy)- 2-((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
301		((2-(((S)-3,3-dimethyl-1-oxo-1- ((2S,4S)-4-phenoxy-2-((R)-2- phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
302		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-phenylthiazol-2- yl)carbamoyl)azepan-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
303		((2-(((S)-3,3-dimethyl-1-((S)-2- (methyl(5-phenylthiazol-2- yl)carbamoyl)azepan-1-yl)-1- oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
304		((2-(((S)-1-((S)-2-(ethyl(5- phenylthiazol-2- yl)carbamoyl)azepan-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
305		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-phenylthiophen-2- yl)carbamoyl)pyrrolidin-1-yl)butan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
306		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-((5-phenylthiophen-2- yl)carbamoyl)azepan-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
307		((2-(((S)-1-((2S,3R)-3-ethoxy-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
308		((2-(((S)-1-((2S,3S)-3-ethoxy-2- ((R)-2-phenylmorpholine-4- carbonyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
309		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
310		((4-((E)-4-(((S)-3,3-dimethyl-1-oxo- 1-((S)-2-(1,2,3,4- tetrahydroquinoline-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)amino)-4-oxobut-2-en-2- yl)phenyl)difluoromethyl)phosphonic acid
311		((2-(((S)-3,3-dimethyl-1-oxo-1-((S)- 2-(1,2,3,4-tetrahydroquinoline-1- carbonyl)pyrrolidin-1-yl)butan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
312		((2-(((S)-3,3-dimethyl-1-((S)-2- (methyl(phenyl)carbamoyl)pyrrolidin- 1-yl)-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
313		((2-(((S)-1-((S)-2-((4- chlorophenyl)(3-(dimethylamino)-3- oxopropyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
314		((2-(((S)-1-((S)-2-((4- bromophenyl)(3-(dimethylamino)-3- oxopropyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
315		((2-(((S)-1-((S)-2-(benzofuran-5- yl(3-(dimethylamino)-3- oxopropyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
316		((2-(((S)-1-((S)-2-(benzo[d]thiazol- 5-yl(3-(dimethylamino)-3- oxopropyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
317		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3- oxopropyl)(naphthalen-2- yl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
318		((2-(((S)-1-((S)-2-([1,1′-biphenyl-4- yl(3-(dimethylamino)-3- oxopropyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
319		((2-(((S)-1-((S)-2-((3- bromophenyl)(3-(dimethylamino)-3- oxopropyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
320		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3-oxopropyl)(3- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
321		((2-(((S)-1-cyclopropyl-2-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-2- oxoethyl)carbamoyl)benzo[b]thiophen- 5-yl)difluoromethyl)phosphonic acid
322		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-3-ethyl-1-oxopentan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
323		((2-(((S)-1-cyclohexyl-2-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-2- oxoethyl)carbamoyl)benzo[b]thiophen- 5-yl)difluoromethyl)phosphonic acid
324		((2-(((S)-2-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-2-oxo-1- phenylethyl)carbamoyl)benzo[b] thiophen-5- yl)difluoromethyl)phosphonic acid
325		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-3-(4-fluorophenyl)-1-oxopropan- 2-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
326		((2-(((S)-3-(4-bromophenyl)-1-((S)- 2-((3-(dimethylamino)-3- oxopropyl)(4-(thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-1-oxopropan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
327		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
328		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-1-oxo-4-phenylbutan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
329		((2-(((S)-1-((S)-2-((3- (dimethylamino)-3-oxopropyl)(4- (thiazol-2- yl)phenyl)carbamoyl)pyrrolidin-1- yl)-3-(naphthalen-2-yl)-1- oxopropan-2- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
330		(difluoro(2-(((5S,8S,10aR)-3- methyl-6-oxo-8-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5-yl)methyl)phosphonic acid
331		(difluoro(2-(((5S,8S,10aR)-3- methyl-6-oxo-8-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid
332		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(1,2,3,4-tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
333		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(1,2,3,4-tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
334		((7-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(1,2,3,4-tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid
335		((2-(((5S,8S,10aR)-3-acetyl-8- (benzylcarbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
336		((2-(((5S,8S,10aR)-3-acetyl-8- (benzyl(methyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
337		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(((S)-1- phenylethyl)carbamoyl)decahydro pyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
338		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(((R)-1- phenylethyl)carbamoyl)decahydro pyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
339		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((2-phenylpropan-2- yl)carbamoyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
340		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((1- phenylcyclopropyl)carbamoyl)deca hydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
341		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-((4-phenyltetrahydro-2H-pyran-4- yl)carbamoyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
342		((2-(((5S,8S,10aR)-3-acetyl-8- (benzyl(cyclohexyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
343		((2-(((5S,8S,10aR)-3-acetyl-8-(5- fluoro-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
344		((2-(((5S,8,10aR)-3-acetyl-8-(6- fluoro-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
355		((2-(((5S,8S,10aR)-3-acetyl-8-(7- fluoro-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
356		((2-(((5S,8S,10aR)-3-acetyl-8-(8- fluoro-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
357		((2-(((5S,8S,10aR)-3-acetyl-8-(7- methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
358		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(7-(trifluoromethyl)-1,2,3,4- tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
359		((2-(((5S,8S,10aR)-3-acetyl-8- (isoindoline-2-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
360		((2-(((5S,8S,10aR)-3-acetyl-8- (methyl(phenyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
361		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8- (phenylcarbamoyl)decahydropyrrolo [1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid
362		((2-(((5S,8S,10aR)-3-acetyl-8- (diphenylcarbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
363		(difluoro(2-(((3S,6S,9aS)-5-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2- carbonyl)octahydro-1H-pyrrolo[1,2- a]azepin-6-yl)carbamoyl)-1H-indol- 5-yl)methyl)phosphonic acid
364		(difluoro(2-(((5S,8S,10aR)-3- isobutyryl-6-oxo-8-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5-yl)methyl)phosphonic acid
365		(difluoro(2-(((5S,8S,10aR)-3-(1- methylpiperidine-4-carbonyl)-6- oxo-8-(1,2,3,4- tetrahydroisoquinoline-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5-yl)methyl)phosphonic acid
366		((2-(((5S,8S,10aR)-3-acetyl-8-(6- chloro-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
367		((2-(((5S,8S,10aR)-3-acetyl-8- (morpholine-4-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
368		((2-(((5S,8S,10aR)-3-acetyl-8-(1,4- oxazepane-4-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
369		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(2,3,4,5-tetrahydro-1H- benzo[c]azepine-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
370		((2-(((5S,8S,10aR)-3-acetyl-8-((4- bromophenyl)(phenyl)carbamoyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
371		((2-(((5S,8S,10aR)-3-acetyl-8-((4- chlorophenyl)(cyclohexyl)carbamoyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
372		((2-(((5S,8S,10aR)-3-acetyl-8-(3,4- dihydro-2H-benzo[b][1,4]oxazine-4- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
373		((2-(((5S,8S,10aR)-3-acetyl-8-(6- iodo-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
374		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(2,3,4,5-tetrahydro-1H- benzo[d]azepine-3- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
375		((2-(((5S,8S,10aR)-3-acetyl-8-((4- chlorophenyl)(methyl)carbamoyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
376		((2-(((5S,8S,10aR)-3-acetyl-8-((4- fluorophenyl)(methyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
377		((2-(((5,8S,10aR)-3-acetyl-8-(5- chloroisoindoline-2-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
378		((2-(((5S,8S,10aR)-3-acetyl-8-(4- chloroisoindoline-2-carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)- 1H-indol-5- yl)difluoromethyl)phosphonic acid
379		((2-(((3S,6S,9aS)-3-((4- chlorophenyl)(methyl)carbamoyl)- 5-oxooctahydro-1H-pyrrolo[1,2- a]azepin-6- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
380		((2-(((3S,65,9aR)-3-((4- chlorophenyl)(methyl)carbamoyl)- 5-oxooctahydro-1H-pyrrolo[1,2- a]azepin-6- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
381		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(piperidine-1- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
382		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(2-azaspiro[4.4]nonane-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
383		((2-(((5,8S,10aR)-3-acetyl-6-oxo- 8-(2-azaspiro[4.5]decane-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
384		ethyl hydrogen ((2-(((5S,85,10aR)- 3-acetyl-6-oxo-8-(2- azaspiro[4.6]undecane-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonate
385		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(2-azaspiro[4.6]undecane-2- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
386		ethyl hydrogen ((2-(((5S,8S,10aR)- 3-acetyl-6-oxo-8-(1- azaspiro[4.4]nonane-1- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonate
387		((2-(((5S,8S,10aR)-3-acetyl-6-oxo- 8-(1-azaspiro[4.4]nonane-1- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
388		((2-(((5S,8S,10aR)-3-acetyl-8-((4- chlorophenyl)(ethyl)carbamoyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
389		((2-(((5S,8S,10aR)-3-acetyl-8-((4- chlorophenyl)(isopropyl)carbamoyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
390		((2-(((5S,8S,10aR)-3-acetyl-8-(3- isopropyl-3-methylpyrrolidine-1- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
391		((2-(((5S,85,10aR)-3-acetyl-6-oxo- 8-(7-azaspiro[4.6]undecane-7- carbonyl)decahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
392		((2-(((5S,8S,10aR)-3-acetyl-8-(3- carbamoyl-3- (trifluoromethyl)pyrrolidine-1- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
393		((2-(((5S,8S,10aR)-3-acetyl-8-(3- methyl-3-phenylpyrrolidine-1- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
394		((2-(((5S,8S,10aR)-3-acetyl-8-((4- bromophenyl)(methyl)carbamoyl)- 6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid
395		((2-(((5S,8S,10aR)-3-acetyl-8-(3- cyclopropyl-3-methylpyrrolidine-1- carbonyl)-6- oxodecahydropyrrolo[1,2- a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid

Further Forms of Compounds Disclosed Herein

Pharmaceutically Acceptable Salts

In certain embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In certain embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, 7-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

In certain embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(C_1-4 alkyl)₄, and the like.

Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

Solvates

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates are within the scope of the invention.

It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention.

In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Isomers/Stereoisomers

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the invention.

In certain embodiments, the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention.

In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.

Tautomers

In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Pharmaceutical Compositions

In certain embodiments, the compound described herein is administered as a pure chemical. In certain embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21^st Ed. Mack Pub. Co., Easton, PA (2005)).

Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

In certain embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection. In certain embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In certain embodiments, the pharmaceutical composition is formulated as a tablet.

Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In certain embodiments, the present method involves the administration of about 0.1 μg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 μg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject's physiological response.

By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. In certain embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

Preparation, Characterization, and Biological Assay of the Compounds

The compounds of the present disclosure may be prepared by a variety of methods, including standard chemistry. In certain embodiments, the compounds of the present disclosure may be prepared by following the general synthetic routes depicted in the schemes given below:

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) Pd/C, H₂, EtOH, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) NaBH(OAc)₃, AcOH, DCM, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) IM-1, HATU, DIPEA, DMF, rt; (e) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) TFA, DCM, rt; (c) NaBH(OAc)₃, 37% HCHO aq., THF, rt; (d) DEA, DCM, rt; (e) (1) IM-1, HATU, DIPEA, DMF, rt; (2) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) TMSI, BSTFA, DCM, 0° C.; (c) P(OEt)₃, toluene, rt; (d) NBS, DMF, rt; (e) Boc-proline, PCl₅, CHCl₃, reflux; (f) HATU, DIPEA, DMF, rt; (g) TFA, DCM, rt; (h) IM-1, HATU, DIPEA, DMF, rt; (i) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) NCS, DMF, 60° C.; (b) Boc-proline, PCl₅, CHCl₃, reflux; (c) LiOH, water, MeOH, rt; (d) Boc-proline, PCl₅, CHCl₃, reflux; (e) CuI, KI, DMEDA, dioxane, reflux; (f) LiOH, water, MeOH, rt; (g) sat. NaHCO₃aq., Boc₂O, THF, rt; (h) MeNH₂, HATU, DIPEA, DMF, rt; (i) TFA, DCM, rt; (j) HATU, DIPEA, DMF, rt; (k) TFA, DCM, rt; (1) IM-1, HATU, DIPEA, DMF, rt; (m) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) NBS, CH₃CN, rt; (b) Boc-proline, PCl₅, CHCl₃, reflux; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) LiOH, water, MeOH, rt; (h) sat. NaHCO₃aq., Boc₂O, THF, rt; (i) MeNH₂, HATU, DIPEA, DMF, rt; (j) TFA, DCM, rt; (k) HATU, DIPEA, DMF, rt; (1) TFA, DCM, rt; (m) IM-1, HATU, DIPEA, DMF, rt; (n) TMSI, BSTFA, DCM, 0° C.; (o) LiOH, water, MeOH, rt; (p) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) DIC, Oxyma, DIPEA, DMF, 95° C.; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) DIC, Oxyma, DIPEA, DMF, 95° C.; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) NaH, MeI/EtI, DMF, rt; (h) TDA, DCM, rt.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) DEA, DCM, rt; (g) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) DEA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) Ethylbromoacetate, NaH, TBAC, THF, rt; (h) Pd/C, H₂, EtOH, rt; (i) HATU, DIPEA, DMF, rt; (j) TFA, DCM, rt; (k) aniline, PCl₅, CHCl₃, 50° C.; (1) HATU, DIPEA, DMF, rt; (m) TFA, DCM, rt; (n) IM-1, HATU, DIPEA, DMF, rt; (o) TMSI, BSTFA, DCM, 0° C.

(a) EtOH, reflux; (b) DCM/TFA, rt; (c) HATU, DIPEA, DMF, rt; (d) DCM/TFA, rt; (e) HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) HATU, DIPEA, DMF, rt; (h) Lawesson's reagent, THF, reflux; (i) DCM, DEA, rt; (j) HATU, DIPEA, DMF, rt; (k) DCM/TFA, rt; (1) HATU, DIPEA, DMF, rt; (m) TMSI, BSTFA, DCM, 0° C.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC/MS) were collected using a SHIMADZU LCMS-2020EV or Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C18 2.7 μm 4.6×100 mm; Flow rate 0.8 mL/min; Solvent A (100/0.1 water/formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.5 mL/min; Solvent A (0.1% formic acid water), Solvent B (acetonitrile); gradient: hold 5% B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min.

Biological Assays

The biological activities of the compounds of the present application can be assessed with methods and assays known in the art.

Evaluation of the activity of the inhibitors may be accomplished by fluorescence polarization (FP) experiments. A representative general protocol is the following:

Fluorescence polarization (FP) experiments are performed in black round-bottom plates using the CLARIOstar microplate reader. To each well, fluorescein-labeled tracer and STAT5 or STAT6 protein are added in assay buffer. The polarization values indicating compound binding to STAT5 or STAT6 are measured at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. The inhibition constants are determined as the concentration of the STAT5 or STAT6 at which 50% of the ligand is bound.

Methods of Use

In certain aspects, the present disclosure provides methods of inhibiting a STAT5 and/or STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of inhibiting a STAT5 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of inhibiting a STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for inhibiting a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides methods of degrading a STAT5 and/or STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of degrading a STAT5 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides methods of degrading a STAT6 protein in a subject or biological sample, comprising administering a compound desclosed herein to the subject or contacting a compound disclosed herein with the biological sample (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a STAT5 and/or STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a STAT5 protein in a subject or biological sample.

In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a STAT6 protein in a subject or biological sample.

In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject, comprising administering a compound disclosed herein to the subject (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder.

In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder.

In certain aspects, the present disclosure provides methods of treating a disease or disorder in a patient, comprising administering a compound disclosed herein to the subject (e.g., in a therapeutically effective amount).

In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder.

In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder.

In some embodiments, the disease or disorder is mediated by a STAT5 and/or STAT6 protein. In some embodiments, the disease or disorder is cancer.

In some embodiments, the disease or disorder is mediated by a STAT5 protein. In some embodiments, the disease or disorder is cancer.

In some embodiments, the disease or disorder is mediated by a STAT6 protein. In some embodiments, the disease or disorder is cancer.

In certain embodiments, the disease or disorder is breast cancer, colorectal cancer, lung cancer, prostate cancer, liver cancer, hematological malignancies, T-cell lymphoma, acute leukemia and chronic myeloid leukemia, solitary fibrous tumor, solid tumors, asthma, atopic dermatitis, eosinophilic esophagitis or food allergies.

In certain embodiments, the subject is a mammal.

In certain embodiments, the subject is a human.

Definitions

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

Chemical Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5′ Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, I N 1972).

The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C_1-6 alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6 alkyl.

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

“Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C_1-20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C_1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C_1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C_1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C_1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). Examples of C_1-6 alkyl groups include methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C_1-10 alkyl (e.g., —CH₃). In certain embodiments, the alkyl group is substituted C_1-10 alkyl. Common alkyl abbreviations include Me (—CH₃), Et (—CH₂CH₃), i-Pr (—CH(CH₃)₂), n-Pr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃), or i-Bu (—CH₂CH(CH₃)₂).

“Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkelene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—), hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene (—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—, —CH₂C(CH3)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like.

“Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C_2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C_2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2-8 alkenyl”).

In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C_2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C_2-4 alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C_2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C_2-10 alkenyl.

“Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (—CH═CH—) and propenylene (e.g., —CH═CHCH₂—, —CH₂—CH═CH—). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (—C(CH₃)═CH—, —CH═C(CH₃)—), substituted propylene (e.g., —C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —CH═CHC(CH₃)₂—, —CH(CH₃)—CH═CH—, —C(CH₃)₂—CH═CH—, —CH₂—C(CH₃)═CH—, —CH₂—CH═C(CH₃)—), and the like.

“Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C_2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C_2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C_2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C_{2 -8} alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C_2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C_2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C_2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C_2-4 alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C_2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C_2-10 alkynyl.

“Alkynylene” as used herein, refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1-8 alkyl”).

In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1-7 alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC_1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC_1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC_1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC_1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC_1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC₁ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC_2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC_1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC_1-10 alkyl.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC_2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC_2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC_2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC_2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC_2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC_2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC_2-10 alkenyl.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC_2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC_2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC_2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC_2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC_2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC_2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC_2-10 alkynyl.

Analogous to “alkylene,” “alkenylene,” and “alkynylene” as defined above, “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” as used herein, refer to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. “Heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl).

Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C_6-14 aryl. In certain embodiments, the aryl group is substituted C_6-14 aryl.

“Arylene” as used herein, refers to an aryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “arylene” group, it is understood that the range or number refers to the range or number of carbons in the aryl group. An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein.

“Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

“Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

In certain embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.

Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein.

“Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C_3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C_3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C_5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C_5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C_5-6 carbocyclyl”). Exemplary C_3-6 carbocyclyl include, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl include, without limitation, the aforementioned C_3-6 carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C_3-10 carbocyclyl include, without limitation, the aforementioned C_3-8 carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like.

In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C_3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C_3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C_3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C_3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C_5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C_5-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C_5-6 carbocyclyl”). Examples of C_5-6 carbocyclyl include cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C_3-6 carbocyclyl include the aforementioned C_5-6 carbocyclyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8 carbocyclyl include the aforementioned C_3-6 carbocyclyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C_3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C_3-12 carbocyclyl.

As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C_3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C_3-12 carbocyclyl.

“Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

“Spiro carbocyclyl” or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded.

“Bridged carbocyclyl” or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded.

“Carbocyclylene” as used herein, refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the carbocyclylene group. When a range or number of carbons is provided for a particular “carbocyclyl” group, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein.

“Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl.

“Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of ring members designates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

“Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.

“Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.

“Heterocyclylene” as used herein, refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocyclylene group. When a range or number of ring members is provided for a particular “heterocyclylene” group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein.

“Alkoxy” as used herein, refers to the group —OR, wherein R is alkyl as defined herein. C_1-6 alkoxy refers to the group —OR, wherein each R is C_1-6 alkyl, as defined herein. Exemplary C_1-6 alkyl is set forth above.

“Alkylamino” as used herein, refers to the group —NHR or —NR₂, wherein each R is independently alkyl, as defined herein. C_1-6 alkylamino refers to the group —NHR or —NR₂, wherein each R is independently C_1-6 alkyl, as defined herein. Exemplary C_1-6 alkyl is set forth above.

“Oxo” refers to ═O. When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.

“Halo” or “halogen” refers to fluoro (F), chloro (C₁), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

“Protecting group” as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

Common types of hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), β-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)). silyl ethers (e. g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)).

Common types of amino-protecting groups include but not limited to carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2-nitrophenylsulfenyl (Nps)).

Common types of thiol-protecting groups include but not limited to sulfide (e.g., p-methylbenzyl (Meb), t-butyl, acetarnidornethyl(Acm), and triphenylmethyl (Trityl)).

Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn). S-t-butyl ester, silyl esters, and orthoesters) and oxazoline.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

“Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66 (1):1-79 (January 77).

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

“Pharmaceutically acceptable metabolically cleavable group” refers to a group which is cleaved in vivo to yield the parent molecule of the structural formula indicated herein. Examples of metabolically cleavable groups include —COR, —COOR, —CONR₂ and —CH₂OR radicals, where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups.

“Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylactically effective amount” refers to the effective amount for prophylactic treatment.

“Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

“Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of πelectrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

As used herein and unless otherwise indicated, the term “enantiomerically pure (R)-compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9% by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound.

As used herein and unless otherwise indicated, the term “enantiomerically pure (S)-compound” or “(S)-compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound.

In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.

The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

EXAMPLES

In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1. Synthetic Schemes

Reaction conditions: (a) Cd powder, DMF, rt; (b) t-BuOLi n hexane 1M, THF, t-BuOH, rt; (c) CuCl, DMF, rt; (d) TFA, DCM, rt

Reaction conditions: (a) P(OEt)₃, 100° C.; (b) Ti(O-i-Pr)₄, BnOH, 100° C.; (c) NaH, Cbz-Cl, THF, 0° C. to rt; (d) NFBS, NaHMDS, THF, −78° C. to rt; (e) H₂/Pd—C, THF, rt Synthesis of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

Reaction conditions: (a) Oxalyl Chloride, DMF, DCM, 0° C. to rt; (b) BnOH, TEA, DCM, rt; (c) CuI, KI, Dioxane, DMEDA, 110° C., sealed; (d) BrCdCF₂PO₃Et₂, CuI, DMF, rt; (e) Pd/C, H₂, MeOH, rt.

Benzyl 7-bromo-2-naphthoate

To a 100 mL round bottom flask equipped with a magnetic stirring bar was added 7-bromo-2-naphthoic acid 4-1 (1.0 g, 3.9 mmol, 1.0 equiv) and anhydrous DCM (50 mL). The suspension was cooled with ice/water bath before adding oxalyl chloride (1.5 g, 11.7 mmol, 3.0 equiv) and DMF (0.3 mL). The solution was stirred at this temperature for 30 minutes and recovered to room temperature. The suspension would become clear solution after 1.5 h. Removed all the solvent and excess oxalyl chloride in vacuum. The residual crude product 4-2 was used directly for the next step without further purification.

To a 100 mL round bottom flask equipped with a magnetic stirring bar was added previous crude acyl chloride 4-2 and anhydrous DCM (50 mL). The solution was cooled with ice/water bath before adding benzyl alcohol (0.8 g, 0.8 mL, 7.8 mmol, 2.0 equiv) and triethylamine (1.2 g, 1.6 mL, 11.7 mmol, 3.0 equiv). The solution was recovered to room temperature and stirred for 1 h before quenched with ammonium chloride aqueous solution. Extracted with DCM (50 mL×3) and dried with anhydrous sodium sulfate. Filtered and the solvent was removed under vacuum. The residual crude product was purified by flash column chromatography (PE:EA=10:1) to afford the desired benzylic ester 4-3 as a white solid (1.1 g, 85% yield).

Benzyl 7-iodo-2-naphthoate

To a 50 mL sealed bottle equipped with a magnetic stirring bar was filled with argon before adding Benzyl 7-bromo-2-naphthoate 4-3 (1.0 g, 2.9 mmol, 1.0 equiv), copper(I) iodide (110 mg, 0.58 mmol, 0.2 equiv), potassium iodide (1.0 g, 5.8 mmol, 2.0 equiv), N,N′-Dimethylethane-1,2-diamine (51 mg, 62 μL, 0.58 mmol, 0.2 equiv) and anhydrous 1,4-dioxane (20 mL). The reaction system was changed to argon atmosphere for another three times before reacted under 110° C. for 24 h. Cooled to room temperature and quenched with ammonium chloride aqueous solution. Extracted with EtOAc (50 mL×3) and washed with brine before dried with anhydrous sodium sulfate. Filtered and the solvent was removed under vacuum. The residual crude product was purified by flash column chromatography (PE:EA=10:1) to afford the mixture of desired iodide 4-4 and starting material 4-3 as a white solid (0.85 g, 4-4: 4-3=3:1 monitored by LC-MS). This mixture can be used directly for the next step without further purification.

Benzyl 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate

To a 50 mL round bottom bottle equipped with a magnetic stirring bar was filled with argon before adding the previous mixture of 4-4 and 4-3 (0.85 g, 4-4: 4-3=3:1, 2.1 mmol, 1.0 equiv), copper(I) iodide (0.8 g, 4.2 mmol, 2.0 equiv) and Cadmium reagent DMF solution A (13 mL, 0.33M, 4.2 mmol, 2.0 equiv). The reaction system was changed to argon atmosphere for another three times before stirred at room temperature for 24 h. Quenched with ammonium chloride aqueous solution and Extracted with EtOAc (50 mL×3), washed with brine for three times and dried with anhydrous sodium sulfate. Filtered and the solvent was removed under vacuum. The residual crude product was purified by flash column chromatography (PE:EA=1:1) to afford the desired phosphate 4-5 as a white solid (0.5 g, 70% yield).

7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoic acid (IM-5)

To a 50 mL round bottom bottle equipped with a magnetic stirring bar was filled with argon before adding Benzyl 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate 4-5 (130 mg, 0.28 mmol, 1.0 equiv), methanol (5 mL) and 10% Pd/C (30 mg). The reaction system was changed to hydrogen atmosphere for three times before stirred at room temperature for 30 min. Filtered to remove Pd/C and the solvent was removed under vacuum. The residual crude product was purified by HPLC (MeCN/H2O 35%-100%, 65 min, 60 mL/min, the product came out when MeCN is 46.5%) to afford the desired carboxylic acid IM-5 as a white solid (86 mg, 85% yield).

¹H NMR (400 MHz, Methanol-d₄) δ 8.73 (s, 1H), 8.28 (s, 1H), 8.21-8.13 (m, 1H), 8.07 (dd, J=20.0, 8.4 Hz, 2H), 7.82-7.73 (m, 1H), 4.31-4.16 (m, 4H), 1.31 (t, J=7.2 Hz, 6H).

UPLC-MS calculated for C₁₆H₁₈F₂O₅P [M+H]⁺: 359.09, found: 359.38.

Reaction conditions: (a) TBSCL, DIPEA, DCM, rt; (b) H₂, Pd/C, EtOH, rt; (c) Boc-Dap(Z)—OH, EDC, HOBt, DIPEA, DCM, rt; (d) TBAF, THF; (e) Dess-Martin periodinane, DCM, rt: (f) H₂, Pd/C, MeOHSynthesis detail for IM-6 can be found the following publication.: Peng, Y., Sun. H. and Wang, S., 2006. Design and synthesis of a 1, 5-diazabicyclo [6, 3, 0] dodecane amino acid derivative as a novel dipeptide reverse-turn mimetic. Tetrahedron letters, 47(27), pp. 4769-4770.

Reaction conditions: (a) HATU, DIPEA, CH₃CN, rt; (b) TFA, DCM, rt; (c) Ph₃Bi, Cu(OAc)₂, TEA, DCM, rt; (d) TFA, DCM, rt; (e) HATU, DIPEA, CH₃CN, rt; (f) TFA, DCM, rt; (g) HATU, DIPEA, CH₃CN, rt; (h) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) Ac₂O, DCM, TEA, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) HATU, DIPEA, CH₃CN, rt; (e) PCL5, CHCl3, 50° C.; (f) TMSI, BSTFA, DCM, 0° C.; (g) HCHO, sodium triacetoxyborohydride.

Reaction conditions: (a) HATU, DIPEA, CH₃CN, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, CH₃CN, rt; (d) diethylamine, DCM, rt; (e) HATU, DIPEA, CH₃CN, rt; (f) TFA, DCM, rt; (g) TMSI, BSTFA, DCM, 0° C.; (h) HATU, DIPEA, DMF, rt; (i) TFA, DCM, rt; (j) CbzCl, DIPEA, DCM, rt; (k) LiOH monohydrate, MeOH, water, rt; (1) HATU, DIPEA, DMF, rt; (m) H₂, Pd/C, EtOH, rt; (n) HATU, DIPEA, DMF, rt; (o) TFA, DCM, rt; (p) Ac₂O, DIPEA, DMF, rt; (q) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) Pd/C, H₂, EtOH, rt; (e) HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.

(a) EtOH, reflux; (b) DCM/TFA, rt; (c) HATU, DIPEA, DMF, rt; (d) DCM/TFA, rt; (e) HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) HATU, DIPEA, DMF, rt; (h) Lawesson's reagent, THF, reflux; (i) DCM, DEA, rt; (j) HATU, DIPEA, DMF, rt; (k) DCM/TFA, rt; (1) HATU, DIPEA, DMF, rt; (in) TMSI, BSTFA, DCM, 0° C.; (n) HATU, DIPEA, DMF, rt; (o) NH4OAc, AcOH, reflux; (p) TFA, DCM, rt; (q) Boc-Tle-OH, HATU, DIPEA, DMF, rt; (r) TFA, DCM, rt; (s) HATU, DIPEA, DMF, rt; (t) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) Fmoc-OSU, TEA, CH₃CN, H₂O, rt; (b) HATU, DIPEA, DMF, rt; (c) TFA, DCM, rt; (d) HATU, DIPEA, CH₃CN, rt; (e) TFA, DCM, rt; (f) HATU, DIPEA, CH₃CN, rt; (g) diethylamine, DCM, rt; (h) Ac₂O, TEA, DCM, rt: (i) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, CH₃CN, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, CH₃CN, rt; (d) BnBr, CH₃CN, 50° C.; (e) NaBH₄, EtOH, rt; (f) TFA, DCM, rt; (g) HATU, DIPEA, DMF, rt; (h) H₂, Pd/C, EtOH, rt; (i) TMSI, BSTFA, DCM, 0° C.; (j) HATU, DIPEA, DMF, rt; (k) TFA, DCM, rt; (1) NaBH(OAc)₃, 37% HCHO aq., THF, rt; (m) DEA, DCM, rt; (n) HATU, DIPEA, DMF, rt; (o) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) P(OEt)₃, toluene, rt; (b) NBS, DMF, rt; (c) Boc-L-proline, PCl₅, CHCl₃, 50° C.; (d) CuI, KI, DMEDA, dioxane, 110° C.; (e) HATU, DIPEA, DMF, rt; (f) TFA, DCM, rt; (g) HATU, DIPEA, DMF, rt; (h) TMSI, BSTFA, DCM, 0° C.; (k) NCS, DMF, 60° C.

Reaction conditions: (a) P(OEt)₃, toluene, rt; (b) NBS, DMF, rt; (c) Boc-L-proline, PCl₅, CHCl₃, 50° C.; (d) CuI, KI, DMEDA, dioxane, 110° C.; (e) HATU, DIPEA, DMF, rt; (f) TFA, DCM, rt; (g) HATU, DIPEA, DMF, rt; (h) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) NBS, CH₃CN, rt; (b) Boc-proline, PCl₅, CHCl₃, reflux; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) LiOH, water, MeOH, rt; (h) sat. NaHCO₃aq., Boc₂O, THF, rt; (i) MeNH₂, HATU, DIPEA, DMF, rt; (j) TFA, DCM, rt; (k) HATU, DIPEA, DMF, rt; (1) TFA, DCM, rt; (m) IM-1, HATU, DIPEA, DMF, rt; (n) TMSI, BSTFA, DCM, 0° C.; (o) LiOH, water, MeOH, rt; (p) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) DEA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) Ethylbromoacetate, NaH, TBAC, THF, rt; (h) Pd/C, H₂, EtOH, rt; (i) HATU, DIPEA, DMF, rt; (j) TFA, DCM, rt; (k) aniline, PCl₅, CHCl₃, 50° C.; (1) HATU, DIPEA, DMF, rt; (m) TFA, DCM, rt; (n) IM-1, HATU, DIPEA, DMF, rt; (o) TMSI, BSTFA, DCM, 0° C.; (p) LiOH monohydrate, MeOH, water, rt; (q) MeNH₂, HATU, DIPEA, DMF, rt; (r) LiOH monohydrate, MeOH, water, rt; (s) methylamine, HATU, DIPEA, DMF, rt; (t) dimethylamine, HATU, DIPEA, DMF, rt.

Reaction conditions: (a) NaBH(OAc)₃, AcOH, DCM, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) IM-1, HATU, DIPEA, DMF, rt; (e) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) HATU, DIPEA, DMF, rt; (f) Pd/C, H₂, EtOH, rt; (g) Ac₂O, DIPEA, DMF, rt; (h) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) DIC, Oxyma, DIPEA, DMF, 95° C.; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) IM-1, HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) HATU, DIPEA, DMF, rt; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) HATU, DIPEA, DMF, rt; (f) DEA, DCM, rt; (g) TMSI, BSTFA, DCM, 0° C.

Reaction conditions: (a) DIC, Oxyma, DIPEA, DMF, 95° C.; (b) TFA, DCM, rt; (c) HATU, DIPEA, DMF, rt; (d) TFA, DCM, rt; (e) HATU, DIPEA, DMF, rt; (f) TMSI, BSTFA, DCM, 0° C.; (g) NaH, MeI/EtI, DMF, rt; (h) TDA, DCM, rt.

Reaction conditions: (a) ethylacrylate, AcOH, 90° C.; (b) PCl5, CHCl3, 50° C.; (c) Boc₂O, TEA, CH₃CN, rt; (d) LiOH, MeOH, water, rt; (e) HATU, DIPEA, DMF, rt; (f) TFA, DCM, rt; (g) HATU, DIPEA, DMF, rt; (h) TFA, DCM, rt; (i) HATU, DIPEA, DMF, rt; (j) TMSI, BSTFA, DCM, rt, 0° C.

To a round bottom flask equipped with a magnetic stirring bar was added 4-(thiazol-2-yl)aniline Compound 1 (2.5 g, 14.2 mmol), acetic acid (8 ml), and ethylacrylate (1.3 ml, 0.9 equiv.). The suspension was stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residual crude product was purified by flash column chromatography to yield Compound 2 in 52% yield (2.0 g). 1H NMR (400 MHz, DMSO) δ 7.79 (d, J=3.4 Hz, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.56 (d, J=3.4 Hz, 1H), 7.32 (s, 1H), 6.66 (d, J=8.7 Hz, 2H), 4.08 (q, J=7.1 Hz, 2H), 3.35 (t, J=6.7 Hz, 2H), 2.59 (t, J=6.7 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H). 13C NMR (400 MHz, DMSO) δ 171.46, 168.52, 150.44, 142.03, 127.77, 120.35, 117.74, 112.06, 60.00, 38.43, 33.51, 14.07. ESI-MS calculated for C9H8N2S+ 276.35, found [M+H]+ 276.89.

Boc-L-proline (5.8 g, 5 equiv.) was dissolved in CHCl3 (50 ml). At room temperature, PCl5 (5.6 g, 5 equiv.) was slowly added over a period of 10 min. After the addition, the mixture was stirred for 10 min at room temperature. To this mixture was added Compound 2 (1.5 g, 5.4 mmol) and the mixture was stirred at 50° C. for 20 min. The volatile components were removed on a rotary evaporator. The obtained crude oil was purified by reverse phase semi-preparative HPLC. The resulting colorless oil Compound 3 was dissolved in CH₃CN (20 ml). To the solution was added triethylamine (3 ml, 3.8 equiv.), followed by Boc2O (1.75 g, 1.5 equiv.). The colorless mixture was stirred for 2 hours at room temperature. The volatile components were then removed by vacuum and the crude was purified by flash column chromatography to yield Compound 4 in 39% (1.0 g, 2 steps yield). 1H NMR (400 MHz, DMSO) δ 8.05 (d, J=8.5 Hz, 2H), 7.94 (d, J=3.3 Hz, 1H), 7.77 (d, J=3.3 Hz, 1H), 7.58-7.08 (m, 2H), 4.12 (m, 1H), 4.10-3.75 (m, 4H), 3.43-3.23 (m, 2H), 2.55 (m, 2H), 1.86 (s, 3H), 1.70 (m, 1H), 1.42 (s, 9H), 1.14 (t, J=7.1 Hz, 3H). 13C NMR (400 MHz, DMSO) δ 171.34, 170.35, 165.75, 153.27, 143.64, 132.39, 128.88, 127.10, 120.49, 77.07, 59.61, 56.69, 46.48, 44.92, 32.39, 30.55, 29.63, 27.93, 22.42, 13.52. ESI-MS calculated for C24H31N3O5S+473.59, found [M+H]+374.06.

Compound 4 (450 mg, 0.95 mmol) was dissolved in MeOH (5 ml) and water (1 ml) and the mixture was placed in an ice bath. LiOH monohydrate (200 mg, 5 equiv.) was added to the mixture and then it was stirred for 30 min at room temperature. The mixture was placed in an ice bath again and neutralized by slowly adding TFA. The volatile components were removed on a rotary evaporator and the residue was purified by flash column chromatography to yield Compound 5 in 73% (310 mg). 1H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 8.05 (d, J=8.0 Hz, 3H), 7.95 (d, J=3.3 Hz, 1H), 7.78 (d, J=3.3 Hz, 1H), 7.44 (s, 2H), 4.11 (m, 1H), 3.99-3.69 (m, 2H), 3.39-3.26 (m, 2H), 3.13 (s, 2H), 1.85 (m, 4H). 13C NMR (400 MHz, DMSO) δ 171.78, 171.30, 165.79, 143.65, 132.34, 128.87, 127.10, 120.47, 78.39, 56.69, 46.50, 45.01, 32.31, 30.56, 29.38, 27.96, 23.04, 22.57. ESI-MS calculated for C₂₂H77N3O5S+ 445.53, found [M+H]+ 346.20.

HATU (140 mg, 0.37 mmol, 1.1 equiv.) was added to a solution of Compound 5 (150 mg, 0.33 mmol, 1 equiv.), dimethylamine (330 μl, 0.67 mmol, 2 equiv.) in 2M THF solution, and triethylamine (0.23 ml, 1.65 mmol, 5 equiv.) in CH₃CN (5 ml). The mixture was stirred at room temperature for 30 min. The yellow solution was concentrated in vacuum and the crude was purified by flash column chromatography to yield Boc-protected Compound 6. Boc protection was removed by DCM/TFA at room temperature for 30 min. The volatile components were removed in vacuum to yield Compound 6 as a TFA salt in 80% (128 mg). 1H NMR (400 MHz, CDCl3) δ 8.11-8.03 (m, 2H), 7.75-7.71 (m, 1H), 7.59 (d, J=3.2 Hz, 1H), 7.45 (d, J=7.9 Hz, 2H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 3.89 (d, J=6.6 Hz, 1H), 3.46-3.42 (m, 2H), 3.02 (s, 3H), 2.91 (s, 3H), 2.75 (d, J=7.5 Hz, 1H), 2.69-2.50 (m, 1H), 2.02-1.96 (m, 1H), 1.93-1.85 (m, 3H). ESI-MS calculated for C19H24N4O2S+ 372.49, found [M+H]+ 372.99.

To Compound 6 (128 mg, 0.26 mmol), CH3CN (5 ml), triethylamine (0.18 ml, 2.5 mmol, 5 equiv.), Boc-L-tert-leucine (90 mg, 0.39 mmol, 1.5 equiv.), and HATU (118 mg, 0.31 mmol, 1.2 equiv.) were added. The mixture was stirred at room temperature for 30 min. The yellow solution was concentrated in vacuum and the crude was purified by flash column chromatography to yield Boc-protected Compound 7. Boc protection was removed by DCM/TFA at room temperature for 30 min. The volatile components were removed in vacuum to yield Compound 7 as a TFA salt in 85% (107 mg). 1H NMR (400 MHz, MeOD) δ 8.00 (d, J=8.2 Hz, 2H), 7.90 (d, J=3.3 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 4.33 (t, J=7.7 Hz, 1H), 3.96-3.90 (m, 3H), 3.75-3.68 (m=, 1H), 3.60-3.55 (m, 1H), 3.00 (s, 3H), 2.83 (s, 3H), 2.69 (t, J=7.4 Hz, 2H), 2.10-1.80 (m, 3H), 1.80-1.60 (m, 1H), 1.13 (s, 9H). ESI-MS calculated for C25H35N5O3S+ 485.65, found [M+H]+ 486.21.

To Compound 7 (107 mg, 0.22 mmol), CH3CN (5 ml), triethylamine (0.15 ml, 1.1 mmol, 5 equiv.), benzothiophene head IM-4 (97 mg, 0.26 mmol, 1.2 equiv.), and HATU (100 mg, 0.26 mmol, 1.2 equiv.) were added. The mixture was stirred at room temperature for 30 min. The yellow solution was concentrated in vacuum and the crude was purified by flash column chromatography to yield Compound 8 in 68% (147 mg). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 8.00 (d, J=1.4 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.94-7.88 (m, 3H), 7.66-7.60 (m, 1H), 7.51-7.44 (m, 2H), 7.38 (d, J=3.3 Hz, 1H), 7.24 (d, J=9.4 Hz, 1H), 4.92 (d, J=9.4 Hz, 1H), 4.35 (t, J=7.6 Hz, 1H), 4.25-4.13 (m, 5H), 4.04-3.93 (m, 1H), 3.91-3.70 (m, 2H), 3.07 (s, 3H), 2.92 (s, 3H), 2.85-2.70 (m, 2H), 2.12-2.08 (m, 1H), 1.98-1.87 (m, 2H), 1.87-1.74 (m, 1H), 1.34-1.30 (m, 6H), 1.17 (s, 9H). ESI-MS calculated for C39H48F2N5O7PS2+ 831.93, found [M+H]+ 832.12.

To a round bottom flask were added Compound 8 (150 mg, 0.17 mmol, 1 equiv.), DCM (2 ml) and CF3CON(TMS)2 (0.27 ml, 1.0 mmol, 6 equiv.). The solution was cooled in an ice bath. To the ice cooled reaction mixture, 1M of TMS-I in DCM (0.9 ml, 0.9 mmol, 5 equiv.) was added dropwise and the mixture was stirred for 10 min in an ice bath. The volatile components were removed under vacuum at below 5° C. The residue was dissolved in a mixed solvent of CH₃CN (3 ml) and water (1 ml). The resulting solution was purified by HPLC to yield 309 in 80% (150 mg). ¹H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.43 (d, J=9.0 Hz, 1H), 8.11 (m, 1H), 8.06-7.95 (m, 3H), 7.92 (m, J=3.2 Hz, 1H), 7.79 (d, J=3.2 Hz, 1H), 7.55 (m, 2H), 4.77 (d, J=9.0 Hz, 1H), 4.19 (m, 1H), 3.93-3.70 (m, 3H), 3.70-3.57 (m, 1H), 2.94 (m, 4H), 2.77 (m, 4H), 2.66-2.53 (m, 2H), 2.06-1.92 (m, 1H), 1.85 (m, 3H), 1.10 (s, 9H). ESI-MS calculated for C₃₀H₄₀F₂N₅O₇PS₂⁺ 775.82, found [M+H]⁺ 775.89.

Reaction conditions: (a) Boc₂O, DMAP, CH₃CN, rt; (b) LiEt₃BH, THF, −70° C.; (c) allyltributylstannane, Me₃SiOTf, DCM, −70° C.; (d) HCl, dioxane, 0° C.; (e) CbzCl, DIPEA, DCM, 0° C.; (f) 9-BBN, H₂O₂, aq. NaOH, THF; (g) (COCl)₂, DMSO, TEA, DCM, −60° C.; (h) t-BuOK, DCM, −70° C.; (i) Boc₂O, DMAP, THF; (j) H₂, Pd/C, THF; (k) NaOH, MeOH; (1) HATU, DIPEA, DCM; (in) FTA, DCM, rt; (n) HATU, DIPEA, DMF, rt; (o) PCl₅, CHCl₃, 50° C.; (p) TMSI, BSTFA, DCM, 0° C.

Example 2. Characterization Data

TABLE 2
Characterization Data Summary
Cpd.		Synthetic
No.	LC-MS data	Scheme
1	LC-MS [M + H] += 787.96	6
2	LC-MS [M + H] += 779.18	6
3	LC-MS [M + H] += 708.11	7
4	LC-MS [M + H] += 744.28	7
5	LC-MS [M + H] += 695.32	7
6	LC-MS [M + H] += 731.51	7
7	LC-MS [M + H] += 722.70	7
8	LC-MS [M + H] += 619.22	8
9	LC-MS [M + H] += 632.44	8
10	LC-MS [M + H] += 631.35	9
11	LC-MS [M + H] += 631.35	9
12	LC-MS [M + H] += 617.41	9
13	LC-MS [M + H] += 646.36	9
14	LC-MS [M + H] += 667.38	9
15	LC-MS [M + H] += 627.30	9
16	LC-MS [M + H] += 617.49	9
17	LC-MS [M + H] += 631.30	10
18	LC-MS [M + H] += 618.36	10
19	LC-MS [M + H] += 617.27	10
20	LC-MS [M + H] += 604.32	10
21	LC-MS [M + H] += 617.30	10
22	LC-MS [M + H] += 604.28	10
23	LC-MS [M + H] += 657.34	8
24	LC-MS [M + H] += 644.42	8
25	LC-MS [M + H] += 630.95	10
26	LC-MS [M + H] += 618.17	10
27	LC-MS [M + H] += 651.96	8
28	LC-MS [M + H] += 644.26	11
29	LC-MS [M + H] += 631.23	11
30	LC-MS [M + H] += 660.17	9
31	LC-MS [M + H] += 660.17	9
32	LC-MS [M + H] += 681.43	9
33	LC-MS [M + H] += 600.19	10
34	LC-MS [M + H] += 686.17	11
35	LC-MS [M + H] += 746.23	12
36	LC-MS [M + H] += 658.26	12
37	LC-MS [M + H] += 930.31	13
38	LC-MS [M + H] += 680.32	15
39	LC-MS [M + H] += 796.02	6
40	LC-MS [M + H] += 693.22	14
41	LC-MS [M + H] += 634.51	9
42	LC-MS [M + H] += 853.18	13
43	LC-MS [M + H] += 758.04, 759.98	15
44	LC-MS [M + H] += 761.32	13
45	LC-MS [M + H] += 757.17, 759.19	15
46	LC-MS [M + H] += 744.14, 746.07	15
47	LC-MS [M + H] += 860.19, 862.14	16
48	LC-MS [M + H] += 860.19, 862.14	16
49	LC-MS [M + H] += 839.91, 892.07	16
50	LC-MS [M + H] += 839.91, 892.07	16
51	LC-MS [M + H] += 844.09, 845.94	16
52	LC-MS [M + H] += 844.09, 845.94	16
53	LC-MS [M + H] += 822.17	16
54	LC-MS [M + H] += 788.18, 790.15	16
55	LC-MS [M + H] += 816.17, 818.11	16
56	LC-MS [M + H] += 859.24, 861.24	16
57	LC-MS [M + H] += 873.27, 875.20	16
58	LC-MS [M + H] += 626.32	9
59	LC-MS [M + H] += 626.33	9
60	LC-MS [M + H] += 640.38	9
61	LC-MS [M + H] += 640.37	9
62	LC-MS [M + H] += 654.46	9
63	LC-MS [M + H] += 612.37	9
64	LC-MS [M + H] += 664.43	9
65	LC-MS [M + H] += 664.41	9
66	LC-MS [M + H] += 664.47	9
67	LC-MS [M + H] += 664.36	9
68	LC-MS [M + H] += 669.35	9
69	LC-MS [M + H] += 648.40	9
70	LC-MS [M + H] += 648.40	9
71	LC-MS [M + H] += 634.33	9
72	LC-MS [M + H] += 622.17	9
73	LC-MS [M + H] += 656.33	9
74	LC-MS [M + H] += 700.16, 701.98	9
75	LC-MS [M + H] += 690.43	9
76	LC-MS [M + H] += 692.50	9
77	LC-MS [M + H] += 602.26	9
78	LC-MS [M + H] += 627.27	9
79	LC-MS [M + H] += 613.32	9
80	LC-MS [M + H] += 613.30	9
81	LC-MS [M + H] += 669.59	9
82	LC-MS [M + H] += 711.39	9
83	LC-MS [M + H] += 749.39	9
84	LC-MS [M + H] += 655.41	9
85	LC-MS [M + H] += 697.41	9
86	LC-MS [M + H] += 735.38	9
87	LC-MS [M + H] += 655.21	9
88	LC-MS [M + H] += 697.32	9
89	LC-MS [M + H] += 735.42	9
90	LC-MS [M + H] += 669.21	9
91	LC-MS [M + H] += 711.36	9
92	LC-MS [M + H] += 655.29	9
93	LC-MS [M + H] += 697.34	9
94	LC-MS [M + H] += 735.28	9
95	LC-MS [M + H] += 655.32	9
96	LC-MS [M + H] += 697.46	9
97	LC-MS [M + H] += 735.27	9
98	LC-MS [M + H] += 662.40	9
99	LC-MS [M + H] += 662.41	9
100	LC-MS [M + H] += 696.61	9
101	LC-MS [M + H] += 712.28	9
102	LC-MS [M + H] += 682.35	9
103	LC-MS [M + H] += 698.26	9
104	LC-MS [M + H] += 750.23	9
105	LC-MS [M + H] += 676.40	9
106	LC-MS [M + H] += 677.88	9
107	LC-MS [M + H] += 691.97	9
108	LC-MS [M + H] += 696.35	9
109	LC-MS [M + H] += 681.97	9
110	LC-MS [M + H] += 699.97	9
111	LC-MS [M + H] += 700.32	9
112	LC-MS [M + H] += 697.89	9
113	LC-MS [M + H] += 715.87	9
114	LC-MS [M + H] += 731.80	9
115	LC-MS [M + H] += 734.34	9
116	LC-MS [M + H] += 680.29	8
117	LC-MS [M + H] += 680.41	8
118	LC-MS [M + H] += 705.20	7
119	LC-MS [M + H] += 705.32	7
120	LC-MS [M + H] += 705.32	7
121	LC-MS [M + H] += 705.43	7
122	LC-MS [M + H] += 707.46	8
123	LC-MS [M + H] += 706.22	9
124	LC-MS [M + H] += 678.28	9
125	LC-MS [M + H] += 676.35	9
126	LC-MS [M + H] += 700.35	9
127	LC-MS [M + H] += 670.31	9
128	LC-MS [M + H] += 671.22	9
129	LC-MS [M + H] += 714.35	9
130	LC-MS [M + H] += 665.33	9
131	LC-MS [M + H] += 665.37	9
132	LC-MS [M + H] += 702.27	9
133	LC-MS [M + H] += 678.40	9
134	LC-MS [M + H] += 692.41	9
135	LC-MS [M + H] += 712.33	9
136	LC-MS [M + H] += 712.30	9
137	LC-MS [M + H] += 678.39	9
138	LC-MS [M + H] += 664.16	9
139	LC-MS [M + H] += 663.36	9
140	LC-MS [M + H] += 665.34	9
141	LC-MS [M + H] += 712.29	8
142	LC-MS [M + H] += 712.35	8
143	LC-MS [M + H] += 650.42	17
144	LC-MS [M + H] += 678.39	8
145	LC-MS [M + H] += 658.39	8
146	LC-MS [M + H] += 636.32	8
147	LC-MS [M + H] += 646.31	8
148	LC-MS [M + H] += 648.37	8
149	LC-MS [M + H] += 666.31	8
150	LC-MS [M + H] += 678.32	8
151	LC-MS [M + H] += 680.31	8
152	LC-MS [M + H] += 636.24	8
153	LC-MS [M + H] += 646.26	8
154	LC-MS [M + H] += 648.30	8
155	LC-MS [M + H] += 670.29	8
156	LC-MS [M + H] += 666.31	8
157	LC-MS [M + H] += 703.33	7
158	LC-MS [M + H] += 703.41	7
159	LC-MS [M + H] += 737.31	7
160	LC-MS [M + H] += 754.28	7
161	LC-MS [M + H] += 728.30	7
162	LC-MS [M + H] += 739.30	7
163	LC-MS [M + H] += 791.24	7
164	LC-MS [M + H] += 717.37	7
165	LC-MS [M + H] += 718.31	7
166	LC-MS [M + H] += 727.42	9
167	LC-MS [M + H] += 727.42	9
168	LC-MS [M + H] += 763.41	9
169	LC-MS [M + H] += 763.41	9
170	LC-MS [M + H] += 743.32	18
171	LC-MS [M + H] += 743.32	18
172	LC-MS [M + H] += 760.92	18
173	LC-MS [M + H] += 647.93	9
174	LC-MS [M + H] += 647.93	9
175	LC-MS [M + H] += 718.98	18
176	LC-MS [M + H] += 705.00	18
177	LC-MS [M + H] += 705.00	18
178	LC-MS [M + H] += 752.85	7
179	LC-MS [M + H] += 678.32	8
180	LC-MS [M + H] += 676.51	8
181	LC-MS [M + H] += 634.13	8
182	LC-MS [M + H] += 690.98	8
183	LC-MS [M + H] += 691.95	8
184	LC-MS [M + H] += 690.62	8
185	LC-MS [M + H] += 676.21	8
186	LC-MS [M + H] += 676.25	8
187	LC-MS [M + H] += 648.11	8
188	LC-MS [M + H] += 704.95	8
189	LC-MS [M + H] += 725.25	8
190	LC-MS [M + H] += 724.13	8
191	LC-MS [M + H] += 708.50	8
192	LC-MS [M + H] += 710.16	8
193	LC-MS [M + H] += 682.14	8
194	LC-MS [M + H] += 739.35	8
195	LC-MS [M + H] += 712.17	8
196	LC-MS [M + H] += 710.15	8
197	LC-MS [M + H] += 696.23	8
198	LC-MS [M + H] += 696.13	8
199	LC-MS [M + H] += 668.31	8
200	LC-MS [M + H] += 725.20	8
201	LC-MS [M + H] += 825.56	8
202	LC-MS [M + H] += 726.12	8
203	LC-MS [M + H] += 782.23	8
204	LC-MS [M + H] += 620.35	8
205	LC-MS [M + H] += 778.78	16
206	LC-MS [M + H] += 778.81	16
207	LC-MS [M + H] += 768.83	8
208	LC-MS [M + H] += 768.82	8
209	LC-MS [M + H] += 818.91	8
210	LC-MS [M + H] += 832.95	8
211	LC-MS [M + H] += 690.94	9
212	LC-MS [M + H] += 690.92	9
213	LC-MS [M + H] += 650.88	9
214	LC-MS [M + H] += 647.96	9
215	LC-MS [M + H] += 647.94	9
216	LC-MS [M + H] += 727.40	8
217	LC-MS [M + H] += 727.36	8
218	LC-MS [M + H] += 727.40	8
219	LC-MS [M + H] += 754.37	8
220	LC-MS [M + H] += 740.42	8
221	LC-MS [M + H] += 762.41	8
222	LC-MS [M + H] += 732.15	8
223	LC-MS [M + H] += 764.41	8
224	LC-MS [M + H] += 796.31	8
225	LC-MS [M + H] += 796.25	8
226	LC-MS [M + H] += 762.29	8
227	LC-MS [M + H] += 798.35	8
228	LC-MS [M + H] += 762.29	8
229	LC-MS [M + H] += 776.42	8
230	LC-MS [M + H] += 766.37	8
231	LC-MS [M + H] += 766.35	8
232	LC-MS [M + H] += 782.37	8
233	LC-MS [M + H] += 761.25	8
234	LC-MS [M + H] += 782.34	8
235	LC-MS [M + H] += 796.35	8
236	LC-MS [M + H] += 780.31	8
237	LC-MS [M + H] += 784.28	8
238	LC-MS [M + H] += 784.34	8
239	LC-MS [M + H] += 800.29	8
240	LC-MS [M + H] += 816.36	8
241	LC-MS [M + H] += 780.37	8
242	LC-MS [M + H] += 816.32	8
243	LC-MS [M + H] += 834.30	8
244	LC-MS [M + H] += 738.47	8
245	LC-MS [M + H] += 742.43	8
246	LC-MS [M + H] += 780.37	8
247	LC-MS [M + H] += 601.29	19
248	LC-MS [M + H] += 631.29	19
249	LC-MS [M + H] += 685.37	19
250	LC-MS [M + H] += 716.35	19
251	LC-MS [M + H] += 643.45	19
252	LC-MS [M + H] += 657.46	19
253	LC-MS [M + H] += 643.43	19
254	LC-MS [M + H] += 683.45	19
255	LC-MS [M + H] += 677.27	19
256	LC-MS [M + H] += 691.28	19
257	LC-MS [M + H] += 691.26	19
258	LC-MS [M + H] += 691.25	19
259	LC-MS [M + H] += 695.26	19
260	LC-MS [M + H] += 695.24	19
261	LC-MS [M + H] += 695.28	19
262	LC-MS [M + H] += 711.28	19
263	LC-MS [M + H] += 711.22	19
264	LC-MS [M + H] += 757.15	19
265	LC-MS [M + H] += 698.60	19
266	LC-MS [M + H] += 706.34	8
267	LC-MS [M + H] += 679.14	20
268	LC-MS [M + H] += 691.94	20
269	LC-MS [M + H] += 691.31	8
270	LC-MS [M + H] += 699.18	8
271	LC-MS [M + H] += 699.18	8
272	LC-MS [M + H] += 663.92	8
273	LC-MS [M + H] += 777.31	8
274	LC-MS [M + H] += 692.98	8
275	LC-MS [M + H] += 679.08	8
276	LC-MS [M + H] += 679.07	8
277	LC-MS [M + H] += 754.08	8
278	LC-MS [M + H] += 733.89	8
279	LC-MS [M + H] += 689.94	8
280	LC-MS [M + H] += 665.07	8
281	LC-MS [M + H] += 723.08	8
282	LC-MS [M + H] += 743.02	8
283	LC-MS [M + H] += 712.12	8
284	LC-MS [M + H] += 728.04	8
285	LC-MS [M + H] += 748.03	8
286	LC-MS [M + H] += 755.05	8
287	LC-MS [M + H] += 703.88	8
288	LC-MS [M + H] += 711.32	8
289	LC-MS [M + H] += 725.97	8
290	LC-MS [M + H] += 705.31	12
291	LC-MS [M + H] += 719.29	12
292	LC-MS [M + H] += 733.42	12
293	LC-MS [M + H] += 775.31	12
294	LC-MS [M + H] += 801.32	12
295	LC-MS [M + H] += 789.36	12
296	LC-MS [M + H] += 809.28	12
297	LC-MS [M + H] += 823.40	12
298	LC-MS [M + H] += 741.43	8
299	LC-MS [M + H] += 756.18	8
300	LC-MS [M + H] += 770.14	8
301	LC-MS [M + H] += 756.25	8
302	LC-MS [M + H] += 739.09	8
303	LC-MS [M + H] += 719.51	21
304	LC-MS [M + H] += 733.20	21
305	LC-MS [M + H] += 675.89	8
306	LC-MS [M + H] += 703.97	8
307	LC-MS [M + H] += 708.08	8
308	LC-MS [M + H] += 708.08	8
309	LC-MS [M + H] += 775.89	22
310	LC-MS [M + H] += 617.98	1
311	LC-MS [M + H] += 634.01	14
312	LC-MS [M + H] += 607.96	14
313	LC-MS [M + H] += 727.08	22
314	LC-MS [M + H] += 771.00, 772.93	22
315	LC-MS [M + H] += 733.11	22
316	LC-MS [M + H] += 750.10	22
317	LC-MS [M + H] += 743.15	22
318	LC-MS [M + H] += 769.16	22
319	LC-MS [M + H] += 770.99, 772.13	22
320	LC-MS [M + H] += 775.95	22
321	LC-MS [M + H] += 760.11	22
322	LC-MS [M + H] += 790.10	22
323	LC-MS [M + H] += 802.15	22
324	LC-MS [M + H] += 769.11	22
325	LC-MS [M + H] += 828.04	22
326	LC-MS [M + H] += 887.91, 889.87	22
327	LC-MS [M + H] += 878.15	22
328	LC-MS [M + H] += 824.06	22
329	LC-MS [M + H] += 860.07	22
330	LC-MS [M + H] += 630	7
331	LC-MS [M + H] += 647	7
332	LC-MS [M + H] += 658	7
333	LC-MS [M + H] += 675	7
334	LC-MS [M + H] += 669	7
335	LC-MS [M + H] += 632	7
336	LC-MS [M + H] += 646	7
337	LC-MS [M + H] += 646	7
338	LC-MS [M + H] += 646	7
339	LC-MS [M + H] += 660	7
340	LC-MS [M + H] += 658	7
341	LC-MS [M + H] += 702	7
342	LC-MS [M + H] += 714	7
343	LC-MS [M + H] += 675.9	7
344	LC-MS [M + H] += 675.9	7
355	LC-MS [M + H] += 676	7
356	LC-MS [M + H] += 676	7
357	LC-MS [M + H] += 672	7
358	LC-MS [M + H] += 726	7
359	LC-MS [M + H] += 644	7
360	LC-MS [M + H] += 632	7
361	LC-MS [M + H] += 618	7
362	LC-MS [M + H] += 694	7
363	LC-MS [M + H] += 601	23
364	LC-MS [M + H] += 686	7
365	LC-MS [M + H] += 741	7
366	LC-MS [M + H] += 692	7
367	LC-MS [M + H] += 612	7
368	LC-MS [M + H] += 626	7
369	LC-MS [M + H] += 672	7
370	LC-MS [M + H] += 774	7
371	LC-MS [M + H] += 734	7
372	LC-MS [M + H] += 660	7
373	LC-MS [M + H] += 784	7
374	LC-MS [M + H] += 762	7
375	LC-MS [M + H] += 666	7
376	LC-MS [M + H] += 650	7
377	LC-MS [M + H] += 678	7
378	LC-MS [M + H] += 678	7
379	LC-MS [M + H] += 626	23
380	LC-MS [M + H] += 626	23
381	LC-MS [M + H] += 627	7
382	LC-MS [M + H] += 667	7
383	LC-MS [M + H] += 681	7
384	LC-MS [M + H] += 723	7
385	LC-MS [M + H] += 695	7
386	LC-MS [M + H] += 695	7
387	LC-MS [M + H] += 667	7
388	LC-MS [M + H] += 697	7
389	LC-MS [M + H] += 711	7
390	LC-MS [M + H] += 669	7
391	LC-MS [M + H] += 695	7
392	LC-MS [M + H] += 724	7
393	LC-MS [M + H] += 703	7
394	LC-MS [M + H] += 727/729	7
395	LC-MS [M + H] += 667	7

Example 3. Biological Assay

Fluorescence polarization (FP) experiments were performed in 96-well, black round-bottom plates (Microfluor 2, Fisher Scientific) using the CLARIOstar microplate reader (BMG Labtech). To each well, 5 nM of fluoresceinlabeled tracer and 200 nM of STAT5 and/or STAT6 protein were added to a final volume of 100 μl in the assay buffer (PBS pH7.4+0.01% BGG+0.01% Tween-20, 2 mM DTT). The plate was mixed on a shaker for 15 m and incubated at room temperature for 1 h to reach equilibrium. The polarization values in millipolarization (mP) units were measured at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. All experimental data were analyzed using Prism 8.0 software (GraphPad Software), and the inhibition constants were determined by nonlinear curve fitting as the concentration of the STAT5 and/or STAT6 at which 50% of the ligand is bound.

TABLE 3
Summary of Bio Assay Data
	Cpd.	Binding
	No.	STAT6	STAT5A
	1	B	D
	2	B	C
	3	C	D
	4	B	C
	5	D	D
	6	C	D
	7	C	D
	8	D	D
	9	C	D
	10	C	D
	11	C	D
	12	C	D
	13	C	D
	14	C	D
	15	C	C
	16	C	D
	17	C	C
	18	D	D
	19	C	D
	20	D	D
	21	C	D
	22	D	D
	23	C	C
	24	D	D
	25	D	C
	26	D	D
	27	C	D
	28	D	D
	29	D	D
	30	D	D
	31	D	B
	32	D	D
	33	D	D
	34	D	D
	35	D	D
	36	D	D
	37	B	C
	38	C	C
	39	B	C
	40	B	C
	41	C	D
	42	B	C
	43	B	B
	44	B	C
	45	B	C
	46	B	B
	47	B
	48	B
	49	B
	50	B
	51	B
	52	B
	53	C
	54	B
	55	B
	56	B
	57	B
	58	C	D
	59	C	D
	60	C	D
	61	C	D
	62	C	D
	63	C	D
	64	B	D
	65	C	D
	66	C	D
	67	A	D
	68	C	D
	69	C	D
	70	C	D
	71	C	D
	72	C	D
	73	C	D
	74	C	D
	75	C	D
	76	C	D
	77	C	D
	78	D	D
	79	D	D
	80	D	D
	81	D	D
	82	D	D
	83	D	D
	84	D	D
	85	D	D
	86	D	D
	87	D	D
	88	D	D
	89	D	D
	90	D	D
	91	D	D
	92	D	D
	93	D	D
	94	D	D
	95	D	D
	96	D	D
	97	D	D
	98	C	D
	99	B	C
	100	C	D
	101	C	D
	102	B	D
	103	C	C
	104	C	C
	105	C	D
	106	B	C
	107	C	D
	108	C	D
	109	B	D
	110	C	D
	111	B	D
	112	B	D
	113	B	C
	114	B	C
	115	C	D
	116	B	C
	117	B	C
	118	B	C
	119	C	D
	120	C	D
	121	C	D
	122	B	D
	123	C	D
	124	B	C
	125	B	C
	126	B	C
	127	B	C
	128	C	D
	129	B	C
	130	B	D
	131	C	D
	132	B	B
	133	C	D
	134	C	D
	135	B	C
	136	B	C
	137	C	D
	138	B	D
	139	C	D
	140	B	D
	141	B	C
	142	C	D
	143	C	D
	144	B	C
	145	B	D
	146	B	C
	147	B	D
	148	B	C
	149	B	D
	150	C	D
	151	C	D
	152	C	D
	153	C	D
	154	C	D
	155	D	D
	156	C	D
	157	C	D
	158	B	D
	159	C	D
	160	C	D
	161	B	D
	162	B	D
	163	C	D
	164	C	D
	165	C	C
	166	C	D
	167	C	D
	168	C	D
	169	C	D
	170	B	C
	171	C	D
	172
	173	C	D
	174	C	D
	175	B	C
	176	C	C
	177	C	D
	178	B	C
	179	B	C
	180	B	C
	181	D	D
	182	C	B
	183	B	C
	184	B	C
	185	C	C
	186	D	C
	187	C	D
	188	C	B
	189	B	C
	190	B	C
	191	C	D
	192	D	D
	193	D	D
	194	C	B
	195	A	C
	196	A	C
	197	C	D
	198	B	C
	199	C	D
	200	C	B
	201	C	B
	202	C	C
	203	C	B
	204	C	D
	205	C	C
	206	C	B
	207	C	C
	208	C	B
	209	C	D
	210	C	C
	211	B	C
	212	C	C
	213	C	D
	214	C	D
	215	C	D
	216	D	D
	217	A
	218	B
	219	A
	220	B
	221	B
	222	B
	223	A
	224	A
	225	B
	226	B
	227	B
	228	B
	229	C
	230	B
	231	B
	232	B
	233	A
	234	B
	235	C
	236	C
	237	B
	238	B
	239	C
	240	B
	241	C
	242	B
	243	B
	244	C
	245	B
	246	B
	247		C
	248		D
	249		C
	250		D
	251		D
	252		D
	253		D
	254		C
	255		B
	256		C
	257		C
	258		D
	259		C
	260		B
	261		C
	262		C
	263		D
	264		C
	265	B
	266	C
	267
	268
	269	B
	270	B
	271	B
	272	B
	273	B
	274	B
	275	B
	276	B
	277	A
	278	B
	279	B
	280	A
	281	A
	282	A
	283	B
	284	B
	285	B
	286	B
	287	B
	288	B
	289	A
	290	B
	291	B
	292	B
	293	B
	294	B
	295	B
	296	B
	297	B
	298
	299	B
	300	A
	301	A
	302		B
	303		C
	304		C
	305	C	B
	306	D	C
	307	B	C
	308	C	C
	309	B	C
	310	C	D
	311	C	C
	312	C	C
	313	B	C
	314	B	C
	315	B	C
	316	B	C
	317	B	C
	318	C	C
	319	C	D
	320	C	D
	321		C
	322		B
	323		C
	324		C
	325		B
	326		C
	327		C
	328		B
	329		C
	330	D
	331	D
	332	D
	333	D
	334	D
	335	D
	336	C
	337	C
	338	D
	339	D
	340	D
	341	C
	342	C
	343	C
	344	D
	355	D
	356	D
	357	D
	358	D
	359	B
	360	D
	361	D
	362	C
	363	D
	364	D
	365	D
	366	D
	367	D
	368	D
	369	D
	370	C
	371	D
	372	D
	373	C
	374	D
	375	D
	376	D
	377	D
	378	D
	379	D
	380	D
	381	D
	382	D
	383	D
	384	D
	385	D
	386	D
	387	D
	388	D
	389	C
	390	D
	391	D
	392	D
	393	D
	394	D
	395	D
	“A”: < 0.1 μM; “B”: 0.1-1 μM; “C”: 1-10 μM; “D”: > 10 μM.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein when one of R5a and R5b is hydrogen, then the other one of R5a and R5b is not:

3. The compound of claim 1 or 2, wherein Ring A is 5- to 10-membered heteroaryl.

4. The compound of claim 1 or 2, wherein Ring A is

5. The compound of claim 1, wherein the compound is a compound of Formula I-a or I-b:

6. The compound of any one of claims 1-5, wherein Ring B is 5- to 8-membered heterocyclyl.

7. The compound of claim 1, wherein the compound is a compound of Formula I-a-i to I-b-iii

8. The compound of any one of claims 1-7, wherein each R4 is independently C1-6 alkyl, C6-10 aryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C1-6 alkyl)-(C6-10 aryl), —(C1-6 alkyl)-(5- to 10-membered heteroaryl), —(C1-6 alkyl)-(3- to 12-membered heterocyclyl), wherein the alkyl, carbocyclyl, heterocyclyl, or aryl, is optionally substituted with one or more R4a.

9. The compound of claim 8, wherein each R4a is independently halogen, —CN, —NO2, —OH, —NH2, —B(OH)2, C1-6 alkyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C1-6 alkyl)-(C6-10 aryl), —(C1-6 alkyl)-(C3-12 carbocyclyl), —NRbC(═O)Ra, —ORb, —C(═O)Ra, or —C(═O)NRcRd, wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

10. The compound of any one of claims 1-7, wherein one R4 and one RB, together with the intervening atoms, form 3- to 12-membered heterocyclyl optionally substituted with one or more R4b.

11. The compound of claim 1, wherein the compound is a compound of Formula I-a-i-1 or I-b-i-1

12. The compound of claim 26, wherein the compound is a compound of Formula I-a-i-2 or I-b-i-2

13. The compound of any one of claims 1-12, wherein each R4b is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, or —C(═O)Ra, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

14. The compound of any one of claims 11-13, wherein r is 0 or 1.

15. The compound of any one of claims 1-14, wherein R1a and R1b are both hydrogen.

16. The compound of any one of claims 1-15, wherein each R2 is independently halogen.

17. The compound of claim 16, wherein each R2 is fluoride.

18. The compound of any one of claims 1-17, wherein each RA is independently halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

19. The compound of any one of claims 1-18, wherein m is 0.

20. The compound of any one of claims 1-19, wherein R3 is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

21. The compound of any one of claims 1-20, wherein each RB is independently 5- to 10-membered heteroaryl, —NRcRd, —ORb, —C(═O)Ra, or —C(═O)ORb, wherein the heteroaryl is optionally substituted with one or more RB-1.

22. The compound of claim 21, wherein each RB-1 is independently C1-6 alkyl, —C(═O)ORb, or —C(═O)NRcRd.

23. The compound of any one of claims 1-22, wherein n is 0 or 1.

24. The compound of any one of claims 1-23, wherein

25. The compound of claim 24, wherein R5a and R5b are independently hydrogen, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C1-6 alkyl)-(C6-10 aryl), wherein the alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R5c.

26. The compound of claim 25, wherein each R5, is independently halogen, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —(C1-6 alkyl)-(5- to 10-membered heteroaryl), —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

27. The compound of claim 24, wherein one of R5a and R5b is hydrogen, and the other one of R5a and R5b is 5- to 10-membered heteroaryl substituted with C6-10 aryl, wherein the aryl is optionally substituted with one or more Ru.

28. The compound of any one of claims 1-23, wherein

29. The compound of any one of claims 1-23, wherein

30. The compound of claim 28 or 29, wherein each R5d is independently oxo, halogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, —S(═O)2Ra, —ORb, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, haloalkyl, carbocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

31. The compound of claim 29 or 30, wherein Ring E is C6-10 aryl or C3-12 carbocyclyl.

32. The compound of any one of claims 29-30, wherein each R5e is independently halogen, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

33. The compound of claim 1, wherein the compound is a compound of Formula (II):

34. The compound of claim 41, wherein when one of R5a and R5b is hydrogen, then the other one of R5a and R5b is not:

35. The compound of claim 1, wherein the compound is selected from compounds described in Table 1 and pharmaceutically acceptable salts thereof.

36. A pharmaceutical composition comprising the compound of any one of claims 1-35, and a pharmaceutically acceptable excipient.

37. A method of inhibiting a STAT5 protein in a subject or biological sample comprising administering a compound of any one of claims 1-35 to the patient or contacting a compound of any one of claims 1-35 with the biological sample.

38. A method of inhibiting a STAT6 protein in a subject or biological sample comprising administering a compound of any one of claims 1-35 to the patient or contacting a compound of any one of claims 1-35 with the biological sample.

39. Use of a compound of any one of claims 1-35 in the manufacture of a medicament for inhibiting a STAT5 protein in a subject or biological sample.

40. A method of inhibiting a STAT6 protein in a subject or biological sample comprising administering a compound of any one of claims 1-35 to the patient or contacting a compound of any one of claims 1-35 with the biological sample.

41. A compound of any one of claims 1-35 for use in inhibiting a STAT5 protein in a subject or biological sample.

42. A compound of any one of claims 1-35 for use in inhibiting a STAT6 protein in a subject or biological sample.

43. A method of treating a STAT5-mediated disease or disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-35.

44. A method of treating a STAT6-mediated disease or disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-35.

45. Use of a compound of any one of claims 1-35 in the manufacture of a medicament for treating a STAT5-mediated disease or disorder.

46. Use of a compound of any one of claims 1-35 in the manufacture of a medicament for treating a STAT6-mediated disease or disorder.

47. A compound of any one of claims 1-35 for use in treating a STAT5-mediated disease or disorder.

48. A compound of any one of claims 1-35 for use in treating a STAT6-mediated disease or disorder.

49. The method, use, or compound for use of any one of claims 51-56, wherein the disease or disorder is breast cancer, colorectal cancer, lung cancer, prostate cancer, liver cancer, hematological malignancies, T-cell lymphoma, acute leukemia and chronic myeloid leukemia, solitary fibrous tumor, solid tumors, asthma, atopic dermatitis, eosinophilic esophagitis or food allergies.