Patent Grant
12144816
The present disclosure pertains to compounds that inhibit the activity of an anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) protein, compositions containing the compounds, and methods of treating cancer involving over-expressed or dysregulated Mcl-1 protein.
Abnormal regulation of apoptosis is now recognized to play an important role in the development of cancer. The apoptosis pathway can be initiated by various extracellular and intracellular stresses, including growth factor deprivation, DNA damage, oncogene induction, and cytotoxic drugs (Danial, N. N. and Korsmeyer, S J. Cell (2004) 116, 205-219). The death signal leads to the oligomerization of the pro-apoptotic proteins Bax and Bak. Upon activation, they permeabilize the mitochondrial outer membrane and release apoptogenic factors into the cytoplasm. This process is tightly regulated by both pro-apoptotic (Bax, Bak, Bad, Bid, Bim, Bmf, NOXA, PUMA) and anti-apoptotic (Bcl-2, Bcl-xL, Bcl-w, Bcl2-A1, Mcl-1) members of the Bcl-2 family of proteins. Recent data suggests that the anti-apoptotic Bcl-2 proteins function to protect the cell from apoptotic insults, primarily by preventing disruption of mitochondrial outer membrane integrity by binding to the pro-apoptotic proteins as described in Adams, J. M. and Cory S. Oncogene (2007) 20, 1324-1337, Willis, S. N. et al. Science (2007) 315,856-859. Because tumor cells are under stress, alterations in their apoptotic signaling pathways are believed to be crucial for survival. Recent data implicates down-regulated apoptosis in the onset of cancer. Research has shown, for example, that anti-apoptotic proteins, are over-expressed in many cancer cell types as described in Beroukhim, R. et al. Nature (2010) 463, 899-905; Zhang J. Y., Nature Reviews Drug Discovery, (2002) 1, 101; Kirkin, V. et al. Biochimica et Biophysica Acta (2004) 1644, 229-249; and Amundson, S. A. et al. Cancer Research (2000) 60, 6101-6110. This dysregulation results in the survival of cells that would otherwise have undergone apoptosis such as cancer cells. This suggests that neutralizing the function of anti-apoptotic Bcl-2 proteins may offer an effective strategy for the elimination of cancer cells. In addition, resistance to chemotherapy which is a major cause of treatment failure and poor prognosis in many cancers can be caused by the upregulation of anti-apoptotic Bcl-2 family proteins.
An important anti-apoptotic member of the Bcl-2 family is Myeloid cell leukemia-1 (Mcl-1). Mcl-1 is one of the most frequently amplified anti-apoptotic genes in human cancers including prostate, lung, pancreatic, breast, ovarian, and cervical cancers, as well as melanoma, B-cell chronic lymphocytic leukemia (B-CLL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (Beroukhim et al. Nature (2010) 463, 899-905). Moreover, its overexpression is implicated as a resistance factor for multiple therapies including widely prescribed microtubule-targeted agents for breast cancers, such as paclitaxel and vincristine as well as Gemcitabine, a first-line treatment option for pancreatic cancer (Wei et al. Cancer Chemother Pharmacol (2008) 62, 1055-1064 and Wertz et al. Nature (2011) 471, 110-114). These data suggest that Mcl-1 is an important target for a wide variety of cancers.
In many cancer cell types, the cancer cell's survival is attributed to the dysregulation of the apoptotic pathway caused by the over-expression of one or more anti-apoptotic Bcl-2 protein family members. Because of the important role for Bcl-2 family of proteins in regulating apoptosis in both cancerous and non-cancerous cells, and the inter-cell variability of Bcl-2 family protein expression, it could be advantageous to have a small molecule inhibitor that selectively targets and preferably binds to one type or a subset of anti-apoptotic Bcl-2 protein(s). A selective compound also may confer certain advantages in the clinical setting, by providing flexibility to select a dosing regimen to reduce on-target toxic effects in normal cells.
Because Mcl-1 protein is an important Bcl-2 family member associated with a number of diseases, there is a need for compounds which bind to and inhibit the activity of Mcl-1 protein.
In some embodiments, the present disclosure provides compounds, and pharmaceutically acceptable compositions thereof, that are effective as inhibitors of Mcl-1.
Compounds of the present disclosure, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with MCi-1. Such diseases, disorders, or conditions include those described herein.
Compounds provided by this disclosure are also useful for the study of Mcl-1 in biological and pathological phenomena and the comparative evaluation of new Mcl-1 inhibitors in vitro or in vivo.
In one aspect, the present disclosure provides inhibitors of Mcl-1. In some embodiments, such compounds include those of formula (I):
or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from a covalent bond or an optionally substituted bivalent straight or branched C1-6 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy-, -Cy- is an optionally substituted bivalent ring independently selected from phenylene, 3-8 membered saturated or partially unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L2 is an optionally substituted bivalent straight or branched C3-6 hydrocarbon chain wherein one or two methylene units of L2 are optionally and independently replaced with —O—, —S—, or —N(R′)—, and wherein two substituents of L2 are optionally taken together to form an optionally substituted bivalent ring selected from 3-8 membered saturated or partially unsaturated carbocyclylene or 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R′ is independently selected from hydrogen or optionally substituted C1-4 alkyl; R1 is selected from hydrogen, halogen, R, —OR, —SR, —S(O)R, —S(O)2R, —S(O)2N(R)2, —N(R)2, —C(O)N(R)2, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —N(R)S(O)2N(R)2, —C(O)OH, —C(O)Rx, —S(O)2OH, —S(O)Ry, or —S(O)2Ry; R2 is selected from —C(O)-L3-Rz, —C(O)N(R)-L3-Rz, —C(O)N(R)—C(R)2-L3-Rz, —C(O)O-L3-Rz or —C(O)S-L3-Rz; L3 is selected from a covalent bond or an optionally substituted bivalent straight or branched C1-8 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)2—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, or —S(O)2N(R)—; Rz is selected from hydrogen, -Cy-R, R, —OR. —SR, —S(O)R, —S(O)2R, —S(O)2N(R)2, —N(R)2, —C(O)N(R)2, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —N(R)S(O)2N(R)2, —C(O)OH, —C(O)Rx, —S(O)2OH, or —S(O)2Ry, or is selected from:
Rx is selected from —C(O)OR, —N(R)S(O)2CF3, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, or —N(R)S(O)2R; Ry is selected from —N(R)C(O)CF3, —N(R)C(O)R, or —N(R)C(O)N(R)2; each R is independently selected from hydrogen or an optionally substituted group selected from C1-12 aliphatic or a ring selected from a 3-10 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 12-15 membered tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R3 is an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of R4, R5, and R6 is independently selected from R, halogen, —CN, —NO2, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)2, —N(R′)2, —S(O)2N(R′)2, —N(R′)S(O)2CF3, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)2R′, —N(R′)C(O)OR′, and —N(R′)S(O)2R′; R7 is selected from hydrogen, halogen, —CN, —NO2, —C(O)OR, —OCF3, —OR, —SR, —S(O)2OR, —P(O)(OH)2, —C(O)N(R)2, —N(R)2, —S(O)2N(R)2, —N(R)S(O)2CF3, —C(O)N(R)S(O)2R, —S(O)2N(R)C(O)OR, —S(O)2N(R)C(O)N(R)2, —C(O)R, —C(O)N(R)S(O)2CF3, —N(R)C(O)R, —OC(O)R, —OC(O)N(R)2, —C(NR)N(R)2, —N(R)C(NR)N(R)2, —S(O)R, —S(O)2R, —N(R)C(O)OR, or —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic or a ring selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and optionally R1 and R2, R1 and R7, R4 and R5, R5 and R6 and/or R6 and R7 are taken together with their intervening atoms to form an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In other embodiments are compounds of formula (I), or a pharmaceutically acceptable salt, thereof, wherein L is selected from a covalent bond or an optionally substituted bivalent straight or branched C1-6 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy-; -Cy- is an optionally substituted bivalent ring independently selected from phenylene, 3-8 membered saturated or partially unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L2 is an optionally substituted bivalent straight or branched C3-6 hydrocarbon chain wherein one or two methylene units of L2 are optionally and independently replaced with —O—, —S—, or —N(R′)—, and wherein two substituents of L2 are optionally taken together to form an optionally substituted bivalent ring selected from 3-8 membered saturated or partially unsaturated carbocyclylene or 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R′ is independently selected from hydrogen or optionally substituted C1-4 alkyl; R1 is selected from hydrogen, halogen, R, —OR, —SR, —S(O)R, —S(O)ZR, —S(O)2N(R)2, —N(R)2, —C(O)N(R)2, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —N(R)S(O)2N(R)2, —C(O)OH, —C(O)Rx, —S(O)2OH, —S(O)Ry, or —S(O)2Ry; R2 is selected from —C(O)-L3-Rz, —C(O)N(R)-L3-Rz, —C(O)N(R)—C(R)2-L3-Rz, —C(O)O-L3-Rz or —C(O)S-L3-Rz; L3 is selected from a covalent bond or an optionally substituted bivalent straight or branched C1-8 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)2—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, or —S(O)2N(R)—; Rz is selected from hydrogen, -Cy-R, R, —OR, —SR, —S(O)R, —S(O)2R, —S(O)2N(R)2. —N(R)2, —C(O)N(R)2, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —N(R)S(O)2N(R)2, —C(O)OH, -C(O)Rx, —S(O)2OH, or —S(O)2Ry, or is selected from:
Rx is selected from —C(O)OR, —N(R)S(O)2CF3, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, or —N(R)S(O)2R; Ry is selected from —N(R)C(O)CF3, —N(R)C(O)R, or —N(R)C(O)N(R)2; each R is independently selected from hydrogen or an optionally substituted group selected from C1-12 aliphatic or a ring selected from a 3-10 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R3 is an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of R4, R5, and R6 is independently selected from R, halogen, —CN, —NO2, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)2—N(R′)2, —S(O)2N(R)2, —N(R′)S(O)2CF3, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)2R′, —N(R′)C(O)OR′, and —N(R′)S(O)2R′; R7 is selected from hydrogen, halogen, —CN, —NO2, —C(O)OR, —OCF3, —OR, —SR, —S(O)2OR, —P(O)(OH)2, —C(O)N(R)2, —N(R)2, —S(O)2N(R)2, —N(R)S(O)2CF3, —C(O)N(R)S(O)2R, —S(O)2N(R)C(O)OR, —S(O)2N(R)C(O)N(R)2, —C(O)R, —C(O)N(R)S(O)2CF3, —N(R)C(O)R, —OC(O)R, —OC(O)N(R)2, —C(NR)N(R)2, —N(R)C(NR)N(R)2, —S(O)R, —S(O)R, —N(R)C(O)OR, or —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic or a ring selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and optionally R1 and R2, R1 and R7, R4 and R5, R5 and R6 and/or R6 and R7 are taken together with their intervening atoms to form an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic or polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).
The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.
As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
The term “halogen” means F, Cl, Br, or I.
The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may be optionally substituted. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, or 5 to 15 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole, 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-1-one, 1,2,3,4-tetrahydropyrazino[1,2-a]indole, and 3,4-dihydropyrazino[1,2-a]indol-1(2H)-one. A heteroaryl group may be mono-, bicyclic, or tricyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).
A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted.” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH2)0-4R∘; —(CH2)0-4OR∘; —O(CH2)0-4R∘, —O—(CH2)0-4C(O)OR∘; —(CH2)0-4CH(OR∘)2; —(CH2)0-4SR∘; —(CH2)0-4Ph, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1Ph which may be substituted with R∘; —CH═CHPh, which may be substituted with R∘; —(CH2)0-4(CH2)0-1-pyridyl which may be substituted with R∘; —NO2; —CN; —N3; —(CH2)0-4N(R∘)2; —(CH2)0-4N(R∘)C(O)R∘; —N(R∘)C(S)R∘; —(CH2)0-4N(R∘)C(O)NR∘2; —N(R∘)C(S)NR∘2; —(CH2)0-4N(R∘)C(O)OR∘; —N(R∘)N(R∘)C(O)R∘; —N(R∘)N(R∘)C(O)NR∘2; —N(R∘)N(R∘)C(O)OR∘; —(CH2)0-4C(O)R∘; —C(S)R∘; —(CH2)0-4C(O)OR∘; —(CH2)0-4C(O)SR∘; —(CH2)0-4C(O)OSiR∘3; —(CH2)0-4OC(O)R∘; —OC(O)(CH2)0-4SR—; —(CH2)0-4SC(O)R∘; —(CH2)0-4C(O)NR∘2; —(CH2)0-4C(O)N(R∘)S(O)2R∘; —C(S)NR∘2; —C(S)SR∘; —SC(S)SR∘, —(CH2)0-4OC(O)NR∘2; —C(O)N(OR∘)R∘; —C(O)C(O)R∘; —C(O)CH2C(O)R∘; —C(NOR∘)R∘; —(CH2)0-4SSR∘; —(CH2)0-4S(O)R∘; —(CH2)0-4S(O)2R∘; —(CH2)0-4—S(O)2OR∘; —(CH2)0-4OS(O)?R∘; —S(O)2NR∘2; —S(O)2N(R∘)C(O)R∘; —(CH2)0-4S(O)R∘; —N(R∘)S(O)2NR∘2; —N(R∘)S(O)2R∘; —N(OR∘)R∘; —C(NH)NR∘2; —P(O)2R∘; —P(O)R∘2; —OP(O)R∘2; —OP(O)(OR∘)2; —SiR∘3; —(C1-4 straight or branched alkylene)O—N(R∘)2; or —(C1-4 straight or branched alkylene)C(O)O—N(R∘)2, wherein each R∘ may be substituted as defined below and is independently hydrogen, an optionally substituted group selected from C1-12 aliphatic or a ring selected from a 3-10 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, —CH2Ph, —O(CH2)0-1Ph, or —CH2-(5-6 membered heteroaryl ring), or, notwithstanding the definition above, two independent occurrences of R∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
Suitable monovalent substituents on R∘ (or the ring formed by taking two independent occurrences of R∘ together with their intervening atoms), are independently halogen. —(CH2)0-2R●, -(haloR●), —(CH2)0-2OH, —(CH2)0-2OR, —(CH2)0-2CH(OR●)2; —O(haloR●), —CN, —N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, (CH2)0-2SR●, —(CH2)0-2S(O)R●, —(CH2)0-2S(O)2R●, —(CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR●, —(CH2)0-2NR●2, —NO2, —SiR●3, —OSiR●3, —C(O)SR●, —(C1-4 straight or branched alkylene)C(O)OR●, or —SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted with one or more halogens, and is independently selected from an C1-12 aliphatic or a ring selected from a 3-10 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, —CH2Ph, or —O(CH2)0-1Ph. Suitable divalent substituents on a saturated carbon atom of R∘ include ═O and ═S.
Suitable divalent substituents on a suitable carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on the aliphatic group of R* include halogen. —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)R●, —C(O)OH, —C(O)OR●, —C(O)NR●2, —SR●, —S(O)R●, —S(O)2R●, —NH2, —NHR●, —NR●2, or —NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R†, —NR†2, —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH2C(O)R†, —S(O)2R†, —S(O)2NR†2, —C(S)NR†2, —C(NH)NR†2, —C(NR†)NR†2, or —N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on the aliphatic group of R† are independently halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —C(O)NR●2, —SR●, —S(O)R●, —S(O)2R●, —NH2, —NHR●, —NR●2, or —NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
In one aspect, disclosed is a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, L1, and L2 are as defined above.
In certain embodiments, R2 is selected from —C(O)-L3-Rz, —C(O)N(R)-L3-Rz, —C(O)N(R)—C(R)2-L3-Rz, or —C(O)S-L3-Rz.
In certain embodiments, L2 is selected from:
In certain embodiments, L2 is
In certain embodiments, R4 is hydrogen; R5 is hydrogen; and R6 is halogen, C1-C6-haloalkyl, or cyclopropyl.
In certain embodiments, R6 is chloro.
In certain embodiments, the compound of formula (I) has formula (I-a) or (I-b):
or a pharmaceutically acceptable salt thereof, wherein: L4 is independently selected from a covalent bond or an optionally substituted bivalent straight or branched C1-8 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)2—, —C(O)—, —C(O)N(R)—. —S(O)—. —S(O)2—, or —S(O)2N(R)—; -Cy′-is an optionally substituted bivalent ring independently selected from phenylene, 3-8 membered saturated or partially unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic arylene or heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Rw is selected from hydrogen, -Cy′—R, R, —OR, —SR, —S(O)R, —S(O)2R, —S(O)2N(R)2, —N(R)2, —C(O)N(R)2, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —N(R)S(O)2N(R)2, —C(O)OH, —C(O)OR, —C(O)Rx, —S(O)2OH, or —S(O)2Ry, or is selected from:
Rx is selected from —C(O)OR, —N(R)S(O)2CF3, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, or —N(R)S(O)2R; R is selected from —N(R)C(O)CF3, —N(R)C(O)R, or —N(R)C(O)N(R)2; each R is independently selected from hydrogen or an optionally substituted group selected from C1-12 aliphatic or a ring selected from a 3-10 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R5, R6, R8, R9, R10, R11, and R12 is independently selected from R, halogen, —CN, —NO2, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)2—N(R′)2, —S(O)2N(R)2, —N(R′)S(O)2CF3, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)2R′, —N(R′)C(O)OR′, and —N(R′)S(O)2R′; each R′ is independently selected from hydrogen or optionally substituted C1-4 alkyl; and R7 is selected from hydrogen, halogen, —CN, —NO2, —C(O)OR, —OCF3, —OR, —SR, —S(O)2OR, —P(O)(OH)2, —C(O)N(R)2, —N(R)2, —S(O)2N(R)2, —N(R)S(O)2CF3, —C(O)N(R)S(O)2R, —S(O)2N(R)C(O)OR, —S(O)2N(R)C(O)N(R)2, —C(O)R, —C(O)N(R)S(O)2CF3, —N(R)C(O)R, —OC(O)R, —OC(O)N(R)2, —C(NR)N(R)2, —N(R)C(NR)N(R)2, —S(O)R, —S(O)2R, —N(R)C(O)OR, or —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic or a ring selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, of formula (I-a) or (I-b), or a pharmaceutically acceptable salt thereof. L4 is independently selected from a covalent bond or an optionally substituted bivalent straight or branched C1-8 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)2—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, or —S(O)2N(R)—; -Cy′-is an optionally substituted bivalent ring independently selected from phenylene, 3-8 membered saturated or partially unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic arylene or heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Rw is selected from hydrogen, R, -Cy′—R, —OR, —SR, —S(O)R, —S(O)2R, —S(O)2N(R)2, —N(R)2, —C(O)N(R)2, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R. —N(R)S(O)2N(R)2, —C(O)OH, —C(O)OR, —C(O)R′, —S(O)2OH, or —S(O)2Ry, or is selected from:
Rx is selected from —C(O)OR, —N(R)S(O)2CF3, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, or —N(R)S(O)2R; Ry is selected from —N(R)C(O)CF3, —N(R)C(O)R, or —N(R)C(O)N(R)2; each R is independently selected from hydrogen or an optionally substituted group selected from C1-12 aliphatic or a ring selected from a 3-10 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 12-15 membered tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R5, R6, R8, R9, R10, R11, and R12 is independently selected from R, halogen, —CN, —NO2, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)2—N(R′)2, —S(O)2N(R′)2, —N(R′)S(O)2CF3, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)2R′, —N(R′)C(O)OR′, and —N(R′)S(O)2R′; each R′ is independently selected from hydrogen or optionally substituted C1-4 alkyl; and R7 is selected from hydrogen, halogen, —CN, —NO2, —C(O)OR, —OCF3, —OR, —SR, —S(O)2OR, —P(O)(OH)2, —C(O)N(R)2, —N(R)2, —S(O)2N(R)2, —N(R)S(O)2CF3, —C(O)N(R)S(O)2R, —S(O)2N(R)C(O)OR, —S(O)2N(R)C(O)N(R)2, —C(O)R, —C(O)N(R)S(O)2CF3, —N(R)C(O)R, —OC(O)R, —OC(O)N(R)2, —C(NR)N(R)2, —N(R)C(NR)N(R)2, —S(O)R, —S(O)2R, —N(R)C(O)OR, or —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic or a ring selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, the compound of formula (I) has formula:
In certain embodiments, formula (I-a-1) is formula (I-a-7).
In certain embodiments, R3 is selected from:
In certain embodiments, R3 is selected from
In certain embodiments, R7 is an optionally substituted group selected from phenyl and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen. Exemplary optional substituents include, but are not limited to, halogen, oxo (═O), ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, heteroarylalkyl, arylalkyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylene, aryloxy, arylthio, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, diarylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, alkoxycarbonyl, aryloxycarbonyl, amide, carbamate, acyl, boronic acid, and boronic ester.
In certain embodiments, R7 is
and Ra and Rb are each independently hydrogen, hydroxy, alkyl, heteroalkyl, heterocyclyl, or heterocyclylalkyl, wherein said alkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl are independently substituted by 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, oxo (═O), ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, heteroarylalkyl, arylalkyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylene, aryloxy, arylthio, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, diarylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, alkoxycarbonyl, aryloxycarbonyl, amide, carbamate, acyl, boronic acid, and boronic ester.
In certain embodiments, Ra and Rb are selected from:
In certain embodiments, R7 is selected from:
In certain embodiments, R7 is selected from:
In certain embodiments, R7 is selected from;
In certain embodiments, R7 is
In certain embodiments, L4-Rw is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In other embodiments, L4-Rw is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 1,2,3,4-tetrahydropyrazino[1,2-a]indole, or an optionally substituted 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
In certain embodiments, L4-Rw is
Rj is C1-C4-alkyl or C1-C4-alkoxy; and Rk is C1-C4-alkyl.
In certain embodiments, L4-Rw is
In certain embodiments, the optionally substituted 4-8 membered heterocyclic ring formed by R20 and R21 together with the nitrogen to which they are attached is selected from the group consisting of
In certain embodiments, the compound of formula (I) is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
The compounds of the present disclosure can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference as to the subject matter referenced herein.
The compounds of the disclosure may be prepared using the exemplary reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effective. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. One having ordinary skill in the art may adjust one or more of the conditions described herein. One skilled in the art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of the disclosure falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods can be used.
In some embodiments, provided compounds of this invention may be prepared as shown in Scheme 1. Indole 3 can be assembled by using Japp-Klingemann reaction described by, but not limited to, F. G. Salituro, et al. J. Med. Chem. (1990) 33, 2944-2946 as follows. Aniline 1 is converted to the corresponding benzenediazonium intermediate followed by condensation with ethyl 2-oxocyclopentanecarboxylate to give hydrazone 2. Intramolecular Fisher indole cyclization of the intermediate 2 is followed to give indole 3. The ethyl ester functional group at the flexible linker of indole 3 can be selectively reduced with excess BH3, and the resulting alcohol 4 can be condensed with phenols or hydroxy-heterocycles via Mitsunobu reaction to give the ether 5 using, but not limited to, DEAD or Dt-BuAD. Indole acid 6 can be generated by saponification of compounds 5 with appropriate bases, such as Cs2CO3, K2CO3, LiOH or NaOH, at a number of conditions that are routine for those skilled in the art of organic synthesis. Indole amides 7 can be produced by coupling of compounds 6 with suitable amines using coupling reagents, but not limited to, PyBOP, DCC, EDC, HBTU, or TBTU at a number of conditions that are routine for those skilled in the art of organic synthesis.
In some embodiments, compounds of Formula 11 containing Ar or heteroaryl substituents as R7 group may be synthesized by procedures illustrated in Scheme 2. Compounds of Formula 8, wherein X=Cl, Br, I, triflates or diazoderivatives, can be prepared as previously described in Scheme 1. A variety of boronic acids 9 or borates 10, which are commercially available or can be prepared, can be coupled with intermediates 8 via e.g., Suzuki coupling protocol to afford biaryl adducts 11 (Miyaura, N., Suzuki. A., Chem. Rev. (1995), 2457). In some embodiments, one exemplary such procedure entails treatment of the aryl bromide or iodide 8 with an aryl boronic acid in the presence of a catalytic Pd species, such as Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(OAc)2, Pd2(dba)3 and a suitable ligand such as PPh3, AsPh3, etc., or other such Pd catalyst, and a base such as Na2CO3, Cs2CO3, K2CO3, Ba(OH)2 or Et3N. Alternatively, biaryl adducts 11 can be prepared from Pinacol borates 12 which can be prepared from compounds 8 via Pd, such as Pd(PPh3)4, Pd(PPh3)2C12, Pd(OAc)2, Pd2(dba)3, catalyzed coupling of bis(pinacolato)diboron. Intermediates 12 can be coupled with a variety of aryl-halides or heteroaryl-halides 13 using Suzuki coupling protocol described above to give compounds 11. In some embodiments, a provided approach allows for great diversity in the subsequent coupling of indole boronic acids or borates with commercially available haloaromatic derivatives.
In some embodiments, provided compounds of Formula 18 may be prepared by procedures outlined in Scheme 3. Compounds of Formula 14 can be reacted with compounds of Formula 15, wherein X is Cl, Br, I, OMs, or OTs with a base such as NaH, K2CO3, Cs2CO3, Et3N, or DIPEA in a suitable solvent such as DMF, THF, ether, DME, or the like, to give compounds of Formula 16. Applying the same reaction sequence as described in Scheme 1, compounds of Formula 16 can undergo saponification followed by coupling reaction to give compounds of Formula 18.
In some embodiments, compounds of Formula 21 can be synthesized by procedures depicted in Scheme 4 via selective sequential coupling reactions in one-pot. An amino group of compounds 19 can be coupled with compounds of Formula 17 as illustrated in Scheme 1 to afford intermediates 20. In the same pot, suitable carboxylic acids can be coupled to the sulfonamide group of compounds of Formula 20 using coupling reagents, but not limited to, PyBOP, DCC, EDC, HBTU, or TBTU at a number of conditions that are routine for those skilled in the art of organic synthesis, to yield acylsulfonamides of Formula 21.
Alternatively, compounds of Formula 25 can be prepared by procedures illustrated in Scheme 5 by similar sequential coupling reactions. Compounds of Formula 17 can undergo coupling reactions with an amine functional group of compounds 22 as shown Scheme 1 to give intermediates 23. An ester group of Formula 23 can be saponificated using aqueous based, such as Cs2CO3, K2CO3, LiOH or NaOH, at a number of conditions that are routine for those skilled in the art of organic synthesis to generated compounds of Formula 24. Subsequent coupling reactions of acids 24 with suitable sulfonamides using coupling reagents at a number of conditions that are routine for those skilled in the art of organic synthesis to afford reverse acylsulfonamides of Formula 25.
Exemplary method for preparing compounds of Formula 28, wherein the N1 position of indole and the amide NH is tethered to form rings, is described in Scheme 6 and proceeds from compounds of Formula 26. Optionally substituted di-bromo alkanes 27 can be used to react with indole amides 26. The cyclization may be accomplished with a variety of bases, but not limited to, DBU, Et3N, DIPEA, Cs2CO3, K2CO3, NaH, or t-BuONa in a suitable solvent such as DMF, toluene, THF, DME, CH3CN, 1,4-dioxane or the like, to afford compounds of Formula 28 at a number of conditions that are routine for those skilled in the art of organic synthesis. Compounds of Formula 28 can be employed to subsequent reactions as depicted in above Schemes.
An alternate route to substituted tricyclic indole amides is shown in Scheme 7 and described here. The tricyclic amide intermediates of Formula 30 can be prepared by alkylation of the indole NH of ester 14 with optionally substituted cyclic sulfamidates 29 followed by cyclization upon removal of the Boc-protecting group (see, for example, Richter H. G. F. Bioorg. Med. Chem. Lett. 2010, 5713). The size and stereochemistry of the newly formed cyclic amide can be controlled by size and preset stereo-configuration of the reagent 29. The NH group of Formula 30 can undergo alkylation reactions with compounds of Formula 31, wherein X is Cl, Br, I, OMs, or OTs with a base such as NaH, K2CO3, Cs2CO3, Et3N, or DIPEA in a suitable solvent such as DMF, THF, ether, DME, or the like, to give compounds of Formula 28. Corresponding compounds of Formulae 32 and 33 can be prepared from the ester 28 by saponification and coupling of sulfonamides to the carboxylic acid functional group of compounds 32 as described in Scheme 5. Alternatively, a variety of aryl or heteroaryl halides of Formula 34, wherein X is Br, I, or OTf can be coupled to the NH group of Formula 30 in the presence of a catalytic Pd species, such as Pd(OAc)2, Pd2(dba)3 and a suitable ligand such as Xantphos and a base such as Na2CO3, Cs2CO3, or K2CO3 to generate compounds of Formula 35. Same saponification and coupling of sulfonamide coupling protocols described above can also be applied to prepare corresponding compounds of Formulae 36 and 37.
In some embodiments, compounds of Formula 39 containing tetrazole moiety can be generated by the procedure depicted in Scheme 8. A nitrile group of compounds 38 can undergo cyclization reaction with NaN3 in the presence salt such as NH3Cl, Et3N—HCl or catalytic amount of I2, AlCl3 or TMSCl in a suitable solvent such as DMF, PhNO2 or NMP at a number of conditions that are routine for those skilled in the art of organic synthesis to give tetrazoles of Formula 39.
The NH group of Formula 30 can undergo cross-coupling reactions with a variety of aryl or heteroaryl halides of Formula 40, wherein X is Br, I. or OTf in the presence of a catalytic Pd species, such as Pd(OAc)2, Pd2(dba)3 and a suitable ligand such as Xantphos and a base such as Na2CO3, Cs2CO3, or K2CO3 to generate compounds of Formula 22. Alternatively, compounds of Formula 30 can be produced using the Ullman coupling conditions in the presence of CuI and a suitable ligand such as (trans)-1,2-N,N′-dimethylaminocyclohexane or L-Proline and a base such as Cs2CO3, K2CO3 or K2PO4 in a suitable solvent such as toluene or DMF. The R7 and Rw of Formula 21 and 22 can be further elaborated such as saponification, substitution, alkylation of NH or OH, halogenation, amidation and construction of heterocycles under a number of functional group modification conditions that are routine for those skilled in the art of organic synthesis.
The following abbreviations are employed in the Examples and elsewhere herein:
The following Examples are offered as illustrative as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical symbols have their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the Schemes and other methods disclosed herein or may be prepared using same.
General Coupling Procedure A:
A mixture of lactam (1.0 eq), bromide (2.0 eq). Pd2(dba)3 (0.1 eq), Xantphos (0.2 eq), and Cs2CO3 (2.5 eq) 1,4-Dioxane (1 mL) was sparged with Ar gas for 5 minutes. The reaction mixture was sealed and heated to 110° C. for 18 h. The reaction mixture was cooled to ambient temperature, poured to DCM/water (10 mL, 1:1). The organic layer was separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase HPLC or flash chromatography.
General Coupling Procedure B:
A mixture of lactam (1.0 eq), bromide (2.0 eq), CuI (0.5 eq), (trans)-1,2-N,N′-dimethylaminocyclohexane (1.0 eq), and K2CO3 (2.5 eq) in toluene (1 mL) was sparged with Ar gas for 5 min. The reaction mixture was sealed and heated to 110° C. for 18 h. Same work up and purification protocols described in general coupling procedure A were followed to obtain a desire product.
General Coupling Procedure C:
A mixture of lactam (1.0 eq), bromide (2.0 eq), CuI (0.5 eq), (trans)-1,2-N,N′-dimethylaminocyclohexane (1.0 eq), and K3PO4 (2.5 eq) in DMF (1 mL) was sparged with Ar gas 5 minutes. The reaction mixture was sealed and heated to 120° C. for 18 h. Same work up and purification protocols described in general coupling procedure A were followed to obtain a desire product.
General Saponification Procedure D:
To a solution of ester in a mixture of THF, MeOH, and H2O (3 mL, 0.5 mL, 0.5 mL), was added LiOH (5 mg). The reaction was heated to 50° C. for 3 h then cooled to ambient temperature. The crude reaction mixture was concentrated in vacuo, and the residue was purified by reverse phase HPLC.
General Peptide Coupling Procedure E:
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol) and HATU (8 mg, 0.021 mmol) in DMF (1 mL) was added diisopropylethylamine (5 mg, 0.039 mmol), and the reaction was stirred at room temperature for 15 min. The appropriate amine was added, and the reaction was stirred at room temperature until complete by LCMS. Same work up and purification protocols described in general coupling procedure A were followed to obtain a desire product.
General Procedure F: Headpiece Bromination & Alkylation
To a solution of indole or indazole (0.28 mmol) in DMF (2 mL) was added NBS (51 mg, 0.28 mmol) at 0° C., and the reaction was stirred 1 h. The reaction as diluted into DCM/H2O (20 mL, 1:1), the layers separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was dissolved in DMF (2 mL), sodium hydride was added (14 mg, 0.34 mmol), and the reaction was allowed to stir 5 min at room temperature. Alkyl iodide (0.34 mmol) was added and the reaction was allowed to stir for 1 h. The reaction was diluted with DCM (10 mL), quenched with H2O (10 mL), the layers separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were concentrated in vacuo. The crude residue was purified by flash chromatography.
General Procedure G: Headpiece Alkylation
To a solution of substituted indole/indazole or naphthoic acid/quinolone carboxylic acid (0.20 mmol) in DMF (2 mL) was added NaH (10 mg, 0.24 mmol) at room temperature and stirred for 5 min at room temperature. Alkyl iodide (0.24 mmol) was added, and the reaction was stirred for 1 h. The work up described in general coupling procedure A was followed. The crude residue was purified by flash chromatography.
General Procedure H: Alkylation of Indole Hydroxy Group
A mixture of hydroxyl-indole (1.0 eq), Cs2CO3 (3.0 eq) and the appropriate electrophile in DMF (0.05 M) was heated to 60 to 90° C. until complete by LCMS. The work up described in general coupling procedure A was followed. The crude residue was purified by flash chromatography.
General Procedure I: Alkylation of Indole Nitrogen After Coupling to Tricyclic Core
A mixture of NH-indole (1.0 eq), Cs2CO3 (3.0 eq) and the appropriate electrophile in DMF (0.05 M) was heated to 60 to 90° C. until complete by LCMS. The work up described in general coupling procedure A was followed. The crude residue was purified by flash chromatography.
General Procedure J: Mesylation and SN2 Displacement of 2-Hydroxymethyl Pyrimidine
To a solution of hydroxymethyl-pyrimidine (1.0 eq) in DCM (0.03 M) was added DIPEA (5.0 eq) followed by mesyl chloride (3.0 eq). The reaction mixture was stirred at RT for 2 h then concentrated in vacuo. The residue was dissolved in DMF (0.05 M), and DIPEA (5.0 eq) and the appropriate amine (5-10 eq) were added in sequence. The reaction mixture was stirred from 25 to 50° C. until complete by LCMS. The work up described in general coupling procedure A was followed. The crude reaction mixture was used for subsequent saponification without further purification.
To a stirring mixture of 2-bromo-3-chloroaniline (20 mmol) in 1 M HCl (25 mL) and water (5 mL) at 0° C. was added NaNO2 (1.38 g, 20 mmol) in water (20 mL), CH3COONa (9.23 g, 112 mmol) in water (25 mL) and ethyl 2-oxocyclopentane carboxylate (3.0 mL, 20 mmol) in sequence. The reaction mixture was stirred for 15 min at 0° C. then warmed to 20° C. over 2 h and extracted with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a red oil in 7.1 g (90% crude).
To a solution of 5-(2-(2-bromo-3-chlorophenyl)hydrazono)-6-ethoxy-6-oxohexanoic acid (7.1 g, 18 mmol) in EtOH (30 mL) was added conc. H2SO4 (7.5 mL), slowly. The reaction mixture was refluxed for 1.5 h. The reaction was quenched by pouring into ice then extracted with CH2Cl2. The combined organic layer was washed with sat. NaHCO3, water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hex/EtOAc 25% gradient) to give the title compound as an off-white solid in 4.4 g (11 mmol). MS (ES) 402.0 (M+H).
To a solution of ethyl 7-bromo-6-chloro-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (1.9 g, 4.8 mmol) in THF (20 mmol) was added BH3 in THF (20 mL, 20 mmol) at 20° C. The reaction mixture was stirred for 15 h at 20° C. and quenched by addition of MeOH then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient 0-50%) to give the title compound as a white solid (1.4 g, 3.9 mmol). MS (ES) 360.1 (M+H).
To a solution of ethyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (101 mg, 0.28 mmol), PPh3 (110 mg, 0.51 mmol) and 3,5-diMe-4-Cl-phenol (81 mg, 0.52 mmol) in THF (3.5 mL) was added Dt-BuAD (99 mg, 0.51 mmol) at 20° C. The reaction mixture was stirred for 15 h at 20° C. then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient 0-10%) to give the title compound (105 mg, 0.21 mmol) as a colorless oil. MS (ES) 498.0 (M+H).
To a solution of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (319 mg, 0.64 mmol) in dioxane (3.0 ml) and water (2.0 ml) at 20 was added 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (168 mg, 0.71 mmol). Pd(PPh3)4 (37 mg, 0.032 mmol) and K2CO3 (267 mg, 1.94 mmol). The mixture was degassed then heated to 125° C. in Biotage Initiator for 40 min. The reaction was quenched by addition of water, extracted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient 0-15%) to give the title compound (238 mg, 0.45 mmol) as a white solid. MS (ES) 528.2 (M+H).
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (360 mg, 0.68 mmol) in anhydrous DMF (2 mL) was added NaH (60%) (25 mg, 0.70 mmol) at 0° C. and stirred for 3 min. tert-Butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.70 mmol) was added. The reaction mixture was stirred in the ice bath for 20 min and then at RT for overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (2×30 mL), dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/acetone=80:20) to give the title compound (305 mg, 65%). MS (ES) 686.3 (M+H), Rf=1.29.
To a solution of ethyl (R)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (218 mg, 0.32 mol) in anhydrous DCM (5.0 mL) at 0° C. was added TFA (1.5 mL) dropwise. The reaction mixture was warmed to RT and stirred for 2 h then concentrated in vacuo. The residue was dissolved in anhydrous ethanol (10 mL) then anhydrous K2CO3 (829 mg, 1.92 mmols) was added. The reaction mixture was stirred at RT for overnight then diluted with ethyl acetate (60 mL) and washed with brine (2×30 mL). The organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/methanol=0-10% gradient) to give the title compound (150 mg, 87%). MS (ES) 539.5 (M+H), Rf=0.95.
The title compound (210 mg, 52%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (300 mg, 0.55 mmol), ethyl 7-bromo-1H-indole-2-carboxylate (300 mg, 1.10 mmol), copper iodide (50 mg, 0.26 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (80 mg, 0.56 mmol), and K2CO3 (250 mg, 1.81 mmol). MS (ES) 726.3 (M+H).
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (360 mg, 0.683 mol) in anhydrous DMF (2 mL) was added NaH (60%) (25 mg, 0.62 mol) at 0° C. and stirred for 3 min. tert-Butyl 2-oxo-1,3-oxazinane-3-carboxylate was added. The reaction mixture was stirred in the ice bath for 20 min then at RT overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (2×30 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, eluent 20% ethyl acetate in hexanes) to give the title compound (305 mg, 65%). 1H NMR: δ 7.58 (d, J=10.7 Hz, 1H), 7.23 (d, J=10.7 Hz, 1H), 6.64 (s, 2H), 4.42-4.35 (m, 3H), 4.32-4.24 (m, 1H), 4.18-4.08 (m, 1H), 3.98 (t, J=7.5 Hz, 2H), 3.88 (s, 3H), 3.24 (t, J=9.0 Hz, 2H), 2.76 (q, J=7.0 Hz, 2H), 2.34 (s, 6H), 2.13 (t, J=7.0 Hz, 2H), 2.09 (s, 3H), 2.03 (s, 3H), 1.48 (t, J=7.0 Hz, 2H), 1.43 (t, J=9.0 Hz, 3H), 1.42 (s, 9H); 13C NMR: (125 MHz in CDCl3) δ 162.3, 156.7, 155.6, 146.4, 138.0, 137.2, 136.9, 134.2, 126.8, 126.1, 126.0, 125.0, 121.7, 120.9, 116.4, 114.4, 113.5, 78.9, 67.4, 60.7, 42.8, 37.9, 36.2, 31.2, 30.5, 28.3, 21.8, 20.9, 14.3, 12.3, 10.3; LCMS: RT=2.320 min; >98% purity at 215 nm and 254 nm; MS (ES) 685.0 (M+H).
To a solution of ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (218 mg, 0.32 mol) in anhydrous CH2Cl2 at 0° C. was added TFA (1.5 mL) dropwise. The reaction mixture was warmed to RT, stirred for 2 h then concentrated in vacuo. The residue was dissolved in anhydrous ethanol (10 mL) then anhydrous K2CO3 (829 mg, 1.92 mmols) was added. The reaction mixture was stirred at RT for overnight. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with brine (2×30 mL). The organic layers were dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, CH2Cl2/methanol=0-10% gradient) to give the title compound (150 mg, 87%). 1H NMR: (500 MHz in CDCl3) δ□ 7.62 (d, J=10.7 Hz, 2H), 7.25 (d, J=10.7 Hz, 2H), 6.65 (s, 2H), 6.23 (t, J=7.5 Hz, 1H), 4.06-3.93 (m, 4H), 3.90 (s, 3H), 3.22-3.15 (m, 4H), 2.35 (s, 6H), 2.20 (quint., J=8.7 Hz, 2H), 2.06 (s, 3H), 2.04 (s, 3H), 1.82-1.66 (m, 2H); 13C NMR: (125 MHz in CDCl3) δ 166.4, 156.8, 145.8, 138.1, 136.9, 135.8, 132.9, 131.6, 126.7, 125.9, 121.7, 121.2, 120.8, 115.1, 114.5, 113.5, 67.4, 41.0, 38.5 36.1, 30.2, 30.1, 20.9, 20.4, 12.1, 10.0; LCMS: RT=1.896 min., >98% purity at 215 nm and 254 nm; MS (ES) 539.0 (M+H).
The title compound (66 mg, 76%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (70 mg, 0.13 mmol, 1.0 eq), methyl 3-bromobenzoate (55 mg, 0.26 mmol, 2.0 eq), CuI (10 mg, 0.052 mmol, 0.40 eq), rac-N,N-dimethylcyclohexane-1,2-diamine (15 mg, 0.105 mmol, 0.81 eq), and K2CO3 (55 mg, 0.40 mmol, 3.0 eq). 1H NMR: (500 MHz in CDCl3) δ 7.98-7.94 (m, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.24 (d, J=8.5 Hz, 1H), 6.61 (s, 2H), 4.16-4.06 (m, 2H), 3.96 (t, J=6.0, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.76-3.67 (m, 2H), 3.16 (oct, J=7.5 Hz, 2H), 2.29 (s, 6H), 2.23-2.16 (m, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 1.92-1.80 (m, 2H); 13C NMR: (125 MHz in CDCl3) δ 166.2, 164.0, 156.8, 146.0, 142.3, 137.7, 136.9, 135.2, 133.0, 132.0, 131.4, 130.7, 129.3, 127.8, 126.7, 126.6, 125.9, 121.5, 121.2, 120.7, 115.5, 114.5, 113.2, 67.3, 52.2, 48.2, 40.7, 36.2, 30.2, 29.5, 20.8, 20.6, 12.3, 10.0; LCMS: RT=2.092 min, >98% purity at 215 nm and 254 nm; MS (ES) 673.0 (M+H).
To a solution of methyl 6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylate (40 mg, 0.055 mmol) in THF (0.5 mL) was added NBS (10 mg, 0.058 mmol) then stirred for 15 h at RT. LiOH (0.14 ml, 0.28 mmol, 2N) was added, and the mixture was heated to 70° C. for additional 6 h. The reaction was concentrated in vacuo, and the crude residue was dissolved in DMSO (1 mL) and filtered. The DMSO solution was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-90% CH3CN, 0.10% TFA) to yield the title compound (28 mg, 65%) as an off-white solid. MS (ES) 790.2 (M+H).
The title compound was prepared (22 mg, 0.029 mmol) as a white solid according to procedures described in Example 2 Step D substituting NBS with NCS (7.4 mg, 0.055 mmol). MS (ES) 746.2 (M+H).
The title compound (6.2 mg, 16%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-4-carboxylate (19 mg, 0.070 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.288 min, MS (ES) 714.1 (M+H).
The title compound (3.7 mg, 9.3%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-7-carboxylate (25 mg, 0.092 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.360 min, MS (ES) 714.1 (M+H).
The title compound (13 mg, 34%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), 7-bromo-1-methyl-1H-indole-3-carbonitrile (30 mg, 0.14 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (60 mg, 0.19 mmol). LCMS: RT=1.555 min, MS (ES) 693.1 (M+H).
To a solution of 6-bromo-1H-benzo[d]imidazole-4-carboxylic acid (200 mg, 0.84 mmol) in THF (5 mL) and MeOH (1 mL) at 0° C. was added trimethylsilyldiazomethane in Et2O (2.0 M, 0.63 mL, 1.3 mmol). The reaction was stirred for 1 h at 0° C. then warmed to RT. The reaction was quenched by addition of AcOH dropwise and concentrated in vacuo. The crude residue was diluted with DCM (20 mL) and washed with brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. To a solution of the crude residue in DMF (2 mL) was added NaH (30 mg, 1.25 mmol) at RT and stirred for 30 min. Methyl iodide (120 mg, 0.84 mmol) was added, and the reaction was stirred for 4 h at RT. The reaction mixture was cooled to −78° C. and quenched with MeOH. The mixture was diluted into DCM/H2O (20 mL, 1:1), the organic layer separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 20-80% MeCN 0.1% TFA) to afford the title compound (83 mg, 37%).
The title compound (3 mg, 8%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 6-bromo-1-methyl-1H-benzo[d]imidazole-4-carboxylate (35 mg, 0.13 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.048 min, MS (ES) 713.0 (M+H).
The title compound (67 mg, 76%) was prepared following General coupling procedure A using methyl 2-chloro-6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methy)isonicotinate (72 mg, 0.1 mmol), tert-butyl piperazine-1-carboxylate (22 mg, 0.12 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), Xantphos (3.5 mg, 0.006 mmol), and Cs2CO3 (49 mg, 0.15 mmol) followed by saponification using General Procedure D. LCMS. RT=2.025 min, MS (ES) 858.3 (M+H).
To a solution of tert-butyl 4-(6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-4-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate in CH2Cl2 (1 mL) was added TFA (0.5 mL) and the mixture was stirred at room temperature for 12 h. The reaction mixture was extracted in CH2Cl2 (3×15 mL), dried (anhyd. Na2SO4) and concentrated in vacuo to give the crude title compound. MS (ES) 772.2 (M+H).
To a solution of methyl 2-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(piperazin-1-yl)isonicotinate (15 mg, 0.02 mmol), in CH2Cl2 (1 mL) at room temperature was added triethylamine (6 μL, 0.04 mmol) followed by furan-2-carbonyl chloride (4 μL, 0.04 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (2 mL) and extracted in CH2Cl2 (3×5 mL), dried and concentrated in vacuo. The residue was dissolved in THF, MeOH, and H2O (3 mL, 0.5 mL, 0.5 mL), and LiOH (5 mg) was added and the reaction was heated to 50° C. for 3 h. The crude was purified by reverse phase HPLC (Phenomenex Gemini C18. H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (16 mg, 94%). LCMS: RT=1.785 min, MS (ES) 852.4 (M+H).
Title compound (54 mg, 63%) was prepared according to General saponification procedure D using methyl 2-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(piperazin-1-yl)isonicotinate (87 mg, 0.11 mmol). LCMS: RT=1.605 min, MS (ES) 758.3 (M+H).
To a solution of methyl 4-amino-1H-indole-6-carboxylate (100 mg, 0.526 mmol) in DMF (3 mL) was added NaH (63 mg, 1.6 mmol) and stirred at RT for 15 min. 2-Bromo-N,N-dimethylethan-1-amine (96 mg, 0.631 mmol) was added, and the resulting mixture was stirred for 30 min then quenched by TFA (0.081 mL, 1.0 mmol). The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 0-50% MeCN 0.1% TFA) to give the title compound (50 mg, 36%) product. MS (ES) 262.3 (M+H).
To a solution of 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (70 mg, 0.14 mmol), methyl 4-amino-1-(2-(dimethylamino)ethyl)-1H-indole-6-carboxylate (40 mg, 0.15 mmol) and DMAP (34 mg, 0.28 mmol) in DCM (2 mL) was added EDC (54 mg, 0.28 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 0-50% MeCN 0.1% TFA) to give the title compound (24 mg, 23%). LCMS: RT=1.695 min. MS (ES) 742.8 (M+H).
To a solution of methyl 4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1-(2-(dimethylamino)ethyl)-1H-indole-6-carboxylate (24 mg, 0.032 mmol) and 1,3-dibromopropane (9.8 μl, 0.097 mmol) in DMF (0.5 mL) was added Cs2CO3 (53 mg, 0.16 mmol) then stirred at rt for 20 h. The reaction mixture was filtered, and the filterate was concentrated. The residue was dissolved in THF (1 mL) and LiOH (0.2 mL, 2N) and stirred at 60° C. overnight. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 30-80% MeCN 0.1% TFA) to give the title compound (9 mg, 36%). LCMS: RT=1.671 min, MS (ES) 768.7 (M+H).
To a solution of methyl 6-bromo-1H-indazole-4-carboxylate (100 mg, 0.392 mmol) in DMF (5 mL) was added NaH (30 mg, 1.25 mmol) at RT. The reaction mixture was stirred for 30 min, followed by addition of 4-(2-bromoethyl)morpholine (120 mg, 0.619 mmol). After 4 h, the reaction was quenched with water then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 20-75% MeCN 0.1% TFA) to separate the regioisomeric indazole intermediates. The desire region-isomer was dissolved in THF (5 mL) and MeOH (1 mL) and trimethylsilyldiazomethane (2.0 M in Et2O, 0.25 mL, 0.50 mmol) was added. The reaction was stirred for 30 min at RT then quenched by addition of AcOH dropwise and concentrated in vacuo to afford the title compound (21 mg, 15%).
The title compound (4.6 mg, 10%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 6-bromo-2-(2-morpholinoethyl)-2H-indazole-4-carboxylate (20 mg, 0.054 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by, saponification using General Procedure D. LCMS: RT=1.048 min, MS (ES) 812.1 (M+H).
The title compound (2.7 mg, 7%) was prepared following General coupling procedure A using 8-chloro-1 l-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 7-bromo-1-methyl-1H-indazole-3-carboxylate (12 mg, 0.045 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.843 min, MS (ES) 712.7 (M+H).
The title compound (34 mg, 24%) was prepared following the same procedure as Example 12, Step A.
The title compound (7.4 mg, 17%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 6-bromo-1-(2-morpholinoethyl)-1H-indazole-4-carboxylate (34 mg, 0.092 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.661 min, MS (ES) 811.8 (M+H).
To a solution of 7-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-3-carbonitrile (10 mg, 0.014 mmol) in DMF (1 mL) was added NaN3 (10 mg, 0.15 mmol) and ammonium chloride (10 mg, 0.19 mmol). The reaction was capped and heated to 130° C. for 72 h then cooled to RT. The work up described in general coupling procedure A was followed then purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (2 mg, 19%). LCMS: RT=1.980 min, MS (ES) 735.9 (M+H).
The title compound (6.1 mg, 16%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 7-bromo-2-methyl-2H-indazole-3-carboxylate (12 mg, 0.045 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (29 mg, 0.11 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.463 min, MS (ES) 713.0 (M+H).
To a solution of methyl 2-((8-chloro-1l-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(piperazin-1-yl)isonicotinate (15 mg, 0.02 mmol), in CH2Cl2 (0 mL) at RT was added triethylamine (6 μL, 0.04 mmol) followed by acetyl chloride (3 μL 0.04 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (2 mL) and extracted in CH2Cl2 (3×5 mL), dried and evaporated. The crude material was subjected to saponification conditions following General Procedure D followed by purification by reverse phase HPLC (Phenomenex Gemini C18. H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (14 mg, 88%). LCMS: RT=1.721 min, MS (ES) 800.4 (M+H).
The title compound (2 mg, 5%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 5-bromo-2,3-dihydrobenzofuran-7-carboxylate (30 mg, 0.12 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (29 mg, 0.11 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.825 min, MS (ES) 700.8 (M+H).
The title compound (53% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-ethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-bromoquinoline-8-carboxylate followed by saponification using General Procedure D. MS (ES) 724.3 (M+H).
To a solution of (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-ethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 46 mmol) in anhydrous DMF (2 mL) was added NaH (60%) (3 mg, 78 mmol) at 0° C. under N2 atmosphere and stirred for 10 min. Methyl 6-(bromomethyl)nicotinate (1.7 eq.) was added to the reaction mixture and stirred for 10 min at 0° C. and 1 h at RT. The reaction mixture was diluted with ethyl acetate (20 mL), washed with brine (2×10 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was subjected to saponification conditions following General Procedure D followed by purification by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 50-95% MeCN 0.1% TFA) to give the title compound (68% yield). MS (ES) 688.3 (M+H) Rf=0.79.
The title compound (52% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-ethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromobenzoate followed by saponification using General Procedure D. MS (ES) 673.2 (M+H).
The title compound (56 mg, 77%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (54 mg, 0.1 mmol), methyl 2-(5-bromo-1-methyl-1H-indol-3-yl)acetate (34 mg, 0.12 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), Xantphos (3.5 mg, 0.006 mmol), and Cs2CO3 (49 mg, 0.15 mmol) followed by saponification using General Procedure D. LCMS: RT=1.756 min, MS (ES) 726.3 (M+H).
The title compound (85% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-ethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromobenzoate followed by saponification using General Procedure D. MS (ES) 673.2 (M+H); 1H-NMR (CDCl3) δ 8.14 (d, 2H, J=8 Hz), 8.10 (m, 1H), 7.47 (d, 1H, J=8 Hz) 7.75 (m, 1H), 7.32-7.28 (m, 1H), 6.65 (s, 2H), 4.11 (tr, 2H, J=8 Hz), 3.97 (multiple s, m, 5H), 3.52-3.34 (m, 2H), 2.33 (s, 6H), 2.30-2.09 (overlapped multiple s, tr, 10H), 1.64 (m, 2H), 0.57 (tr, 3H, J=8 Hz).
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-1H-indole-2-carboxylate (1.25 g, 2.37 mmol) in anhydrous acetonitrile (20 mL) was added cesium carbonate (1.5 g, 4.74 mmol) follow by tert-butyl (R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.8 mmols). The reaction mixture was stirred at 80° C. for overnight. Additional cesium carbonate (0.5 eq) and tert-butyl (R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.5 eq) were added to the mixture and the reaction was heated for additional 6 h at 80° C. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (100 mL). The solution was washed with brine (3×50 mL), dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in anhydrous DCM (30 mL) and cooled to 0° C. then TFA (10 eq) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to dryness then re-dissolved in anhydrous EtOH (20 mL). Anhydrous K2CO3 (15 eq.) was added and the reaction mixture was stirred at RT for 2 h then concentrated to ⅓ of original volume and diluted with ethyl acetate (100 mL). The solution was washed with brine (3×50 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf. DCM/methanol=0-5% gradient) to give the title compound (80% for 3 steps). MS (ES) 553.2 (M+H), Rf=0.84; 1H-NMR (CDCl3) δ 7.66 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 6.65 (s, 2H), 5.77 (m, 1H), 4.03 (tr, 2H, J=8 Hz), 3.99 (s, 3H), 3.52-3.50 (m, 1H), 3.49-3.38 (m, 1H), 3.38-3.34 (m, 2H), 2.35 (s, 6H), 2.19 (tr, 2H, J=8 Hz), 2.09 (2s, 6H), 1.59 (m, 2H), 1.26 (tr, 3H, J=8 Hz).
The title compound was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one and methyl 7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate followed by saponification using General Procedure D. MS (ES) 717.2 (M+H).
The title compound (45% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 8-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate followed by saponification using General Procedure D. MS (ES) 717.2 (M+H).
To a solution of methyl 2-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(piperazin-1-yl)isonicotinate (15 mg, 0.02 mmol), in CH2Cl (1 mL) at RT was added Et3N (6 μL, 0.04 mmol) followed by 5-methylfuran-2-sulfonyl chloride (6 μL, 0.04 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (2 mL) and extracted in CH2Cl2 (3×5 mL), dried and concentrated. The crude material was subjected to saponification conditions following General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (13 mg, 69%). LCMS: RT=2.019 min, MS (ES) 902.3 (M+H).
The title compound (28 mg, 22%) was prepared following General Procedure G using methyl 4-bromo-1H-indazole-6-carboxylate (100 mg, 0.393 mmol), NaH (15 mg, 0.625 mmol), and 2-bromo-N,N-dimethylethan-1-amine (120 mg, 0.515 mmol).
The title compound (22 mg, 51%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 4-bromo-2-(2-(dimethylamino)ethyl)-2H-indazole-6-carboxylate (20 mg, 0.061 mmol), Pd2(dba)3 (5 mg, 0.0054 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D using LiOH (5 mg, 0.21 mmol). LCMS: RT=1.631 min, MS (ES) 770.2 (M+H), 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.24 (d, J=1.2 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.48 (d, J=1.1 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 6.73 (s, 2H), 4.98 (t, J=6.7 Hz, 2H), 4.13 (t, J=6.8 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 3.78 (s, 3H), 3.76-3.74 (m, 4H), 3.09-3.00 (m, 2H), 2.77 (s, 3H), 2.76 (s, 3H), 2.24 (s, 6H), 2.13-1.99 (m, 5H), 1.93 (s, 3H), 1.75 (quint, J=8.0 Hz, 2H).
The title compound (45% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-ethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-bromo-1-methyl-1H-indole-4-carboxylate followed by saponification using General Procedure D. MS (ES) 727.2 (M+H).
The title compound (39 mg, 30%) was prepared following the procedure described Example 12, Step A using methyl 6-bromo-1H-indazole-4-carboxylate (100 mg, 0.392 mmol), NaH (30 mg, 1.25 mmol), 2-bromo-N,N-dimethylethan-1-amine HBr salt (130 mg, 0.56 mmol), and trimethylsilyldiazomethane (2.0 M in Et2O, 0.1 mL, 0.2 mmol).
The title compound (17 mg, 40%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 6-bromo-1-(2-(dimethylamino)ethyl)-1H-indazole-4-carboxylate (20 mg, 0.061 mmol), Pd2(dba)3 (5 mg, 0.0054 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D using LiOH (5 mg, 0.21 mmol). LCMS: RT=1.656 min, MS (ES) 770.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=0.8 Hz, 1H), 8.25 (t, J=1.3 Hz, 1H), 7.90 (d, J=1.7 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.74 (s, 2H), 4.97 (t, J=6.7 Hz, 2H), 4.08 (t, J=8.0 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.83-3.70 (m, 5H), 3.62-3.59 (m, 2H), 3.06 (t, J=8.0 Hz, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2.22 (s, 6H), 2.15-2.00 (m, 5H), 1.96-1.83 (m, 5H).
To a solution of methyl 6-bromo-1H-indole-4-carboxylate (200 mg, 0.79 mmol) in DMF (5 mL) was added NaH (38 mg, 0.95 mmol) and stirred at rt for 15 min. (2-(Chloromethoxy)ethyl)trimethylsilane (197 mg, 1.2 mmol) was added, and the resulting mixture was stirred for additional 30 min. The reaction was quenched by addition of MeOH (1 mL) then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-25% gradient) to give the title compound (270 mg, 89%) as a colorless oil. LCMS: RT=1.939 min, MS (ES) 384.1 (M+H)
The title compound (187 mg, 80%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (150 mg, 0.278 mmol), methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-4-carboxylate (128 mg, 0.334 mmol), Pd2(dba)3 (5 mg, 0.0054 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (181 mg, 0.556 mmol). LCMS: RT=2.461 min, MS (ES) 842.3 (M+H).
A mixture of methyl 6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-4-carboxylate (170 mg, 0.202 mmol), TBAF (2.0 ml, 2.0 mmol) was heated to 100° C. under microwave irradiation in Biotage Initiator for 20 min. The reaction was quenched by addition of H2O (5 mL) then extracted with DCM (10 mL×2). The combined organic solution was concentrated and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to give the title compound (80 mg, 56%). LCMS: RT=2.065 min, MS (ES) 712.3 (M+H).
To a solution of methyl 6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-4-carboxylate (20 mg, 0.028 mmol) in DMF (0.5 mL) was added NaH (4.5 mg, 0.11 mmol) then stirred for 20 min. 4-(2-Bromoethyl)morpholine (16 mg, 0.084 mmol) was added, and the resulting mixture was stirred at rt for 20 h. The reaction was quenched by MeOH (0.5 mL), acidified with TFA and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 30-80% MeCN 0.1% TFA) to give the title compound (9.8 mg, 43%). LCMS: RT=1.670 min, MS (ES) 811.3 (M+H).
4-(8-Chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-(methylsulfonyl)-1H-indole-6-carboxylic acid Step A. Preparation of methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carboxylate e
The title compounds were prepared according to procedures described in Example 31 Step A using methyl 4-bromo-1H-indole-6-carboxylate. MS (ES) 384.1 (M+H).
The title compound was prepared according to the procedure in Example 31 Step B substituting methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-4-carboxylate with methyl 4-bromo-14(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carboxylate. MS (ES) 842.3 (M+H).
The title compound (50 mg, 59%) was prepared according to the procedure in Example 31 Step C using methyl 4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carboxylate (100 mg, 0.12 mmol) and TBAF (0.593 mL, 0.593 mmol). LCMS: RT=2.056 min, MS (ES) 712.2 (M+H).
To a solution of methyl 4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-6-carboxylate (25 mg, 0.035 mmol) in DMF (1 mL) was added NaH (4.21 mg, 0.105 mmol) and stirred for 15 min. MsCl (8.20 μl, 0.11 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was concentrated and the residue was dissolved into THF (0.3 mL) and LiOH (0.2 mL, 2N) then stirred at 60° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 40-90% MeCN 0.1% TFA) to give the title compound (4 mg, 15%) as an off-white solid. LCMS: RT=1.979 min, MS (ES) 775.9 (M+H).
The title compound (42% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromobenzo[d][1,3]dioxole-5-carboxylate followed by saponification using General Procedure D. MS (ES) 703.2 (M+H).
To a solution of methyl 2-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(piperazin-1-yl)isonicotinate (15 mg, 0.02 mmol), in CH2Cl2 (1 mL) at room temperature was added triethylamine (6 μL, 0.04 mmol) followed by dimethylcarbamic chloride (4 μL, 0.04 mmol) then the mixture was stirred at RT for 1 h. The mixture was diluted with water (2 mL) and extracted in CH2Cl2 (3×5 mL), dried and concentrated. The crude material was subjected to saponification conditions following General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (11 mg, 66%). LCMS: RT=1.761 min, MS (ES) 829.3 (M+H).
The title compound (88% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromo-2-chlorobenzoate followed by saponification using General Procedure D. MS (ES) 693.2 (M+H).
The title compound (26 mg, 65%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 4-bromo-2-methyl-2H-indazole-6-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (5 mg, 0.0054 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D using LiOH (5 mg, 0.21 mmol). LCMS. RT=1.873 min, MS (ES) 713.1 (M+H).
To a solution of 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (50 mg, 0.1 mmol) in DMF (2 mL) were added methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (15 mg, 0.1 mmol), HBTU (76 mg, 0.2 mmol), triethylamine (42 μL, 0.3 mmol), and the mixture was stirred at RT for 10 h. Water (5 mL) was added to the mixture and extracted with CH2Cl2 (3×5 mL). The organic layer was dried (anhyd. Na2SO4) and concentrated. To the solution crude in DMF (3 mL) were added 1,3-dibromopropane (42 μL, 0.4 mmol) and Cs2CO3 (130 mg, 0.4 mmol). The mixture was stirred at 40° C. for 6 h, filtered, diluted with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The organic layer was dried (anhyd. Na2SO4) and concentrated in vacuo. The crude material was subjected to saponification conditions following General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (34 mg, 52%). LCMS: RT=2.088 min, MS (ES) 650.2 (M+H).
To a solution of methyl 2-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(piperazin-1-yl)isonicotinate (15 mg, 0.02 mmol), in CH2Cl2 (0 mL) at room temperature was added triethylamine (6 μL, 0.04 mmol) followed by 2-phenylethane-1-sulfonyl chloride (8 mg, 0.04 mmol) and the mixture was stirred at RT for 1 h. The mixture was diluted with water (2 mL) and extracted with CH2Cl2 (3×5 mL), dried and concentrated. The crude material was subjected to saponification conditions following General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (17 mg, 92%). LCMS: RT=1.959 min, MS (ES) 926.3 (M+H).
The title compound (44 mg, 39%) was prepared following the procedure described Example 12, Step A using methyl 6-bromo-1H-indazole-4-carboxylate (100 mg, 0.392 mmol) and ethyl bromide (85 mg, 0.78 mmoL).
The title compound (6 mg, 18%) was prepared following General Procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 6-bromo-1-ethyl-1H-indazole-4-carboxylate (20 mg, 0.071 mmol), Pd2(dba)3 (4 mg, 0.0044 mmol). Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS. RT=1.977 min, MS (ES) 727.2 (M+H).
The title compound (70 mg, 55%) was prepared following the procedure described Example 12, Step A using methyl 4-bromo-1H-indazole-6-carboxylate (100 mg, 0.393 mmol) and 2-bromo-N,N-dimethylethan-1-amine (120 mg, 0.515 mmol).
The title compound (26 mg, 60%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 4-bromo-1-(2-(dimethylamino)ethyl)-1H-indazole-6-carboxylate (20 mg, 0.061 mmol), Pd2(dba)3 (5 mg, 0.0054 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.666 min, MS (ES) 770.3 (M+H).
The title compound (48% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-ethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-bromo-1-methyl-1H-indole-7-carboxylate followed by saponification using General Procedure D. MS (ES) 726.2 (M+H).
The title compound (13 mg, 10%) was prepared following the procedure described Example 12, Step A using methyl 6-bromo-1H-indazole-4-carboxylate (100 mg, 0.392 mmol), sodium hydride (30 mg, 1.25 mmol), 2-bromo-N,N-dimethylethan-1-amine HBr salt (130 mg, 0.56 mmol).
The title compound (12 mg, 28%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 6-bromo-2-(2-(dimethylamino)ethyl)-2H-indazole-4-carboxylate (13 mg, 0.039 mmol), Pd2(dba)3 (5 mg, 0.0054 mmol). Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.662 min, MS (ES) 770.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.90-7.83 (m, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.73 (s, 2H), 5.03 (t, J=6.6 Hz, 2H), 4.04 (t, J=7.1 Hz, 2H), 3.96 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 3.69 (dt, J=25.3, 6.3 Hz, 4H), 3.06 (t, J=7.4 Hz, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2.22 (s, 6H), 2.08 (q, J=6.8 Hz, 2H), 2.02 (s, 3H), 1.91 (s, 3H), 1.79 (q, J=7.9, 7.3 Hz, 2H).
To a solution of 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (54 mg, 0.1 mmol) in DMF (2 mL) was added NaH (5 mg, 0.12 mmol) and the mixture was stirred at RT for 10 min. Methyl 2-(bromomethyl)isonicotinate (28 mg, 0.12 mmol, 1.2 eqv.) was added to the mixture followed by TBAI (37 mg, 0.1 mmol) and stirred for additional 2 h. The mixture was diluted with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was subjected to saponification conditions following General Procedure D using 2 M LiOH (1 mL) and purified by reverse phase HPLC (Phenomenex Gemini C18. H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (59 mg, 88%). LCMS: RT=1.849 min, MS (ES) 674.2 (M+H).
The title compound (154 mg, 93%) was prepared using the procedure described in Example 39 Step A using methyl 6-bromo-1H-indazole-4-carboxylate (110 mg, 0.43 mmol), (2-(chloromethoxy)ethyl)trimethylsilane (110 mg, 0.65 mmol), and sodium hydride (10 mg, 0.43 mmol) and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient).
The title compound was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylate (32 mg, 0.083 mmol), Pd2(dba)3 (8 mg, 0.0087 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (50 mg, 0.15 mmol).
Methyl 6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylate was dissolved in TBAF (1.0 M in THF, 3 mL). The reaction was irradiated in the microwave at 100° C. for 1 h. Water (0.5 mL) and LiOH (5 mg, 0.21 mmol) were added, and the reaction was heated to 50° C. for additional 1 h. The work up described in general coupling procedure A was followed then purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (8 mg, 200% two Steps). LCMS. RT=1.837 min, MS (ES) 699.3 (M+H).
The title compound (21 mg, 52%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 4-bromo-1-methyl-1H-indazole-6-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (5 mg, 0.0054 mmol), Xantphos (8 mg, 0.013 mmol), and CS2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.849 min, MS (ES) 713.2 (M+H), 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.58 (d, J=1.1 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 6.72 (s, 2H), 4.15 (s, 3H), 4.12 (t, J=6.0 Hz, 2H) 3.97 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 3.76 (t, J=3.8 Hz, 2H), 3.04 (d, J=8.0 Hz, 2H), 2.23 (s, 6H), 2.13-2.00 (m, 5H), 1.93 (s, 3H), 1.75 (m, 2H).
To a solution of 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (50 mg, 0.1 mmol) in DMF (2 mL) were added tert-butyl 6-amino-3,4-dihydroquinoline-1(2H)-carboxylate (25 mg, 0.1 mmol), HBTU (76 mg, 0.2 mmol), triethylamine (42 μL, 0.3 mmol), and the mixture was stirred at RT for 10 h. Water (5 mL) was added to the mixture and it was extracted in CH2Cl2 (3×5 mL). The organic layer was dried over Na2SO4 and concentrated. To the solution of crude in DMF (3 mL) were added 1,3-dibromopropane (42 μL, 0.4 mmol), Cs2CO3 (130 mg, 0.4 mmol), and the mixture was stirred at 40° C. for 6 h. The mixture was filtered, diluted with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The organic layer was dried over Na2SO4 and concentrated. The crude residue was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. The mixture was stirred at room temperature for 6 h. Saturated aqueous NaHCO3 (8 mL) was added to the mixture and extracted with DCM (3×5 mL). The organic layer was dried over Na2SO4, and concentrated. To a solution of crude in DMF (1 mL) was added NaH (5 mg, 0.12 mmol) and the mixture was stirred at room temperature for 10 min. Ethyl bromoacetate (14 μL. (0.12 mmol) was added to the mixture and stirred at RT for 2 h. The reaction mixture was quenched with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was subjected to saponification conditions following General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (15 mg, 21%). LCMS: RT=2.023 min, MS (ES) 728.2 (M+H).
The title compound (10 mg, 58%) was prepared following the procedure described Example 38 using methyl 2-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(piperazin-1-yl)isonicotinate (15 mg, 0.02 mmol) and cyclopropanesulfonyl chloride (6 μL, 0.04 mmol) followed by saponification conditions following General Procedure D. LCMS: RT=1.931 min, MS (ES) 862.3 (M+H).
The title compound (40% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate followed by saponification using General Procedure D. MS (ES) 713.2 (M+H).
To a solution of methyl 3-bromo-1H-indazole-6-carboxylate (0.27 mmol) in DMF (3 mL) was added sodium hydride (10 mg, 0.69 mmol), and the reaction was stirred 5 min at RT. 4-(2-Chloroethyl)morpholine (1.1 mmol) was added, and the reaction was stirred for additional 1 h. The reaction was diluted with EtOAc (10 mL), washed with H2O (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-40% gradient) to afford the title compound (76 mg, 75%).
A flame dried flask was charged with Pd2(dba)3 (1 mg, 0.5 mol %), Xantphos (2 mg, 1 mol %), cesium carbonate (27 mg, 0.084 mmol), 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (30 mg, 0.056 mmol), methyl 3-bromo-1-(2-morpholinoethyl)-1H-indazole-6-carboxylate (24 mg, 0.067 mmol), and 1,4-dioxane (1 mL). The reaction mixture was degassed for 10 min under argon and stirred for 16 h at 110° C. then concentrated in vacuo. The residue was filtered through silica pad with DCM/MeOH (3/1) then concentrated in vacuo. To a solution of crude methyl 3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-(2-morpholinoethyl)-1H-indazole-6-carboxylate (0.056 mmol) in mixture of methanol and dioxane (1 mL/2 mL) was added sodium hydroxide (0.2 mL, 2 M solution). The reaction mixture was stirred for 3 h at room temperature and then concentrated in vacuo. The residue was purified by reverse phase preparatory HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 5-95% CH3CN 0.1% TFA) to afford the title compound (17 mg, 36%). LCMS: RT=0.669 min (non polar method, >99%, ELSD); MS (ES) 812.2 [M+H]; 1H NMR (DMSO, 400 MHz) δ (ppm) 8.41 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (dd, J=8.4, 1.2 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 6.71 (s, 2H), 4.92-4.79 (m, 2H), 4.05 (t, J=6.0 Hz, 2H), 3.99-3.95 (m, 4H), 3.85 (t, J=6.0 Hz, 2H), 3.76 (s, 3H), 3.71-3.55 (m, 6H), 3.26-3.10 (m, 2H), 3.07 (t, J=6.8 Hz, 2H), 2.21 (s, 6H), 2.12-2.01 (m, 2H), 2.02 (s, 3H), 1.92 (s, 3H), 1.85-1.62 (m, 2H).
The title compound (40 mg, 87%) was prepared according to procedures described in Example 49 Step B by substituting 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one with (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol). LCMS: RT=0.697 min (non polar method, >99%, ELSD); MS (ES) 812.3 [M+H]; 1H NMR (DMSO, 400 MHz) δ (ppm) 8.41 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.72 (dd, J=8.4, 1.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.71 (s, 2H), 4.91-4.85 (m, 2H), 4.48-4.43 (m, 2H), 4.25-4.18 (m, 2H), 4.02-3.99 (m, 4H), 3.96-3.92 ((m, 1H), 3.77 (s, 3H), 3.75-3.51 (m, 4H), 3.39-3.16 (m, 4H), 3.23 (s, 6H), 2.10 (s, 1.5H), 2.10 (s, 1.5H), 2.10-1.97 (m, 2H), 1.89 (s, 1.5H), 1.02 (d, J=6.0 Hz, 3H).
The title compound (84% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromo-1-methyl-1H-indole-7-carboxylate followed by saponification using General Procedure D. MS (ES) 712.3 (M+H); 1H-NMR (CDCl3) δ 7.89 (d, 1H, J=8 Hz), 7.79 (d, 1H, J=8 Hz), 7.34 (d, 1H, J=8 Hz) 7.11 (m, 1H), 7.02 (m, 1H), 6.62 (s, 2H), 6.40 (m, 1H), 4.5 (m, 1H), 4.18 (tr, 2H, J=8 Hz), 4.02 (s, 3H), 3.97 (s, 3H), 3.90-3.88 (m, 2H), 3.52-3.36 (m, 2H), 2.33 (s, 6H), 2.30-2.09 (overlapped multiple s, tr, 8H), 1.28 (two d, 3H, J=8 Hz).
The title compound (84% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-1-methyl-1H-indole-4-carboxylate followed by saponification using General Procedure D. MS (ES) 712.3 (M+H); 1H-NMR (CDCl3) δ 7.95 (d, 1H, J=8 Hz), 7.75 (d, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz) 7.13 (m, 1H), 7.02 (m, 1H), 6.99 (m, 1H), 6.62 (s, 2H), 4.02 (s, 3H), 4.00 (tr, 2H, J=8 Hz), 3.78 (s, 3H), 3.90-3.88 (m, 1H), 3.52-3.35 (m, 2H), 2.33 (s, 6H), 2.30-2.18 (overlapped multiple s, tr, m, 10H), 1.28 (two d, 3H, J=8 Hz).
The title compound (6.0 mg, 18%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 6-bromo-1-methyl-1H-indazole-4-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0044 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=2.014 min, MS (ES) 713.2 (M+H).
The title compound (7.3 mg, 22%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 7-bromo-2-methyl-2H-indazole-3-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0044 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS RT=2.066 min, MS (ES) 713.2 (M+H).
The title compound (25 mg, 62%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one and methyl 7-bromo-1-methyl-1H-indole-4-carboxylate followed by saponification using General Procedure D. MS (ES) 712.3 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 7.73 (s, 1H), 7.70 (s, 1H), 7.44 (d, J=2.8 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.10 (dd, J=12.0, 8.0 Hz, 1H), 7.02 (d, J=3.2 Hz, 1H), 6.73 (s, 2H), 4.20-4.08 (m, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.75-3.68 (m, 1H), 3.53-3.45 (m, 1H), 3.16-3.08 (m, 1H), 2.99-2.91 (m, 1H), 2.25 (s, 6H), 2.15-2.03 (m, 2H), 2.05 (s, 1.5H), 2.00 (s, 1.5H), 1.94 (s, 1.5H), 1.89 (s, 1.5H), 1.8-1.6 (m, 2H).
The title compound (74 mg, 26%) was prepared following General Procedure G using methyl 6-bromo-1H-indazole-4-carboxylate (200 mg, 0.784 mmol). NaH (36 mg, 1.5 mmol), and 4-(2-bromoethyl)morpholine (225 mg, 1.16 mmol).
The title compound (7.1 mg, 19%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 6-bromo-1-(2-morpholinoethyl)-1H-indazole-4-carboxylate (30 mg, 0.081 mmol), Pd2(dba)3 (4 mg, 0.0044 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.783 min, MS (ES) 811.9 (M+H).
The title compound (42 mg, 15%) was prepared following General Procedure G using methyl 6-bromo-1H-indazole-4-carboxylate (200 mg, 0.784 mmol), NaH (36 mg, 1.5 mmol), and 4-(2-bromoethyl)morpholine (225 mg, 1.16 mmol).
The title compound (5.4 mg, 14%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 6-bromo-2-(2-morpholinoethyl)-2H-indazole-4-carboxylate (30 mg, 0.081 mmol), Pd2(dba)3 (4 mg, 0.0044 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.726 min, MS (ES) 812.3 (M+H).
To a solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.456 g, 28.67 mmol) in DMF (57 ml) was added NaH (1.72 g, 43.0 mmol) and stirred for 15 min. (2-(Chloromethoxy)ethyl)trimethylsilane (6.59 ml, 37.28 mmol) was added to the reaction mixture and stirred at RT for additional 2 h. The reaction was diluted with DCM (50 mL) then quenched by H2O (50 mL). The layers were separated and aqueous phase was extracted with DCM (2×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title product (5.23 g, 52%). LCMS: RT=1.318 min, MS (ES) 353.2 (M+H).
A solution of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (1.76 g, 3.55 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.50 g, 4.26 mmol), Pd(PPh3)4 (0.250 g, 0.178 mmol) and K2CO3 (1.47 g, 10.65 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was irradiated at 140° C. for 45 min under microwave. The reaction mixture was concentrated in vacuo and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-70% gradient) to afford the title as a white solid (1.60 g, 70%). LCMS: RT=1.30 min, MS (ES) 644.2 (M+H).
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (150 mg, 0.233 mmol) and tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (66.2 mg, 0.279 mmol) in DMF (2 ml) was added NaH (12 mg, 0.30 mmol), and the resulting mixture was stirred at rt for 2 h. Saturated aq. NH4Cl (20 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL×3). The combined organics were concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-30% gradient) to give the title product. LCMS: RT=2.232 min, MS (ES) 801.4 (M+H).
To a stirred solution of ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (115 mg, 0.143 mmol) in DCM (3 mL) was added TFA (0.055 mL, 0.717 mmol), and the resulting solution was stirred at 40° C. overnight. The reaction was quenched with saturated aq. NaHCO3 (5 ML), the mixture was extracted with DCM (10 mL×3). The combined organic solution was dried and concentrated to give the crude title compound, which was used for the next step without further purification. LCMS: RT=1.288 min, MS (ES) 701.4 (M+H).
To a solution of ethyl 1-(3-aminopropyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (100 mg, 0.142 mmol) in MeOH (2 mL) was added K2CO3 (98 mg, 0.712 mmol), and the mixture was stirred for 2 h at 50° C. then filtered. The filtrate was concentrated and purified by flash chromatography (Combi-flash Rf, MeOH/DCM=0-10% gradient) to give the title compound (74 mg, 79% two steps). LCMS: RT=1.617 min, MS (ES) 655.3 (M+H).
The title compound (38 mg, 34%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (74 mg, 0.113 mmol), methyl 6-bromo-1-methyl-1H-indole-4-carboxylate (36.3 mg, 0.135 mmol), Pd2(dba)3 (2 mg, 0.0023 mmol), Xantphos (3.9 mg, 0.0068 mmol), and Cs2CO3 (74 mg, 0.23 mmol). LCMS: RT=1.807 min, MS (ES) 842.4 (M+H).
A mixture of methyl 6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylate (32 mg, 0.038 mmol) and TBAF (380 μl, 0.380 mmol) was heated to 100° C. under microwave irradiation in Biotage Initiator for 30 min. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 40-85% MeCN 0.1% TFA) to give the title compound (16 mg, 60%). LCMS: RT=1.852 min, MS (ES) 698.2 (M+H).
The title compound (6.2 mg, 18%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 7-bromo-1-methyl-1H-indazole-3-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0044 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS. RT=1.984, 2.014 min, MS (ES) 713.2 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 8.22-8.11 (m, 1H), 7.67-7.59 (m, 1H), 7.34-7.23 (m, 2H), 7.19-7.07 (m, 1H), 6.53 (s, 1.3H), 6.50 (s, 0.7H), 4.50-4.32 (m, 1H), 4.28-4.17 (m, 1H), 4.14 (d, J=3.0 Hz, 1H), 4.06 (s, 1H), 4.01 (s, 1H), 3.96-3.82 (m, 5H), 3.58-3.20 (m, 3H), 2.24 (s, 6H), 2.19-2.15 (m, 3H), 2.14-2.07 (m, 2H), 2.03 (s, 0.7H), 2.02 (s, 0.3H), 1.98 (s, 2H), 1.25 (d, J=6.4 Hz, 0.6H), 1.19 (d, J=6.4 Hz, 1.4H), 1.14 (d, J=6.4 Hz, 0.3H), 1.08 (d, J=6.4 Hz, 0.7H).
The title compound was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one, methyl 8-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate. MS (ES) 731.3 (M+H).
To a solution of methyl 4-amino-3-bromo-5-hydroxybenzoate (250 mg, 1.02 mmol) in DMF (5 mL) was added dibromoethane (350 mg, 1.9 mmol) and K2CO3 (300 mg, 2.2 mmol). The reaction was heated to 80° C. for 20 h then cool to RT. The reaction was diluted with DCM/H2O (40 mL, 1:1), the organic layer separated, and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (90 mg, 32%).
The title compound (35 mg, 74%) was prepared following General Procedure G using methyl 5-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (45 mg, 0.17 mmol), sodium hydride (9 mg, 0.38 mmol), and methyl iodide (40 mg, 0.28 mmol).
The title compound (2.3 mg, 7%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 5-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (25 mg, 0.087 mmol), Pd2(dba)3 (4 mg, 0.0044 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=1.953 min, MS (ES) 729.9 (M+H).
The title compound (43 mg, 27%) was prepared following the same procedure as described in Example 66 Step A using methyl 3-bromo-4-hydroxy-5-methoxybenzoate (100 mg, 0.381 mmol), CS2CO3 (200 mg, 0.615 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (130 mg, 0.543 mmol).
Crude Methyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-methoxybenzoate was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), methyl 3-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-methoxybenzoate (30 mg, 0.068 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (50 m, 0.153 mmol). To a solution of crude product in THF (3 mL) was added TBAF (1.0 M, 0.05 mL, 0.05 mmol). The reaction was stirred at 40° C. for 1 h then diluted into DCM/H2O (10 mL, 1:1), extracted with DCM (2×5 mL) and concentrated in vacuo. The residue was then subjected to General Procedure D to afford the title compound (2 mg, 7%). LCMS: RT=1.858 min, MS (ES) 749.2 (M+H).
The title compound (31 mg, 87%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 5-bromo-1-naphthoate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.083 min, MS (ES) 709.2 (M+H).
The title compound (13 mg, 53%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), methyl 6-bromobenzo[d]isoxazole-3-carboxylate (20 mg, 0.078 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (50 m, 0.153 mmol). LCMS: RT=1.995 min, MS (ES) 656.2 (M+H).
The title compound (101 mg, 66%) was prepared following the procedure described in Example 66 step 1 using methyl 3-bromo-4-hydroxy-5-methoxybenzoate (100 mg, 0.381 mmol), 1-(2-bromoethoxy)-2-fluorobenzene (120 mg, 0.547 mmol), and Cs2CO3 (200 mg, 0.615 mmol).
The title compound (4 mg, 13%) was obtained following the procedures described in General Procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), methyl 3-bromo-4-(2-(2-fluorophenoxy)ethoxy)-5-methoxybenzoate (30 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (50 m, 0.153 mmol) followed by General Procedure D. LCMS: RT=2.051 min, MS (ES) 842.8 (M+H).
To a solution of methyl 3-bromo-4-hydroxy-5-methoxybenzoate (100 mg, 0.381 mmol) in DMF (3 mL) was added Cs2CO3 (200 mg, 0.615 mmol) followed by (2-bromoethyl)benzene (100 mg, 0.541 mmol). The reaction was stirred at 50° C. until complete as determined by LCMS. The reaction was then cooled to RT, diluted into DCM/H2O (20 mL, 1:1). The layers were separated and the aqueous layer was extracted with DCM (2×10 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (80 mg, 57%).
The title compound (8 mg, 27%) was obtained following the procedures described in General Procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), methyl 3-bromo-5-methoxy-4-phenethoxybenzoate (25 mg, 0.068 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (50 in, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.230 min, MS (ES) 809.2 (M+H).
The title compound (107 mg, 64%) was prepared following the procedure described in Example 66 Step A substituting (2-bromoethyl)benzene with (3-bromopropoxy)(tert-butyl)dimethylsilane (130 mg, 0.514 mmol).
The title compound (4 mg, 14%) was prepared following the same procedure as described in Example 62 Step B substituting methyl 3-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-methoxybenzoate with methyl 3-bromo-4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5-methoxybenzoate (30 mg, 0.069 mmol). LCMS: RT=1.847 min, MS (ES) 763.3 (M+H).
The title compound (32 mg, 90%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-6-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (0 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.992 min, MS (ES) 712.3 (M+H).
The title compound (22 mg, 31%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (54 mg, 0.1 mmol), methyl 7-bromo-1-methyl-1H-indole-3-carboxylate (32 mg, 0.12 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), Xantphos (3.5 mg, 0.006 mmol), and Cs2CO3 (49 mg, 0.15 mmol) followed by saponification using General Procedure D. LCMS: RT=2.043 min, MS (ES) 712.2 (M+H).
The title compound was prepared following the procedure described Example 58 Step C to E using ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylate, and tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. MS (ES) 656.2 (M+H).
The title compound (30 mg, 47%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.076 mmol), methyl 6-bromo-1-methyl-1H-indole-4-carboxylate (25 mg, 0.092 mmol), Pd2(dba)3 (1.4 mg, 0.0015 mmol), Xantphos (2.7 mg, 0.0046 mmol), and Cs2CO3 (49 mg, 0.15 mmol). LCMS: RT=2.011 min, MS (ES) 842.3 (M+H).
The title compound (16 mg, 66%) was prepared following the procedure described Example 58 Step G using methyl (R)-6-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-4-carboxylate (30 mg, 0.036 mmol) and TBAF (356 μl, 0.356 mmol). LCMS: RT=1.893 min, MS (ES) 698.2 (M+H).
The title compound (29 mg, 59% two steps) was prepared according to procedures described in Example 70 B to C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.076 mmol) and methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (25 mg, 0.092 mmol). LCMS: RT=1.895 min, MS (ES) 698.2 (M+H).
The title compound was prepared according to procedures described in Example 58 step F to G using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one and methyl 4-bromo-1-methyl-1H-indole-6-carboxylate. LCMS: RT=1.843 min, MS (ES) 698.2 (M+H).
The title compound (28 mg, 82%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (27 mg, 0.05 mmol), methyl 5-chloropyrazine-2-carboxylate (10 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.841 min, MS (ES) 679.2 (M+H).
The title compound (73 mg, 96%) was prepared following General Procedure F using methyl-indole-7-carboxylate (50 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), NaH (14 mg, 0.34 mmol) and MeI (21 μL, 0.34 mmol). LCMS: RT=1.646 min, MS (ES) 268.1 (M+H).
The title compound (23 mg, 65%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-7-carboxylate (16 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.038 min, MS (ES) 712.2 (M+H).
The title compound (31 mg, 87%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-7-carboxylate (16 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.092 min. MS (ES) 712.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=8.6 Hz, 1H), 7.62-7.53 (m, 2H), 7.49 (d, J=2.8 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.09 (td, J=7.7, 2.2 Hz, 1H), 6.72 (s, 2H), 4.48 (dd, J=13.0, 3.8 Hz, 1H), 4.23-4.08 (m, 1H), 3.98 (dt, J=6.4, 3.4 Hz, 2H), 3.84 (s, 3H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.40-3.15 (m, 3H), 2.25 (s, 6H), 2.12 (s, 1.5H), 2.08 (d, J=12.0 Hz, 2H), 2.04 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.08 (d, J=6.4 Hz, 3H).
The title compound (28 mg, 79%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (16 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.003 min, MS (ES) 712.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J=3.5, 1.5 Hz, 1H), 7.87-7.71 (m, 2H), 7.57 (dd, J=9.4, 1.9 Hz, 2H), 7.30 (d, J=8.6 Hz, 1H), 6.73 (s, 2H), 4.48 (dd, J=13.0, 3.8 Hz, 1H), 4.24-4.09 (m, 1H) 3.99 (tt, J=6.4, 3.2 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 1.5H), 3.77 (s, 1.5H), 3.72-3.59 (m, 1H), 3.23 (dt, J=13.4, 7.4 Hz, 2H), 2.24 (s, 6H), 2.12 (s, 1.5H), 2.07 (dd, J=12.7, 6.0 Hz, 2H), 2.03 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.19-0.93 (m, 3H).
Example 91 was separated using reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA, 10 mins gradient) to give the title compound as the first eluting atropisomer (13 mg, 37%). LCMS: RT=1.970 min, MS (ES) 712.0 (M+H).
Example 91 was separated using reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA, 10 mins gradient) to give the title compound as a second eluting atropisomer (11 mg, 31%). LCMS: RT=1.989 min, MS (ES) 712.0 (M+H).
The title compound (32 mg, 90%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 6-bromo-1-methyl-1H-indole-3-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.041 min, MS (ES) 712.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J=1.3 Hz, 1H), 8.00 (dd, J=8.5, 2.7 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.56 (t, J=2.5 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.21 (dt, J=8.5, 2.2 Hz, 1H), 6.74 (s, 2H), 4.49 (dd, J=13.0, 3.8 Hz, 1H), 4.21-4.09 (m, 1H), 3.99 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 1.5H), 3.78 (s, 1.5H), 3.40-3.13 (M, 3H), 2.26 (s, 6H), 2.12 (s, 15H), 2.07 (d, J=6.9 Hz, 2H), 2.03 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.05 (d, J=6.4 Hz, 3H).
The title compound (28 mg, 79%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (16 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.942 min, MS (ES) 712.3 (M+H).
The title compound (20 mg, 70%) was prepared following General coupling procedure A using (8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (27 mg, 0.05 mmol), methyl 6-bromo-1-methyl-1H-indole-3-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.968 min, MS (ES) 712.3 (M+H).
To a solution of methyl 6-bromo-1H-indazole-4-carboxylate (200 mg, 0.79 mmol) in DMF (5 mL) was added NaH (40 mg, 1.63 mmol), and the reaction was stirred for 30 min at RT. 1-Bromo-2-methoxyethane (165 mg, 1.18 mmol) was added and the reaction was stirred overnight. The reaction was quenched with MeOH at −78° C., then diluted with DCM/H2O (60 mL, 1:1), the organic layer was separated, the aqueous layer was extracted with DCM (2×20 mL), the organic fractions combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (39 mg, 16%).
The title compound (4 mg, 11%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 6-bromo-1-(2-methoxyethyl)-1H-indazole-4-carboxylate (20 mg, 0.064 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.948 min, MS (ES) 757.3 (M+H).
The title compound (70 mg, 62%) was prepared following General Procedure F using methyl-indole-7-carboxylate (70 mg, 0.40 mmol), NBS (71 mg, 0.40 mmol), NaH (20 mg, 0.48 mmol) and ethyl iodide (38 μL, 0.48 mmol). LCMS: RT=1.731 min, MS (ES) 282.1 (M+H).
The title compound (34 mg, 96%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-ethyl-1H-indole-7-carboxylate (16 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.135 min, MS (ES) 726.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=8.6 Hz, 1H), 7.65-7.44 (m, 3H), 7.30 (d, J=8.6 Hz, 1H), 7.15-7.03 (m, 1H), 6.72 (s, 2H), 4.48 (dd, J=13.0, 3.8 Hz, 1H), 4.43-4.26 (m, 2H), 4.24-4.09 (m, 2H), 3.99 (s, 3H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.68-3.57 (m, 2H), 3.41-3.14 (m, 2H), 2.25 (s, 6H), 2.12 (s, 1.5H), 2.11-2.04 (m, 2H), 2.04 (s, 15H), 1.98 (s, 15H), 1.89 (s, 15H), 1.26 (td, J=7.1, 1.4 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H).
The title compound (13 mg, 39%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 4-bromo-1-methyl-1H-indazole-6-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.014 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.018 min, MS (ES) 713.2 (M+H).
The title compound (4 mg, 12%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 5-bromo-1-methyl-1H-indazole-7-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.014 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.934 min, MS (ES) 713.2 (M+H).
A mixture of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (25 mg, 0.050 mmoL), (2,6-dimethylphenyl)boronic acid (10 mg, 0.068 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), dicyclohexyl(2-(phenanthren-9-yl)phenyl)phosphane (6 mg, 0.014 mmol), and potassium phosphate (30 mg, 0.142 mmol) was purged with Ar for 5 min then toluene (1 mL) was added. The reaction was heated to 110° C. for 16 h then cooled to RT. The reaction was diluted into DCM/H2O (10 mL, 1:1), the layers were separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried by passage through a phase separator, concentrated in vacuo, and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (22 mg, 88%).
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2,6-dimethylphenyl)-1H-indole-2-carboxylate (96 mg, 0.18 mmol) and tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (50 mg, 0.21 mmol) in DMF (4 mL) was added NaH (6 mg, 0.25 mmol), and the reaction was stirred for 16 h at RT. The work up described in general coupling procedure A was followed and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (72 mg, 57%).
To a solution of ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2,6-dimethylphenyl)-1H-indole-2-carboxylate (72 mg, 0.11 mmol) in dioxane (3 mL) was added HCl (4.0 M in dioxanes, 0.5 mL, 2.0 mmol). The reaction was stirred for 16 h at RT then concentrated in vacuo. The residue was dissolved in MeOH (5 mL), and K2CO3 (50 mg, 0.30 mmol) was added. The reaction was allowed to stir 20 h at 50° C. The work up described in general coupling procedure A was followed and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (33 mg, 59%). LCMS: RT=2.317 min, MS (ES) 535.2 (M+H).
The title compound (10 mg, 30%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 6-bromo-1-ethyl-1H-indazole-4-carboxylate (20 mg, 0.070 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and cesium carbonate (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.036 min, MS (ES) 727.2 (M+H).
The title compound (30 mg, 84%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-6-carboxylate (16 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.031 min, MS (ES) 712.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.70-7.60 (m, 2H), 7.48 (dd, J=8.4, 4.4 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.72 (s, 2H), 4.48 (dd, J=12.9, 3.8 Hz, 1H), 4.25-4.07 (m, 1H), 3.99 (td, J=6.4, 2.0 Hz, 2H), 3.88 (s, 3H), 3.78 (s, 1.5H), 3.77 (s, 15H), 3.39-3.15 (m, 3H), 2.25 (s, 6H), 2.12 (s, 15H), 2.11-2.05 (m, 2H), 2.03 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.08 (d, J=6.4 Hz, 3H).
The title compound (36 mg, 49%) was prepared following General Procedure G using methyl 3-bromo-1H-indole-6-carboxylate (51 mg, 0.20 mmol), sodium hydride (10 mg, 0.24 mmol), 4-(2-chloroethyl)morpholine (36 mg, 0.24 mmol) and KI (40 mg, 0.24 mmol). LCMS: RT=1.515 min, MS (ES) 367.1 (M+H).
The title compound (8 mg, 20%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-(2-morpholinoethyl)-1H-indole-6-carboxylate (19 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.719 and 1.745 min, MS (ES) 810.9 (M+H).
To a solution of methyl 4-amino-3-bromo-5-hydroxybenzoate (250 mg, 1.02 mmol) in THF (10 mL) was added NaHCO3 (150 mg, 1.8 mmol) and chloroacetyl chloride (170 mg, 1.5 mmol) at 0° C. The reaction was stirred for 2 h and warm to RT. K2CO3 (150 mg, 1.1 mmol) was added, and the reaction was heated to 65° C. then cooled to RT. The mixture was diluted with DCM/H2O (40 mL, 1:1) and extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford methyl 5-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (86 mg, 30%). The product (40 mg, 0.14 mmol) was dissolved in DMF (3 mL), NaH (7 mg, 0.30 mmol) was added. The reaction was stirred at RT for 30 min, and EtBr (30 mg, 0.28 mmol) was added. The reaction was stirred for 3 h at RT then diluted with DCM/H2O (20 mL, 1:1). The organic layer was separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried by passage through a phase separator and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf. Hex/EtOAc=0-100% gradient) to afford the title compound (28 mg, 65%).
The title compound (1 mg, 4%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 5-bromo-4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (20 mg, 0.063 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (35 mg, 0.107 mmol) followed by saponification using General Procedure D. LCMS: RT=2.034 min, MS (ES) 757.8 (M+H).
The title compound (3 mg, 9%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2,6-dimethylphenyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.037 mmol), methyl 6-bromo-1-methyl-1H-indole-4-carboxylate (20 mg, 0.063 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (35 mg, 0.107 mmol) followed by saponification using General Procedure D. LCMS: RT=1.531 min, MS (ES) 708.3 (M+H).
The title compound (43 mg, 18%) was prepared following the procedure described in Example 82 Step A substituting 1-bromo-2-methoxyethane with 2-bromopropane (190 mg, 1.54 mmol).
The title compound (5 mg, 15%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 6-bromo-1-isopropyl-1H-indazole-4-carboxylate (20 mg, 0.067 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.048 min, MS (ES) 741.3 (M+H).
The title compound (19 mg, 38% two steps) was prepared according to procedures described in Example 70 B to C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.076 mmol) and methyl 6-bromo-1-methyl-1H-indazole-4-carboxylate (23 mg, 0.084 mmol). LCMS: RT=1.859 min, MS (ES) 699.2 (M+H).
The title compound (138 mg, 88%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (100 mg, 0.184 mmol), methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-4-carboxylate (78 mg, 0.20 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (121 mg, 0.37 mmol). MS (ES) 842.3 (M+H).
A mixture of methyl (R)-6-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-4-carboxylate (138 mg, 0.164 mmol), TBAF (0.819 mL, 0.819 mmol) in THF (1 mL) was heated at 100° C. under microwave irradiation in Biotage Initiator for 20 min. The reaction was quenched with H2O (5 mL) then extracted with DCM (10 mL×2). The combined organic solution was concentrated and the residue was purified by flash chromatography (Combi-flash Rf, MeOH/DCM=0-5% gradient) to give the title compound (80 mg, 69%) as a white solid. LCMS: RT=2.115 min, MS (ES) 712.2 (M+H).
To a solution of methyl (R)-6-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-J H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-4-carboxylate (40 mg, 0.056 mmol) in DMF (0.5 mL) was added NaH (4.5 mg, 0.11 mmol) and stirred for 20 min. 4-(2-Bromoethyl)morpholine (22 mg, 0.11 mmol) was added, and the resulting mixture was heated to 50° C. for 2 days. The reaction was quenched by MeOH (0.5 mL) and acidified with TFA then concentrated in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 30-85% MeCN 0.1% TFA) to give the title compound (14 mg, 30%). LCMS: RT=1.714 min, MS (ES) 811.3 (M+H).
The title compound (25 mg, 56% two steps) was prepared according to procedures described in Example 70 B to C using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (50 mg, 0.076 mmol) and methyl 6-bromo-1-methyl-1H-indazole-4-carboxylate (23 mg, 0.084 mmol). LCMS: RT=1.859 min, MS (ES) 699.2 (M+H).
The title compound (58% yield) was prepared according to procedures described in Example 94 Step A to C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carboxylate. LCMS: RT=1.735 min, MS (ES) 811.3 (M+H).
The title compound (6 mg, 18%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 4-bromo-2-methyl-2H-indazole-6-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.014 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.949 min, MS (ES) 713.2 (M+H).
The title compound (3 mg, 9%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 5-bromo-1-methyl-1H-indazole-7-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (8 mg, 0.014 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.991 min, MS (ES) 713.2 (M+H).
The title compound (12 mg, 38%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (40 mg, 0.074 mmol), methyl 6-bromo-1-ethyl-1H-indole-4-carboxylate (25 mg, 0.089 mmol), Pd2(dba)3 (1.4 mg, 0.0015 mmol), Xantphos (2.6 mg, 0.0045 mmol), and Cs2CO3 (48 mg, 0.15 mmol) followed by saponification using General Procedure D. LCMS: RT=2.220 min, MS (ES) 740.3 (M+H).
The title compound was prepared along with Example 96 as a byproduct. MS (ES) 698.2 (M+H).
The title compound was prepared along with Example 94 as a byproduct. MS (ES) 698.2 (M+H).
The title compound (21 mg, 59%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 6-bromoquinoline-2-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.025 min, MS (ES) 710.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J=8.6, 1.7 Hz, 1H), 8.14 (t, J=8.6 Hz, 2H), 8.09-8.00 (m, 1H), 7.96 (ddd, J=9.0, 2.4, 1.0 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 6.74 (s, 2H), 4.68-4.46 (m, 2H), 4.26-4.14 (m, 3H), 4.00 (s, 3H), 3.79 (s, 3H), 3.44-3.14 (m, 2H), 2.25 (s, 6H), 2.12 (s, 1.5H), 2.11-2.05 (m, 2H), 2.03 (s, 1.5H), 2.00 (s, 1.5H), 1.90 (s, 1.5H), 1.05 (d, J=6.4 Hz, 3H).
The title compound (58 mg, 68%) was prepared following General Procedure G using 7-bromo-1H-indole-3-carboxylic acid (70 mg, 0.29 mmol), NaH (26 mg, 0.64 mmol) and EtI (51 μL, 0.64 mmol). LCMS: RT=1.803 min, MS (ES) 296.1 (M+H).
The title compound (8 mg, 22%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), ethyl 7-bromo-1-ethyl-1H-indole-3-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 L 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.042 min, MS (ES) 726.3 (M+H).
The title compound (76 mg, 95%) was prepared following General Procedure G using methyl 3-bromo-1H-indole-6-carboxylate (72 mg, 0.28 mmol), sodium hydride (14 mg, 0.34 mmol) and EtI (28 μL, 0.34 mmol). LCMS: RT=1.682 min, MS (ES) 282.1 (M+H).
The title compound (35 mg, 96%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-ethyl-1H-indole-6-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.064 min, MS (ES) 726.3 (M+H).
The title compound (34 mg, 96%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 8-bromoquinoline-3-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.010 min, MS (ES) 710.2 (M+H).
The title compound (39 mg, 51%) was prepared following General Procedure F using methyl 1H-indole-4-carboxylate (50 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), NaH (14 mg, 0.34 mmol), and MeI (21 μL, 0.34 mmol). LCMS: RT=1.414 min, MS (ES) 268.1 (M+H).
The title compound (16 mg, 45%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-4-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.936 and 1.963 min, MS (ES) 712.3 (M+H).
The title compound (73 mg, 23%) was prepared following the procedure describe in Example 82 Step A substituting 1-bromo-2-methoxyethane with (2-bromoethoxy)(tert-butyl)dimethylsilane (375 mg, 1.57 mmol).
The title compound (3 mg, 9%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 6-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indazole-4-carboxylate (30 mg, 0.073 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol). Following isolation of the coupling product, the crude residue was dissolved in THF (3 mL) and TBAF (1.0 M, 0.1 mL, 0.1 mmol) was added and the reaction was allowed to stir overnight at RT. The crude reaction mixture was concentrated and carried forward to saponification following General Procedure D. LCMS. RT=1.786 min, MS (ES) 742.9 (M+H).
The title compound was prepared according to procedures described in Example 70 B to C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-1-methyl-1H-indole-3-carboxylate. MS (ES) 699.2 (M+H).
The title compound (88 mg, 69%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (100 mg, 0.15 mmol), methyl 3-bromo-1-methyl-1H-indole-6-carboxylate (41 mg, 0.15 mmol), Cut (1.5 mg, 0.0078 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (2.2 mg, 0.015 mmol), and K2CO3 (42 mg, 0.31 mmol). MS (ES) 842.3 (M+H).
The title compound was prepared according to procedures described in Example 70° C. using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carboxylate. LCMS: RT=1.900 min, MS (ES) 698.2 (M+H).
The title compound (28 mg, 79%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 6-bromo-1-methyl-1H-indole-2-carboxylate (14 mg, 0.06 mmol), Cut (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.091 and 2.114 min, MS (ES) 712.3 (M+H).
The title compound (89% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromoimidazo[1,5-a]pyridine-1-carboxylate followed by saponification using General Procedure D. MS (ES) 701.3 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 8.08 (t, J=10.0 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.29-7.26 (m, 1H), 6.93 (t, J=6.8 Hz, 1H), 6.71 (s, 2H), 4.55-4.50 (m, 1H), 4.30-4.25 (m, 2H), 3.97 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 3.33-3.15 (m, 2H), 2.23 (s, 6H), 2.11 (s, 1.5H), 2.09-2.01 (m, 2H), 2.02 (s, 1.5H), 1.97 (s, 1.5H), 1.88 (s, 1.5H), 1.09 (d, J=5.6 Hz, 3H).
The title compound (49% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 2-bromoimidazo[1,2-a]pyridine-8-carboxylate followed by saponification using General Procedure D. MS (ES) 701.4 (M+H).
The title compound (26 mg, 73%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 4-bromo-1-methyl-1H-indole-2-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.076 min, MS (ES) 712.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=3.1 Hz, 0.5H), 7.72 (d, J=3.1 Hz, 0.5H), 7.49-7.37 (m, 2H), 7.31 (dd, J=9.7, 5.1 Hz, 2H), 7.13-7.05 (m, 1H), 6.70-6.55 (m, 2H), 4.57-4.40 (m, 1H), 4.37-4.17 (m, 2H), 4.10 (s, 3H), 3.97 (s, 1.5H), 3.96 (s, 1.5H), 3.62 (dd, J=11.9, 4.2 Hz, 1H), 3.40 (ddt, J=42.4, 13.8, 7.3 Hz, 3H), 2.32 (s, 6H), 2.26 (s, 1.5H), 2.25 (s, 1.5H), 2.22 (d, J=7.0 Hz, 2H), 2.11 (s, 1.5H), 2.09 (s, 1.5H), 1.27 (d, J=6.4 Hz, 1.5H), 1.20 (d, J=6.5 Hz, 1.5H).
The title compound (28 mg, 79%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 5-bromo-1-methyl-1H-indole-2-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.084 min, MS (ES) 712.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J=8.6 Hz, 1H), 7.66-7.54 (m, 2H), 7.36-7.26 (m, 2H), 7.23 (t, J=0.9 Hz, 1H), 6.73 (s, 2H), 4.44 (dd, J=13.0, 3.8 Hz, 1H), 4.05 (s, 3H), 3.98 (tt, 0.1=6.3, 2.9 Hz, 3H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.63 (t, J=13.5 Hz, 1H), 3.22 (dt, J=13.2, 7.2 Hz, 2H), 2.26 (s, 6H), 2.12 (s, 1.5H), 2.10-2.04 (m, 2H), 2.03 (s, 1.5H), 1.97 (s, 1.5H), 1.88 (s, 15H), 1.04 (d, J=6.4 Hz, 3H).
The title compound (41% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and 6-bromobenzo[d]isoxazole. MS (ES) 656.4 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 7.73 (d, J=8.8 Hz, 1H), 7.63 (dd, J=8.4, 2.8 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.72 (s, 2H), 4.45-4.41 (m, 1H), 4.24-4.13 (m, 2H), 3.97 (t, J=6.0 Hz, 2H), 3.76 (s, 3H), 3.32-3.15 (m, 2H), 2.24 (s, 6H), 2.08 (s, 1.5H), 2.07-2.02 (m, 2H), 1.98 (s, 1.5H), 1.94 (s, 1.5H), 1.85 (s, 1.5H), 0.94 (d, J=6.4 Hz, 3H)
The title compound (25 mg, 70%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 5-bromo-1-methyl-1H-indazole-3-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.998 min, MS (ES) 713.2 (M+H).
The title compound (54 mg, 48%) was prepared following the procedure described in Example 82 Step A using methyl 7-bromo-1H-indazole-3-carboxylate (100 mg, 0.392 mmol), sodium hydride (18 mg, 0.75 mmol), and EtBr (80 mg, 0.74 mmol).
The title compound (9.5 mg, 29%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 7-bromo-2-ethyl-2H-indazole-3-carboxylate (20 mg, 0.071 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.138 min, MS (ES) 727.3 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 7.86 (ddd, J=8.4, 3.9, 0.9 Hz, 1H), 7.73 (dd, J=8.6, 2.9 Hz, 1H), 7.43-7.36 (m, 1H), 7.35-7.24 (m, 2H), 6.68-6.62 (m, 2H), 4.84 (q, J=7.2 Hz, 2H), 4.64-4.49 (m, 1H), 4.36-4.20 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.96 (d, J=2.7 Hz, 3H), 3.79 (t, J=13.5 Hz, 1H), 3.44 (ddt, J=17.8, 11.7, 6.3 Hz, 2H), 2.33 (s, 6H), 2.28-2.19 (m, 5H), 2.12 (s, 1.5H), 2.09 (s, 1.5H), 1.49 (td, J=7.2, 5.8 Hz, 3H), 1.34 (d, J=6.3 Hz, 1.5H), 1.26 (d, J=6.4 Hz, 1.5H).
The title compound (22 mg, 20%) was prepared in the same reaction as described in Example 117 Step A.
The title compound (3 mg, 9%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 7-bromo-1-ethyl-1H-indazole-3-carboxylate (20 mg, 0.071 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.058 min, MS (ES) 727.2 (M+H).
The title compound (1 mg, 3%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 7-bromo-1-methyl-1H-indole-3-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS. RT=2.032 min, MS (ES) 710.2 (M+H).
Ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (1.647 g, 3.30 mmol) was combined with (4,6-dimethylpyrimidin-5-yl)boronic acid (1.2 g, 7.90 mmol), Pd2(dba)3 (0.30 g, 0.33 mmol), and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (SPhos) (0.406 g, 0.990 mmol) in 30 mL 1:1 THF/Toluene in a pressure tube. The mixture was treated with K3PO4 (1.16 mL, 11.6 mmol) and was stirred 10 minutes at RT under Ar flush. The reaction was heated to 110° C. and stirred for 24 h. The mixture was cooled, poured in 150 mL EtOAc and stirred with 50 mL saturated ammonium chloride. The organic layer was dried over anhydrous MgSO4 and was concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/DCM=0-50% gradient) to give the title compound (970 mg, 56%) as an amber foam. 1H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 8.93 (s, 1H), 7.68 (dd, J=8.6, 0.6 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 6.62 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 3.97 (t, J=6.1 Hz, 2H), 3.28 (dd, J=8.1, 6.8 Hz, 2H), 2.32 (s, 6H), 2.20 (s, 6H), 2.21-2.10 (m, 2H), 1.36-1.20 (m, 3H); 13C NMR (101 MHz, cdcl3) δ 165.98, 161.85, 157.76, 156.71, 137.03, 134.32, 130.42, 127.16, 127.11, 126.11, 124.93, 124.67, 121.97, 118.44, 114.45, 67.35, 61.10, 30.24, 22.26, 21.21, 20.96, 14.32.
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-1H-indole-2-carboxylate (500 mg, 0.952 mmol) and tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (300 mg, 1.26 mmol) in DMF (20 mL) was added NaH (60 mg, 1.50 mmol), and the reaction was stirred at RT for 3 h. The reaction was diluted with DCM/H2O (60 mL, 1:1), and the layers were separated. The aqueous layer was extracted with DCM (2×30 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (525 mg, 81%).
To a solution of ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-1H-indole-2-carboxylate in dioxane (20 mL) was added HCl in dioxane (4.0 M, 3.0 mL, 12 mmol), and the reaction was stirred for 72 h at RT. The reaction was concentrated in vacuo, and the crude residue was taken up in MeOH (30 mL). K2CO3 (300 mg, 2.17 mmol) was added, and the reaction was stirred for 6 h at 50° C. The reaction was concentrated in vacuo, and the residue extracted with DCM (3×30 mL) and washed with H2O (30 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was then purified by flash chromatography (Combi-flash Rf, CH2Cl2/methanol=0-10% gradient) to afford the title compound (243 mg, 58%). LCMS: RT=1.947 min, MS (ES) 537.3 (M+H).
The title compound (19 mg, 53%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 6-bromo-1-methyl-1H-indazole-3-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.024 min, MS (ES) 713.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.57-7.98 (m, 1H), 7.82-7.69 (m, 1H), 7.63 (dd, J=12.1, 7.1 Hz, 1H), 7.29 (dd, J=8.6, 4.6 Hz, 2H), 6.74 (s, 2H), 4.74-4.45 (m, 1H), 4.45-4.32 (m, 1H), 4.25-4.08 (m, 2H), 4.01 (s, 3H), 4.00-3.95 (m, 1H), 3.79 (s, 1.5H), 3.78 (s, 1.5H), 3.74-3.60 (m, 1H), 2.77-2.62 (m, 1H), 2.26 (s, 6H), 2.12 (s, 1.5H), 2.06-2.00 (m, 2H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.76 (s, 1.5H), 1.05 (d, J=6.3 Hz, 3H).
The title compound (42 mg, 37%) was prepared following the procedure described in Example 82 Step A using methyl 7-bromo-1H-indazole-5-carboxylate (100 mg, 0.392 mmol), NaH (18 mg, 0.75 mmol), and EtBr (80 mg, 0.74 mmol).
The title compound (3 mg, 9%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 7-bromo-1-ethyl-1H-indazole-5-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS. RT=2.033 min, MS (ES) 727.2 (M+H).
The title compound (64 mg, 61%) was prepared following the procedure described in Example 82 Step A using methyl 7-bromo-1-methyl-1H-indazole-5-carboxylate (100 mg, 0.392 mmol), NaH (18 mg, 0.75 mmol), and MeI (75 mg, 0.52 mmol).
The title compound (5 mg, 15%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 7-bromo-1-methyl-1H-indazole-5-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.926 min, MS (ES) 712.9 (M+H).
The title compound (29 mg, 26%) was prepared in the same reaction as described in Example 122 Step A.
The title compound (3.9 mg, 12%) was prepared following General Procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 7-bromo-2-ethyl-2H-indazole-5-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.895 min, MS (ES) 726.9 (M+H).
The title compound (4 mg, 11%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.050 mmol), methyl 4-bromo-1-methyl-1H-indazole-3-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (5 mg, 0.0055 mmol), Xantphos (7 mg, 0.012 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.944 min, MS (ES) 713.2 (M+H).
The title compound (8 mg, 20%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.052 mmol), methyl 4-bromo-1-methyl-1H-indazole-3-carboxylate (30 mg, 0.11 mmol), Pd2(dba)3 (5 mg, 0.0055 mmol), Xantphos (7 mg, 0.012 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.944 min, MS (ES) 713.2 (M+H). The title compound was separated using reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-90% CH3CN, 0.1% TFA) during the final purification step to give as a separated atropisomer (1st fraction, absolute stereochemistry undetermined). MS (ES) 713.2 (M+H).
The title compound was separated along with Example 141 as a separated atropisomer (2nd fraction). MS (ES) 713.2 (M+H).
To a solution of methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (20 mg, 0.028 mmol) in DMF (0.5 mL) was added NaH (1.4 mg, 0.034 mmol) and stirred for 15 min at RT. 4-(Bromomethyl)tetrahydro-2H-pyran (5.5 mg, 0.031 mmol) was added, and the resulting mixture was stirred overnight then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-70% gradient) to give the title compound (20 mg, 88%) as white foam. LCMS: RT=2.107 min, MS (ES) 810.3 (M+H).
The title compound (10 mg, 51%) was prepared following General Procedure D for saponification using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (20 mg, 0.025 mmol). LCMS: RT=2.124 min, MS (ES) 796.3 (M+H).
The title compound was prepared following the procedure described in Example 109 Step A and B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromo-1-methyl-1H-indole-5-carboxylate. LCMS: RT=1.872 min, MS (ES) 698.2 (M+H).
The title compound (2 mg, 6%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 6-bromo-1-methyl-1H-indole-4-carboxylate (20 mg, 0.067 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.012 min, MS (ES) 710.2 (M+H).
The title compound (8 mg, 23%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 6-bromo-1-isopropyl-1H-indazole-4-carboxylate (20 mg, 0.067 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS. RT=2.119 min, MS (ES) 741.3 (M+H).
The title compound (12 mg, 34%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-(2H)-one (27 mg, 0.050 mmol), methyl 4-bromo-2-methyl-2H-indazole-3-carboxylate (25 mg, 0.074 mmol), Pd2(dba)3 (5 mg, 0.0055 mmol), Xantphos (7 mg, 0.012 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.940, 1.971 min, MS (ES) 713.2 (M+H)
The title compound was separated using reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-90% CH3CN, 0.1% TFA) during the final purification step to give as a separated atropisomer (1st fraction, absolute stereochemistry undetermined). LCMS: RT=1972 min, MS (ES) 713.2 (M+H).
The title compound (35 mg, 93%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-(2H)-one (27 mg, 0.05 mmol), tert-butyl 4-bromo-1H-indole-1-carboxylate (18 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol). Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol). LCMS: RT=2.453 min, MS (ES) 754.30 (M+H).
To a solution of tert-butyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-1-carboxylate (35 mg, 0.046 mmol) in DCM (2 mL) was added TFA (2 mL), and the mixture was stirred at room temperature for 6 h. Saturated aqueous NaHCO3(8 mL) was added to the mixture and extracted in DCM (3×5 mL). The organic layer was dried (anhyd. Na2SO4), evaporated. The residue was dissolved in DMF (1 mL), and NaH (5 mg, 0.12 mmol, 1.2 eqv.) was added then stirred at RT for 10 min. Ethyl bromoacetate (14 μL, 0.12 mmol, 1.2 eqv.) was added to the mixture and stirred at RT for 2 h. The reaction was quenched with water (5 mL) and extracted with DCM (3×5 mL). The organic layer was dried (anhyd. Na2SO4) and concentrated. The residue was subjected to saponification using General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (16 mg, 45%). LCMS: RT=1.748 min, MS (ES) 712.2 (M+H).
The title compound (43% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate followed by saponification using General Procedure D. MS (ES) 700.4 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 9.00 (dd, J=7.2, 3.6 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.58 (dd, J=7.2, 1.2 Hz, 1H), 7.29 (d, J=8.8, 1.2 Hz, 1H), 6.73 (s, 2H), 4.37-4.19 (m, 3H), 4.13-3.95 (m, 2H), 3.76 (d, J=8.8 Hz, 3H), 3.36-3.15 (m, 2H), 2.24 (s, 6H), 2.09-2.05 (m, 2H), 2.08 (s, 1.5H), 1.99 (s, 1.5H), 1.97 (s, 1.5H), 1.87 (s, 1.5H), 0.95 (dd, J=9.2, 6.8 Hz, 3H).
The title compound was prepared according to procedures described in Example 58 step F to G using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one and aniline. MS (ES) 601.2 (M+H)
To a solution of 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-2-phenyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (0.05 mmol) in DMF (1 mL) was added NaH (0.08 mmol) at RT, and the reaction was stirred for 30 min. Methyl 2-chloroacetate (0.1 mmol) was added, and the reaction was stirred for 5 h at RT then diluted with DCM/H2O (20 mL, 1:1). The organic layer was separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic extracts were concentrated in vacuo. The crude reaction product was then saponified and purified following the procedure described in General Procedure D to afford the title compound (71% yield). MS (ES) 659.2 (M+H).
To a solution of methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (20 mg, 0.028 mmol) and (1-methylpiperidin-4-yl)methanol (7.25 mg, 0.056 mmol) in Toluene (932 μl) was added 2-(tributyl-15-phosphanylidene)acetonitrile (140 μl, 0.056 mmol) and stirred at 50° C. for 20 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to give the title compound (15 mg, 65%). LCMS: RT=1.901 min, MS (ES) 823.3 (M+H).
The title compound (5 mg, 34%) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (15 mg, 0.018) and methyl 6-(bromomethyl)nicotinate. LCMS: RT=1.740 min, MS (ES) 809.4 (M+H).
The title compound (66% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-bromoquinoline-8-carboxylate followed by saponification using General Procedure D. MS (ES) 710.2 (M+H); 1H-NMR (MeOH-d3) δ 9.12 (dd, 1H, J1=2 Hz, J1=5 Hz), 9.90 (dd, 1H, J1=2 Hz, J1=5 Hz), 8.81 (m, 1H), 8.33 (m, 1H) 7.93 (m, 1H), 7.78 (d, 1H, J=8 Hz), 7.32 (d, 1H, J=8 Hz), 6.63 (s, 2H), 4.46 (m, 2H), 4.35 (m, 1H), 4.01-3.96 (m, 2H), 3.87 (multiple s, 3H), 3.77-3.74 (m, 1H), 3.49-3.38 (m, 2H), 3.11-3.08 (m, 1H), 2.27 (s, 6H), 2.23-2.02 (multiple s and m, 8H), 1.18 and 1.16 (two d, 3H, J=8 Hz).
The title compound (78% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate followed by saponification using General Procedure D. MS (ES) 699.2 (M+H).
The title compound (74% yield) was prepared following same procedures described in Example 24 substituting tert-butyl (R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide with tert-butyl (4R,5S)-4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. MS (ES) 553.4 (M+H); 1H-NMR (CDCl3) δ 7.70 (d, 1H, 3=8 Hz), 7.29 (d, 1H, J=8 Hz), 6.64 (s, 2H), 5.82 (m, 1H), 4.05-3.90 (m, 6H), 3.52-3.50 (m, 1H), 3.47-3.31 (m, 3H), 2.35 (s, 6H), 2.17 (overlapped tr and multiple s, 8H), 1.21 (d, 0.751, J=8 Hz), 1.19 (d, 0.75H, J=8 Hz), 1.05 (d, 1.5H, J=8 Hz), 1.03 (d, 1.5H, 3=8 Hz), 0.88 (d, 0.75H, J=8 Hz), 0.82 (d, 0.75H, J=8 Hz)
The title compound (62% yield) was prepared following General coupling procedure A using (3R,4R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromobenzoate followed by saponification using General Procedure D. MS (ES) 673.2 (M+H).
The title compound (73% yield) was prepared following General coupling procedure A using (3R,4R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromobenzoate followed by saponification using General Procedure D. MS (ES) 673.3 (M+H).
The title compound (8% yield) was prepared following General coupling procedure A using (3R,4R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-bromo-1-methyl-1H-indole-4-carboxylate followed by saponification using General Procedure D. MS (ES) 726.3 (M+H).
The title compound (55% yield) was prepared according to procedures described in Example 136 step A and B by substituting aniline with 8-bromoquinoline. MS (ES) 710.2 (M+H)
A mixture of ethyl 7-bromo-1-methyl-1H-indole-5-carboxylate (200 mg, 0.71 mmol), methylboronic acid (57.9 mg, 0.97 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane (79 mg, 0.193 mmol), K3PO4 (253 mg, 1.29 mmol) and PdOAc2 (22 mg, 0.097 mmol) was degassed for 10 min under Ar. Toluene (1.5 ml) was added and the resulting mixture was heated at 100° C. for 3 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-20% gradient) to give the title compound (140 mg, 99%). LCMS. RT=1.558 min, MS (ES) 218.2 (M+H).
To a stirred solution of ethyl 1,7-dimethyl-1H-indole-5-carboxylate (140 mg, 0.64 mmol) in DMF (2 mL) was added NBS (115 mg, 0.64 mmol) at 0° C. After 1 h, the reaction was quenched by addition of H2O (10 mL). The mixture was extracted with DCM (10 mL×2). The combined organic solution was washed with H2O (20 mL), dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-10% gradient) to give the title compound (176 mg, 92%) as a yellow solid.
The title compound (33 mg, 50%) was prepared following General coupling procedure B using R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.093 mmol), ethyl 3-bromo-1,7-dimethyl-1H-indole-5-carboxylate (33 mg, 0.11 mmol), CuI(0.9 mg, 0.005 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (1.3 mg, 0.0093 mmol), and K2CO3 (26 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=2.018 min, MS (ES) 726.3 (M+H).
The title compound (14 mg, 60%) was prepared according to procedures described in Example 137 Step A and B using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (20 mg, 0.028 mmol) and (1-methylpiperidin-4-yl)methanol (18 mg, 0.14 mmol). MS (ES) 698.2 (M+H).
The title compound (12.7 mg, 38%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 5-bromoquinoline-8-carboxylate (20 mg, 0.075 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.008 min, MS (ES) 708.3 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 9.20 (s, 1H), 9.00 (dd, J=4.4, 1.6 Hz, 1H), 8.87 (d, J=7.8 Hz, 1H), 8.32 (dd, J=8.6, 1.6 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.64 (dd, J=8.6, 4.3 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 6.61 (s, 2H), 3.99 (h, J=6.4 Hz, 5H), 3.77 (dt, J=14.2, 5.7 Hz, 1H), 3.20 (dt, J=12.5, 7.4 Hz, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.33 (s, 6H), 2.21 (quint, J=6.0 Hz, 2H), 1.95-1.92 (m, 1H), 1.83-1.78 (m, 1H).
The title compound (8.3 mg, 25%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 5-bromo-1-naphthoate (20 mg, 0.075 mmol), CuI(5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.107 min, MS (ES) 707.2 (M+H); 1H NMR (500 MHz, Chloroform-d) 69.14 (s, 1H), 9.05 (t, J=9.7 Hz, 1H), 8.33 (dd, J=7.3, 4.3 Hz, 1H), 8.17 (d, J=10.0 Hz, 0.5H), 7.91 (d, J=10.0 Hz, 0.5H), 7.81 (dd, J=8.7, 1.7 Hz, 1H), 7.63 (dt, J=15.9, 8.0 Hz, 1H), 7.52 (q, J=8.5 Hz, 1H), 7.44 (d, J=10.0 Hz, 0.5H), 7.36 (dd, J=11.5, 8.0 Hz, 1.5H), 6.60 (d, J=9.0 Hz, 2H), 4.42 (dd, J=12.9, 3.8 Hz, 1H), 4.01 (q, J=6.0 Hz, 2H), 3.83-3.75 (m, 1H), 3.49-3.33 (m, 3H), 2.48 (s, 1.5H), 2.46 (s, 1.5H), 2.31 (s, 9H), 2.22 (h, J=7.5 Hz, 2H), 1.31 (d, J=3.9 Hz, 1.5H), 1.29 (d, J=3.9 Hz, 1.5H).
The title compound was prepared following the procedure described in Example 109 Step A and B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one and 8-bromoquinoline. MS (ES) 698.2 (M+H).
The title compound (6.3 mg, 19%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 5-bromo-1-naphthoate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=2.079 min, MS (ES) 707.2 (M+H).
The title compound (8.1 mg, 25%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 6-bromo-1-methyl-1H-indole-4-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.075 min, MS (ES) 710.2 (M+H), 1H NMR (500 MHz, Chloroform-d) δ 9.15 (s, 1H), 7.82-7.72 (m, 2H), 7.64 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.24 (d, J=3.1 Hz, 1H), 7.14 (d, J=3.2 Hz, 1H), 6.62 (s, 2H), 4.41 (dd, J=13.0, 3.6 Hz, 1H), 4.00 (t, J=6.2 Hz, 2H), 3.83 (s, 3H), 3.73 (d, J=6.0 Hz, 1H), 3.60 (d, J=12.7 Hz, 1H), 3.47-3.32 (m, 2H), 2.46 (s, 3H), 2.31 (s, 6H), 2.28 (s, 3H), 2.22 (q, J=6.9 Hz, 2H), 1.20 (d, J=6.4 Hz, 3H).
The title compound (16.3 mg, 49%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 3-bromo-1-methyl-1H-indole-6-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.061 min, MS (ES) 710.2 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 9.25 (s, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.63 (d, J=1.9 Hz, 1H), 7.58-7.51 (m, 1H), 7.34 (d, J=8.6 Hz, 1H), 6.65 (s, 2H), 4.35-4.30 (m, 4H), 4.01 (t, J=6.2 Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 3.18 (t, J=7.5 Hz, 2H), 2.45 (s, 6H), 2.34 (s, 6H), 2.23 (dd, J=10.0, 4.5 Hz, 2H), 1.73 (s, 2H).
The title compound (5.7 mg, 17%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 8-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.975 min, MS (ES) 715.2 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 9.25 (s, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.63 (d, J=1.9 Hz, 1H), 7.58-7.51 (m, 1H), 7.34 (d, J=8.6 Hz, 1H), 6.65 (s, 2H), 4.35-4.30 (m, 4H), 4.01 (t, J=6.2 Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 3.18 (t, J=7.5 Hz, 2H), 2.45 (s, 6H), 2.34 (s, 6H), 2.23 (dd, J=10.0, 4.5 Hz, 2H), 1.73 (s, 2H).
The title compound (9 mg, 27%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 6-bromo-1-methyl-1H-indazole-4-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.960 min, MS (ES) 711.3 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 9.22 (s, 1H), 8.51 (d, J=0.9 Hz, 1H), 7.83-7.76 (m, 2H), 7.74-7.70 (m, 1H), 7.36 (d, J=8.6 Hz, 1H), 6.65 (s, 2H), 4.11 (s, 3H), 4.02 (t, J=6.1 Hz, 2H), 3.89 (t, J=6.4 Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.22 (dd, J=8.3, 6.5 Hz, 2H), 2.40 (s, 6H), 2.32 (s, 6H), 2.20 (s, 2H), 1.90-1.85 (m, 2H).
The title compound (7.5 mg, 23%) was prepared following General coupling procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (25 mg, 0.046 mmol), methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (20 mg, 0.074 mmol), Pd2(dba)3 (4 mg, 0.0043 mmol), Xantphos (6 mg, 0.010 mmol), and Cs2CO3 (50 mg, 0.153 mmol) followed by saponification using General Procedure D. LCMS: RT=1.964 min, MS (ES) 710.2 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.25 (s, 1H), 8.02 (ddd, J=8.8, 4.1, 1.5 Hz, 1H), 7.79 (dd, J=8.6, 6.2 Hz, 1H), 7.37 (dd, J=24.7, 8.6 Hz, 2H), 7.16 (s, 1H), 6.65 (d, J=4.6 Hz, 2H), 4.01 (t, J=6.1 Hz, 2H), 3.90 (s, 2H), 3.84 (s, 3H), 3.79 (t, J=6.0 Hz, 2H), 3.21 (t, J=9.0 Hz, 2H), 2.40 (s, 6H), 2.32 (s, 6H), 2.25 (quint, J=6.0 Hz, 2H), 1.84-1.80 (m, 2H).
The title compound (22 mg, 62%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 2-chloroquinoline-5-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.323 min, MS (ES) 710.2 (M+H).
The title compound (56 mg, 61%) was prepared following General Procedure F using 1H-indole-5-carboxylic acid (46 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), NaH (25 mg, 0.62 mmol) and 1-iodopropane (61 μL, 0.48 mmol). LCMS: RT=1.761 min, MS (ES) 324.2 (M+H).
The title compound (29 mg, 78%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), propyl 3-bromo-1-propyl-1H-indole-5-carboxylate (15 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.104 min, MS (ES) 740.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J=1.6 Hz, 1H), 7.84-7.69 (m, 2H), 7.62 (dd, J=8.2, 1.7 Hz, 2H), 7.29 (d, J=8.6 Hz, 1H), 6.73 (s, 2H), 4.48 (dt, J=12.7, 3.2 Hz, 1H), 4.28-4.10 (m, 4H), 3.98 (s, 3H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.71-3.56 (m, 2H), 3.44-3.10 (m, 2H), 2.24 (s, 6H), 2.12 (s, 1.5H), 2.11-2.04 (m, 2H), 2.03 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.80 (h, J=7.4 Hz, 2H), 1.09 (d, J=6.4 Hz, 3H), 0.88 (td, J=7.4, 2.7 Hz, 3H).
To a stirred solution of 7-bromo-5-methyl-1H-indole (300 mg, 1.43 mmol) in DMF (1 mL) was added TFAA (0.24 mL, 1.71 mmol) dropwise at 0° C. The reaction solution was warmed up to rt and stirred overnight. The reaction was quenched with H2O (10 mL) then extracted with DCM (10 mL×2). The combined organic solution was dried and concentrated in vacuo. The residue was dissolved in H2O (1 mL) and NaOH (200 mg, 5.0) mmol) was added. The reaction mixture was refluxing for 3 h then neutralized with HCl (6N). The resulting mixture was extracted with EtOAc (20 mL×2). The combined organic solution was dried, concentrated and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 20-80% MeCN 0.1% TFA) to give the title compound (100 mg, 30%). LCMS: RT=1.252 min, MS (ES) 254.1 (M+H).
To a stirred solution of 7-bromo-5-methyl-1H-indole-3-carboxylic acid (100 mg, 0.394 mmol) in DMF (1 mL) was added NaH (38 mg, 1.57 mmol) at 0° C. After 15 min, MeI (0.098 mL, 1.574 mmol) was added, and the resulting mixture was stirred for 1 h. The reaction was quenched with H2O (3 mL) then extracted with DCM (10 mL×2). The combined organic solution was dried, concentrated to give the title compound. It was used for next step without further purification. MS (ES) 282.1 (M+H).
The title compound (70 mg, 60%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (200 mg, 0.37 mmol), methyl 7-bromo-1,5-dimethyl-1H-indole-3-carboxylate (115 mg, 0.41 mmol), Pd2(dba)3 (20 mg, 0.022 mmol). Xantphos (43 mg, 0.074 mmol), and Cs2CO3 (242 mg, 0.74 mmol) followed by saponification using General Procedure D. During the final purification step, the title compound was isolated as a separated atropisomer (1st fraction, absolute stereochemistry undetermined). LCMS: RT=2.044 min, MS (ES) 726.3 (M+H).
The title compound was prepared following the procedure described in Example 109 Step A and B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and ethyl 3-bromo-1,7-dimethyl-1H-indole-5-carboxylate. MS (ES) 712.2 (M+H).
The title compound (25 mg, 74%) was prepared according to procedures described in Example 137 Step A and B using ethyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,7-dimethyl-1H-indole-5-carboxylate (34 mg, 0.046 mmol) and (1-methylpiperidin-4-yl)methanol (30 mg, 0.23 mmol). LCMS: RT=1.767 min, MS (ES) 823.3 (M+H).
The title compound was isolated along with Example 159 as a separated atropisomer (2nd fraction, absolute stereochemistry undetermined). LCMS: RT=2.074 min, MS (ES) 726.3 (M+H).
The title compound (20 mg, 56%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indazole-5-carboxylate (17 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.994 min, MS (ES) 713.2 (M+H).
The title compound (51 mg, 61%) was prepared following General Procedure F using 1H-indole-5-carboxylic acid (46 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), NaH (25 mg, 0.62 mmol) and EtI (53 μL, 0.62 mmol). LCMS: RT=1.756 min, MS (ES) 296.1 (M+H).
The title compound (34 mg, 94%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), ethyl 3-bromo-1-ethyl-1H-indole-5-carboxylate (15 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.155 min, MS (ES) 726.3 (M+H).
The title compound (27 mg, 76%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indazole-7-carboxylate (15 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.058 min, MS (ES) 713.2 (M+H).
The title compound (28 mg, 30%) was prepared following General Procedure Fusing 1H-indole-5-carboxylic acid (46 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), NaH (25 mg, 0.62 mmol) and 2-iodopropane (61 μL, 0.62 mmol). LCMS: RT=1.765 min, MS (ES) 324.2 (M+H).
The title compound (13 mg, 37%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), isopropyl 3-bromo-1-isopropyl-1H-indole-5-carboxylate (15 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.087 min, MS (ES) 740.2 (M+H).
The title compound (87% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate followed by saponification using General Procedure D. MS (ES) 713.3 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 7.83 (d, J=4.8 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.75 (d, J=3.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 6.70 (s, 2H), 6.44 (dd, J=8.4, 3.2 Hz, 1H), 4.71-4.64 (m, 1H), 4.20-4.10 (m, 2H), 3.99-3.95 (m, 2H), 3.89 (s, 3H), 3.73 (s, 3H), 3.33-3.20 (m, 2H), 2.23 (s, 6H), 2.09 (s, 1.5H), 2.09-2.03 (m, 2H), 2.00 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.00 (dd, J=6.4, 3.6 Hz, 3H).
The title compound (3.8 mg, 12%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 7-bromo-1-methyl-1H-indole-3-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.056 min, MS (ES) 710.1 (M+H); 1H NMR (500 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.25 (d, J=7.9 Hz, 0.7H), 8.21 (d, J=7.9 Hz, 0.3H), 7.79 (s, 0.7H), 7.77 (s, 1.3H), 7.36 (d, J=8.9 Hz, 1.3H), 7.32 (d, J=7.8 Hz, 0.7H), 7.05 (d, J=7.6 Hz, 1.3H), 7.00 (d, J=7.6 Hz, 0.7H), 6.62 (s, 1.3H), 6.57 (s, 0.7H), 4.16 (dd, J=13.5, 3.5 Hz, 1H), 4.08-3.96 (m, 2H), 3.93 (s, 1H), 3.84-3.71 (m, 3H) 3.54 (dd, J=23.0, 13.2 Hz, 1H), 3.37 (dq, J=14.4, 7.2 Hz, 2H), 2.44 (s, 3H), 2.34-2.28 (m, 6H), 2.26 (s, 3H), 2.23-2.16 (m, 2H), 1.30 (d, J=6.5 Hz, 2H), 1.19 (d, J=6.5 Hz, 1H).
The title compound (90% yield) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate followed by saponification using General Procedure D. MS (ES) 713.3 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 8.47 (d, J=4.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.15 (d, J=5.2 Hz, 1H), 7.08 (s, 1H), 6.70 (s, 2H), 4.68-4.63 (m, 1H), 4.18-4.09 (m, 2H), 4.06 (s, 3H), 4.02-3.95 (m, 2H), 3.76 (s, 3H), 3.37-3.16 (m, 2H), 2.25 (s, 3H), 2.22 (s, 6H), 2.06 (s, 1.5H), 2.03-1.99 (m, 2H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 0.99 (d, J=6.4 Hz, 3H).
To a solution of methyl 2-oxoindoline-4-carboxylate (100 mg, 0.523 mmol) in DCE (5 mL) were added POBr3 (880 mg, 3.05 mmol) and imidazole (140 mg, 2.06 mmol). The reaction was heated to 80° C. and stirred for 16 h. The reaction was cooled to RT, quenched with H2O (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (27 mg, 20%).
The title compound (21 mg, 75%) was prepared following General Procedure F using methyl 2-bromo-1H-indole-4-carboxylate, NaH (6 mg, 0.25 mmol) and MeI (30 mg, 0.211 mmol).
The title compound (9.7 mg, 29%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 2-bromo-1-methyl-1H-indole-4-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.116 min, MS (ES) 712.1 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 7.84 (dt, J=7.7, 1.4 Hz, 1H), 7.56 (dd, J=8.6, 5.8 Hz, 1H), 7.41 (t, J=7.4 Hz, 1H), 7.22-7.14 (m, 2H), 6.88 (s, 1H), 6.46 (d, J=1.5 Hz, 2H), 4.29-4.09 (m, 2H), 3.87-3.83 (m, 2H), 3.79 (s, 3H), 3.52 (s, 1.5H), 3.51 (s, 1.5H), 3.47-3.37 (m, 1H), 3.27 (dtd, J=12.5, 7.3, 5.0 Hz, 1H), 3.19 (dt, J=13.6, 7.4 Hz, 1H), 2.17 (s, 6H), 2.10 (s, 1.5H), 2.09 (s, 1.5H), 2.05-2.02 (m, 2H), 1.93 (s, 1.5H), 1.91 (s, 1.5H), 1.07 (br. s, 1.5H), 1.03 (br. S, 1.5H).
The title compound (30 mg, 84%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 5-bromo-1-methyl-1H-indole-3-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (I mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.018 min, MS (ES) 712.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J=0.9 Hz, 1H), 7.94 (t, J=2.1 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.23 (td, J=8.9, 2.1 Hz, 1H), 6.74 (s, 2H), 4.49 (dd, J=12.9, 3.8 Hz, 1H), 4.21-4.10 (m, 1H), 4.01-3.94 (m, 3H), 3.88 (s, 3H), 3.78 (s, 15H), 3.77 (s, 15H), 3.23 (h, J=6.9 Hz, 2H), 2.25 (s, 6H), 2.12 (s, 15H), 2.07 (q, J=7.1, 6.5 Hz, 2H), 2.03 (s, 1.5H), 1.98 (s, 1.5H), 1.88 (s, 1.5H), 1.05 (dd, J=6.5, 3.8 Hz, 3H).
The title compound (26 mg, 73%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 4-bromoquinoline-6-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.816 min, MS (ES) 710.2 (M+H).
To a solution of 4-bromo-1H-indole-3-carboxylic acid (700 mg, 2.92 mmol) in THF (20 mL) and MeOH (1 mL) was added trimethylsilyldiazomethane (2.0 M solution in Et2O, 1.6 mL, 3.2 mmol) was added at 0° C., and the reaction mixture was stirred for 2 h then warmed to RT. The reaction was quenched with AcOH, concentrated in vacuo, and the crude residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to give methyl 4-bromo-1H-indole-3-carboxylic acid (513 mg, 69% yield). The title compound (52 mg, 93%) was prepared following General Procedure F using methyl 4-bromo-1H-indole-3-carboxylic acid (50 mg, 0.20 mmol), NaH (9 mg, 0.375 mmol) and EtBr (40 mg, 0.367 mmol).
The title compound (11.6 mg, 35%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 4-bromo-1-ethyl-1H-indole-3-carboxylate (20 mg, 0.071 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS. RT=1.996, 2.029 min, MS (ES) 726.1 (M+H).
The title compound (33 mg, 23%) was prepared following the procedures described in Example 170 Step A using methyl 2-oxoindoline-5-carboxylate (100 mg, 0.52 mmol), POBr3 (400 mg, 1.4 mmol), imidazole (100 mg, 1.47 mmol), and Step B using NaH (6 mg, 0.25 mmol) and MeI (30 mg, 0.21 mmol).
The title compound (8.9 mg, 27%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 2-bromo-1-methyl-1H-indole-5-carboxylate (20 mg, 0.074 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.097 min, MS (ES) 712.2 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 8.38 (s, 111), 8.00 (ddd, J=8.6, 3.0, 1.6 Hz, 1H), 7.72 (dd, J=8.6, 4.6 Hz, 1H), 7.39-7.30 (m, 2H), 6.62 (s, 2H), 6.41 (d, J=2.4 Hz, 1H), 4.44-4.24 (m, 2H), 4.03-4.00 (m, 2H), 3.96 (s, 3H), 3.69 (s, 1.5H), 3.68 (s 1.5H), 3.62-3.53 (m, 1H), 3.44 (dt, J=14.1, 7.3 Hz, 1H), 3.35 (dt, J=13.1, 7.5 Hz, 1H), 2.33 (d, J=1.3 Hz, 6H), 2.26 (s, 1.5H), 2.24 (s, 1.5H), 2.23-2.18 (m, 2H), 2.09 (s, 1.5H), 2.08 (s, 1.5H), 1.23 (d, J=6.2 Hz, 1.5H), 1.22 (d, J=6.2 Hz, 1.5H).
The title compound (9 mg, 25%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indazole-4-carboxylate (17 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.948 min, MS (ES) 713.2 (M+H).
The title compound (5.4 mg, 20%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), methyl 3-bromo-1-methyl-1H-indole-6-carboxylate (20 mg, 0.074 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (40 mg, 0.29 mmol) followed by saponification using General Procedure D. LCMS: RT=2.020 min, MS (ES) 710.2 (M+H).
The title compound (11.2 mg, 43%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (20 mg, 0.074 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (40 mg, 0.29 mmol) followed by saponification using General Procedure D. LCMS: RT=2.018 min, MS (ES) 710.2 (M+H); 1H NMR (500 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.30 (s, 1H), 8.00 (d, J1=10.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.36 (d, J=5.0 Hz, 1H), 7.35 (d, J=10.0 Hz, 1H), 6.62 (s, 2H), 4.38 (dd, J=13.1, 3.7 Hz, 1H), 4.00 (s, 2H), 3.83 (s, 3H), 3.74 (s, 1H), 3.62 (d, J=12.7 Hz, 1H), 3.39 (m, 2H), 2.44 (s, 3H), 2.31 (s, 6H), 2.29 (s, 3H), 2.25-2.18 (m, 3H), 1.24 (d, J=6.5 Hz, 3H).
The title compound (45 mg, 80%) was prepared following General Procedure G using ethyl 7-bromo-1H-indole-2-carboxylate (54 mg, 0.20 mmol), NaH (10 mg, 0.24 mmol) and MeI (15 μL, 0.24 mmol). LCMS: RT=1.882 min, MS (ES) 282.1 (M+H).
The title compound (16 mg, 45%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), ethyl 7-bromo-1-methyl-1H-indole-2-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.059 min, MS (ES) 712.2 (M+H).
The title compound (absoluted configuration unknown, 6 mg, 17%) was isolated from Example 175 using reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA, 10 mins gradient) as the second eluting stereoisomer. LCMS: RT=1.961 min, MS (ES) 713.2 (M+H).
The title compound (74 mg, 53%) was prepared following the procedures described in Example 170 Step A using methyl 2-oxoindoline-6-carboxylate (100 mg, 0.52 mmol), POBr3 (400 mg, 1.39 mmol), and imidazole (100 mg, 1.47 mmol) and Step B using NaH (15 mg, 0.63 mmol) and MeI (60 mg, 0.42 mmol).
The title compound (11.9 mg, 36%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 2-bromo-1-methyl-1H-indole-6-carboxylate (20 mg, 0.074 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS. RT=2.096 min, MS (ES) 712.2 (M+H); 1H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J=3.0 Hz, 1H), 7.66 (dt, J=8.3, 1.8 Hz, 1H), 7.52 (dd, J=8.6, 4.6 Hz, 1H), 7.41 (dd, J=8.3, 1.5 Hz, 1H), 7.13 (dd, J=8.6, 6.0 Hz, 1H), 6.42 (d, J=2.2 Hz, 2H), 6.16 (s, 1H), 4.28-4.02 (m, 2H), 3.90-3.78 (m, 2H), 3.74 (s, 3H), 3.51 (s, 1.5H), 3.50 (s, 1.5H), 3.41-3.31 (m, 1H), 3.29-3.22 (m, 1H), 3.14 (m, 1H), 2.13 (s, 6H), 2.05 (s, 1.5H), 2.03 (s, 1.5H), 2.02-1.97 (m, 2H), 1.88 (d, J=6.2 Hz, 3H), 1.03 (d, J=3.9 Hz, 1.5H), 0.97 (d, J=5.6 Hz, 1.5H).
The title compound (58 mg, 94%) was prepared following the procedure described in Example 173 Step A using methyl 4-bromo-1H-indole-3-carboxylate (50 mg, 0.20 mmol), NaH (9 mg, 0.38 mmol), and 1-bromo-2-methoxyethane (50 mg, 0.36 mmol).
The title compound (13.7 mg, 39%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 4-bromo-1-(2-methoxyethyl)-1H-indole-3-carboxylate (25 mg, 0.080 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=1.956, 1.908 min, MS (ES) 756.1 (M+H).
The title compound (51 mg, 97% yield) was prepared following the procedure described in Example 173 Step A using methyl 4-bromo-1H-indole-3-carboxylate (50 mg, 0.20 mmol), NaH (9 mg, 0.38 mmol), and MeI (50 mg, 0.35 mmol).
The title compound (11 mg, 34%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 4-bromo-1-methyl-1H-indole-3-carboxylate (20 mg, 0.074 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=1.952, 1.988 min, MS (ES) 712.00 (M+H).
The title compound was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-1,5-dimethyl-1H-indole-3-carboxylate followed by saponification using General Procedure D. MS (ES) 726.3 (M+H).
The title compound was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-bromoquinoline-2-carboxylate followed by saponification using General Procedure D. MS (ES) 710.2 (M+H); 1H NMR (MeOD, 400 MHz) δ (ppm) 8.56 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.08 (dd, J=7.6, 1.2 Hz, 1H), 7.83 (s, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.70 (s, 2H), 4.33-4.29 (m, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.85 (s, 3H), 3.72-3.62 (m, 2H), 3.51-3.31 (m, 2H), 2.28 (s, 6H), 2.24 (s, 1.5H), 2.22-2.15 (m, 2H), 2.17 (s, 1.5H), 2.09 (s, 1.5H), 2.09 (s, 1.5H), 2.02 (s, 1.5H), 1.31 (s, 3H).
The title compound (28 mg, 79%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 6-bromo-2-naphthoate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.120 min, MS (ES) 709.0 (M+H).
The title compound was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 5-bromo-2-naphthoate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol). Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound as the first eluting stereoisomer (absoluted configuration unknown). LCMS: RT=2.047 min, MS (ES) 709.0 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.84-8.65 (m, 1H), 8.16-7.94 (m, 2H), 7.86-7.67 (m, 2H), 7.68-7.56 (m, 1H), 7.49 (td, J=21.2, 7.8 Hz, 1H), 7.37-7.31 (m, 1H), 6.71-6.49 (m, 2H), 4.50 (qd, J=12.8, 4.0 Hz, 1H), 4.42-4.20 (m, 1H), 4.07-3.96 (m, 2H), 3.93 (s, 0.75H), 3.92 (s, 1.5H), 3.91 (s, 0.75H), 3.54-3.35 (m, 3H), 2.32 (s, 6H), 2.29-2.24 (m, 2H), 2.21 (s, 0.75H), 2.20 (s, 1.5H), 2.19 (s, 0.75H), 2.11 (s, 0.75H), 2.10 (s, 0.75H), 2.09 (s, 1.5H), 1.40-1.21 (m 3H).
The title compound was isolated along with Example 186 as the second eluting stereoisomer (absoluted configuration unknown). MS (ES) 709.0 (M+H).
The title compound (29 mg, 82%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(21)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-naphthoate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.123 and 2.140 min, MS (ES) 709.0 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.84 (dd, J=8.1, 1.8 Hz, 1H), 8.25 (t, J=1.9 Hz, 1H), 8.12 (s, 1H), 8.05-7.94 (m, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.71-7.56 (m, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.11 (s, 0.5H), 6.98 (s, 0.5H), 6.74 (s, 2H), 4.68-4.48 (m, 1H), 4.27-4.13 (m, 1H), 4.08-3.92 (m, 2H), 3.79 (s, 3H), 3.29 (ddt, J=41.8, 13.5, 6.4 Hz, 3H), 2.24 (s, 6H), 2.13 (s, 1.5H), 2.09 (s, 1.5H), 2.08-2.03 (m, 2H), 2.00 (s, 1.5H), 1.90 (s, 1.5H), 1.05 (dd, J=6.5, 1.6 Hz, 3H).
The title compound (21 mg, 59%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 4-bromo-1-naphthoate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.091 min, MS (ES) 709.0 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.91 (dd, J=8.9, 3.3 Hz, 1H), 8.27-8.12 (m, 1H), 7.92 (t. J=9.3 Hz, 1H), 7.82-7.76 (m, 1H), 7.75-7.47 (m, 3H), 7.40-7.27 (m, 1H), 6.70 (d, J=4.6 Hz, 2H), 4.77-4.52 (m, 1H), 4.36-4.09 (m, 1H), 4.04-3.86 (m, 2H), 3.78 (s, 1.5H), 3.75 (s, 1.5H), 3.67-3.54 (m, 2H), 3.26-3.10 (m, 1H), 2.24 (s, 6H), 2.14 (s, 1.5H), 2.12-2.06 (m, 2H), 2.05 (s, 15H), 2.01 (s, 1.5H), 1.92 (s, 1.5H), 1.24-1.08 (m, 3H).
The title compound (18 mg, 51%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 1-bromo-2-naphthoate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.065 and 2.092 min, MS (ES) 709.0 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.20-8.05 (m, 2.5H), 8.01 (dd, J=8.7, 2.1 Hz, 1H), 7.91-7.85 (m, 0.5), 7.78 (dd, J=8.6, 2.7 Hz, 1H), 7.74-7.60 (m, 1.5H), 7.58 (d, J=7.6 Hz, 0.5H), 7.33 (dd, J=8.6, 2.1 Hz, 1H), 6.70 (d, J=4.8 Hz, 2H), 4.40 (dq, J=10.5, 6.2, 5.2 Hz, 1H), 4.29-4.14 (m, 1H), 3.95 (t, J=6.5 Hz, 2H), 3.78 (s, 1.5H), 3.75 (s, 1.5H), 3.30-3.14 (m, 3H), 2.22 (s, 6H), 2.16 (s, 1H), 2.13 (s, 0.5H), 2.10 (s, 0.5H), 2.07 (s, 1H), 2.05 (s, 0.5H), 2.04-1.98 (m, 2H), 1.96 (s, 1H), 1.92 (s, 0.5H), 1.87 (s, 1H), 1.32-1.10 (m, 3H).
The title compound (7 mg, 20%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 8-bromo-1-naphthoate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.012 min, MS (ES) 709.0 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.13 (dd, J=7.5, 2.1 Hz, 1H), 8.04 (dd, J=8.3, 1.2 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.63-7.53 (m, 2H), 7.52-7.42 (m, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.75 (s, 2H), 4.49 (dd, J=13.8, 3.9 Hz, 1H), 4.29-4.10 (m, 1H), 3.95 (q, J=6.4 Hz, 2H), 3.80 (s, 1.5H), 3.78 (s, 1.5H), 3.26-3.04 (m, 3H), 2.24 (s, 6H), 2.13 (s, 1.5H), 2.11-2.04 (m, 2H), 2.03 (s, 1.5H), 2.00 (s, 1.5H), 1.91 (s, 1.5H), 1.17 (d, J=6.5 Hz, 3H).
The title compound (11 mg, 30%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 7-bromo-4-methoxy-1-methyl-1H-indole-2-carboxylate (18 mg, 0.06 mmol), Pd2(dba)3(1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3(25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.094 min, MS (ES) 742.0 (M+H).
The title compound (61 mg, 51%) was prepared following General procedure Fusing 5-(trifluoromethyl)-1H-indole (80 mg, 0.43 mmol), NBS (100 mg, 0.561 mmol), NaH (18 mg, 0.75 mmol), and MeI (90 mg, 0.63 mmol).
The title compound (7.6 mg, 29%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), 3-bromo-1-methyl-5-(trifluoromethyl)-1H-indole (20 mg, 0.072 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. The title compound was separated using reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-90% CH3CN, 0.1% TFA) during the final purification step to give as a separated atropisomer (2nd fraction, absolute stereochemistry undetermined). LCMS: RT=2.293, min, MS (ES) 736.0 (M+H).
The title compound (19 mg, 54%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 7-bromobenzofuran-2-carboxylate (13 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.103 min, MS (ES) 699.0 (M+H).
The title compound (8 mg, 24%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 7-bromo-2,3-dihydro-1H-inden-1-one (11 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.069 min, MS (ES) 669.1 (M+H).
The title compound (29 mg, 83%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 5-bromobenzofuran-2-carboxylate (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.130 min, MS (ES) 699.0 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=2.2 Hz, 2H), 7.74 (d, J=2.5 Hz, 1H), 7.68 (d, J=1.0 Hz, 1H), 7.49 (ddd, J=8.9, 3.6, 2.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.73 (s, 2H), 4.47 (d, J=11.4 Hz, 2H), 4.19-4.11 (m, 1H), 3.99 (s, 3H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.74-3.61 (m, 2H), 3.22 (dt, J=13.4, 7.4 Hz, 2H), 2.26 (s, 6H), 2.12 (s, 1.5H), 2.08 (d, J=13.1 Hz, 2H), 2.03 (s, 1.5H), 1.97 (s, 1.5H), 1.88 (s, 1.5H), 1.04 (d, J=6.4 Hz, 3H).
The title compound (35 mg, 59%) was prepared following General Procedure G using methyl 4-bromo-1H-indole-2-carboxylate (51 mg, 0.20 mmol), NaH (10 mg, 0.24 mmol) and 2-iodopropane (15 μL, 0.44 mmol). LCMS: RT=1.901 min, MS (ES) 296.0 (M+H).
The title compound (21 mg, 57%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 4-bromo-1-isopropyl-1H-indole-2-carboxylate (15 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.192 and 1.257 min, MS (ES) 740.1 (M+H).
The title compound (53 mg, 75%) was prepared following General Procedure G using methyl 4-bromo-1H-indole-2-carboxylate (51 mg, 0.20 mmol), NaH (10 mg, 0.24 mmol) and 4-(bromomethyl)tetrahydro-2H-pyran (32 μL, 0.24 mmol). LCMS: RT=1.776 min, MS (ES) 352.0 (M+H).
The title compound (31 mg, 78%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 4-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-2-carboxylate (21 mg, 0.06 mmol), Pd2(dba)3 (I mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using Procedure D. LCMS: RT=2.079 min, MS (ES) 796.0 (M+H).
The title compound (115 mg, 38%) was prepared following General procedure F using 6-(trifluoromethyl)-1H-indole (200 mg, 1.08 mmol), NBS (240 mg, 1.35 mmol), NaH (70 mg, 2.92 mmol), and MeI (220 mg, 1.55 mmol).
The title compound (7.4 mg, 28%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), 3-bromo-1-methyl-6-(trifluoromethyl)-1H-indole (20 mg, 0.072 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. The title compound was separated using reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-90% CH3CN, 0.1% TFA) during the final purification step to give as a separated atropisomer (2nd fraction, absolute stereochemistry undetermined). LCMS: RT=2.312 min, MS (ES) 736.0 (M+H); 1H NMR (400 MHz, Chloroform-d) 7.74 (dd, J=8.6, 3.5 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.41-7.34 (m, 1H), 7.34-7.28 (m, 2H), 6.61 (s, 2H), 4.41 (d, J=11.9 Hz, 1H), 4.22 (s, 1H), 4.05 (s, 3H), 4.00 (tt, J=6.2, 3.1 Hz, 2H), 3.88 (s, 2H), 3.85 (s, 1H), 3.64 (d, J=12.6 Hz, 1H), 3.39 (m, 2H), 2.31 (d, J=2.0 Hz, 6H), 2.27 (s, 3H), 2.22 (m, 5H), 1.23 (d, J=5.5 Hz, 1H), 1.19 (d, J=5.5 Hz, 2H).
The title compound (6.9 mg, 26%) was separated as the 1st eluting atropisomer with Example 193. LCMS: RT=2.267 min, MS (ES) 736.0 (M+H).
The title compound (24 mg, 43%) was prepared following General Procedure G using 7-bromo-5-methyl-1H-indole-2-carboxylic acid (51 mg, 0.20 mmol), NaH (16 mg, 0.40 mmol) and MeI (26 μL, 0.40 mmol). LCMS: RT=1.761 min, MS (ES) 282.1 (M+H).
The title compound (22 mg, 61%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 7-bromo-1,5-dimethyl-1H-indole-2-carboxylate (17 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=1.163 min, MS (ES) 726.1 (M+H).
The title compound (6.5 mg, 24%) was separated as the 1st eluting atropisomer with Example 199. LCMS. RT=2.285 min, MS (ES) 736.0 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J=8.6 Hz, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.32 (dd, J=8.8, 3.8 Hz, 2H), 6.61 (s, 2H), 4.40 (s, 1H), 4.09 (s, 4H), 4.03-3.93 (m, 2H), 3.89 (s, 2H), 3.86 (s, 1H), 3.66 (s, 1H), 3.52-3.27 (m, 2H), 2.35 (s, 3H), 2.32 (s, 6H), 2.23-2.11 (m, 5H), 1.26 (s, 3H).
The title compound (24 mg, 72%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 4-bromo-2,3-dihydro-1H-inden-1-one (II mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.104 min, MS (ES) 669.1 (M+H).
The title compound (12 mg, 33%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (16 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol). The title compound was isolated as the first eluting stereoisomer from reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA). LCMS: RT=2.146 min, MS (ES) 726.1 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J=1.6, 0.6 Hz, 1H), 7.98 (dd, J=8.7, 1.6 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.38 (dd, J=8.8, 0.7 Hz, 1H), 7.34-7.30 (m, 2H), 6.64 (s, 2H), 4.47 (dd, J=12.6, 3.8 Hz, 1H), 4.13 (s, 1H), 4.02 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.71 (dd, J=12.5, 1.7 Hz, 1H), 3.41 (ddt, J=37.4, 13.2, 7.4 Hz, 2H), 2.33 (s, 6H), 2.26 (s, 3H), 2.25-2.17 (m, 2H), 2.0) (s, 3H), 1.27 (d, J=6.5 Hz, 3H).
The title compound (26 mg, 36%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (54 mg, 0.1 mmol), methyl 7-bromo-1-methyl-1H-indole-3-carboxylate (32 mg, 0.12 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), Xantphos (3.5 mg, 0.006 mmol), and Cs2CO3 (49 mg, 0.15 mmol). LCMS: RT=2.162 and 2.193 min, MS (ES) 726.3 (M+H).
The title compound (34 mg, 98%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 3-bromo-1-methyl-1H-indole-6-carbonitrile (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol). LCMS: RT=2.165 min, MS (ES) 693.1 (M+H).
The title compound (10 mg, 27%) was isolated as the second eluting stereoisomer along with Example 204 from reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA). LCMS: RT=2.167 min, MS (ES) 726.1 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=1.5 Hz, 1H), 7.98 (dd, J=8.7, 1.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.33-7.28 (m, 2H), 6.64 (s, 2H), 4.43 (dd, J=12.8, 3.8 Hz, 1H), 4.34-4.24 (m, 1H), 4.02 (tt. J=6.2, 3.3 Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.70 (dd, J=12.8, 1.6 Hz, 1H), 3.54-3.23 (m, 2H), 2.33 (s, 6H), 2.24 (s, 3H), 2.23-2.15 (m, 2H), 2.09 (s, 3H), 1.24 (d, J=6.5 Hz, 3H).
The title compound (33 mg, 95%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 3-bromo-1-methyl-1H-indole-5-carbonitrile (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol). LCMS: RT=1.214 min, MS (ES) 693.0 (M+H).
The title compound (26 mg, 75%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 3-bromo-1-methyl-1H-indole-7-carbonitrile (14 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol). MS (ES) 693.2 (M+H).
The title compound (2 mg, 8%) was prepared following General coupling procedure B using ((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 4-bromo-1-methyl-1H-indole-2-carboxylate (20 mg, 0.074 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.071 min, MS (ES) 710.1 (M+H).
A mixture of methyl 4-bromo-1H-indole-6-carboxylate (125 mg, 0.49 mmol), 1-(trifluoromethyl)-1λ3-benzo[d][1,2]iodoxyl-3(1H)-one (100 mg, 0.54 mmol), and copper (I) acetate (5 mg, 0.04 mmol) were dissolved in MeOH (5 mL). The reaction mixture was purged with Ar for 5 min, sealed, and stirred at RT for 4 h. The reaction was then heated to 40° C. for 36 h. The reaction was cooled to RT, diluted with DCM/H2O (20 mL, 1:1), the layers separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford methyl 4-bromo-2-(trifluoromethyl)-1H-indole-6-carboxylate (44 mg, 28% yield). The resultant product was methylated following General coupling procedure G using NaH (6 mg, 0.25 mmol) and MeI (40 mg, 0.28 mmol) to afford the title compound (28 mg, 61% two steps).
The title compound (3 mg, 8%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 4-bromo-1-methyl-2-(trifluoromethyl)-1H-indole-6-carboxylate (28 mg, 0.083 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.187 min, MS (ES) 780.0 (M+H).
The title compound (8% yield) was prepared following General coupling procedure A using (S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromo-1-methyl-1H-indole-5-carboxylate followed by saponification using General Procedure D. MS (ES) 712.2 (M+H).
The title compound (4.8 mg, 18%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), methyl 5-bromo-2-naphthoate (15 mg, 0.056 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.065 min, MS (ES) 707.0 (M+H).
The title compound was isolated as a separated atropisomer (1st fraction, absolute stereochemistry undetermined) from mixture of atropisomers. MS (ES) 712.2 (M+H).
The title compound was isolated as a separated atropisomer (2nd fraction, absolute stereochemistry undetermined) from mixture of atropisomers. MS (ES) 712.2 (M+H).
The title compound was separated from diasteromeric (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one using reverse phase HPLC. Absolute stereochemistry was determined by single crystal X-ray structure. [α]d25=−138.7.
The title compound was separated from diasteromeric (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one using reverse phase HPLC along with Example 216. Absolute stereochemistry was determined by single crystal X-ray structure. [α]d25=−182.4.
The title compound (5.8 mg, 22%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 5-bromo-2-naphthoate (15 mg, 0.057 mmol), CuI(5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.037 min, MS (ES) 706.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.63 (d, J=1.6 Hz, 1H), 8.00 (dt, J=8.9, 1.1 Hz, 1H), 7.89 (dt, J=17.6, 8.8 Hz, 1.5H), 7.74 (dd, J=8.6, 2.1 Hz, 1H), 7.67 (d, J=8.8 Hz, 0.5 Hz), 7.52 (ddd, J=13.5, 8.3, 7.3 Hz, 1H), 7.44 (dd, J=7.3, 1.2 Hz, 0.5H), 7.34 (dd, J=7.4, 1.1 Hz, 0.5H), 7.30 (s, 1H), 7.19 (s, 1H), 6.53 (s, 1H), 6.51 (s, 1H), 4.39 (dd, J=26.2, 11.3 Hz, 1H), 3.92 (q, J=5.9 Hz, 2H), 3.70 (s, 1H), 3.32 (dtt, J=27.9, 13.5, 7.1 Hz, 3H), 2.43 (s, 1.5H), 2.42 (s, 1.5H), 2.27 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.13 (q, J=6.9 Hz, 2H), 1.23 (d, J=6.8 Hz, 1.5H), 1.21 (d, J=6.8 Hz, 1.5H).
The title compound (2.5 mg, 9%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), ethyl 7-bromo-1-methyl-1H-indole-2-carboxylate (15 mg, 0.053 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.039 min, MS (ES) 710.1 (M+H).
The title compound (4.5 mg, 17%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (20 mg, 0.037 mmol), methyl 4-bromoquinoline-6-carboxylate (10 mg, 0.037 mmol), CuI(5 mg, 0.026 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=1.786 min, MS (ES) 708.0 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 9.11 (s, 1H), 8.65 (s, 1H), 8.41 (q, J=8.8 Hz, 2H), 7.79 (d, J=8.6 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.32 (d, J=4.5 Hz, 1H), 6.62 (s, 2H), 4.11-3.96 (m, 4H), 3.90 (s, 2H), 3.22 (t, J=7.4 Hz, 2H), 2.36 (s, 6H), 2.30 (s, 6H), 2.24 (quint, J=7.1, 6.6 Hz, 2H), 1.86 (br s, 2H).
The title compound (5.2 mg, 52%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (10 mg, 0.078 mmol), and 7 M ammonia in MeOH (0.05 mL, 0.35 mmol). LCMS: RT=1.924 min, MS (ES) 711.0 (M+H).
To a solution of 6-(methylsulfonyl)-1H-indole (50 mg, 0.26 mmol) in DMF (3 mL) was added NaH (14 mg, 0.58 mmol) and stirred at RT for 30 min. MeI (70 mg, 0.49 mmol) was added and the reaction was stirred at RT for 3 h, diluted into DCM (10 mL), quenched with H2O (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to give 1-methyl-6-(methylsulfonyl)-1H-indole. The product was dissolved in DMF (3 mL), cooled to 0° C., and NBS (60 mg, 0.34 mmol) was added. After 30 min, the reaction was diluted into DCM (20 mL), washed with 10% aqueous Na2S2O3, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (52 mg, 70%).
The title compound (18.3 mg, 65%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), 3-bromo-1-methyl-6-(methylsulfonyl)-1H-indole (20 mg, 0.069 mmol), CuI(5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol). LCMS: RT=2.015, 2.034 min, MS (ES) 745.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 8.04 (t, J=1.0 Hz, 1H), 7.75-7.60 (m, 3H), 7.39 (d, J=6.0 Hz, 1H), 7.31 (dd, J=8.0, 4.0 Hz, 1H), 6.62 (d, J=1.6 Hz, 2H), 4.42 (dt, J=12.2, 4.2 Hz, 1H), 4.35-4.18 (m, 1H), 4.01 (td, J=5.4, 4.5, 2.5 Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.66-3.56 (m, 1H), 3.51-3.29 (m, 2H), 3.10 (s, 3H), 2.33 (s, 6H), 2.28-2.14 (m, 5H), 2.09 (s, 1.5H), 2.07 (s, 1.5H), 1.26 (d, J=6.4 Hz, 1.5H), 1.19 (d, J=6.4 Hz, 1.5H).
The title compound (17.4 mg, 67%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), 3-bromo-1-methyl-5-nitro-1H-indole (20 mg, 0.078 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol). LCMS: RT=2.136, 2.159 min, MS (ES) 712.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 8.50 (dd, J=6.2, 2.2 Hz, 1H), 8.18 (dd, J=9.1, 2.2 Hz, 1H), 7.71 (dd, J=8.6, 2.2 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 7.37 (s, 0.5H), 7.32-7.29 (m, 1.5H), 6.66-6.61 (m, 2H), 4.49-4.23 (m, 2H), 4.06-3.98 (m, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.65 (dd, J=12.3, 7.2 Hz, 1H), 3.53-3.29 (m, 2H), 2.33 (s, 6H), 2.28-2.16 (m, 5H), 2.08 (d, J=1.4 Hz, 3H), 1.26 (d, J=6.4 Hz, 1.5H), 1.24 (d, J=6.4 Hz, 1.5H).
The title compound (11.8 mg, 45%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 8-bromoquinoline-5-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=1.990 min, MS (ES) 707.8 (M+H).
The title compound (13.9 mg, 52%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 8-bromoquinoline-4-carboxylate (20 mg, 0.075 mmol). CuI (5 mg, 0.026 mmol). (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=2.012 min, MS (ES) 707.8 (M+H).
The title compound (71 mg, 70%) was prepared following the procedure described in Example 86 Steps B and C using ethyl 7-bromo-1-methyl-1H-indole-2-carboxylate (100 mg, 0.56 mmol), tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (180 mg, 0.81 mmol). NaH (24 mg, 1.0 mmol), HCl (4.0 M in dioxanes, 2 mL, 8.0 mmol), and K2CO3 (150 mg, 1.09 mmol).
The title compound (18 mg, 86%) was prepared following General Procedure G using 6-bromo-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.075 mmol), NaH (3 mg, 0.13 mmol), and MeI (20 mg, 0.14 mmol).
The title compound (6.1 mg, 18%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), 6-bromo-2-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (18 mg, 0.0(4 mmol), CuI(5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (20 mg, 0.15 mmol). MS (ES) 736.9 (M+H).
The title compound (15.4 mg, 58%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 8-bromoquinoline-3-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=2.002 min, MS (ES) 707.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 9.39 (d, J=1.9 Hz, 1H), 9.22 (s, 1H), 8.88 (d, J=2.0 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.88-7.77 (m, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 6.62 (s, 2H), 4.71 (s, 1H), 4.00 (t, J=6.1 Hz, 2H), 3.75 (s, 1H), 3.52 (s, 1H), 3.39 (m, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 2.31 (s, 6H), 2.23 (quint, J=7.0, 6.3 Hz, 2H), 1.33 (d, J=5.9 Hz, 3H).
A mixture of 2-chloro-4,6-dimethylpyrimidine (1.0 g, 7.0 mmol), 1-methylpiperazine (750 mg, 7.5 mmol), and K2CO3 (1.5 g, 10.9 mmol) in MeCN (10 mL) was heated to 50° C. for 72 h. Reaction was diluted with DCM/H2O (60 mL, 1:1), the organic layer was separated, and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.39 g, 96%).
To a solution of 4,6-dimethyl-2-(4-methylpiperazin-1-yl)pyrimidine (1.39 g, 6.75 mmol) in CHCl3 (10 mL) and NBS (1.25 g, 7.02 mmol) was added. The reaction was heated to 65° C. for 10 min then cooled to RT. The reaction mixture was diluted with DCM/H2O (60 mL, 1:1) and extracted with DCM (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound (1.66 g, 86%).
To a solution of 5-bromo-4,6-dimethyl-2-(4-methylpiperazin-1-yl)pyrimidine (250 mg, 0.88 mmol) in toluene/THF (4 mL %1 mL) was added triisopropyl borate (250 mg, 1.33 mmol), and the reaction was cooled to −40° C. n-Butyllithium (2.5 M, 0.48 mL, 1.20 mmol) was added over 1 h and stirred for 30 min, then warmed to −20° C. over 1 h. The reaction was quenched with 1 M HCl, the organic layer was removed, and the aqueous layer was adjusted to pH 7 with IM NaOH. The aqueous layer was extracted with 10% iPrOH in CHCl3 (3×30 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (140 mg, 56%).
A mixture of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (100 mg, 0.20 mmol), (4,6-dimethyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)boronic acid (75 mg, 0.32 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), S-Phos (25 mg, 0.061 mmol), and potassium phosphate (130 mg, 0.61 mmol) in THF (3 mL) and toluene (3 mL) was sparged with Ar for 5 min. The reaction was heated to 110° C. for 24 h then cooled to RT and diluted with DCM/H2O (20 mL, 1:1). The layers were separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf. Hex/EtOAc=0-100% gradient) to give the title compound (52 mg, 42%).
The title compound (31 mg, 58%) was prepared following the procedures described in Example 120 Steps B and C using ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-indole-2-carboxylate (52 mg, 0.083 mmol), tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (30 mg, 0.13 mmol), NaH (8 mg, 0.20 mmol), HCl in dioxanes (4.0 M, 0.5 mL, 2.0 mmol), and K2CO3 (30 mg, 0.22 mmol).
The title compound (13 mg, 33%) was prepared following General coupling procedure B using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (31 mg, 0.049 mmol), methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (30 mg, 0.11 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=1.760 min, MS (ES) 808.0 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.18 (s, 1H), 6.64 (s, 2H), 5.04 (d, J=11.2 Hz, 2H), 4.11 (t, J=6.4 Hz, 2H), 4.00 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 3.77 (t, J=6.2 Hz, 4H), 3.56 (s, 2H), 3.21 (t, J=7.4 Hz, 2H), 2.92 (s, 5H), 2.31 (s, 6H), 2.28-2.19 (m, 2H), 2.12 (s, 6H), 1.91 (d, J=6.0 Hz, 2H).
The title compound (15 mg, 59%) was prepared following General Procedure G using 6-bromo-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.075 mmol), NaH (3 mg, 0.13 mmol), and isovaleryl bromide (25 mg, 0.17 mmol).
The title compound (4.7 mg, 13%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), 6-bromo-2-isopentyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (15 mg, 0.045 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=2.177 min, MS (ES) 793.0 (M+H).
The title compound (11 mg, 30%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 8-bromo-4-chloroquinoline-2-carboxylate (19 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.089 min, MS (ES) 743.9 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.31 (dt, J=7.8, 1.5 Hz, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.04-7.90 (m, 2H), 7.77 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 6.72 (s, 2H), 4.77-4.55 (m, 1H), 4.27-4.12 (m, 1H), 3.96 (t, J=6.5 Hz, 2H), 3.78 (s, 1.5H), 3.76 (s, 1.5H), 3.35-3.12 (m, 3H), 2.23 (s, 6H), 2.13 (s, 1.5H), 2.11-2.04 (m, 2H), 2.02 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.37-1.16 (m, 3H).
The title compound (96 mg, 88%) was prepared following General Procedure F using methyl 1H-indole-5-carboxylate (50 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), NaH (14 mg, 0.34 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (60 μL, 0.34 mmol). LCMS: RT=1.979 min, MS (ES) 384.0 (M+H).
The title compound (30 mg, 72%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carboxylate (23 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-diethylaminoxy clohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.257 min, MS (ES) 828.0 (M+H).
The title compound (II mg, 30%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 7-bromo-5-chlorobenzofuran-2-carboxylate (19 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D The title compound was isolated as a separated atropisomer (1st fraction, absolute stereochemistry undetermined) by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA). LCMS: RT=2.138 min, MS (ES) 732.9 (M+H).
The title compound (210 mg, 52%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (300 mg, 0.55 mmol), ethyl 7-bromo-1H-indole-2-carboxylate (300 mg, 1.10 mmol), CuI (50 mg, 0.26 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (80 mg, 0.56 mmol), and K2CO3 (250 mg, 1.81 mmol).
The title compound (6.8 mg, 35%) was obtained following General Procedure D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (20 mg, 0.027 mmol) and isolated as a separated atropisomer (1st fraction, absolute stereochemistry undetermined) by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-90% CH3CN, 0.1% TFA). LCMS: RT=1.954 min, MS (ES) 697.9 (M+H).
The title compound was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 7-bromo-1H-indole (12 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol).
The title compound (17 mg, 51%) was prepared following General procedure G using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(1H-indol-7-yl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one, NaH (5 mg, 0.12 mmol) and MeI (8 μL, 0.12 mmol). LCMS: RT=2.169 and 2.194 min, MS (ES) 667.9 (M+H).
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carbonitrile (69 mg, 0.1 mmol) in DMF (2 mL) were added sodium azide (33 mg, 0.5 mmol), ammonium chloride (27 mg, 0.5 mmol) and the mixture was heated at 120° C. for 12 h then cooled to ambient temperature. The reaction mixture was quenched with H2O (5 mL), extracted with CH2Cl2(3×15 ML), dried (anhyd. Na2SO4), and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (25 mg, 34%) as the second eluting atropisomer (absolute configuration undetermined). LCMS: RT=2.007 min, MS (ES) 736.0 (M+H).
The title compound (13 mg, 80%) was prepared according to the procedure for Example 235 using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carbonitrile (15 mg, 0.022 mmol). LCMS: RT=2.045 min, MS (ES) 736.0 (M+H).
The title compound (9 mg, 27%) was prepared following General coupling procedure B as the first eluting atropisomer (absolute configuration undetermined) using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 3-bromobenzofuran (13 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol). LCMS: RT=2.260 min, MS (ES) 655.0 (M+H).
The title compound (23 mg, 58%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol), ethyl 7-bromo-1-methyl-1H-indole-2-carboxylate (30 mg, 0.11 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), Xantphos (15 mg, 0.026 mmol), and Cs2CO3 (80 mg, 0.246 mmol) followed by saponification using General Procedure D. LCMS. RT=1.957 min, MS (ES) 709.9 (M+H).
The title compound (16 mg, 44%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 8-bromo-4-chloroquinoline-2-carboxylate (19 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.019 and 2.034 min, MS (ES) 739.9 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.20 (dd, J=8.4, 1.3 Hz, 1H), 7.83 (ddd. J=7.4, 3.1, 1.5 Hz, 1H), 7.78-7.68 (m, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.73 (s, 2H), 4.88-4.49 (m, 1H), 4.31-4.18 (m, 1H), 4.15 (s, 3H), 3.97 (t, J=6.4 Hz, 2H), 3.78 (s, 1.5H), 3.75 (s, 1.5H), 3.34-3.15 (m, 3H), 2.24 (s, 6H), 2.13 (s, 1.5H), 2.11-2.04 (m, 2H), 2.02 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.36-1.15 (m, 3H).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carboxylate (15 mg, 0.019 mmol) in DCM (1 mL) was added TFA (1 mL), and the mixture was stirred at RT for 6 h. Saturated aqueous NaHCO3(8 mL) was added to the mixture and extracted with DCM (3×5 mL). The organic layer was dried (anhyd. Na2SO4) and concentrated in vacuo. The crude product was alkylated following General procedure G using NaH (5 mg, 0.12 mmol) and 4-(2-bromoethyl)tetrahydro-2H-pyran (6 mg, 0.031 mmol) followed by saponification using General Procedure D to afford the title compound (8 mg, 52%). LCMS: RT=2.168 min, MS (ES) 810.3 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) in DMF (1 mL) was added NaH (2 mg, 0.08 mmol), and the reaction was stirred at RT for 30 min. Benzyl bromide (5 mg, 0.029 mmol) was added, and the reaction was stirred for 16 h at RT then diluted with DCM/H2O (20 mL, 1:1). The mixture was extracted with DCM (2×5 mL), dried by passing through a phase separator and concentrated in vacuo. The crude reaction product was then saponified and purified following General Procedure D to afford the title compound (6.9 mg, 64% yield). LCMS: RT=2.084 min, MS (ES) 787.8 (M+H).
The title compound (8.1, 42% yield) was prepared in the same procedure as described in Example 233 as the 2nd fraction. LCMS: RT=1.953 min, MS (ES) 697.9 (M+H).
The title compound (37 mg, 88%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carboxylate (23 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3(25 mg, 0.075 mmol). LCMS: RT=2.451 min, MS (ES) 841.9 (M+H).
To a solution of ethyl 7-bromo-1H-indole-5-carboxylate (97 mg, 0.36 mmol) in DMF (2 mL) was added NaH (17 mg, 0.43 mmol) and the mixture was stirred at RT for 10 min. Methyl iodide (27 μL, 0.43 mmol) was added to the mixture and stirred at ambient temperature for 2 h. The mixture was diluted with water (5 mL) and was extracted in CH2Cl2 (3×5 mL). The organic layer was dried (anhyd. Na2SO4) and concentrated. The crude was subjected to General Procedure B using sodium cyanide (22 mg, 0.43 mmol), CuI (7 mg, 0.04 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (57 μL, 0.36 mmol), and K2CO3 (120 mg, 0.72 mmol) and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-20% gradient). To a solution of resulted ethyl 7-cyano-1-methyl-1H-indole-5-carboxylate in DMF (2 mL) was added and NBS (51 mg, 0.28 mmol) at 0° C. and stirred for 1 h. Same work up and purification protocols described in general coupling procedure A were followed to afford the title compound (52 mg, 47%). LCMS: RT=1.672 min, MS (ES) 307.0 (M+H).
The title compound (25 mg, 68%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), ethyl 3-bromo-7-cyano-1-methyl-1H-indole-5-carboxylate (19 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.006 min, MS (ES) 736.9 (M+H).
The title compound (7.3 mg, 84%) was prepared following the procedure described Example 241 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (8 mg, 0.011 mmol), NaH (2 mg, 0.05 mmol) and 3-chloromethylpyridine HCl salt (5 mg, 0.031 mmol). LCMS: RT=1.760, 1.786 min, MS (ES) 789.0 (M+H).
The title compound (II mg, 33%) was prepared following General coupling procedure B as the second eluting atropisomer (absolute configuration undetermined) along with Example 237. LCMS: RT=2.238 min, MS (ES) 655.0 (M+H).
The title compound (4 mg, 37%) was prepared following the procedure described Example 241 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) NaH (2 mg, 0.05 mmol) and 2-bromomethylpyridine HBr salt (5 mg, 0.020 mmol). LCMS: RT=1.839 min (major), 1.867 min (minor), MS (ES) 789.0 (M+H).
The title compound (5.7 mg, 53%) was prepared following the same procedure as described for Example 247, substituting 3-bromomethylpyridine HBr with 4-bromomethylpyridine HBr salt (5 mg, 0.020 mmol). LCMS: RT=1.817 min, MS (ES) 788.8 (M+H).
The title compound (2.1 mg, 19%) was separated from Example 247 by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) as the 1 eluting atropisomer (absolute stereochemistry undetermined). LCMS: RT=1.839 min, MS (ES) 789.0 (M+H).
The title compound (65 mg, 81%) was prepared following General Procedure F using methyl 7-methyl-1H-indole-6-carboxylate (50 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), NaH (14 mg, 0.34 mmol) and MeI (22 μL, 0.34 mmol). LCMS: RT=1.602 min, MS (ES) 282.1 (M+H).
The title compound (27 mg, 74%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 3-bromo-1,7-dimethyl-1H-indole-6-carboxylate (15 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.043 min, MS (ES) 726.0 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J=8.6 Hz, 1H), 7.49 (d, J=3.3 Hz, 1H), 7.39 (dd, J=8.4, 2.7 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.21 (dd, J=8.4, 4.7 Hz, 1H), 6.72 (s, 2H), 4.44 (dd, J=13.0, 3.9 Hz, 2H), 4.11 (s, 3H), 3.98 (tt, J=6.4, 2.7 Hz, 2H), 3.78 (s, 1.5H), 3.77 (s 1.51H), 3.58 (t, J=11.2 Hz, 1H), 3.39-3.16 (m, 2H), 2.95 (s, 3H), 2.25 (s, 6H), 2.12 (s, 1.5H), 2.11-2.04 (m, 2H), 2.04 (s, 1.5H), 1.97 (s, 1.5H), 1.88 (s, 1.5H), 1.07 (d, J=6.5 Hz, 3H).
The title compound (28 mg, 38%) was isolated along with Example 235 as the first eluting atropisomer (absolute configuration undetermined). LCMS: RT=1.981 mm. MS (ES) 736.0 (M+H).
The title compound (11.5 mg, 42%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 4-bromo-1-methyl-1H-indole-3-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=1.954 min, MS (ES) 709.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.45-7.30 (m, 3H), 7.16 (dd, J=5.4, 3.0 Hz, 1H), 7.06 (d, J=4.4 Hz, 1H), 6.56 (s, 2H), 4.38 (dd, J=12.3, 4.0 Hz, 1H), 3.92 (qd, J=7.8, 6.3, 4.7 Hz, 2H), 3.80 (s, 3H), 3.71 (s, 1H), 3.49-3.17 (m, 3H), 2.52 (s, 3H), 2.33 (d, J=8.0 Hz, 1H), 2.29-2.19 (m, 8H), 2.17-2.04 (m, 2H), 1.28 (d, J=6.4 Hz, 3H).
The title compound (20 mg, 56%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), methyl 4-bromoquinoline-8-carboxylate (16 mg, 0.06 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), Xantphos (2 mg, 0.003 mmol), and Cs2CO3 (25 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.030 min, MS (ES) 709.9 (M+H); H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=5.0 Hz, 1H), 8.70-8.48 (m, 1H), 8.19 (dt, J=8.5, 1.8 Hz, 1H), 7.83 (ddd, J=15.6, 8.6, 4.4 Hz, 3H), 7.34 (d, J=8.6 Hz, 1H), 6.70 (d, J=5.4 Hz, 2H), 4.92-4.62 (m, 1H), 4.40-4.12 (m, 2H), 3.97 (t, J=6.4 Hz, 2H), 3.79 (s, 3H), 3.39-3.13 (m, 2H), 2.23 (s, 6H), 2.14 (s, 1.5H), 2.04 (s, 3H), 2.02-1.97 (m, 2H), 1.92 (s, 1.5H), 1.15 (dd, J=6.5, 3.1 Hz, 3H).
The title compound (7.6 mg, 92%) was prepared following the procedure described Example 241 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (8 mg, 0.011 mmol), NaH (2 mg, 0.08 mmol) and bromomethylcyclopropane (5 mg, 0.075 mmol). LCMS: RT=2.096 min, MS (ES) 751.9 (M+H).
The title compound (1.3 mg, 5%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 8-bromo-1-naphthoate (20 mg, 0.075 mmol), copper iodide (5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification and purification following General Procedure D. LCMS: RT=1.976 min, MS (ES) 706.9 (M+H).
The title compound (2.6 mg, 25% yield) was prepared following the same procedure as described in Example 245 substituting 3-chloromethylpyridine HCl with 1-bromo-2-methoxyethane (5 mg, 0.036 mmol). LCMS: RT=2.016 min, MS (ES) 755.8 (M+H).
To a solution of 1-methyl-1H-indol-5-amine (60 mg, 0.41 mmol) in DCM (3 mL) was added DIPEA (100 mg, 0.78 mmol) followed by acetyl chloride (40 mg, 0.513 mmol) at RT, and the reaction was stirred for 10 min. The reaction was quenched by the addition of MeOH, diluted into DCM/H2O (20 mL, 1:1), the layers were separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried concentrated in vacuo. The crude residue was dissolved in DMF (3 mL), and NBS (75 mg, 0.42 mmol) was added. The reaction was stirred for 1 h at RT and determined to be complete by LCMS. The reaction was diluted into DCM (20 mL) and washed with 10% aqueous Na2S2O3 solution. The organic layer was dried, concentrated, and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (40 mg, 36%).
The title compound (15.2 mg, 75%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (15 mg, 0.028 mmol), N-(3-bromo-1-methyl-1H-indol-5-yl)acetamide (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), and K2CO3 (30 mg, 0.22 mmol). MS (ES) 724.9 (M+H).
The title compound (15 mg, 93%) was prepared according to the procedure for Example 235 using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-7-carbonitrile (15 mg, 0.022 mmol) and sodium azide (7 mg, 0.11 mmol). LCMS: RT=2.004 and 2.028 min, MS (ES) 736.0 (M+H).
The title compound (12 mg, 33%) was isolated along with Example 232 as the 2nd eluting atropisomer (absolute configuration undetermined). LCMS: RT=2.245 min, MS (ES) 732.9 (M+H).
The title compound (21 mg, 59%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol), 1-(3-bromo-1-methyl-1H-indol-5-yl)ethan-1-one (13 mg, 0.06 mmol), CuI (5 mg, 0.025 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 μL, 0.05 mmol), and K2CO3 (25 mg, 0.075 mmol). LCMS: RT=2.078 and 2.099 min, MS (ES) 710.0 (M+H).
To solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (100 mg, 0.12 mmol) in THF (2 mL) was added TBAF (0.59 mL, 0.59 mmol). The reaction mixture was heated to 100° C. for 20 min under microwave. The solvent was removed in vacuo and residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound as brown oil (75 mg, 88%). LCMS: RT=0.984 min, MS (ES) 712.2 (M+H).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (41 mg, 0.057 mmol) in DMF (1.5 mL) was added NaH (5 mg, 0.11 mmol). After 15 min, 3-(bromomethyl)-1-methylpyrrolidine (20 mg, 0.11 mmol) was added to reaction mixture and stirred overnight. The solvent was concentrated in vacuo and residue was filtered through silica pad with DCM/MeOH (3/1) then solvent was removed in vacuo. The residue was re-dissolved in mixture of methanol and dioxane (1 mL/2 mL), and sodium hydroxide (0.2 mL, 2 M solution) was added. The reaction mixture was stirred for 3 h at room temperature and then concentrated in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (18 mg, 49%). LCMS: RT=non polar method: 0.712 min, MS (ES) 795.3 (M+H).
The title compound (15 mg, 41%) was prepared according to the procedure used in Example 261 Step B by substituting 3-(bromomethyl)-1-methylpyrrolidine for 4-(bromomethyl)tetrahydro-2H-pyran. LCMS: RT=non polar method: 0.976 min, MS (ES) 796.3 (M+H).
The title compound (13 mg, 40%) was prepared according to the procedure used in Example 261 Step B by substituting 3-(bromomethyl)-1-methylpyrrolidine for 1-(2-bromoethyl)pyrrolidine. LCMS: RT=non polar method: 0.766 min, MS (ES) 795.3 (M+H); 1H NMR (MeOD, 400 MHz) δ (ppm) 8.27 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.64 (s, 2H), 4.62-4.47 (m, 3H), 4.32-4.30 (m, 1H), 4.02-3.95 (m, 2H), 3.89 (s, 2H), 3.78-3.68 (m, 4H), 3.52-3.30 (m, 2H), 3.20-3.13 (m, 2H), 2.68 (s, 2H), 2.29 (s, 6H), 2.25-2.03 (m, 4H), 2.20 (s, 3H), 2.04 (s, 3H), 1.25 (t, J=6.0 Hz, 3H).
The title compound (14 mg, 53%) was prepared following General coupling procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), methyl 1-chloroisoquinoline-6-carboxylate (20 mg, 0.90 mmol), CuI (5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K3PO4 (30 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.299 min, MS (ES) 709.9 (M+H).
To a solution of tert-butyl 4-((1-methyl-1H-indol-5-yl)sulfonyl)piperazine-1-carboxylate (65 mg, 0.17 mmol) in DMF (2 mL) was added NBS (35 mg, 0.20 mmol), and the reaction was stirred at RT until complete as determined by LCMS. The reaction was diluted into DCM (20 mL), washed with 10% aqueous Na2S2O3 (10 mL), dried, and concentrated in vacuo to afford the title compound (66 mg, 85%).
The title compound (25 mg, 49% crude) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), tert-butyl 44(3-bromo-1-methyl-1H-indol-5-yl)sulfonyl)piperazine-1-carboxylate (30 mg, 0.066 mmol). CuI (5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K2CO3.
To a solution of the crude reaction product from Step B in dioxane (2 mL) was added HCl in dioxane (4.0 M, 0.5 mL, 2.0 mmol), and the reaction was stirred for 16 h at RT. The reaction mixture was concentrated in vacuo, and half of the material was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (7.3 mg, 48% yield two steps). LCMS: RT=1.848 min, MS (ES) 816.0 (M+H).
The title compound (4.8 mg, 48%) was prepared following General Procedure E employing (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (10 mg, 0.078 mmol), and ammonia in MeOH (7.0 M, 0.05 mL, 0.35 mmol). LCMS: RT=2.061 min, MS (ES) 711.0 (M+H).
To a solution of 1-methyl-1H-indole-5-sulfonyl chloride (40 mg, 0.17 mmol) in DCM (2 mL) was added DIPEA (40 mg, 0.31 mmol). Methylamine hydrochloride (30 mg, 0.45 mmol) was added, and the reaction was stirred at RT until complete by LCMS then concentrated in vacuo. The crude residue was then brominated following the procedure described in Example 265 Step A using NBS (35 mg, 0.20 mmol) to afford the title compound (37 mg, 71%).
The title compound (9 mg, 32%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), 3-bromo-N,1-dimethyl-1H-indole-5-sulfonamide (25 mg, 0.083 mmol), CuI (5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol). LCMS: RT=2.059 min, MS (ES) 760.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J=11.2 Hz, 1H), 7.73 (ddd, J=9.3, 7.6, 1.8 Hz, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.40-7.28 (m, 2H), 6.63 (s, 2H), 4.51 (dd, J=40.0, 11.5 Hz, 1H), 4.20 (d, J=21.5 Hz, 1H), 4.08 (s, 1.5H), 4.05 (s, 1.5H), 3.99 (t, J=6.2 Hz, 2H), 3.86 (s, 3H), 3.70 (t. J=12.6 Hz, 1H), 3.51-3.28 (m, 2H), 2.62 (s, 1.5H), 2.60 (s, 1.5H), 2.34 (s, 1.5H), 2.32 (s, 6H), 2.28 (s, 1.5H), 2.24-2.09 (m, 5H), 1.23 (d, J=5.9 Hz, 3H).
The title compound (107 mg, 71%) was prepared following General Procedure G using methyl 3-bromo-1H-indole-5-carboxylate (100 mg, 0.39 mmol). NaH (24 mg, 0.59 mmol), and (2-(chloromethoxy)ethyl)trimethylsilane (0.11 mL, 98.5 mg, 0.59 mmol).
The title compound (93 mg, 82%) was prepared following General Procedure B using methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carboxylate (78 mg, 0.20 mmol), (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-(2H)-one (61 mg, 0.11 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (14 mg, 0.098 mmol), CuI (9.4 mg, 0.049 mmol) and K2CO3 (54.7 mg, 0.40 mmol). MS (ES) 842.3 (M+H).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carboxylate (110 mg, 0.13 mmol) in THF (0.5 mL) was added TBAF (1.18 mL, 1.17 mmol, 1.0 M in THF), and the reaction mixture was stirred as 40° C. for 24 h. The reaction was cooled to RT, quenched with saturated NH4Cl aq. solution and extracted with EtOAc (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient followed by DCM/MeOH=0-10% gradient) to afford the title compound (40 mg, 43%). MS (ES) 712.3 (M+H).
The title compound (5.1 mg, 21%, 2 steps) was prepared following General Procedure G using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (23 mg, 0.032 mmol), NaH (1.9 mg, 0.048 mmol), 1-bromo-2-methoxyethane (30 mg, 0.275 mmol) followed by saponification and purification following General Procedure D. LCMS: RT=1.947 min, MS (ES) 756.3 (M+H).
The title compound (5.6 mg, 55%) was prepared following General Procedure E using ((R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (10 mg, 0.078 mmol), and ammonia in MeOH (7.0 M, 0.05 mL, 0.35 mmol). LCMS: RT=2.015 min. MS (ES) 708.9 (M+H).
The title compound (6.8 mg, 68%) was prepared following General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (10 mg, 0.078 mmol), and ammonia in MeOH (7.0 M, 0.05 mL, 0.35 mmol). LCMS: RT=2.001 min, MS (ES) 711.0 (M+H).
The title compound (14 mg, 13%) was prepared following General Procedure B using ethyl 7-bromo-1H-indole-2-carboxylate (80 mg, 0.30 mmol), (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (80 mg, 0.15 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (47 μL, 42.4 mg, 0.30 mmol), CuI (28.4 mg, 0.15 mmol) and K2CO3 (61.8 mg, 0.45 mmol). MS (ES) 704.3 (M+H).
The title compound was prepared following General Procedure G using ethyl (R)-7-(10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4,7-dimethyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (14 mg, 0.019 mmol), NaH (4.6 mg, 0.11 mmol), 2-(bromomethyl)pyridine hydrobromide (14.4 mg, 0.058 mmol) followed by saponification using General Procedure D. The title compound was isolated as a partially separated the first eluting isomer (2.2 mg, 15%, absolute configuration undetermined). LCMS: RT=1.877 min, MS (ES) 767.3 (M+H).
The title compound (14.9 mg, 37%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol), methyl 7-bromo-1,5-dimethyl-1H-indole-2-carboxylate (25 mg, 0.089 mmol), Pd2(dba)3 (6 mg, 0.0065 mmol), Xantphos (8 mg, 0.013 mmol), and Cs2CO3 (60 mg, 0.19 mmol) followed by saponification using General Procedure D. LCMS: RT=2.092, 2.119 min, MS (ES) 723.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.82 (dd, J=8.7, 1.1 Hz, 1H), 7.48 (s, 0.7H), 7.44 (s, 0.3H) 7.39-7.34 (m, 2H), 6.95 (d, J=1.5 Hz, 1H), 6.63 (s, 1.3H), 6.61 (s, 0.7H), 4.20 (d, J=21.5 Hz, 2H), 4.06-3.93 (m, 4H), 3.85-3.71 (m, 1H), 3.53 (dd, J=12.6, 5.4 Hz, 1H), 3.45-3.32 (m, 2H), 2.52 (s, 1H), 2.50 (s, 2H), 2.43 (s, 2H), 2.40 (s, 1H), 2.34 (s, 1H), 2.33 (s, 2H), 2.32 (s, 6H), 2.25-2.18 (m, 2H), 1.32 (d, J=6.4 Hz, 2H), 1.22 (d, J=6.5 Hz, 1H).
The title compound (13.2 mg, 39%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 3-bromo-1-methyl-1H-indazole-4-carboxylate (20 mg, 0.075 mmol), CuI (5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K2CO3 (30 mg, 0.22 mmol) followed by saponification using General Procedure D. LCMS: RT=1.935 min, MS (ES) 711.0 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 9.17 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.34 (dd, J=7.8, 5.4 Hz, 3H), 6.51 (s, 2H), 4.36 (s, 1H), 4.07 (s, 3H), 3.92 (s, 2H), 3.74 (s, 2H), 3.36 (s, 1H), 3.21 (dt, J=13.7, 7.4 Hz, 1H), 2.49 (s, 3H), 2.26 (s, 6H), 2.24-2.10 (m, 5H), 1.27 (d, J=5.7 Hz, 3H).
The title compound (49 mg, 75%) was prepared following the procedure described in Example 265 Step A using 1-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-indole (80 mg, 0.17 mmol) and NBS (35 mg, 0.20 mmol).
The title compound (22.6 mg, 73%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol), 3-bromo-1-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-indole (30 mg, 0.081 mmol), CuI(5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K2CO3 (25 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=1.868 min, MS (ES) 829.9 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 7.97 (di. J=1.6 Hz, 0.5H), 7.90 (d, J=2.0 Hz, 0.5H) 7.75 (dd, J=8.6, 5.5 Hz, 1H), 7.63 (ddd, J=13.7, 8.7, 1.7 Hz, 1H), 7.51 (s, 0.5H), 7.49 (s, 0.5H), 7.37 (s, 1H), 7.32 (dd, J=8.6, 1.9 Hz, 1H), 6.65 (s, 1H), 6.64 (s, 1H), 4.50 (dd, J=12.8, 4.0 Hz, 0.5H), 4.28 (d, J=12.4 Hz, 1.5H), 4.11-3.96 (m, 5H), 3.94-3.70 (m, 7H), 3.64-3.27 (m, 3H), 3.15-2.87 (m, 4H), 2.82 (s, 1.5H), 2.79 (s, 1.5H), 2.34 (s, 3H), 2.33 (s, 3H), 2.32 (s, 1.5H), 2.28 (s, 1.5H), 2.25-2.19 (m, 2H), 2.14 (d, J=2.6 Hz, 3H), 1.32 (d, J=6.1 Hz, 1.5H), 1.18 (d, J=6.3 Hz, 1.5H).
The title compound (98 mg, 81%) was prepared following General Procedure F using 2-methyl-1H-indole-5-carboxylic acid (75 mg, 0.43 mmol), NBS (90 mg, 0.51 mmol), NaH (42 mg, 1.75 mmol), and MeI (200 mg, 1.41 mmol).
The title compound (12.5 mg, 35%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), methyl 3-bromo-1,2-dimethyl-1H-indole-5-carboxylate (30 mg, 0.11 mmol), CuI (5 mg, 0.026 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (8 mg, 0.056 mmol), and K2CO3 (30 mg, 0.22 mmol) followed by saponification using General Procedure D. LCMS: RT=2.109 min. MS (ES) 726.0 (M+H).
The title compound was isolated by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA, 10 mins gradient) as a partially separated the 2nd eluting isomer (absolute configuration undetermined). LCMS: RT=1.897 min, MS (ES) 767.3 (M+H).
The title compound (3.2 mg, 32%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (10 mg, 0.078 mmol), and ammonia in MeOH (7.0 M, 0.05 mL, 0.35 mmol). LCMS: RT=2.011 min, MS (ES) 711.0 (M+H).
To a solution of (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-5-(piperazin-1-ylsulfonyl)-1H-indol-3-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (15 mg, 0.018 mmol) in DCM (3 mL) was added DIPEA (10 mg, 0.078 mmol) followed by acetyl chloride (5 mg, 0.037 mmol). The reaction was stirred at RT for 10 min. The reaction was quenched with MeOH, diluted with DCM/H2O (10 mL, 1:1) and extracted with DCM (2×5 mL). The combined organic extracts were dried, concentrated in vacuo, and purified by reverse phase HPLC (Phenomenex Gemini C18. H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (12.1 mg, 77%). LCMS: RT=2.245, 2.262 min, MS (ES) 858.0 (M+H).
The title compound (21 mg, 20% yield) was prepared following General Procedure B using ethyl 7-bromo-1H-indole-2-carboxylate (79.8 mg, 0.30 mmol), 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (80 mg, 0.15 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (47 μL, 42.4 mg, 0.30 mmol), CuI (28.4 mg, 0.15 mmol) and K2CO3 (61.8 mg, 0.45 mmol). MS (ES) 724.3 (M+H).
The title compound (5.7 mg, 32%, 2 steps) was prepared following General Procedure G using ethyl 7-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-2-carboxylate (17 mg, 0.023 mmol), NaH (2.8 mg, 0.069 mmol), 2-(bromomethyl)pyridine hydrobromide (8.9 mg, 0.035 mmol) followed by saponification using General Procedure D. LCMS: RT=1.845 min, MS (ES) 787.1 (M+H). 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.59 (s, 1H), 8.01-7.97 (m, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.39-7.34 (m, 1H), 7.30-7.23 (m, 2H), 7.06 (d, J=7.3 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.59 (s, 2H), 6.41 (d, J=17.8 Hz, 1H), 6.12 (d, J=17.0 Hz, 1H), 4.09-3.97 (m, 2H), 3.84-3.79 (m, 1H), 3.70-3.59 (m, 2H), 3.38-3.36 (m, 1H), 2.89-2.84 (m, 1H), 2.42 (s, 3H), 2.32 (s, 6H), 2.28 (s, 3H), 2.16-2.12 (m, 1H), 2.05-1.94 (m, 2H), 1.88-1.83 (m, 1H), 1.64-1.57 (m, 1H).
The title compound (3.5 mg, 31%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and 2-aminopyridine (5 mg, 0.053 mmol). The reaction was stirred for 16 h at room temperature followed by 8 h at 50° C. LCMS: RT=1.994 min, MS (ES) 787.9 (M+H).
The title compound (6.6 mg, 58%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and pyridin-2-ylmethanamine (5 mg, 0.046 mmol). After 16 hr the reaction was complete. LCMS: RT=1.861 min, MS (ES) 802.0 (M+H).
The title compound (8.5 mg, 75%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and N-methyl-1-(pyridin-3-yl)methanamine (5 mg, 0.041 mmol). After 16 h the reaction was complete. LCMS: RT=1.860 min, MS (ES) 816.0 (M+H).
The title compound (6.6 mg, 58%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and 4-aminopyridine (5 mg, 0.053 mmol). The reaction was stirred for 16 h at room temperature followed by 8 h at 50° C. LCMS. Ry=1.875 min, MS (ES) 787.9 (M+H).
The title compound (8.3 mg, 73%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and pyridin-4-ylmethanamine (5 mg, 0.046 mmol). After 16 h the reaction was be complete. LCMS: RT=1.825 min, MS (ES) 802.0 (M+H).
The title compound (6.3 mg, 57%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and aniline (5 mg, 0.053 mmol). The reaction was stirred for 16 h at room temperature followed by 8 h at 50° C. LCMS: RT=2.234 min, MS (ES) 787.0 (M+H).
The title compound (6.8 mg, 67%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and methylamine hydrochloride (5 mg, 0.074 mmol). After 16 h the reaction was complete. LCMS: RT=2.029 min, MS (ES) 725.0 (M+H).
The title compound (8.8 mg, 78%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and pyridin-3-ylmethanamine (5 mg, 0.046 mmol). After 16 h the reaction was complete. LCMS: RT=1.841 min, MS (ES) 802.0 (M+H).
The title compound (14.6 mg, 78%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (15 mg, 0.028 mmol), 3-bromo-1-methyl-1H-indole (11.7 mg, 0.056 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (8.9 μL, 8.0 mg, 0.056 mmol), CuI (5.3 mg, 0.028 mmol) and K2CO3 (11.6 mg, 0.084 mmol). LCMS: RT=2.151 min, MS (ES) 667.9 (M+H); 1H NMR (400 MHz, CDCl3) S 7.59 (dd, J=8.6, 2.3 Hz, 1H), 7.40 (dd, J=7.9, 3.8 Hz, 1H), 7.28-7.26 (m, 1H), 7.22-7.21 (m, 1H), 7.18-7.16 (m, 1H), 7.10 (d, J=5.3 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.54 (s, 2H), 4.31-4.26 (m, 1H), 4.24-4.10 (m, 1H), 3.95-3.90 (m, 2H), 3.80 (d, J=3.2 Hz, 3H), 3.73 (s, 3H), 3.56 (ddd, J=12.5, 7.9, 1.5 Hz, 1H), 3.40-3.33 (m, 1H), 3.31-3.24 (m, 1H), 2.24 (s, 6H), 2.12 (s, 3H), 1.95 (d, J=2.9 Hz, 3H), 1.19-1.15 (m, 2H), 1.10 (d, J=6.4 Hz, 3H).
The title compound (8.0 mg, 76%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and dimethylamine hydrochloride (5 mg, 0.061 mmol). After 16 h the reaction was complete. LCMS: RT=2.085 min, MS (ES) 739.0 (M+H).
The title compound (7.8, 72%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and pyrrolidine (5 mg, 0.070 mmol). After 16 hr the reaction was complete. LCMS: RT=2.193 min, MS (ES) 765.0 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 7.85-7.69 (m, 2H), 7.48-7.28 (m, 4H), 6.62 (d, J=1.8 Hz, 2H), 4.53-4.36 (m, 1H), 4.154.09 (m, 4H), 3.99 (t, J=6.1 Hz, 2H), 3.88-3.79 (m, 3H), 3.74-3.49 (s, 4H), 3.37 (ddt, J=34.7, 13.6, 7.1 Hz, 2H), 2.34 (s, 1.5H), 2.32 (s, 3H), 2.31 (s, 3H), 2.28 (s, 1.5H), 2.22-2.13 (m, 6H), 2.05-1.81 (br. s, 4H), 1.24 (m, 3H).
The title compound (6.7 mg, 60%) was prepared following General Procedure E employing (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol), HATU (10 mg, 0.026 mmol), DIPEA (20 mg, 0.155 mmol), and 3-aminopyridine (5 mg, 0.053 mmol). The reaction was stirred for 16 h at room temperature followed by 8 h at 50° C. LCMS: RT=1.882 min, MS (ES) 787.9 (M+H).
The title compound (27 mg, 19%) was prepared following General Procedure G using methyl 3-bromo-1H-indole-6-carboxylate (100 mg, 0.39 mmol), NaH (94.6 mg, 2.36 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (220 mg, 1.2 mmol). MS (ES) 367.0 (M+H).
The title compound (2.5 mg, 6%, 2 steps) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol), methyl 3-bromo-1-(2-morpholinoethyl)-1H-indole-6-carboxylate (27 mg, 0.074 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (7.0 μL, 6.4 mg, 0.044 mmol), CuI (4.3 mg, 0.022 mmol) and K2CO3 (27.0 mg, 0.21 mmol) followed by saponification using General Procedure D. The title compound was isolated as the 2d eluting isomer from the final purification by reverse phase HPLC (absolute configuration undetermined). LCMS: RT=1.837 min, MS (ES) 811.3 (M+H).
The title compound (11.5 mg, 25%, 2 steps) was isolated as the 1st eluting isomer from the final reverse phase HPLC along with Example 292. LCMS: RT=1.815 min, MS (ES) 811.3 (M+H).
A mixture of ethyl 7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (180 mg, 0.278 mmol), tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (100 mg, 0.42 mmol), and Cs2CO3 (200 mg, 0.61 mmol) in MeCN (10 mL) was heated to 80° C. for 16 h. After which time, an additional portion of tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (30 mg, 0.0.13 mmol) was added. The reaction was heated an additional 6 h, cooled to RT then diluted with EtOAc/H2O (40 mL, 1:1). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (194 mg, 87%).
To a solution of ethyl 7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (194 mg, 0.24 mmol) in 1,4-dioxane (20 mL) was added a solution of 4 M HCl in dioxanes (1 mL, 4 mmol). The reaction was stirred overnight then concentrated in vacuo. The crude residue taken up in MeOH (10 mL) then K2CO3 (300 mg, 2.17 mmol) was added. The reaction was heated to 50° C. for 5 h, concentrated then dissolved in DCM/H2O (60 mL, 1:1). The organic layer was separated, and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (117 mg, 74% 2 steps).
The title compound (78 mg, 53%) was prepared following General coupling procedure B using 7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (115 mg, 0.17 mmol), methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (100 mg, 0.37 mmol), CuI (10 mg, 0.052 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (15 mg, 0.10 mmol), and K2CO3 (75 mg, 0.54 mmol).
The title compound (4 mg, 80%) was prepared following General Procedure D using methyl 3-(7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-5-carboxylate (5 mg, 0.0059 mmol) and LiOH (2 mg, 0.083 mmol). LCMS: RT=2.155 min, MS (ES) 829.9 (M+H).
The title compound was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.055 mmol), methyl 7-bromo-5-methyl-1H-indole-2-carboxylate (30 mg, 0.112 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N-dimethylaminocyclohexane (8 mg, 0.056 mmol), K3PO4 (40 mg, 0.19 mmol).
The title compound (9.3 mg, 21%, 2 steps) was prepared following the same procedure as described for Example 247 using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate NaH (6 mg, 0.25 mmol) and 2-(Bromomethyl)pyridine HBr salt (30 mg, 0.119 mmol) followed by saponification using General Procedure D. LCMS: RT=2.096, 2.121 min, MS (ES) 802.9 (M+H).
The title compound was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol), methyl 7-bromo-5-methyl-1H-indole-2-carboxylate (30 mg, 0.112 mmol). CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), K3PO4 (40 mg, 0.19 mmol).
The title compound (5.7 mg, 13%, 2 steps) was prepared following the same procedure as described for Example 247 using methyl methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate, NaH (6 mg, 0.25 mmol) and 2-(Bromomethyl)pyridine HBr salt (30 mg, 0.119 mmol) followed by saponification using General Procedure D. LCMS: RT=1.956 min, MS (ES) 801.0 (M+H).
The title compound was prepared following General coupling procedure B using (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one, methyl 6-(benzyloxy)-4-bromo-1-methyl-1H-indole-2-carboxylate, CuI, (trans)-1,2-N,N′-dimethylaminocyclohexane, and K2CO3 followed by saponification and purification following General Procedure D. LCMS: RT=2.337 min, MS (ES) 818.2 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (20 mg, 0.028 mmol) in DMF (2 mL) was added Cs2CO3 (40 mg, 0.123 mmol). KI (20 mg, 0.12 mmol), and 2-(chloromethyl)thiazole (25 mg, 0.19 mmol), and the reaction was heated to 90° C. for 4 h. The reaction was then cooled to RT and diluted with DCM/H2O (20 mL, 1:1). The organic layer was separated, and the aqueous layer was extracted with DCM (2×5 mL). The combined organic extracts were dried and concentrated in vacuo. The crude product was saponified and purified following the procedure described in General Procedure D to afford the title compound (2.2 mg, 10%, 2 steps). LCMS: RT=2.067 min, MS (ES) 795.0 (M+H).
The title compound was prepared following General coupling procedure B using (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-(2H)-one, methyl 7-(benzyloxy)-4-bromo-1-methyl-1H-indole-2-carboxylate. CuI, (trans)-1,2-N,N′-dimethylaminocyclohexane, and K2CO3 followed by saponification and purification following General Procedure D. LCMS. RT=2.329 min, MS (ES) 817.9 (M+H).
The title compound (11.7 mg, 32%) was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol), 7-bromo-1-methyl-1H-indole-2-carbonitrile (17 mg, 0.068 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), K3PO4 (30 mg, 0.14 mmol). LCMS: RT=2.221 min, MS (ES) 693.0 (M+H).
The title compound (47 mg, 47%) was prepared following General Procedure E using 4-bromo-1-methyl-1H-indole-2-carboxylic acid (100 mg, 0.39 mmol). HATU (200 mg, 0.526 mmol), DIPEA (200 mg, 1.55 mmol), and ammonia in methanol (7.0 M, 0.25 mL, 1.75 mmol).
A solution of 4-bromo-1-methyl-1H-indole-2-carboxamide (47 mg, 0.17 mmol) in POCl3 (2 mL) was heated to 100° C. for 2 h. The reaction was cooled to RT and poured into ice/aqueous NaHCO3. The aqueous layer was extracted with DCM (3×10 mL), the combined organic reactions were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100%) to afford the title compound (32 mg, 73% yield).
The title compound (25 mg, 65%) was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol), 4-bromo-1-methyl-1H-indole-2-carbonitrile (26 mg, 0.11 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), K3PO4 (50 mg, 0.24 mmol). LCMS: RT=2.276 min, MS (ES) 693.0 (M+H); 1H NMR (400 MHz, Chloroform-d) δ 7.74 (dd, J=8.6, 1.7 Hz, 1H), 7.53-7.43 (m, 1H), 7.40-7.27 (m, 2H), 7.13-7.02 (m, 2H), 6.65-6.60 (m, 2H), 4.48 (d, J=11.6 Hz, 1H), 4.32-4.14 (m, 2H), 4.05-4.00 (m, 4H), 3.95 (s, 3H), 3.59 (d, J=12.4 Hz, 1H), 3.46 (dt, J=14.2, 7.5 Hz, 1H), 3.33 (dt, =14.0, 7.5 Hz, 1H), 2.33 (s, 5H), 2.29 (s, 1.5H), 2.26 (1.5H), 2.22-2.17 (m, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H), 1.24 (d, J=4.8 Hz, 1.5H), 1.18 (d, J=6.4 Hz, 1.5H).
The title compound (15 mg, 36%) was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol), methyl 7-bromo-4-methoxy-1H-indole-2-carboxylate (30 mg, 0.11 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), K3PO4 (40 mg, 0.19 mmol).
The title compound (7.2 mg, 43%) was prepared following the procedure described Example 247 using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate, NaH (6 mg, 0.25 mmol) and 2-(bromomethyl)pyridine HBr salt (30 mg, 0.12 mmol). LCMS: RT=2.061 min, MS (ES) 816.9 (M+H).
To a solution of (P, R)-6-(benzyloxy)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid (6 mg, 0.0072 mmol) in MeOH (3 mL) was added Pd/C (10% wt, 2 mg, 0.0018 mmol). The reaction was flushed with hydrogen then stirred under H2 for 6 h at RT. The reaction was filtered, concentrated in vacuo, and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (4 mg, 72% yield). LCMS: RT=2.007 min, MS (ES) 727.9 (M+H).
The title compound (6.3 mg, 58%) was prepared following the procedure described Example 247 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol), NaH (5 mg, 0.12 mmol) and 4-(chloromethyl)thiazole (10 mg, 0.075 mmol) followed by saponification using General Procedure D. LCMS: RT=2.099, 2.129 min, MS (ES) 794.9 (M+H).
The title compound (3.3 mg, 59%) was prepared following the same procedure as Example 303 using (M, R)-6-(benzyloxy)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid (6 mg, 0.0072 mmol) and Pd/C (10% wt, 2 mg, 0.0019 mmol). LCMS: RT=2.020 min, MS (ES) 727.9 (M+H).
The title compound was prepared according to the procedure used in Example 261 Step B by substituting 3-(bromomethyl)-1-methylpyrrolidine with 1-(2-bromoethyl)pyrrolidine. LCMS: RT=non polar method: 0.976 min, MS (ES) 795.3 (M+H).
The title compound (4 mg, 21%) was prepared according to the procedure for Example 235 using (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carbonitrile (18 mg, 0.026 mmol) and sodium azide (10 mg, 0.15 mmol). LCMS: RT=2.145, 2.172 min, MS (ES) 736.0 (M+H).
The title compound was prepared according to the procedure used in Example 261 Step B by substituting 3-(bromomethyl)-1-methylpyrrolidine with 4-(bromomethyl)tetrahydro-2H-pyran. MS (ES) 796.3 (M+H); 1H-NMR (MeOH-d3) S 8.19 (d, 1H, J=8 Hz), 7.79-7.75 (m, 2H), 7.487.47 (m, 2H) 7.31 (d, 1H, J=8 Hz), 6.62 (s, 2H), 4.50-4.47 (m, 1H), 4.304.28 (m, 1H) 4.06 (tr, 2H, J=8 Hz), 3.99 (s, 3H), 3.92 (s, 3H), 3.36-3.60 (m, 2H), 3.50-3.40 (m, 4H), 2.33 (s, 6H), 2.29-2.16 (multiples s (3H), tr (2H), total 5H), 2.08 (s, 1.5H), 2.01 (s, 1.5H), 1.54-1.46 (m, 2H), 1.45-1.40 (m, 2H), 1.31 (m, 1H), 1.23-1.19 (multiple d, 3H).
The title compound was prepared according to the procedure used in Example 261 Step B by substituting 3-(bromomethyl)-1-methylpyrrolidine with 2-bromo-N,N-dimethylethan-1-amine. MS (ES) 769.3 (M+H)
The title compound (5.5 mg, 92%) was prepared following General Procedure D using methyl (M, R)-6-benzyloxy-4-[7-chloro-10-[3-(4-chloro-3,5-dimethyl-phenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-1-methyl-indole-2-carboxylate (6 mg, 0.0072 mmol). LCMS: RT=2.349 min, MS (ES) 817.9 (M+H).
The title compound (2 mg, 31%) was prepared according to the procedure used in Example 298 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (6 mg, 0.0083 mmol), Cs2CO3 cesium carbonate (20 mg, 0.061 mmol), KI (10 mg, 0.0.060 mmol), and 5-(chloromethyl)pyrimidine (20 mg, 0.15 mmol) followed by saponification using General Procedure D. LCMS: RT=2.006 min, MS (ES) 790.0 (M+H).
The title compound (4 mg, 81%) was prepared following General Procedure D using methyl (M, R)-7-benzyloxy-4-[7-chloro-10-[3-(4-chloro-3,5-dimethyl-phenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-1-methyl-indole-2-carboxylate (5 mg, 0.0060 mmol). LCMS: RT=2.192 min, MS (ES) 817.9 (M+H).
The title compound was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol), methyl 7-bromo-4-methoxy-1H-indole-2-carboxylate (30 mg, 0.11 mmol), CuI (5 mg, 0.026 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (8 mg, 0.056 mmol), K3PO4 (40 mg, 0.19 mmol).
The title compound (12.8 mg, 28% 3 steps) was prepared following the procedure described Example 241 using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (from Step A), NaH (6 mg, 0.25 mmol) and 2-(bromomethyl)pyridine HBr salt (30 mg, 0.12 mmol) followed by saponification using General Procedure D. LCMS: RT=1.941, 1.965 min, MS (ES) 819.0 (M+H).
The title compound (4.2 mg, 19%) was prepared following the procedure described Example 298 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (20 mg, 0.028 mmol), Cs2CO3 (40 mg, 0.123 mmol). KI (20 mg, 0.12 mmol), and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (25 mg, 0.186 mmol) followed by saponification using General Procedure D to afford the title compound. LCMS: RT=2.063 min. MS (ES) 793.9 (M+H).
The title compound (4.9 mg, 45%) was prepared following the procedure described Example 241 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol), NaH (3 mg, 0.12 mmol), and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (10 mg, 0.076 mmol) followed by saponification using General Procedure D. LCMS: RT=2.072 min, MS (ES) 793.9 (M+H).
To a solution of (2-bromophenyl)hydrazine hydrochloride (223 mg, 1.0 mmol) in MeOH (5 mL) was added ethyl pyruvate (0.1 mL, 116 mg 1.0 mmol) followed by conc. HCl (5 mL). The reaction mixture was stirred at 70° C. for 4 h then cooled to RT, quenched with sat. NaHCO3 aq. solution and extracted with DCM (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (227 mg, 85% yield). LCMS: RT=1.618 min, MS (ES) 268.0 (M+H).
The title compound (38 mg, 37% yield) was prepared following General Procedure G using methyl 7-bromo-3-methyl-1H-indole-2-carboxylate (100 mg, 0.37 mmol). LCMS: RT=1.828 min, MS (ES) 282.0 (M+H); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.9 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 6.87 (t, J=7.8 Hz, 1H), 4.25 (s, 3H), 3.87 (s, 3H), 2.44 (s, 3H).
The title compound (20 mg, 33%) was prepared following General Procedure B, using methyl 7-bromo-1,3-dimethyl-1H-indole-2-carboxylate (35 mg, 0.124 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (44.6 mg, 0.083 mmol). LCMS: RT=2.244, 2.267 min, MS (ES) 739.9 (M+H).
The title compound (3.1 mg, 15%) was prepared following General procedure D using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,3-dimethyl-1H-indole-2-carboxylate (20 mg, 0.027 mmol). LCMS: RT=2.096 min, MS (ES) 726.0 (M+H); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.0 Hz, 1H), 7.74-7.68 (m, 1H), 7.36-7.33 (m, 1H), 7.23-7.10 (m, 2H), 6.64-6.59 (m, 2H), 4.52-4.46 (m, 1H), 4.30-4.25 (m, 2H), 4.13-4.11 (m, 4H), 4.01-3.97 (m, 4H), 3.42-3.36 (m, 2H), 2.63-2.61 (m, 3H), 2.39-2.32 (m, 9H), 2.24-2.15 (m, 5H), 1.31-1.28 (m, 3H).
The title compound was prepared according to General Procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromo-1,6-dimethyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.71 min, MS (ES) 726.2 (M+H) (LC method III). 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.26 (s, 1H), 7.22 (s, 1H), 6.92 (s, 1H), 6.60 (s, 2H), 4.40 (dd, J=12.4, 3.6 Hz, 1H), 4.19 (d, J=4.8 Hz, 1H), 4.03-3.96 (m, 5H), 3.90 (s, 3H), 3.58 (d, J=12.4 Hz, 1H), 3.49-3.31 (m, 2H), 2.51 (s, 3H), 2.30 (s, 6H), 2.21-2.17 (m, 5H), 2.04 (s, 3H), 1.24 (d, J=6.4 Hz, 3H).
The title compound was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrano[1,2-a]indol-1(2H)-one and methyl 4-bromo-1-methyl-1H-indole-2-carboxylate. MS (ES) 842.3 (M+H).
The title compound (77 mg, 90%) was prepared following the procedure described Example 261 Step A using methyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (100 mg, 0.12 mmol) and TBAF (0.59 mL, 0.59 mmol). MS (ES) 712.2 (M+H).
The title compound (17 mg, 38% 2 steps) was prepared following the procedure described Example 261 Step B using methyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (41 mg, 0.057 mmol), NaH (5 mg, 0.113 mmol) and 1-(2-bromoethyl)pyrrolidine (20 mg, 0.113 mmol) followed by saponification using General Procedure D. LCMS: RT=0.863 min (LC method IV), MS (ES) 795.8 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 7.79 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.06 (s, 2H), 6.70 (s, 2H), 4.59-4.40 (m, 2H), 4.20-4.11 (m, 1H), 4.04 (s, 3H), 3.97-3.93 (m, 2H), 3.65-3.60 (m, 2H), 3.55-3.50 (m, 2H), 3.12-2.90 (m, 2H), 2.53 (s, 3H), 2.22 (s, 6H), 2.18 (s, 2H), 2.05 (d, J=4.0 Hz, 3H), 2.03-1.90 (m, 2H), 2.05 (s, 3H), 1.85-1.82 (m, 2H), 1.08-1.05 (M, 4H).
The title compound was prepared according to General Procedure B using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-(benzyloxy)-4-bromo-1-methyl-1H-indole-2-carboxylate. LCMS: RT=1.772 min, MS (ES) 831.8 (M+H) (LC method II).
To a solution of methyl (R)-7-(benzyloxy)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (25 mg, 0.030 mmol) in MeOH (5 mL) was added Pd/C (10 wt. %, 5 mg, 0.0046 mmol), and the reaction was stirred for 18 h under H2 atmosphere at RT. The reaction mixture was filtered through celite and concentrated to afford the title compound (21 mg, 94%). LCMS: RT=2.090 min, MS (ES) 742.0 (M+H).
The title compound (4.0 mg, 36%) was prepared according to General Procedure H using methyl (M, R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-7-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 3-(bromomethyl)-1-methylpyrrolidine (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=1.825 min, MS (ES) 825.0 (M+H).
The title compound (3.0 mg, 27%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 3-(bromomethyl)-1-methylpyrrolidine (10 mg, 0.056 mmol) followed by saponification using General Procedure K. LCMS. RT=1.876 min. MS (ES) 795.0 (M+H).
The title compound was prepared according to General Procedure B using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-(benzyloxy)-7-bromo-1-methyl-1H-indole-2-carboxylate. MS (ES) 832.2 (M+H).
The title compound (17 mg, 45%) was prepared following the procedure described Example 319 Step B using methyl (M, R)-4-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (42 mg, 0.051 mmol) and Pd/C (10 wt. %, 20 mg, 0.019 mmol). LCMS: RT=1.944 min, MS (ES) 727.9 (M+H).
The title compound (4.4 mg, 64%) was prepared according to General Procedure D using methyl (M, R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-hydroxy-1-methyl-1H-indole-2-carboxylate (7 mg, 0.0094 mmol). LCMS: RT=1.946 min, MS (ES) 727.9 (M+H).
The title compound (2.9 mg, 27%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-bromo-N,N-dimethylethan-1-amine (10 mg, 0.066 mmol) followed by saponification using General Procedure D. LCMS: RT=1.861, 1.882 min, MS (ES) 769.0 (M+H).
The title compound (4.3 mg, 41%) was prepared according to General Procedure H using methyl (M, R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-7-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure D. LCMS: RT=2.044 min, MS (ES) 786.0 (M+H).
The title compound (44 mg, 61%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (54 mg, 0.1 mmol) and methyl 7-bromo-5-methyl-1H-indole-2-carboxylate (80 mg, 0.3 mmol). LCMS: RT=2.221 min, MS (ES) 726.0 (M+H).
The title compound (6 mg, 53%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 4-(bromomethyl)tetrahydro-2H-pyran (5 mg, 0.028 mmol) followed by saponification using General Procedure D. LCMS: RT=2.217 MS (ES) 809.8 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, J=8.6 Hz, 1H), 7.48 (s, 0.75H), 7.44 (s, 0.25H), 7.34-7.28 (m, 1H), 7.26-7.23 (m, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.69 (s, 1.5H), 6.68 (s, 0.5H), 4.33-4.26 (m, 2H), 4.25-4.18 (m, 2H), 3.78 (s, 1.5H), 3.76 (s, 0.5H), 3.75 (s, 1H), 3.63-3.60 (m, 1H), 3.33-3.13 (m, 3H), 3.06-2.91 (m, 3H), 2.37 (s, 2H), 2.35 (s, 1H), 2.23 (s, 6H), 2.14 (s, 0.5H), 2.13 (s, 1H), 2.08 (s, 1.5H), 2.06-1.96 (m, 4H), 1.93 (s, 1H), 1.90 (s, 0.5H), 1.83 (s, 1.5H), 1.17-1.08 (m, 3H), 1.05-0.96 (M, 2H), 0.93-0.75 (m, 3H).
The title compound (3.6 mg, 33%) was prepared according to General Procedure H using methyl (M, R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure D. LCMS: RT=2.047 min, MS (ES) 786.0 (M+H).
The title compound (2.7 mg, 25%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(bromomethyl)tetrahydrofuran (10 mg, 0.061 mmol) followed by saponification using General Procedure D. LCMS: RT=2.105 min, MS (ES) 781.9 (M+H).
The title compound was prepared according to General Procedure B using (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-(benzyloxy)-4-bromo-1-methyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.99 min, MS (ES) 818.0 (M+H) (LC method III). 1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J=8.8 Hz, 1H), 7.47-7.22 (m, 7H), 6.93 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.60 (s, 2H), 5.20 (s, 2H), 4.48-4.26 (m, 5H), 3.97-3.94 (m, 5H), 3.78-3.27 (m, 3H), 2.29 (s, 6H), 2.20-2.16 (m, 5H), 2.03 (s, 3H), 1.13 (d, J=6.4 Hz, 3H).
The title compound was prepared according to General Procedure B using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-(benzyloxy)-4-bromo-1-methyl-1H-indole-2-carboxylate followed by saponification using General Procedure K. LCMS: RT=1.823 min, MS (ES) 831.8 (M+H) (LC methodII).
The title compound (34 mg, 77%) was prepared following the procedure described Example 319 Step B using methyl (M, R)-6-(benzyloxy)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (50 mg, 0.060 mmol) and Pd/C (10 wt. %, 7 mg, 0.0065 mmol). LCMS: RT=2.067 min, MS (ES) 742.0 (M+H).
The title compound (5.1 mg, 60%) was prepared according to General Procedure H using methyl (M, R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-6-hydroxy-1-methyl-1H-indole-2-carboxylate (8 mg, 0.011 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure K. LCMS: RT=2.029 min, MS (ES) 786.0 (M+H).
The title compound (3.6 mg, 17%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)pyrimidine (20 mg, 0.16 mmol), followed by saponification using General Procedure D. LCMS: RT=2.026 min, MS (ES) 790.0 (M+H).
The title compound (7 mg, 62%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 3-(bromomethyl)-1-methylpyrrolidine hydrobromide (7 mg, 0.028 mmol) followed by saponification using General Procedure D. LCMS: RT=1.962 MS (ES) 808.9 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 9.69 (bs, 1H), 7.90-7.73 (m, 1H), 7.60-7.47 (m, 1H), 7.41-7.29 (M, 2H), 7.28-7.16 (m, 0.5H), 7.09-6.98 (m, 0.5H), 6.71 (s, 2H), 4.58-4.49 (m, 3H), 4.42-4.09 (m, 3H), 4.08-4.01 (m, 1H), 3.99 (s, 3H), 3.77 (s, 1.5H), 3.75 (s, 1.5H), 3.30-3.13 (m, 3H), 2.75-2.62 (m, 3H), 2.37 (s, 1.5H), 2.35 (s, 1.5H), 2.24 (s, 6H), 2.12 (s, 1.5H), 2.07 (s, 1.5H), 2.06-2.04 (M, 2H), 2.04-2.03 (m, 1H), 2.03-2.01 (m, 2H), 1.99 (s, 1.5H), 1.91 (s, 1.5H), 1.17-1.05 (m, 3H).
The title compound (4.1 mg, 46%) was prepared according to General Procedure H using methyl (M, R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-6-hydroxy-1-methyl-1H-indole-2-carboxylate (8 mg, 0.011 mmol) and 3-(bromomethyl)-1-methylpyrrolidine (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=1.795 min, MS (ES) 825.0 (M+H).
The title compound (7 mg, 70%) was prepared according to General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylic acid (10 mg, 0.014 mmol) and ammonia in MeOH (7.0 M, 0.25 mL). LCMS: RT=2.017, 2.043 min, MS (ES) 724.9 (M+H).
The title compound was prepared according to General Procedure B using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-(benzyloxy)-7-bromo-1-methyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.430, 2.457 min, MS (ES) 817.8 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J=8.8 Hz, 1H), 7.32-7.30 (m, 7H), 7.14 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.61 (s, 1.5H), 6.59 (s, 0.5H), 5.07 (s, 2H), 4.24-4.17 (m, 3H), 4.03-3.88 (m, 7H), 3.41-3.29 (m, 3H), 2.29 (s, 6H), 2.22-2.18 (m, 5H), 2.03 (s, 3H), 1.25 (d, J=6.0 Hz, 2H), 1.18 (d, J=6.0 Hz, 1H).
The title compound (4.8 mg, 48%) was prepared according to General Procedure H using methyl (M, R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-6-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.0138 mmol) and MeI (5 mg, 0.035 mmol) followed by saponification using General Procedure D. LCMS: RT=2.034 min, MS (ES) 742.0 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.23 (s, 1H), 6.80-6.72 (M, 2H), 6.63 (s, 2H), 4.46-4.36 (m, 1H), 4.18 (s, 1H), 4.05 (s, 3H), 4.02-3.94 (m, 5H), 3.93 (s, 3H), 3.59 (d, J=12.4 Hz, 1H), 3.48-3.30 (m, 2H), 2.32 (s, 6H), 2.27-2.17 (m, 5H), 2.08 (s, 3H), 1.25 (d, J=6.2 Hz, 3H).
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carbonitrile (15 mg, 0.02 mmol) in EtOH (1 mL) at RT was added NH2OH·HCl (6 mg, 0.088 mmol) followed by K2CO3 (9 mg, 0.066 mmol). The mixture was heated at 80° C. for 8 h then concentrated in vacuo. The crude material was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (12 mg, 75%). LCMS: RT=1.791 min, MS (ES) 726.0 (M+H).
The title compound (52 mg, 88%) was prepared following General Procedure G using 7-bromo-5-methyl-1H-indole-2-carboxylic acid (51 mg, 0.20 mmol) and MeI (39 μL, 0.80 mmol). LCMS: RT=1.783 min, MS (ES) 296.2 (M+H).
The title compound (11 mg, 30%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromo-1,3,5-trimethyl-1H-indole-2-carboxylate (18 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.137 MS (ES) 739.9 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 7.83-7.68 (m, 1H), 7.48 (s, 0.5H), 7.43 (s, 0.5H), 7.33-7.24 (m, 1H), 7.16 (s, 0.5H), 6.94 (s, 0.25H), 6.93 (s, 0.25H), 6.69 (s, 1H), 6.68 (s, 1H), 4.36-4.27 (m, 1H), 4.26-4.09 (m, 1H), 4.02-3.93 (m, 2H), 3.91 (s, 1.5H), 3.92 (s, 1.5H), 3.80 (s, 0.75H), 3.77 (s, 0.75H), 3.76 (0.75H), 3.75 (s, 0.75H), 3.71-3.61 (m, 2H), 3.21-3.11 (m, 1H), 2.39 (s, 1.5H), 2.36 (s, 1.5H), 2.22 (s, 6H), 2.10 (s, 1.5H), 2.08 (s, 1.5H), 2.06-2.03 (m, 2H), 1.96 (s, 1.5H), 1.94 (s, 1.5H), 1.91 (s, 3H), 1.87 (s, 1.5H), 1.15 (d, J=6.2 Hz, 1.5H), 1.04 (d, J=6.2 Hz, 1.5H).
The title compound (32 mg, 74%) was prepared according to General Procedure E using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (40 mg, 0.056 mmol) and acetohydrazide (15 mg, 0.20 mmol). LCMS: RT=2.098 min, MS (ES) 768.0 (M+H).
(R)—N-acetyl-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carbohydrazide (10 mg, 0.013 mmol) was dissolved in POCl3 (1 mL) and heated to 95° C. for 1 h. The reaction mixture was cooled to RT, poured into ice/aqueous NaHCO3 (50 mL), and the mixture was then stirred for 15 min. The aqueous layer was extracted with DCM (3×15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (5.3 mg, 54%). LCMS: RT=2.051 min, MS (ES) 750.0 (M+H).
The title compound (107 mg, 71%) was prepared following General Procedure G using methyl 3-bromo-1H-indole-5-carboxylate (100 mg, 0.39 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (0.11 mL, 98.5 mg, 0.59 mmol). LCMS: RT=1.977 min, MS (ES) 384.0 (M+H).
The title compound (93 mg, 82%) was prepared following General Procedure B using methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carboxylate (78 mg, 0.20 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (60.8 mg, 0.11 mmol). LCMS: RT=2.393 min, MS (ES) 842.0 (M+H).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-5-carboxylate (110 mg, 0.13 mmol) in THF (0.5 mL) was added TBAF (1.18 mL, 1.17 mmol, 1.0 M in THF), and the reaction mixture was stirred at 40° C. for 24 h. The reaction was quenched with sat. NH4Cl aq. solution and extracted with EtOAc (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound (40 mg, 43%). LCMS: RT=2.077 min, MS (ES) 711.9 (M+H).
The title compound (7 mg, 81%, 2 steps) was prepared following General Procedure G, using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (8 mg, 0.011 mmol) and 2-(bromomethyl)pyridine hydrobromide (4.2 mg, 0.017 mmol) followed by General Procedure D. LCMS: RT=1.887 min, MS (ES) 789.0 (M+H). 1H NMR (500 MHz, DMSO-d) S 8.52 (s, 2H), 8.11 (s, 2H), 7.85 (s, 2H), 7.82 (t, J=7.3 Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.37-7.34 (m, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.16 (t, J=7.1 Hz, 2H), 6.71 (s, 4H), 5.63 (s, 4H), 4.50-4.47 (m, 2H), 4.16-4.13 (m, 2H), 3.97 (m, 4H), 3.77-3.76 (m, 6H), 3.70 (d, J=13.0 Hz, 1H), 3.66 (d, J=13.1 Hz, 1H), 3.32-3.29 (m, 2H), 3.25-3.20 (m, 2H), 2.23 (s, 12H), 2.11 (s, 3H), 2.07-2.04 (m, 4H), 2.02 (s, 3H), 1.96 (s, 3H), 1.87 (s, 3H), 1.07 (d, J=6.2 Hz, 6H).
The title compound (13 mg, 35%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromo-1,3,5-trimethyl-1H-indole-2-carboxylate (18 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.191 MS (ES) 738.0 (M+H).
The title compound (4.3 mg, 37%) was prepared following General Procedure G using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate and 2-bromo-N,N-dimethylethan-1-amine hydrobromide (5.4 mg, 0.023 mmol) followed by saponification using General Procedure D. LCMS: RT=1.824 min, MS (ES) 769.0 (M+H).
A solution of (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid (10 mg, 0.014 mmol) and N-isocyano-1,1,1-triphenyl-λ5-phosphinimine (20 mg, 0.066 mmol) in DCM (2 mL) was stirred at 40° C. for 7 days. The reaction mixture was then diluted with DCM (10 mL), washed with H2O (5 mL), dried by passage through a phase separator, and concentrated. The crude reaction mixture was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (4.4 mg, 43%). LCMS: RT=2.083 min, MS (ES) 736.0 (M+H).
The title compound (252 mg, 94%) was prepared following the procedure described Example 319 Step B using ethyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (300 mg, 0.35 mmol) and Pd/C (10 wt. %, 40 mg, 0.037 mmol). LCMS: RT=2.093 min, MS (ES) 755.8 (M+H).
The title compound (13.6 mg, 69%) was prepared according to General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (20 mg, 0.026 mmol) and MeI (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=2.028 min, MS (ES) 742.0 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J=8.6 Hz, 1H), 7.40-7.29 (m, 2H), 7.10 (d, J=2.3 Hz, 0.66H), 7.06 (d, J=2.3 Hz, 0.34H), 6.88-6.83 (m, 1H), 6.63 (s, 1.3H), 6.61 (s, 0.7H), 4.47-4.18 (m, 2H), 4.06-3.95 (m, 7H), 3.91 (s, 0.7H), 3.90 (s, 0.3H), 3.87 (s, 2H), 3.86 (s, 1H), 3.58 (d, J=12.2 Hz, 0.3H), 3.53 (d, J=12.2 Hz, 0.7H), 3.45-3.30 (m, 2H), 2.32 (s, 6H), 2.28 (s, 3H), 2.22-2.15 (M, 2H), 2.10 (s, 1H), 2.08 (s, 2H), 1.30 (d, J=6.5 Hz, 2H), 1.22 (d, J=6.6 Hz, 1H).
The title compound (2.8 mg, 26%) was prepared following the procedure described Example 341 using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carboxylic acid (10 mg, 0.014 mmol) and N-isocyano-1,1,1-triphenyl-λ5-phosphinimine (20 mg, 0.066 mmol). LCMS: RT=2.115 min, MS (ES) 736.0 (M+H).
The title compound (7.1 mg, 71%) was prepared according to General Procedure H using methyl (M, R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-7-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and MeI (5 mg, 0.035 mmol) followed by saponification using General Procedure D. LCMS: RT=2.044 min, MS (ES) 742.0 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.21 (s, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 6.62 (s, 2H), 4.37 (s, 4H), 4.17 (s, 1H), 4.04-3.94 (m, 8H), 3.54 (d, J=12.5 Hz, 1H), 3.46-3.27 (m, 2H), 2.32 (s, 6H), 2.26 (s, 3H), 2.24-2.14 (m, 2H), 2.08 (s, 3H), 1.27 (d, J=6.4 Hz, 3H).
The title compound was prepared according to General Procedure B using (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-(benzyloxy)-7-bromo-1-methyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.430, 2.457 min, MS (ES) 817.8 (M+H).
The title compound (2.2 mg, 21%) was prepared following the procedure described Example 341 using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.014 mmol) and N-isocyano-1,1,1-triphenyl)-λ5-phosphinimine (20 mg, 0.066 mmol). LCMS. RT=2.043 min, MS (ES) 736.0 (M+H).
The title compound (1.8 mg, 17%) was prepared following the procedure described Example 341 using (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid (10 mg, 0.014 mmol) and N-isocyano-1,1,1-triphenyl-λ5-phosphinimine (20 mg, 0.066 mmol). LCMS: RT=2.089 min, MS (ES) 735.9 (M+H).
The title compound was prepared according to General Procedure B using (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromo-6-fluoro-1-methyl-1H-indole-5-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.176 min, MS (ES) 729.9 (M+H).
The title compound was prepared according to General Procedure B using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 8-bromo-2-naphthoate followed by saponification using General Procedure D. LCMS: RT=2.233 min, MS (ES) 708.9 (M+H).
The title compound (12 mg, 60%) was prepared following General Procedure G using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-5-(I H-tetrazol-5-yl)-1H-indol-3-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.03 mmol) and MeI (4 μL, 0.05 mmol) and isolated as the first eluting isomer by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 40-90% MeCN 0.1% TFA). LCMS: RT=2.033 min, MS (ES) 750.0 (M+H).
The title compound (35 mg, 94%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromo-4-methoxy-1H-indole-2-carboxylate (43 mg, 0.15 mmol). LCMS: RT=2.116 min, MS (ES) 742.0 (M+H).51.
The title compound (6 mg, 53% yield) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (15 mg, 0.02 mmol) and MeI (5 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=1.766 MS (ES) 756.0 (M+H).
The title compound (115 mg, 76%) was prepared following General Procedure G using methyl 4-bromo-1H-indole-2-carboxylate (100 mg, 0.39 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (0.11 mL, 98.5 mg, 0.59 mmol).
The title compound (125 mg, 99%) was prepared following General Procedure B using methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (96 mg, 0.25 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (85 mg, 0.139 mmol). LCMS: RT=2.466 min, MS (ES) 842.0 (M+H).
To a solution of methyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (125 mg, 0.148 mmol) in THF (0.5 mL) was added TBAF (3.7 mL, 3.7 mmol, 1.0 M in THF), and the reaction mixture was irradiated under microwave for 10 h at 120° C. The reaction was cooled to RT, quenched with sat. NH4Cl aq. solution and extracted with EtOAc (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was redissolved in THF (6 mL) and MeOH (0.6 mL) then trimethylsilyl diazomethane (0.114 mL, 0.228 mmol, 2.0 M in Et2O) was added. After 1 h of stirring at RT, the reaction was quenched with glacial acetic acid then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) (57 mg, 54% yield, 2 steps). LCMS: RT=2.090 min, MS (ES) 712.0 (M+H).
The title compound (8 mg, 53%, 2 steps) was prepared following General Procedure G using methyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (13 mg, 0.019 mmol) and 2-(bromomethyl)pyridine hydrobromide (6.2 mg, 0.025 mmol) followed by saponification using General Procedure D. LCMS: RT=1.869 min. MS (ES) 788.9 (M+H).
The title compound (01 mg, 75%, 2 steps) was prepared following General Procedure G using methyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (13 mg, 0.019 mmol) and 1-bromo-2-methoxyethane (3 μL, 4.4 mg, 0.032 mmol) followed by saponification using General Procedure D. LCMS: RT=2.040 min, MS (ES) 756.0 (M+H).
The title compound (4.5 mg, 45%) was prepared according to General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid (10 mg, 0.013 mmol) and ammonia in MeOH (7.0 M, 0.25 mL). LCMS. RT=2.012 min, MS (ES) 754.9 (M+H).
The title compound was prepared according to General Procedure B using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromo-6-fluoro-1-methyl-1H-indole-5-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.74 min, MS (ES) 730.0 (M+H) (LC method III).
The title compound (22 mg, 58%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromo-5-isopropyl-1H-indole-2-carboxylate (45 mg, 0.15 mmol). LCMS: RT=2.295 min, MS (ES) 754.0 (M+H).
The title compound (12 mg, 80%) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-isopropyl-1H-indole-2-carboxylate (15 mg, 0.02 mmol) and MeI (5 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.186 MS (ES) 754.0 (M+H).
To a solution of (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylic acid (20 mg, 0.028 mmol) in DCM (1 mL) was added DMF (1 μL) and oxalyl chloride (3.8 μL), sequentially. The reaction mixture was stirred for 30 min at RT then concentrated. The residue was dissolved in dry DCM (1 mL) and ammonia (10 μL, 0.5 M in 1,4-dioxane) was added. The reaction mixture was stirred at RT for 15 min then concentrated. The residue was purified by HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 50% to 100% CH3CN for 5 min, 0.1% TFA) to give the title compound (16 mg, 80%). MS (ES) 712.1 (M+H), Rf=0.88
The title compound (4 mg, 20%) was isolated as the second eluting isomer along with Example 350. LCMS: RT=2.110 min, MS (ES) 749.9 (M+H).
The title compound (16 mg, 96%) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-isopropyl-1H-indole-2-carboxylate (15 mg, 0.02 mmol) and 2-(bromomethyl)pyridine hydrobromide (7.6 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=1.971 MS (ES) 831.0 (M+H).
The title compound (7.2 mg, 64% yield) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)-6-methoxypyridine (10 mg, 0.064 mmol) followed by saponification using General Procedure D. LCMS: RT=2.105 min, MS (ES) 819.0 (M+H).
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (115 mg, 0.16 mmol) in DCM (3 mL) was added NMM (18 mg, 0.18 mmol), hydroxylamine hydrochloride (13 mg, 0.18 mmol) and DMAP (2 mg, 0.02 mmol). The reaction mixture was stirred at RT for 12 h then quenched with water (5 mL). The mixture was extracted with DCM (3×5 mL). The organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (49 mg, 42%). LCMS: RT=1.897 min, MS (ES) 726.9 (M+H).
The title compound (11 mg, 54%) was prepared following General Procedure G using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenol)propyl)-4-methyl-2-(1-methyl-7-(1H-tetrazol-5-yl)-1H-indol-3-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.03 mmol) and methyl iodide (4 μL, 0.05 mmol) and isolated as the first eluting isomer. LCMS: RT=2.074 min, MS (ES) 750.0 (M+H).
The title compound (8.9 mg, 80%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)-5-methylpyridine (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=1.885 min, MS (ES) 802.9 (M+H).
The title compound (12 mg, 75%) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-isopropyl-1H-indole-2-carboxylate (15 mg, 0.02 mmol) and 1-bromo-2-methoxyethane (4.2 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=2.208 MS (ES) 798.0 (M+H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromo-6-chloro-1-methyl-1H-indole-5-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.81 min, MS (ES) 745.9 (M+H). (LC method III).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (15 mg, 0.02 mmol) in DMF (1 mL) was added hydrazine hydrate (0.5 mL, 2.4 mmol, 50% solution), and the mixture was heated at 60° C. for 6 h. The reaction was quenched with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The organic layer was dried (anhyd. Na2SO4) and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (13 mg, 89%). LCMS: RT=1.768 min, MS (ES) 726.0 (M+H).
The title compound (2.5 mg, 16%, 2 steps) was prepared following General Procedure G using methyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (13 mg, 0.019 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (5.1 mg, 0.027 mmol) followed by saponification using General Procedure D. LCMS: RT=1.843 min, MS (ES) 811.0 (M+H).
The title compound was prepared according to General Procedure I using (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 8-bromo-2-naphthoate followed by saponification using General Procedure D. LCMS: RT=2.237 min, MS (ES) 708.9 (M+H).
The title compound (3 mg, 20%, 2 steps) was prepared following General Procedure G using methyl (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (13 mg, 0.019 mmol) and 1-(2-bromoethyl)pyrrolidine hydrobromide (10.2 mg, 0.039 mmol) followed by saponification using General Procedure D. LCMS: RT=1.855 min, MS (ES) 795.0 (M+H).
The title compound (14 mg, 69%) was prepared following General Procedure G using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-6-(1H-tetrazol-5-yl)-1H-indol-3-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.03 mmol) and MeI (4 μL, 0.05 mmol). LCMS: RT=2.125 min, MS (ES) 750.0 (M+H).
The title compound (6.6 mg, 60% yield) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)-4-methylpyridine (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=1.842, 1.862 min, MS (ES) 802.9 (M+H).
The title compound (6 mg, 30%) was isolated as the second eluting isomer along with Example 362. LCMS: RT=2.119 min, MS (ES) 749.9 (M+H).
A mixture of 2-((benzyloxy)methyl)-5-bromo-4,6-dimethylpyrimidine (800 mg, 2.26 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (864 mg, 3.4 mmol), Pd(dppf)Cl2 (165 mg, 0.23 mmol) and KOAc (353 mg, 4.5 mmol) in 1,4-dioxane (20 mL) was sparged for 1 min with N2 gas. The reaction mixture was stirred at 100° C. for 15 h. The reaction mixture was cooled to RT, quenched with H2O and extracted with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-25% gradient) to afford the title compound (560 mg, 70%).
To a solution of 2-((benzyloxy)methyl)-4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (2.2 g, 6.2 mmol) in MeOH (30 mL) was added aqueous KH2F (4.5 M, 15 mL). The mixture was stirred at RT for 15 min then concentrated in vacuo. The residue was dissolved in hot acetone then filtered. The filtrate was concentrated in vacuo, and the residue was recrystallized in hot acetone and Et2O to afford the title compound as a white solid (1.6 g, 77%).
To a solution of 2-((benzyloxy)methyl)-4,6-dimethyl-5-(trifluoro-14-boranyl)pyrimidine potassium salt (1.4 g, 4.2 mmol) in MeCN (20 mL) was added H2O (13 μM, 12.6 mmol) and TMSCl (1.35 g, 12.6 mmol). The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound (790 mg, 69%).
A mixture of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (260 mg, 0.52 mmol), (2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)boronic acid (214 mg, 0.78 mmol), dicyclohexyl(2-(phenanthren-9-yl)phenyl)phosphane (25 mg, 0.055 mmol), Pd2(dba)3 (19 mg, 0.018 mmol), and K2CO3 (136 mg, 1.0 mmol) in PhMe (2.0 mL)/THF (2.0 mL)/H2O (0.2 mL) was degassed and heated at 110° C. for 24 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (210 mg, 62%). MS (ES) 646.2 (M+H)
To a solution of ethyl 7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (180 mg, 0.28 mmol) and tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (150 mg, 0.63 mmol) in MeCN (10 mL) was added Cs2CO3 (200 mg, 0.62 mmol). The reaction was heated at 80° C. for 24 h, then cooled to RT. The reaction mixture was diluted with DCM/H2O (50 mL, 1:1) then layers were separated. The aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (194 mg, 87%). LCMS: RT=1.724 min, MS (ES) 803.0 (M+H) (LC method II).
To a solution of ethyl 7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (194 mg, 0.24 mmol) 1,4-dioxane (10 mL) was added HCl in dioxanes (4.0 M, 1.0 mL, 4.0 mmol), and the reaction mixture was stirred at RT overnight. The reaction was concentrated, and the residue was dissolved in MeOH (20 mL). K2CO3 (300 mg, 2.2 mmol) was added, and the reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was concentrated, and the residue was dissolved in DCM/H2O (40 mL, 1:1). The layers were separated, and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (117 mg, 74%). LCMS: RT=2.219 min, MS (ES) 657.0 (M+H).
The title compound (78 mg, 53%) was prepared according to General Procedure B using 7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-8-chloro-11-(3-(4-chloro-3,5 dimethylphenoxy)propyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (115 mg, 0.17 mmol) and methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (100 mg, 0.37 mmol). LCMS: RT=2.439 min, MS (ES) 843.9 (M+H).
To a solution of methyl 3-(7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-5-carboxylate (78 mg, 0.092 mmol) in a mixture of EtOH/MeOH/EtOAc (2 mL/mL/1 mL) was added HCl in dioxanes (4.0 M, 0.25 mL, 1.0 mmol) followed by Pd/C (10 wt. %, 20 mg, 0.018 mmol). The reaction mixture was stirred under H2 atmosphere at RT for 96 h. The reaction mixture was filtered through celite, rinsed with DCM and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (34 mg, 49%). LCMS: RT=2.023 min, MS (ES) 753.9.0 (M+H).
The title compound (5.2 mg, 15%) was prepared according to General Procedure J using methyl 3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-5-carboxylate (34 mg, 0.045 mmol) and pyrrolidine (15 mg, 0.21 mmol) followed by saponification using General Procedure D. LCMS: RT=1.778 min. MS (ES) 793.0 (M+H).
The title compound (2 mg, 18%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(bromomethyl)oxetane (10 mg, 0.066 mmol) followed by saponification using General Procedure D. LCMS: RT=2.034 min, MS (ES) 767.9 (M+H).
The title compound (4.3 mg, 72% yield) was prepared according to General Procedure L using (R)-1-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)isoquinoline-6-carboxylic acid (6 mg, 0.0085 mmol) and ammonia in MeOH (7.0 M, 0.25 mL). LCMS: RT=1.940 min, MS (ES) 708.9 (M+H).
The title compound (2.4 mg, 48%) was prepared according to General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylic acid (5 mg, 0.0069 mmol) and ammonia in MeOH (7.0 M, 0.25 mL). LCMS: RT=2.064 min, MS (ES) 723.0 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.82 (dd, J=8.6, 2.3 Hz, 1H), 7.52-7.34 (m, 3H), 7.02-6.90 (m, 1H), 6.64 (s, 1.5H), 6.61 (s, 0.5H), 4.30-4.10 (m, 2H), 4.07-03.93 (m, 4H), 3.85-3.70 (m, 1H), 3.58-3.48 (m, 1H), 3.42-3.33 (m, 2H), 2.54 (s, 0.75H), 2.52 (s, 2.25H), 2.47 (s, 0.75H), 2.44 (s, 2.25H), 2.40-2.35 (m, 2H), 2.34 (s, 6H), 2.24-2.17 (m, 3H), 1.36-1.20 (m, 3H).
The title compound was prepared according to General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid and ammonia in MeOH. LCMS: RT=2.004 min, MS (ES) 711.2 (M+H).
The title compound (7.8 mg, 69%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)-4-methoxypyridine hydrochloride salt (5 mg, 0.026 mmol) followed by saponification using General Procedure D. LCMS: RT=1.835, 1.858 min, MS (ES) 819.0 (M+H).
To a solution of methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (10 mg, 0.012 mmol) in DMF (0.5 mL) was added NH4OH (1 mL). The reaction mixture was stirred at 90° C. for 72 h. The crude reaction mixture was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (2.0 mg, 20%). LCMS: RT=1.869 min, MS (ES) 799.9 (M+H).
The title compound (7.4 mg, 69%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 3-(bromomethyl)-3-methyloxetane (10 mg, 0.061 mmol) followed by saponification using General Procedure D. LCMS: RT=2.035 min, MS (ES) 781.9 (M+H).
The title compound (7.9 mg, 72%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)-6-methylpyridine (5 mg, 0.035 mmol) followed by saponification using General Procedure D. LCMS: RT=1.850 min, MS (ES) 802.9 (M+H).
The title compound (10.2 mg, 90)%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)-5-methoxypyridine hydrochloride salt (10 mg, 0.053 mmol) followed by saponification using General Procedure D. LCMS: RT=1.911 min, MS (ES) 819.0 (M+H).
The title compound (3.3 mg, 91%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 3-(bromomethyl)oxetane (10 mg, 0.066 mmol) followed by saponification using General Procedure D. LCMS: RT=2.009 min, MS (ES) 768.0 (M+H).
The title compound (7.2 mg, 72%) was prepared according to General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylic acid (10 mg, 0.0069 mmol) and ammonia in MeOH (7.0 M, 0.25 mL). LCMS: RT=2.018 min, MS (ES) 708.9 (M+H).
The title compound (2.5 mg, 17%) was prepared following the procedure described Example 379 using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (15 mg, 0.019 mmol) and NH4OH (1 mL). LCMS: RT=1.809, 1.831 min, MS (ES) 787.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 7.82 (dd, J=8.6, 2.6 Hz, 1H), 7.67 (d, J=7.9 Hz, 0.75H), 7.62 (d, J=7.9 Hz, 0.25H), 7.38 (d, J=8.6 Hz, 0.25H), 7.37 (d, J=8.6 Hz, 0.75H), 7.25-6.95 (m, 3H), 6.64 (s, 1.5H), 6.60 (s, 0.5H), 4.46-4.13 (m, 2H), 4.05-3.97 (m, 4H), 3.85-3.71 (m, 1H), 3.55-3.32 (m, 3H), 2.51 (s, 0.75H), 2.49 (s, 2.25H), 2.33 (s, 9H), 2.25-2.17 (m, 2H), 1.31 (d, J=6.5 Hz, 2.25H), 1.22 (d, J=6.5 Hz, 0.75H).
The title compound (3.7 mg, 33%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(1-chloroethyl)pyridine hydrochloride (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=1.862 min, MS (ES) 802.9 (M+H).
The title compound (2.3 mg, 21%) was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (10 mg, 0.014 mmol) and 2-(chloromethyl)-3-methylpyridine hydrochloride (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=1.850 min, MS (ES) 802.9 (M+H).
3-Bromo-1-methyl-1H-pyrazole (100 mg, 0.62 mmol), PdCl2(dppf)·DCM (25 mg, 0.03 mmol), K2CO3 (745 μL, 1.86 mmol, 2.5 M aq. solution) were added to a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (196 mg, 0.76 mmol) in MeCN (2.5 mL). The reaction mixture was degassed using Ar then stirred at 95° C. for 13 hr. The reaction mixture was cooled to RT, filtered through Celite pad and extracted with DCM (3×5 mL). The combined organic layers were dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-25% gradient) to provide the title compound (120 mg, 91%). LCMS: RT=1.237 min, MS (ES) 212.2 (M+H).
NIS (134 mg, 0.60 mmol) was added to a solution of 1-methyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-indole (120 mg, 0.57 mmol) in DMF (5.7 mL) at 0° C. The reaction was warmed to RT and stirred for 2 h. The reaction was quenched with water and extracted with EtOAc (3×10 mL). The combined organic layer was washed with water, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-50% gradient) to afford the title compound (95 mg, 50%). LCMS: RT=1.491 min, MS (ES) 337.9 (M+H).
The title compound (23 mg, 66%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 3-iodo-1-methyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-indole (30 mg, 0.089 mmol). LCMS: RT=2.057 min, MS (ES) 748.9 (M+H).
The title compound (110 mg, 83%) was prepared following the procedure described Example 388, Step A using 2-bromopyridine (60 μL, 0.63 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (200 mg, 0.78 mmol). LCMS: RT=0.973 min, MS (ES) 209.1 (M+H).
The title compound (160 mg, 91%) was prepared following the procedure described Example 388, Step Busing 1-methyl-5-(pyridin-2-yl)-1H-indole (110 mg, 0.53 mmol). LCMS: RT=1.146 min, MS (ES) 334.9 (M+H).
The title compound (37 mg, 88%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol) and 3-iodo-1-methyl-5-(pyridin-2-yl)-1H-indole (36 mg, 0.11 mmol). LCMS: RT=1.895 min, MS (ES) 745.0 (M+H).
The title compound (259 mg, 84%) was prepared following the procedure described Example 373, Step E using of ethyl 7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (250 mg, 0.39 mmol), tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (150 mg, 0.63 mmol) and Cs2CO3 (250 mg, 0.77 mmol). LCMS: RT=1.737 min, MS (ES) 803.0 (M+H).
The title compound (143 mg, 68%) was prepared following the procedure described Example 373, Step F using ethyl (R)-7-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-1H-indole-2-carboxylate (259 mg, 0.32 mmol), HCl in dioxanes (4.0 M, 1.0 mL, 4.0 mmol) and K2CO3 (250 mg, 1.8 mmol). LCMS: RT=1.270 min, MS (ES) 657.0 (M+H).
The title compound (123 mg, 67%) was prepared according to General Procedure B using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (143 mg, 0.22 mmol) and methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (120 mg, 0.45 mmol). LCMS: RT=2.336 min, MS (ES) 843.9 (M+H).
To a solution of methyl (R)-3-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (123 mg, 0.15 mmol) in MeOH (5 mL) and EtOAc (1 mL) was added HCl in dioxane (4.0 M, 0.25 mL, 1.0 mmol) followed by Pd/C (10 wt. %, 10 mg, 0.0093 mmol). The reaction mixture was stirred under H2 atmosphere at 35° C. for 24 h. The reaction was filtered through celite, rinsed with DCM, and concentrated to afford the title compound (92 mg, 84%). LCMS: RT=2.066 min, MS (ES) 754.0 (M+H).
The title compound (8.2 mg, 60%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (13 mg, 0.017 mmol) and pyrrolidine (50 mg, 0.70 mmol) followed by saponification using General Procedure D. LCMS. RT=1.841 min, MS (ES) 793.0 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.95 (dd, J=8.8, 1.5 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.32 (dd, J=8.7, 4.7 Hz, 2H), 6.64 (s, 2H), 4.61 (s, 2H), 4.43-4.11 (m, 3H), 4.01 (t, J=6.2 Hz, 2H), 3.82 (s, 3H), 3.81-3.78 (m, 1H), 3.67 (d, J=13.0 Hz, 1H), 3.50-3.26 (m, 2H), 3.23-3.08 (m, 2H), 2.41 (s, 3H), 2.33 (s, 6H), 2.28-2.14 (m, 9H), 1.23 (d, J=6.3 Hz, 3H).
The title compound (50 mg, 72%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.090 mmol) and 5-bromo-3-iodo-1-methyl-1H-indole (60 mg, 0.18 mmol). LCMS: RT=2.277 min, MS (ES) 746.8 (M+H).
1-Methylpyrazole-4-boronic acid pinacol ester (20 mg, 0.094 mmol), PdCl2(dppf)·DCM (2 mg, 0.002 mmol), K2CO3 (56 μL, 0.14 mmol, 2.5 M aq. solution) were added to a solution of (R)-2-(5-bromo-1-methyl-1H-indol-3-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(0.1, 3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (35 mg, 0.047 mmol) in MeCN (1 mL). The reaction mixture was degassed using Ar and stirred at 95° C. for 1 h. The cooled reaction mixture was filtered through Celite followed by silica gel and the filterate was concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/MeCN gradient to 30-95% MeCN 0.1% TFA) to afford the title compound (25 mg, 71%). LCMS: RT=2.071 min, MS (ES) 748.0 (M+H).
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (9 mg, 0.0113 mmol) in DCM (1 mL) was added oxalyl chloride (2.2 μL, 0.026 mmol), followed by catalytic amount of DMF. The reaction mixture was stirred for 1 h at RT then concentrated in vacuo. The residue was re-dissolved in dry DCM (1 mL), and ammonia (10 uL, 0.5 M in 1-4-dioxane) was added. The reaction mixture was stirred at RT for 15 min and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 25-95% MeCN 0.1% TFA) to give the title compound (3.2 mg, 36%). LCMS: RT=0.783 min (LC method IV), MS (ES) 794.1 (M+H).
The title compound was prepared according to General Procedure E using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (25 mg, 0.035 mmol) and N-hydroxyacetimidamide (10 mg, 0.135 mmol). The crude product was carried forward to Step B without further purification. LCMS: RT=1.916 min, MS (ES) 768.0 (M+H).
To a solution of (R)—N-((3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carbonyl)oxy)acetimidamide from Step A in EtOH/H2O (3:1.4 mL) was added sodium acetate (10 mg, 0.121 mmol), and the mixture was stirred at 70° C. for 16 h. The reaction was cooled to RT and diluted into DCM/H2O (10 mL, 1:1). The layers were separated, and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (8.1 mg, 31%). LCMS: RT=2.138 min, MS (ES) 749.8 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J=2.0 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.78 (dd, J=8.6, 2.1 Hz, 1H), 7.50 (dd, J=8.6, 1.8 Hz, 1H), 7.38-7.24 (m, 2H), 6.63 (s, 2H), 4.564.36 (m, 1H), 4.274.13 (m, 1H), 4.08-3.96 (m, 5H), 3.86 (s, 3H), 3.70 (d, J=12.3 Hz, 1H), 3.50-3.30 (m, 2H), 2.49 (s, 1.5H), 2.47 (s, 1.5H), 2.34 (s, 15H), 2.32 (s, 6H), 2.31 (s, 1.5H), 2.24-2.18 (m, 5H), 1.30-1.23 (m, 3H).
The title compound (61 mg, 58%) was prepared following the procedure described Example 388, Step A using 2-bromopyrimidine (80 mg, 0.50 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (159 mg, 0.62 mmol). LCMS: RT=1.103 min, MS (ES) 210.1 (M+H).
The title compound (82 mg, 84%) was prepared following the procedure described Example 388, Step B using 1-methyl-5-(pyrimidin-2-yl)-1H-indole (61 mg, 0.29 mmol). LCMS: RT=1.456 min, MS (ES) 335.9 (M+H).
The title compound (15 mg, 43%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 3-iodo-1-methyl-5-(pyrimidin-2-yl)-1H-indole (30 mg, 0.089 mmol). LCMS: RT=2.086 min, MS (ES) 746.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.77 (d, J=4.8 Hz, 1H), 8.76 (d, J=4.9 Hz, 1H), 8.63 (dd, J=5.1, 1.5 Hz, 1H), 8.38 (dt, J=9.0, 1.5 Hz, 1H), 7.68 (dd, J=8.5, 2.6 Hz, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.30-7.25 (m, 2H), 7.12 (dt, J=8.5, 4.8 Hz, 1H), 6.61 (s, 2H), 4.53-4.46 (m, 1H), 4.35-4.20 (m, 1H), 4.02-3.97 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.75 (ddd, J=16.3, 12.7, 1.5 Hz, 1H), 3.47-3.31 (m, 2H), 2.29 (s, 6H), 2.24-2.19 (m, 5H), 2.06 (d, J=2.1 Hz, 3H), 1.29 (d, J=6.8 Hz, 1.4H), 1.22 (d, 1=6.4 Hz, 1.5H).
The title compound was prepared according to General Procedure E using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (20 mg, 0.028 mmol) and N-hydroxyacetimidamide (10 mg, 0.135 mmol). The crude product was carried forward to Step 2 without purification. LCMS: RT=1.930 min, MS (ES) 766.0 (M+H).
The title compound (8.1 mg, 31%) was prepared following the procedure described Example 393 Step B using (R)—N-((3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carbonyl)oxy)acetimidamide and sodium acetate (10 mg, 0.121 mmol). LCMS: RT=2.187 min, MS (ES) 747.8 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 9.23 (s, 1H), 8.31-8.18 (m, 1H), 8.03 (dd, J=8.7, 1.6 Hz, 1H), 7.88-7.80 (m, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.38 (m, 1H), 7.25 (s, 1H), 6.64 (s, 2H), 4.42 (dd, J=24.4, 9.9 Hz, 1H), 4.02 (t, J=6.1 Hz, 2H), 3.87 (s, 2H), 3.85 (d, J=2.5 Hz, 1H), 3.72-3.69 (m, 1H), 3.61 (d, J=12.6 Hz, 1H), 3.52-3.30 (m, 2H), 2.54 (s, 3H), 2.47 (s, 3H), 2.38 (s, 3H), 2.32 (s, 6H), 2.23 (t, J=6.9 Hz, 2H), 1.27 (d, J=6.5 Hz, 3H).
The title compound (9.5 mg, 48%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxylmethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (18 mg, 0.024 mmol) and N-methyl piperazine (100 mg, 1.0 mmol) followed by saponification using General Procedure D. LCMS: RT=1.799 min, MS (ES) 821.8 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 7.92 (dd, J=8.7, 1.5 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.36-7.26 (m, 3H), 6.64 (s, 2H), 4.57 (s, 2H), 4.33 (dd, J=13.3, 3.2 Hz, 1H), 4.06-3.87 (m, 6H), 3.81 (s, 3H), 3.81-3.68 (m, 6H), 3.51-3.30 (m, 2H), 2.95 (s, 3H), 2.40 (s, 3H), 2.33 (s, 6H), 2.25-2.17 (m, 5H), 1.24 (d, J=6.4 Hz, 3H).
The title compound (5.5 mg, 29%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (18 mg, 0.024 mmol) and 3-hydroxypyrrolidine (100 mg, 1.4 mmol) followed by saponification using General Procedure D. LCMS: RT=1.787 min, MS (ES) 808.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.34-7.26 (m, 3H), 6.64 (s, 2H), 4.70 (s, 2H), 4.38-3.89 (m, 6H), 3.82 (s, 3H), 3.81-3.59 (m, 4H), 3.50-3.30 (m, 2H), 2.41 (s, 3H), 2.33 (s, 6H), 2.26-2.17 (m, 7H), 1.24 (d, J=4.4 Hz, 3H).
The title compound (9 mg, 46%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(0H)-yl)-1-methyl-1H-indole-5-carboxylate (18 mg, 0.024 mmol) and morpholine (100 mg, 1.4 mmol) followed by saponification using General Procedure D. LCMS: RT=1.809, min, MS (ES) 808.9 (M+H).
The title compound was prepared following General Procedure B using 8-chloro-1 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one and methyl 7-bromo-1,5-dimethyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. MS (ES) 724.2 (M+H).
The title compound was prepared according to procedures described in Example 318 step A and B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-1,5-dimethyl-1H-indole-2-carboxylate. MS (ES) 726.2 (M+H).
The title compound was prepared following General Procedure D using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylate. LCMS: RT=0.873 min (LC method IV), MS (ES) 712.6 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 7.72 (d, J=8.8 Hz, 1H), 7.47 (s, 1H), 7.29 (dd, J=8.8, 2.8 Hz, 1H), 7.25 (s, 1H), 6.98 (s, 1H), 6.92 (s, 2H), 4.374.16 (m, 1H), 4.03 (s, 3H), 3.98 (t, J=6.0 Hz, 2H), 3.68-3.62 (m, 1H), 3.46-3.40 (m, 1H), 2.43 (s, 3H), 2.28 (s, 6H), 2.22 (s, 3H), 2.17 (t, J=6.4 Hz, 2H), 2.08-2.03 (m, 2H), 2.04 (s, 3H), 1.29 (d, J=6.0 Hz, 3H).
To a solution of 7-bromo-5-methyl-1H-indole-2-carboxylic acid (1.5 g, 5.9 mmol) in THF (50 mL) and MeOH (6 mL) was added trimethylsilyl diazomethane (4.4 mL, 8.9 mmol, 2.0 M in Et2O), and the reaction mixture was stirred at RT for 1 h. The reaction was quenched with glacial acetic acid then concentrated. The residue was dissolved in DCM (30 mL), and Et3N (2.94 mL, 2.15 g, 21.1 mmol), DMAP (0.144 g, 1.18 mmol) and di-tert-butyl dicarbonate (1.76 mL, 1.67 g, 7.67 mmol) were added. The reaction mixture was stirred at RT for 3 h then quenched with sat. NH4Cl aq. solution and extracted with DCM (3×25 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (1.7 g, 78%, 2 steps). LCMS: RT=1.900 min, MS (ES) 390.0 (M+Na); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=3.2 Hz, 2H), 7.21 (s, 1H), 3.92 (s, 3H), 2.41 (s, 3H), 1.69 (s, 9H).
To a solution of 1-tert-butyl) 2-methyl 7-bromo-5-methyl-1H-indole-1,2-dicarboxylate (1.7 g, 4.6 mmol) in CCl4 (46 mL) was added AIBN (189 mg, 1.15 mmol) and NBS (822 mg, 4.6 mmol). The reaction mixture was reflux for 3 h then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient). The crude mixture of products obtained was dissolved in MeCN (25 mL) then NMO (1.77 g, 15.2 mmol) and molecular sieves (4 Å, 6 g) were added. The reaction mixture was stirred at RT for 4 h then quenched with sat. NH4Cl aq. solution and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (500 mg, 29%, 2 steps). LCMS: RT=1.699 min, MS (ES) 403.8 (M+Na); 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.04 (d, J=1.2 Hz, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.28 (s, 1H), 3.85 (s, 3H), 1.63 (s, 9H).
To a solution of 1-(tert-butyl) 2-methyl 7-bromo-5-formyl-1H-indole-1,2-dicarboxylate (220 mg, 0.58 mmol) in DCM (3.5 mL) was added TFA (0.6 mL, 0.894 g, 7.8 mmol) and stirred at RT for 16 h. The reaction mixture was quenched with sat. NH4Cl aq. solution and extracted with DCM (3×10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was re-dissolved in DMF (5.5 mL) then K2CO3 (0.56 g, 4.1 mmol) and MeI (72 μL, 163 mg, 1.15 mmol) were added and stirred for 4 h at 60° C. The reaction was quenched with sat. NH4C aq. solution and extracted with DCM (3×10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was re-dissolved in DCM (5.6 mL) and Et3N (1 mL). Pyrrolidine (52 μL, 44 mg, 0.624 mmol) and Na(OAc)3BH (220 mg, 1.04 mmol) were added and stirred at RT for 4 h. The reaction mixture was quenched with aqueous saturated NaHCO3 solution and extracted with DCM (3×10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (118 mg, 58%, 3 steps). LCMS: RT=1.246 min, MS (ES) 351.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 4.37 (s, 3H), 3.83 (s, 3H), 3.57 (s, 2H), 2.47-2.43 (m, 4H), 1.73-1.70 (m, 4H).
The title compound (1.1 mg, 3%, 2 steps) was prepared following General Procedure B using methyl 7-bromo-1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-indole-2-carboxylate (20 mg, 0.057 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.057 mmol) followed by saponification using General Procedure D. LCMS: RT=1.851 min, MS (ES) 794.8 (M+H).
The title compound (1.5 mg, 74%) was prepared following General Procedure E using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(2-morpholinoethyl)-1H-indole-6-carboxylic acid (2.0 mg, 2.5 μmol). LCMS: RT=1.782 min, MS (ES) 810.0 (M+H).
The title compound (48 mg, 43%) was prepared following the procedure described Example 388, Step A using 2-bromo-1-methyl-1H-1,2,4-triazole (85 mg, 0.525 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (165 mg, 0.65 mmol) LCMS: RT=1.077 min, MS (ES) 213.1 (M+H).
The title compound (46 mg, 61%) was prepared following the procedure described Example 388, Step B using 1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (48 mg, 0.23 mmol). LCMS: RT=1.306 min, MS (ES) 338.7 (M+H).
The title compound (15 mg, 43%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 3-iodo-1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (30 mg, 0.089 mmol). LCMS: RT=1.953 min, MS (ES) 749.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.23 (s, 1H), 8.86 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.67 (dd, J=8.6, 2.5 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29-7.22 (m, 2H), 6.61 (s, 2H), 4.47 (dt, J=12.6, 3.0 Hz, 1H), 4.34-4.19 (m, 1H), 4.01-3.97 (m, 2H), 3.95 (d, J=3.2 Hz, 3H), 3.87 (s, 3H), 3.82 (s, 3H), 3.72-3.65 (m, 1H), 3.45-3.30 (m, 2H), 2.29 (s, 6H), 2.23-2.16 (m, 5H), 2.04 (s, 3H), 1.25 (d, J=6.7 Hz, 1.5H), 1.20 (d, J=6.5 Hz, 1.5H).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (225 mg, 0.31 mmol) in DCM (20 mL) at 0° C. was added BBr3 (1.0 M, 1.0 mL, 1.0 mmol), and the mixture was stirred for 1 h. The reaction was diluted with DCM (20 mL) and quenched with H2O (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with sat. aq. NaHCO3(20 mL), dried over MgSO4, filtered, and concentrated to afford the crude title compound (122 mg, 62% yield), which was used in subsequent reactions without further purification. LCMS: RT=1.687 min, MS (ES) 637.9 (M+H).
To a solution of cyclopropyl methanol (50 mg, 0.69 mmol) in DMF (2 mL) was added NaH (60 wt. %, 25 mg, 0.625 mmol) at RT, and the mixture was stirred for 30 min. (R)-3-(10-(3-Bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol) was added to the mixture, and the reaction was stirred at 50° C. for 15 h. The reaction was diluted DCM/H2O (10 mL, 1:1). The organic layer was separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were dried and concentrated. The crude reaction mixture was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (7.8 mg, 53%). LCMS: RT=1.666 min, MS (ES) 628.0 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.97 (dd, J=8.7, 1.5 Hz, 1H), 7.76 (dd, J=8.6, 2.8 Hz, 1H), 7.38-7.27 (m, 3H), 4.41 (d, J=11.5 Hz, 1H), 4.28-4.10 (m, 1H), 3.97 (s, 3H), 3.83 (s, 3H), 3.68 (d, J=12.0 Hz, 1H), 3.50 (t, J=6.5 Hz, 2H), 3.37-3.20 (m, 4H), 2.25 (d, J=10.1 Hz, 3H), 2.13-1.97 (m, 5H), 1.28-1.18 (m, 3H), 1.11-1.01 (m, 1H), 0.56-0.46 (m, 2H), 0.22-0.16 (m, 2H).
To a solution of (R)-3-(10-(3-bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol) in DMF (2 mL) was added 3-hydroxytoluene (20 mg, 0.19 mmol) and Cs2CO3 (30 mg, 0.092 mmol). The reaction was stirred at 50° C. for 15 h then diluted with DCM/H2O (10 mL, 1:1). The organic layer was separated, and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (5.8 mg, 37%). LCMS: RT=1.822 min, MS (ES) 664.0 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.98 (d, J=8.8, 1.6 Hz, 1H), 7.73 (dd, J=8.6, 2.4 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.32-7.27 (m, 2H), 7.12 (t, J=7.8 Hz, 1H), 6.76-6.66 (m, 3H), 4.45-4.37 (m, 1H), 4.26-4.13 (m, 1H), 4.07-3.93 (m, 5H), 3.84 (s, 3H), 3.68 (d, J=12.8 Hz, 1H), 3.49-3.31 (m, 2H), 2.31-2.18 (m, 8H), 2.12 (s, 1.5H), 2.08 (s, 1.5H), 1.28-1.20 (m, 3H).
The title compound (5.0 mg, 36%) was prepared following the procedure described Example 404 Step B using methanol (50 mg, 1.56 mmol), NaH (60 wt. %, 25 mg, 0.625 mmol) and (R)-3-(10-(3-Bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol). LCMS: RT=1.525 min, MS (ES) 588.0 (M+H).
The title compound (4.5 mg, 27%) was prepared following the procedure described Example 405 using (R)-3-(10-(3-bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol) and 4-chloro-3-methylphenol (20 mg, 0.14 mmol). LCMS: RT=1.909 min, MS (ES) 697.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.6, 2.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.29-7.25 (m, 2H), 7.17 (d, J=8.7 Hz, 1H), 6.75 (s, 1H), 6.64 (dd, J=8.8, 3.0 Hz, 1H), 4.41 (d, J=12.6 Hz, 1H), 4.22-4.12 (m, 1H), 4.05-3.95 (m, 5H), 3.83 (s, 3H), 3.68 (d, J=13.9 Hz, 1H), 3.45-3.29 (m, 2H), 2.29 (s, 4.5H), 2.25 (s, 1.5H), 2.20 (t, J=6.5 Hz, 2H), 2.13 (s, 1.5H), 1.98 (s, 1.5H), 1.18-1.07 (m, 3H).
The title compound (4.3 mg, 28%) was prepared following the procedure described Example 405 using (R)-3-(10-(3-bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol) and phenol (20 mg, 0.21 mmol). LCMS: RT=1.765 min, MS (ES) 649.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 8.00 (dd, J=8.7, 1.6 Hz, 1H), 7.75 (dd, J=8.6, 2.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.35-7.24 (m, 4H), 6.96-6.85 (m, 3H), 4.46-4.18 (m, 2H), 4.09-3.99 (m, 5H), 3.86 (s, 3H), 3.70 (d, J=12.7 Hz, 1H), 3.56-3.31 (m, 2H), 2.31 (s, 1H), 2.26 (s, 2H), 2.25-2.22 (m, 2H), 2.14 (s, 2H), 2.11 (s, 1H), 1.27 (d, J=5.8 Hz, 1H), 1.24 (d, J=5.1 Hz, 2H).
The title compound (4.7 mg, 29%) was prepared following the procedure described Example 405 using (R)-3-(10-(3-bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol) and 4-chlorophenol (20 mg, 0.16 mmol). LCMS: RT=1.845 min, MS (ES) 684.0 (M+H). 1H NMR (4(0) MHz, Chloroform-d) δ 8.30 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.71 (dd, J=8.6, 2.6 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.32-7.28 (m, 2H), 7.21-7.15 (m, 2H), 6.84-6.75 (m, 2H), 4.41 (d, J=12.6 Hz, 1H), 4.26-4.11 (m, 1H), 4.04-3.94 (m, 5H), 3.84 (s, 3H), 3.68 (d, J=10.4 Hz, 1H), 3.50-3.31 (m, 2H), 2.31-2.16 (m, 5H), 2.11 (s, 1.5H), 2.09 (s, 1.5H), 1.25 (d, J=5.2 Hz, 1.5H), 1.22 (d, J=5.2 Hz, 1.5H).
The title compound (4.8 mg, 31%) was prepared following the procedure described Example 405 using (R)-3-(10-(3-bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol) and 4-fluorophenol (20 mg, 0.18 mmol). LCMS: RT=1.776 min, MS (ES) 667.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.00 (dd, J=8.7, 1.6 Hz, 1H), 7.73 (dd, J=8.5, 2.6 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.36-7.28 (m, 2H), 7.00-6.90 (m, 2H), 6.88-6.75 (m, 2H), 4.44-4.19 (m, 2H), 4.05-3.96 (m, 5H), 3.86 (s, 3H), 3.70 (d, J=12.6 Hz, 1H), 3.50-3.30 (m, 2H), 2.30 (s, 1.5H), 2.27 (s, 1.5H), 2.22 (p, J=6.8 Hz, 2H), 2.13 (s, 1.5H), 2.11 (s, 1.5H), 1.27 (d, J=5.1 Hz, 1.5H), 1.24 (d, J=5.1 Hz, 1.5H).
The title compound (8 mg, 80%) was prepared following General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1,3-dimethyl-1H-indole-2-carboxylic acid (10 mg, 0.013 mmol). LCMS: RT=1.752 min, MS (ES) 754.9 (M+H).
The title compound (6.3 mg, 62%) was prepared following General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-methyl-1H-indole-2-carboxylic acid (10 mg, 0.013 mmol). LCMS: RT=2.002 min, MS (ES) 741.0 (M+H).
To a solution of 3-bromo-1-methyl-1H-indole-5-carboxylic acid (75 mg, 0.30 mmol) and DIPEA (100 mg, 0.78 mmol) in DMF (2 mL) was added HATU (120 mg, 0.32 mmol). The reaction mixture was stirred at RT for 10 min then cyclohexanecarbohydrazide (50 mg, 0.35 mmol) was added. The reaction was allowed to stir for 2 h at RT. The reaction was diluted into DCM/H2O (20 mL, 1:1), and the layers were separated. The aqueous layer was extracted with DCM (2×10 mL), and the combined organic layer was dried and concentrated. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (66 mg, 59%). LCMS: RT=1.361 min, MS (ES) 379.9 (M+H).
A solution of 3-bromo-N′-(cyclohexanecarbonyl)-1-methyl-1H-indole-5-carbohydrazide (66 mg, 0.17 mmol) in POCl3 (2 mL) was heated to 95° C. for 1 h. The cooled reaction mixture was quenched by pouring into ice/sat. aq. NaHCO3(50 mL), and the resulting mixture was stirred for 15 min then extracted with DCM (3×15 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (32 mg, 51%). LCMS. RT=1.814 min, MS (ES) 360.0 (M+H).
The title compound (12.4 mg, 41%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.038 mmol) and 2-(3-bromo-1-methyl-1H-indol-5-yl)-5-cyclohexyl-1,3,4-oxadiazole (21 mg, 0.61 mmol) followed by saponification using General Procedure D. LCMS: RT=1.674, 1.706 min, MS (ES) 817.9 (M+H) (Ultra aqueous method).
The title compound (31 mg, 90%) was prepared according to General Procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and 4-bromo quinoline-6-carbonitrile (16 mg, 0.06 mmol). LCMS: RT=2.039 min, MS (ES) 691.0 (M+H).
The title compound (26 mg, 80%) was prepared according to the procedure for Example 235 using (R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)quinoline-6-carbonitrile (30 mg, 0.04 mmol), sodium azide (14 mg, 0.22 mmol) and ammonium chloride (12 mg, 0.22 mmol). LCMS: RT=1.844 min, MS (ES) 733.9 (M+H).
The title compound (2.9 mg, 29%) was prepared following the procedure described Example 379 using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (10 mg, 0.012 mmol) and NH4OH (0 mL). LCMS: RT=1.900, 1.934 min, MS (ES) 801.9 (M+H).
The title compound (279 mg, 72%) was prepared according to General Procedure B using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (300 mg, 0.46 mmol) and methyl 7-iodo-5-methyl-1H-indole-2-carboxylate (300 mg, 0.952 mmol). LCMS: RT=2.387 min, MS (ES) 843.9 (M+H).
The title compound was prepared according to General Procedure I using methyl (R)-7-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (48 mg, 0.057 mmol) and MeI (14 mg, 0.10 mmol). LCMS: RT=2.464 min, MS (ES) 857.9 (M+H).
The title compound (33 mg, 73%, Steps B and C) was prepared following the procedure described Example 390 step D using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylate (0.057 mmol). LCMS: RT=2.175, 2.208 min, MS (ES) 767.9 (M+H).
The title compound (7.6 mg, 44%) was prepared according to General Procedure J using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylate (16 mg, 0.021 mmol) and morpholine (50 mg, 0.57 mmol) followed by saponification using General Procedure D. LCMS: RT=1.959, 2.022 min, MS (ES) 822.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J=8.6 Hz, 0.25H), 7.78 (d, J=8.6 Hz, 0.75H), 7.38-7.25 (m, 3H), 6.95-6.83 (s, 1H), 6.63 (s, 1.5H), 6.61 (s, 0.5H), 4.64 (d, J=14.7 Hz, 1H), 4.52-4.40 (m, 2H), 4.25-4.03 (m, 4H), 4.02-3.96 (m, 2H), 3.93 (s, 3H), 3.88-3.78 (s, 2H), 3.45-3.31 (m, 3H), 2.48 (s, 3H), 2.41 (s, 2.25H), 2.40 (s, 0.75H), 2.33 (s, 6H), 2.26-2.17 (m, 5H), 1.31-1.14 (m, 3H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-1,2-dimethyl-1H-indole-3-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.87 min, MS (ES) 726.2 (M+H) (LC method III). 1H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.31-7.26 (m, 2H), 6.98 (d, J=8.0 Hz, 1H), 6.61 (s, 1.5H), 6.58 (s, 0.5H), 4.51-4.20 (m, 2H), 3.99-3.81 (m, 6H), 3.71-3.32 (m, 5H), 2.77 (s, 2H), 2.76 (s, 1H), 2.31 (s, 6H), 2.21-2.17 (m, 5H), 2.07-2.03 (m, 3H), 1.25 (d, J=6.0 Hz, 2H), 1.13 (d, J=6.0 Hz, 1H).
The title compound (110 mg, 95%) was prepared following the procedure described Example 388 Step A using 2-bromo-4-methylpyrimidine (90 mg, 0.52 mmol). LCMS: RT=0.901 min, MS (ES) 224.1 (M+H).
The title compound (110 mg, 64%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(4-methylpyrimidin-2-yl)-1H-indole (110 mg, 0.49 mmol). LCMS: RT=1.489 min, MS (ES) 349.9 (M+H).
The title compound (22 mg, 62%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 3-iodo-1-methyl-5-(4-methylpyrimidin-2-yl)-1H-indole (31 mg, 0.089 mmol). LCMS: RT=2.060 min, MS (ES) 760.9 (M+H).
The title compound (60 mg, 39%) was prepared following the procedure described Example 388 Step A using 2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (120 mg, 0.64 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (203 mg, 0.79 mmol). LCMS: RT=0.925 min, MS (ES) 238.2 (M+H).
The title compound (75 mg, 82%) was prepared following the procedure described Example 388 Step B using 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1-methyl-1H-indole (60 mg, 0.25 mmol). LCMS: RT=1.240 min, MS (ES) 363.9 (M+H).
The title compound (20 mg, 56%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-3-iodo-1-methyl-1H-indole (32 mg, 0.089 mmol). LCMS: RT=1.932 min, MS (ES) 774.9 (M+H).
The title compound (80 mg, 39%) was prepared following the procedure described Example 388 Step A using 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol (170 mg, 0.73 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (245 mg, 0.95 mmol). LCMS. RT=1.339 min, MS (ES) 283.0 (M+H).
The title compound (100 mg, 72%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (80 mg, 0.28 mmol). LCMS: RT=1.561 min, MS (ES) 408.9 (M+H).
The title compound (20 mg, 38%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (35 mg, 0.065 mmol) and 3-iodo-1-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (51 mg, 0.13 mmol). LCMS: RT=2.104 min, MS (ES) 818.9 (M+H).
TFA (1 mL) was added to a solution of (4R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.020 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted DCM and washed with water. Sat. aq. NaHCO3 was added at 0° C. and extracted with DCM (3×5 mL). The combined organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-2% gradient) to afford the title compound (17 mg, 95%). LCMS: RT=1.906 min, MS (ES) 735.9 (M+H).
The title compound (49 mg, 45%) was prepared following General coupling procedure E using 3-bromo-1-methyl-1H-indole-5-carboxylic acid (75 mg, 0.30 mmol), DIPEA (100 mg, 0.78 mmol), HATU (120 mg, 0.32 mmol) and benzohydrazide (50 mg, 0.37 mmol). LCMS: RT=1.278 min, MS (ES) 373.9 (M+H).
The title compound (22 mg, 47%) was prepared following the procedure described Example 413 Step B using N′-benzoyl-3-bromo-1-methyl-1H-indole-5-carbohydrazide (49 mg, 0.13 mmol). LCMS: RT=1.742 min, MS (ES) 353.9 (M+H).
The title compound (17.8 mg, 59% yield) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.038 mmol) and 2-(3-bromo-1-methyl-1H-indol-5-yl)-5-phenyl-1,3,4-oxadiazole (22 mg, 0.062 mmol) followed by saponification using General Procedure D. LCMS: RT=2.470, 2.503 min, MS (ES) 811.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.40-8.32 (m, 1H), 8.18-8.10 (m, 2H), 8.03 (ddd, J=8.7, 4.9, 1.5 Hz, 2H), 7.78 (dd, J=8.6, 2.1 Hz, 1H), 7.62-7.49 (m, 3H), 7.39-7.27 (m, 2H), 6.63 (s, 2H), 4.61-4.45 (m, 1H), 4.28-4.15 (m, 1H), 4.07-3.95 (m, 5H), 3.90 (s, 3H), 3.73 (d, J=12.5 Hz, 11H), 3.52-3.31 (m, 2H), 2.38-2.29 (m, 9H), 2.29-2.13 (m, 5H), 1.29 (d, J=6.5 Hz, 3H).
The title compound (5.2 mg, 52%) was prepared following General Procedure E using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-tri methyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-isopropyl-1-methyl-1H-indole-2-carboxylic acid (10 mg, 0.013 mmol). LCMS: RT=2.111 min, MS (ES) 753.0 (M+H).
The title compound (41 mg, 43%) was prepared following the procedure described Example 413 Step A using 1-methyl-1H-indole-5-carbohydrazide (70 mg, 0.37 mmol) and cyclopropanecarbonyl chloride (110 mg, 1.06 mmol). LCMS: RT=0.907 min, MS (ES) 258.1 (M+H).
The title compound (11 mg, 28% yield) was prepared following the procedure described Example 413 Step B using N-(cyclopropanecarbonyl)-1-methyl-1H-indole-5-carbohydrazide (41 mg, 0.16 mmol). LCMS: RT=1.341 min, MS (ES) 240.1 (M+H).
The title compound (12 mg, 82% yield) was prepared according to General Procedure F using 2-cyclopropyl-5-(1-methyl-1H-indol-5-yl)-1,3,4-oxadiazole (11 mg, 0.046 mmol). LCMS: RT=1.538 min, MS (ES) 318.0 (M+H).
The title compound (11.2 mg, 39%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.037 mmol) and 2-(3-bromo-1-methyl-1H-indol-5-yl)-5-cyclopropyl-1,3,4-oxadiazole (12 mg, 0.038 mmol) followed by saponification using General Procedure B. LCMS: RT=2.314, 2.342 min, MS (ES) 775.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.26-8.16 (m, 1H), 7.89 (t, J=7.5 Hz, 1H), 7.77 (dd, J=8.6, 2.0 Hz, 1H), 7.47 (dd, J=8.7, 1.0 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.35-7.28 (m, 1H), 6.63 (s, 2H), 4.55-4.45 (m, 1H), 4.27-4.13 (m, 1H), 4.08-3.96 (m, 5H), 3.87 (s, 3H), 3.70 (d, J=12.5 Hz, 1H), 3.50-3.29 (m, 2H), 2.38-2.27 (m, 9H), 2.27-2.12 (m, 5H), 1.25 (m, 8H).
The title compound (143 mg, 91%) was prepared following the procedure described Example 388 Step A using 3-bromopyridazine (120 mg, 0.76 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (239 mg, 0.93 mmol). LCMS: RT=1.005 min, MS (ES) 210.1 (M+H).
The title compound (160 mg, 80%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(pyridazin-3-yl)-1H-indole (143 mg, 0.60 mmol). LCMS: RT=1.251 min, MS (ES) 335.8 (M+H).
The title compound (20 mg, 59%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 3-iodo-1-methyl-5-(pyridazin-3-yl)-1H-indole (30 mg, 0.089 mmol). LCMS: RT=1.938 min, MS (ES) 746.8 (M+H).
The title compound (14 mg, 69%) was prepared following General Procedure NGeneral Procedure G using (R)-2-(6-(2H-tetrazol-5-yl)quinolin-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.03 mmol) and methyl iodide (4 μL, 0.05 mmol). LCMS: RT=1.909 min, MS (ES) 747.9 (M+H).
The title compound (12.7 mg, 73%) was prepared according to General Procedure J using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylate (16 mg, 0.021 mmol) and N-methyl piperazine (50 mg, 0.20 mmol) followed by saponification using General Procedure D. LCMS: RT=1.841, 1.871 min, MS (ES) 835.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 7.78 (dd, J=8.7, 2.5 Hz, 1H), 7.37-7.20 (m, 3H), 6.92-6.76 (m, 1H), 6.62 (s, 1.5H), 6.60 (s, 05H), 4.62 (d, J=15.5 Hz, 1H), 4.47-4.38 (m, 2H), 4.09 (s, 1H), 4.03-3.61 (m, 13H), 3.34 (t, J=7.5 Hz, 2H), 3.16-3.06 (m, 1H), 2.92 (s, 2.25H), 2.89 (s, 0.75H), 2.44 (s, 2.25H), 2.42 (s, 0.75H), 2.41 (s, 2.25H), 2.39 (s, 0.75H), 2.28-2.16 (m, 5H), 1.23 (d, J=6.4 Hz, 2.25H), 1.13 (d, J=6.4 Hz, 0.75H).
The title compound (7.6 mg, 73%) was prepared following General Procedure E using (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (10 mg, 0.013 mmol) and phenylhydrazine hydrochloride (4 mg, 0.026 mmol). LCMS: RT=2.079 min, MS (ES) 802.0 (M+H).
Aminoethanol (193 μL, 3.20 mmol) and ZnCl2 (6 μL, 0.13 mmol) were added to a solution of 1-methyl-1H-indole-5-carbonitrile (100 mg, 0.64 mmol) in toluene (3 mL). The reaction mixture was stirred at 135° C. for 4 days. The reaction solution was cooled and concentrated. The residue was diluted with water and extracted with DCM (3×10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-5% gradient) to afford the title compound (30 mg, 23%). LCMS: RT=0.775 min, MS (ES) 201.1 (M+H).
The title compound was prepared following the procedure described Example 388, Step B using 2-(1-methyl-1H-indol-5-yl)-4,5-dihydrooxazole (15 mg, 0.070 mmol). The crude compound (25 mg) was used for the next step without further purification. LCMS: RT=1.142 min, MS (ES) 326.9 (M+H).
The title compound (25 mg, 73%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 2-(3-iodo-1-methyl-1H-indol-5-yl)-4,5-dihydrooxazole (24 mg, 0.074 mmol). LCMS: RT=1.883 min, MS (ES) 737.8 (M+H).
Hydroxylamine hydrochloride (116 mg, 1.66 mmol) and K3PO4 (408 mg, 1.92 mmol) were added to a solution of 1-methyl-1H-indole-5-carbonitrile (200 mg, 1.28 mmol) in DMF (4 mL). The reaction mixture was stirred at 95° C. for 16 h then acetyl chloride (137 μL, 1.92 mmol) was added at RT. The solution was stirred at 105° C. for additional 36 h. The reaction mixture was diluted EtOAc and washed with water, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-3% gradient) to afford the title compound (21 mg, 64%). LCMS: RT=1.304 min, MS (ES) 214.1 (M+H).
The title compound was prepared following the procedure described Example 388, Step B using 5-methyl-3-(1-methyl-1H-indol-5-yl)-1,2,4-oxadiazole (21 mg, 0.10 mmol). The crude compound (55 mg) was used for the next step without further purification. LCMS: RT=1.594 min, MS (ES) 339.9 (M+H).
The title compound (22 mg, 63%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 3-(3-iodo-1-methyl-1H-indol-5-yl)-5-methyl-1,2,4-oxadiazole (25 mg, 0.074 mmol). LCMS: RT=2.121 min, MS (ES) 750.8 (M+H).
The title compound (90 mg, 98%) was prepared following the procedure described Example 388 Step A using 2-bromopyrazine (70 mg, 0.44 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (170 mg, 0.66 mmol). LCMS: RT=1.296 min, MS (ES) 210.1 (M+H).
The title compound was prepared following the procedure described Example 388 Step B using 1-methyl-5-(pyrazin-2-yl)-1H-indole (90 mg, 0.43 mmol). The crude compound (120 mg) was used for the next step without further purification. LCMS: RT=1.530 min, MS (ES) 335.8 (M+H).
The title compound (28 mg, 67%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol) and 3-iodo-1-methyl-5-(pyrazin-2-yl)-1H-indole (30 mg, 0.089 mmol). LCMS: RT=2.096 min, MS (ES) 746.9 (M+H).
Racemic mixture of atropisomeric 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one was separated by preparative normal phase HPLC using chiral AD column. Optically pure atropisomers were isolated and absolute configurations were undetermined. 1st eluted isomer [α]D25=+9.9°, 2nd eluted isomer [α]D25=+6.1°
The title compound was prepared according to General Procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (1st eluted isomer) and 6-bromo-1-methyl-1H-indole-4-carboxylic acid followed by saponification using General Procedure D. LCMS: RT=2.163 min, MS (ES) 711.9 (M+H).
The title compound (4.2 mg, 38%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (10 mg, 0.013 mmol) and 1-methylpiperazin-2-one (10 mg, 0.088 mmol) followed by saponification using General Procedure D. LCMS: RT=1.782 min, MS (ES) 835.9 (M+H).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethyl-2-(piperazin-1-ylmethyl)pyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (8 mg, 0.0098 mmol) in DCM (1 mL) was added DIPEA (5 mg, 0.038 mmol) followed by acetyl chloride (3 mg, 0.038 mmol) in DCM (0.5 mL) at 0° C. The reaction mixture was stirred for 15 min at 0° C. then quenched with MeOH. The quenched mixture was diluted with DCM (5 mL) and washed with H2O (5 mL). The organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (2.1 mg, 25%). LCMS: RT=1.789 min, MS (ES) 849.9 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (15 mg, 0.021 mmol) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (10 mg, 0.045 mmol) in MeCN (1 mL) was added Cs2CO3 (15 mg, 0.0416 mmol), and the reaction mixture was stirred at 80° C. for 18 h. The reaction was cooled to RT and diluted into DCM/H2O (10 mL, 1:1). The layers were separated and extracted with DCM (2×5 mL). The combined organic layer was dried and concentrated to give the crude title compound which was used without further purification. LCMS: RT=2.289 min, MS (ES) 890.9 (M+Na).
To a solution of crude ethyl (R)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate in DCM (3 mL) was added TFA (0.5 mL), and the reaction mixture was stirred for 6 h at RT then concentrated. The residue was dissolved in MeOH (3 mL), and K2CO3 (10 mg, 0.072 mmol) was added. The reaction mixture was stirred at 50° C. for 4 h then concentrated. The residue was dissolved in DCM/H2O (10 mL, 1:1). The layers were separated and extracted with DCM (2×5 mL). The combined organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (5.3 mg, 35%). LCMS: RT=2.116, 2.153 min, MS (ES) 723.0 (M+H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-4-chloro-1-methyl-1H-indole-3-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.212, 2.254 min, MS (ES) 745.8 (M+H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-5-methoxy-1-methyl-1H-indole-3-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.182, 2.217 min, MS (ES) 741.9 (M+H).
The title compound (6.9 mg, 62%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (10 mg, 0.013 mmol) and 1-methylpiperidin-4-amine (20 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=1.762 min, MS (ES) 835.9 (M+H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-4-fluoro-1H-indole-3-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.70, 2.73 min, MS (ES) 716.2 (M+H) (LC method III).
The title compound (8.9 mg, 77%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (10 mg, 0.013 mmol) and 1-(2-methoxyethyl)piperazine (40 mg, 0.28 mmol) followed by saponification using General Procedure D. LCMS: RT=1.850 min, MS (ES) 865.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.92 (dd, J=8.8, 1.4 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.35-7.28 (m, 3H), 6.64 (s, 2H), 4.51-4.38 (m, 2H), 4.30 (dd, J=13.5, 3.8 Hz, 1H), 4.01 (dt, J=6.2, 3.0 Hz, 2H), 3.91-3.71 (m, 14H), 3.44-3.29 (m, 8H), 2.39 (s, 3H), 2.33 (s, 6H), 2.29-2.19 (m, 5H), 1.25 (d, J=6.4 Hz, 3H).
The title compound was prepared according to General Procedure A using 8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (2nd eluted isomer) and 6-bromo-1-methyl-1H-indole-4-carboxylic acid followed by saponification using General Procedure D. LCMS: RT=2.163 min, MS (ES) 711.9 (M+H).
The title compound (17 mg, 79%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (20 mg, 0.039 mmol) and piperazine (50 mg, 0.58 mmol) followed by saponification using General Procedure D. LCMS: RT=1.727 min, MS (ES) 807.9 (M+H).
To a solution of methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (30 mg, 0.04 mmol) in DMF (1 mL) was added sodium acetate (14 mg, 0.16 mmol) and hydroxylamine hydrochloride (11 mg, 0.16 mmol), and the mixture was stirred at RT for 15 h. The reaction was quenched with water (10 mL) then extracted with DCM (3×5 mL). The organic layer was dried and concentrated. The residue was dissolved in THF (1 mL) and 1,1′-carbonyldiimidazole (17 mg, 0.08 mmol) and DBU (18 μL, 12 mmol) were added. The mixture was irradiated in a Biotage microwave at 120° C. for 20 min then concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (7.8 mg, 26%). LCMS: RT=2.033 min, MS (ES) 751.8 (M+H).
The title compound (10.6 mg, 89%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (10 mg, 0.013 mmol) and 4-(piperidin-4-yl)morpholine (50 mg, 0.29 mmol) followed by saponification using General Procedure D. LCMS: RT=1.848 min, MS (ES) 891.9 (M+H).
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carbohydrazide (15 mg, 0.02 mmol) in DMF (1 mL) was added 1,1′-carbonyldiimidazole (7 mg, 0.04 mmol) followed by Et3N (6 μL, 0.04 mmol), and the mixture was stirred at RT for 6 h then concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18. H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (6.1 mg, 40%). LCMS: RT=1.982 min, MS (ES) 751.8 (M+H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and 7-bromo-4-methoxy-1-methyl-1H-indole-3-carboxylic acid followed by saponification using General Procedure D. LCMS: RT=2.76, 2.81 min, MS (ES) 742.2 (M+H)(LC method III). 1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.32-7.26 (m, 1H), 7.02-7.00 (m, 1H), 6.80-6.77 (m, 1H), 6.60 (s, 2H), 4.23-4.18 (m, 2H), 4.13 (s, 3H), 3.98-3.87 (m, 5H), 3.71-3.32 (m, 5H), 3.77 (s, 3H), 3.56-3.52 (m, 1H), 3.35-3.31 (m, 2H), 2.31 (s, 6H), 2.21-2.15 (m, 5H), 2.03 (s, 3H), 1.23-1.17 (m, 3H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and 7-bromo-4-fluoro-1H-indole followed by saponification using General Procedure D. LCMS: RT=3.04 min, MS (ES) 672.0 (M+H) (LC method III).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and 7-bromo-4-fluoro-1-methyl-1H-indole-3-carboxylic acid followed by saponification using General Procedure D. LCMS: RT=2.77 min, MS (ES) 730.1 (M+H) (LC method III).
The title compound (5.3 mg, 48%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (10 mg, 0.013 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (30 mg, 0.29 mmol) followed by saponification using General Procedure D. LCMS: RT=1.788 min, MS (ES) 823.9 (M+H).
The title compound was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-5-chloro-1-methyl-1H-indole-3-carboxylate followed by saponification using General Procedure D. LCMS: RT=2.284 min, MS (ES) 745.8 (M+H).
The title compound (70 mg, 78%) was prepared following the procedure described Example 388 Step A using 2-bromo-5-methylpyrimidine (70 mg, 0.44 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (156 mg, 0.61 mmol). LCMS: RT=1.156 min, MS (ES) 224.1 (M+H).
The title compound was prepared following the procedure described Example 388 Step B using 1-methyl-5-(5-methylpyrimidin-2-yl)-1H-indole (70 mg, 0.31 mmol). The crude compound (100 mg) was used for the next step without further purification. LCMS: RT=1.507 min, MS (ES) 350.8 (M+H).
The title compound (29 mg, 69%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol) and 3-iodo-1-methyl-5-(5-methylpyrimidin-2-yl)-1H-indole (31 mg, 0.089 mmol). LCMS: RT=2.132 min, MS (ES) 760.9 (M+H).
The title compound (5.9 mg, 58%) was prepared according to General Procedure J using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (10 mg, 0.013 mmol) and dimethylamine hydrochloride salt (20 mg, 0.25 mmol) followed by saponification using General Procedure D. LCMS: RT=1.811 min, MS (ES) 766.9 (M+H).
The title compound was prepared following the procedure described Example 318 Step C using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylate and 4-(bromomethyl)tetrahydro-2H-pyran. LCMS: RT=1.63 min. MS (ES) 810.7 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 7.76 (dd, J=8.8, 1.6 Hz, 1H), 7.48 (s, 1H), 7.29 (dd, J=8.8, 1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 6.95 (s, 1H), 6.70 (s, 2H), 4.39-4.31 (m, 1H), 4.20-4.16 (m, 2H), 3.97-3.94 (m, 2H), 3.91 (s, 3H), 3.86-3.80 (m, 2H), 2.67-2.63 (m, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 2.35-2.31 (m, 2H), 2.22 (s, 6H), 2.12 (s, 3H), 2.01 (s, 3H), 1.95-1.95 (m, 2H), 1.89-1.87 (m, 2H), 1.43-1.29 (m, 1H), 1.17-1.03 (m, 4H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol), PPh3 (10 mg, 0.038 mmol) and 2-(4-methylpiperazin-1-yl)ethan-1-ol (8 mg, 0.055 mmol) in THF (1 mL) was added di-tert-butyl (E)-diazene-1,2-dicarboxylate (10 mg, 0.044 mmol) at RT. The reaction mixture was stirred for 18 h at RT, then heated to 60° C. for additional 5 h. The reaction was cooled to RT and diluted with DCM/H2O (10 mL, 1:1). The aqueous layer was extracted with DCM (2×5 mL). The combined organic layer was dried and concentrated. The crude product was saponified following General Procedure D. The crude reaction mixture was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (2.2 mg, 19%). LCMS: RT=1.779 min, MS (ES) 853.9 (M+H).
2N HCl (2 mL) was added to a solution of 3-iodo-1-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (150 mg, 0.37 mmol) in MeOH (1 mL) at 0° C. The reaction was warmed to RT and stirred for 4 h. The reaction mixture was diluted with EtOAc, quenched with Sat. aq. NaHCO3 at 0° C. and extracted with EtOAc (3×5 mL). The combined organic layer was dried and concentrated to give the title compound (80 mg), which was used for the next step without further purification. LCMS: RT=0.211 min, MS (ES) 324.9 (M+H).
NaH (4 mg, 0.15 mmol) was added to a solution of 3-iodo-1-methyl-5-(1H-1,2,4-triazol-3-yl)-1H-indole (40 mg, 0.12 mmol) in DMF (1 mL) at 0° C. After 10 min, 1-bromo-2-methylpropane (16.1 μL, 0.15 mmol) was added slowly. The reaction was warmed to RT and stirred for 15 h. The reaction was quenched with water and extracted with EtOAc (3×10 mL). The combined organic layer was washed with water, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-20% gradient) to provide the title compound (35 mg, 74%). LCMS: RT=1.564 min, MS (ES) 380.8 (M+H).
The title compound (40 mg, 91%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol) and 3-iodo-5-(1-isobutyl-1H-1,2,4-triazol-3-yl)-1-methyl-1H-indole (34 mg, 0.089 mmol). LCMS: RT=2.132 min, MS (ES) 791.9 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=24.5 Hz, 1H), 8.20 (d, J=11.2 Hz, 1H), 7.98 (dd, J=9.0, 1.7 Hz, 1H), 7.68 (dd, J=8.8, 3.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.29-7.23 (m, 2H), 6.61 (s, 2H), 4.50-4.41 (m, 1H), 4.31-4.20 (m, 1H), 4.00-3.95 (m, 4H), 3.90 (s, 3H), 3.83 (s, 3H), 3.74-3.67 (m, 1H), 3.46-3.30 (m, 2H), 2.34-2.27 (m, 7H), 2.22-2.18 (m, 5H), 2.06 (s, 3H), 1.26 (d, J=6.4 Hz, 1.5H), 1.23 (d, J=6.9 Hz, 1.5H), 0.97 (d, J=6.9 Hz, 6H).
The title compound (2.6 mg, 24%) was prepared following the procedure described Example 453 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 2-(dimethylamino)ethan-1-ol (5 mg, 0.056 mmol). LCMS: RT=1.810 min, MS (ES) 798.9 (M+H).
The title compound (30 mg, 45%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.09 mmol) and methyl 7-bromo-5-methyl-1H-indole-2-carboxylate (58 mg, 0.19 mmol). LCMS: RT=2.16 min, MS (ES) 726 (M+H).
The title compound (25 mg, 34%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-3-carboxylate (60 mg, 0.08 mmol) and 2-(chloromethyl)-4-methylpyridine HCl (29 mg, 0.17 mmol) followed by saponification using General Procedure D. LCMS: RT=1.38 min, MS (ES) 817 (M+H).
To a mixture of methyl 7-bromo-5-methyl-1H-indole-2-carboxylate (200 mg, 0.75 mmol) followed by CuI (7 mg, 0.04 mmol) and NaI (224 mg, 1.5 mmol) was added a solution of (trans)-1,2-N,N′-dimethylaminocyclohexane (11 mg, 0.07 mmol) in 1-pentanol (1 mL). The reaction mixture was sealed and stirred at 120° C. for 24 h. The reaction was cooled to RT and diluted with 30% NH4OH (5 mL) in water (20 mL) and extracted with DCM. The combined organics were dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-5% gradient) to give the title compound (205 mg, 74%). LCMS: RT=2.04 min, MS (ES) 372 (M+H).
The title compound (80 mg, 73%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (75 mg, 0.14 mmol) and pentyl 7-iodo-5-methyl-1H-indole-2-carboxylate (103 mg, 0.28 mmol). LCMS: RT=2.42 min, MS (ES) 782 (M+H).
The title compound (45 mg, 68%) was prepared following General Procedure I using pentyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (80 mg, 0.10 mmol) and 2-(chloromethyl)-6-methylpyridine (36 mg, 0.26 mmol) followed by saponification using General Procedure D as TFA salt. LCMS: RT=1.40 min, MS (ES) 817 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J=8.6 Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.01 (m, 1H), 6.87 (s, 0.5H), 6.86 (s, 0.5H), 6.74 (s, 1H), 6.70 (s, 1H), 6.11-6.24 (m, 2H), 5.74 (s, 2H), 4.01 (m, 2H), 3.88 (m, 1H), 3.73 (s, 15H), 3.70 (s, 1.5H), 3.24-3.28 (m, 1H), 3.08 (m, 11H), 2.32-2.38 (m, 5H), 2.23 (s, 3H), 2.21 (s, 3H), 2.08 (s, 1.5H), 2.06 (s, 1.5H), 1.95-1.99 (m, 2H), 1.91 (s, 1.5H), 1.89 (s, 1.5H), 1.85 (s, 1.5H), 1.75 (s, 1.5H), 1.03 (t, J=6.8 Hz, 3H).
The title compound (4.7 mg, 42%) was prepared following the procedure described Example 453 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 2-morpholinoethan-1-ol (8 mg, 0.061 mmol). LCMS: RT=1.794 min, MS (ES) 840.9 (M+H).
The title compound (3.7 mg, 35%) was prepared according to General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 3-(bromomethyl)oxetane (5 mg, 0.033 mmol) followed by saponification using General Procedure D. LCMS: RT=1.990 min, MS (ES) 797.8 (M+H).
The title compound (2.1 mg, 19%) was prepared following the procedure described Example 453 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 2-(pyrrolidin-1-yl)ethan-1-ol (8 mg, 0.069 mmol). LCMS: RT=1.799 min, MS (ES) 824.9 (M+H).
The title compound (5.2 mg, 50%) was prepared according to General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 1-bromo-2-methoxyethane (5 mg, 0.036 mmol) followed by saponification using General Procedure D. LCMS: RT=2.009 min, MS (ES) 785.8 (M+H).
The title compound (35 mg, 75%) was prepared following the procedure described Example 454 Step B using 3-iodo-1-methyl-5-(1H-1,2,4-triazol-3-yl)-1H-indole (40 mg, 0.12 mmol) and (bromomethyl)cyclopropane (14.4 μL, 0.15 mmol). LCMS: RT=1.498 min, MS (ES) 378.9 (M+H).
The title compound (38 mg, 87%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol) and 5-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-3-iodo-1-methyl-1H-indole (34 mg, 0.089 mmol). LCMS: RT=2.034 min, MS (ES) 789.0 (M+H).
The title compound was prepared following the procedure described Example 318 Step C using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,5-dimethyl-1H-indole-2-carboxylate and 1-(2-bromoethyl)pyrrolidine. LCMS: RT=1.37 min, MS (ES) 809.7 (M+H); 1H NMR (DMSO, 400 MHz) δ (ppm) 7.90 (d, J=8.8 Hz, 1H), 7.49 (s, 1H), 7.31 (dd, J=8.8, 2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 6.96 (d, J=10.0 Hz, 1H), 6.69 (s, 2H), 4.46-4.36 (m, 2H), 4.17-4.11 (m, 1H), 3.98-3.91 (m, 2H), 3.92 (s, 3H), 3.65-3.60 (m, 2H), 3.09-3.01 (m, 2H), 2.64-2.61 (m, 2H), 2.53 (s, 3H), 2.38 (s, 3H), 2.32-2.31 (m, 2H), 2.22 (s, 6H), 2.05 (d, J=4.0 Hz, 3H), 2.06-1.95 (m, 2H), 1.93 (s, 3H), 1.90-1.84 (m, 2H), 1.22-1.05 (m, 4H).
2-Chloro-4-methoxypyrimidine (80 mg, 0.55 mmol), Pd[P(t-Bu)3]2 (28 mg, 0.060 mmol), Cs2CO3 (270 mg, 0.83 mmol) were added to a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (185 mg, 0.72 mmol) in dioxane (2.2 mL). The reaction mixture was degassed using Ar. The reaction was stirred at 90° C. for 5 h, quenched with water and extracted with DCM (3×5 mL). The combined organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-20% gradient) to provide the title compound (19 mg, 14%). LCMS: RT=0.163 min, MS (ES) 240.1 (M+H).
The title compound was prepared following the procedure described Example 388 Step B using 5-(4-methoxypyrimidin-2-yl)-1-methyl-1H-indole (19 mg, 0.080 mmol). The crude compound (30 mg) was used for the next step without further purification. LCMS: RT=1.248 min, MS (ES) 365.8 (M+H).
The title compound (35 mg, 80%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol) and 3-iodo-5-(4-methoxypyrimidin-2-yl)-1-methyl-1H-indole (30 mg, 0.089 mmol). LCMS: RT=2.106 min, MS (ES) 776.8 (M+H).
The title compound (63 mg, 48%) was prepared following the procedure described Example 464 Step A using 2-chloro-5-methoxypyrimidine (80 mg, 0.55 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (185 mg, 0.72 mmol). LCMS: RT=1.086 min, MS (ES) 240.1 (M+H).
The title compound was prepared following the procedure described Example 388 Step B using 5-(5-methoxypyrimidin-2-yl)-1-methyl-1H-indole (63 mg, 0.26 mmol). The crude compound (85 mg) was used for the next step without further purification. LCMS: RT=1.601 min, MS (ES) 365.8 (M+H).
The title compound (35 mg, 80%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.056 mmol) and 3-iodo-5-(5-methoxypyrimidin-2-yl)-1-methyl-1H-indole (32 mg, 0.089 mmol). LCMS: RT=2.106 min, MS (ES) 776.8 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J=8.1 Hz, 2H), 8.47 (dd, J=6.6, 1.4 Hz, 1H), 8.26 (ddd, J=8.7, 3.6, 1.7 Hz, 1H), 7.70 (dd, J=8.6, 2.7 Hz, 1H), 7.43 (dd, J=8.7, 2.8 Hz, 1H), 7.30-7.24 (m, 2H), 6.60 (s, 2H), 7.48 (td, J=13.4, 3.7 Hz, 1H), 4.30-4.19 (m, 1H), 4.02-3.98 (m, 2H), 3.95-3.93 (m, 6H), 3.83-3.73 (m, 4H), 3.47-3.30 (m, 2H), 2.28 (s, 6H), 2.25-2.18 (m, 5H), 2.09 (d, J=5.3 Hz, 3H), 1.30 (d, J=6.5 Hz, 1.5H), 1.22 (d, J=6.6 Hz, 1.5H).
The title compound (6 mg, 37%) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (15 mg, 0.02 mmol) and 2-(bromomethyl)pyridine hydrobromide (7.6 mg, 0.03 mmol) followed by primary carboxamide formation using General Procedure E. LCMS: RT=1.859 MS (ES) 817.9 (M+H).
The title compound (32 mg, 90%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromo-1H-indole-3-carboxylate (39 mg, 0.15 mmol). LCMS: RT=2.070 min, MS (ES) 711.9 (M+H).
The title compound (10.1 mg, 63%) was prepared according to General Procedure 1 using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 3-(chloromethyl)pyridine hydrochloride (7 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.806 MS (ES) 788.8 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 8.47-8.39 (m, 1H), 8.20-8.14 (m, 2H), 8.00-7.91 (m, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.33-7.28 (m, 2H), 7.20-7.11 (m, 1H), 7.04-6.94 (m, 1H), 6.72 (s, 2H), 5.65-5.58 (m, 1H), 4.02-3.97 (m, 2H), 3.93-3.88 (m, 2H), 3.74 (s, 1.5H), 3.72 (s, 1.5H), 3.42-3.34 (m, 1H), 3.16-3.11 (m, 2H), 2.96-2.87 (m, 2H), 2.23 (s, 6H), 2.07 (s, 1.5H), 2.06-2.02 (m, 2H), 1.98 (s, 1.5H), 1.90 (s, 1.5H), 1.80 (s, 1.5H), 1.06-1.00 (m, 3H).
The title compound (8.7 mg, 55%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 2-(bromomethyl)pyridine hydrobromide (10 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.923 MS (ES) 788.8 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.38-7.24 (m, 2H), 7.23-7.16 (m, 1H), 6.97-6.89 (m, 1H), 6.72 (s, 2H), 6.50-6.42 (m, 1H), 5.71-5.58 (m, 1H), 4.04-3.99 (m, 3H), 3.83-3.78 (m, 2H), 3.73 (s, 1.5H), 3.70 (s, 15H), 3.42-3.31 (m, 1H), 3.31-3.23 (m, 1H), 3.22-3.12 (m, 1H), 2.68-2.56 (m, 1H), 2.15-2.09 (m, 2H), 2.22 (s, 6H), 2.08 (s, 1.5H), 1.98 (s, 1.5H), 1.84 (s, 1.5H), 1.74 (s, 1.5H), 1.06-0.94 (m, 3H).
The title compound (20 mg, 57%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (75 mg, 0.14 mmol) and ethyl 7-bromo-5-(trifluoromethoxy)-1H-indole-2-carboxylate (98 mg, 0.28 mmol) followed by saponification following General Procedure D. LCMS: RT=2.07 min, MS (ES) 782 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.6 Hz, 1H), 7.68 (bs, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.16 (bs, 1H), 6.72 (s, 2H), 4.66-4.69 (m, 1H), 4.11-4.18 (m, 1H), 3.98 (m, 2H), 3.77 (s, 1.5H), 3.76 (s, 1.5H), 3.45-3.53 (m, 1H), 3.18-3.36 (m, 2H), 2.22 (s, 6H), 2.03-2.12 (m, 5H), 1.98 (s, 15H), 1.89 (s, 15H), 1.11 (d, J=6.4 Hz, 3H).
The title compound (35 mg, 61%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (70 mg, 0.10 mmol) and 2-bromoethyl methyl ether (20 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.06 min, MS (ES) 770 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=8.4 Hz, 1H), 7.50 (s, 0.5H), 7.45 (s, 0.5H), 7.33 (m, 1H), 7.27 (m, 1H), 6.96 (s, 0.5H), 6.94 (s, 0.5H), 6.71 (s, 1H), 6.70 (s, 1H), 4.94 (m, 1H), 4.68 (m, 2H), 4.43 (m, 2H), 4.18 (m, 1H), 3.99 (t, J=5.5 Hz, 2H), 3.79 (s, 1.5H), 3.77 (s, 1.5H), 3.71 (m, 1H), 3.35 (m, 2H), 3.22 (m, 2H), 3.00 (s, 1.5H), 2.95 (s, 1.5H), 2.39 (s, 1.5H), 2.36 (s, 1.5H), 2.24 (s, 6H), 2.14 (m, 1H), 1.88-2.07 (m, 5H), 1.17 (d, J=6.4 Hz, 1.5H), 1.06 (d, J=6.4 Hz, 1.5H).
The title compound (310 mg, 77%) was prepared following the procedure described Example 388 Step A using 3-bromo-1-methyl-1H-1,2,4-triazole (200 mg, 1.23 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (567 mg, 1.52 mmol). LCMS: RT=1.488 min, MS (ES) 329.1 (M+H).
The title compound (380 mg, 89%) was prepared following the procedure described Example 388 Step B using 5-(1-methyl-1H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (310 mg, 0.94 mmol). LCMS: RT=1.740 min, MS (ES) 454.9 (M+H).
The title compound (150 mg, 63%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (150 mg, 0.28 mmol) and 3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (202 mg, 0.45 mmol). LCMS: RT=2.209 min, MS (ES) 865.9 (M+H).
TBAF (2 mL, 1 M solution in THF) was added to a solution of (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-(2H)-one (150 mg, 0.17 mmol) in THF (1.7 mL). The reaction was irradiated under microwave at 70° C. for 30 min (3 times). Additional TBAF (1 mL) was added to the reaction then irradiated under microwave at 75° C. for 1 h (3 times). The reaction was quenched with water and extracted with DCM (3×10 mL). The combined organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-3% gradient) to provide the title compound (95 mg, 75%). LCMS: RT=1.864 min, MS (ES) 735.9 (M+H).
The title compound (12.6 mg, 80%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 4-(bromomethyl)pyridine hydrobromide (10 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.751 MS (ES) 788.8 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 8.55-8.47 (m, 1H), 8.40-8.32 (m, 1H), 8.28-8.21 (m, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.80-7.68 (m, 1H), 7.37-7.23 (m, 2H), 7.09-7.00 (m, 1H), 6.96 (t, J=8.1 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H), 5.75-5.61 (m, 1H), 4.06-3.95 (m, 3H), 3.89-3.85 (m, 2H), 3.73 (s, 1.5H), 3.70 (s, 1.5H), 3.39-3.27 (m, 2H), 3.18-3.06 (m, 1H), 2.74-2.65 (m, 1H), 2.23 (s, 6H), 2.08 (s, 1.5H), 2.06-2.02 (m, 2H), 1.98 (s, 1.5H), 1.87 (s, 1.5H), 1.75 (s, 1.5H), 1.05-0.96 (m, 3H).
The title compound (30 mg, 43%) was prepared following General coupling procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (60 mg, 0.111 mmol) and methyl 3-bromoimidazo[1,2-a]pyridine-6-carboxylate (40 mg, 0.156 mmol) followed by saponification using General Procedure D. LCMS: RT=0.858 min (LC method IV), MS (ES) 699.5 (M+H), 1H NMR (DMSO, 400 MHz) δ (ppm) 8.81 (s, 1H), 7.92 (d, J=10.0 Hz, 2H), 7.82 (d, J=10.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.70 (s, 2H), 4.67-4.63 (m, 1H), 4.20-4.18 (m, 2H), 3.97-3.95 (m, 2H), 3.78 (s, 3H), 2.49 (s, 6H), 2.22-2.15 (m, 2H), 2.06 (s, 3H), 2.00-1.95 (m, 2H), 1.87 (s, 3H), 1.10 (d, J=6.8 Hz, 3H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (34 mg, 0.04 mmol) and 2-(chloromethyl)-4-methylpyridine HCl (22 mg, 0.13 mmol) in DMF (0.7 mL) was added Cs2CO3 (68 mg, 0.21 mmol). The mixture was stirred under Ar at 80° C. overnight then an additional 2-(chloromethyl)-4-methylpyridine HCl (22 mg, 0.13 mmol) and Cs2CO3 (100 mg) were added. The reaction was stirred under Ar at 100° C. for 24 h. The title compound (21 mg, 50%) was isolated according to work up and purification protocols described in general coupling procedure A followed by saponification using General Procedure D as TFA salt. LCMS: RT=2.00 min, MS (ES) 887 (M+H).
The title compound (39 mg, 32%) was prepared following the procedure described Example 454 Step B using 3-iodo-1-methyl-5-(1H-1,2,4-triazol-3-yl)-1H-indole (100 mg, 0.31 mmol) and 3-(chloromethyl)oxetane (30 μL, 0.090 mmol). LCMS: RT=1.339 min, MS (ES) 395.8 (M+H). LCMS: RT=1.498 min, MS (ES) 378.9 (M+H).
The title compound (22 mg, 59%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.046 mmol) and 3-iodo-1-methyl-5-(1-(oxetan-3-ylmethyl)-1H-1,2,4-triazol-3-yl)-1H-indole (37 mg, 0.093 mmol). LCMS: RT=1.963 min, MS (ES) 805.9 (M+H).
The title compound (6.6 mg, 38%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (15 mg, 0.020 mmol) and 2-(chloromethyl)-4-methoxypyridine HCl salt (10 mg, 0.052 mmol) followed by saponification using General Procedure D. LCMS: RT=1.883 min, MS (ES) 846.8 (M+H).
The title compound (7.5 mg, 45%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (15 mg, 0.020 mmol) and 2-(chloromethyl)-6-methylpyridine (10 mg, 0.071 mmol) followed by saponification using General Procedure D. LCMS: RT=1.895 min, MS (ES) 830.8 (M+H).
The title compound (5.2 mg, 31%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (15 mg, 0.020 mmol) and 2-(chloromethyl)-5-methylpyridine HCl salt (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=1.909 min, MS (ES) 830.8 (M+H).
The title compound was prepared according to General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (45 mg, 0.06 mmol) and MeI (16 mg, 0.11 mmol) followed by saponification using General Procedure D. LCMS: RT=2.12 min, MS (ES) 796 (M+H).
The title compound (7.2 mg, 45%) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 2-(chloromethyl)-4-methylpyridine HCl (7 mg, 0.04 mmol) followed by saponification using General Procedure D. The title compound was isolate as the 2nd eluting stereoisomer by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 40-90% MeCN 0.1% TFA). LCMS: RT=1.888 min, MS (ES) 802.9 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=5.6 Hz, 0.5H), 8.38 (d, J=5.6 Hz, 0.5H), 8.28 (t, J=8.0 Hz, 1H), 7.90 (s, 0.5H), 7.84 (s, 0.5H), 7.68-7.61 (m, 1H), 7.40-7.29 (m, 2H), 7.10-7.02 (m, 2H), 6.61 (s, 1H), 6.60 (s, 1H), 5.80-5.75 (m, 1H), 4.51-4.34 (m, 1H), 4.23-4.07 (m, 1H), 3.98 (s, 1.5H), 3.97 (s, 1.5H), 3.94-3.75 (m, 3H), 3.58-3.49 (m, 0.5H), 3.47-3.39 (m, 0.5H), 3.20-2.86 (m, 2H), 2.80-2.60 (m, 1H), 2.44 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H), 2.28 (s, 1.5H), 2.24 (s, 1.5H), 2.10 (s, 1.5H), 2.07 (s, 1.5H), 2.04-1.96 (m, 1H), 1.94-1.86 (m, 1H), 1.26 (d, J=6.8 Hz, 1.5H), 1.19 (d, J=6.8 Hz, 1.5H).
The title compound (3.6 mg, 33%) was prepared according to General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 2-(bromomethyl)pyridine HBr salt (10 mg, 0.040 mmol) followed by saponification using General Procedure D. LCMS: RT=1.859 min, MS (ES) 818.8 (M+H).
A solution of methyl 4-(benzyloxy)-7-bromo-1H-indole-2-carboxylate (200 mg, 0.71 mmol), CuI (10 mg, 0.052 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (15 mg, 0.11 mmol), and NaI (250 mg, 1.67 mmol) in 1,4-dioxane (2 mL) was sparged with Ar for 5 min, then sealed and heated to 110° C. for 48 h. The reaction was cooled to RT and diluted with DCM (20 mL). The organic solution was washed with 10% aq. NH4OH (20 mL), and the aqueous layer was extracted with DCM. The combined organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (196 mg, 84%). LCMS: RT=1.433 min, MS (ES) 331.8 (M+H).
The title compound (156 mg, 61%) was prepared according to General Procedure B using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-1043-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (200 mg, 0.30 mmol) and methyl 7-iodo-4-methoxy-1H-indole-2-carboxylate (196 mg, 0.59 mmol). LCMS: RT=2.293 min, MS (ES) 859.8 (M+H).
The title compound (26 mg, 47%) was prepared according to General Procedure I using methyl (R)-7-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (50 mg, 0.058 mmol) and 2-(bromomethyl)pyridine HBr salt (40 mg, 0.16 mmol). LCMS. RT=2.175 min, MS (ES) 950.8 (M+H).
The title compound was prepared following the procedure described Example 390 Step D using methyl (R)-7-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (26 mg, 0.027 mmol) and carried forward without further purification. LCMS: RT=0.864 mm. MS (ES) 860.8 (M+H) (LC method II).
The title compound (4.0 mg, 33% 2 steps) was prepared according to General Procedure J using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (12 mg, 0.014 mmol) and dimethylamine HCl salt (25 mg, 0.31 mmol) followed by saponification using General Procedure D. LCMS: RT=1.754 min, MS (ES) 873.9 (M+H).
The title compound (11 mg, 19%) was prepared according to General Procedure I using methyl (R)-7-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (50 mg, 0.058 mmol) and MeI (25 mg, 0.18 mmol). LCMS: RT=2.386 min, MS (ES) 873.9 (M+H).
The crude title compound was prepared following the procedure described
The title compound (3.0 mg, 29% 2 steps) was prepared according to General Procedure J using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and dimethylamine HCl salt (25 mg, 0.31 mmol) followed by saponification using General Procedure D. LCMS: RT=1.860 min, MS (ES) 796.9 (M+H).
The title compound (5.6 mg, 35%) was isolated as the 1st eluting stereoisomer along with Example 480. LCMS: RT=1.870 min, MS (ES) 802.9 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.56-8.42 (m, 0.75H), 8.40-8.35 (m, 0.25H), 8.33-8.21 (m, 1H), 7.90 (s, 0.25H), 7.84 (s, 0.75H), 7.72-7.57 (m, 1H), 7.43-7.29 (m, 2H), 7.16-7.06 (m, 2H), 6.61 (s, 1H), 6.58 (s, 1H), 5.84-5.66 (m, 1H), 4.24-4.13 (m, 2H), 3.96 (s, 2H), 3.94 (s, 1H), 3.92-3.86 (m, 1H), 3.83-3.70 (m, 2H), 3.63-3.51 (m, 1H), 3.48-3.34 (m, 1H), 3.25-2.87 (m, 2H), 2.43 (s, 2H), 2.41 (s, 1H), 2.34 (s, 6H), 2.31 (s, 1H), 2.26 (s, 2H), 2.23 (s, 2H), 2.12-2.06 (m, 2H), 2.05 (s, 1H), 1.28-1.16 (m, 1H), 1.23-1.04 (m, 2H).
The title compound (7.3 mg, 71%) was prepared according to General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and (bromomethyl)cyclopropane (8 mg, 0.059 mmol) followed by saponification using General Procedure D. LCMS: RT=2.337, 2.378 min, MS (ES) 781.9 (M+H).
To a solution of 7-bromo-5-nitro-1H-indole (1 g, 4.1 mmol) in DMF (12 mL) was added trifluoroacetic anhydride (3.3 mL, 16.4 mmol) at 0° C. The reaction mixture was warmed to RT and stirred for overnight then poured into brine and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash RE, hex/EtOAc=0-100% gradient) to give the title compound. (1.30 g, 94%) 1H-NMR (DMSO-d6) δ 8.98 (d, 1H, J=4 Hz), 8.7 (s, 1H), 8.43 (d, 1H, J=4 Hz), 19F NMR-75.2 (s)
1-(7-Bromo-5-nitro-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (1.30 g, 3.9 mmol) was refluxed in NaOH aq. solution (30 mL, 20%) for 2 h. The reaction mixture was cooled to RT and neutralized with conc. HCl. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to yield the title compound (0.9 g, 98%). 1H NMR (DMSO-d6) δ 8.90 (d, 1H, J=4 Hz), 8.30 (s, 1H), 8.27 (d, 1H, J=4 Hz).
To a suspension of 7-bromo-5-nitro-1H-indole-3-carboxylic acid (0.9 g, 3.8 mmol) in MeOH (30 mL) was added H2SO4 (0.3 mL). The reaction mixture was refluxed for overnight then concentrated. The residue was dissolved in EtOAc, washed with sat. NaHCO3 aq. Solution, dried and concentrated to yield the title compound. (0.8 g, 84%). 1H NMR (DMSO-d6) δ 8.82 (d, 1H, J=4 Hz), 8.31 (s, 1H), 8.20 (d, 1H, J=4 Hz), 3.85 (s, 3H).
The title compound (0.75 g, 89%) was prepared following General Procedure G using methyl 7-bromo-5-nitro-1H-indole-3-carboxylate (0.8 g, 2.7 mol) in DMF (10 mL) and MeI (340 μL, 5.4 mmol). 1H NMR (DMSO-d6) δ 8.87 (d, 1H, J=4 Hz), 8.48 (s, 1H), 8.27 (d, 1H, J=4 Hz), 4.24 (s, 3H), 3.88 (s, 3H).
To a solution of methyl 7-bromo-1-methyl-5-nitro-1H-indole-3-carboxylate (0.75 g, 2.4 mmol) in 1,4-dioxane (60 mL) was added HCl aq. solution (30 mL, 1.2N) followed by Tin chloride (2.7 g, 1.2 mmol). The reaction mixture was refluxed for 3 h, cooled to RT, neutralized with NaOH and extracted with EtOAc. The organic layer was dried, concentrated and the residue was purified by flash chromatography (Combi-flash RE DCM/MeOH=0-15% gradient) to give the title compound (0.55 g, 82%). 1H NMR (DMSO-d6) δ 7.96 (d, 1H, J=4 Hz), 7.22 (s, 1H), 6.81 (d, 1H, J=4 Hz), 5.0 (broad s, 2H), 4.00 (s, 3H), 3.76 (s, 3H).
To a solution of methyl 5-amino-7-bromo-1-methyl-1H-indole-3-carboxylate (0.55 g, 2.0 mmol) in THF (5 mL) was added 1.2N aq. NaOH aq. solution (5 mL, 6.0 mM) and (Boc)2O (920 mg, 4.0 mmol). The reaction mixture was stirred overnight at RT then quenched with MeOH and water (50 mL). The mixture was extracted with EtOAc and the combined organic layer was dried, concentrated and the residue was purified by flash chromatography (Combi-flash Rf, hex/EtO=0-100% gradient) to give the title compound (0.60 g, 81%). 1H NMR (DMSO-d6) δ 9.42 (broad s, 1H), 8.23 (d, 1H, J=4 Hz), 8.12 (s, 1H), 7.60 (d, 1H, J=4 Hz), 4.11 (s, 3H), 3.79 (s, 3H), 1.49 (s, 9H).
The title compound (400 mg, 78%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (330 mg, 0.6 mmol) and methyl 7-bromo-5-((tert-butoxycarbonyl)amino)-1-methyl-1H-indole-3-carboxylate (350 mg, 0.9 mmol). MS (ES) 841.2 (M+H).
To a solution of methyl (R)-5-((tert-butoxycarbonyl)amino)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (40 mg, 0.047 mol) in DMF (2 mL) was added NaH (60%, 3.8 mg, 0.094 mol) under N2 at 0° C. and stirred for 10 min. 1-(2-Bromoethyl)pyrrolidine (14.5 mg, 0.080 mmol) was added and the mixture was stirred for 10 min at 0° C. then at RT for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with brine (2×10 mL), dried, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient). The purified intermediate was dissolved in 4N HCl in 1,4-dioxane and the reaction mixture was heated at 60° C. for 5 h then concentrated. The residue was dissolved in a mixture of 1,4-dioxane and MeOH (4 mL, 1:1) and aq. NaOH solution (2 M, 1 mL) was added. The reaction was stirred for 3 h at RT then neutralized with aq. HCl (1.2 M). The mixture was concentrated and purified by HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 50% to 95% CH3CN for 4 min, 0.1% TFA) to give the title compound. MS (ES) 824.2 (M+H)
The title compound (7.1 mg, 66%) was prepared according to General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 3-(chlormethyl)pyridine HCl salt (8 mg, 0.049 mmol) followed by saponification using General Procedure D. LCMS: RT=1.913, 1.944 min, MS (ES) 818.8 (M+H).
Ethyl-7-bromo-6-chloro-3-(3-((4-chloro-3,5-dimethylhexa-2,4-dien-1-yl)oxy)propyl)-1H-indole-2-carboxylate (1.6 g, 3.0 mmol), Pd2(dba)3 (550 g, 0.6 mmol), Sphos (0.62 g, 1.5 mmol), K2CO3 (1.24 g, 9 mmol) and (4-(methoxymethoxy)-2,6-dimethylphenyl)boronic acid (1.26 g, 6.0 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The mixture was sparged with Ar for 5 min then irradiated under microwave for 1 h at 110° C. in Biotage Initiator. The reaction mixture was cooled to RT, diluted with EtOAc/water (80 mL, 1:1). The aqueous layer was extracted with EtOAc, and the combined organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-60% gradient) to give the title compound. (1.5 g, 85%). 1H-NMR (CDCl3) δ 8.24 (s, 1H), 7.62 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 6.91 (s, 2H), 6.64 (s, 1H), 6.55 (s, 1H), 5.27 (s, 2H) 5.27 (q, 2H, J1=12 Hz. J2=8 Hz), 4.01 (tr, 1H, J=8 Hz), 3.58 (s, 3H), 3.29 (tr, 2H, J=4 Hz), 2.36 (s, 3H), 2.30 (s, 3H), 2.19 (tr, 2H, J=4 Hz), 1.98 (s, 6H), 1.41 (tr, 3H, J=8 Hz).
To a solution of ethyl-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4-(methoxymethoxy)-2,6-dimethylphenyl)-1H-indole-2-carboxylate (1.45 g, 0.0025 mol) in MeCN (30 mL) was added Cs2CO3 (1.2 g, 0.0037 mol) and tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.88 gr, 0.0037 mol), and the mixture was stirred at 80° C. for overnight. Additional Cs2CO3 (0.5 eq) and tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.5 eq) were added to the reaction and stirred for additional 6 h at 80° C. The reaction mixture was concentrated to half of its original volume then diluted with EtOAc (150 mL). The solution was washed with brine, dried and concentrated to give the crude title compound. It was used for the next step without purification. 1H-NMR (CDCl3) δ 7.59 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 6.92 (s, 2H), 6.53 (s, 2H), 5.27 (s, 2H) 4.41 (q, 2H, J1=12 Hz, J2=8 Hz), 4.12-4.10 (m, 1H), 4.01 (tr, 1H, J=8 Hz), 3.83-3.81 (m, 1H), 3.73-3.71 (m, 1H), 3.54 (s, 3H), 3.17 (m, 1H), 2.34 (s, 6H), 2.16 (tr, 2H, J=4 Hz), 2.06 (s, 3H), 2.00 (s, 3H), 2.19 (tr, 2H, J=4 Hz), 1.46 (tr, 3H. J=8 Hz), 1.38 (s, 9H), 1.20 (d, 3H, J=8 Hz).
Ethyl (R)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4-(methoxymethoxy)-2,6-dimethylphenyl)-1H-indole-2-carboxylate was dissolved in 1,4-dioxane (10 mL) and TFA (1.9 mL, 0.025 mol) and the reaction mixture was heated at 70° C. for overnight, then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-50% gradient) to give the title compound (1.1 gr, 74% for 2 steps). 1H-NMR (CDCl3) δ 7.66 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 6.90 (d, 1H, J=4 Hz), 6.86 (d, 1H, J=4 Hz), 6.65 (s, 2H), 5.84 (broad s, 1H) 5.25 (s, 2H), 3.79 (tr, 2H, J=4 Hz), 4.01-3.78 (m, 1H), 3.68 (dd, 1H, J1=2 Hz, J2=12 Hz), 3.56 (s, 3H), 3.42-3.38 (m, 2H), 3.34-3.11 (m, 1H), 2.35 (s, 6H), 2.23 (tr, 2H, J=4 Hz), 2.11 (s, 3H), 2.06 (s, 3H), 1.02 (d, 3H, J=8 Hz).
(R)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4-(methoxymethoxy)-2,6-dimethylphenyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one was dissolved in 1,4-dioxane (2 mL) and 4N HCl in 1,4-dioxane (20 μL) and stirred at 50° C. for overnight. The reaction mixture was concentrated and the residue was purified by HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 50% to 95% CH3CN for 4 min, 0.1% TFA) to give the title compound. 1H-NMR (CDCl3) δ 7.65 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 6.73 (d, 1H, J=4 Hz), 6.69 (d, 1H, J=4 Hz), 6.68 (d, 1H, J=4 Hz) 6.65 (s, 2H), 5.79 (broad s, 1H), 4.04 (tr, 2H, J=4 Hz), 4.01-3.78 (m, 1H), 3.68 (dd, 1H, J1=2 Hz, J2=12 Hz), 3.45-3.35 (m, 2H), 3.13-3.10 (m, 1H), 3.09 (s, 6H), 2.23 (tr, 2H, J=4 Hz), 2.23 (s, 3H), 1.87 (s, 3H), 1.02 (d, 3H, J=8 Hz); MS (ES) 551.3 (M+H).
The title compound (72 mg, 95%) was prepared following General Procedure F using 1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (46 mg, 0.28 mmol) and MeI (53 μL, 0.85 mmol). LCMS: RT=1.704 min, MS (ES) 268.3 (M+H).
The title compound (18 mg, 50%) was prepared according to General Procedure I using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 3-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (16.1 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=1.894 MS (ES) 712.9 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J=8.1 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.7 Hz, 11H), 7.74 (d, J=8.7 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 4.51 (d, J=13.1 Hz, 1H), 4.47 (d, J=13.1 Hz, 1H), 4.39-4.28 (m, 1H), 4.00-3.92 (m, 2H), 3.88 (s, 3H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.40-3.30 (m, 1H), 3.28-3.18 (m, 1H), 2.24 (s, 6H), 2.11 (s, 1.5H), 2.09-2.04 (m, 2H), 2.02 (s, 1.5H), 1.96 (s, 1.5H), 1.87 (s, 1.5H), 1.15 (d, J=6.3 Hz, 1.5H), 1.12 (d, J=6.3 Hz, 1.5H).
To a solution of 7-bromo-5-methyl-1H-indole (100 mg, 0.45 mmol) in DMF (3 mL) was added K2CO3 (435 mg, 3.15 mmol) and MeI (60 μL, 135 mg, 0.90 mmol). The reaction mixture was stirred at 60° C. for 4 h then quenched with sat. NH4Cl aq. solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was dissolved in toluene (0.4 mL), and ethylchloroformate (46 μL, 52.3 mg, 0.48 mmol) and Me2AlCl (0.4 mL, 0.4 mmol, 1.0 M solution in hexanes) were added. The reaction mixture was stirred at RT for 15 min then quenched with sat. NH4Cl aq. solution and extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (110 mg, 93% 2 steps). LCMS: RT=1.770 min, MS (ES) 295.9 (M+H).
To a solution of ethyl 7-bromo-1,5-dimethyl-1H-indole-3-carboxylate (110 mg, 0.37 mmol) in CCl4 (4 mL) was added AIBN (15.2 mg, 0.093 mmol) and NBS (66 mg, 0.37 mmol) at 60° C. The reaction mixture was refluxed for 3 h then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (120 mg, 90%). LCMS: RT=1.772 min, MS (ES) 375.9 (M+H).
To a solution of ethyl 7-bromo-5-(bromomethyl)-1-methyl-1H-indole-3-carboxylate (31 mg, 0.083 mmol) in DMF (0.8 mL) was added NaOAc (13.6 mg, 0.166 mmol), and the reaction mixture was stirred at RT for 24 h. The reaction was quenched with sat. NH4Cl aq. solution and extracted with DCM. The combined organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (25 mg, 85%). LCMS: RT=1.620 min, MS (ES) 375.9 (M+Na); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=1.2 Hz, 1H), 7.64 (s, 1H), 7.35 (d, J=1.3 Hz, 1H), 5.09 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 4.10 (s, 3H), 2.04 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).
The title compound (8 mg, 32% yield) was prepared following General Procedure A using ethyl 5-(acetoxymethyl)-7-bromo-1-methyl-1H-indole-3-carboxylate (12 mg, 0.033 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (18.3 mg, 0.033 mmol). LCMS: RT=2.031, 2.055 min, MS (ES) 769.9 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-3-carboxylate (20 mg, 0.026 mmol) in DCM (0.2 mL) was added 4 A molecular sieves (50 mg) and PCC (12 mg, 0.052 mmol), and the reaction mixture was stirred at rt for 30 min then quenched with sat. NH4Cl aq. solution and extracted with DCM. The combined organic layer was dried and concentrated. The residue was re-dissolved in DCM (0.2 mL) and Et3N (0.03 mL) then N-methyl piperazine (2 μL, 1.7 mg, 0.017 mmol) and Na(OAc)3BH (5.9 mg, 0.028 mmol) were added. The reaction mixture was stirred at rt for 4 h then quenched with sat. NaHCO3 aq. solution and extracted with DCM. The combined organic layer was dried and concentrated. Subsequent saponification was carried out following General Procedure D. The crude was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN, 0.1% TFA) to afford the title compound (2.1 mg, 10%, 3 steps). LCMS: RT=1.809 min, MS (ES) 823.9 (M+H).
The title compound (6.8 mg, 42%) was prepared according to General Procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 2-(chloromethyl)-6-methylpyridine (6 mg, 0.04 mmol) followed by saponification using General Procedure D. The title compound was isolate as the 2nd eluting stereoisomer by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 40-90% MeCN 0.1% TFA). LCMS. RT=1.917 min, MS (ES) 802.9 (M+H).
The title compound (4.7 mg, 34% 2 steps) was prepared according to General Procedure J using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (13 mg, 0.015 mmol) and N-methylpiperazine (30 mg, 0.30 mmol) followed by saponification using General Procedure D. LCMS: RT=1.771 min, MS (ES) 928.8 (M+H).
The title compound (8.3 mg, 52%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (15 mg, 0.020 mmol) and 1-bromo-2-methoxyethane (5 mg, 0.036 mmol) followed by saponification using General Procedure D. LCMS: RT=2.048 min, MS (ES) 783.8 (M+H).
The title compound (4.2 mg, 26%) was isolated along with Example 491 as a separated atropisomer (1st fraction, absolute stereochemistry undetermined). LCMS: RT=1.888 min, MS (ES) 802.9 (M+H).
The title compound (4.6 mg, 10%, 2 steps) was isolated along with ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-3-carboxylate from Example Step D as a byproduct followed by saponification following General Procedure D. LCMS: RT=2.173, 2.227 min, MS (ES) 805.7 (M+H).
The title compound (160 mg, 86%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4-(methoxymethoxy)-2,6-dimethylphenyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (120 mg, 2.0 mmol) and methyl 3-bromo-1-methyl-1H-indole-5-carboxylate (110 mg, 4.0 mol). MS (ES) 782.4 (M+H).
The title compound (16 mg, 86%) was prepared following the procedure described Example 488 Step D using methyl-(R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-6-(4-(methoxymethoxy)-2,6-dimethylphenyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylate (20 mg, 0.026 mmol) followed by saponification following General Procedure D. 1H-NMR (DMSO-d6) δ 9.45 (broad s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.80 (d, 1H, J=8 Hz), 7.75 (d, 1H. J=8 Hz), 7.55 (d, 1H, J=8 Hz), 7.50 (s, 1H), 7.30 (d, 1H, J=8 Hz), 6.72 (s, 2H), 6.65 (d, 1H, J=8 Hz), 4.38 (dd, 1H, J1=2 Hz, J2=12 Hz), 3.97 (tr, 2H, J=4 Hz), 3.82 (s, 3H), 3.62 (m, 1H), 3.68 (dd, 1H, J1=2 Hz, J2=12 Hz), 3.45-3.35 (m, 1H), 2.27 (s, 6H), 2.06 (tr, 2H, J=4 Hz), 1.96 (s, 3H), 1.82 (s, 3H), 1.01 (d, 3H, J=8 Hz), MS (ES) 724.2 (M+H).
The title compound (140 mg, 93%) was prepared following the procedure described Example 488 Step D using methyl 3-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-6-(4-(methoxymethoxy)-2,6-dimethylphenyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-3a,7a-dihydro-1H-indole-5-carboxylate (160 mg, 0.2 mmol). 1H-NMR (CDCl3) δ 8.27 (s, 1H), 7.95 (d, 1H, J=8 Hz), 7.67 (d, 1H, J=8 Hz), 7.37 (d, 1H, J=8 Hz), 6.73 (d, 1H, J=4 Hz), 6.69 (d, 1H, J=4 Hz) 6.63 (s, 2H), 4.34 (dd, 1H, J1=2 Hz, J2=12 Hz), 4.00 (tr, 2H, J=4 Hz), 3.79 (s, 3H), 3.80 (m, 2H), 3.62 (dd, 1H, J1=2 Hz, J2=12 Hz), 3.45-3.35 (m, 1H), 2.35 (s, 6H), 2.23 (tr, 2H, J=4 Hz), 2.09 (s, 3H), 1.95 (s, 3H), 1.22 (d, 3H, J=8 Hz).
To a solution of methyl 3-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4-hydroxy-2,6-dimethylphenyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-3a,7a-dihydro-1H-indole-5-carboxylate (20 mg, 0.027 mol) in anhydrous DMF (2 mL) was added NaH (60%, 3.8 mg, 0.094 mol) at 0° C. under N2 atmosphere. The reaction mixture was stirred for 10 min then 2-(bromomethyl)pyridine (7.9 mg, 0.046 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min then warmed to RT and stirred for additional 1 h. The reaction mixture was diluted with ethyl acetate (20 mL), washed with brine, dried and concentrated. The residue was dissolved in a mixture of 1,4-dioxane and MeOH (4 mL, 1:1) and aq. NaOH (2 M, 1 mL) solution was added. The reaction was stirred for 5 h at RT then neutralized with aq. HCl (1.2 M). The mixture was concentrated and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 45-95% MeCN 0.1% TFA) to give the title compound. 1H-NMR (DMSO-d6) δ 8.61 (s, 1H), 8.10 (d, 1H, J=2 Hz), 7.93-7.91 (m, 1H), 7.80-7.78 (m, 1H), 7.77 (d, 1H, J=8 Hz), 7.63 (m, 1H), 7.56 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.39 (m, 1H), 7.32 (d, 1H, J=8 Hz), 7.29 (s, 1H), 6.97 (s, 1H), 6.72 (s, 2H), 5.52 (s, 2H), 4.39 (dd, 1H, J1=2 Hz, J2=12 Hz), 4.03 (tr, 2H, J=4 Hz), 3.82 (s, 3H), 3.75 (m, 2H), 3.48 (dd, 1H, J1=2 Hz, J2=12 Hz), 3.45-3.35 (m, 1H), 2.24 (s, 6H), 2.07 (tr, 2H, J=4 Hz), 1.89 (s, 3H), 1.82 (s, 3H), 1.08 (d, 3H, J=8 Hz); MS (ES) 815.3 (M+H).
The title compound was prepared following the procedure described Example 486 Step H using methyl (R)-5-((tert-butoxycarbonyl)amino)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (40 mg, 0.047 mol) and 2-bromo-N,N-dimethylethan-1-amine (12.3 mg, 0.080 mmol). MS (ES) 798.2 (M+H).
The title compound (167 mg, 91%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (150 mg, 0.20 mmol) and 2-bromo-6-(bromomethyl)pyridine (102 mg, 0.41 mmol). LCMS: RT=2.37 min, MS (ES) 909 (M+H).
A solution of ethyl (R)-1-((6-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (25 mg, 0.03 mmol) in morpholine (0.5 mL) was stirred at 110° C. for overnight. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was dried and concentrated. The residue was saponified following General Procedure D to give the title compound (15 mg, 56%) as TFA salt. LCMS: RT=2.05 min, MS (ES) 888 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.29-7.34 (m, 2H), 6.83 (m, 1H), 6.77 (s, 2H), 6.50 (m, 1H), 6.22 (m, 1H), 5.58 (m, 1H), 5.25 (m, 1H), 4.59 (m, 1H), 4.05 (m, 2H), 3.8 (m, 11H), 3.72 (s, 1.5H), 3.69 (s, 1.5H), 3.37-3.40 (m, 1H), 3.13-3.26 (m, 4H), 2.98-3.08 (m, 2H), 2.90-2.96 (m, 2H), 2.65-2.72 (m, 2H), 2.36 (s, 3H), 2.22 (s, 6H), 2.04 (s, 3H), 1.77-1.94 (m, 5H), 1.02 (m, 3H).
The title compound (104 mg, 85%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (150 mg, 0.20 mmol) and 4-bromo-2-(chloromethyl)pyridine. LCMS: RT=2.33 min, MS (ES) 909 (M+H).
The title compound (18 mg, 66%) was prepared following the procedure described in Example 499 Step B using ethyl (R)-1-((4-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-H-indole-2-carboxylate (25 mg, 0.03 mmol). LCMS: RT=1.96 min, MS (ES) 888 (M+H).
The title compound (5.9 mg, 37%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 2-(chloromethyl)-5-methylpyridine hydrochloride (3.5 mg, 0.04 mmol) followed by saponification using General Procedure D. The title compound was isolate as the 1st eluting stereoisomer by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 40-90% MeCN 0.1% TFA). LCMS: RT=2.047 min, MS (ES) 802.9 (M+H).
The title compound (60 mg, 76%) was prepared following General Procedure B using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (60 mg, 0.090 mmol) and 3-iodo-1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (62 mg, 0.18 mmol). LCMS: RT=2.166 min, MS (ES) 867.9 (M+H).
To a solution of (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (60 mg, 0.070 mmol) in MeOH (4.6 mL) was added HCl solution (1 mL) followed by Pd/C (50 mg). The reaction mixture was stirred at RT for 20 h under H2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The crude title compound (45 mg) was used for the next step without further purification. LCMS: RT=1.961 min, MS (ES) 777.9 (M+H).
DIPEA (13.1 μL, 0.080 mmol) and MsCl (5.4 μL, 0.070 mmol) were added to a solution of (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-2-(1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (45 mg, 0.060 mmol) in DCM (0.5 mL) at 0° C. The reaction was warm to RT and stirred for 1 h then concentrated. The crude compound (40 mg) was used for the next step without further purification. LCMS: RT=2.079 min, MS (ES) 855.8 (M+H).
1-Methylpiperazine (15.6 μL, 0.14 mmol) was added to a solution of (R)-(5-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-6-yl)-4,6-dimethylpyrimidin-2-yl)methyl methanesulfonate (20 mg, 0.020 mmol) in DMF (1 mL). The reaction was stirred at 60° C. for 1 h, quenched with water then extracted with DCM. The combined organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/MeCN gradient to 42-95% MeCN 0.1% TFA). The isolated TFA salt was neutralized using sat. aq. NaHCO3 to afford the title compound (7 mg, 35% yield). LCMS: RT=1.814 min, MS (ES) 859.9 (M+H). 1H NMR (400 MHz, Chloroform-d) S 8.19 (d, J=1.0 Hz, 1H), 8.05 (s, 1H), 8.01 (dd, J=8.5, 1.2 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.61 (s, 2H), 4.40 (dd, J=12.5, 3.3 Hz, 1H), 4.00-3.97 (m, 4H), 3.94 (s, 3H), 3.81 (s, 3H), 3.79-3.66 (m, 3H), 3.51-3.30 (m, 6H), 3.12-2.97 (m, 3H), 2.76 (s, 3H), 2.39 (s, 3H), 2.29 (s, 6H), 2.26 (s, 3H), 2.24-2.19 (m, 2H), 1.23 (d, J=6.5 Hz, 3H).
The title compound (12 mg, 61%) was prepared following the procedure described Example 502 Step D using morpholine (12.1 μL, 0.14 mmol) and (R)-(5-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-6-yl)-4,6-dimethylpyrimidin-2-yl)methyl methanesulfonate (20 mg, 0.020 mmol). LCMS: RT=1.878 min, MS (ES) 846.8 (M+H).
The title compound (15 mg, 55%) was prepared following the procedure described in Example 499 Step B using ethyl (R)-1-((4-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (25 mg, 0.03 mmol) and piperidine (0.5 mL). LCMS: RT=2.08 min, MS (ES) 886 (M+H).
The title compound (21 mg, 78%) was prepared following the procedure described in Example 517 Step B using ethyl (R)-1-((6-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (25 mg, 0.03 mmol) and piperidine (0.5 mL). LCMS: RT=2.09 min, MS (ES) 886 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.22-7.29 (m, 2H), 6.84 (s, 1H), 6.76 (s, 2H), 6.50 (bs, 1H), 6.19-6.22 (bs, 1H), 5.30-5.48 (m, 2H), 4.57 (m, 1H), 4.04 (bs, 2H), 3.83 (m, 1H), 3.73 (s, 1.5H), 3.69 (s, 1.5H), 3.39 (m, 1H), 3.14-3.26 (m, 3H), 2.97 (m, 2H), 2.76 (m, 2H), 2.36 (s, 3H), 2.22 (s, 6H), 2.04 (s, 3H), 1.94 (s, 1H), 1.85 (s, 1H), 1.75 (bs, 2H), 1.16-1.25 (m, 6H), 1.03 (m, 3H).
The title compound (1.5 mg, 25%) was prepared following General Procedure D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-3-carboxylate (6.2 mg, 0.008 mmol). LCMS: RT=2.041, 2.066 min, MS (ES) 741.9 (M+H).
The title compound (6.3 mg, 39% yield) was isolated along with Example 501 as a separated atropisomer (2nd fraction, absolute stereochemistry undetermined). LCMS: RT=2.155 min, MS (ES) 802.9 (M+H).
The title compound was prepared following the procedure described Example 497 Step B using methyl 3-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4-hydroxy-2,6-dimethylphenyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-3a,7a-dihydro-1H-indole-5-carboxylate (20 mg, 0.027 mol) and 1-(2-bromoethyl)pyrrolidine (8.5 mg, 0.046 mmol). 1H-NMR (MeOH-d4) δ 8.23 (d, 1H, J=1 Hz), 7.94 (dd, 1H, J=1.5 Hz, J=10 Hz), 7.75 (d, 1H, J=8 Hz), 7.50 (d, 11H, J=8 Hz), 7.34 (s, 1H), 7.30 (d, 1H, J=8 Hz), 6.96 (s, 1H), 6.91 (s, 1H), 6.64 (s, 2H), 4.41 (tr, 2H, J=4 Hz), 4.39 (dd, 1H, J1=2 Hz. J2=12 Hz), 3.99-3.67 (m, 2H), 3.87 (s, 3H), 3.75 (m, 2H), 3.69 (tr, 2H, J=4 Hz), 3.58 (dd, 1H, J1=2 Hz, J2=12 Hz), 3.49-3.45 (m, 1H), 2.31 (s, 6H), 2.21 (tr, 2H, J=4 Hz), 2.20-2.18 (m, 4H), 2.12 (s, 3H), 2.09-2.06 (m, 4H), 1.98 (s, 3H), 1.23 (d, 3H, J=8 Hz); MS (ES) 821.3 (M+H),
The title compound was prepared following the procedure described Example 497, Step B using methyl 3-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4-hydroxy-2,6-dimethylphenyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-3a,7a-dihydro-1H-indole-5-carboxylate (20 mg, 0.027 mol) and 2-bromo-N,N-dimethylethan-1-amine (7.0 mg, 0.046 mmol). MS (ES) 795.5 (M+H),
The title compound (3.6 mg, 33%) was prepared according to General Procedure G using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.01 mmol) and 2-bromo-N,N-dimethylethan-1-amine hydrobromide (7 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=1.844 min, MS (ES) 768.9 (M+H).
The title compound (7.2 mg, 65%) was prepared according to General Procedure G using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.01 mmol) and 1-(2-bromoethyl)pyrrolidine hydrobromide (7 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=1.899 min, MS (ES) 794.9 (M+H).
The title compound (11.9 mg, 79%) was prepared according to General Procedure 1 using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-H-indole-3-carboxylate (15 mg, 0.02 mmol) and 1-bromo-2-methoxyethane (3 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=2.234 min, MS (ES) 755.8 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (20 mg, 0.026 mmol) in DMF (1 mL) was added Cs2CO3 (25 mg, 0.77 mmol) and tert-butyl 3-bromopyrrolidine-1-carboxylate (15 mg, 0.060 mmol). The reaction was heated to 80° C. for 16 h, then diluted with DCM/H2O (10 mL, 1:1). The layers were separated, and the aqueous layer was extracted with DCM (2×5 mL). The combined organic extracts were dried by passage through a phase separator and concentrated. LCMS: RT=2.373 min, MS (ES) 946.8 (M+Na). The crude reaction product was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The reaction was stirred for 4 h at RT then concentrated. LCMS: RT=2.017, 2.088 min, MS (ES) 824.8 (M+H). The residue was dissolved in MeCN (2 mL) and K2CO3 (20 mg, 0.14 mmol) and MeI (8 mg, 0.057 mmol) were added in sequence. The reaction was stirred for 1 h at RT then diluted with DCM/H2O (10 mL, 1:1). The layers were separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried and concentrated. LCMS: RT=2.062, 2.116 min, MS (ES) 952.9 (M). The residue was saponified according to General Procedure D to afford the title compound (3 mg, 14% yield). LCMS: RT=1.868 min, MS (ES) 824.8 (M).
A solution of ethyl (R)-1-((4-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.06 mmol), Pd(OAc)2 (1 mg, 0.005 mmol), tricyclohexylphosphine tetrafluoroborate (4 mg, 0.011 mmol), K3PO4 (23 mg, 0.11 mmol), Vinylboronic acid pinacol ester (0.011 mL, 0.07 mmol) in 5:1 DME/water (1 mL) was purged with Ar and stirred at 80° C. overnight. The solution was cooled to RT, diluted with EtOAc, filtered through Celite, washing with EtOAc and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) followed by saponification following General Procedure D to give the title compound (28 mg, 78%) as TFA salt. LCMS: RT=2.09 min, MS (ES) 829 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.20 (m, 11H), 7.73 (d, J=8.6 Hz, 1H), 7.57 (s, 11H), 7.40 (s, 1H), 7.26-7.32 (m, 2H), 6.86 (m, 1H), 6.71 (s, 2H), 6.57 (bs, 1H), 6.40-6.50 (m, 11H), 6.08-6.27 (m, 1H), 5.73-5.81 (m, 1H), 5.45-5.60 (m, 1H), 5.31-5.35 (m, 1H), 3.96 (m, 2H), 3.84 (m, 1H), 3.73 (s, 3H), 3.26-3.34 (m, 1H), 3.06 (m, 1H), 2.53 (m, 2H), 2.37 (s, 3H), 2.21 (s, 6H), 2.07 (s, 3H), 1.70-1.97 (m, 5H), 1.02 (m, 3H).
The title compound (15 mg, 54% TFA salt) was prepared following the procedure described in Example 499 Step B using ethyl (R)-1-((4-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (32 mg, 0.04 mmol) and 1-methylpiperazine (0.5 mL, 4.6 mmol). LCMS: RT=1.75 min, MS (ES) 901 (M+H).
The title compound (18 mg, 55% TFA salt) was prepared following the procedure described in Example 499 Step B using ethyl (R)-1-((6-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (30 mg, 0.03 mmol) and 1-methylpiperazine (0.5 mL, 4.6 mmol). LCMS: RT=2.02 min, MS (ES) 901 (M+H).
The title compound (21 mg, 49%) was prepared following the procedure described in Example 514 using ethyl (R)-1-((6-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.06 mmol). LCMS: RT=2.24 min, MS (ES) 829 (M+H).
The title compound (5.8 mg, 29%) was prepared according to General Procedure G using (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(pyrimidin-4-ylmethyl)-1H-indole-2-carboxylic acid (18 mg, 0.025 mmol) and pyrimidin-4-ylmethyl methanesulfonate (15 mg, 0.080 mmol) followed by saponification using General Procedure D. LCMS: RT=2.021 min, MS (ES) 789.8 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol), triphenylphosphine (10 mg, 0.038 mmol) and 1-methylpiperidin-4-ol (20 mg, 0.17 mmol) in THF (1 mL) was added di-tert-butyl (E)-diazene-1,2-dicarboxylate (10 mg, 0.044 mmol) at RT. The reaction was stirred for 18 h at RT, then heated to 60° C. for 16 h. The reaction was cooled to RT, diluted with DCM/H2O (10 mL, 1:1) and extracted with DCM. The combined organic extracts were dried and concentrated. The crude product was saponified following General Procedure D and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (4.5 mg, 42%). LCMS: RT=1.839 min, MS (ES) 824.8 (M+H).
The title compound (14 mg, 83%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (15 mg, 0.020 mmol) and 2-(chloromethyl)-4-methylpyridine HCl salt (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=2.022 min, MS (ES) 830.8 (M+H).
The title compound (8.6 mg, 41%) was isolated along with Example 513 following the procedure described in Example 513. LCMS: RT=1.897, 1.929 min, MS (ES) 810.9 (M+H).
The title compound (1.5 mg, 14%) was prepared according to General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 2-fluoropyridine (8 mg, 0.082 mmol) followed by saponification using General Procedure D. LCMS: RT=2.207, 2.246 min, MS (ES) 804.9 (M+H).
The title compound was prepared following the procedure described Example 486 Step H using methyl (R)-5-((tert-butoxycarbonyl)amino)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (40 mg, 0.047 mol) and 2-(bromomethyl)pyridine (13.8 mg, 0.080 mmol). MS (ES) 818.2 (M+H),
NaH (8.5 mg, 0.35 mmol) was added to a solution of 5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (35 mg, 0.18 mmol) in DMF (2 mL) at 0° C. After 30 min, 2-bromoethyl methyl ether (22 μL, 0.23 mmol) was added slowly. The reaction was warmed to RT and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc (3×10 mL). The combined organic layer was washed with water, dried and concentrated to give the crude title compound (34 mg), which was used for the next step without further purification. LCMS: RT=1.172 min, MS (ES) 257.1 (M+H).
NIS (30 mg, 0.13 mmol) was added to a solution of 1-(2-methoxyethyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (34 mg, 0.13 mmol) in DMF (1.3 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with water, dried and concentrated to give the crude title compound (50 mg), which was used for the next step without further purification. LCMS: RT=1.241 min, MS (ES) 383.8 (M+H).
The title compound (30 mg, 68%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.060 mmol) and 3-iodo-1-(2-methoxyethyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (50 mg, 0.11 mmol). LCMS: RT=2.167 min, MS (ES) 793.9 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.05 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.72 (s, 2H), 4.50-4.44 (m, 1H), 4.36 (t, J=4.5 Hz, 2H), 4.19-4.16 (m, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.87 (s, 3H), 3.77 (d, J=4.8 Hz, 3H), 3.70 (d, J=5.2 Hz, 2H), 3.66-3.63 (m, 1H), 3.39-3.31 (m, 1H), 3.25-3.19 (m, 4H), 2.22 (s, 5H), 2.12-2.03 (m, 5H), 1.97-1.88 (m, 3H), 1.10 (d, J=6.2 Hz, 3H).
Bis(pinacolato)diboron (434 mg, 1.71 mmol), KOAc (419 mg, 4.27 mmol) and PdCl2(dppf)·DCM (58 mg, 0.07 mmol) were added to a solution of 2-(5-bromo-1H-indol-1-yl)-1-morpholinoethan-1-one (460 mg, 1.42 mmol) in toluene (2.9 mL) under Ar atmosphere. The reaction was stirred at 90° C. for 18 h then filtered through Celite and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-1% gradient) to provide the title compound (520 mg, quant.). LCMS: RT=1.527 min, MS (ES) 371.1 (M+H).
3-Bromo-1-methyl-1H-1,2,4-triazole (50 mg, 0.31 mmol), PdCl2(dppf)·DCM (13 mg, 0.020 mmol), K2CO3 (370 μL, 0.93 mmol, 2.5 M aq. solution) were added to a solution of 1-morpholino-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethan-1-one (149 mg, 0.40 mmol) in MeCN (1.5 mL). The reaction mixture was degassed using Ar and stirred at 85° C. for 16 h. The reaction mixture was filtered through Celite, and the filtrate concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-3% gradient) to provide the title compound (100 mg, quant.). LCMS: RT=1.155 min, MS (ES) 323.1 (M+H).
The crude title compound (65 mg) was prepared following the procedure described Example 524 Step B using 2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-1-morpholinoethan-1-one (55 mg, 0.17 mmol). LCMS: RT=1.245 min, MS (ES) 451.8 (M+H).
The title compound (15 mg, 31%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.060 mmol) and 2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-1-morpholinoethan-1-one (50 mg, 0.11 mmol). LCMS: RT=2.008 min, MS (ES) 862.9 (M+H).
The title compound (270 mg, 82%) was prepared following the procedure described Example 525 Step B using 3-Bromo-1-methyl-1H-1,2,4-triazole (150 mg, 0.93 mmol) and 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (483 mg, 1.20 mmol). LCMS: RT=1.858 min, MS (ES) 357.1 (M+H).
The title compound (100 mg, 27%) was prepared following the procedure described Example 524 Step B using 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (270 mg, 0.76 mmol). LCMS: RT=2.077 min, MS (ES) 483.0 (M+H).
The title compound (67 mg, 67%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (60 mg, 0.11 mmol) and 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-iodo-5-(I-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (99 mg, 0.21 mmol). LCMS: RT=1.683 min, MS (ES) 893.0 (M+H).
TBAF (75 μL, 0.070 mmol) was added to a solution of (R)-2-(1-(2-(tert-butyldimethylsilyl)oxy)ethyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (67 mg, 0.070 mmol) in THF (1 mL) at 0° C. The reaction was stirred at 0° C. for 30 min then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-2% gradient) to afford the title compound (34 mg, 59%). LCMS: RT=2.005 min, MS (ES) 779.9 (M+H).
The crude title compound (37 mg) was prepared following the procedure described Example 502 Step C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(1-(2-hydroxyethyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (34 mg, 0.060 mmol), DIPEA (9.9 μL, 0.060 mmol) and MsCl (4.1 μL, 0.050 mmol). LCMS: RT=2.056 min. MS (ES) 857.9 (M+H).
1-Methylpiperazine (29 μL, 0.26 mmol) was added to a solution of (R)-2-(3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl methanesulfonate (37 mg, 0.040 mmol) in DMF (1 mL). The reaction was stirred at 90° C. for 5 days. The reaction mixture was quenched with water and extracted with DCM. The combined organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/MeCN gradient to 45-95% MeCN 0.1% TFA) followed by neutralization using sat. aq. NaHCO3 to provide the title compound (9 mg, 24%) LCMS: RT=1.827 min, MS (ES) 861.9 (M+H).
LiOH (2.22 mL, 4.44 mmol, 2 M Solution) was added to a solution of methyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)acetate (700 mg, 2.22 mmol) in THF/MeOH/H2O (8.9 mL, 4:1:1) at 0° C. The reaction was stirred at 0° C. for 1 h then concentrated. The residue was diluted with water and acidified with 2N HCl. The mixture was extracted with EtOAc. The combined organic layer was dried and concentrated to give the crude title compound (630 mg), which was used for the next step without further purification. LCMS: RT=1.473 min, MS (ES) 302.1 (M+H).
BOP (441 mg, 1.00 mmol), pyrrolidine (273 μL, 3.32 mmol) and N-methylmorpholine (456 μL, 4.15 mmol) were added to a solution of 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)acetic acid (250 mg, 0.83 mmol) in DMF (5.5 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with water, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-2% gradient) to afford the title compound (150 mg, 51%). LCMS: RT=1.606 min, MS (ES) 355.0 (M+H).
The title compound (38 mg, 44% yield) was prepared following the procedure described Example 525 Step B using 3-Bromo-1-methyl-1H-1,2,4-triazole (45 mg, 0.28 mmol) and 1-(pyrrolidin-1-yl)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethan-1-one (157 mg, 0.44 mmol). LCMS: RT=1.087 min, MS (ES) 310.0 (M+H).
The crude title compound (45 mg) was prepared following the procedure described Example 524 Step B using 2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (38 mg, 0.12 mmol). LCMS: RT=0.177 min, MS (ES) 435.9 (M+H).
The title compound (15 mg, 32% yield) was prepared following General Procedure I using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.060 mmol) and 2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (48 mg, 0.11 mmol). LCMS: RT=2.081 min, MS (ES) 846.9 (M+H).
A solution of ethyl (R)-1-((6-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.05 mmol) and piperazine (24 mg, 0.27 mmol) in dioxane (0.5 mL) was stirred in a sealed vial at 110° C. overnight. The solution was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic solution were washed with brine, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-8% gradient, with 1% conc. NH4OH) to give the title compound (30 mg, 60%). LCMS: RT=2.20 min, MS (ES) 915 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-indole-2-carboxylate (30 mg, 0.03 mmol) and Et3N (0.01 mL, 0.08 mmol) in DCM (0.50 mL) at 0° C. under Ar was added dropwise a solution of acetyl chloride (5 mg, 0.07 mmol) in DCM (0.2 mL). After 15 minutes, the ice-bath was removed and the solution was stirred at RT for 2 h. The reaction mixture was diluted with DCM and methanol, and concentrated. The residue was saponified following General Procedure D to give the title compound (15 mg, 44%) as TFA salt. LCMS: RT=2.11 min, MS (ES) 929 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.25-7.34 (m, 2H), 6.86 (m, 1H), 6.78 (s, 2H), 6.51 (d, J=8.5 Hz, 1H), 6.23 (m, 1H), 5.57 (m, 1H), 5.29 (m, 1H), 4.12-4.45 (bm, 4H), 4.07 (m, 2H), 3.80 (m, 1H), 3.72 (s, 3H), 3.43 (m, 1H), 2.95-3.35 (m, 5H), 2.89 (m, 3H), 2.72 (m, 1H), 2.36 (s, 3H), 2.22 (s, 6H), 2.04-2.19 (m, 3H), 1.72-1.94 (m, 6H), 1.04 (m, 3H).
The title compound (5 mg, 15% yield) was isolated as a byproduct from the reaction of Example 526 Step E. LCMS: RT=2.20) min, MS (ES) 797.8 (M+H).
The title compound (75 mg, 53%) was prepared following the procedure described Example 524 Step A using 3-iodo-1-methyl-5-(1H-1,2,4-triazol-3-yl)-1H-indole (120 mg, 0.37 mmol), NaH (18 mg, 0.74 mmol) and 2-bromoethyl methyl ether (45 μL, 0.48 mmol). LCMS: RT=1.527 min, MS (ES) 382.9 (M+H).
The title compound (20 mg, 45%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.060 mmol) and 3-iodo-5-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)-1-methyl-1H-indole (43 mg, 0.11 mmol). LCMS: RT=2.211 min, MS (ES) 793.9 (M+H).
The title compound (100 mg, quant.) was prepared following the procedure described Example 525 Step B using 2-bromopyrimidine (50 mg, 0.31 mmol) and 1-morpholino-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethan-1-one (151 mg, 0.41 mmol). LCMS: RT=1.155 min, MS (ES) 323.1 (M+H).
The crude title compound (100 mg) was prepared following the procedure described Example 524 Step B using 1-morpholino-2-(5-(pyrimidin-2-yl)-1H-indol-1-yl)ethan-1-one (100 mg, 0.31 mmol). LCMS: RT=1.439 min, MS (ES) 448.8 (M+H).
The title compound (10 mg, 22%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.060 mmol) and 2-(3-iodo-5-(pyrimidin-2-yl)-1H-indol-1-yl)-1-morpholinoethan-1-one (50 mg, 0.11 mmol). LCMS: RT=2.184 min, MS (ES) 860.8 (M+H).
The title compound (5.2 mg, 47%) was prepared according to General Procedure G using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-H-indole-5-carboxylate (10 mg, 0.01 mmol) and 4-(chloromethyl)thiazole HCl (5 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=2.085 min, MS (ES) 794.8 (M+H).
To a solution of 2-(piperidin-1-yl)acetic acid (8.6 mg, 0.06 mmol) in DMF (0.5 mL) were added HATU (23 mg, 0.06 mmol) and DIPEA (11 μL, 0.06 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. then methyl (R)-5-amino-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (30 mg, 0.04 mmol) was added at 0° C. The reaction mixture was warmed to RT and stirred for 10 h. The reaction mixture was diluted with ethyl acetate (10 mL), washed with brine, dried and concentrated. The residue was saponified in a mixture of 1,4-dioxane and MeOH (4 mL, 1:1) using NaOH (2 M, 1 mL). The crude was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 45% to 95% CH3CN, 0.1% TFA) to give the title compound. 1H-NMR (MeOH-d4) δ 8.35 and 8.29 (two d, total 1H, J=8 Hz), 7.91 (s, 1H), 7.79 (d, 1H, J=8 Hz), 7.63 and 7.61 (two d, total 1H, J=8 Hz), 7.73 (d, 1H, J=8 Hz), 6.64 and 6.62 (two s, total 2H), 4.70-7.60 (m, 1H), 4.50-4.34 (m, 2H), 4.14 (s, 2H), 3.98-3.72 (multiples s, total 6H), 3.80-3.78 (m, 2H), 3.66-3.63 (m, 2H), 3.15-3.10 (m, 4H), 2.28 (s, 6H), 2.16-1.96 (multiple s and tr, total 8H), 1.90-1.87 (multiple m, total 4H), 1.60 (m, 2H), 1.30 and 1.19 (multiple d, total 3H); MS (ES) 852.2 (M+H).
The title compound (4.8 mg, 43%) was prepared according to General Procedure G using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.01 mmol) and 3-(bromomethyl)-1-methylpyrrolidine hydrobromide (7 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=1.817 min, MS (ES) 794.9 (M+H).
The title compound (391 mg, 53%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (500 mg, 0.93 mmol) and methyl 5-(benzyloxy)-7-iodo-1H-indole-2-carboxylate (600 mg, 1.43 mmol). LCMS: RT=1.764 min, MS (ES) 815.8 (M+H).
The title compound (164 mg, 90%) was prepared according to General Procedure 1 using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (180 mg, 0.22 mmol) and methyl iodide (75 mg, 0.53 mmol). LCMS: RT=1.959 min (LC method II), MS (ES) 829.8 (M+H) (Ultra Aqueous method).
To a solution of methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (164 mg, 0.20 mmol) in MeOH (10 mL) was added HCl in dioxane (4.0 M, 0.5 mL) followed by Pd/C (10 wt. %, 20 mg, 0.019 mmol). The reaction mixture was stirred for 24 h under H2 atmosphere, filtered through celite, rinsed with DCM, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (141 mg, 96%). LCMS: RT=1.335 min (LC method II), MS (ES) 739.9 (M+H).
The title compound (6.1 mg, 31%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (20 mg, 0.027 mmol) and MeI (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=2.212 min, MS (ES) 739.9 (M+H).
The title compound (320 mg, 53%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (400 mg, 0.74 mmol) and methyl 5-(benzyloxy)-7-iodo-1H-indole-2-carboxylate (400 mg, 0.98 mmol). LCMS: RT=1.722 min, MS (ES) 817.9 (M+H).
The title compound (72 mg, 65%) was prepared according to General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (100 mg, 0.12 mmol) and 2-(chloromethyl)-6-methylpyridine hydrochloride salt (75 mg, 0.53 mmol). LCMS: RT=1.375 min (LC method II), MS (ES) 922.9 (M+H).
The title compound (59 mg, 91%) was prepared following the procedure described Example 535, Step C using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (72 mg, 0.078 mmol). LCMS: RT=0.930 min (LC method II), MS (ES) 832.8 (M+H).
The title compound (6.4 mg, 43%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(0H)-yl)-5-hydroxy-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (15 mg, 0.018 mmol) and MeI (5 mg, 0.035 mmol) followed by saponification using General Procedure D. LCMS: RT=1.959, 1.990 min, MS (ES) 832.8 (M+H).
The title compound (88 mg, 41%) was prepared according to General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (200 mg, 0.24 mmol) and 2-(bromomethyl)pyridine hydrobromide salt (200 mg, 0.80 mmol). LCMS: RT=1.384 min (LC method II), MS (ES) 908.8 (M+H).
The title compound (74 mg, 94%) was prepared following the procedure described Example 535 Step C using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (88 mg, 0.090 mmol). LCMS: RT=0.926 min (LC method II), MS (ES) 818.8 (M+H).
The title compound (7.5 mg, 48%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (15 mg, 0.018 mmol) and 1-bromo-2-methoxyethane (5 mg, 0.036 mmol) followed by saponification using General Procedure D. LCMS: RT=1.953 min, MS (ES) 862.9 (M+H).
The title compound (6.6 mg, 44%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (15 mg, 0.018 mmol) and MeI (5 mg, 0.035 mmol) followed by saponification using General Procedure D. LCMS. RT=1.972 min, MS (ES) 818.8 (M+H).
The title compound (6.1 mg, 29%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (20 mg, 0.027 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure D. LCMS: RT=2.181 min, MS (ES) 783.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.92-7.87 (m, 1H), 7.42-7.38 (m, 1H), 7.18 (d, J=2.2 Hz, 0.7H), 7.13-7.08 (m, 1H), 6.98 (d, J=2.2 Hz, 0.3H), 6.71 (s, 1.5H), 6.67 (s, 1.5H), 4.69-4.63 (m, 0.5H), 4.36-4.30 (m, 0.5H), 4.08 (quart, J=5.6 Hz, 2H), 4.01 (s, 1H), 4.00-3.94 (m, 2H), 3.90 (s, 2H), 3.72-3.59 (m, 4H), 3.29 (s, 3H), 3.27-3.16 (m, 2H), 2.30 (s, 1H), 2.25 (s, 2H), 2.23 (s, 4H), 2.22 (s, 2H), 2.18 (s, 2H), 2.16 (s, 1H), 2.07-2.03 (m, 2H), 1.17 (d, J=6.5 Hz, 2H), 1.08 (d, J=6.5 Hz, 1H)
The title compound (4.4 mg, 28%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (15 mg, 0.018 mmol) and 1-bromo-2-methoxyethane (5 mg, 0.036 mmol) followed by saponification using General Procedure D. LCMS: RT=1.944 min, MS (ES) 876.9 (M+H).
The title compound was prepared following the procedure described Example 533 using methyl (R)-5-amino-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (30 mg, 0.04 mmol) and 3-(dimethylamino)propanoic acid (7.0 mg, 0.06 mmol). MS (ES) 826.2 (M+H).
The title compound was prepared following the procedure described Example 533 using methyl (R)-5-amino-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate (30 mg, 0.04 mmol) and dimethylglycine (6.2 mg, 0.06 mmol). MS (ES) 812.2 (M+H).
The title compound (3.6 mg, 32%) was prepared according to General Procedure G using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.01 mmol) and 1-(2-bromoethyl)piperidine hydrobromide (8 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=1.90) min, MS (ES) 808.9 (M+H).
To a solution of 1-(tert-butyl) 2-methyl 7-bromo-5-formyl-1H-indole-1,2-dicarboxylate (295 mg, 0.77 mmol) in DCM (7.3 mL) was added TFA (0.71 mL, 1.06 g, 9.3 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with sat. NH4Cl aq. solution and extracted with DCM. The combined organic layer was dried, filtered and concentrated. The residue was re-dissolved in MeOH (6 mL)/THF (0.9 mL) and NaBH4 (42 mg, 1.2 mmol) were added at RT. The reaction mixture was stirred for 30 min then quenched with sat. NH4Cl aq. solution and extracted with DCM. The combined organic layer was dried, filtered and concentrated. The crude product was re-dissolved in DCM (4 mL), and MOMCl (92 μL, 98 mg, 1.22 mmol) and iPr2EtN (0.56 mL, 414 mg, 3.2 mmol) were added in sequence. The reaction mixture was stirred at RT for 24 h then quenched with sat. NH4Cl aq. solution and extracted with DCM. The combined organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (80 mg, 32% 3 steps). LCMS: RT=1.512 min, MS (ES) 327.8 (M+H). 1H NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 7.63 (s, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 4.74 (s, 2H), 4.67 (s, 2H), 3.98 (s, 3H), 3.45 (s, 3H).
The title compound was prepared according to General Procedure A using methyl 7-bromo-5-((methoxymethoxy)methyl)-1H-indole-2-carboxylate. (20 mg, 0.061 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (32 mg, 0.061 mmol). MS (ES) 786.2 (M+H).
The title compound was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-((methoxymethoxy)methyl)-1H-indole-2-carboxylate. MS (ES) 800.2 (M+H).
To a solution of methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-((methoxymethoxy)methyl)-1-methyl-1H-indole-2-carboxylate in THF (1 mL) and MeOH (0.5 mL) was added conc. HCl (0.3 mL) at RT. The reaction mixture was stirred for 16 h at RT. The reaction was quenched with sat. NaHCO3 aq. solution and extracted with DCM (3×10 mL). The combined organic layer was dried, filtered and concentrated to give the crude title compound, which was used to the next step directly.
The crude methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate was dissolved in DCM (0.15 mL), and Dess-Martin periodinane (5 mg, 0.011 mmol) was added. The reaction mixture was stirred at RT for 1 h. The reaction was quenched with sat. sodium thiosulfate aq. solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (9 mg, 20% 4 steps). LCMS: RT=2.445 min, MS (ES) 753.9 (M+H).
To a solution of methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-J H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-formyl-1-methyl-1H-indole-2-carboxylate (9 mg, 0.012 mmol) in DCM (0.15 mL) and Et3N (0.03 mL) were added N-methyl piperazine (2 μL, 1.7 mg, 0.017 mmol) and Na(OAc)3BH (5.9 mg, 0.028 mmol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction was quenched with sat. NaHCO3 aq. solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. Subsequent saponification was carried out following General Procedure D then purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN, 0.1% TFA) to afford the title compound (2.3 mg, 21%, 2 steps). LCMS: RT=1.762 min, MS (ES) 823.9 (M+H).
To a solution of (R)-3-(10-(3-bromopropyl)-7-chloro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-5-carboxylic acid (15 mg, 0.024 mmol) in DMF (2 mL) were added 1-naphthol (20 mg, 0.14 mmol) and Cs2CO3 (30 mg, 0.092 mmol). The reaction was heated to 50° C. until complete by LCMS. The reaction was diluted with DCM/H2O (10 mL, 1:1). The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layer was dried and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA) to afford the title compound (11.6 mg, 69%). LCMS: RT=2.066 min, MS (ES) 699.9 (M+H). 1H NMR (400 MHz, Chloroform-d6) δ 8.31 (s, 1H), 8.29-8.25 (m, 1H), 7.98 (dt, J=8.7, 1.5 Hz, 1H), 7.79-7.72 (m, 2H), 7.49-7.29 (m, 6H), 7.26-7.24 (m, 1H), 6.76 (d, J=7.5 Hz, 1H), 4.43-4.33 (m, 1H), 4.24-4.10 (m, 3H), 4.03-3.94 (m, 3H), 3.83 (s, 3H), 3.71-3.44 (m, 3H), 2.40 (quint, J=6.6 Hz, 2H), 2.27 (s, 1.5H), 2.20 (s, 1.5H), 2.11 (s, 1.5H), 2.05 (s, 1.5H), 1.20 (d, J=5.0 Hz, 1.5H), 1.16 (d, J=5.0 Hz, 1.5H).
BOP reagent (529 mg, 1.20 mmol), 1-methylpiperazine (442 μL, 3.98 mmol) and N-methylmorpholine (548 μL, 4.98 mmol) were added to a solution of 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)acetic acid (300 mg, 1.00 mmol) in DMF (6.6 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-2% gradient) to afford the title compound (240 mg, 63%). LCMS: RT=1.128 min, MS (ES) 384.1 (M+H).
The title compound (68 mg, 65%) was prepared following the procedure described Example 388 Step A using 1-(4-methylpiperazin-1-yl)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethan-1-one (154 mg, 0.40 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (50 mg, 0.31 mmol). LCMS: RT=0.885 min, MS (ES) 339.1 (M+H).
The title crude compound (44 mg) was prepared following the procedure described Example 388 Step B using 2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one (68 mg, 0.20 mmol). LCMS: RT=0.224 min, MS (ES) 464.8 (M+H).
The title compound (5 mg, 10%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one (44 mg, 0.10 mmol). LCMS: RT=1.794 min, MS (ES) 874.9 (M+H).
To a solution of ethyl 7-bromo-5-(bromomethyl)-1-methyl-1H-indole-3-carboxylate (292 mg, 0.78 mmol) in MeCN (14 mL) were added NMO (44 mg, 0.38 mmol) and 4 A molecular sieves (250 mg) and stirred at RT for 4 h. The reaction was quenched with aq. sat. NH4Cl solution and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-60% gradient) to afford ethyl 7-bromo-5-formyl-1-methyl-1H-indole-3-carboxylate. The title compound (120 mg, 43% 3 steps) was prepared following the procedure described Example 544 Step A using ethyl 7-bromo-5-formyl-1-methyl-1H-indole-3-carboxylate. LCMS: RT=1.850 min, MS (ES) 377.9 (M+Na). 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 4.74 (s, 2H), 4.67 (s, 2H), 4.38 (q, J=7.1 Hz, 2H), 4.17 (s, 3H), 3.45 (s, 3H), 1.42 (t, J=7.1 Hz, 3H).
The title compound was prepared following General coupling procedure A using ethyl 7-bromo-5-((methoxymethoxy)methyl)-1-methyl-1H-indole-3-carboxylate (57 mg, 0.161 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (86 mg, 0.161 mmol).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-((methoxymethoxy)methyl)-1-methyl-1H-indole-3-carboxylate (from Step B) in THF (3 mL) and MeOH (1.5 mL) was added Conc. HCl (0.9 mL) and stirred for 16 h at RT. The reaction mixture was quenched with aq. sat. NaHCO3 solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The crude product obtained was re-dissolved in DCM (1.6 mL). Dess-Martin periodinane (68 mg, 0.16 mmol) was added and stirred at RT for 1 h. Then, the reaction mixture was quenched with aq. sat. Na2S2O3 solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound (57 mg, 47%, 3 steps). LCMS: RT=2.386, 2.406, 2.449 min, MS (ES) 767.8 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-formyl-1-methyl-1H-indole-3-carboxylate (19 mg, 0.025 mmol) in DCM (0.25 mL) and Et3N (0.05 mL) was added 4-(4-chlorophenoxy)piperidine (2.6 mg, 0.030 mmol) followed by Na(OAc)3BH (10.6 mg, 0.050 mmol). After stirring at RT for 4 h, the reaction mixture was quenched with aq. sat. NH4Cl solution (2 mL) and extracted with DCM (3×5 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. Subsequent saponification was carried out following general procedure D using 2 M NaOH. The crude was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN, 0.1% TFA) and concentrated to afford the title compound (4.3 mg, 21%, 2 steps). LCMS: RT=2.078, 2.104 min, MS (ES) 934.8 (M+H). 1H NMR (600 MHz, DMSO-d6) δ 8.02-7.95 (m, 2H), 7.76 (d, J=8.6 Hz, 1H), 7.32-7.29 (m, 1H), 7.28 (d, J=8.9 Hz, 2H), 7.18 (d, J=9.6 Hz, 0.5H), 6.98-6.95 (m, 2.5H), 6.70 (d, J=14.5 Hz, 2H), 4.24-4.13 (m, 1H), 4.00-3.93 (m, 2H), 3.82 (s, 1H), 3.79-3.77 (m, 2.2H), 3.75-3.73 (m, 2.6H), 3.68 (d, J=13.0 Hz, 0.6H), 3.64 (d, J=13.0 Hz, 0.4H), 3.62-3.56 (m, 1.7H), 3.54-3.48 (m, 0.4H), 3.30-3.27 (m, 0.7H), 3.27-3.15 (m, 1.4H), 2.69 (br s, 2H), 2.29-2.22 (m, 7.6H), 2.12-2.11 (m, 2H), 2.06-1.99 (m, 4H), 1.96 (s, 1H), 1.94-1.89 (m, 2.5H), 1.88 (s, 1.5H), 1.62-1.54 (m, 2H), 1.19-1.15 (m, 2H), 1.06 (dd, J=6.6, 2.2 Hz, 1H).
The title compound (100 mg, 90%) was prepared following the procedure described Example 388 Step A using 1-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (172 mg, 0.57 mmol) and 2-bromopyrimidine (70 mg, 0.44 mmol). LCMS: RT=1.329 min, MS (ES) 254.1 (M+H).
The title compound (133 mg, 89%) was prepared following the procedure described Example 388 Step B using 1-(2-methoxyethyl)-5-(pyrimidin-2-yl)-1H-indole (100 mg, 0.39 mmol). LCMS: RT=1.658 min, MS (ES) 379.9 (M+H).
The title compound (40 mg, 82%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-(2-methoxyethyl)-5-(pyrimidin-2-yl)-1H-indole (42 mg, 0.10 mmol). LCMS: RT=2.243 min, MS (ES) 790.9 (M+H).
The title compound was prepared (4.3 mg, 21%, 2 steps) following the procedure described in Example 547 step D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-formyl-1-methyl-1H-indole-3-carboxylate (19 mg, 0.025 mmol) and morpholine (2.6 mg, 2.6 μL, 0.030 mmol). LCMS: RT=1.886, 1.922 min, MS (ES) 810.9 (M+H).
The title compound was prepared (4.0 mg, 20%, 2 steps) following the procedure described in Example 547 step Dosing ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-formyl-1-methyl-1H-indole-3-carboxylate (19 mg, 0.025 mmol) and pyrrolidine (2.1 mg, 0.030 mmol). LCMS: RT=1.907, 1.943 min, MS (ES) 794.8 (M+H).
The title compound (60%) was prepared following the procedure described Example 533 using methyl (R)-5-amino-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate and 3-(4-methylpiperazin-1-yl)propanoic acid. MS (ES) 881.2 (M+H).
The title compound (222 mg, 72%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (250 mg, 0.34 mmol) and 4-bromo-2-(chloromethyl)-pyridine (174 mg, 0.84 mmol). LCMS: RT=2.43 min., MS (ES) 909 (M+H).
To a solution of ethyl (R)-1-((4-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (85 mg, 0.09 mol) in pentanol (0.5 mL) was added piperazine (40 mg, 0.47 mmol). The reaction was sealed and stirred at 125° C. overnight. The reaction mixture was cooled to RT and diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, DCM/methanol=0-6% gradient) to give the title compound (66 mg, 74%). LCMS: RT=1.92 min., MS (ES) 957 (M+H).
To a solution of pentyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1-((4-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-indole-2-carboxylate (66 mg, 0.07 mol) in DCM (1.0 mL) at 0° C. under Ar was added Et3N (17 mg, 0.17 mmol) followed by acetyl chloride (11 mg, 0.14 mmol) then diluted with DCM (0.4 mL). The reaction was warmed to RT and stirred 3 h. The reaction was diluted with DCM and water. The aqueous layer was separated and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude title compound (69 mg, 100%). LCMS: RT=2.06 min., MS (ES) 999 (M+H).
The title compound (40 mg, 62%, 2 steps) was prepared following General Procedure D using pentyl (R)-1-((4-(4-acetylpiperazin-1-yl)pyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (69 mg, 0.07 mmol). LCMS: RT=1.87 min., MS (ES) 929 (M+H).
The title compound was obtained as a byproduct of Example 552 step D. LCMS: RT=1.71 min., MS (ES) 887 (M+H).
The title compound (62%) was prepared following the procedure described Example 533 using methyl (R)-5-amino-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-3-carboxylate and 2-(4-methylpiperazin-1-yl)acetic acid. MS (ES) 867.2 (M+H).
The title compound (9.6 mg, 61%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and 4-(bromomethyl)pyridine HBr (10 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.811 min, MS (ES) 788.80 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=5.7 Hz, 2H), 8.16 (s, 1H), 7.82-7.74 (m, 3H), 7.56 (d, J=8.7 Hz, 1H), 7.50 (t, J=6.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 1H), 6.73 (s, 2H), 5.76 (s, 2H), 4.53 (t, J=3.4 Hz, 0.5H), 4.50 (t, J=3.6 Hz, 0.5H), 4.28-4.11 (m, 1H), 3.99 (dt, J=6.2 & 2.2 Hz, 2H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.75-3.69 (m, 1H), 3.41-3.29 (m, 1H), 3.28-3.18 (m, 1H), 2.24 (s, 6H), 2.13 (s, 1.5H), 2.10-2.04 (m, 2H), 2.03 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.10 (d, J=6.4 Hz, 3H).
To a solution of ethyl (R)-1-((4-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (102 mg, 0.11 mol) in DMF (1.0 mL) was added Zn(CN)2 (18 mg, 0.16 mmol) and Pd(PPh3)4 (13 mg, 0.01 mmol). The reaction mixture was degassed, sealed and stirred at 110° C. for 3 h. The reaction mixture was cooled to RT and diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, DCM/methanol=0-2.5% gradient) to give the title compound (74 mg, 77%). LCMS: RT=1.65 min., MS (ES) 856 (M+H).
The title compound (40 mg, 62%) was prepared following General Procedure D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((4-cyanopyridin-2-yl)methyl)-5-methyl-1H-indole-2-carboxylate (74 mg, 0.09 mmol). LCMS: RT=2.25 min., MS (ES) 828 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=5.0 Hz, 0.5H), 8.42 (d, J=5.0 Hz, 0.5H), 7.68 (m, 1H), 7.54 (m, 2H), 7.38 (m, 1H), 7.25 (m, 1H), 6.81 (m, 2H), 6.71 (s, 2H), 6.02 ((m, 1H), 5.62-5.88 (bm, 1H), 4.54 (m, 1H), 3.87-3.95 (bm, 3H) 3.74 (s, 1.5H), 3.72 (s, 1.5H), 3.39 (m, 1H), 3.03-3.21 (bm, 3H), 2.38 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.99-2.08 (bm, 4H), 1.86 (s, 1.5H), 1.74 (s, 1.5H) 1.01 (m, 3H).
The title compound (293 mg, 95%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (250 mg, 0.34 mmol, 1.0 eq) and 2-bromo-6-(bromomethyl)-pyridine (119 mg, 0.47 mmol). LCMS: RT=2.44 min., MS (ES) 909 (M+H).
The title compound (53 mg, 84%) was prepared following the procedure described Example 556, Step A using ethyl (R)-1-((6-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (67 mg, 0.07 mol). LCMS: RT=1.62 min., MS (ES) 856 (M+H).
The title compound (17 mg, 29%) was prepared following General Procedure D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((6-cyanopyridin-2-yl)methyl)-5-methyl-1H-indole-2-carboxylate (53 mg, 0.06 mmol). LCMS: RT=2.23 min., MS (ES) 828 (M+H).
The title compound (6.1 mg, 27%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (20 mg, 0.027 mmol) and 4-(2-chloroethyl)morpholine HCl (10 mg, 0.054 mmol) followed by saponification using General Procedure D. LCMS. RT=1.853 min, MS (ES) 838.9 (M+H).
The title compound (94 mg, 95%) was prepared following the procedure described Example 39) Step D using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-1043-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (115 mg, 0.175 mmol) and Pd/C (10 wt %, 20 mg, 0.019 mmol) by hydrogenating in MeOH (5 mL) with HCl (4.0 M in dioxanes, 0.5 mL) for 6 h at 40° C. LCMS: RT=0.946 min (Method B), MS (ES) 566.9 (M+H).
The title compound (55 mg, 96%) was prepared following General Procedure J using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.088 mmol), MsCl (30 mg, 0.26 mmol), and N-methyl piperazine (50 mg, 0.50 mmol). The crude reaction product was carried forward without further purification. LCMS: RT=1.658 min, MS (ES) 648.9 (M+H).
The title compound was prepared (2.4 mg, 9%) following General Procedure B using: (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethyl-2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.031 mmol) and methyl 3-bromo-1-(2-methoxyethyl)-1H-indole-5-carboxylate (25 mg, 0.081 mmol) followed by saponification using General Procedure D. LCMS: RT=1.769 min, MS (ES) 865.9 (M+H).
The title crude compound (120 mg) was prepared following the procedure described Example 388 Step A using N,N-dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)acetamide (152 mg, 0.46 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (50 mg, 0.31 mmol). LCMS: RT=0.169 min, MS (ES) 284.1 (M+H).
The title compound (70 mg, 40%) was prepared following the procedure described Example 388 Step B using N,N-dimethyl-2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)acetamide (120 mg, 0.42 mmol). LCMS: RT=1.118 min, MS (ES) 409.9 (M+H)
The title compound (9.5 mg, 21%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-N,N-dimethylacetamide (46 mg, 0.11 mmol). LCMS: RT=1.971 min, MS (ES) 819.9 (M+H).
The title compound (16 mg, 99%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and 2-(bromomethyl)pyridine HBr (10 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.913 min (Method B), MS (ES) 788.80 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=4.8 Hz, 1H), 8.12 (s, 1H), 7.84-7.76 (m, 2H), 7.75-7.71 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.34 (t, J=5.7 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.20-7.14 (m, 1H), 6.73 (s, 2H), 5.57 (s, 2H), 4.59-4.43 (m, 1H), 4.23-4.08 (m, 1H), 3.98 (dt, J=6.0 & 2.7 Hz, 2H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.74-3.64 (m, 1H), 3.40-3.28 (m, 1H), 3.28-3.17 (m, 1H), 2.23 (s, 6H), 2.12 (s, 1.5H), 2.10-2.04 (m, 2H), 2.03 (s, 1.5H), 1.97 (s, 1.5H), 1.88 (s, 1.5H), 1.09 (d, J=6.4 Hz, 3H).
To a solution of 1-bromo-2-nitrobenzene (0.97 g, 4.8 mmol) in 50% aq. NaOH (0.3 mL) was added Zn dust (0.9 g, 13.9 mmol) in small portions while maintaining the reaction temperature below 80° C. The mixture was diluted with water (6 mL) and 20% aq. NaOH (12 mL) then zinc dust (1.2 g, 18.7 mmol) was added in one portion. The resulting mixture was heated at 80° C. for 1 h, cooled to RT and poured slowly to 10% sulfuric acid (20 mL) at 0° C. The mixture was stirred for 30 min then extracted with diethyl ether. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-80% gradient) to afford the title compound (165 mg, 20%). LCMS: RT=1.818 min, MS (ES) 340.8 (M+H).
To a solution of 1,2-bis(2-bromophenyl)hydrazine (165 mg, 0.5 mmol) in MeOH (5 mL), dimethyl but-2-ynedioate (41 μL, 92 mg, 0.65 mmol) was added and refluxed for 16 h. The reaction was quenched with aq. sat. NH4Cl solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-80% gradient) to afford the title compound (30 mg, 19%). 1H NMR (400 MHz, CDCl3) δ 9.34 (br s, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.54 (dd. J=7.6, 0.8 Hz, 1H), 7.17 (t, J=8.1 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 3H).
To a solution of dimethyl 7-bromo-1H-indole-2,3-dicarboxylate (30 mg, 0.10 mmol) in MeCN (1 mL) was added Cs2CO3 (78.2 mg, 0.24 mmol) followed by tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (26.8 mg, 0.12 mmol). The reaction was heated at 75° C. for 16 h then quenched with aq. sat. NH4Cl solution and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was re-dissolved in DCM (0.6 mL), TFA (138 mg, 1.2 mmol) was added and stirred at RT for 16 h. The reaction was quenched with aq. sat. NaHCO3 and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The crude product was redissolved in CH3CN (1.6 mL). Cs2CO3 (78 mg, 0.24 mmol) was added and heated at 70° C. for 12 h. Then, the reaction mixture was quenched with aq. sat. NH4Cl solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The crude product was re-dissolved in DMF (1 mL). NaH (12 mg, 0.3 mmol) followed by MeI (63 μL, 142 mg, 1.0 mmol) were added and stirred at RT for 1 h. Then, the reaction mixture was quenched with aq. sat. NH4Cl solution and extracted with DCM. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (7 mg, 20% yield, 4 steps). LCMS: RT=1.337 min, MS (ES) 337.0 (M+H).
The title compound (1.5 mg, 10%, 2 steps) was prepared following General coupling procedure A using methyl 6-bromo-2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-10-carboxylate (7 mg, 0.02 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (11 mg, 0.02 mmol) followed by saponification using General Procedure D. LCMS: RT=2.154, 2.186 min, MS (ES) 780.9 (M+H).
The title compound (12 mg, 76%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and 3-(bromomethyl)pyridine HBr (10 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.804 min (Method B), MS (ES) 788.80 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.72-8.65 (m, 1H), 8.64-8.57 (m, 1H), 8.12 (s, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.83-7.80 (m, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.59-7.52 (m, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.73 (s, 2H), 5.59 (s, 2H), 4.50 (t, J=3.5 Hz, 0.5H), 4.47 (t, J=3.6 Hz, 0.5H), 4.25-4.09 (m, 1H), 3.98 (dt, J=6.3 & 2.2 Hz, 2H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.75-3.65 (m, 1H), 3.39-3.28 (m, 1H), 3.27-3.17 (m, 1H), 2.23 (s, 6H), 2.12 (s, 1.5H), 2.10-2.04 (m, 2H), 2.03 (s, 1.5H), 1.97 (s, 1.5H), 1.88 (s, 1.5H), 1.09 (d, J=6.5 Hz, 3H).
To a solution of methyl 7-bromo-5-((tert-butoxycarbonyl)amino)-1-methyl-1H-indole-3-carboxylate (450 mg, 1.17 moml) in DMF (5 mL) was added NaH (95 mg, 2.4 mmol) at 0° C. under N2 stirred for 10 min. MeI (2.0 mmol) was added to the reaction mixture and stirred at 0° C. for 10 min then at RT for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound (440 mg, 94%). 1H-NMR (DMSO-d6) δ 8.0 (s, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 4.20 (s, 3H), 3.91 (s, 3H), 3.31 (s, 1H), 1.49 (s, 9H).
The title compound (78%) was prepared following General coupling procedure A using methyl 7-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-1-methyl-1H-indole-3-carboxylate and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one. MS (ES) 855.3 (M+H)
(R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(methylamino)-1H-indole-3-carboxylate was dissolved in DCM/TFA (5/1) and stirred for 2 h at RT. The reaction mixture was concentrated in vacuo to afford the title compound (95%) which was carried to the next step without further purification.
The title compound (65%) was prepared following General procedure G using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(methylamino)-1H-indole-3-carboxylate and 2-(bromomethyl)pyridine followed by saponification using General Procedure D. MS (ES) 832.1 (M+H)
The title compound (84 mg, 93%) was prepared following General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (80 mg, 0.098 mmol) and 2-(chloromethyl)-4-methylpyridine HCl (30 mg, 0.17 mmol). LCMS: RT=1.299 min (Method B), MS (ES) 920.8 (M+H).
The title compound (73 mg, 96%) was prepared following the procedure described Example 390 Step D using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((4-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (84 mg, 0.092 mmol) and Pd/C (10 wt. %, 10 mg, 0.0092 mmol) by hydrogenating in MeOH (5 mL) with HCl for 5 h at RT. LCMS: RT=0.839, 0.864 min (Method B), MS (ES) 830.8 (M+H).
The title compound (5.9 mg, 39%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((4-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (15 mg, 0.018 mmol) and MeI (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=1.979 min, MS (ES) 830.8 (M+H).
The title compound (86 mg, 96%) was prepared following General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (80 mg, 0.098 mmol) and 2-(chloromethyl)-6-methylpyridine (30 mg, 0.21 mmol). LCMS: RT=1.319, 1.354 min (Method B), MS (ES) 920.8 (M+H).
The title compound (51 mg, 66%) was prepared following the procedure described Example 390 Step D using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (86 mg, 0.093 mmol) and Pd/C (10 wt. %, 10 mg, 0.0092 mmol) by hydrogenating in MeOH (5 mL) with HCl for 5 h at RT. LCMS: RT=0.888 min (Method B), MS (ES) 830.8 (M+H).
The title compound (7.1 mg, 39%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (17 mg, 0.020 mmol) and 2-bromo-N,N-dimethylethan-1-amine (10 mg, 0.043 mmol) followed by saponification using General Procedure D. LCMS: RT=0.476 min (Method B), MS (ES) 887.8 (M+H). 1H NMR (CDCl3, 400 MHz) δ (ppm) 9.18 (s, 0.34H), 9.14 (s, 0.66H), 7.85-7.81 (m, 1H), 7.66-7.63 (m, 1H), 7.31 (dd, J=8.6, 2.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.00-6.92 (m, 1H), 6.87-6.65 (m, 3H), 6.58 (s, 1.34H), 6.54 (s, 0.66H), 6.24-6.11 (m, 1.34H), 5.88-5.65 (m, 0.66H), 4.59-4.55 (m, 1H), 4.43 (dd, J=13.0, 4.0 Hz, 0.66H), 4.28-4.22 (m, 1.34H), 3.92-3.56 (m, 4H), 3.41-3.30 (m, 2H), 3.01 (s, 1H), 2.98 (s, 2H), 2.92 (s, 3H), 2.89-2.81 (m, 1H), 2.66 (s, 1H), 2.64 (s, 1H), 2.50 (s, 2H), 2.47 (s, 1H), 2.40 (s, 2H), 2.35 (s, 2H), 2.33 (s, 6H), 2.25 (s, 1H), 1.86-1.72 (m, 2H), 1.45 (d, J=5.8 Hz, 1H), 1.21 (d, J=6.8 Hz, 2H).
The title compound (220 mg, 66%) was prepared following the procedure described Example 388 Step A using 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (492 mg, 1.23 mmol) and 2-bromopyrimidine (150 mg, 0.94 mmol). LCMS: RT=2.077 min, MS (ES) 354.1 (M+H).
The title compound (140 mg, 94%) was prepared following the procedure described Example 420 Step C using 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(pyrimidin-2-yl)-1H-indole (220 mg, 0.62 mmol). LCMS: RT=1.122 min, MS (ES) 240.1 (M+H).
The title compound (78 mg, 85%) was prepared following General Procedure J using 2-(5-(pyrimidin-2-yl)-1H-indol-1-yl)ethan-1-ol (140 mg, 0.59 mmol) and pyrrolidine (233 μL, 2.84 mmol). LCMS: RT=0.167 min, MS (ES) 293.1 (M+H).
The title compound (37 mg, 33%) was prepared following the procedure described Example 388 Step B using 5-(pyrimidin-2-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole (78 mg, 0.27 mmol). LCMS: RT=1.282 min, MS (ES) 418.9 (M+H).
The title compound (16.5 mg, 31%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (35 mg, 0.06 mmol) and 3-iodo-5-(pyrimidin-2-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole (37 mg, 0.09 mmol). LCMS: RT=1.959 min, MS (ES) 828.9 (M+H).
The title compound (13 mg, 23%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (35 mg, 0.06 mmol) and 3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-(pyrimidin-2-yl)-1H-indole (44 mg, 0.10 mmol). LCMS: RT=1.870 min, MS (ES) 858.0 (M+H).
The title compound (10.4 mg, 63%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and 1-(2-Bromoethyl)-4-methylpiperazine dihydrobromide (15 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.745 min, MS (ES) 823.90 (M+H).
The title compound (7.2 mg, 43%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (15 mg, 0.021 mmol) and 4-(bromomethyl)-2-methyl-2H-1,2,3-triazole (10 mg, 0.039 mmol) followed by saponification using General Procedure D. LCMS: RT=2.165, 2.138 min, MS (ES) 792.8 (M+H). 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.72-7.66 (m, 2H), 7.50 (s, 0.34H), 7.49 (s, 0.66H), 7.30 (d, J=8.6 Hz, 0.34), 7.29 (d, J=8.6 Hz, 0.66H), 7.23-7.02 (m, 3H), 6.61 (s, 1.34H), 6.58 (s, 0.66H), 6.21 (d, J=16.6 Hz, 1H), 6.17 (d, J=16.6 Hz, 1H), 5.85-5.55 (m, 1H), 4.48-4.19 (m, 2H), 4.15-3.93 (m, 4H), 3.89 (s, 4H), 3.88-3.83 (m, 1.5H), 3.72-3.64 (m, 0.5H), 3.46-3.24 (m, 3H), 2.30 (s, 2H), 2.29 (s, 4H), 2.23-2.10 (m, 5H), 2.07-2.00 (m, 3H), 1.25 (d, J=6.5 Hz, 1H), 1.19 (d, J=6.5 Hz, 2H).
The title compound (9.8 mg, 55%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (17 mg, 0.020 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure D. LCMS: RT=1.959 min. MS (ES) 874.8 (M+H). 1H NMR (CDCl3, 400 MHz) δ (ppm) 9.11 (s, 0.66H), 9.10 (s, 0.34H), 7.81 (t, J=7.6 Hz, 1H), 7.69-7.65 (m, 1H), 7.41 (s, 0.34H), 7.36 (s, 0.66H), 7.33-7.28 (m, 1H), 7.21-7.08 (m, 2H), 6.91 (d, J=2.2 Hz, 0.34H), 6.86 (d, J=2.2 Hz, 0.66H), 6.78-6.69 (m, 0.66H), 6.65-6.60 (m, 0.33H), 6.57 (s, 1.3H), 6.56 (s, 0.66H), 6.26-5.82 (m, 2H), 4.39-4.08 (m, 3H), 3.83-3.64 (m, 5H), 3.45 (s, 3H), 3.37-3.21 (m, 1H), 3.12-2.94 (m, 1H), 2.60 (s, 1H), 2.48 (s, 2H), 2.43 (s, 1H), 2.38 (s, 2H), 2.35-2.28 (m, 9H), 2.22 (s, 1H), 1.90-1.67 (m, 2H), 1.21 (d, J=6.4 Hz, 2H), 1.09-0.98 (m, 1H).
The title compound (8.3 mg, 49%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (17 mg, 0.020 mmol) and MeI (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=1.984 min, MS (ES) 830.8 (M+H). 1H NMR (CDCl3, 400 MHz) δ (ppm) 9.14 (s, 0.66H), 9.13 (s, 0.34H), 7.90-7.84 (m, 1H), 7.71-7.66 (m, 1H), 7.44-7.39 (m, 1H), 7.31 (t, J=8.5 Hz, 1H), 7.23 (d, J=7.8 Hz, 0.34H), 7.17 (d, J=7.8 Hz, 0.66H), 7.10 (d, J=2.3 Hz, 1H), 6.83 (d, J=2.4 Hz, 0.34H), 6.80 (d, J=2.4 Hz, 0.66H), 6.78-6.64 (m, 1H), 6.57 (s, 1.34H), 6.55 (s, 0.66H), 6.26-6.21 (m, 1.34H), 5.93 (d, J=17.8 Hz, 0.66H), 4.49 (d, J=12.4 Hz, 0.66H), 4.34 (dd, J=13.0, 3.9 Hz, 0.34H), 3.86 (s, 3H), 3.82-3.68 (m, 3H), 3.41 (d, J=13.3 Hz, 1H), 3.12-2.96 (m, 1H), 2.62 (s, 1H), 2.58-2.54 (m, 3H), 2.45 (s, 1H), 2.41 (s, 2H), 2.35 (s, 2H), 2.33 (s, 6H), 2.25 (s, 1H), 1.8-1.72 (m, 2H), 1.22 (d, J=6.5 Hz, 2H), 1.18-1.11 (m, 1H).
The title compound (6.7 mg, 42%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((4-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (15 mg, 0.018 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure D. LCMS: RT=1.954 min, MS (ES) 874.9 (M+H). 1H NMR (CDCl3, 400 MHz) δ (ppm) 9.11 (s, 1H), 8.39 (d, J=5.8 Hz, 0.34H), 8.31 (d, J=5.8 Hz, 0.66H), 7.68-7.64 (m, 1H), 7.45 (s, 1H), 7.30 (d, J=8.6 Hz, 0.34H), 7.29 (d, J=8.6 Hz, 0.66H), 7.28-7.20 (m, 1H), 7.15 (d, J=2.2 Hz, 0.66H), 7.13 (d, J=2.2 Hz, 0.34H), 6.91 (d, J=2.2 Hz, 0.34H), 6.88 (d, J=2.2 Hz, 0.66H), 6.87-6.76 (m, 1H), 6.57 (s, 2H), 6.23-6.13 (m, 1H), 5.84 (d, J=16.9 Hz, 1H), 4.32-4.10 (m, 3H), 3.86-3.66 (m, 5H), 3.45 (s, 3H), 3.40-3.33 (m, 1H), 3.02-2.97 (m, 1H), 2.73-2.62 (m, 1H), 2.41 (s, 1H), 2.38 (s, 2H), 2.36 (s, 1H), 2.35-2.31 (m, 8H), 2.29 (s, 2H), 2.21 (s, 1H), 1.89-1.77 (m, 2H), 1.20 (d, J=6.5 Hz, 2H), 1.09-1.04 (m, 1H).
The title compound (32 mg, 77%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (38 mg, 0.11 mmol). LCMS: RT=2.098 min, MS (ES) 746.8 (M+H).
The title compound (88.6 mg, 88%) was prepared following General Procedure F using 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (46 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), and MeI (53 μL, 0.85 mmol). LCMS: RT=1.712 min, MS (ES) 269.0 (M+H).
The title compound (22 mg, 62%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and 3-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (22 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS RT=2.063 min (Method B), MS (ES) 712.8 (M+H). 1H NMR (4(0) MHz, DMSO-d6) δ 8.87 (t, J=1.6 Hz, 1H), 8.44 (t, J=1.6 Hz, 1H), 7.80-7.73 (m, 2H), 7.30 (d, J=8.6 Hz, 1H), 6.72 (s, 2H), 4.56-4.49 (m, 2H), 4.25-4.10 (m, 1H), 4.04-3.93 (m, 2H), 3.88 (s, 3H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.43-3.29 (m, 1H), 3.28-3.17 (m, 1H), 2.23 (s, 6H), 2.12 (s, 1.5H), 2.09 (s, 1.5H), 2.07-2.02 (m, 2H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.06 (d, J=6.5 Hz, 3H).
The title compound (145 mg, 54%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (200 mg, 0.37 mmol) and methyl 7-bromo-5-methyl-1H-indole-2-carboxylate (200 mg, 0.746 mmol). LCMS: RT=1.581 min, MS (ES) 723.9 (M+H).
The title compound (13.3 mg, 48%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (25 mg, 0.034 mmol) and 2-(chloromethyl)-6-methylpyridine (10 mg, 0.071 mmol) followed by saponification using General Procedure D. LCMS: RT=2.023 min, MS (ES) 814.8 (M+H).
The title compound (13.2 mg, 47%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (25 mg, 0.034 mmol) and 2-(chloromethyl)-4-methylpyridine HCl (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=2.012 min, MS (ES) 814.8 (M+H).
The title compound (37 mg, 74%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.07 mmol) and 2-(2-bromoethoxy)propane (28 mg, 0.17 mmol) followed by saponification using General Procedure D. LCMS: RT=2.32 min, MS (ES) 798 (M+H).
The title compound (40 mg, 75%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.07 mmol) and 2-bromoethyl ethyl ether (18 mg, 0.12 mmol) followed by saponification using General Procedure D. LCMS: RT=2.28 min, MS (ES) 784 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 0.5H), 7.75 (s, 0.5H), 7.48 (s, 0.5H), 7.43 (s, 0.5H), 7.29 (m, 1H), 7.20 (m, 1H), 6.93 (m, 1H), 6.70 (s, 1H), 6.67 (s, 1H), 4.94 (m, 1H), 4.88 (m, 1H), 4.63 (m, 1H), 4.41 (m, 2H), 4.15 (m, 1H), 3.94 (t, J=6.2 Hz, 2H), 3.77 (s, 1.5H), 3.75 (s, 1.5H), 3.71 (m, 1H), 3.45 (m, 1H), 3.36 (m, 1H), 3.07-3.26 (bm, 4H), 2.37 (s, 1.5H), 2.35 (s, 1.5H), 2.22 (s, 3H), 2.21 (s, 3H), 2.11 (m, 2H), 2.00 (m, 3H), 1.91-1.95 (m, 1H), 1.86 (s, 1H), 1.15 (d, J=6.5 Hz, 1.5H), 1.04 (d, J=6.5 Hz, 1.5H), 0.74 (m, 3H).
The title compound (74 mg, 58%) was prepared following General Procedure G using methyl 3-bromo-1H-indole-5-carboxylate (100 mg, 0.39 mmol) and 2-bromo-N,N-dimethylethan-1-amine HBr (180 mg, 0.77 mmol). LCMS: RT=1.154 min, MS (ES) 324.9 (M+H).
The title compound (6.3 mg, 23% yield) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethyl-2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.031 mmol) and methyl 3-bromo-1-(2-(dimethylamino)ethyl)-1H-indole-5-carboxylate (20 mg, 0.062 mmol) followed by saponification using General Procedure D. LCMS: RT=0.476 min, MS (ES) 887.8 (M+H).
The title compound (480 mg, 57%) was prepared following the procedure described Example 388 Step A using 1-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (934 mg, 3.10 mmol) and 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (600 mg, 2.59 mmol). LCMS. RT=1.408 min, MS (ES) 327.1 (M+H).
The title compound (650 mg, 98%) was prepared following the procedure described Example 388 Step B using 1-(2-methoxyethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (480 mg, 1.47 mmol). LCMS: RT=1.674 min, MS (ES) 452.8 (M+H).
2N HCl (3 mL) was added to a solution of 3-iodo-1-(2-methoxyethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (650 mg, 1.44 mmol) in DMF (15 mL) at 0° C. After 5 h, the reaction mixture was diluted with EtOAc, iPrOH and Sat. aq NaHCO3 at 0° C. The solution was extracted with EtOAc. The combined organic layers were dried and concentrated to afford the crude title compound (500 mg), which was used for the next step without further purification. LCMS: RT=0.188 min, MS (ES) 368.8 (M+H).
The title crude compound (73 mg) was prepared following General Procedure G using 3-iodo-1-(2-methoxyethyl)-5-(1H-1,2,4-triazol-3-yl)-1H-indole (6 (0 mg, 0.160 mmol) and 3-(chloromethyl)oxetane (17.4 μL, 0.18 mmol). LCMS: RT=1.336 min, MS (ES) 438.9 (M+H).
The title compound (29 mg, 61%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and iodo-1-(2-methoxyethyl)-5-(1-(oxetan-3-ylmethyl)-1H-1,2,4-triazol-3-yl)-1H-indole (49 mg, 0.11 mmol). LCMS: RT=2.077 min, MS (ES) 848.8 (M+H).
The title compound (69 mg, 28%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (180 mg, 0.33 mmol) and methyl 7-iodo-4-methoxy-1H-indole-2-carboxylate (200 mg, 0.60 mmol). LCMS: RT=1.386, 1.422 min, (Method B) MS (ES) 741.9 (M+H).
The title compound (12.5 mg, 44%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (23 mg, 0.031 mmol) and 2-(chloromethyl)-4-methylpyridine hydrochloride (10 mg, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=1.952, 1.982 min, MS (ES) 832.8 (M+H).
The title compound (42 mg, 41%) was prepared following General Procedure J using 2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethan-1-ol (105 mg, 0.33 mmol) and morpholine (283 μL 3.28 mmol). LCMS: RT=0.163 min, MS (ES) 312.1 (M+H).
The title compound (55 mg, 93%) was prepared following the procedure described Example 388 Step B using 4-(2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)morpholine (42 mg, 0.13 mmol). LCMS: RT=0.168 min, MS (ES) 437.8 (M+H).
The title compound (30 mg, 64%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 4-(2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)morpholine (49 mg, 0.11 mmol). LCMS: RT=1.825 min, MS (ES) 847.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.11 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.62 (s, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.72 (s, 2H), 4.62 (t, J=7.2 Hz, 2H), 4.51-4.46 (m, 1H), 4.20-4.18 (m, 1H), 4.00-3.95 (m, 3H), 3.88 (s, 3H), 3.77 (d, J=4.8 Hz, 3H), 3.70 (dd, J=11.6, 7.4 Hz, 3H), 3.62-3.57 (m, 2H), 3.36-3.19 (m, 4H), 2.54 (s, 3H), 2.22 (s, 6H), 2.12-2.04 (m, 5H), 1.98-1.89 (m, 3H), 1.12-1.10 (m, 3H).
The title compound (6.1 mg, 38%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((4-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (15 mg, 0.018 mmol) and 2-bromo-N,N-dimethylethan-1-amine hydrobromide (10 mg, 0.043 mmol) followed by saponification using General Procedure D. LCMS: RT=1.660 min, MS (ES) 887.8 (M+H).
The title compound (65.1 mg, 85%) was prepared following General Procedure F using methyl 5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (49 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), and MeI (53 μL, 0.85 mmol). LCMS: RT=1.165 min, MS (ES) 269.9 (M+H).
The title compound (19.5 mg, 55%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (22 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.154 min (Method B), MS (ES) 713.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.48 (s, 0.5H), 8.45 (s, 0.5H), 7.76 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.74 (s, 2H), 4.61-4.52 (m, 0.5H), 4.50-4.44 (m, 0.5H), 4.41-4.30 (m, 1H), 4.27-4.15 (m, 1H), 3.99 (d, J=5.8 Hz, 2H), 3.92 (s, 3H), 3.80 (s, 1.5H), 3.78 (s, 1.5H), 3.30-3.20 (m, 2H), 2.24 (s, 6H), 2.12 (s, 1.5H), 2.08 (t, J=6.9 Hz, 1H), 2.03 (s, 1.5H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.12 (d, J=6.6 Hz, 3H).
The title compound (54 mg, 56%) was prepared following General Procedure J using 2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethan-1-ol (105 mg, 0.33 mmol) and pyrrolidine (161 μL, 1.97 mmol). LCMS: RT=0.158 min, MS (ES) 296.1 (M+H).
The title compound (40 mg, 52%) was prepared following the procedure described Example 388 Step B using 5-(1-methyl-1H-1,2,4-triazol-3-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole (54 mg, 0.18 mmol). LCMS: RT=1.122 min, MS (ES) 421.9 (M+H).
The title compound (40 mg, 87%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole (40 mg, 0.10 mmol). LCMS: RT=1.855 min, MS (ES) 831.9 (M+H).
The title compound (13.8 mg, 57%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (23 mg, 0.031 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure D. LCMS: RT=2.165, 2.196 min, MS (ES) 785.8 (M+H).
The title compound (39 mg, 94%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and ethyl 5-(benzyloxy)-7-bromo-1H-indole-3-carboxylate (22 mg, 0.06 mmol). LCMS: RT=1.619 min, MS (ES) 831.9 (M+H).
The title compound (33 mg, 79%) was prepared according to General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (39 mg, 0.02 mmol) and 2-(bromomethyl)pyridine HBr (19 mg, 0.074 mmol) followed by saponification using General Procedure D. LCMS: RT=1.502 min, MS (ES) 895.9 (M+H).
The crude title compound (65 mg) was prepared following General Procedure G using 3-iodo-1-(2-methoxyethyl)-5-(1H-1,2,4-triazol-3-yl)-1H-indole (60 mg, 0.16 mmol) and (bromomethyl)cyclopropane (19 μL, 0.20 mmol). LCMS: RT=1.605 min, MS (ES) 422.9 (M+H).
The title compound (28 mg, 60%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-(2H)-one (30 mg, 0.06 mmol) and 5-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-3-iodo-1-(2-methoxyethyl)-1H-indole (47 mg, 0.11 mmol). LCMS: RT=2.182 min, MS (ES) 832.9 (M+H).
The title compound (2 mg, 12%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (15 mg, 0.019 mmol) and 2-bromo-N,N-dimethylethan-1-amine HBr (15 mg, 0.064 mmol) followed by saponification using General Procedure D. LCMS. RT=1.717 min, MS (ES) 875.8 (M+H).
To a solution of 1-(tert-butyl) 2-ethyl 7-bromo-5-formyl-1H-indole-1,2-dicarboxylate (585 mg, 1.47 mmol) in DCM (14 mL) was added TFA (1.13 mL, 14.7 mmol) and stirred at RT for 16 h. The reaction was quenched with aq. sat. NH4Cl solution and extracted with DCM. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was redissolved in DMF (8 mL). K2CO3 (1.22 g, 8.82 mmol) and MeI (275 μL, 626 mg, 4.41 mmol) were added and heated to 60° C. for 4 h. The reaction mixture was quenched with aq. sat. NH4Cl solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-60% gradient) to afford the title compound (360 mg, 79%, 2 steps). LCMS: RT=1.886 min, MS (ES) 309.9 (M+H).
To a solution of the ethyl 7-bromo-5-formyl-1-methyl-1H-indole-2-carboxylate (356 mg, 1.15 mmol) in THF (1 mL) and MeOH (10 mL) was added NaBH4 (65 mg, 1.72 mmol) and stirred at rt for 5 min. The reaction was quenched with aq. sat. NH4Cl and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The crude product was redissolved in DCM. MOMCl (262 μL, 278 mg, 3.45 mmol) followed by iPr2EtN (1 mL, 742 mg, 5.75 mmol) were added and stirred at RT for 16 h. The reaction was quenched with aq. sat. NH4Cl and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-50% gradient) to afford the title compound (336 mg, 82%, 2 steps). LCMS: RT=1.971 min, MS (ES) 355.9 (M+H).
Coupling reaction was carried out following general procedure A using ethyl 7-bromo-5-((methoxymethoxy)methyl)-1-methyl-1H-indole-2-carboxylate (336 mg, 0.94 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (509 mg, 0.94 mmol). To a solution of the resulting ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-((methoxymethoxy)methyl)-1-methyl-1H-indole-2-carboxylate in THF (10 mL) and MeOH (5 mL) was added Conc. HCl (2.4 mL), and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with aq. sat. NaHCO3 and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound compound (289 mg, 40%, 2 steps). LCMS: RT=2.274, 2.302, 2.324 min, MS (ES) 769.9 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (7.6 mg, 0.01 mmol) in acetone (0.12 mL) at 0° C. was added water (15 μL) and Conc. H2SO4 (5 μL). CrO3 (3 mg, 0.03 mmol) was added to the reaction, slowly warmed to rt and stirred for 90 min. The reaction was quenched with iPrOH (1 mL), filtered through Celite pad and washed with EtOAc. The filtrate was dried over MgSO4, filtered and concentrated. The title compound (1.6 mg, 20%, 3 steps) was prepared following General Procedure E using crude (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-2-(ethoxycarbonyl)-1-methyl-1H-indole-5-carboxylic acid and morpholine (50 μL, 50 mg, 0.58 mmol) followed by saponification using General procedure D. LCMS. RT=2.006, 2.035, 2.088 min, MS (ES) 824.8 (M+H).
The title compound (1.8 mg, 10%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-((6-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (15 mg, 0.019 mmol) and 2-bromo-N,N-dimethylethan-1-amine (15 mg, 0.064 mmol) followed by saponification using General Procedure D. LCMS: RT=1.685 min, MS (ES) 889.8 (M+H).
The title compound (13.3 mg, 51%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (23 mg, 0.031 mmol) and 2-(chloromethyl)-6-methylpyridine (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=1.985, 1.953 min, MS (ES) 832.8 (M+H).
The title compound (13.2 mg, 47%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (25 mg, 0.034 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.072 mmol) followed by saponification using General Procedure D. LCMS: RT=2.288, 2.302 min, MS (ES) 767.8 (M+H). 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.10 (s, 1H), 7.92 (d, J=8.6 Hz, 0.34H), 7.91 (d, J=8.6 Hz, 0.66H), 7.43 (d, J=8.6 Hz, 0.34H), 7.41 (d, J=8.6 Hz, 0.66H), 7.23-7.19 (m, 1H), 7.16-6.98 (m, 2H), 6.73 (s, 1.34H), 6.69 (s, 0.66H), 4.71-4.64 (m, 0.34H), 4.35 (dd, J=13.4, 3.4 Hz, 0.66H), 4.13-4.07 (m, 2H), 4.03 (s, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.92 (s, 2H), 3.75-3.59 (m, 4H), 3.39-3.17 (m, 5H), 2.32 (s, 1H), 2.27 (s, 2H), 2.25 (s, 4H), 2.24 (s, 2H), 2.20 (s, 2H), 2.18 (s, 1H), 2.07 (quint, J=6.7 Hz, 2H), 1.19 (d, J=6.4 Hz, 2H), 1.10 (d, =6.6 Hz, 1H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (11 mg, 0.014 mmol) in DMF (0.1 mL) at 0° C. was added NaH (0.8 mg, 0.021 mmol) and stirring 10 min. I-Bromo-2-methoxyethane (2 μL, 2.9 mg, 0.021 mmol) was added, warmed to rt and stirred for 4 h. The reaction was quenched with aq. sat. NH4Cl and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. Subsequent saponification was followed using General procedure D. The title compound (8.0 mg, 71%, 2 steps) was obtained by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA). LCMS: RT=2.147, 2.180, 2.234 min, MS (ES) 799.9 (M+H).
The title compound (29 mg, 55%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.07 mmol), and 2-chloro-N,N-dimethylacetamide (10 mg, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.21 min, MS (ES) 797 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 7.75 (m, 11H), 7.50 (s, 0.5H), 7.45 (s, 0.5H), 7.32 (m, 0.5H), 7.30 (m, 10.5H), 7.26 (s, 0.5H), 7.23 (s, 0.5H), 6.86 (m, 1H), 6.70 (s, 1H), 6.69 (s, 1H), 5.84 (m, 1H), 4.92 (m, 1H), 4.55 (m, 1H), 4.10 (m, 1H), 3.97 (m, 2H), 3.75 (m, 3H), 3.58 (m, 1H), 3.22 (m, 2H), 2.60 (m, 3H), 3.51 (m, 3H), 2.37 (s, 1.5H), 2.35 (s, 1.5H), 2.22 (s, 6H), 2.11 (m, 2H), 1.97 (m, 3H), 1.89 (m, 1.5H), 1.84 (s, 1.5H), 1.11 (d, J=6.4 Hz, 3H).
The title compound (40 mg, 70%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.07 mmol) and 4-(2-chloroethyl)-morpholine HCl (25 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.03 min, MS (ES) 825 (M+H).
The title compound (20 mg, 36%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.07 mmol) and 4-(chloroacetyl)morpholine (13 mg, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.17 min, MS (ES) 839 (M+H).
The title compound (30 mg, 47%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.07 mmol) and 2-(chloromethyl)-4,6-dimethylpyridine (26 mg, 0.17 mmol) followed by saponification using General Procedure D. LCMS: RT=2.05 min, MS (ES) 831 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 7.73 (m, 1H), 7.57 (bs, JH), 7.41 (m, 1H), 7.27 (m, 2H), 6.96 (m, 1H), 6.87 (m, 1H), 6.69 (m, 2H), 6.09 (m, 2H), 4.61 (m, 1H), 3.96 (m, 2H) 3.87 (m, 1H), 3.72 (m, 3H), 3.50 (m, 1H), 3.24-3.33 (bm, 2H), 3.02-3.10 (bm, 2H), 2.39 (s, 1.5H), 2.37 (s, 1.5H), 2.23 (s, 3H), 2.21 (s, 3H), 2.04-2.10 (bm, 5H), 1.94-2.00 (bm, 3H), 1.87 (m, 1H), 1.78 (s, 2H), 1.03 (m, 3H).
The title compound (25 mg, 42%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (40 mg, 0.05 mmol) and 2-(2-(chloromethyl)pyridin-4-yl)-4,5-dihydrooxazole (27 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.14 min, MS (ES) 872 (M+H).
To a solution of 4,6-Dimethylpyrimidine (7.17 g, 66.3 mmol) in MeOH (18 mL), H2O (66 mL) and H2SO4 (5.0 mL, conc.) was added ammonium persulfate (32.2 g, 141.2 mmol) at RT, and the reaction was heated to 60° C. and stirred overnight. The reaction mixture was concentrated to remove MeOH basified with aq. K2CO3, extracted with DCM followed by 10% i-PrOH in CHCl3. Combined organic fractions were dried over MgSO4, filtered, and concentrated. The crude title compound (8.69 g, 95%) was obtained as a yellow solid and carried forward without further purification. 1H NMR: (400 MHz in CDCl3) δ 6.96 (s, 1H), 4.77 (s, 2H), 2.51 (s, 6H); LCMS: RT=0.096 min, MS (ES) 139.17 (M+H).
To a solution of (4,6-dimethyl pyrimidin-2-yl)methanol (3.0 g, 21.7 mmol) in DCM (72 mL) was added Et3N (6.06 mL, 43.4 mmol), followed by MsCl (2.86 mL, 36.9 mL) at 0° C. The reaction mixture was stirred for 3 h at RT, quenched with sat. NH4Cl (50 mL), and extracted with DCM. The combined organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-90% gradient) to afford the title compound (4.32 g, 92%). 13C NMR (CDCl3, 100 MHz) δ 167.3, 162.4, 119.4, 71.2, 38.8, 23.8; LCMS: RT=0.344 min, MS (ES) 217.3 (M+H).
To a solution of (4,6-dimethylpyrimidin-2-yl)methyl methanesulfonate (4.68 g, 21.7 mmol) in EtOH (108 mL) was added bromine (3.34 mL, 65.13 mmol) at 0° C. The reaction was warmed to RT and stirred overnight. Solvent was removed in vacuo. The reaction mixture was diluted with DCM, washed with aqueous Na2S2O3, and the combined organic layer was concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-50% gradient) to afford the title compound (4.5 g, 70%). 1H NMR: (400 MHz in CDCl3) δ 4.47 (s, 2H), 2.63 (6H); LCMS: RT=0.754 min, MS (ES) 278.9 (M+H).
To a solution of 5-bromo-2-(bromomethyl)-4,6-dimethyl pyrimidine (4.5 g, 16.4 mmol) in THF (160 mL) was added Raney-Nickel (30 g). The reaction mixture was vigorously stirred at RT overnight, diluted with DCM then filtered through Celite pad. The filtrate was dried over MgSO4, filtered, concentrated to afford the crude title compound as a green solid obtained and carried forward without further purification. 1H NMR: (400 MHz in MeOD) δ 2.55 (s, 6H), 2.51 (s, 3H); LCMS: RT=0.746 min, MS (ES) 201.07 (M+H).
A mixture of 5-bromo-2,4,6-trimethylpyrimidine (1.0 g, 4.97 mmol) and triisopropoxy borate (2.52 mL, 10.94 mmol) in THF (4.97 mL)/toluene (15.0 mL) was added n-BuLi (6.83 mL, 10.94 mmol) at −40° C. The reaction mixture was warmed to −20° C., quenched with HCl solution (1N, 10 mL), diluted with water and extracted with DCM. The combined organic layer was dried over MgSO4 and concentrated to afford the crude title compound that was carried forward without further purification. 1H NMR: (400 MHz in MeOD) δ 3.58 (s, OH), 2.46 (s, 6H), 2.42 (s, 3H); LCMS: RT=0.085 min, MS (ES) 166.09 (M+H).
A solution of ethyl 3-(3-(11-oxidanyl)propyl)-7-bromo-6-chloro-1H-indole-2-carboxylate (124 mg, 0.25 mmol), (2,4,6-trimethylpyrimidin-5-yl)boronic acid (83 mg, 0.5 mmol). Sphos (51 mg, 0.125 mmol), Pd2(dba)3 (37 mg, 0.04 mmol) and K3PO4 (186 mg, 0.875 mmol) in THF (1.5 ml)/toluene (1.5 mL) was heated at 110° C. overnight. The Reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-80% gradient) to afford the title compound (40 mg, 30%). LCMS: RT=1.004 min, MS (ES) 540.21 (M+H).
A solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2,4,6-trimethylpyrimidin-5-yl)-1H-indole-2-carboxylate (156 g, 0.29 mmol), tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (96 mg, 0.41 mmol), and Cs2CO3 (151 mg, 0.46 mmol) in MeCN (3 ml) was stirred at 60° C. for 12 h. The reaction mixture was concentrated and the residue was diluted with EtOAc (10 mL)/water (10 mL), extracted with EtOAc, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-30% gradient) to afford the title compound (192 mg, 95%). LCMS: RT=1.231 min, MS (ES) 697.31 (M+H).
The title compound (81 mg, 50%) was prepared following the procedure described Example 1 Step G using (R)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2,4,6-trimethylpyrimidin-5-yl)-1H-indole-2-carboxylate (192 mg, 0.27 mmol), 1H NMR: (400 MHz in MeOD) δ 7.76 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.63 (s, 2H), 4.48-4.69 (m, 1H), 3.97 (dt, J=6.0, 1.6 Hz, 2H), 3.71-3.65 (m, 2H), 3.42-3.35 (m, 2H), 2.76 (s, 3H), 2.32 (s, 3H), 2.31 (s, 6H), 2.21-2.16 (m, 2H), 2.15 (s, 3H), 1.01 (d, J=6.0 Hz, 3H); LCMS: RT=0.857 min, >98% purity at 215 nm and 254 nm MS (ES) 551.20 (M+H).
The title compound was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(2,4,6-trimethyl pyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromo-1-methyl-1H-indole-5-carboxylate followed by saponification (29 mg, 0.07 mmol) using General Procedure D. 1H NMR: (400 MHz in MeOD) δ 8.25 (d, J=1.2 Hz, 1H), 7.94 (dd, J=8.8, 1.6 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.65 (s, 2H), 4.43 (dd, J=12.8, 3.6 Hz, 1H), 3.99 (dt, J=6.0, 2.4 Hz, 2H), 3.88 (s, 3H), 3.90-3.75 (m, 1H), 3.67 (dd, J=12.8, 1.2 Hz, 1H), 3.55-3.46 (m, 1H), 3.41-3.34 (m, 1H), 2.77 (s, 3H), 2.39 (s, 3H), 2.29 (s, 6H), 2.24 (s, 3H), 2.28-2.15 (m, 2H), 1.26 (d, J=6.4 Hz, 3H); LCMS: RT=0.766 min, >98% purity at 215 nm and 254 nm; MS (ES) 724.24 (M+H).
The crude title compound (200 mg) was prepared following General Procedure G using 3-iodo-1-(2-methoxyethyl)-5-(1H-1,2,4-triazol-3-yl)-1H-indole (150 mg, 0.41 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (105 μL, 0.49 mmol). LCMS: RT=0.196 min, MS (ES) 412.9 (M+H).
The title compound (110 mg, 70%) was prepared following the procedure described Example 420 Step C using 5-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-1,2,4-triazol-3-yl)-3-iodo-1-(2-methoxyethyl)-1H-indol (200 mg, 0.38 mmol). LCMS: RT=1.317 min, MS (ES) 412.9 (M+H).
The crude title compound (46 mg) was prepared following General Procedure J using 2-(3-(3-iodo-1-(2-methoxyethyl)-1H-indol-5-yl)-1H-1,2,4-triazol-1-yl)ethan-1-ol (110 mg, 0.27 mmol) and 1-methylpiperazine (82 μL, 0.73 mmol). LCMS: RT=0.166 min, MS (ES) 494.8 (M+H).
The title compound (27 mg, 54%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-(2-methoxyethyl)-5-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-1,2,4-triazol-3-yl)-1H-indole (45 mg, 0.09 mmol). LCMS: RT=1.879 min, MS (ES) 904.9 (M+H).
The crude title compound (210 mg) was prepared following the procedure described Example 388 Step B using 2-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethan-1-ol (160 mg, 0.66 mmol). LCMS: RT=1.217 min, MS (ES) 368.8 (M+H).
The title compound (23 mg, 29%) was prepared following General Procedure J using 2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethan-1-ol (210 mg, 0.57 mmol) and piperazin-2-one (54 mg, 0.54 mmol). LCMS: RT=1.099 min, MS (ES) 450.9 (M+H).
The crude title compound (200 mg) was prepared following General Procedure G using 4-(2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)piperazin-2-one (23 mg, 0.05 mmol) and MeI (4 μL, 0.06 mmol). LCMS: RT=1.123 min, MS (ES) 464.8 (M+H).
The title compound (2.1 mg, 5%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.05 mmol) and 4-(2-(3-iodo-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)-1-methylpiperazin-2-one (24 mg, 0.05 mmol). LCMS: RT=1.855 min, MS (ES) 874.9 (M+H).
The title compound (68%) was prepared following General procedure E using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(methylamino)-1H-indole-3-carboxylate and 2-(4-methylpiperazin-1-yl)acetic acid followed by saponification using General Procedure D. 1H-NMR (MeOH-d4), δ 8.16 and 8.12 (s, total 1H), 8.00 (s, 1H), 7.79 (d, 1H, J=12 Hz), 7.34 (d, 1H, J=12 Hz), 7.25 and 7.09 (two s, total 1H), 6.64 and 6.63 (two s, total 2H), 4.46-4.37 (m, 1H), 4.00-3.96 (m, 2H), 3.87-3.76 (multiples s, total 5H), 3.79-3.76 (m, 2H), 3.51-3.48 (m, 2H), 3.24-3.22 (m, 4H), 3.34 (s, 2H), 2.85 (s, 6H), 2.29 (s, 6H), 2.24-2.23 (multiple s, total 3H), 2.18 and 2.15 (multiple d, total 4H, J=4 Hz), 2.02 (m, 2H), 2.01 and 2.99 (multiple d, total 4H. J=4 Hz), 1.29-1.21 (multiple d, total 3H, J=8 Hz); MS (ES) 881.2 (M+H).
The title compound (37 mg, 99%) was prepared according to General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-(I H)-yl)-1H-indole-3-carboxylate (39 mg, 0.02 mmol) and 2-(bromomethyl)pyridine HBr (19 mg, 0.074 mmol). LCMS: RT=2.443 MS (ES) 922.90 (M+H).
To a solution of ethyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylate (37 mg, 0.04 mmol) in ethanol (2 mL) was added Pd/C (18.5 mg, 10%) and the mixture was stirred under H2 for 10 h. The reaction mixture was filtered through a pad of silica gel and eluted with DCM. The filtrate was concentrated and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-20% gradient) to afford the title compound (28 mg, 90%). LCMS RT=1.988 min, MS (ES) 833.8 (M+H).
The title compound (11 mg, 67%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol) and MeI (5 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.122 min (Method B), MS (ES) 818.0 (M+H).
The title compound (13 mg, 73%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol) and 1-bromo-4-methylpentane (12 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.153 min, MS (ES) 890.80 (M+H).
The title compound was prepared (140 mg, 77%, 2 steps) following the procedure described Example 595 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (185 mg, 0.24 mmol) and MeI (22 μL, 51 mg, 0.36 mmol). LCMS: RT=2.159, 2.193, 2.245 min, MS (ES) 755.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J=8.6 Hz, 1H), 7.66 (s, 0.6H), 7.61 (s, 0.3H), 7.35-7.27 (m, 2.4H), 7.08-7.05 (m, 0.6H), 6.74-6.67 (m, 2H), 4.73-4.65 (m, 0.4H), 4.49-4.44 (m, 2H), 4.37 (dd, J=13.2, 3.6 Hz, 0.6H), 4.29-4.14 (m, 1H), 4.06 (s, 1H), 4.02-3.92 (m, 4H), 3.82-3.75 (m, 3.2H), 3.74-3.63 (m, 1H), 3.29 (s, 3H), 3.27-3.14 (m, 1.4H), 2.23 (br s, 6H), 2.15-2.10 (m, 2H), 2.10-1.96 (m, 4.6H), 1.94-1.87 (m, 2H), 1.18 (d, J=6.4 Hz, 2H), 1.07 (d, J=6.1 Hz, 1.2H).
The title compound (70%) was prepared following General procedure E using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(methylamino)-1H-indole-3-carboxylate and dimethyl-L-alanine followed by saponification using General Procedure D. MS (ES) 840.3 (M+H).
The title compound (16 mg, 93%) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol) and 1-bromo-2-methoxyethane (8 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.052 min, MS (ES) 862.8 (M+H).
The title compound (11 mg, 63% yield) was prepared according to General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol) and 1-bromo-2-ethoxyethane (9 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.126 min, MS (ES) 876.9 (M+H).
The title compound (47%) was prepared following General procedure E using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(methylamino)-1H-indole-3-carboxylate and dimethylglycine followed by saponification using General Procedure D. MS (ES) 826.2 (M+H).
The title compound (75%) was prepared following General procedure E using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(methylamino)-1H-indole-3-carboxylate and 2-(piperidin-1-yl)acetic acid followed by saponification using General Procedure D. 1H-NMR (MeOH-d4), δ 8.18 and 8.13 (s, total 1H), 8.03 (s, 1H), 7.80 (d, 1H, J=12 Hz), 7.32 (d, 1H, J=12 Hz), 7.14 and 7.13 (two s, total 1H), 6.64 and 6.63 (two s, total 2H), 4.46-4.42 (m, 1H), 4.04-4.02 (m, 2H), 3.99-3.82 (multiples s, total 6H), 3.50-3.39 (m, 4H), 3.39 (multiples s, total 3H), 3.35-3.30 (m, 4H), 2.89-2.86 (m, 2H), 2.29 (s, 6H), 2.24-2.08 (multiple s, total 3H), 2.02 (m, 2H), 2.08 and 2.00 (two s, total 3H), 1.84-1.78 (m, 6H), 1.29-1.21 (multiple d, total 3H, J=8 Hz); MS (ES) 865.3 (M+H).
The title compound (82%) was prepared following General procedure E using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(methylamino)-1H-indole-3-carboxylate and 2-(pyrrolidin-1-yl)acetic acid followed by saponification using General Procedure D. MS (ES) 852.3 (M+H).
The title compound was prepared (1.2 mg, 11%, 2 steps) following the procedure described Example 595 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (11 mg, 0.014 mmol) and 2-bromo-N,N-dimethylethan-1-amine HCl (4.9 mg, 0.021 mmol). LCMS: RT=1.900, 1.931 min. MS (ES) 812.8 (M+H).
The crude title compound (50 mg) was prepared following General Procedure J using 2-(3-(1-(2-methoxyethyl)-1H-indol-5-yl)-1H-1,2,4-triazol-1-yl)ethan-1-ol (110 mg, 0.27 mmol) and morpholine (35 μL, 0.41 mmol). LCMS: RT=0.184 min, MS (ES) 481.9 (M+H).
The title compound (II mg, 22%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 4-(2-(3-(3-iodo-1-(2-methoxyethyl)-1H-indol-5-yl)-1H-1,2,4-triazol-1-yl)ethyl)morpholine (50 mg, 0.10 mmol). LCMS: RT=1.920 min, MS (ES) 891.9 (M+H).
The title compound (4.6 mg, 42%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and 3-(bromomethyl)-3-methyloxetane (5 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=2.111 min, MS (ES) 781.80 (M+H).
The title compound (15 mg, 91%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 2-(bromomethyl)pyridine HBr (10 mg, 0.04 mmol). LCMS: RT=2.132 min, MS (ES) 818.8 (M+H).
The title compound (100 mg, 69%) was prepared following General Procedure G using 3-iodo-1-(2-methoxyethyl)-5-(1H-1,2,4-triazol-3-yl)-1H-indole (100 mg, 0.27 mmol) and 1-Boc-3-(bromomethyl)azetidine (136 mg, 0.54 mmol). LCMS: RT=1.772 min, MS (ES) 481.8 (M+H).
TFA (0.3 mL) was added to a solution of tert-butyl 3-((3-(3-iodo-1-(2-methoxyethyl)-1H-indol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)azetidine-1-carboxylate (100 mg, 0.19 mmol) in DCM (0.5 mL) at 0° C. The reaction was stirred at RT for 1 h, concentrated and diluted with DCM. The solution was washed with sat. aq. NaHCO3, dried and concentrated to afford the crude title compound (75 mg) that was used for the next step without further purification. LCMS: RT=1.258 min, MS (ES) 437.8 (M+H).
Acetyl chloride (19 μL, 0.26 mmol) and DIPEA (48 μL, 0.27 mmol) was added to a solution of 5-(1-(azetidin-3-ylmethyl)-1H-1,2,4-triazol-3-yl)-3-iodo-1-(2-methoxyethyl)-1H-indole (75 mg, 0.17 mmol) in DCM (1 mL) at 0° C. The reaction was warm to RT and stirred for 3 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-3% gradient) to afford the title compound (50 mg, 60%). LCMS: RT=1.407 min, MS (ES) 479.8 (M+H).
The title compound (22 mg, 44%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 1-(3-((3-(3-iodo-1-(2-methoxyethyl)-1H-indol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)azetidin-1-yl)ethan-1-one (49 mg, 0.10 mmol). LCMS: RT=2.033 min, MS (ES) 889.9 (M+H).
The title compound (8.8 mg, 53%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 2-(chloromethyl)-4-methylpyridine (10 mg, 0.04 mmol). LCMS: RT=2.036 min, MS (ES) 832.8 (M+H).
The title compound (8.2 mg, 54%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and 2-bromoacetonitrile (5 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.951 min, MS (ES) 755.80 (M+H).
The title compound (6.7 mg, 40%) was prepared according to General Procedure I using methyl (R)-747-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 2-(chloromethyl)-6-methylpyridine (10 mg, 0.04 mmol) as the 2nd eluted isomer from reverse phase HPLC. LCMS: RT=2.034 min, MS (ES) 832.8 (M+H).
The title compound (5.2 mg, 11%) was isolated along with Example 621 as the 1st eluted isomer from reverse phase HPLC. LCMS: RT=1.998 min, MS (ES) 832.8 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-J H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (135 mg, 0.175 mmol) in DCM (2 mL) was added iPr2EtN (47 μL, 34 mg, 0.263 mmol) followed by MsCl (13.3 μL, 20 mg, 0.175 mmol). After stirring for 10 min, morpholine (46 μL, 46 mg, 0.53 mmol) was added and stirred for additional 30 min. The reaction was quenched with aq. sat. NH4Cl and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. Subsequent saponification following General procedure D to afford the title compound (100 mg, 70%, 2 steps). LCMS. RT=1.913, 1.963 min, MS (ES) 810.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 7.79-7.73 (m, 1H), 7.51-7.46 (m, 0.9H), 7.34-7.28 (m, 1.1H), 7.16-7.12 (m, 0.3H), 7.02 (br s, 0.7H), 6.97-6.90 (m, 0.7H), 6.74-6.67 (m, 2H), 4.71-4.64 (m, 0.3H), 4.36-4.29 (m, 0.7H), 4.26-4.14 (m, 1.1H), 4.11 (s, 0.9H), 4.01 (s, 1.7H), 4.00-3.94 (m, 2.2H), 3.81-3.77 (m, 2.4H), 3.76 (br s, 0.9H), 3.73-3.60 (m, 1.2H), 3.59-3.54 (m, 4H), 3.53-3.45 (m, 2.2H), 3.39-3.26 (m, 2H), 3.25-3.15 (m, 1.2H), 2.27-2.19 (m, 6H), 2.15-2.10 (m, 2H), 2.08-2.02 (m, 2.8H), 2.01 (s, 0.8H), 1.97 (s, 0.8H), 1.92 (s, 0.7H), 1.89 (s, 1.3H), 1.75-1.66 (m, 0.3H), 1.63-1.44 (m, 0.7H), 1.20-1.15 (m, 2.1H), 1.09-1.03 (m, 1.3H).
The crude title compound (150 mg) was prepared following General Procedure G using 3-iodo-1-(2-methoxyethyl)-5-(1H-1,2,4-triazol-3-yl)-1H-indole (120 mg, 0.33 mmol) and 4-bromomethyltetrahydropyran (117 μL, 0.65 mmol). LCMS: RT=1.517 min. MS (ES) 466.9 (M+H).
The title compound (26 mg, 53%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-(2-methoxyethyl)-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-1H-indole (52 mg, 0.11 mmol). LCMS: RT=2.167 min, MS (ES) 876.9 (M+H).
The title compound (14 mg, 89%) was prepared according to General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-3-carboxylate (15 mg, 0.02 mmol) and 1-bromo-2-methoxyethane (10 mg, 0.04 mmol). LCMS: RT=2.029 min, MS (ES) 785.8 (M+H).
The title compound has was (6.0 mg, 40%, 3 steps) following the procedure described Example 591 step D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (13 mg, 0.018 mmol) and N-methyl piperazine (50 μL, 45 mg, 0.45 mmol). LCMS: RT=1.852, 1.879 min, MS (ES) 837.9 (M+H).
The title compound (39 mg, 61%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (50 mg, 0.07 mmol) and 2-(chloromethyl)-4-ethylpyridine (21 mg, 0.14 mmol) followed by saponification using General Procedure D. LCMS: RT=2.07 min, MS (ES) 831 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (8 mg, 0.011 mmol) in DCM (0.1 mL) was added Dess-Martin periodinane reagent (5 mg, 0.011 mmol) and stirred at RT for 30 min. The reaction was quenched with aq. sat. Na2S2O3 solution and extracted with DCM. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The resulting crude product was redissolved in DCM (0.2 mL) and Et3N (0.04 mL), 1-methylpiperazin-2-one (2.6 μL, 2.6 mg, 0.026 mmol) and Na(OAc)3BH (4.7 mg, 0.022 mmol) were added to the reaction mixture and stirred at RT for 4 h. The reaction was quenched with aq. sat. NH4Cl and extracted with DCM. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Subsequent saponification was followed using General procedure D to afford the title compound (1.5 mg, 17%, 3 steps). LCMS: RT=1.856, 1.895 min, MS (ES) 837.9 (M+H).
The title compound was prepared (1.8 mg, 12%, 3 steps) following the procedures described Example 591 in step D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (13 mg, 0.018 mmol) and 1-(piperazin-1-yl)ethan-1-one (50 μL, 0.39 mmol). LCMS: RT=1.941, 1.966 min, MS (ES) 865.8 (M+H).
The title compound was prepared (2.1 mg, 14%, 3 steps) following the procedures described in Example 591 step D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (13 mg, 0.018 mmol) and 1-methylpiperazin-2-one (50 μL, 0.44 mmol). LCMS: RT=1.966 min, MS (ES) 851.8 (M+H).
The title compound (2.2 mg, 13%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (15 mg, 0.020 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (10 mg, 0.054 mmol) followed by saponification using General Procedure D. LCMS: RT=2.181 min, MS (ES) 827.8 (M+H).
The title compound (105 mg, 35%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (200 mg, 0.37 mmol) and methyl 4-(benzyloxy)-7-iodo-1H-indole-2-carboxylate (300 mg, 0.74 mmol). LCMS: RT=1.596, 1.627 min, MS (ES) 817.8 (M+H).
The title compound (31 mg, 78%) was prepared following General Procedure I using methyl (R)-4-(benzyloxy)-7-(7-chloro-1043-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (35 mg, 0.043 mmol) and 2-(chloromethyl)-4-methylpyridine HBr (15 mg, 0.085 mmol). LCMS: RT=1.314, 1.343, 1.403 min, MS (ES) 922.8 (M+H).
The title compound (16.2 mg, 58%) was prepared following the procedure described Example 390 Step D using methyl (R)-4-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-((4-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (31 mg, 0.034 mmol) and Pd/C (10 wt. %, 10 mg, 0.0093 mmol) by hydrogenating in MeOH (5 mL) for 16 h at RT. LCMS: RT=0.902, 0.860 min (Method B), MS (ES) 832.9 (M+H).
The title compound (10.8 mg, 63%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihy dipropylamino[1,2-a]indol-2(1H)-yl)-4-hydroxy-1-((4-methylpyridin-2-yl)methyl)-1H-indole-2-carboxylate (11 mg, 0.013 mmol) and 1-bromo-2-methoxyethane (5 mg, 0.036 mmol) followed by saponification using General Procedure D. LCMS: RT=1.977, 2.005 min, MS (ES) 876.9 (M+H).
The title compound (9.6 mg, 58%) was prepared following General Procedure H using methyl (R)-747-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (15 mg, 0.020 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (10 mg, 0.054 mmol) followed by saponification using General Procedure D. LCMS: RT=2.132, 2.161 min, MS (ES) 876.9 (M+H). 1H NMR (CDCl3, 400 MHz) δ (ppm) (7.77 (d, J=8.6 Hz, 1H), 7.34-7.31 (m, 1H), 7.28-7.21 (m, 1H), 7.08-6.96 (m, 11H), 6.88-6.83 (m, 0.66H), 6.74-6.70 (m, 0.34H), 6.60 (s, 1.34H), 6.58 (s, 0.66H), 4.45-4.07 (m, 8H), 4.01-3.92 (m, 4H), 3.91-3.81 (m, 3H), 3.77-3.71 (m, 2H), 3.63-3.56 (m, 2H), 3.40 (s, 2H), 3.39 (s, 1H), 3.37-3.30 (m, 2H), 2.45 (s, 1H), 2.35-2.31 (m, 2H), 2.30 (s, 6H), 2.29-2.25 (m, 2H), 2.20-2.09 (m, 3H), 1.31-1.22 (m, 2H), 1.21-1.11 (m, 1H).
The title compound (10.2 mg, 46%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (20 mg, 0.028 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (10 mg, 0.054 mmol) followed by saponification using General Procedure D. LCMS: RT=2.182, 2.210 min, MS (ES) 799.9 (M+H).
The title compound (6.4 mg, 38%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (15 mg, 0.021 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (10 mg, 0.054 mmol) followed by saponification using General Procedure D. LCMS: RT=2.292, 2.316 min, MS (ES) 811.8 (M+H).
The title compound (6.4 mg, 18%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 3-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (16 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=1.267 min, MS (ES) 710.8 (M+H).
The title compound (135 mg, 96%) was prepared following the procedure described Example 388 Step A using N,N-dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)acetamide (248 mg, 0.75 mmol) and 2-bromopyrimidine (80 mg, 0.50 mmol). LCMS: RT=1.181 min. MS (ES) 281.1 (M+H).
The crude title compound (150 mg) was prepared following the procedure described Example 388 Step B using N,N-dimethyl-2-(5-(pyrimidin-2-yl)-1H-indol-1-yl)acetamide (135 mg, 0.48 mmol). LCMS: RT=1.384 min, MS (ES) 406.8 (M+H).
The title compound (16 mg, 36%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-5-(pyrimidin-2-yl)-1H-indol-1-yl)-N,N-dimethylacetamide (45 mg, 0.11 mmol). LCMS: RT=2.123 min, MS (ES) 816.9 (M+H).
The title compound (66 mg, 49%) was prepared following the procedure described Example 388 Step A using N,N-dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)acetamide (185 mg, 0.56 mmol) and 2-((3-bromo-1H-1,2,4-triazol-1-yl)methyl)pyridine (90 mg, 0.38 mmol). LCMS: RT=0.167 min, MS (ES) 361.0 (M+H).
The crude title compound (100 mg) was prepared following the procedure described Example 388 Step B using N,N-dimethyl-2-(5-(1-(pyridin-2-ylmethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)acetamide (66 mg, 0.18 mmol). LCMS: RT=0.199 min, MS (ES) 486.9 (M+H).
The title compound (14 mg, 27%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-5-(1-(pyridin-2-ylmethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-N,N-dimethylacetamide (54 mg, 0.11 mmol). LCMS: RT=1.943 min, MS (ES) 896.8 (M+H).
The title compound (130 mg, 98%) was prepared following the procedure described Example 388 Step A using N,N-dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)acetamide (175 mg, 0.53 mmol) and 2-((3-bromo-1H-1,2,4-triazol-1-yl)methyl)-6-methylpyridine (90 mg, 0.36 mmol). LCMS: RT=1.069 min, MS (ES) 375.0 (M+H).
The title compound (100 mg, 58%) was prepared following the procedure described Example 388 Step B using N,N-dimethyl-2-(5-(1-((6-methylpyridin-2-yl)methyl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)acetamide (130 mg, 0.35 mmol). LCMS: RT=1.231 min, MS (ES) 500.8 (M+H).
The title compound (35 mg, 69%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-5-(1-((6-methylpyridin-2-yl)methyl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)-N,N-dimethylacetamide (56 mg, 0.11 mmol). LCMS: RT=1.895 min, MS (ES) 910.9 (M+H).
The title compound (26 mg, 34%) was prepared following General Procedure F using methyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate (49 mg, 0.28 mmol), NBS (51 mg, 0.28 mmol), and MeI (21 μL, 0.34 mmol). LCMS: RT=1.083 min, MS (ES) 268.9 (M+H).
The title compound (12 mg, 34%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (16 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.131 MS (ES) 710.8 (M+H).
To a solution of methyl (R)-1-((4-bromopyridin-2-yl)methyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (110 mg, 0.12 mol) in (4:1) dioxane/water (1.5 mL) was added 2-isopropenyl boronic acid pinacol ester (41 mg, 0.25 mmol) and Pd(PPh3)4 (14 mg, 0.01 mmol) and K2CO3 (34 mg, 0.25 mmol). The reaction was stirred under Ar at 90° C. for 5 h then cooled to RT. The reaction mixture was diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, CH2Cl2/methanol=0-3% gradient) to give the title compound (75 mg, 71%). LCMS: RT=1.41 min., MS (ES) 857 (M+H).
The title compound (63 mg, 75%) was prepared following General Procedure D using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1-((4-(prop-1-en-2-yl)pyridin-2-yl)methyl)-1H-indole-2-carboxylate (75 mg, 0.09 mmol). LCMS: RT=2.11 min., MS (ES) 843 (M+H).
The title compound (40 mg, 96%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(pyrimidin-2-yl)-1H-indole (37 mg, 0.11 mmol). LCMS: RT=2.301 min, MS (ES) 743.8 (M+H).
The crude title compound (150 mg) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (176 mg, 0.68 mmol) and 3-bromo-1,5-dimethyl-1H-1,2,4-triazole (100 mg, 0.57 mmol) LCMS: RT=1.153 min, MS (ES) 227.1 (M+H).
The crude title compound (190 mg) was prepared following the procedure described Example 388 Step B using 5-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-1-methyl-1H-indole (150 mg, 0.66 mmol). LCMS: RT=1.189 min, MS (ES) 352.9 (M+H).
The title compound (28 mg, 66%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 5-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-3-iodo-1-methyl-1H-indole (39 mg, 0.11 mmol). LCMS: RT=2.016 min, MS (ES) 762.9 (M+H).
The title compound (22 mg, 62%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (16 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.200 MS (ES) 711.9 (M+H).
The title compound (7 mg, 51%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and 4-(bromomethyl)-1,2-difluorobenzene (5 mg, 0.03 mmol) followed by saponification using General Procedure D. LCMS: RT=2.109 min (Method B), MS (ES) 823.8 (M+H).
Cs2CO3 (4.40 g, 13.5 mmol), CuI (257 mg, 1.35 mmol) and 2-bromopyrimidine (1.40 g, 8.79 mmol) were added to a solution of 5-bromo-1H-1,2,4-triazole (1.00 g, 6.76 mmol) in DMF (13.5 mL). The reaction mixture was stirred at 120° C. for 18 h under Ar. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with water, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf. Hex/EtOAc=0-70% gradient) to afford the title compound (340 mg, 22%). LCMS: RT=0.194 min, MS (ES) 226.0 (M+H).
The title compound (53 mg, 43%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (137 mg, 0.53 mmol) and 2-(3-bromo-1H-1,2,4-triazol-1-yl)pyrimidine (100 mg, 0.44 mmol). LCMS: RT=1.373 min, MS (ES) 227.0 (M+H).
The crude title compound (35 mg) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1-(pyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (53 mg, 0.19 mmol). LCMS: RT=1.614 min, MS (ES) 402.9 (M+H).
The title compound (20 mg, 43%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1-(pyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (34 mg, 0.08 mmol). LCMS: RT=2.205 min, MS (ES) 812.8 (M+H). 1H NMR (400 MHz, CDCl3) δ 9.25 (d, J=5.0 Hz, 1H), 8.82 (dd. J=4.8, 2.5 Hz, 2H), 8.43 (s, 1H), 8.28-8.24 (m, 1H), 7.67 (dd, J=8.6, 2.7 Hz 1H), 7.43 (dd. J=8.7, 1.6 Hz, 1H), 7.33-7.28 (m, 2H), 7.27-7.22 (m, 1H), 6.61 (s, 2H), 4.47-4.51 (m, 1H), 4.35-4.23 (m, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.66 (t, J=11.8 Hz, 1H), 3.47-3.30 (m, 2H), 2.29 (s, 6H), 2.24-2.17 (m, 5H), 2.00 (s, 3H), 1.26-1.20 (m, 3H).
The title compound (58 mg, 14%) was prepared following the procedure described Example 646 Step A using 1-methyl-5-(1H-1,2,4-triazol-3-yl)-1H-indole (300 mg, 1.51 mmol) and 2-bromopyridine (144 μL, 1.51 mmol). LCMS: RT=2.205 min, MS (ES) 812.8 (M+H).
The title compound (58 mg, 69%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (58 mg, 0.21 mmol). LCMS: RT=1.854 min, MS (ES) 401.8 (M+H).
The title compound (30 mg, 67% yield) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (67 mg, 0.17 mmol). LCMS: RT=2.357 min, MS (ES) 811.8 (M+H).
The title compound (60 mg, 96%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (78 mg, 0.30 mmol) and 2-Bromo-[1,2,4]triazolo[1,5-a]pyridine (50 mg, 0.25 mmol). LCMS: RT=1.262 min, MS (ES) 249.1 (M+H).
The crude title compound (56 mg) was prepared following the procedure described Example 388 Step B using 2-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (60 mg, 0.24 mmol). LCMS: RT=1.605 min, MS (ES) 374.8 (M+H).
The title compound (40 mg, 92%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (52 mg, 0.14 mmol). LCMS: RT=2.182 min, MS (ES) 784.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=7.0 Hz, 1H), 8.30 (s, 1H), 8.08 (d, J=9.6 Hz, 1H), 7.78-7.75 (m, 2H), 7.64-7.60 (m, 2H), 7.51 (s, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.14 (t, J=6.8 Hz, 1H), 6.70 (s, 2H), 4.53-4.48 (m, 1H), 4.21-4.18 (m, 1H), 4.05-3.98 (m, 2H), 3.85 (s, 3H), 3.77 (d, J=4.5 Hz, 3H), 3.72-3.67 (m, 1H), 3.83-3.22 (m, 2H), 2.19 (s, 6H), 2.13-2.04 (m, 5H), 1.99-1.90 (m, 3H), 1.13-1.11 (m, 3H).
The title compound (5.1 mg, 46%, 3 steps) was prepared following the procedures described Example 628 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 4-methoxypiperidine (20 μL, 18.6 mg, 0.16 mmol). LCMS: RT=1.961, 1.988 min MS (ES) 838.9 (M+H).
The title compound (6.5 mg, 57%, 3 steps) was prepared following the procedures described Example 628 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (10 mg, 0.013 mmol) and 4-(2-methoxyethoxy)piperidine (20 μL, −20 mg, 0.13). LCMS: RT=1.953, 2.012 min, MS (ES) 882.9 (M+H).
The title compound (61 mg, 80%) was prepared following General Procedure F using methyl 1H-pyrrolo[3,2-b]pyridine-5-carboxylate (49 mg, 0.28 mmol). NBS (51 mg, 0.28 mmol), and MeI (53 μL, 0.85 mmol). LCMS: RT=1.077 min, MS (ES) 268.9 (M+H).
The title compound (17 mg, 48%) was prepared according to General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and 3-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (16 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.051 MS (ES) 710.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.16 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.75 (s, 2H), 4.52-4.45 (m, 1H), 4.35-4.29 (m, 1H), 4.06-3.95 (m, 2H), 3.89 (s, 3H), 3.78-3.69 ((m, 1H), 3.44-3.33 (m, 1H), 3.32-3.22 (m, 1H), 2.27 (s, 3H), 2.24 (s, 6H), 2.18 (s, 3H), 2.15-2.03 (m, 2H), 1.17 (d, J=6.4 Hz, 3H).
The title compound (8.8 mg, 49%) was prepared following General Procedure I from ethyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol), 2-(chloromethyl)-4,6-dimethylpyridine hydrochloride (19 mg, 0.10 mmol) followed by hydrogenation procedure described in step B example 605. The crude material was subjected to General Procedure H using 1-bromo-2-methoxyethane (8 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=1.965 min, MS (ES) 890.8 (M+H).
The title compound (100 mg, 95%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (129 mg, 0.50 mmol) and 5-bromopyrimidine (80 mg, 0.50 mmol). LCMS: RT=1.391 min, MS (ES) 210.1 (M+H).
The title compound (140 mg, 88%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(pyrimidin-5-yl)-1H-indole (100 mg, 0.48 mmol). LCMS: RT=1.618 min, MS (ES) 335.8 (M+H).
The title compound (30 mg, 72%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(pyrimidin-5-yl)-1H-indole (22 mg, 0.07 mmol). LCMS: RT=2.231 min, MS (ES) 745.9 (M+H). 1H NMR (400 MHz, DMSO-d) S 9.13 (s, 2H), 9.11 (s, 1H), 7.88 (d, J=6.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.65 (s, 2H), 7.53 (s, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.71 (s, 2H), 4.57-4.52 (m, 11H), 4.21-4.12 (m, 11H), 4.00-3.96 (M, 2H), 3.85 (s, 3H), 3.77 (d, J=6.2 Hz, 4H), 3.37-3.18 (m, 2H), 2.21 (s, 6H), 2.11-2.03 (m, 5H), 1.98-1.89 (M, 3H), 1.12 (d, J=5.7 Hz, 3H).
The title compound (6.3 mg, 40%) was prepared following General Procedure I from ethyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol), MeI (6 μL, 0.10 mmol) followed by hydrogenation procedure described in step B example 605. The crude material was subjected to General Procedure H using 1-bromo-2-methoxyethane (8 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.172 min, MS (ES) 785.8 (M+H).
The crude title compound (70 mg) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (28 mg, 0.14 mmol). LCMS: RT=2.320 min, MS (ES) 816.8 (M+H).
The title compound (31 mg, 49%) was prepared following the procedure described Example 581 Step C using (4R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-2-(1-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (70 mg, 0.09 mmol). LCMS: RT=2.046 min, MS (ES) 732.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.31 (br s, 1H), 7.88 (t, J=8.5 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 6.73 (s, 2H), 4.46 (dd. J=13.1, 3.5 Hz, 1H), 3.99 (t, J=5.7 Hz, 5H), 3.83 (s, 6H), 3.71-3.60 (m, 2H), 3.39-3.22 (m, 2H), 2.28 (s, 3H), 2.23 (s, 6H), 2.18 (s, 3H), 2.12-2.05 (m, 2H), 1.13 (d, J=6.5 Hz, 3H).
The title compound (15 mg, 94%) was prepared following General Procedure I from ethyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol), 1-bromo-2-methoxyethane (8 μL, 0.08 mmol) followed by hydrogenation procedure described in step B example 605. LCMS: RT=2.131 min, MS (ES) 799.7 (M+H).
The title compound (12 mg, 72%) was prepared following General Procedure H from ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(2-methoxyethyl)-1H-indole-3-carboxylate (15 mg, 0.018 mmol), 1-bromo-2-methoxyethane (8 μL, 0.08 mmol) followed by saponification using General Procedure D. LCMS: RT=2.178 min, MS (ES) 829.8 (M+H).
The title compound (28 mg, 95%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (24 mg, 0.033 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (20 mg, 0.084 mmol). LCMS: RT=2.199, 2.232 min (Method B), MS (ES) 883.9 (M+H).
To a solution of methyl (R)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (28 mg, 0.032 mmol) in THF (3 mL) was added TBAF (1.0 M, 200 uL, 0.20 mmol) at RT, and the reaction mixture was stirred for 4 h. LiOH (10 mg, 0.42 mmol) was added to the reaction, followed by MeOH (1 mL) and H2O (1 mL). The reaction was heated to 35° C. and stirred for 18 h. The crude reaction was diluted with DCM/H2O (20 mL, 1:1). The layers were separated and extracted with DCM. The combined organic extract was dried and concentrated in vacuo. The crude reaction product was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-95% CH3CN, 0.1% TFA to yield the title compound (12.9 mg, 47%). LCMS: RT=2.196, 2.228 min, MS (ES) 755.8 (M+H).
The title compound (23 mg, 63%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 8-bromo-6-methylquinoline-3-carboxylate (16.8 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS. RT=2.232 MS (ES) 723.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.19 (dd, J=4.6 & 1.9 Hz, 1H), 8.98 (t, J=1.6 Hz, 1H), 7.99 (s, 1H), 7.80-7.71 (m, 2H), 7.31 (d, J=8.5 Hz, 1H), 6.70 (s, 2H), 4.69-4.49 (m, 1H), 4.28-4.12 (m, 1H), 3.96 (1 J=6.3 Hz, 2H), 3.78 (s, 1.5H), 3.76 (s, 1.5H), 3.66-3.53 (m, 1H), 3.32-3.24 (m, 1H), 3.23-3.13 (m, 1H), 2.55 (s, 3H), 2.23 (s, 6H), 2.13 (s, 1.5H), 2.04 (s, 1.5H), 2.03-2.01 (m, 2H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.19 (d, J=5.9 Hz, 3H).
The title compound (100 mg, 53%) was prepared following the procedure described Example 646 Step A using 1H-1,2,3-triazole (71.4 μL, 1.23 mmol) and 5-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (200 mg, 0.95 mmol). LCMS: RT=1.183 min, MS (ES) 200.1 (M+H).
The title compound (106 mg, 65%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.50 mmol). LCMS: RT=1.512 min, MS (ES) 325.9 (M+H).
The title compound (38 mg, 93%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[3,2-b]pyridine (27 mg, 0.08 mmol). LCMS. RT=2.297 min, MS (ES) 735.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=8.3 Hz, 1H), 8.27 (dd, J=8.9, 2.4 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.96-7.94 (m, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.73 (s, 2H), 4.42-4.34 (m, 1H), 4.27-4.22 (m, 2H), 4.03-3.97 (m, 2H), 3.93 (s, 3H), 3.78 (d, J=8.6 Hz, 3H), 3.37-3.21 (m, 2H), 2.23 (s, 6H), 2.12-2.03 (m, 5H), 1.97-1.88 (m, 3H), 1.16 (d, J=5.7 Hz, 3H).
The title compound (72 mg, 47%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (100 mg, 0.19 mmol) and methyl 5-(benzyloxy)-7-iodo-1H-indole-2-carboxylate (150 mg, 0.37 mmol). LCMS: RT=1.834 min, MS (ES) 815.8 (M+H).
The title compound (70 mg, 88%) was prepared following General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (75 mg, 0.092 mmol) and 1-bromo-2-methoxyethane (30 mg, 0.22 mmol). LCMS: RT=1.932, 1.959 min (Method B), MS (ES) 873.8 (M+H).
The title compound (58 mg, 92%) was prepared following the procedure described Example 390 Step D using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(2-methoxyethyl)-1H-indole-2-carboxylate (70 mg, 0.12 mmol) and Pd/C (10 wt. %, 20 mg, 0.019 mmol) by hydrogenating in MeOH (5 mL) for 16 h at RT. LCMS: RT=1.515, 1.550 min, MS (ES) 783.9 (M+H).
The title compound (9.4 mg, 47%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(4,6-dimethylpyrimidin-5-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(2-methoxyethyl)-1H-indole-2-carboxylate (20 mg, 0.026 mmol) and MeI (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=1.491 min, MS (ES) 783.9 (M+H).
The title compound (10 mg, 28%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 8-bromoquinoline-4-carboxylate (16 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.184 MS (ES) 709.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (t, J=4.8 Hz, 1H), 8.69 (d, J=8.2 Hz, 1H), 8.02-7.90 (m, 1H), 7.85-7.81 (m, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.70 (s, 2H), 4.69-4.45 (m, 1H), 4.31-4.10 (m, 1H), 3.95 (t, J=6.6 Hz, 2H), 3.77 (s, 1.5H), 3.75 (s, 1.5H), 3.68-3.50 (m, 1H), 3.37-3.22 (m, 1H), 3.21-3.08 (m, 1H), 2.23 (s, 6H), 2.13 (s, 1.5H), 2.04 (s, 1.5H), 2.03-2.00 (m, 2H), 1.98 (s, 1.5H), 1.89 (s, 1.5H), 1.19 (d, J=5.7 Hz, 3H).
The title compound (50 mg, 18%) was prepared following the procedure described Example 646 Step A using 1H-1,2,3-triazole (108 μL, 1.86 mmol) and of 5-bromo-1-methyl-1H-indole (300 mg, 1.43 mmol). LCMS: RT=1.516 min, MS (ES) 199.1 (M+H).
The title compound (80 mg, 98%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(2H-1,2,3-triazol-2-yl)-1H-indole (50 mg, 0.25 mmol). LCMS: RT=1.830 min, MS (ES) 324.9 (M+H).
The title compound (31 mg, 75%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(2H-1,2,3-triazol-2-yl)-1H-indole (27 mg, 0.08 mmol). LCMS: RT=2.345 min, MS (ES) 734.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.02 (m, 3H), 7.90 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.56 (d, J=3.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.71 (s, 2H), 4.52-4.46 (m, 1H), 4.20-4.12 (m, 1H), 4.02-3.95 (m, 2H), 3.86 (s, 3H), 3.77 (d, J=5.2 Hz, 3H), 3.70-3.65 (m, 1H), 3.36-3.19 (m, 2H), 2.21 (s, 6H), 2.12-2.03 (m, 5H), 1.97-1.88 (m, 3H), 1.10 (d, J=6.4 Hz, 3H).
The title compound (96 mg, 74%) was prepared following General Procedure C using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (100 mg, 0.15 mmol) and 3-iodo-1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (70 mg, 0.21 mmol). LCMS: RT=1.616 min, MS (ES) 866.8 (M+H).
The title compound (80 mg, 93%) was prepared following the procedure described Example 390 Step D using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-2-(1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (96 mg, 0.11 mmol) and Pd/C (10 wt. %, 15 mg, 0.014 mmol) by hydrogenating in MeOH (5 mL) with HCl (4.0 M in dioxanes, 0.5 mL) for 16 h at RT. LCMS: RT=1.155 min, MS (ES) 776.8 (M+H).
The title compound (8.4 mg, 37%) was prepared following General Procedure J using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-4-methyl-2-(1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indol-3-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (20 mg, 0.026 mmol) and 1-methylpiperazin-2-one (15 mg, 0.13 mmol). LCMS: RT=0.962 min, MS (ES) 872.8 (M+H).
The title compound (100 mg) was isolated from Example 659 Step A. LCMS: RT=0.195 min, MS (ES) 200.1 (M+H).
The crude title compound (175 mg) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.50 mmol). LCMS: RT=1.272 min, MS (ES) 325.9 (M+H).
The title compound (23 mg, 56%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (27 mg, 0.08 mmol). LCMS: RT=2.295 min, MS (ES) 735.9 (M+H).
The title compound (49 mg, 86%) was prepared following General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (53 mg, 0.065 mmol) and 1-bromo-2-methoxyethane (25 mg, 0.18 mmol). LCMS: RT=1.829, 1.858 min (Method B), MS (ES) 875.8 (M+H).
The title compound (43 mg, 98%) was prepared following the procedure described Example 390 Step D using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(2-methoxyethyl)-1H-indole-2-carboxylate (49 mg, 0.056 mmol) and Pd/C (10 wt. %, 10 mg, 0.0093 mmol) by hydrogenating in MeOH (5 mL) with HCl (4.0 M in dioxanes, 0.5 mL) for 16 h at RT. LCMS: RT=1.461, 1.485 min, MS (ES) 785.8 (M+H).
The title compound (7.8 mg, 39%) was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(H)-yl)-5-hydroxy-1H-indole-2-carboxylate (20 mg, 0.025 mmol) and MeI (10 mg, 0.070 mmol) followed by saponification using General Procedure D. LCMS: RT=2.262 min, MS (ES) 785.8 (M+H).
The title compound (17 mg, 48%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 7-bromoquinoline-2-carboxylate (16 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=2.223 MS (ES) 709.9 (M+H).
The title compound (3.6 mg, 29%) was prepared according to General Procedure I using methyl 3-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(((R)-pyrrolidin-2-yl)methyl)-1H-indole-5-carboxylate (10 mg, 0.013 mmol) and MeI (4 μL, 0.056 mmol) followed by saponification using General Procedure D. LCMS: RT=1.913 min, MS (ES) 808.9 (M+H).
The title compound (75 mg, 27%) was isolated from Example 662 Step A. LCMS: RT=1.335 min, MS (ES) 199.2 (M+H).
The title compound (60 mg, 54%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1H-1,2,3-triazol-1-yl)-1H-indole (75 mg, 0.38 mmol). LCMS: RT=1.509 min, MS (ES) 324.9 (M+H).
The title compound (35 mg, 86%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1H-1,2,3-triazol-1-yl)-1H-indole (27 mg, 0.08 mmol). LCMS: RT=2.212 min, MS (ES) 734.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.92-7.90 (m, 2H), 7.75 (d, J=8.8 Hz, 1H), 7.70 (s, 2H), 7.60 (s, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.72 (s, 2H), 4.55-4.50 (m, 1H), 4.20-4.12 (m, 1H), 4.00-3.95 (m, 2H), 3.87 (s, 3H), 3.77 (d, J=5.3 Hz, 3H), 3.71-3.63 (m, 1H), 3.35-3.18 (m, 2H), 2.22 (s, 6H), 2.11-2.02 (m, 5H), 1.97-1.88 (m, 3H), 1.10 (d, J=6.5 Hz, 3H).
The title compound (28 mg, 79%) was prepared according to General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (27 mg, 0.05 mmol) and methyl 4-bromoquinoline-2-carboxylate (16 mg, 0.06 mmol) followed by saponification using General Procedure D. LCMS: RT=1.489 min (Method B), MS (ES) 709.9 (M+H).
The title compound (234 mg, 28%) was prepared following the procedure described Example 646 Step A using 2-bromomethylpyrimidine (775 mg, 4.48 mmol) and 5-bromo-1H-1,2,4-triazole (510 mg, 3.45 mmol). LCMS: RT=1.125 min, MS (ES) 240.0 (M+H).
The title compound (100 mg, 69%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (192 mg, 0.75 mmol) and 2-(3-bromo-1H-1,2,4-triazol-1-yl)-4-methylpyrimidine (120 mg, 0.50 mmol). LCMS: RT=1.409 min, MS (ES) 291.1 (M+H).
The title compound (135 mg, 94%) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1-(4-methylpyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (100 mg, 0.34 mmol). LCMS: RT=1.709 min, MS (ES) 416.8 (M+H).
The title compound (36 mg, 78%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1-(4-methylpyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (35 mg, 0.08 mmol). LCMS: RT=2.294 min, MS (ES) 826.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J=3.4 Hz, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.23 (d, J=4.3 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.51 (d, J=3.0 Hz, 1H), 7.45 (d, J=4.91 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 6.70 (s, 2H), 4.53-4.47 (m, 1H), 4.21-4.15 (m, 1H), 4.00-3.97 (m, 2H), 3.85 (s, 3H), 3.77 (d, J=4.7 Hz, 3H), 3.73-3.67 (m, 1H), 3.39-3.20 (m, 2H), 2.58 (s, 3H), 2.12-2.04 (m, 5H), 1.98-1.89 (m, 3H), 1.13-1.11 (m, 3H).
The title compound (3.7 mg, 22%) was prepared following General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(2-methoxyethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol) and 2-bromo-N,N-dimethylethan-1-amine hydrobromide (9.3 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.969 min, MS (ES) 842.9 (M+H).
The title compound (6 mg, 38%) was prepared following procedure described in Example 673 from ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(2-methoxyethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol), MeI (6 μL, 0.08 mmol) followed by saponification using General Procedure D. The title compound was isolated as the second eluted isomer from the reverse phase HPLC purification. LCMS: RT=2.239 min, MS (ES) 785.8 (M+H).
The title compound (5 mg, 32%) was prepared following General Procedure H from ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(2-methoxyethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol), methyl iodide (6 μL, 0.08 mmol) followed by saponification using General Procedure D. The title compound was isolated as the first eluted isomer from the reverse phase HPLC purification. LCMS: RT=2.206 min, MS (ES) 785.8 (M+H).
The title compound (15 mg, 17%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (105 mg, 0.41 mmol) and 3-bromo-5-(methoxymethyl)-1-methyl-1H-1,2,4-triazole (70 mg, 0.34 mmol). LCMS: RT=1.363 min, MS (ES) 257.1 (M+H).
The title compound (22 mg, quant.) was prepared following the procedure described Example 388 Step B using 5-(5-(methoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl)-1-methyl-1H-indole (15 mg, 0.06 mmol). LCMS: RT=1.517 min, MS (ES) 382.9 (M+H).
The title compound (27 mg, 61%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-5-(5-(methoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl)-1-methyl-1H-indole (22 mg, 0.06 mmol). LCMS: RT=2.212 mm, MS (ES) 792.9 (M+H).
The title compound (83 mg, 95%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (109 mg, 0.42 mmol) and 3-bromo-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 0.35 mmol). LCMS: RT=0.210 min, MS (ES) 249.1 (M+H).
The title compound (75 mg, 60%) was prepared following the procedure described Example 388 Step B using 3-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine (83 mg, 0.33 mmol). LCMS: RT=1.133 min, MS (ES) 374.8 (M+H).
The title compound (50 mg, 86%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (40 mg, 0.07 mmol) and 3-(3-iodo-1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine (36 mg, 0.10 mmol). LCMS: RT=2.081 min, MS (ES) 784.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.62-8.57 (m, 1H), 7.96 (s, 1H), 7.92-7.87 (m, 1H), 7.75 (t, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.57-7.51 (m, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.11-7.06 (m, 1H), 6.69 (s, 2H), 4.53-4.49 (m, 1H), 4.19-4.10 (m, 1H), 4.00-3.95 (m, 2H), 3.90 (s, 3H), 3.77-3.70 (m, 4H), 3.33-3.20 (m, 2H), 2.20 (s, 6H), 2.10-2.01 (m, 5H), 1.96-1.87 (m, 3H), 1.08 (d, J=6.3 Hz, 3H).
The title compound (11 mg, 61%) was prepared following General Procedure H using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-(2-methoxyethyl)-1H-indole-3-carboxylate (17 mg, 0.02 mmol) and 1-(2-bromoethyl)-4-methylpiperazine dihydrobromide (15 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=1.887 min, MS (ES) 897.9 (M+H).
To a solution of 1-(tert-butyl) 2-ethyl 7-bromo-5-formyl-1H-indole-1,2-dicarboxylate (67 mg, 0.17 mmol) in DCM (0 mL) was added TFA (129 μL, 194 mg, 1.7 mmol) and stirred at RT for 16 h. The reaction was quenched with aq. sat. NH4Cl and extracted with DCM. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. To a solution of the crude product in DMF (1 mL) was added Cs2CO3 (366 mg, 1.08 mmol) and 1-bromo-2-methoxyethane (78 μL, 114 mg, 0.82 mmol) and stirred at 40° C. for 16 h. The reaction was quenched with aq. sat. NH4C and ßextracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-60% gradient) to afford the title compound (29 mg, 49%, 2 steps). LCMS: RT=1.893 min, MS (ES) 353.9 (M+H).
The title compound (30 mg, 68%, 2 steps) was prepared following the reduction by NaBH4 and OH protection by MOMCl procedures described Example 544 Step A using ethyl 7-bromo-5-formyl-1-(2-methoxyethyl)-1H-indole-2-carboxylate (29 mg, 0.082 mmol). LCMS: RT=2.010 min, MS (ES) 399.9 (M+H).
The title compound (8 mg, 24%, 2 steps) was prepared following the procedure described Example 591 Step C using ethyl 7-bromo-1-(2-methoxyethyl)-5-((methoxymethoxy)methyl)-1H-indole-2-carboxylate (30 mg, 0.075 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (40 mg, 0.075 mmol). LCMS: RT=1.574, 1.595, 1.643 min, (Method B) MS (ES) 813.9 (M+H).
The title compound (2.2 mg, 27%, 2 steps) was prepared following the procedure described Example 595 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-(2-methoxyethyl)-1H-indole-2-carboxylate (8 mg, 0.01 mmol) and MeI (3.0 mg, 0.021 mmol). LCMS: RT=2.245, 2.272, 2.318 min, MS (ES) 799.9 (M+H).
The title compound (8 mg, 29%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (27 mg, 0.037 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (30 mg, 0.16 mmol) followed by saponification using General Procedure D. LCMS: RT=1.517, 1.552 min, MS (ES) 813.9 (M+H).
5-Methyl-1H-tetrazole (60 mg, 0.71 mmol), CuI (68 mg, 0.36 mmol), K2CO3 (308 mg, 2.23 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (79 μLL, 0.36 mmol) were added to a solution of 5-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (196 mg, 0.93 mmol) in DMF (1.4 mL). The reaction mixture was stirred at 100° C. for 3 days under Ar. The reaction mixture was filtered through Celite pad. Water was added to the filtrate and extracted with EtOAc. The combined organic layers were washed with water, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-2% gradient) to afford the title compound (90 mg, 59%). LCMS: RT=0.205 min, MS (ES) 215.1 (M+H).
The crude title compound (90 mg) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(5-methyl-2H-tetrazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (90 mg, 0.42 mmol). LCMS: RT=1.411 min, MS (ES) 340.9 (M+H).
The title compound (38 mg, 64%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (40 mg, 0.07 mmol) and 3-iodo-1-methyl-5-(5-methyl-1H-tetrazol-1-yl)-1H-pyrrolo[3,2-b]pyridine (38 mg, 0.11 mmol). LCMS: RT=2.315 min, MS (ES) 750.9 (M+H).
To a solution of methyl (E)-2-(2-(4-acetamido-2-bromophenyl)hydrazono)propanoate (500 mg, 1.53 mmol) in dry DMF (2 mL) was added NaH (245 mg, 6.12 mmol) followed by MeI (285 μL, 4.6 mmol) at 0° C. The reaction mixture was warmed to RT and stirred for 5 h. The reaction was quenched by pouring into brine and extracted with EtOAc. The organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-5% gradient) to afford the title compound (430 mg, 80%). 1H-NMR (CDCl3) S 7.50 (s, 1H), 7.22 (m, 1H), 7.14 (s, 1H), 3.87 (s, 2H), 3.39 (s, 3H), 3.26 (s, 1H), 1.92 (s, 3H), 1.70 (s, 1H).
A solution of methyl (E)-2-(2-(2-bromo-4-(N-methylacetamido)phenyl)-2-methylhydrazono)propanoate (150 mg, 0.42 mmol) in glacial acetic acid (8 mL) and PPA, 0.5 mL) was heated at 90° C. for 1 h. The reaction mixture was concentrated, and the residue was diluted with water. The mixture was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-30% gradient) to afford the title compound (100 mg, 70%). 1H-NMR (DMSO-d6) δ 7.70 (s, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 4.38 (s, 3H), 3.87 (s, 3H), 3.15 (s, 3H), 1.76 (s, 3H).
To a solution of methyl 7-bromo-1-methyl-5-(N-methylacetamido)-1H-indole-2-carboxylate (100 mg, 0.30 mmol) in dioxane (2 mL) was added HCl (2 mL, 4 M in dioxane). The reaction mixture was stirred at 55° C. for 3 h then concentrated to afford the title compound (83 mg, 95%), which was used in next step without further purification. MS (ES) 297/299 (M+H).
To a solution of methyl 7-bromo-1-methyl-5-(methylamino)-1H-indole-2-carboxylate (40 mg, 0.134 mmol) in DCE (2 mL) was added acetaldehyde (0.2 mmol) and stirred for 30 min at RT. NaBH(OAc)3 (0.27 mmol) was added to the reaction mixture and stirred at RT for 3 h. The reaction mixture was removed concentrated and in vacuum and the residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-10% gradient) to afford the title compound. MS (ES) 325.3/327.3 (M+H).
The title compound (28%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-5-(ethyl(methyl)amino)-1-methyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. MS (ES) 769.2 (M+H).
The crude title compound (43 mg) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1H-1,2,4-triazol-1-yl)-1H-indole (31 mg, 0.16 mmol). LCMS: RT=1.469 min, MS (ES) 324.9 (M+H).
The title compound (30 mg, 73%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(1H-1,2,4-triazol-1-yl)-1H-indole (23 mg, 0.07 mmol). LCMS: RT=2.263 min, MS (ES) 734.8 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.16 (s, 1H), 7.86 (d, J=4.8 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (s, 2H), 7.57 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.71 (s, 2H), 4.54-4.48 (m, 1H), 4.21-4.12 (m, 1H), 4.00-3.95 (m, 2H), 3.86 (s, 3H), 3.77 (d, J=5.3 Hz, 3H), 3.70-3.63 (m, 1H), 3.36-3.18 (m, 2H), 2.22 (s, 6H), 2.12-2.03 (m, 5H), 1.97-1.88 (m, 3H), 1.10 (d, J=6.4 Hz, 3H).
The title compound was prepared following the procedure described Example 680 Step D using methyl 7-bromo-1-methyl-5-(methylamino)-1H-indole-2-carboxylate and 2-methoxyacetaldehyde. MS (ES) 355.3/357.3 (M+H).
The title compound (36%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-5-((2-methoxyethyl)(methyl)amino)-1-methyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. 1H-NMR (MeOH-d4) δ 8.02 (s, 0.6H), 7.91 (s, 0.4H), 7.80 (d, 1H, J=12 Hz), 7.58 (s, 0.4), 749 (d, 1H, J=12 Hz), 7.35-7.32 (two s, 2H), 6.63 and 6.61 (two s, total 2H), 4.46-4.23 (m, 1H), 4.23 and 4.22 (two s, total 1H), 4.09 (two s, total 2H), 4.00 (m, 2H), 3.81 (s, 1H), 3.76-3.61 (m, 6H), 3.40 (two s, total 3H), 2.67 (two s, 6H), 2.25 (s, 6H), 2.18-2.15 (two s, total 3H), 2.02 (m, 2H), 2.00 (two s, total 3H), 1.31 (d, 2H, J=8 Hz), 1.19 (d, 1H, J=8 Hz); MS (ES) 799.2 (M+H)
The title compound was prepared following the procedure described Example 680 Step D using methyl 7-bromo-1-methyl-5-(methylamino)-1H-indole-2-carboxylate and formaldehyde. MS (ES) 311.3/313.3 (M+H).
The title compound (23%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 7-bromo-5-(dimethylamino)-1-methyl-1H-indole-2-carboxylate followed by saponification using General Procedure D. MS (ES) 755.3 (M+H).
The title compound (11 mg, 19% yield) was obtained along with Example 679 from Step C. LCMS. RT=2.380 min, MS (ES) 772.8 (M+Na).
The title compound (25 mg, 43%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (75 mg, 0.10 mmol) and 1-bromo-2-(trifluoromethoxy)ethane (49 mg, 0.25 mmol) followed by saponification using General Procedure D. LCMS: RT=1.55 min, MS (ES) 738 (M+H).
The title compound (25 mg, 43%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (75 mg, 0.10 mmol) and 1-bromo-3-methoxypropane (39 mg, 0.25 mmol) followed by saponification using General Procedure D. LCMS: RT=1.55 min, MS (ES) 784 (M+H).
The title compound (13 mg, 93%) was prepared according to General Procedure E using (R)-3-(7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (14 mg, 0.02 mmol) and ammonia (100 μL, 2 M in methanol). LCMS: RT=1.873 min, MS (ES) 711.8 (M+H).
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-pyrrolo[3,2-h]pyridine-5-carboxamide (13 mg, 0.018 mmol) in DCM (1 mL) were added trifluoromethanesulfonic anhydride (7 μL, 0.04 mmol), triethylamine (6 μL, 0.04 mmol), and the mixture was stirred at room temperature for 2 h. Water (10 mL) was added to the mixture and extracted in DCM. The organic layers was dried and concentrated to afford the title compound (10 mg, 78%). LCMS: RT=1.604 min (Method B), MS (ES) 693.90 (M+H).
To a solution of (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (10 mg, 0.014 mmol) in DMF (1 mL) were added sodium azide (6.5 mg, 0.11 mmol), ammonium chloride (5.5 mg, 0.11 mmol) and the mixture was heated at 120° C. for 6 h. The reaction mixture was extracted in DCM, dried and concentrated. The crude was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient to 35-95% MeCN 0.1% TFA) to afford the title compound (7 mg, 68%). LCMS: RT=1.342 min (Method B), MS (ES) 736.9 (M+H).
The title compound was prepared (5.0 mg, 43%, 2 steps) following the procedures described Example 607 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (11 mg, 0.014 mmol) and 4-(chloromethyl)thiazole hydrochloride (5 mg, 0.021 mmol). LCMS: RT=2.145, 2.172, 2.224 min, MS (ES) 838.8 (M+H).
1-Methyl-1H-indole-5-diazonium tetrafluoroborate (200 mg, 0.82 mmol) and AgNO3 (208 mg, 1.22 mmol) were suspended in THF (4 mL) under Ar and cooled at −78° C. Et3N (171 μL, 1.22 mmol) was added dropwise and stirred for 10 min then TMSCHN2 (408 μL, 0.98 mmol) was added slowly. The mixture was stirred 1 h at −78° C. and warmed to RT. A solution of CsF (124 mg, 0.82 mmol) in MeOH (0.5 mL) was added and the mixture was stirred 1.5 h at RT. EtOAc and brine were added and the organic phase was separated, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-30% gradient) to afford the title compound (50 mg, 30%). LCMS: RT=1.493 min, MS (ES) 200.1 (M+H).
The crude title compound (45 mg) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(2H-tetrazol-2-yl)-1H-indole (50 mg, 0.25 mmol). LCMS: RT=1.752 min, MS (ES) 325.9 (M+H).
The title compound (35 mg, 86%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-1-methyl-5-(2H-tetrazol-2-yl)-1H-indole (24 mg, 0.07 mmol). LCMS: RT=2.279 min. MS (ES) 735.9 (M+H).
To a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.0 mmol) in DCM (6 mL) was added Et3N (279 μL, 2.0 mmol) followed by MsCl (117 μL, 1.5 mmol). The mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried, concentrated and purified by flash chromatography (Combi-flash Rf, Hex 100%) to afford the title compound (166 mg, 59%). LCMS RT=1.589 min, MS (ES) 224.1 (M+H-56).
The title compound (12 mg, 96%) was prepared according to General Procedure I using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (15 mg, 0.02 mmol) and methyl tert-butyl (S)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (8 mg, 0.03 mmol). LCMS: RT=1.864 min (Method B), MS (ES) 894.90 (M+H).
To a solution of methyl 1-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-3-((S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (12 mg, 0.013 mmol) in DCM (1 mL) was added TFA (200 μL, 2.61 mmol), and the mixture was stirred at RT for 3 h. The reaction mixture was washed with sat. NaHCO3 aq. solution (3 mL) and extracted with DCM. The organic layer was dried, concentrated and purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-100% gradient) to afford the title compound (10 mg, 90%). LCMS RT=1.892 min, MS (ES) 794.8 (M+H).
To a solution of methyl 3-((R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(((S)-pyrrolidin-2-yl)methyl)-1H-indole-5-carboxylate (10 mg, 0.012 mmol) in DCM (0.5 mL) were added Et3N (4 μL, 0.028 mmol) and formaldehyde (1 mg, 0.028 mmol). The mixture was stirred at RT for 10 min then washed with water (3 mL) and extracted with DCM. The organic layer was dried, concentrated and saponified using General Procedure D to yield the title compound (7.7 mg, 69%). LCMS: RT=1.918 MS (ES) 794.9 (M+H).
The title compound (52 mg, 47%, 2 steps) was prepared following the procedure described Example 544 Step A using 1-(tert-butyl) 2-ethyl 7-bromo-5-formyl-1H-indole-1,2-dicarboxylate (127 mg, 0.32 mmol). LCMS: RT=1.796 mm, MS (ES) 341.9 (M+H).
The title compound (10 mg, 13%, 2 steps) was prepared following General coupling procedure A using ethyl 7-bromo-5-((methoxymethoxy)methyl)-1H-indole-2-carboxylate (30 mg, 0.088 mmol) and (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (47 mg, 0.088 mmol) followed by NH alkylation using General procedure I with 2-(bromomethyl)pyridine HBr (19 mg, 0.075 mmol) by substituting Cs2CO3 with K2CO3 (31 mg, 0.225 mmol). LCMS: RT=2.277, 2.333 min, MS (ES) 890.9 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-J H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-((methoxymethoxy)methyl)-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (9 mg, 0.041 mmol) in THF (0.25 mL) and MeOH (0.15 mL) was added conc. HCl (0.02 mL). After stirring at RT for 16 h, the reaction was quenched with aq. sat. NaHCO3 solution and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was dissolved in DMF (0.5 mL), and NaH (3.0 mg, 0.061 mmol) was added at 0° C. After stirring at 0° C. for 5 min, MeI (3.8 μL, 8.7 mg, 0.061 mmol) was added then warmed to RT and stirred for 4 h. The reaction was quenched with aq. sat. NH4Cl and extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. Subsequent saponification following general procedure D afforded the title compound (6.5 mg, 30%, 2 steps). LCMS: RT=2.035, 2.057 min, MS (ES) 832.8 (M+H).
The title compound was prepared (4.0 mg, 33%, 2 steps) following the procedures described Example 607 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (11 mg, 0.014 mmol) and 3-(chloromethyl)oxetane (5 mg, 0.021 mmol). LCMS: RT=2.129, 2.157, 2.207 min, MS (ES) 811.9 (M+H). 1H NMR (600 MHz, DMSO-d6) δ 7.76-7.75 (m, 1H), 7.67-7.63 (m, 0.6H), 7.63-7.59 (m, 0.4H), 7.33-7.26 (m, 2.3H), 7.09-7.05 (m, 0.7H), 6.71 (s, 1.2H), 6.68 (s, 0.8H), 4.71-4.63 (m, 0.6H), 4.62-4.56 (m, 1.2H), 4.55-4.47 (m, 1.2H), 4.45-4.40 (m, 0.6H), 4.39-4.33 (m, 1H), 4.29 (dt, J=6.0, 3.0 Hz, 1.2H), 4.26-4.20 (m, 1H), 4.19-4.13 (m, 0.6H), 4.07-4.03 (m, 1H), 3.98-3.95 (m, 1.6H), 3.94 (s, 2H), 3.79-3.77 (m, 1.2H), 3.75 (s, 0.6H), 3.74-3.72 (m, 0.4H), 3.72-3.66 (m, 0.6H), 3.65-3.63 (m, 1H), 3.45-3.37 (m, 1.6H), 3.36-3.28 (m, 1H), 3.27-3.22 (m, 0.6H), 3.21-3.14 (m, 1H), 2.25-2.19 (m, 6.5H), 2.14-2.10 (m, 1.8H), 2.06-2.01 (m, 3.2H), 2.00-1.99 (m, 0.7H), 1.98-1.96 (m, 1H), 1.92-1.90 (m, 0.7H), 1.89 (s, 1.3H), 1.19-1.15 (m, 2.2H), 1.06 (d, J=6.6 Hz, 1.1H).
The title compound was prepared (4.0 mg, 35% ß, 2 steps) following the procedures described in the synthesis of example 607 using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(hydroxymethyl)-1-methyl-1H-indole-2-carboxylate (11 mg, 0.014 mmol) and 4-(2-chloroethyl)morpholine HCl (3.8 mg, 0.021 mmol). LCMS: RT=1.960, 1.989 min, MS (ES) 854.9 (M+H).
The title compound (174 mg, 62%) was prepared according to method described in Example 690 step A using tert-butyl (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.0 mmol). LCMS RT=1.522 min, MS (ES) 224.1 (M+H−56).
The title compound (6 mg, 54%) was prepared according to steps B-D in Example 690 using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.014 mmol) and tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (8 mg, 0.028 mmol). LCMS: RT=1.911 min, MS (ES) 794.9 (M+H).
AIBN (23 mg, 0.14 mmol) and NBS (92 mg, 0.52 mmol) were added to a solution of 2-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.47 mmol) in CCl4 (5 mL). The reaction mixture was stirred at 85° C. under Ar for 4 h then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM 100%) to afford the title compound (56 mg, 41%). LCMS: RT=1.121 min, MS (ES) 289.7 (M+H).
A mixture of MeOH (15.6 μL, 0.38 mmol) and NaH (9.3 mg, 0.38 mmol) in THF (2 mL) was added to a solution of 2-bromo-8-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine (56 mg, 0.19 mmol) in THF (3 mL) at 0° C. The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried and concentrated. The crude compound (50 mg) was used for the next step without further purification. LCMS: RT=0.205 min, MS (ES) 241.9 (M+H).
The title compound (60 mg, quant.) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (64 mg, 0.25 mmol) and 2-bromo-8-(methoxymethyl)-[1,2,4]triazolo[1,5-a]pyridine (50 mg, 0.21 mmol). LCMS: RT=1.531 min, MS (ES) 293.1 (M+H).
The title compound (61 mg, 71%) was prepared following the procedure described Example 388 Step B using 8-(methoxymethyl)-2-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (60 mg, 0.21 mmol). LCMS: RT=1.778 min, MS (ES) 418.9 (M+H).
The title compound (40 mg, 86%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-1-methyl-1H-indol-5-yl)-8-(methoxymethyl)-[1,2,4]triazolo[1,5-a]pyridine (28 mg, 0.07 mmol). LCMS: RT=2.290 min, MS (ES) 828.9 (M+H).
The title compound (180 mg, 97%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (218 mg, 0.85 mmol) and 2-bromo-5-methyl-[1,2,4]thiazolo[1,5-a]pyridine (150 mg, 0.71 mmol). LCMS: RT=1.654 min, MS (ES) 263.1 (M+H).
The title compound (64 mg, 24%) was prepared following the procedure described Example 388 Step B using 5-methyl-2-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (180 mg, 0.69 mmol). LCMS: RT=1.679 min, MS (ES) 388.9 (M+H).
The title compound (40 mg, 90%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-1-methyl-1H-indol-5-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (26 mg, 0.07 mmol). LCMS: RT=2.208 min, MS (ES) 798.9 (M+H).
To a solution of methyl 4-amino-3-bromo benzoate (1.41 g, 6.52 mmol) was added a solution of NaNO2 (0.675 g, 9.78 mmol) in water (6.52 mL) at RT and stirred for 45 min. The reaction mixture was cooled to 0° C. then SnCl2 (3.83 g, 20 mmol) in con. HCl (12.0 mL) was added. The reaction mixture was stirred for 3 h, diluted with water (30 mL). The precipitate was filtered and washed with ether to afford the title compound (0.994 g, 66%) as a white solid. 1H NMR: (400 MHz in MeOD) δ 8.23 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.4, 2.0 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H); LCMS: RT=0.135 min, MS (ES) 230.9 (M+H).
To a solution of 3-bromo-4-hydrazinylbenzoic acid (1.14 g, 4.91 mmol) in EtOH (25 mL) was added methyl pyruvate (0.54 mL, 5.89 mmol) at 0° C. then stirred for 20 min. Precipitate was filtered and washed with ether to afford the title compound (1.05 g, 68%) as a yellow solid. 1H NMR: (400 MHz in MeOD) δ 8.15 (d, J=1.6 Hz, 1H), 7.95 (dd, J=8.4, 1.6 Hz, 1H), 7.85 (s, NH), 7.65 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 2.23 (s, 3H); LCMS: RT=0.884 min, MS (ES) 314.9 (M+H).
To a solution of (E)-3-bromo-4-(2-(1-methoxy-1-oxopropan-2-ylidene)hydrazinyl)benzoic acid (0.4 g, 1.27 mmol) in DMF (6.4 mL) was added K2CO3 (0.70 g, 5.1 mmol), followed by allyl bromide (0.55 mL, 6.37 mmol). The reaction mixture was stirred for 3 h, diluted with EtOAc, and washed with water. The combined organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-30% gradient) to afford the title compound (0.39 g, 87%). 1H NMR: (400 MHz in CDCl3) δ 12.5 (s, NH), 8.19 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.8, 2.0 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 6.09-5.97 (m, 1H), 5.43-5.37 (m, 1H), 5.31-5.27 (m, 1H), 4.80 (dt, J=5.6, 1.2 Hz, 2H), 3.88 (s, 3H), 2.22 (s, 3H); LCMS: RT=1.215 min, MS (ES) 355.12 (M+H).
To a solution of allyl (E)-3-bromo-4-(2-(1-methoxy-1-oxopropan-2-ylidene)hydrazinyl)benzoate (132 mg, 0.372 mmol) in MeCN (3.0 mL)/DMF (1.0 mL) was added Cs2CO3 (182 mg, 0.56 mmol), followed by MeI (69 mg, 0.484 mmol). The reaction mixture was stirred for 3 h, diluted with EtOAc and washed with water. The combined organic layer was dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-30% gradient) to afford the title compound (134 mg, 97%). LCMS: RT=1.167 min, MS (ES) 369.04 (M+H).
A solution of allyl (E)-3-bromo-4-(2-(1-methoxy-1-oxopropan-2-ylidene)-1-methylhydrazinyl)benzoate (134 mg, 0.364 mmol) in AcOH (3 mL) was heated to 90° C. and PPA (0.3 mL) was added. The reaction mixture was stirred for 2 h at 90° C. then excess organic solvent was removed in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-50% gradient) to afford the title compound (30 mg, 25%). 1H NMR: (400 MHz in CDCl3) δ 8.33 (d, J=1.6 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 7.33 (s, 1H), 6.10-6.01 (m, 1H), 5.42 (dd, J=17.2, 1.2 Hz, 1H), 5.31 (dd. J=10.4, 1.2 Hz 1H), 4.83 (dt, J=5.6, 1.2 Hz, 2H), 4.48 (s, 3H), 3.92 (s, 3H); LCMS: RT=1.311 min, MS (ES) 352.02 (M+H).
The title compound was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and 5-allyl 2-methyl 7-bromo-1-methyl-1H-indole-2,5-dicarboxylate. 1H NMR: (400 MHz in MeOD) δ 8.44 (s, 1H), 7.81 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.61 (s, 2H), 4.39-4.35 (m, 1H), 4.10 (s, 3H), 3.98-3.92 (m, 2H), 3.87 (s, 3H), 3.86-3.84 (m, 2H), 3.46-3.38 (m, 2H), 2.28 (s, 6H), 2.23 (s, 3H), 2.21-2.16 (m, 2H), 2.01 (s, 3H), 1.31 (d, J=6.4 Hz, 3H); LCMS: RT=0.856 min, MS (ES) 756.23 (M+H).
The title compound (180 mg, 97%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (218 mg, 0.85 mmol) and 2-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (150 mg, 0.71 mmol). LCMS: RT=1.404 min, MS (ES) 263.1 (M+H).
The title compound (82 mg, 31%) was prepared following the procedure described Example 388 Step B using 8-methyl-2-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (180 mg, 0.69 mmol). LCMS: RT=1.702 min, MS (ES) 388.9 (M+H).
The title compound (34 mg, 76%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-1-methyl-1H-indol-5-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (26 mg, 0.07 mmol). LCMS: RT=2.231 min, MS (ES) 798.9 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=6.8 Hz, 1H), 8.30 (s, 1H), 7.10 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.04 (t, J=7.2 Hz, 1H), 6.69 (s, 2H), 4.54-4.48 (m, 1H), 4.22-4.15 (m, 1H), 3.99 (t, J=6.6 Hz, 2H), 3.85 (s, 3H), 3.78-3.67 (m, 4H), 3.41-3.21 (m, 2H), 2.55 (s, 3H), 2.18 (s, 6H), 2.12-2.04 (m, 5H), 1.99-1.90 (m, 3H), 1.12 (d, J=6.3 Hz, 3H).
4-Methylmorpholine N-oxide (531 mg, 4.54 mmol) was added to a solution of 2-bromo-8-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine (330 mg, 1.13 mmol) in THF (5 mL). The reaction was refluxed for 30 min. The reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The crude title compound (250 mg) was used for the next step without further purification. LCMS: RT=0.977 min, MS (ES) 226.0 (M+H).
NaH (140.5 mg, 3.63 mmol) was added to a solution of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde (410 mg, 1.81 mmol) in THF/MeOH (12 mL, 10:1) at 0° C. The reaction was stirred for 10 min and then refluxed for 30 min. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The crude title compound (420 mg) was used for the next step without further purification. LCMS: RT=0.974 min, MS (ES) 228.0 (M+H).
tert-Butyldimethylsilyl chloride (833 mg, 5.53 mmol), 4-DMAP (22.5 mg, 0.180 mmol) and Et3N (770 μL, 5.53 mmol) were added to a solution of (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol (420 mg, 1.84 mmol) in DCM (8 mL) at 0° C. The reaction was stirred at RT for 20 h. The reaction was quenched with water and extracted with DCM. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-20% gradient) to afford the title compound (270 mg, 43%). LCMS: RT=2.099 min, MS (ES) 341.9 (M+H).
The title compound (45 mg, 15%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (243 mg, 0.95 mmol) and 2-bromo-8-(((tert-butyldimethylsilyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridine (270 mg, 0.79 mmol). LCMS: RT=2.176 min, MS (ES) 393.1 (M+H).
The title compound (58 mg, quant.) was prepared following the procedure described Example 388 Step B using 8-(((tert-butyldimethylsilyl)oxy)methyl)-2-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (45 mg, 0.11 mmol). LCMS: RT=2.382 min, MS (ES) 518.8 (M+H).
The title compound (50 mg, quant.) was prepared following the procedure described Example 420 Step C using 8-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-iodo-1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (58 mg, 0.11 mmol). LCMS: RT=1.558 min, MS (ES) 404.8 (M+H).
The title crude compound (31 mg) was prepared following General Procedure G using (2-(3-iodo-1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol (50 mg, 0.12 mmol) and 2-bromoethyl methyl ether (15.1 μL, 0.16 mmol). LCMS: RT=1.763 min, MS (ES) 462.9 (M+H).
The title compound (19 mg, 46%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 0.06 mmol) and 2-(3-iodo-1-methyl-1H-indol-5-yl)-8-((2-methoxyethoxy)methyl)-[1,2,4]triazolo[1,5-a]pyridine (26 mg, 0.06 mmol). LCMS: RT=2.248 min, MS (ES) 872.8 (M+H).
The title compound (220 mg, 45%) was prepared following the procedure described Example 646 Step A using 2-bromo-5-methylpyrimidine (421 mg, 2.43 mmol). LCMS: RT=1.146 min, MS (ES) 240.0 (M+H).
The title compound (250 mg, 94%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (283 mg, 1.10 mmol) and 2-(3-bromo-1H-1,2,4-triazol-1-yl)-5-methylpyrimidine (220 mg, 0.92 mmol). LCMS: RT=1.528 min, MS (ES) 291.1 (M+H).
The title compound (45 mg, 13% yield) was prepared following the procedure described Example 388 Step B using 1-methyl-5-(1-(5-methylpyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (250 mg, 0.86 mmol). LCMS: RT=1.748 min, MS (ES) 416.8 (M+H).
The title compound (25 mg, 38%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (40 mg, 0.07 mmol) and 3-iodo-1-methyl-5-(I-(5-methylpyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (45 mg, 0.11 mmol). LCMS: RT=2.269 min, MS (ES) 826.9 (M+H).
The title compound (121 mg, 43%) was prepared according to method described in Example 690 step A using tert-butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.0 mmol). LCMS: RT=1.441 min (Method B), MS (ES) 224.1 (M+H-56).
The title compound (5.6 mg, 50%) was prepared according to steps B-D in Example 690 using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.014 mmol) and tert-butyl (R)-3-(((methylsulfonyl)oxy)methyl) pyrrolidine-1-carboxylate (8 mg, 0.028 mmol). LCMS: RT=2.004 min, MS (ES) 794.9 (M+H).
The title compound (178 mg, 64%) was prepared according to method described in Example 690 step A using tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.0 mmol). LCMS: RT=1.426 min, MS (ES) 224.1 (M+H-56).
The title compound (10 mg, 90%) was prepared according to steps B-D in Example 690 using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.014 mmol) and tert-butyl (S)-3-(((methylsulfonyl)oxy)methyl) pyrrolidine-1-carboxylate (8 mg, 0.028 mmol). LCMS: RT=1.849 min, MS (ES) 792.9 (M+H).
The title compound (16.2 mg, 78%) was prepared according to General Procedure I using (R)-3-(3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indol-5-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.027 mmol) and MeI (6 μL, 0.08 mmol). LCMS: RT=2.249 min, MS (ES) 765.8 (M+H).
The title compound (310 mg, 83%) was prepared following the procedure described Example 646 Step A using 2-bromo-5-methoxypyrimidine (460 mg, 2.43 mmol). LCMS: RT=0.222 min, MS (ES) 255.9 (M+H).
The title crude compound (400 mg) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (398 mg, 1.55 mmol) and 2-(3-bromo-1H-1,2,4-triazol-1-yl)-5-methoxypyrimidine (310 mg, 1.29 mmol). LCMS: RT=1.529 min, MS (ES) 307.0 (M+H).
The title compound (260 mg, 46%) was prepared following the procedure described Example 388 Step B using 5-(1-(5-methoxypyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1-methyl-1H-indole (400 mg, 1.31 mmol). LCMS: RT=1.741 min, MS (ES) 432.9 (M+H).
The title compound (29 mg, 62%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 3-iodo-5-(I-(5-methoxypyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1-methyl-1H-indole (29 mg, 0.07 mmol). LCMS: RT=2.176 min, MS (ES) 842.8 (M+H).
The title compound was This compound was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(2,4,6-trimethylpyrimidin-5-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and 7-iodo-4-methoxy-1H-indole-2-carboxylic acid followed by installation of the 2-methylpyridyl group using General Procedure G. and saponification using General Procedure D. 1H NMR: (400 MHz in MeOD) δ 8.47 (d, J=4.4 Hz, 1H), 8.06 (t, J=7.2 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.56 (t, J=6.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.65 (s, 2H), 6.10 (d, J=18.4 Hz, 1H), 5.95 (d, J=18.4 Hz, 1H), 4.03 (s, 3H), 3.89 (t, J=6.4 Hz, 2H), 3.86-3.69 (m, 2H), 3.48 (d, J=13.2 Hz, 1H), 3.15-3.06 (m, 1H), 2.89-2.79 (m, 1H), 2.75 (s, 3H), 2.35 (s, 3H), 2.31 (s, 6H), 2.18 (s, 3H), 2.01-1.94 (m, 2H), 1.21 (d, J=6.8 Hz, 3H); LCMS: RT=0.850 min, MS (ES) 831.30 (M+H).ß
The title compound (3.4 mg, 31%) was prepared according to steps B-C in Example 690 using methyl (R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-5-carboxylate (10 mg, 0.014 mmol) and tert-butyl (R)-3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (8 mg, 0.028 mmol) followed by saponification using General Procedure D. LCMS: RT=1.963 min, MS (ES) 780.8 (M+H).
The title compound (200 mg, 95%) was prepared following the procedure described Example 388 Step A using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (247 mg, 0.96 mmol) and 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (170 mg, 0.80 mmol). LCMS: RT=1.309 min, MS (ES) 263.1 (M+H).
The title compound (190 mg, 64%) was prepared following the procedure described Example 388 Step B using 7-methyl-2-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.76 mmol). LCMS: RT=1.557 min, MS (ES) 388.9 (M+H).
The title compound (7.5 mg, 17%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 2-(3-iodo-1-methyl-1H-indol-5-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (28 mg, 0.07 mmol). LCMS: RT=2.146 min, MS (ES) 798.9 (M+H).
The crude title compound (250 mg) was prepared following General Procedure J using 2-(3-iodo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethan-1-ol (210 mg, 0.48 mmol) and morpholine (376 μL, 4.36 mmol). LCMS: RT=1.424 min. MS (ES) 407.9 (M+H).
The crude title compound (220 mg) was prepared following the procedure described Example 581 Step C using 4-(2-(3-iodo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)morpholine (250 mg, 0.49 mmol). LCMS: RT=1.132 min, MS (ES) 423.9 (M+H).
The crude title compound (199 mg) was prepared following General Procedure G using 4-(2-(3-iodo-5-(1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)morpholine (220 mg, 0.52 mmol) and 2-bromoethyl methyl ether (63.5 μL, 0.68 mmol). LCMS: RT=1.292 min, MS (ES) 481.9 (M+H).
The title compound (25 mg, 49%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 4-(2-(3-iodo-5-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)morpholine (32 mg, 0.07 mmol). LCMS: RT=1.982 min, MS (ES) 891.9 (M+H).
Diastereomeric mixture of (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one was separated by HPLC (Chiralcel OZ-H column Hex/EtOAc 7/3).
The title compound (206 mg, 75%) was prepared following General Procedure K using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (200 mg, 0.37 mmol) and ethyl 7-iodo-5-methyl-1H-indole-2-carboxylate (200 mg, 0.61 mmol). LCMS: RT=1.708 min, MS (ES) 739.9 (M+H).
The title compound (138 mg, 64%) was prepared following General Procedure I using ethyl (M, R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (206 mg, 0.28 mmol) and 1-bromo-2-methoxyethane (100 mg, 0.72 mmol) followed by saponification using General Procedure D. LCMS: RT=1.503 min, MS (ES) 769.9 (M+H). 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 7.813 (d, J=8.7, Hz, 0.34H), 7.810 (d, J=8.7 Hz, 0.66H), 7.50-7.46 (m, 1H), 7.37 (d, J=8.7 Hz, 0.33H), 7.36 (d, J=8.4 Hz, 0.66H), 7.25-7.18 (m, 1.34H), 6.94 (s, 0.66H), 6.76 (s, 1.34H), 6.74 (s, 0.66H), 5.03-5.00 (M, 0.34H), 4.88-4.81 (m, 0.66H), 4.70 (dd. J=12.5, 4.4 Hz, 0.5H), 4.60-4.57 (m, 0.5H), 4.48-4.45 (m, 1H), 4.31-4.22 (m, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.84 (s, 3H), 3.77 (d, J=13.1, 1H), 3.50-3.25 (m, 4H), 3.05 (s, 2H), 3.00 (s, 1H), 2.43 (s, 2H), 2.40 (s, 1H), 2.28 (s, 2.28, 4H), 2.27 (s, 2H), 2.19 (s, 1H), 2.18 (s, 2H), 2.14-2.04 (m, 2H), 1.97 (s, 1H), 1.92 (s, 2H), 1.21 (d, J=6.5 Hz, 2H), 1.10 (d, J=6.6 Hz, 1H).
The title compound (131 mg, 46% yield) was prepared following the same procedure as Example 709 starting from (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (200 mg, 0.037 mmol). LCMS: RT=1.466, 1.495 min (Method B), MS (ES) 769.9 (M+H). 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 7.772 (d, J=8.6 Hz, 0.66H), 7.768 (d, J=8.6 Hz, 0.34H), 7.47-7.43 (m, 1H), 7.33 (d, J=8.7 Hz, 0.34H), 7.32 (d, J=08.7 Hz, 0.66H), 7.19 (s, 1.34H), 6.93 (s, 0.66H), 6.71 (s, 1.34H), 6.69 (s, 0.66H), 4.97-4.92 (m, 0.34H), 4.77-4.72 (m, 0.66H), 4.66 (dd, J=12.7, 4.4 Hz, 0.34H), 4.55-4.46 (m, 1H), 4.41 (dd, J=13.5, 3.7 Hz, 0.66H), 4.21-4.12 (m, 1H), 3.98 (t, J=6.3 Hz, 2H), 3.79 (s, 1H), 3.77 (s, 2H), 3.67 (d, J=12.8 Hz, 1H), 3.45-3.20 (m, 4H), 3.00 (s, 2H), 2.95 (s, 1H), 2.38 (s, 2H), 2.36 (s, 1H), 2.24 (s, 4H), 2.23 (s, 2H), 2.07-1.97 (m, 8H), 1.15 (d, J=6.5 Hz, 2H), 1.05 (d, J=6.6 Hz, 1H).
The title compound (99 mg, 65%) was prepared following General Procedure K using (M, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (100 mg, 0.19 mmol) and methyl 5-(benzyloxy)-7-iodo-1H-indole-2-carboxylate (150 mg, 0.37 mmol). LCMS: RT=1.756 min, MS (ES) 817.8 (M+H).
The title compound (70 mg, 70%) was prepared following General Procedure I using methyl (M, R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (99 mg, 0.12 mmol) and MeI (40 mg, 0.28 mmol). LCMS: RT=1.847, 1.874 min, MS (ES) 831.9 (M+H).
The title compound (62 mg, 99%) was prepared following the procedure described Example 390 Step D using methyl (M, R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (70 mg, 0.084 mmol) and Pd/C (10 wt. %, 15 mg, 0.014 mmol) by hydrogenating in MeOH (5 mL) with HCl (4.0 M in dioxanes, 0.5 mL) for 16 h at RT. LCMS: RT=1.462, 1.517 min, MS (ES) 741.9 (M+H).
The title compound (36 mg, 53%) was prepared following General Procedure H using methyl (M, R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (64 mg, 0.086 mmol) and 1-bromo-2-methoxyethane (35 mg, 0.25 mmol) followed by saponification using General Procedure D. LCMS: RT=1.393 min, MS (ES) 785.8 (M+H).
The title compound (23 mg, 15% overall yield) was prepared following the same procedure as Example 711 starting from (P, R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (100 mg, 0.19 mmol). LCMS: RT=1.353, 1.388 min, MS (ES) 785.8 (M+H).
The title compound (30 mg, 29%) was prepared following General Procedure I using ethyl (M, R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (94 mg, 0.13 mmol) and 2-(chloromethyl)pyridine hydrochloride (50 mg, 0.31 mmol) followed by saponification using General Procedure D. LCMS: RT=1.255 min, MS (ES) 802.9 (M+H).
The title compound (72 mg, 31%) was prepared following General Procedure I using ethyl (P, R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (72 mg, 0.097 mmol) and 2-(chloromethyl)pyridine hydrochloride (40 mg, 0.24 mmol) followed by saponification using General Procedure D. LCMS: RT=1.227 min, MS (ES) 802.8 (M+H).
To a solution of 2-(4-Aminophenyl)ethan-1-ol (2.0 g, 145 mmol) in DMF (10 mL) was added NBS (2.5 g, 145 mmol) at 0° C. The reaction mixture was warmed to RT and stirred overnight then quenched with brine and extracted with EtOAc. The organic layers were dried and concentrated. and the residue was purified flash chromatography (Combi-flash Rf, hexane-ethyl acetate=0-50% gradient for 15 min) to give the title compound (2.5 g, 80%). 1H-NMR (DMSO-d6) δ 7.18 (d, 1H, J=1.8 Hz), 6.91 (dd, 1H, J i=1.8 Hz, J2=12.0 Hz), 6.72 (d, 1H, J=12 Hz), 5.06 (s, 2H), 4.55 (s, 1H), 3.51 (m, 2H), 2.25 (tr, 2H, 0.1=12 Hz).
To a solution of 2-(4-Amino-3-bromophenyl)ethan-1-ol (2.5 g, 12 mmol) in conc. HCl (25 mL) at −5° C. was added a solution of sodium nitrate (1.2 g, 17 mmol) in water (3 mL) dropwise. The reaction mixture was stirred at −5° C. for 1 h then a solution of SnCl2 (6.8 g, 36 mmol) conc. HCl (5 mL) was added slowly. The reaction mixture was warmed to RT and stirred for 5 h. The mixture was neutralized with NaOH and filtered. The filtrate was extracted with EtOAc and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-40% gradient) to afford the title compound (1.9 g, 66%). 1H-NMR (DMSO-d6) δ 7.21 (d, 1H, J=1.8 Hz), 7.10-7.06 (m, 2H), 6.05 (s, 1H), 4.56 (tr, 2H, J=6 Hz), 4.10 (s, 2H), 3.55 (m, 2H), 2.59 (tr, 2, J=12 Hz).
To a solution of 2-(3-bromo-4-hydrazinylphenol)ethan-1-ol (1.9 g, 8 mmol) in THF (5 mL) was added methyl pyruvate (0.8 mL, 10 mmol). The reaction mixture was heated at 50° C. for 30 min then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound (2.3 g, 90%). 1H-NMR (CDCl3) δ 8.02 (d, 1H, J=1.8 Hz), 7.53 (dd, 1H, J1=1.8 Hz, J2=12.0 Hz), 7.32 (s, 1H), 7.15 (d, 1H, J=12 Hz), 3.78 (s, 3H), 2.84 (tr, 2H, J=12 Hz), 2.15 (s, 3H), 1.32 (tr, 2H, J=12 Hz).
To a solution of methyl (E)-2-(2-(2-bromo-4-(2-hydroxyethyl)phenyl)hydrazono) propanoate (2.3 g, 7 mmol) in MeCN (20 mL) was added Cs2CO3 (2.8 g, 84 mmol) followed by MeI (480 μL, 77 mmol) at RT. The reaction mixture was stirred at RT for 15 h. The reaction was quenched with brine, extracted with EtOAc and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-5% gradient) to afford the title compound (2.4 g, 94%).
The title compound (650 mg, 30%) was prepared following the procedure described Example 680 Step B using methyl (E)-2-(2-(2-bromo-4-(2-hydroxyethyl)phenyl)-2-methylhydrazono)propanoate (2 g, 62 mmol) by heating at 90° C. for 6 h. 1H-NMR (CDCl3) δ 7.44 (s, 1H), 7.41 (s, 1H), 7.18 (s, 1H), 4.47 (s, 3H), 4.31 (tr, 2H, J=12 Hz), 3.90 (s, 3H), 3.29 (tr, 2H, J=12 Hz), 2.06 (s, 3H).
The title compound (98 mg, 80%) was prepared following General coupling procedure A using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-(2-acetoxyethyl)-7-bromo-1-methyl-1H-indole-2-carboxylate. MS (ES) 812.3 (M+H)
To a solution of methyl (R)-5-(2-acetoxyethyl)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (130 mg, 0.16 mmol) in MeOH/THF (3/1.4 mL) was added solid NaOMe (10 mg, 0.176 mmol) at −40° C. The reaction mixture was wormed to RT over 1 h and few drops of water, methanol and silica gel were added then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-10% gradient) to afford the title compound (100 mg, 81%). MS (ES) 770.3 (M+H).
To a solution of methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(2-hydroxyethyl)-1-methyl-1H-indole-2-carboxylate (110 mg, 0.143 mmol) in DCM was added Dess-Martin periodinane (91 mg, 0.22 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with DCM, washed with sat NaHCO3, dried and concentrated to yield the title compound, which was used in next step without further purification. MS (ES) 768.3 (M+H).
To a solution of methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(2-oxoethyl)-1H-indole-2-carboxylate (30 mg, 0.039 mmol) in DCE (2 mL) was added morpholine (6 PL, 0.059 mmol) and stirred at RT for 30 min then NaBH(OAc)3 was added. The reaction mixture was stirred at RT for 1 h then concentrated. The residue was subjected to saponification using General procedure D to give the title compound (20 mg, TFA salt, 54%). MS (ES) 825.3 (M+H).
The title compound (206 mg, 36%) following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (400 mg, 0.61 mmol) and methyl 5-(benzyloxy)-7-iodo-1H-indole-2-carboxylate (420 mg, 1.03 mmol) in toluene instead of DMF. LCMS. RT=2.153 min, MS (ES) 933.9 (M+H).
The title compound (33 mg, 64%) was prepared following General Procedure I using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indole-2-carboxylate (51 mg, 0.054 mmol) and MeI (20 mg, 0.14 mmol). LCMS: RT=2.286 min (Method B), MS (ES) 947.8 (M+H).
The title compound (26 mg, 87%) was prepared following the procedure described Example 390 Step D using methyl (R)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-2-carboxylate (33 mg, 0.035 mmol) and Pd/C (10 wt. %, 10 mg, 0.0093 mmol) by hydrogenating in MeOH (5 mL) for 16 h at RT. LCMS: RT=1.869, 1.928 min (Method B), MS (ES) 857.8 (M+H).
The title compound was prepared following General Procedure H using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-hydroxy-1-methyl-1H-indole-2-carboxylate (26 mg, 0.030 mmol) and 1-bromo-2-methoxyethane (15 mg, 0.11 mmol). The crude reaction mixture was carried forward to the next step without further purification. LCMS: RT=2.059, 2.139 min (Method B), MS (ES) 915.8 (M+H).
In a microwave vial equipped with a stir bar, methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-(2-methoxyethoxy)-1-methyl-1H-indole-2-carboxylate (from Step 4) was dissolved in THF (2 mL). Tetrabutylammonium fluoride (1.0 M, 0.75 mL, 0.75 mmol) was added and the reaction was capped and heated to 110° C. for 45 min. The reaction was diluted into DCM/H2O (1:1, 10 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×5 mL), and the combined organic layers were dried with a phase separator and concentrated in vacuo. The crude reaction product was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-95% CH3CN, 0.1% TFA to yield the title compound (9 mg, 38% yield over Steps 4 and 5). LCMS: RT=1.227 min (Method), MS (ES) 771.9 (M+H).
The title compound (742 mg, 76%) was prepared following General Procedure C using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (750 mg, 1.14 mmol) and ethyl 7-iodo-5-methyl-1H-indole-2-carboxylate (600 mg, 1.82 mmol) in toluene instead of DMF. LCMS: RT=1.944 min, MS (ES) 857.8 (M+H).
The title compound (152 mg, 68%) was prepared following General Procedure I using ethyl (R)-7-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (210 mg, 0.25 mmol) and 1-bromo-2-methoxyethane (80 mg, 0.58 mmol). LCMS: RT=2.023, 2.050 min, MS (ES) 915.9 (M+H).
The title compound (15.6 mg, 51%) was prepared following General Procedure J using ethyl (R)-7-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(2-methoxyethyl)-5-methyl-1H-indole-2-carboxylate (29 mg, 0.035 mmol) and morpholine (25 mg, 0.29 mmol) followed by saponification using General Procedure D. LCMS: RT=2.021 min, MS (ES) 866.8 (M+H).
The title compound (146 mg, 28%) was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (400 mg, 0.61 mmol) and ethyl 7-iodo-5-methyl-1H-indole-2-carboxylate (400 mg, 1.21 mmol) in toluene instead of DMF and stirred for 5 days. LCMS: RT=2.092 min. MS (ES) 855.9 (M+H).
The title compound was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (55 mg, 0.064 mmol) and 1-bromo-2-methoxyethane (20 mg, 0.14 mmol). LCMS: RT=2.217, 2.260 min (Method B), MS (ES) 913.9 (M+H).
To a solution of ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(2-methoxyethyl)-5-methyl-1H-indole-2-carboxylate in THF (2 mL) was added TBAF (1.0 M, 0.75 mL, 0.75 mmol), and the reaction was stirred at 110° C. for 45 min. The reaction was diluted into DCM/H2O (1:1, 10 mL) and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layer was dried and concentrated in vacuo. The crude reaction product was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 40-95% CH3CN, 0.1% TFA to yield the title compound (23.8 mg, 49% 2 steps). LCMS: RT=2.129 min, MS (ES) 755.8 (M+H).
The title compound (22 mg, 57%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1H-indole-2-carboxylate (35 mg, 0.041 mmol) and 2-(chloromethyl)pyridine HCl (30 mg, 0.12 mmol). LCMS: RT=1.838, 1.891 min, MS (ES) 946.9 (M+H).
The title compound (9 mg, 49%) was prepared following the procedure described Example 718 Step C using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-methyl-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (22 mg, 0.023 mmol). LCMS: RT=1.998 min, MS (ES) 788.8 (M+H).
The title compound (180 mg, 69%) was prepared following the procedure described Example 388 Step A using 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (273 mg, 0.68 mmol) and 2-(3-bromo-1H-1,2,4-triazol-1-yl)pyrimidine (140 mg, 0.62 mmol). LCMS: RT=2.019 min, MS (ES) 421.0 (M+H).
The crude title compound (170 mg) was prepared following the procedure described Example 388 Step B using 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(1-(pyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (180 mg, 0.43 mmol). LCMS: RT=2.183 min, MS (ES) 546.9 (M+H).
The crude title compound (170 mg) was prepared from the procedure described Example 420 Step C using 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-iodo-5-(1-(pyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indole (170 mg, 0.31 mmol). LCMS: RT=1.275 min. MS (ES) 432.9 (M+H).
The crude title compound (250 mg) was prepared following General Procedure J using 2-(3-iodo-5-(1-(pyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethan-1-ol (170 mg, 0.39 mmol) and morpholine (338 μL, 3.92 mmol). LCMS: RT=1.317 min, MS (ES) 501.9 (M+H).
The title compound (22 mg, 43%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (30 mg, 0.06 mmol) and 4-(2-(3-iodo-5-(1-(pyrimidin-2-yl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl)morpholine (36 mg, 0.07 mmol). LCMS: RT=1.994 min, MS (ES) 911.8 (M+H).
A solution of 5-bromo-2,3-dimethoxybenzaldehyde (1.0 g, 4.1 mmol) was stirred at 0° C. under Ar in 1:1 MeOH/THF (4 mL). A solution of methyl azidoacetate (1.6 mL, 16.3 mmol) in MeOH (2 mL) was added. The reaction mixture was cooled to −20° C. and a mixture of NaOMe (881 mg, 16.3 mmol) in MeOH (12 mL) was added dropwise. After stirring 15 min, the reaction was placed in an ice-bath and stirred for about 6 h then was left to sit overnight in a freezer. The reaction was quenched with aq. Sat. NH4Cl and diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organics was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, hex/EtOAc=0-12.5% gradient) to give the title compound (903 mg, 65%). LCMS: RT=2.04 min; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J=2.2 Hz, 1H), 7.27 (d, J=2.2 Hz, 1H), 7.04 (s, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H).
A solution of methyl (Z)-2-azido-3-(5-bromo-2,3-dimethoxyphenyl)acrylate (523 mg, 1.53 mmol) in toluene (31 mL) was irradiated under microwave at 200° C. for 15 minutes. The reaction mixture was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-10% gradient) to give the title compound (282 mg, 59%). LCMS: RT=1.71 min, MS (ES) 314 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.35 (s, 1H), 7.22 (s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H).
The title compound (8 mg, 11%) was prepared following General Procedure B using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (50 mg, 0.09 mmol), methyl 7-bromo-4,5-dimethoxy-1H-indole-2-carboxylate (58 mg, 0.19 mmol), CuI (9 mg, 0.05 mmol), (trans)-1,2-N,N′-dimethylaminocyclohexane (7 mg, 0.05 mmol), and K3PO4 (59 mg, 0.28 mmol). LCMS: RT=1.52 min, MS (ES) 772 (M+H).
The title compound (4 mg, 50%) was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4,5-dimethoxy-1H-indole-2-carboxylate (8 mg, 0.01 mmol) and MeI (6 mg, 0.04 mmol) followed by saponification using General Procedure D. LCMS: RT=2.18 min, MS (ES) 772 (M+H).
The title compound (66 mg, 72%) was prepared following General Procedure B using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (60 mg, 0.09 mmol) and 4-(2-(3-iodo-5-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl)ethyl) morpholine (57 mg, 0.12 mmol). LCMS: RT=2.181 min, MS (ES) 1009.8 (M+H).
The title crude compound (19 mg, 33% yield) was prepared following the procedure described Example 390 Step D using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(5-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)-1-(2-morpholinoethyl)-1H-indol-3-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (66 mg, 0.07 mmol). LCMS: RT=1.892 min, MS (ES) 919.9 (M+H).
The title compound (6.5 mg, 32%) was prepared following General Procedure J using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(2-(hydroxymethyl)-4,6-dimethylpyrimidin-5-yl)-2-(5-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)-1-(2-morpholinoethyl)-1H-indol-3-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (19 mg, 0.02 mmol). LCMS. RT=2.080 min, MS (ES) 1015.9 (M+H).
The title compound (30 mg, TFA salt, 81%) was prepared following the procedure described Example 715 Step I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(2-oxoethyl)-1H-indole-2-carboxylate (30 mg, 0.039 mmol) and piperidine (6 μL, 0.059 mmol). MS (ES) 823.3 (M+H).
The title compound (176 mg, 34%) was prepared following General Procedure C using (R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (400 mg, 0.61 mmol) and methyl 7-iodo-4-methoxy-1H-indole-2-carboxylate (400 mg, 1.21 mmol) in toluene instead of DMF. LCMS: RT=1.917 min, MS (ES) 857.8 (M+H).
The title compound was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (45 mg, 0.53 mmol) and 2-(chloromethyl)pyridine HCl (25 mg, 0.15 mmol). LCMS: RT=1.811, 1.860 min (Method B), MS (ES) 948.9 (M+H).
The title compound (6 mg, 14% 2 steps) was prepared following the procedure described Example 718 Step C using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate. LCMS: RT=1.066 min (Method B), MS (ES) 804.9 (M+H).
The title compound (30 mg, TFA salt, 71%) was prepared following the procedure described Example 715 Step I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-5-(2-oxoethyl)-1H-indole-2-carboxylate (30 mg, 0.039 mmol) and 1-methylpiperazine (7 μL, 0.059 mmol). 1H-NMR (DMSO-d6) δ 7.79 (d, 1H, J=6 Hz), 7.60 and 7.55 (s, total 1H), 7.34 (d, 1H, J=6 Hz), 7.31 and 7.30 (two s, total 1H), 7.02 and 7.00 (two s, total 1H), 6.71 and 6.69 (two s, total 2H), 4.62 (m, 11H), 4.39-4.36 (m, 2H), 4.05-3.98 (multiple s and m, total 7H), 3.76-3.66 (several s and m, total 8H), 3.37-3.24 (m, 6H), 3.14-2.98 (m, 2H), 2.85-2.82 (m, 2H), 2.26 (s, 6H), 2.14 and 2.13 (two s, total 2H), 2.06-2.04 (m, total 3H), 2.00 and 1.99 (two s, total 1H), 1.92 and 1.90 (two s, total 2H), 1.21 (d, 2H, J=8 Hz), 1.07 (d, 1H, J=8 Hz); MS (ES) 838.2 (M+H).
The title compound (25 mg, 10%) was prepared following General Procedure B using (R)-6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (200 mg, 0.36 mmol) and ethyl 7-bromo-6-methyl-1H-indole-2-carboxylate (200 mg, 0.72 mmol). LCMS: RT=2.206 min, MS (ES) 740.0 (M+H).
The title compound (17 mg, 68%) was prepared following General Procedure I using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-6-methyl-1H-indole-2-carboxylate (25 mg, 0.03 mmol) and methyl iodide (2.3 μL, 0.04 mmol). LCMS: RT=1.738 min, MS (ES) 753.9 (M+H).
The title compound (6 mg, 37%) was prepared following General Procedure D using ethyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1,6-dimethyl-1H-indole-2-carboxylate (17 mg, 0.02 mmol). LCMS: RT=1.447 min, MS (ES) 725.8 (M+H).
The title compound was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (48 mg, 0.056 mmol) and MeI (20 mg, 0.14 mmol). LCMS: RT=2.040 min, MS (ES) 871.8 (M+H).
The title compound (23.1 mg, 57% 2 steps) was prepared following the procedure described Example 718 Step C using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate. LCMS: RT=2.071 min, MS (ES) 727.9 (M+H).
The title compound was prepared following General Procedure I using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1H-indole-2-carboxylate (48 mg, 0.056 mmol) and 1-bromo-2-methoxyethane (20 mg, 0.14 mmol). LCMS: RT=2.086, 2.124 min (Method B), MS (ES) 915.8 (M+H).
The title compound (12.1 mg, 28% 2 steps) was prepared following the procedure described Example 718 Step C using methyl (R)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-methoxy-1-(2-methoxyethyl)-1H-indole-2-carboxylate. LCMS: RT=2.081 min, MS (ES) 771.9 (M+H).
The title compound (10.2 mg, 34%) was prepared following General Procedure J using ethyl (R)-7-(6-(2-((benzyloxy)methyl)-4,6-dimethylpyrimidin-5-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-(2-methoxyethyl)-5-methyl-1H-indole-2-carboxylate (29 mg, 0.035 mmol) and 1-methylpiperazin-2-one (20 mg, 0.18 mmol) followed by saponification using General Procedure D. LCMS: RT=1.989, 2.021 min, MS (ES) 893.8 (M+H).
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (180 mg, 0.34 mmol) in DMF (10 mL) was added NaH (18 mg, 0.75 mmol) and stirred at RT for 30 min. 4-(2-Bromoethyl)morpholine (100 mg, 0.515 mmol) was added and the reaction mixture was stirred for 5 h at RT. The reaction was quenched with H2O, diluted into DCM/brine (40 mL, 1:1), the organic layer was separated, and extracted with DCM. The combined organic extract was dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Combi-flash Rf, DCM/MeOH=0-20% gradient) to afford the title compound (198 mg, 94% yield).
To a solution of 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20 mg, 0.033 mmol) in DCM (2 mL) and DMF (20 μL) was added oxalyl chloride (5 mg, 0.039 mmol) at RT and stirred for 30 min. Et3N (25 mg, 0.24 mmol) was added to the reaction mixture followed by methyl 3-(methylamino)benzoate (30 mg, 0.18 mmol), and the reaction was stirred at RT until complete by LCMS. The reaction was diluted into DCM/H2O (10 mL, 1:1) and extracted with DCM (2×5 mL). The combined organic extract was concentrated in vacuo and purified by reverse phase preparative HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient 35-95% MeCN 0.1% TFA). The resulting ester intermediate was saponified using General Procedure D to afford the title compound (4 mg, 16% yield). LCMS: RT=1.661 min, MS (ES) 745.8 (M+H).
The title compound (7 mg, 28% yield) was prepared following the same procedure as described in Example 730 employing 3-[[6-chloro-3-[3-(4-chloro-3,5-dimethyl-phenoxy)propyl]-1-(2-morpholinoethyl)-7-(1,3,5-trimethylpyrazol-4-yl)indole-2-carbonyl]-methyl-amino]benzoic acid (20 mg, 0.033 mmol) and 4-(methylamino)benzoate (30 mg, 0.18 mmol). LCMS: RT=1.626 min, MS (ES) 745.8 (M+H).
The title compound was prepared following General procedure E using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (0.043 mmol) and methyl 3-(piperazin-1-yl)benzoate (0.086 mmol), HBTU (0.158 mmol). MS (ES) 702.3 (M+H).
Methyl 3-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate was dissolved in THF and 2N aq. LiOH solution (2:1), and the mixture was stirred for 24 h at ambient temperature. The reaction was acidified with 4 M HCl to pH 7, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo. The residue was purified by the reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-75% CH3CN, 0.1% TFA) to give the title compound. MS (ES) 688.2 (M+H).
The title compound was prepared following the same procedure described in Example 730 Step B using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20 mg, 0.033 mmol) and methylamine hydrochloride (25 mg, 0.38 mmol).
The title compound (1.4 mg, 5% yield) was prepared following General coupling procedure A using the product obtained in Step 1, methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (15 mg, 0.056 mmol), Pd2(dba)3 (3 mg, 0.0032 mmol), Xantphos (6 mg, 0.010 mmol), and cesium carbonate (30 mg, 0.092 mmol), followed by subjection to General Procedure D using LiOH (5 mg, 0.21 mmol). LCMS: RT=1.695 min, MS (ES) 798.7 (M+H).
To a solution of 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (25 mg, 0.05 mmol) in DMF (1 mL) were added methyl 5-(piperazin-1-yl)nicotinate (11 mg, 0.05 mmol), HBTU (70 mg, 0.185 mmol), triethylamine (56 μL, 0.4 mmol), and the mixture was stirred at RT for 10 h. The reaction was quenched with H2O (5 mL) and extracted with DCM (3×5 mL). The combined organic layer was dried and concentrated in vacuo. The residue was dissolved in DMF (1 mL), and NaH (6 mg, 0.15 mmol) was added at RT. The reaction mixture was stirred for 30 min at RT then a solution of 3-(bromomethyl)pyridine hydrobromide (15 mg, 0.06 mmol) in DMF (1 mL) was added dropwise. The resulting reaction mixture was stirred for additional 2 h at RT. The reaction was quenched with water (4 mL) and extracted with DCM (3×5 mL). The organic layer was dried and concentrated. The residue was dissolved in THF (2 mL) and 2 M aq. LiOH solution (1 mL) and the mixture was stirred at RT for 10 h. The reaction mixture was concentrated, acidified to pH 7 with 4 M HCl, and extracted in EtOAc. The organic layer was dried, concentrated and purified by reverse phase HPLC (Phenomenex Gemini C18, H2O/CH3CN gradient from 30-70% CH3CN, 0.1% TFA) to give the title compound (33 mg, 77%) as a white solid. MS (ES) 780.2 (M+H).
To a solution of methyl 3-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate (0.05 mmol) in DMF (1 mL) was added NaH (6 mg, 0.15 mmol) and stirred for 30 min at ambient temperature. A solution of 3-(bromomethyl)pyridine hydrobromide (15 mg, 0.06 mmol) in DMF (1 mL) was added dropwise to the reaction mixture at room temperature and stirred for additional 2 h. The title compound was obtained by following the saponification procedure described Example 734 (80% yield) as a white solid; MS (ES) 779.2 (M+H).
The title compound was prepared following the procedure described Example 732 Step A and B using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid methyl 5-(piperazin-1-yl)picolinate. MS (ES) 689.1 (M+H).
The title compound was prepared following the procedure described Example 734 by substituting methyl 5-(piperazin-1-yl)nicotinate with methyl 5-(piperazin-1-yl)picolinate. MS (ES) 778.3 (M+H).
The title compound was prepared following the procedure described Example 732 Step A and B using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid and methyl 4-(piperazin-1-yl)nicotinate. MS (ES) 689.1 (M+H).
The title compound was prepared following the procedure described Example 734 by substituting methyl 5-(piperazin-1-yl)nicotinate with methyl 2-(piperazin-1-yl)benzoate. MS (ES) 777.3 (M+H).
The title compound was prepared following the procedure described Example 732 Step A and B using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid and methyl 5-(piperazin-1-yl)nicotinate. MS (ES) 689.1 (M+H).
The title compound was prepared following the procedure described Example 734 by substituting methyl 5-(piperazin-1-yl)nicotinate with methyl 2-(piperazin-1-yl)isonicotinate. MS (ES) 778.3 (M+H).
The title compound was prepared following the procedure described Example 734 by substituting methyl 5-(piperazin-1-yl)nicotinate with methyl 4-(piperazin-1-yl)picolinate. MS (ES) 778.3 (M+H).
The title compound was prepared following the procedure described Example 732 Step A and B using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid and methyl 2-(piperazin-1-yl)isonicotinate. MS (ES) 689.1 (M+H).
The title compound was prepared following the procedure described Example 732 Step A and B using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid and methyl 2-(piperazin-1-yl)benzoate. MS (ES) 686.1 (M+H).
To a solution of ethyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,6-dimethylpyrimidin-5-yl)-1H-indole-2-carboxylate (13 mg, 0.025 mmol in THF, MeOH, and H2O (3 mL, 0.5 mL, 0.5 mL), and LiOH (5 mg, 0.21 mmol) was added. The reaction was heated to 50° C. for 3 h. The reaction was acidified with 2 M HCl, diluted with brine (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were dried by passage through a phase separator and concentrated in vacuo. The crude residue was subjected to amide coupling following General Procedure E using methyl pyrrolidine-3-carboxylate (10 mg, 0.078 mmol), HATU (15 mg, 0.39 mmol), and DIPEA (20 mg, 0.15 mmol) followed by saponification using General Procedure D to afford the title compound (2 mg, 14% yield). LCMS: RT=1.792 min, MS (ES) 595.2 (M+H).
The title compound (1.3 mg, 9% yield) was prepared following the reaction sequence and procedures described in Example 745 substituting methyl pyrrolidine-3-carboxylate with methyl 4-aminocyclohexane-1-carboxylate (10 mg, 0.070 mmol). LCMS: RT=1.910 min, MS (ES) 623.2 (M+H). Described reaction sequence resulted in mixture of cis/trans isomers. They were separated but stereochemistry was not determined.
The title compound (1.2 mg, 8% yield) was obtained along with Example 746. LCMS: RT=1.927 min, MS (ES) 623.2 (M+H). Stereochemistry was not determined.
The title compound (2.8 mg, 18% yield) was prepared following the reaction sequence and procedures described in Example 745 substituting methyl pyrrolidine-3-carboxylate with methyl 3-(ammomethyl)benzoate (10 mg, 0.061 mmol). LCMS: RT=1.925 min, MS (ES) 631.2 (M+H).
The in vitro modulation of Bcl-2 family proteins was determined as follows.
Bak Peptide Binding Assay
General
Provided compounds of the present invention can be demonstrated to compete for binding with fluorescently labeled peptides derived from relevant BH3 domains. In some embodiments, a provided compound exhibit selectivity for Mcl-1 over Bcl-xL and Bcl-2.
Fluorescence Polarization Anisotropy Competition Assay
Anisotropy measurements were carried out in 384-well, black, flat-bottom plates (Greiner Bio-one, Monroe, NC, USA). The assay was run using either a fluorescein isothiocyanate-labeled BH3 peptide derived from Bak (FITC-AHx-GQVGRQLAIIGDDINR-NH2) or a fluorescein isothiocyanate-labeled BH3 peptide derived from Bim (FITC-AHx-EARIAQELRRIGDEFNETYTR-NH2) that were purchased from GenScript (Piscataway. NJ) at >95% purity and used without further purification, 10 nM FITC-Bak peptide and 15 nM recombinant Mcl-1 (residues 172-327) were added to assay buffer (3 mM dithiothreitol, 50 mM NaCl, 20 mM Tris, pH 7.5). The Bim based assay was run with 1 nM FITC-Bim peptide and 1.5 nM recombinant Mcl-1 (residues 172-327) added to assay buffer (20 mM TRIS pH 7.5, 50 mM NaCl, 3 mM DTT, 0.01% CHAPS). For selectivity assays, 40 nM Bcl-2 (residues 1-207A96T, G110R, Δ35-91, replaced with Bcl-xL35-50) or 4 nM Bcl-xL (residues 1-209, loop 45-86 deleted) were incubated with 10 nM FITC-Bak in assay buffer.
Compounds are diluted in DMSO in a 10-point, 3-fold serial dilution scheme. For the FITC-BAK assay 2.5 uL compound is added to 47.5 μL of assay buffer containing FITC-Bak and protein, for a final DMSO concentration of 5% and a top concentration of 20 PM. A FITC-Bak peptide alone (100% inhibition) and peptide plus protein (0% inhibition) control is included on each assay plate. For the FITC-Bim assay, compound is added to 40 uL of assay buffer containing protein, 15 minutes prior to addition of 10 μL of the FITC-Bim peptide, for a final DMSO concentration of 0.165% and a top concentration of 200 nM. A FITC-Bim peptide alone (100% inhibition) and peptide plus protein (0% inhibition) control is included on each assay plate. The plate was mixed and incubated for 90 minutes at room temperature. Anisotropy is measured at excitation wavelength 480 nm and emission wavelength 535 nm using an EnVision Multi-label plate reader (PerkinElmer, Wellesley, MA, USA) or a BioTek Cytation 3 (BioTek, Winooski, VT, USA). Fluorescence anisotropy is plotted against compound concentration to generate an IC50 (inhibitor concentration at which 50% of bound peptide is displaced) by fitting the data to a 4-parameter logistic model using XLFit software (Guildford, Surrey, UK). IC50 is converted to a binding dissociation constant (Ki value) according to the formula of Wang Z. FEBS Lett (1996) 3, 245.
Ki=[I]50/([L]50/Kd+[P]0/Kd+1)
where [I]50 is the concentration of the free inhibitor at 50% inhibition, [L]50 is the concentration of the free labeled ligand at 50% inhibition, [P]0 is the concentration of the free protein at 0% inhibition, Kd represents the dissociation constant of the FITC peptide probe.
TR-FRET Binding Assay
Measurements were carried out in OptiPlate-384 White Opaque 384-well plates (Perkin Elmer. Shelton, CT). The assay was run using a fluorescein isothiocyanate-labeled BH3 peptide derived from Bak (FITC-AHx-GQVGRQLAIIGDDINR-NH2) that was purchased from GenScript (Piscataway, NJ) at >95% purity and used without further purification, 300 nM FITC-Bak peptide, 1 nM recombinant Maltose Binding Protein (MBP) tagged Mcl-1 (residues 172-327) and 1 nM terbium conjugated-MBP antibody were added to assay buffer (4.5 mM Monobasic potassium phosphate, 15.5 mM Dibasic potassium phosphate, 1 mM Sodium EDTA, 50 mM NaCl, 1 mM DTT, 0.05% Pluronic F-68, pH 7.5). Compounds are diluted in DMSO in a 16-point, semilog serial dilution scheme. For the BAK FITC TR-FRET assay 50 nL compound is added to 20 μL of assay buffer containing Bak-FITC, MBP tagged Mcl-1 protein and antibody, for a final DMSO concentration of 0.25% and a top concentration of 10 μM. A FITC-Bak peptide alone (100% inhibition) and peptide plus protein (0% inhibition) control is included on each assay plate. The plate was mixed and incubated for 3 hours at room temperature. TR-FRET signal (Delta F) is measured on a Biotek Cytation 3 multimode plate reader equipped with a filter cube containing an Ex 340/30 Em 620/10 nm filter and an Ex 340/30 Em 520 filter. TR-FRET signal is plotted and IC50 and Ki values are calculated in the same manner as the fluorescence polarization anisotropy based competition assays. The results for representative compounds are shown in Table 2 and 3.
Among other things, these data demonstrate the utility of representative compounds as selective inhibitors of the activity of Mcl-1 protein to bind peptides from relevant BH3 domains.
Cellular Viability of Human Tumor Cell Lines
Human cancer cell lines ALMC-1, ALMC-2, K562, H929, and OPM-2 were cultured in media supplemented with 10% fetal bovine serum (FBS). To evaluate compound effect on cellular proliferation, cells were plated at 1,000 cells/well in 96-well tissue culture plates in a total volume of 90 μL medium supplemented with 10% FBS (Sigma, Saint Louis, MO). 24 hours later, 10 μL of compound (in a 2-fold serial dilution) is added to the cells for a top concentration of 50 μM and a final DMSO concentration <1%. After 72 hours, 50 μL of Cell TiterGlo (Promega, Madison, Wisconsin, USA) reagent is added to each well and plates are incubated at room temperature, in the dark, for 30 minutes. Luminescence is measured on a BioTek Cytation 3. Luminescence values are imported into a template in XLFit (Guildford, Surrey, UK) that uses a four-parameter fit to generate an IC50 value for each compound dilution series on the plate.
Apoptosis Assay Protocol (Caspase 3/7 Glo)
Induction of apoptosis was measured by quantifying caspase 3/7 activity using the commercially available Caspase-Glo reagent (Promega, Madison, Wisconsin, USA). This assay relies on the cleavage of a proluminescent substrate by activated caspases, which is then detected on the BioTek Cytation 3. 5000 cells in 90 μL of media (+5% FBS) are plated in each well of a white 96-well plate and incubated overnight at 37° C. in a tissue culture incubator. The following day, compound is diluted in a 10-pt, 2-fold serial dilution scheme for a final top concentration of 50 μM. 10 μL of compound is added directly to the cell assay plate for a final volume of 100 μL. Columns 11 and 12 are reserved for treatment with DMSO to serve as control wells. Plates are incubated for 3 hours. 100 μL of Caspase-Glo reagent is added to each well and plates are incubated at room temperature, in the dark, for 30 minutes. Luminescence is measured on the Cytation 3. Luminescence values are imported into a template in XLFit (Guildford, Surrey, UK) that uses a four-parameter fit to generate an IC50 value for each compound dilution series on the plate.
Among other things, these data demonstrate the utility of representative compounds as inhibitors of cellular proliferation of human cancer cell lines and initiators of apoptosis via caspase 3 and 7 activation in a Mcl-1 sensitive human cancer cell line.
While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.
This patent application is a continuation of U.S. application Ser. No. 16/081,709, filed Aug. 31, 2018, which is the U.S. national stage entry, under 35 U.S.C. § 371, of international application number PCT/US2017/020,699, filed Mar. 3, 2017, which claims the benefit of U.S. provisional application Ser. No. 62/304,124, filed Mar. 4, 2016, and U.S. provisional application Ser. No. 62/402,903, filed Sep. 30, 2016, the entire contents of each being incorporated herein by reference in its entirety.
This invention was made with government support under Award DP1OD006933/DPI CA174419, awarded by the National Institutes of Health, under Contract No. HHSN26120080000IE, awarded by the NCI Experimental Therapeutics (NExT) Program; and under Grant No. P50CA098131, awarded by the NCI SPORE grant in breast cancer. The government has certain rights in the invention.
| Number | Name | Date | Kind |
|---|---|---|---|
| 4703053 | Connor et al. | Oct 1987 | A |
| 4980368 | Thielke et al. | Dec 1990 | A |
| 4994477 | Kempf et al. | Feb 1991 | A |
| 5324725 | Jasserand et al. | Jun 1994 | A |
| 5436264 | Pfister et al. | Jul 1995 | A |
| 6500853 | Seehra et al. | Dec 2002 | B1 |
| 6787651 | Stolle et al. | Sep 2004 | B2 |
| 10533010 | Lee et al. | Jan 2020 | B2 |
| 20030109533 | Lavielle et al. | Jun 2003 | A1 |
| 20050124675 | Hsieh et al. | Jun 2005 | A1 |
| 20090054402 | Wang et al. | Feb 2009 | A1 |
| 20090270497 | Buggy | Oct 2009 | A1 |
| 20100009986 | Zemolka et al. | Jan 2010 | A1 |
| 20100009991 | Terasaka et al. | Jan 2010 | A1 |
| 20110263599 | Song et al. | Oct 2011 | A1 |
| 20120172285 | Walensky et al. | Jul 2012 | A1 |
| 20140005386 | Doemling | Jan 2014 | A1 |
| 20140322229 | Wang et al. | Oct 2014 | A1 |
| 20150336925 | Lee et al. | Nov 2015 | A1 |
| Number | Date | Country |
|---|---|---|
| 639573 | Feb 1995 | EP |
| 2161266 | Mar 2010 | EP |
| 2761070 | Sep 1998 | FR |
| S62181252 | Aug 1987 | JP |
| 3739432 | Jan 2006 | JP |
| 2013537191 | Sep 2013 | JP |
| 2014533734 | Dec 2014 | JP |
| 9742188 | Nov 1997 | WO |
| 9810778 | Mar 1998 | WO |
| 199842710 | Sep 1998 | WO |
| 2006034391 | Mar 2006 | WO |
| 2007112322 | Oct 2007 | WO |
| 2010123507 | Oct 2010 | WO |
| 2011157668 | Dec 2011 | WO |
| 2013112878 | Aug 2013 | WO |
| 2014047427 | Mar 2014 | WO |
| 2015031608 | Mar 2015 | WO |
| 2015148854 | Oct 2015 | WO |
| Entry |
|---|
| Australian Patent Office Action for Application No. 2015235944, dated Aug. 28, 2019, 6 pages. |
| Australian Patent Office Action for Application No. 2015235944, dated May 7, 2020 (10 pages). |
| Australian Patent Office Examination Report No. 1 for Application No. 2017228385 dated Oct. 16, 2020 (64 pages). |
| Australian Patent Office Examination Report No. 2 for Application No. 2017228385 dated Apr. 7, 2021 (3 pages). |
| Brazilian Patent Office Search Report and Written Opinion for Application No. BR112018067775-2 dated Aug. 12, 2021 (7 pages including English translation). |
| Chan et al., “Document No. 150:563639,” retrieved from STN; May 22, 2009. |
| Chilean Patent Office Examination Report for Application No. 201802516 dated Nov. 13, 2019 (17 pages including partial English translation). |
| Chilean Patent Office Examination Report for Application No. 201802516 dated Nov. 2, 2020 (13 pages including statement of relevance). |
| EP14839887.8 Extended European Search Report dated May 30, 2017 (13 pages). |
| EP15768818.5 Extended European Search Report dated Jul. 28, 2107 (16 pages). |
| Eurasian Patent Office Action for Application No. 201891988/28, with English Translation, dated Jun. 5, 2019, 9 pages. |
| European Patent Office action for Application No. 17760914.6 dated Nov. 25, 2021 (3 pages). |
| European Patent Office Examination Report for Application No. 17760914.6 dated Apr. 6, 2021 (4 pages). |
| European Patent Office Examination Report for Application No. 17760914.6 dated Jul. 1, 2020 (4 pages). |
| European Patent Office Extended Search Report for Application No. 17760914.6 dated Jul. 11, 2019 (5 pages). |
| Friberg, “Discovery of Potent Myeloid Cell Leukemia 1 (Mcl 1) Inhibitors Using Fragment Based Methods and Structure Based Design,” manuscript (2014) pp. 1-38, National Institutes of Health. |
| Golub et al., “Molecular classification of cancer: class discovery and class prediction by gene expression monitoring,” Science (1999), vol. 286, 531-537. |
| Hung et al, “Document No. 152:66468, Caplus,” retrieved from STN; Oct. 28, 2009. |
| Intellectual Property Office of India Examination Report for Application No. 201817035157 dated Jun. 29, 2020 (7 pages including English translation). |
| Intellectual Property Office of the Phillipines Bureau of Patents Substantive Examination Report for Application No. 1/2018/501877 dated Oct. 1, 2020 (51 pages). |
| Jansen et al., “Document No. 140:111233, Caplus,” retrieved from STN; Oct. 22, 2009. |
| Japanese Patent Office Action for Application No. 2017502932 dated Dec. 6, 2018, with translation, 19 pages. |
| Japanese Patent Office Action for Application No. 2018-546464 dated Feb. 21, 2021 (12 pages including English translation). |
| Kalaus et al., “Synthesis of vinca alkaloids and related compounds. 63. A new synthetic pathway for preparing alkaloids and related compounds with the aspidosperma skeleton. Total syntheses of (.+−.)-vincadifformine, (.+−.)-tabersonine, and (.+−.)-oxotabersonine.” The Journal of Organic Chemistry. Mar. 1993,58(6):1434-42. |
| Korean Intellectual Property Office Notice of Preliminary Rejection for Application No. 10-2018-7028435 dated Jul. 27, 2021 (11 pages including English translation). |
| Lala et al., “Role of nitric oxide in tumor progression: lessons from experimental tumors,” Cancer and Metastasis Reviews (1998), 17(1), 91-106. |
| Lee et al., “Discovery and biological characterizaton of potent myeloid cell leukemia-1 inhibitors,” article (2016) Febs etters, vol. 591, No. 1, pp. 240-251. |
| Medline Plus, “Cancer” retrieved from http://www.nlm.nih.gov/medlineplus/cancer.html on Jul. 6, 2007. |
| Mexican Institute of Industrial Property office action for Application No. MX/a/2018/010678 dated Nov. 3, 2021 (10 pages including statement of relevance). |
| Mexican Patent Office Action for Application No. MX/a/2018/010678 dated Apr. 20, 2021 (8 pages including English summary). |
| Mexican Patent Office Action for Application No. MX/a/2018/010678 dated Sep. 25, 2020 (52 pages including English translation). |
| National Intellectual Property Adminitration People's Republic of China First Office Action for Application No. 201780027686.5 dated Jul. 23, 2021 (19 pages including English translation). |
| PCT/US2013/060881 International Search Report and Written Opinion dated May 5, 2014 (11 pages). |
| PCT/US2014/053148 International Preliminary Report on Patentability dated Mar. 1, 2016 (2 pages). |
| PCT/US2014/053148 International Search Report and Written Opinion dated Jan. 27, 2015 (12 pages). |
| PCT/US2015/022841 International Search Report and Written Opinion dated Jun. 29, 2015 (12 pages). |
| PCT/US2017/020699 International Search Report and Written Opinion dated May 23, 2017 (9 pages). |
| Philippine Patent Office Action for application 1/2018/501877, dated Sep. 23, 2022 (5 pages). |
| Shaw et al., “Optimization of potent and selective tricyclic indole diazepinone myeloid cell leukemia-1 inhibitors using structure-based design.” Journal of medicinal chemistry. Jan. 11, 2018;61(6):2410-21. |
| Shultz et al. “Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.” Journal of medicinal chemistry. Jun. 17, 2011;54(13):4752-72. |
| State of Israel Ministry of Justice Patent Office Notification of Defects in Patent Application No. 261231 dated Jun. 4, 2020 (29 pages including English translation). |
| Tabatabaeian et al., “Solvent-free, ruthenium-catalyzed, regioselective ring-opening of epoxides, an efficient route to various 3-alkylated indoles.” Tetrahedron Letters. Feb. 25, 2008;49(9):1450-4. |
| Tanaka et al., “Discovery of Potewnt Mcl-1/Bcl-xL dual Inhibitors by Using a Hybridization Strategy Based n Structural Analysis of Target Proteins,” article (2013) ACS Publicatons, J. Med. Chem 56, pp. 9635-9645. |
| Vago et al., “Synthesis of vinca alkaloids and related compounds 95. Attempted build-up of the aspidospermidine skeleton by [4+ 2] cycloaddition. Some unexpected reactions, and formation of a new ring system.” Heterocycles. May 1, 2001;55(5):873-80. |
| Wahyuningsih, et al. Document No. 147:235137, retrieved from STN; entered in STN on Jun. 11, 2007. |
| Zhao et al., “Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin,” article (2017) Bio-Organic & Medicinal Chemistry, vol. 25, No. 12, pp. 3087-3092. |
| Canadian Patent Office Action for application 3,016,182, dated Feb. 17, 2023 (7 pages). |
| Number | Date | Country | |
|---|---|---|---|
| 20230330099 A1 | Oct 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62402903 | Sep 2016 | US | |
| 62304124 | Mar 2016 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16081709 | US | |
| Child | 18064206 | US |
