HK40039964B - Tricyclic compounds - Google Patents

Description

tricyclic compounds

【Technical field】

The present invention relates to certain novel tricyclic compounds (Formula I) that are bromodomain and extra-terminal (BET) inhibitors, their synthesis, and their use in treating diseases. More specifically, the present invention is directed to fused heterocyclic derivatives that are BET inhibitors, methods for preparing these compounds, and methods for treating diseases or conditions in which inhibition of one or more BET bromodomains provides a benefit.

[Background Technology]

Several physiological processes may contribute to epigenetic regulation, including DNA methylation, noncoding RNA-mediated scaffolding and complex formation, and histone modification. Histone modification is a process associated with the post-translational covalent modification of histones, which significantly influences the ability of the associated DNA to be transcribed. Lysine acetylation is a post-translational modification with broad relevance to cell signaling and disease biology. The enzymes that regulate lysine acetylation in histones are called "writers" or histone acetyltransferases (HATs), and the enzymes that regulate lysine deacetylation in histones are called "erasers" or histone deacetylases (HDACs). Bromodomains (BRDs), the "readers" of epigenetic marks, specifically recognize ε-N-acetyllysine (Kac) residues on histone tails.

BRD is a conserved 110 amino acid structural domain composed of four α-helices (αZ, αA, αB and αC) that contains a left-handed bundle (S. Mujtaba, L. Zeng, MM Zhou, Oncogene, 2007 (26), 5521-5527). The α-helices are connected by two loop regions (ZA and BC) and form a surface that interacts with acetylated lysines in nucleosomal histones (C. Dhalluin, J. E. Carlson, L. Zeng et al, Nature, 1999 (399), 491-496). Based on structural/sequence similarity, there are 46 known bromodomain-containing proteins from humans, spanning 8 families. Among them, bromodomains and extra-terminal domains (BET) recognize acetylated lysine residues in histones H3 and H4. The BET family, comprising four members, BRD2, BRD3, BRD4, and BRDT, shares two N-terminal bromodomains and an additional C-terminal domain (ET), exhibiting a high degree of sequence conservation. BRD2 and BRD3 have been reported to bind to histones along actively transcribed genes and may be involved in promoting transcription elongation (Leroy et al., Mol. Cell 2008 30(1), 51-60). BRD4 appears to be involved in the recruitment of the positive transcription elongation factor complex (pTEF-I3), which plays an important role in regulating transcription and increasing transcriptional output by RNA polymerase (Hargreaves et al., Cell, 2009 138(1): 1294-145). Unlike the other three BET proteins that are ubiquitously expressed, BRDT expression is typically testis-specific (M.H. Jones et al, Genomics, 1997 (45), 529-534), and BRDT is essential for spermatogenesis (E. Shang et al, Development, 2007 (134), 3507-3515). The binding of BET proteins to acetylated histones results in the recruitment of BET proteins to the enhancer and promoter regions of genes for active transcription. Thereby, they interact with coactivators, repressors, transcription factors, and transcription machinery to form protein complexes and affect target gene transcription (A. Dey et al, Proc. Natl. Acad. Sci, U.S.A. 2003 (100), 8758-8763). Although BET proteins have similar structures and generally enhance transcription, they regulate different processes based on their binding ligands, which are generally tissue-specific.

It is believed that BET proteins mediate their roles in disease pathogenesis and progression primarily by localizing to super enhancers (SEs) of pathology-related genes and driving their expression (M.A.Dawson et al, Nature, 2011(478), 529-533; B.Chapuy et al, Cancer Cell, 2013(24), 777-790). In cancer, SEs are enriched in oncogenes such as MYC, RUNX1, FOSL2, CCND1, MCL1 and BCL2L1 (B. Chapuy et al, Cancer Cell, 2013(24), 777-790; J. Loven, Cell, 2013(153), 320-334; W. A. Whyte et al, Cell, 2013(153), 307-319; D. Hnisz et al Cell, 2013(155), 934-947). Inhibition of BET proteins has emerged as a promising target for the treatment of human diseases, including virology, heart failure, inflammation, central nervous system (CNS) diseases and various cancers (J.M.Sahni et al, Pharmacol Res, 2017, 1-21; P.Anand et al, Cell, 2013(154), 569-582; C.-Y.Wang et al, Trends Biochem. Sci, 2015(40), 468-479; A.Stathis et al, Cancer Discovery, 2017, 8(1), 1-13). Small molecule BET inhibitors reported in clinical development include RVX-208, GSK-525762A, GSK2820151, OTX-015, CPI-0610, TEN-010/RO6870810, ABBV-075/ABBV-744, BI894999, BMS-986158, INCB054329/INCB057643, ZEN-3694, GS-5829, AZD5153, and Celgene's inhibitor. There is a need to generate additional BET inhibitors with improved properties over existing BET inhibitors, for example, improved activity, safety, pharmacokinetics, and/or pharmacodynamics.

[Summary of the invention]

In one aspect, the present invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

in,

X ₁ is selected from O, S, SO, SO ₂ or NR ₁ ;

R ₁ is selected from hydrogen; deuterium; -CN; -SOR ₁₁ ; -SO ₂ R ₁₁ ; -SO ₂ NR ₁₁ R ₁₂ ; -C _1-6 alkyl; -C _2-6 alkenyl; -C _2-6 alkynyl; carboxyl; -NO ₂ ; -COOR ₁₁ ; -COR ₁₁ ; -CONR ₁₁ R ₁₂ ; -POR ₁₁ R ₁₂ ; -C _5-6 aryl; -C 5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; -C _3-8 heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; or _{-C 3-8 carbocycle} ; and each R ₁ is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, halogen, -OH, oxo, -CN, -C _1-6 alkyl, -C _1-6 alkoxy, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , carboxyl or -C _3-8 carbocycle;

each R ₁₁ and R ₁₂ are independently selected at each occurrence from hydrogen, deuterium, -OH, -NH ₂ , -CN, -C _1-6 alkyl, -C _1-6 alkoxy, -C _5-6 aryl; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; -C _1-6 alkylene-C _3-8 carbocycle; or -C _3-8 carbocycle; and each R ₁₁ and R ₁₂ are independently and optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, and each of the substituents is independently selected at each occurrence from deuterium, halogen, -OH, -CN, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkoxy, carboxyl, -SO ₂ (C _1-6 alkyl) or -C _3-8 carbocycle; or

R ₁₁ and R ₁₂ together with the nitrogen atom to which they are commonly attached form a 4-8 membered heterocyclic ring, and each of the heterocyclic rings may further contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ at each occurrence, and each of the heterocyclic rings is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of the substituents is independently selected from deuterium; halogen; -OH; oxo; -CN; -C _1-6 alkyl; -C _1-6 alkoxy; -SO ₂ (C _1-6 alkyl); -CON(C _1-6 alkyl) ₂ ; -SO ₂ N(C _1-6 alkyl) ₂ ; -NH ₂ ; -NH(C _1-6 alkyl); -N(C _1-6 alkyl) ₂ ; -C 1-6 alkyl containing 1 or 2 heteroatoms selected from N, O or S _3-6 heterocycle; or -C _1-6 alkyl substituted by deuterium;

each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium, halogen, -NH ₂ , -C _1-6 alkoxy, or -C _1-6 alkyl; or

R ₁₃ and R ₁₄ together with the carbon atom to which they are commonly attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently, at each occurrence, optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently, at each occurrence, selected from deuterium, halogen, -OH, -NH ₂ , -CN, -C _1-6 alkyl or -C _1-6 alkoxy;

R ₂ is selected from hydrogen; deuterium; halogen; -OR ₂₁ ; -NR ₂₁ R ₂₂ ; -CN; -SR ₂₁ ; -SOR ₂₁ ; -SO ₂ R ₂₁ ; -SO ₂ NR ₂₁ R ₂₂ ; -C _1-6 alkyl; -C _2-6 alkenyl; -C _2-6 alkynyl; carboxyl; -NO ₂ ; -COOR ₂₁ ; -COR ₂₁ ; -CONR ₂₁ R ₂₂ ; -NR ₂₁ COR ₂₂ ; -NR ₂₁ CONR ₂₁ R ₂₂ ; -NR ₂₁ SO ₂ R ₂₂ ; -NR ₂₁ SO ₂ NR ₂₁ R ₂₂ ; -OCONR ₂₁ R ₂₂ ; -POR ₂₁ R ₂₂ ; -C -C _5-6 aryl; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; -C _3-8 heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; or C _3-8 carbocycle; and each R ₂ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of the substituents at each occurrence is independently selected from deuterium, halogen, -OH, oxo, -CN, -NH ₂ , -C _1-6 alkyl, -C _1-6 alkoxy, carboxyl or -C _3-8 carbocycle;

each R ₂₁ and R ₂₂ are independently selected at each occurrence from hydrogen; deuterium; -OH; NH ₂ ; -CN; -C 1-6 alkyl; -C _1-6 alkoxy; -C _5-6 aryl; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; -C _1-6 alkylene-C _3-8 carbocycle; or -C _3-8 carbocycle; and each R ₂₁ and R ₂₂ are independently selected at each occurrence from hydrogen; deuterium; -OH; NH 2 ; -CN; -C _1-6 alkyl; -C 1-6 alkoxy; -C 5-6 aryl; -C 5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2; -C _{1-6 alkylene-C 3-8 carbocycle; or -C 3-8} carbocycle; and each R 21 and R 22 are independently selected at each occurrence from hydrogen; halogen; -OH, -CN, -NH ₂ , -NH(C _1-6 alkyl), -N(C 1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkoxy, carboxyl, -SO ₂ (C _1-6 alkyl) or -C _3-8 carbocycle; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are commonly attached form a 4-8 membered heterocyclic ring, and each of the heterocyclic rings may further contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ at each occurrence, and each of the heterocyclic rings is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of the substituents is independently selected from deuterium; halogen; -OH; oxo; -CN; -C _1-6 alkyl; -C _1-6 alkoxy; -SO ₂ (C _1-6 alkyl); -CON(C _1-6 alkyl) ₂ ; -SO ₂ N(C _1-6 alkyl) ₂ ; -NH ₂ ; -NH(C _1-6 alkyl); -N(C _1-6 alkyl) ₂ ; -C 1-6 alkyl containing 1 or 2 heteroatoms selected from N, O or S _3-6 heterocycle; or -C _1-6 alkyl substituted by deuterium;

each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium, halogen, -NH ₂ , -C _1-6 alkoxy, or -C _1-6 alkyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are commonly attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently, at each occurrence, optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently, at each occurrence, selected from deuterium, halogen, -OH, -NH ₂ , -CN, -C _1-6 alkyl or -C _1-6 alkoxy;

A is selected from

_Y1 is selected from N or CR _Y1 ;

_Y2 is selected from O, S, CR _Y1 R _Y2 or NR _Y2 ;

each _RY1 and _RY2 , at each occurrence, is independently selected from hydrogen, deuterium, halogen, -OH, _NH2 , -CN, _-C1-6alkyl , or _-C1-6alkoxy ;

each R ₃ and R ₄ at each occurrence is independently selected from hydrogen, deuterium, halogen, -CN, -SOR ₅ , -SO ₂ R ₅ , -SO ₂ NR ₅ R ₆ , -C _1-6 alkyl, -C _1-6 alkoxy, -COR ₅ , -CONR ₅ R ₆ or -POR ₅ R ₆ ; and each R ₃ and R ₄ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH, -NH ₂ , -CN, -C _1-6 alkyl or -C _1-6 alkoxy;

each R ₅ and R ₆ are independently selected at each occurrence from hydrogen; deuterium; -OH; -NH ₂ ; -CN; -C 1-6 alkyl; -C _1-6 alkoxy; -C _5-6 aryl; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; -C _1-6 alkylene-C _3-8 carbocycle; or -C _3-8 carbocycle; and each R ₅ and R ₆ are independently selected at each occurrence from hydrogen; deuterium; -OH; -NH 2 ; -CN; -C _1-6 alkyl; -C 1-6 alkoxy; -C 5-6 aryl; -C 5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2; -C 1-6 alkylene-C 3-8 carbocycle; or -C 3-8 carbocycle; and each R 5 and R 6 are independently selected at each occurrence from hydrogen; deuterium; halogen; -OH, -CN, -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkoxy, carboxyl, -SO ₂ (C _1-6 alkyl) or -C _3-8 carbocycle; or

R ₅ and R ₆ together with the nitrogen atom to which they are commonly attached form a 4-8 membered heterocyclic ring, and each of said heterocyclic rings may further contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ at each occurrence, and each of said heterocyclic rings is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected from deuterium; halogen; -OH; oxo; -CN; -C _1-6 alkyl; -C _1-6 alkoxy; -SO ₂ (C _1-6 alkyl); -CON(C _1-6 alkyl) ₂ ; -SO ₂ N(C _1-6 alkyl) ₂ ; -NH ₂ ; -NH(C 1-6 alkyl); -N(C _1-6 alkyl) ₂ ; a -C _3-6 heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S; or a -C _3-6 heterocyclic ring substituted with deuterium _1-6 alkyl; n is selected from 0, 1, 2, 3, 4, 5 or 6;

W ₁ is selected from hydrogen; deuterium; halogen; -NH ₂ ; -CN; -OH; -NO ₂ ; carboxyl; -C _1-6 alkyl; -C _1-6 alkoxy; -C _1-6 alkylene-C _1-6 alkoxy; -C _5-10 aryl; -C 5-10 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; -C _3-8 heterocycle containing 1, 2, _{3 or} 4 heteroatoms selected from N, O, S, SO or SO ₂ ; or -C _3-8 carbocycle; and each W ₁ is independently, at each occurrence, optionally unsubstituted or substituted;

W ₂ is selected from hydrogen; deuterium; halogen; -NH ₂ ; -CN; -OH; -NO ₂ ; carboxyl; -C _1-6 alkyl; -C _1-6 alkoxy; -C _5-10 aryl; -C _5-10 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; -C _3-8 heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; or -C _3-8 carbocycle; and each W ₂ is independently, at each occurrence, optionally unsubstituted or substituted with a substituent;

Z is selected from hydrogen, deuterium, halogen, -NH ₂ , -CN, -OH, carboxyl, -C _1-6 alkyl or -C _1-6 alkoxy.

In certain embodiments, the compound is represented by Formula I-1:

In formula I-1, "R" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

In certain embodiments, the compound is represented by Formula I-2:

In formula I-2, "S" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

In certain embodiments, the compound is represented by Formula II:

In certain embodiments, the compound is represented by Formula II-1:

In formula II-1, "R" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

In certain embodiments, the compound is represented by Formula II-2:

In formula II-2, "S" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

In certain embodiments, the compound is represented by Formula III:

In certain embodiments, the compound is represented by formula III-1:

In formula III-1, "R" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

In certain embodiments, the compound is represented by formula III-2:

In formula III-2, "S" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

In certain embodiments, the compound is represented by Formula IV:

In certain embodiments, the compound is represented by Formula IV-1:

In formula IV-1, "R" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

In certain embodiments, the compound is represented by Formula IV-2:

In formula IV-2, "S" indicates that when the carbon atom connected to W ₁ , W ₂ and Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

In certain embodiments, wherein R ₁ is selected from hydrogen; deuterium; -SOR ₁₁ ; -SO ₂ R ₁₁ ; -SO ₂ NR ₁₁ R ₁₂ ; -C _1-6 alkyl; -COOR ₁₁ ; -COR ₁₁ ; -CONR ₁₁ R ₁₂ ; -POR ₁₁ R ₁₂ ; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; -C _3-8 heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; or -C _3-8 carbocycle; and each R ₁ is independently, at each occurrence, optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each substituent is independently, at each occurrence, selected from deuterium, halogen, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ or -C _3-8 carbocycle;

each R ₁₁ and R ₁₂ , at each occurrence, is independently selected from hydrogen, deuterium, -C _1-6 alkyl, -C _1-6 alkylene-C _3-8 carbocycle, or -C _3-8 carbocycle; and each R ₁₁ and R ₁₂ , at each occurrence, is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, at each occurrence, is independently selected from deuterium, halogen, -OH, -CN, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkoxy, -SO ₂ (C _1-6 alkyl), or -C _3-8 carbocycle; or

R ₁₁ and R ₁₂ together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic ring, and each of said heterocyclic rings may further contain 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ at each occurrence, and each of said heterocyclic rings is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected from deuterium; halogen; -OH; oxo; -CN; -C _1-6 alkyl; -C _1-6 alkoxy; -SO ₂ (C _1-6 alkyl); -CON(C 1-6 alkyl) ₂ ; -SO ₂ N(C _1-6 alkyl) ₂ ; -NH ₂ ; -NH(C _1-6 alkyl); -N(C _1-6 alkyl) ₂ ; a -C _3-6 heterocyclic ring containing 1, or 2 heteroatoms selected from N, O or S; or a deuterium-substituted -C _3-6 heterocyclic ring. _1-6 alkyl;

each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-6 alkyl; or

R ₁₃ and R ₁₄ together with the carbon atom to which they are commonly attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently, at each occurrence, optionally substituted with 1, 2, 3 or 4 substituents, and each of said substituents is independently, at each occurrence, selected from deuterium, halogen, -OH, -NH ₂ , -CN, -C _1-6 alkyl or -C _1-6 alkoxy;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₁ is selected from hydrogen; deuterium; -SOR ₁₁ ; -SO ₂ R ₁₁ ; -SO ₂ NR ₁₁ R ₁₂ ; -C _1-3 alkyl; -COOR ₁₁ ; -COR ₁₁ ; -CONR ₁₁ R ₁₂ ; -POR ₁₁ R ₁₂ ; -C _5-6 heteroaryl, said -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; -C _3-6 heterocycle, said -C _3-6 heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; or -C _3-6 carbocycle; and each R ₁ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, -F, -Cl, -Br, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, -NH ₂ , -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , or -C _3-6 carbocycle;

each R ₁₁ and R ₁₂ is independently selected at each occurrence from hydrogen, deuterium, -C _1-3 alkyl, -C _1-3 alkylene-C _3-6 carbocycle, or -C _3-6 carbocycle, and each R ₁₁ and R ₁₂ is independently selected at each occurrence from hydrogen, deuterium, -C _1-3 alkyl, -C 1-3 alkylene-C 3-6 carbocycle, or -C 3-6 carbocycle, and each R 11 and R 12 is independently selected at each occurrence from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH ₂ , -NH(C 1-3 alkyl), -N(C _1-3 alkyl) ₂ , -C _1-3 alkyl, -C _1-3 alkoxy, -SO ₂ (C _1-3 alkyl), or -C _3-6 carbocycle; or

R ₁₁ and R ₁₂ together with the nitrogen atom to which they are both attached form a 4-6 membered heterocyclic ring, and each of said heterocyclic rings may further comprise 1, 2 or 3 heteroatoms selected from N, O or SO ₂ at each occurrence, and each of said heterocyclic rings may independently be unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected from deuterium; -F; -Cl; -Br; -OH; oxo; -CN; -C _1-3 alkyl; -C _1-3 alkoxy; -SO ₂ (C _1-3 alkyl); -CON(C _1-3 alkyl) ₂ ; -SO ₂ N(C _1-3 alkyl) ₂ ; -NH ₂ ; -NH(C _1-3 alkyl); -N(C _1-3 alkyl) ₂ ; -C _4-6 heterocyclic ring, said -C _4-6 heterocyclic ring contains 1 heteroatom selected from N or O; or -C _1-3 alkyl substituted by deuterium;

each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-3 alkyl; or

R ₁₃ and R ₁₄ together with the carbon atom to which they are both attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently optionally unsubstituted or substituted with 1, 2, 3 or 4 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -CN, -C _1-3 alkyl or -C _1-3 alkoxy;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₁ is selected from hydrogen; deuterium; -SOR ₁₁ ; -SO ₂ R ₁₁ ; -SO ₂ NR ₁₁ R ₁₂ ; methyl; ethyl; propyl; isopropyl; -COOR ₁₁ ; -COR ₁₁ ; -CONR ₁₁ R ₁₂ ; -POR ₁₁ R ₁₂ ; 5-membered heteroaryl, the 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; 6-membered heteroaryl, the 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; 3-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; 4-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ heteroatoms; a 5-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; a 6-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; a 3-membered carbocycle; a 4-membered carbocycle; a 5-membered carbocycle; or a 6-membered carbocycle; and each R _1, independently at each occurrence, is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each substituent, at each occurrence, is independently selected from deuterium, -F, -Cl, -Br, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), -NH(CH ₂ CH ₂ CH ₃ ), -NH(CH(CH ₃ ) ₂ ), -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), -N(CH ₃ )(CH ₂ CH ₂ CH ₃ ), 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, or 6-membered carbocycle;

each R ₁₁ and R ₁₂ is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -methylene-3-membered carbocycle, -methylene-4-membered carbocycle, -methylene-5-membered carbocycle, -methylene-6-membered carbocycle, -ethylene-3-membered carbocycle, -ethylene-4-membered carbocycle, -ethylene-5-membered carbocycle, -ethylene-6-membered carbocycle, 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, or 6-membered carbocycle; and each R ₁₁ and R ₁₂ is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -methylene-3-membered carbocycle, -methylene-4-membered carbocycle, -methylene-5-membered carbocycle, -ethylene-6-membered carbocycle, 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, or 6-membered carbocycle; and each R 11 and R 12 is independently selected at each occurrence from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), -NH(CH ₂ CH ₂ CH ₃ ), -NH(CH( _CH3 ) ₂ ) _, -N( _CH3 ) ₂ , _-N (CH2CH3) ₂ , -N( _CH3 )( _CH2CH3 ), -N( _CH3 ) _{( CH2CH2CH3} ), methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, _{-SO2CH3 ,} -SO2CH2CH3 _{, -SO2CH2CH2CH3 ,} -SO2CH( _{CH3 ) 2} , 3 _- membered carbocyclic _ring , ₄ -membered carbocyclic ring, 5-membered carbocyclic ring _{, or} 6-membered carbocyclic ring; _or

R ₁₁ and R ₁₂ together with the nitrogen atom to which they are both attached form a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, and each of said heterocyclic rings may further contain 1 or 2 heteroatoms selected from N, O or SO ₂ at each occurrence, and each of said heterocyclic rings is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CH ₂ CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -CON(CH ₂ CH ₃ ) ₂ , -CON(CH ₂ CH ₂ CH ₃ ) ₂ , -CON(CH(CH ₃ ) ₂ ) ₂ , -SO ₂ N(CH ₃ ) ₂ , -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -SO ₂ N(CH(CH ₃ ) ₂ ) ₂ , -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), -NH(CH ₂ CH ₂ CH ₃ ), -NH(CH(CH ₃ ) ₂ ), -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), -N(CH ₃ )(CH ₂ CH ₂ CH ₃ ), deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted propyl, or deuterium-substituted isopropyl;

each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

R ₁₃ and R ₁₄ , together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, or a 6-membered carbocyclic ring, and each carbocyclic ring, independently at each occurrence, is optionally unsubstituted or substituted with 1, 2, 3, or 4 substituents, and each of said substituents, at each occurrence, is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₁ is selected from hydrogen; deuterium; -SOR ₁₁ ; -SO ₂ R ₁₁ ; -SO ₂ NR ₁₁ R ₁₂ ; methyl; ethyl; propyl; isopropyl; -COOR ₁₁ ; -COR ₁₁ ; -CONR ₁₁ R ₁₂ ; -POR ₁₁ R ₁₂ ; a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; a 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; or a 3-membered carbocyclic ring; and each R ₁ is optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), -N(CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), or a 3-membered carbocyclic ring;

each R ₁₁ or R ₁₂ is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -methylene-3-membered carbocycle, or 3-membered carbocycle; and each R ₁₁ or R ₁₂ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , methyl, methoxy, -SO ₂ CH ₃ , or 3-membered carbocycle; or

R ₁₁ and R ₁₂ together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from, and the heterocyclic ring is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently selected at each occurrence from, deuterium, -F, -Cl, -Br, -OH, oxo, -CN, methyl, methoxy, -SO ₂ CH ₃ , -CON(CH ₃ ) ₂ , -SO ₂ N(CH ₃ ) ₂ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₂ D, -CHD ₂ or -CD ₃ ;

each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

R ₁₃ and R ₁₄ together with the carbon atom to which they are attached form a 3-membered carbocyclic ring, and the carbocyclic ring is independently optionally unsubstituted or substituted with 1, 2, 3 or 4 substituents, and each of the substituents at each occurrence is independently selected from deuterium, -OH, methyl, ethyl, propyl or isopropyl;

n is selected from 0 or 1.

In certain embodiments, wherein R ₁ is selected from hydrogen, deuterium, -SOCH ₃ , -SOCH ₂ CH ₃ , -SOCH ₂ CH ₂ CH ₃ , -SOCH(CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CD ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CH ₂ CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ CH(CD ₃ ) ₂ , -SO ₂ NH ₂ , -SO ₂ NH(CH ₃ ), -SO ₂ N(CH ₃ ) ₂ , -SO ₂ NH(CD ₃ ), -SO ₂ N(CD ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -CH ₃ , -CH ₂ D , -CHF ₂ , -CH ₂ F , -CD ₂ H , -CD ₃ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ F , -CH ₂ CHF ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CD ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F , -CH ₂ CH ₂ CD ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CD ₃ ), -CH(CF ₃ ) ₂ , -CH(CD ₃ ) ₂ , -CONH ₂ , -CONH(CH ₃ ), -CON(CH ₃ ) ₂ , -CONH(CD ₃ ), -CON(CD ₃ ) ₂ , -CONH(CH ₂ CH ₃ ), -CON(CH ₂ CH ₃ ) ₂ , -CONH(CH ₂ CH ₂ CH ₃ ), -CON(CH ₂ CH ₂ CH ₃ ) ₂ , -P(O)H ₂ , -P(O)H(CH ₃ ), -PO(CH ₃ ) ₂ , -P(O)H(CD ₃ ), -P(O)(CD ₃ ) ₂ , -P(O)(CH ₂ CH ₃ ) ₂ , -P(O)(CH ₂ CH ₂ CH ₃ ) ₂ , -P(O)(CH(CH ₃ ) ₂ ) ₂ ,

In certain embodiments, wherein R ₁ is selected from -SO ₂ R ₁₁ , -C _1-6 alkyl, or -C _3-8 carbocycle; and each R ₁ , independently at each occurrence, is optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, at each occurrence, is independently selected from deuterium, halogen, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, -NH ₂ , -NH(C _1-6 alkyl), or -N(C _1-6 alkyl) ₂ ;

R ₁₁ is selected from hydrogen, deuterium or -C _1-6 alkyl;

Each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-6 alkyl;

n is selected from 0, 1, 2, 3, 4, 5 or 6.

In certain embodiments, wherein R ₁ is selected from -SO ₂ R ₁₁ , -C _1-3 alkyl, or -C _3-6 carbocycle; and each R ₁ , independently at each occurrence, is optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, at each occurrence, is independently selected from deuterium, halogen, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, -NH ₂ , -NH(C _1-3 alkyl), or -N(C _1-3 alkyl) ₂ ;

R ₁₁ is selected from hydrogen, deuterium or -C _1-3 alkyl;

Each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-3 alkyl;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₁ is selected from -SO ₂ R ₁₁ , methyl, ethyl, propyl, isopropyl, 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, or 6-membered carbocycle; and each R ₁ is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and each substituent is independently at each occurrence selected from deuterium, -F, -Cl, -Br, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), -NH(CH ₂ CH ₂ CH ₃ ), -NH(CH(CH ₃ ) ₂ ), -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), or -N(CH ₃ )(CH ₂ CH ₂ CH ₃ );

R ₁₁ is selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl;

each R ₁₃ and R ₁₄ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₁ is selected from -So ₂ CH ₃ , -SO ₂ CD ₃ , -SO ₂ CH ₂ CH ₃ , -So ₂ CH ₂ CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ CH(CD ₃ ) ₂ , -CH ₃ , -CH ₂ D, -CHF ₂ , -CH ₂ F, -CD ₂ H, -CD ₃ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CD ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CD ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CD ₃ ), -CH(CF ₃ ) ₂ , -CH(CD ₃ ) ₂ ,

In certain embodiments, wherein R ₁ is selected from hydrogen, deuterium, -SO ₂ CH ₃ , -CH ₃ , -CHF ₂ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CF ₃ , -CH(CH ₃ ) ₂ ,

In certain embodiments, wherein R ₁ is selected from -So ₂ CH ₃ , -CH ₃ , -CHF ₂ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CF ₃ , -CH(CH ₃ ) ₂ ,

In certain embodiments, wherein R ₁ is -C _1-6 alkyl.

In certain embodiments, wherein R ₁ is -C _1-3 alkyl.

In certain embodiments, R ₁ is selected from methyl, ethyl, propyl, or isopropyl.

In certain embodiments, wherein R ₁ is methyl.

In certain embodiments, wherein R ₂ is selected from hydrogen; deuterium; halogen; -OR ₂₁ ; -NR ₂₁ R ₂₂ ; -CN; -SR ₂₁ ; -SOR ₂₁ ; -SO ₂ R ₂₁ ; -SO ₂ NR ₂₁ R ₂₂ ; -C _1-6 alkyl; -C _2-6 alkenyl; -COOR ₂₁ ; -COR ₂₁ ; -CONR ₂₁ R ₂₂ ; -NR ₂₁ COR ₂₂ ; -NR ₂₁ SO ₂ R ₂₂ ; -POR ₂₁ R ₂₂ ; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; -C _3-8 heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; or -C _3-8 carbocycle; and each R ₂ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, halogen, -OH, -C _1-6 alkyl, -C _1-6 alkoxy or -C _3-8 carbocycle;

each R ₂₁ and R ₂₂ , at each occurrence, is independently selected from hydrogen, deuterium, -C _1-6 alkyl, -C _1-6 alkylene-C _3-8 carbocycle, or -C _3-8 carbocycle; and each R ₂₁ and R ₂₂ , at each occurrence, is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, at each occurrence, is independently selected from deuterium, halogen, -OH, -CN, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkoxy, -SO ₂ (C _1-6 alkyl), or -C _3-8 carbocycle; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic ring, each of which may further contain 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ at each occurrence, and each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of which is independently selected from deuterium; halogen; -OH; oxo; -CN; -C _1-6 alkyl; -C _1-6 alkoxy; -SO ₂ (C _1-6 alkyl); -CON (C _1-6 alkyl) ₂ ; -So ₂ N (C _1-6 alkyl) ₂ ; -NH ₂ ; -NH (C _1-6 alkyl); -N (C _1-6 alkyl) ₂ ; a -C _3-6 heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S; or a -C 3-6 heterocyclic ring substituted with deuterium; _1-6 alkyl;

Each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-6 alkyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are commonly attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently, at each occurrence, optionally substituted with 1, 2, 3 or 4 substituents, and each of said substituents is independently, at each occurrence, selected from deuterium, halogen, -OH, -NH ₂ , -CN, -C _1-6 alkyl or -C _1-6 alkoxy;

n is selected from 0, 1, 2, 3, 4, 5 or 6. In certain embodiments, wherein R ₂ is selected from hydrogen; deuterium; -F; -Cl; -Br; -OR ₂₁ ; -NR ₂₁ R ₂₂ ; -CN; -SR ₂₁ ; -SOR ₂₁ ; -SO ₂ R ₂₁ ; -SO ₂ NR ₂₁ R ₂₂ ; -C _1-3 alkyl; -C _2-3 alkenyl; -COOR ₂₁ ; -COR ₂₁ ; -CONR ₂₁ R ₂₂ ; -NR ₂₁ COR ₂₂ ; -NR ₂₁ SO ₂ R ₂₂ ; -POR ₂₁ R ₂₂ ; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; -C 3-6 heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or SO ₂ ; or _{-C 3-6 carbocycle} ; and each R ₂ is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, -F, -Cl, -Br, -OH, -C _1-3 alkyl, -C _1-3 alkoxy or -C _3-6 carbocycle;

each R ₂₁ or R ₂₂ is independently selected at each occurrence from hydrogen, deuterium, -C _1-3 alkyl, -C _1-3 alkylene-C _3-6 carbocycle, or -C _3-6 carbocycle; and each R ₂₁ or R ₂₂ is independently, at each occurrence, optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, -CN, -NH ₂ , -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -C _1-3 alkyl, -C _1-3 alkoxy, -SO ₂ (C _1-3 alkyl), or -C _3-6 carbocycle; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic ring, each of which may further contain 1, 2 or 3 heteroatoms selected from N, O or SO ₂ at each occurrence, and each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of which is independently selected from deuterium; -F; -Cl; -Br; -OH; oxo; -CN; -C _1-3 alkyl; -C _1-3 alkoxy; -SO ₂ (C _1-3 alkyl); -CON(C _1-3 alkyl) ₂ ; -SO ₂ N(C _1-3 alkyl) ₂ ; -NH ₂ ; -NH(C ₁ - ₃ alkyl); -N(C _1-3 alkyl) ₂ ; a -C _4-6 heterocyclic ring containing 1 heteroatom selected from N or O; or a -C 4-6 heterocyclic ring substituted with deuterium; _1-3 alkyl;

each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-3 alkyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are commonly attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently, at each occurrence, optionally substituted with 1, 2, 3 or 4 substituents, and each of said substituents is independently, at each occurrence, selected from deuterium, halogen, -OH, -NH ₂ , -CN, -C _1-3 alkyl or -C _1-6 alkoxy;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₂ is selected from hydrogen; deuterium; -F; -Cl; -Br; -OR ₂₁ ; -NR ₂₁ R ₂₂ ; -CN; -SR 21 ; -SOR ₂₁ ; -SO ₂ R ₂₁ ; -SO ₂ NR ₂₁ R ₂₂ ; methyl; ethyl; propyl; isopropyl; ethenyl; propenyl; -COOR 21 ; -COR _{21 ; -CONR 21 R 22 ; -NR 21 COR 22 ; -NR 21 SO 2 R 22 ;} -POR ₂₁ R ₂₂ ; a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected _from N, O, S or SO ₂ ; a 6-membered heteroaryl group containing 1, ₂ or 3 heteroatoms selected from N, O, S or SO ₂ ; _a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S or SO ₂ ; a 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S or SO wherein _each R is independently selected from deuterium, -F, -Cl, -Br, -OH, methyl, _ethyl , propyl, isopropyl, methoxy, ethoxy, propoxy, _isopropyloxy , 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, or ₆ -membered carbocycle _;

each R ₂₁ or R ₂₂ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -methylene-3-membered carbocycle, -methylene-4-membered carbocycle, -methylene-5-membered carbocycle, -methylene-6-membered carbocycle, -ethylene-3-membered carbocycle, -ethylene-4-membered carbocycle, -ethylene-5-membered carbocycle, -ethylene-6-membered carbocycle, 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, or 6-membered carbocycle; and each R ₂₁ or R ₂₂ at each occurrence is independently optionally substituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl, -Br, -OH, -CN, -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), -NH(CH ₂ CH ₂ CH ₃ ), —NH(CH(CH ₃ ) ₂ ), —N(CH ₃ ) ₂ , —N(CH ₂ CH ₃ ) ₂ , —N(CH ₃ )(CH ₂ CH ₃ ), —N(CH ₃ )(CH ₂ CH ₂ CH ₃ ) _, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —SO ₂ CH 3 , —SO 2 CH 2 CH ₃ , —SO ₂ CH 2 CH ₂ CH ₃ , —SO ₂ CH(CH ₃ ) ₂ , _{a 3 -} membered carbocyclic ring, a ₄ -membered carbocyclic ring, a 5-membered carbocyclic ring, or a 6-membered carbocyclic ring; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are commonly attached form a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each of which may further contain 1 or 2 heteroatoms selected from N, O, or SO ₂ at each occurrence, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents at each occurrence, and each of which is independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -SO 2 CH 3 , -SO _{2 CH 2} CH ₃ , -SO ₂ CH 2 CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) 2 , -CON(CH _{3 )} 2 , _-CON (CH 2 CH ₃ ) ₂ , -CON(CH _{2 CH 3} ) _{2 ,} -CON(CH ₂ CH ₂ CH ₃ ) ₂ , -CON(CH(CH ₃ ) ₂ ) ₂ , -So ₂ N(CH ₃ ) ₂ , -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -SO ₂ N(CH(CH ₃ ) ₂ ) ₂ , -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), -NH(CH ₂ CH ₂ CH ₃ ), -NH(CH(CH ₃ ) ₂ ), -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), -N(CH ₃ )(CH ₂ CH ₂ CH ₃ ), deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted propyl, or deuterium-substituted isopropyl;

each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are commonly attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring or a 6-membered carbocyclic ring, and each of said carbocyclic rings, independently at each occurrence, is optionally unsubstituted or substituted with 1, 2, 3 or 4 substituents, and each of said substituents, at each occurrence, is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₂ is independently selected from hydrogen; deuterium; -F; -Cl; -Br; -OR ₂₁ ; -NR ₂₁ R ₂₂ ; -CN; -SR ₂₁ ; -SOR ₂₁ ; -SO ₂ R ₂₁ ; -SO ₂ NR ₂₁ R ₂₂ ; methyl; ethyl; propyl; isopropyl; vinyl; -COOR ₂₁ ; -COR ₂₁ ; -CONR 21 R 22 ; -NR ₂₁ COR ₂₂ ; -NR ₂₁ SO ₂ R ₂₂ ; -POR ₂₁ R ₂₂ ; _a 5-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, S, or SO _{2 ;} a 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, S, or SO ₂ ; or a 3-membered carbocyclic ring; and each R ₂ is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, -F, -Cl, -Br, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or a 3-membered carbocyclic ring;

each R ₂₁ and R ₂₂ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -methylene-3-membered carbocycle, or 3-membered carbocycle; and each R ₂₁ and R ₂₂ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , methyl, methoxy, -5O ₂ CH ₃ , or 3-membered carbocycle; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are attached form a heterocyclic ring selected from, and each of the heterocyclic rings is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of the substituents is independently at each occurrence selected from, deuterium, -F, -Cl, -Br, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, -SO ₂ CH ₃ , -CON(CH ₃ ) ₂ , -SO ₂ N(CH ₃ ) ₂ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₂ D, -CHD ₂ or -CD ₃ ;

each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are commonly attached form a 3-membered carbocyclic ring, and said carbocyclic ring is independently optionally unsubstituted or substituted with 1, 2, 3 or 4 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

n is selected from 0 or 1.

In certain embodiments, wherein R ₂ is selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCF ₂ CH ₃ , -OCH ₂ OH, -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ CH ₂ OH, -OCH ₂ CH ₂ NH ₂ , -OCH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ NHCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCD ₃ , -N(CD ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ CH ₂ ) ₂ , -N(CH ₃ )(CH ₃ CH ₂ ), -NHCH ₂ CH ₂ CH ₃ , -N(CH ₂ CH ₂ CH ₃ ) ₂ , -NHCH(CH ₃ ) ₂ , -N(CH ₃ )(CH(CH ₃ ) ₂ ), -N(CH(CH ₃ ) ₂ ) ₂ , -NHCH ₂ CF ₃ , -CN, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH(CH ₃ ) ₂ , -SOCH ₃ , -SOCH ₂ CH ₃ , -SOCH ₂ CH ₂ CH ₃ ,-SOCH(CH ₃ ) _2. -SO ₂ CH ₃ , -SO ₂ CD ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CH ₂ CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ CH(CD ₃ ) ₂ , -SO ₂ NH ₂ , -SO ₂ NH(CH ₃ ), -SO ₂ N(CH ₃ ) ₂ , -SO ₂ NH(CD ₃ ), -SO ₂ N(CD ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₃ CH ₂ ), -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -CH ₃ , -CH ₂ D, -CD ₂ H, -CD ₃ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CD ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CD ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CD ₃ ), -CH(CF ₃ ) ₂ , -CH(CD ₃ ) ₂ , -CONH ₂ , -CONH(CH ₃ ), -CON(CH ₃ ) ₂ , -CONH(CD ₃ ), -CON(CD ₃ ) ₂ , -CONH(CH ₂ CH ₃ ), -CON(CH ₂ CH ₃ ) ₂ , -CONH(CH ₂ CH ₂ CH ₃ ), -CON(CH ₂ CH ₂ CH ₃ ) ₂ ,-NHCOCH ₃ , -NHCOCH ₂ CH ₃ , -NHCOCH ₂ CH ₂ CH ₃ , -NHCOCH(CH ₃ ) ₂ , -P(O)H ₂ , -P(O)H(CH ₃ ), -PO(CH ₃ ) ₂ , -P(O)H(CD ₃ ), -PO(CD ₃ ) ₂ , -PO(CH ₂ CH ₃ ) ₂ , -PO(CH ₂ CH ₂ CH ₃ ) ₂ , -PO(CH(CH ₃ ) ₂ ) ₂ ,

In certain embodiments, wherein R ₂ is selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCF ₂ CH ₃ , -OCH ₂ OH, -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ CH ₂ OH, -OCH ₂ CH ₂ NH ₂ , -OCH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ NHCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCD ₃ , -N(CD ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ CH ₂ ) ₂ , -N(CH ₃ )(CH ₃ CH ₂ ), -NHCH ₂ CH ₂ CH ₃ , -N(CH ₂ CH ₂ CH ₃ ) ₂ , -NHCH(CH ₃ ) ₂ , -N(CH ₃ )(CH(CH ₃ ) ₂ ), -N(CH(CH ₃ ) ₂ ) ₂ , -NHCH ₂ CF ₃ , -CN, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH(CH ₃ ) ₂ , -SOCH ₃ , -SOCH ₂ CH ₃ , -SOCH ₂ CH ₂ CH ₃ ,-SOCH(CH ₃ ) ₂ , -So ₂ CH ₃ , -SO ₂ CD ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CH ₂ CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ CH(CD ₃ ) ₂ , -SO ₂ NH ₂ , -SO ₂ NH(CH ₃ ), -SO ₂ N(CH ₃ ) ₂ , -SO ₂ NH(CD ₃ ), -SO ₂ N(CD ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₃ CH ₂ ), -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -CH ₃ , -CH ₂ D, -CD ₂ H, -CD ₃ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CD ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CD ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CD ₃ ), -CH(CF ₃ ) ₂ , -CH(CD ₃ ) ₂ , -CONH ₂ , -CONH(CH ₃ ), -CON(CH ₃ ) ₂ , -CONH(CD ₃ ), -CON(CD ₃ ) ₂ , -CONH(CH ₂ CH ₃ ), -CON(CH ₂ CH ₃ ) ₂ , -CONH(CH ₂ CH ₂ CH ₃ ), -CON(CH ₂ CH ₂ CH ₃ ) ₂ ,-NHCOCH ₃ , -NHCOCH ₂ CH ₃ , -NHCOCH ₂ CH ₂ CH ₃ , -NHCOCH(CH ₃ ) ₂ , -P(O)H ₂ , -P(O)H(CH ₃ ), -PO(CH ₃ ) ₂ , -P(O)H(CD ₃ ), -PO(CD ₃ ) ₂ , -PO(CH ₂ CH ₃ ) ₂ , -PO(CH ₂ CH ₂ CH ₃ ) ₂ , -PO(CH(CH ₃ ) ₂ ) ₂ ,

In certain embodiments, wherein R ₂ is selected from hydrogen, deuterium, halogen, -NR ₂₁ R ₂₂ , -SO ₂ R ₂₁ , -SO ₂ NR ₂₁ R ₂₂ , -C _1-6 alkyl, -COOR ₂₁ , -COR ₂₁ , -CONR ₂₁ R ₂₂ , -NR ₂₁ COR ₂₂ , -NR ₂₁ SO ₂ R ₂₂ , -POR ₂₁ R ₂₂ or -C _3-8 carbocycle; and each R _2, independently at each occurrence, is optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents, at each occurrence, is independently selected from deuterium, halogen, -OH, -C _1-6 alkyl or -C _1-6 alkoxy;

each R ₂₁ or R ₂₂ at each occurrence is independently selected from hydrogen, deuterium or -C _1-6 alkyl; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are both attached form a 4-6 membered heterocyclic ring, each of said heterocyclic rings may further contain 1, 2 or 3 heteroatoms selected from N, O, S, or SO ₂ at each occurrence, and each of said heterocyclic rings is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected from deuterium; oxo; -C _1-6 alkyl; -NH(C _1-6 alkyl); or -C _{3-6 heterocyclic} ring containing 1 or 2 heteroatoms selected from N or O;

each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-6 alkyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, -OH or -C _1-6 alkyl;

n is selected from 0, 1, 2, 3, 4, 5 or 6.

In certain embodiments, wherein R ₂ is selected from hydrogen, deuterium, halogen, -NR ₂₁ R ₂₂ , -SO ₂ R ₂₁ , -SO ₂ NR ₂₁ R ₂₂ , -C _1-3 alkyl, -COOR ₂₁ , -COR ₂₁ , -CONR ₂₁ R ₂₂ , -NR ₂₁ COR ₂₂ , -NR ₂₁ SO ₂ R ₂₂ , -POR ₂₁ R ₂₂ , or -C _3-6 carbocycle; and each R ₂ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH, -C _1-3 alkyl, or -C _1-3 alkoxy;

each R ₂₁ or R ₂₂ at each occurrence is independently selected from hydrogen, deuterium or -C _1-3 alkyl; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are attached form a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each of which may further contain 1 or 2 heteroatoms selected from N or O at each occurrence, and each of which is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of which is independently selected from deuterium, oxo, -C _1-3 alkyl, -NH(C _1-3 alkyl), or -C _{4-6 heterocyclic} ring containing 1 heteroatom selected from N, or O;

each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium or -C _1-3 alkyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring, and each of said carbocyclic rings is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, -OH or -C _1-3 alkyl;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein R ₂ is selected from hydrogen, deuterium, -F, -Cl, -Br, -NR ₂₁ R ₂₂ , -So ₂ R ₂₁ , -SO ₂ NR ₂₁ R ₂₂ , methyl, ethyl, propyl, isopropyl, -COOR ₂₁ , -COR ₂₁ , -CONR ₂₁ R ₂₂ , -NR ₂₁ COR ₂₂ , -NR ₂₁ SO ₂ R ₂₂ , -POR ₂₁ R ₂₂ , 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring; and each R ₂ is optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, each of which is independently selected from deuterium, -F, -Cl, -Br, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;

each R ₂₁ or R ₂₂ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, or isopropyl; or

R ₂₁ and R ₂₂ together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each of said heterocyclic rings may further contain 1 heteroatom selected from N or O at each occurrence, and each of said heterocyclic rings may be independently selected from deuterium, oxo, methyl, ethyl, propyl, isopropyl, -NHCH ₃ , -NHCH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , -NHCH(CH ₃ ) ₂ ...

each R ₂₃ and R ₂₄ at each occurrence is independently selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

R ₂₃ and R ₂₄ together with the carbon atom to which they are attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, or a 6-membered carbocyclic ring, and each of said carbocyclic rings is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, -OH, methyl, ethyl, propyl or isopropyl;

n is selected from 0, 1, 2 or 3.

In certain embodiments, wherein _R2 is selected from hydrogen, deuterium, -F, -Cl, -Br, -NH2, _-NHCH3 , -N ₍ CH3) ₂ , _-NHCD3 , -N _{( CD3} ) ₂ , _{-NHCH2CH3 ,} -N( _CH3CH2 ) ₂ , -N( _{CH3 )} ( _{CH3CH2 )} , -NHCH2CH2CH3, -N( _{CH2CH2CH3 ) 2} , -NHCH(CH3 _{) 2} , -N( _CH3 )(CH ₍ CH3) _{2 ) ,} -N _{( CH ( CH3 ) 2 ) 2 , -NHCH2CF3 , -SO2CH3 , -SO2CD3 , -SO2CH2CH3 , -SO2CH2CH2CH3} , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ CH(CD ₃ ) ₂ , -SO ₂ NH ₂ , -SO ₂ NH(CH ₃ ), -SO ₂ N(CH ₃ ) ₂ , -SO ₂ NH(CD ₃ ), -SO ₂ N(CD ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -CH ₃ , -CH ₂ D, -CD ₂ H, -CD ₃ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CD ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CD ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CD ₃ ), -CH(CF ₃ ) ₂ , -CH(CD ₃ ) ₂ , -COOCH ₃ , -COOCH ₂ CH ₃ , -COOCH ₂ CH ₂ CH ₃ , -COOCH(CH ₃ ) ₂ , -CONH ₂ , -CONH(CH ₃ ), -CON(CH ₃ ) ₂ , -CONH(CD ₃ ), -CON(CD ₃ ) ₂ , -CONH(CH ₂ CH ₃ ), -CON(CH ₂ CH ₃ ) ₂ , -CONH(CH ₂ CH ₂ CH ₃ ), -CON(CH ₂ CH ₂ CH ₃ ) ₂ , -NHCOCH ₃ ,-NHCOCH ₂ CH ₃ , -NHCOCH ₂ CH ₂ CH ₃ , -NHCOCH(CH ₃ ) ₂ , -NHSO ₂ CH ₃ , -NHSO ₂ CD ₃ , -NHSO ₂ CH ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₂ CH ₃ , -NHSO ₂ CH(CH ₃ ) ₂ , -P(O)H _{or ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​}

In certain embodiments, wherein _R2 is selected from hydrogen, deuterium, -F, -Cl, -Br, -NH2, _-NHCH3 , -N ₍ CH3) ₂ , _-NHCD3 , -N _{( CD3} ) ₂ , _{-NHCH2CH3 ,} -N( _CH3CH2 ) ₂ , -N( _{CH3 )} ( _{CH3CH2 )} , -NHCH2CH2CH3, -N( _{CH2CH2CH3 ) 2} , -NHCH(CH3 _{) 2} , -N( _CH3 )(CH ₍ CH3) _{2 ) ,} -N _{( CH ( CH3 ) 2 ) 2 , -NHCH2CF3 , -SO2CH3 , -SO2CD3 , -SO2CH2CH3 , -SO2CH2CH2CH3} , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ CH(CD ₃ ) ₂ , -SO ₂ NH ₂ , -SO ₂ NH(CH ₃ ), -SO ₂ N(CH ₃ ) ₂ , -SO ₂ NH(CD ₃ ), -SO ₂ N(CD ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ NH(CH ₂ CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -CH ₃ , -CH ₂ D, -CD ₂ H, -CD ₃ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CD ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CD ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CD ₃ ), -CH(CF ₃ ) ₂ , -CH(CD ₃ ) ₂ , -COOH, -COOCH ₃ , -COOCH ₂ CH ₃ , -COOCH ₂ CH ₂ CH ₃ , -COOCH(CH ₃ ) ₂ , -CONH ₂ , -CONH(CH ₃ ), -CON(CH ₃ ) ₂ , -CONH(CD ₃ ), -CON(CD ₃ ) ₂ , -CONH(CH ₂ CH ₃ ), -CON(CH ₂ CH ₃ ) ₂ , -CONH(CH ₂ CH ₂ CH ₃ ), -CON(CH ₂ CH ₂ CH ₃ ) ₂ ,-NHCOCH ₃ , -NHCOCH ₂ CH ₃ , -NHCOCH ₂ CH ₂ CH ₃ , -NHCOCH(CH ₃ ) ₂ , -NHSO ₂ CH ₃ , -NHSO ₂ CD ₃ , -NHSO ₂ CH ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₂ CH ₃ , -NHSO ₂ CH(CH ₃ ) _{2 or ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​}

In certain embodiments, wherein _R2 is selected from hydrogen, -Cl, -Br, -NH2, _-SO2CH3 , _-SO2NH2 , _-SO2NHCH3 , _{-So2N ( CH3} ) ₂ , _-CH3 , _-COOH , _-COOCH3 , _-CONH2 , _-CONHCH3 , -CON( _CH3 ) ₂ , _-NHCOCH3 , _-NHSo2CH3 , _-PO ( _{CH3 ) 2 ,} or

In certain embodiments, wherein _R2 is selected from hydrogen, -Cl, -Br, -NH2, _{-SO2CH3 , -SO2NH2} , _-SO2NHCH3 , _{-SO2N ( CH3 )2 , -CH3} , _-COOCH3 , -CONH2 _{, -CONHCH3} , -CON( _CH3 ) ₂ , _{-NHCOCH3 , -NHSO2CH3} , -PO( _CH3 ) _{2 ,} or

In certain embodiments, wherein _R2 is

Each of R ₂₃ and R ₂₄ at each occurrence is -C _1-6 alkyl.

In certain embodiments, wherein each R ₂₃ and R ₂₄ at each occurrence is -C _1-3 alkyl.

In certain embodiments, each of R ₂₃ and R ₂₄ at each occurrence is selected from methyl, ethyl, propyl, or isopropyl.

In certain embodiments, wherein _R2 is

In certain embodiments, said A is

In certain embodiments, said A is

In certain embodiments, wherein each R ₃ and R ₄ at each occurrence is independently selected from hydrogen, deuterium, halogen, -CN, -SOR ₅ , -SO ₂ R ₅ , -SO ₂ NH ₂ , -SO ₂ NHR ₅ , -So ₂ NR ₅ R ₆ , -C _1-3 alkyl, -C _1-3 alkoxy, -COR ₅ , -CONH ₂ , -CONHR ₅ , -CONR ₅ R ₆ , -P(O)H ₂ , -P(O)HR ₅ , or -POR ₅ R ₆ ; and each R ₃ and R ₄ at each occurrence is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen, or -OH;

each R ₅ and R ₆ are independently selected at each occurrence from deuterium; -C _1-3 alkyl; -C _5-6 aryl; -C _5-6 heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; or -C _3-6 carbocycle, and each R ₅ and R ₆ are independently optionally substituted at each occurrence or with 1, 2, 3, 4, 5 or 6 substituents, and each of the substituents is independently selected at each occurrence from deuterium, halogen, -C _1-3 alkyl or -C _1-3 alkoxy;

In certain embodiments, wherein each R ₃ and R ₄ at each occurrence is independently selected from hydrogen, deuterium, -F, -Cl, -Br, -CN, -SOR ₅ , -SO ₂ R ₅ , -SO ₂ NH ₂ , -SO _{2 NHR 5 , -SO 2 NR 5 R 6} , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl, -CONH _{2 , -CONHR 5 ,} -CONR ₅ R ₆ , -P(O)H ₂ , -P(O)HR ₅ , or -POR ₅ R ₆ ; and each R ₃ and R ₄ at each occurrence is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl, -Br, or -OH;

each R ₅ and R ₆ are independently selected at each occurrence from deuterium; methyl; ethyl; propyl; isopropyl; phenyl; a 5-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; a 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO ₂ ; a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; or a 6-membered carbocyclic ring; and each R ₅ and R ₆ are independently selected at each occurrence from deuterium; -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In certain embodiments, each _R3 and _{R4, at} each occurrence, _{is independently selected} from hydrogen _, deuterium, -F, -Cl, -Br, -CN _, -SOCH3, _-SOCH2CH3 , -SOCH2CH2CH3, -SOCH(CH3 _{)2 , -SO2CH3} , _{-SO2CH2CH3 , -SO2CH2CH2CH3} , -SO2CH _{( CH3 ) 2 ,} -SO2NH2 _{, -SO2NHCH3 , -SO2NHCH2CH3 ,} -SO2NHCH2CH2CH3 _{, -SO2NHCH ( CH3} ) ₂ , _{-SO2N ( CH3 ) 2 , -SO2N} ( _{CH2CH3 ) 2 , -SO2N} (CH3 _{) 2 ,} )(CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH ₂ CH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -CON(CH ₂ CH ₃ ) ₂ , -CON(CH ₃ )(CH ₂ CH ₃ ), -CON(CH ₂ CH ₂ CH ₃ ) ₂ , -P(O)H ₂ ,-P(O)HCH _{and each} R _{3 and R 4} , _{independently at} each _occurrence , is optionally substituted _{with 1 , 2 , 3 , 4} , ₅ or ₆ substituents, _and each _{of said} substituents _, at each occurrence, is independently selected from deuterium, _-F or methyl.

In certain embodiments, each _R3 and _{R4, at each} occurrence, _is independently selected from hydrogen _, deuterium, -F, -Cl _, -Br _, -CN, -SOCH3, _-SOCD3 , _{-SOCH2CH3 ,} -SOCH2CH2CH3, -SOCH( _{CH3 ) 2 , -SO2CH3} , _{-SO2CD3 ,} -SO2CH2CH3, _{-SO2CH2CH2CH3 , -SO2CH (} CH3 _{) 2 , -SO2NH2 , -SO2NHCH3 , -SO2NHCD3} , _{-SO2NHCH2CH3 , -SO2NHCH2CH2CH3 , -SO2NHCH} ( _CH3 ) _{2 , -SO2N ( CH3 ) 2 ,} -SO ₂ N(CD ₃ ) ₂ , -SO ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ N(CH ₃ )(CH ₂ CH ₃ ), -SO ₂ N(CH ₂ CH ₂ CH ₃ ) ₂ , -CH ₃ , -CD ₃ , -CH ₂ CH ₃ , -CD ₂ CD ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CD ₃ , -CH(CH ₃ ) ₂ , -CH(CD ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CONH ₂ , -CONHCH ₃ , -CONHCD ₃ , -CONHCH ₂ CH ₃ , -CONHCD ₂ CD ₃ , -CONHCH ₂ CH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -CON(CH ₂ CH ₃ ) ₂ , -CON(CH ₃ )(CH ₂ CH ₃ ), -CON(CH ₂ CH ₂ CH ₃ ) ₂ , -P(O)H ₂ , -P(O)HCH ₃ , -P(O)HCH ₂ CH ₃ , -P(O)HCH ₂ CH ₂ CH ₃ , -P(O)HCH(CH ₃ ) ₂ , -PO(CH ₃ ) ₂ , -PO(CH ₂ CH ₃ ) ₂ , -PO(CH ₃ )(CH ₂ CH ₃ ) or -PO(CH ₂ CH ₂ CH ₃ ) ₂ .

In certain embodiments, wherein each R ₃ and R ₄ at each occurrence is independently selected from -C _1-3 alkyl, -CONH ₂ , -CONHR ₅ or -CONR ₅ R ₆ ; and each R ₃ and R ₄ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium or halogen;

Each R ₅ and R ₆ is independently selected at each occurrence from -C _1-3 alkyl or -C _3-6 carbocycle, and each R ₅ and R ₆ is independently selected at each occurrence from 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -C _1-3 alkyl.

In certain embodiments, wherein each R ₃ and R ₄ at each occurrence is independently selected from methyl, ethyl, propyl, isopropyl, -CONH ₂ , -CONHR ₅ or -CONR ₅ R ₆ ; and each R ₃ and R ₄ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl or -Br;

Each R ₅ and R ₆ at each occurrence is independently selected from methyl, ethyl, propyl, isopropyl, 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle or 6-membered carbocycle, and each R ₅ and R ₆ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl, -Br, methyl, ethyl, propyl or isopropyl.

In certain embodiments, wherein each R ₃ or R ₄ is independently selected at each occurrence from -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CONH ₂ , -CONHCH 3 , -CONHCH ₂ CH ₃ , -CONHCH ₂ CH ₂ CH ₃ , -CONHCH(CH 3 ) 2 , -CON(CH ₃ ) _{2 , -CON(CH 2 CH 3 ) 2 , -CON(CH 3 )(CH 2 CH 3 ) , or -CON(CH 2 CH 2 CH 3 ) 2 ; and each R 3 or R 4 is independently selected at each occurrence from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH} 3 , -OCH(CH ₃ ) ₂ , -CONHCH ₃ , -CONHCH _{2 CH 3 , -CONHCH 2 CH 2 CH 3} , -CONHCH(CH ₃ ) 2 , -CON(CH ₃ ) 2 , -CON(CH ₂ CH 3 ) 2 , -CON(CH ₃ )(CH ₂ CH _{3 )} , or -CON(CH 2 CH ₂ CH ₃ ) ₂ ; ₄ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F or methyl.

In certain embodiments, each _R3 or _R4, at each occurrence, is independently _selected from _-CH3 , _-CD3 , -CH2CH3, _-CD2CD3 , _{-CH2CH2CH3, -CH2CH2CD3, -CH(CH3)2 , -CH(CD3)2 , -CONH2 , -CONHCH3 , -CONHCD3 , -CONHCH2CH3 , -CONHCD2CD3 , -CONHCH2CH2CH3 , -CONHCH(CH3)2 , -CON(CH3)2 , -CON ( CH2CH3 ) 2 , -CON ( CH3 ) ( CH2CH3 ) ,} or -CON( _{CH2CH2CH3 ) 2 .}

In certain embodiments, wherein each R ₃ or R ₄ at each occurrence is independently selected from -CH ₃ , -CD ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ ,

In certain embodiments, each R ₃ and R ₄ is independently selected at each occurrence from -C _1-3 alkyl, and said -C _1-3 alkyl is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, or -Br.

In certain embodiments, each R ₃ and R ₄ at each occurrence is independently selected from methyl, ethyl, propyl, or isopropyl; and each R ₃ and R ₄ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl, or -Br.

In certain embodiments, each R ₃ and R ₄ at each occurrence is independently selected from methyl, ethyl, propyl, or isopropyl; and each R ₃ and R ₄ at each occurrence is independently optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium or -F.

In certain embodiments, each _R3 and _R4, at each occurrence, is independently _selected from _{-CH3 , -CH2D} , _{-CD2H ,} -CD3, -CF3, -CH2CH3 _, -CH2CD3 _{, -CH2CF3} , -CH2CH2CH3, _-CH2CH2CH2F , _-CH2CH2CD3 , _{-CH2CH2CF3 ,} -CH ₍ CH3 _{)2 , -CH ( CH3 ) ( CD3 ) ,} -CH( _CF3 ) _{2 ,} or -CH _{( CD3} ) _{2 .}

In certain embodiments, each of R ₃ and R ₄ at each occurrence is selected from -C _1-3 alkyl, or -C _1-3 alkyl substituted with 1, 2, 3, 4, 5, or 6 deuterium.

In certain embodiments, each of R ₃ and R ₄ at each occurrence is selected from methyl, ethyl, propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted propyl, or deuterium-substituted isopropyl.

In certain embodiments, wherein said A is selected from

In certain embodiments, wherein said A is independently selected from

In certain embodiments, wherein W ₁ is selected from hydrogen; deuterium; -F; -Cl; -NH ₂ ; -CN; -OH; carboxyl; -C _1-6 alkyl; -C _1-6 alkoxy; -C _1-3 alkylene-C _1-3 alkoxy; phenyl; 5-membered heteroaryl, the 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O; 6-membered heteroaryl, the 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O; 3-membered heterocyclic ring, the 3-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O; 4-membered heterocyclic ring, the 4-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O; 5-membered heterocyclic ring, the 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O; 6-membered heterocyclic ring, the 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O; 3-membered carbocyclic ring; 4-membered carbocyclic ring; 5-membered carbocyclic ring; or 6-membered carbocyclic ring; and each W ₁ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is selected from deuterium, halogen, -NH ₂ , -CN, -OH, -NO ₂ , carboxyl _{, -C 1-3 alkyl or -C 1-3 alkoxy .}

In certain embodiments, wherein _W is selected from hydrogen; deuterium; -F; -Cl; -NH ₂ ; -CN; -OH; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropyloxy; -CH ₂ OCH ₃ ; -CH ₂ CH ₂ OCH ₃ ; -CH ₂ CH ₂ OCH ₂ CH ₃ ; phenyl; 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N or O; 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N or O; 5-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O; 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O; 5-membered carbocyclic ring; or 6-membered carbocyclic ring; and each _W is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and each substituent is selected at each occurrence from deuterium, -F, -Cl, -NH ₂ , -CN, -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

_{In certain embodiments, wherein W is selected from hydrogen; deuterium; -F; methyl; ethyl; propyl; isopropyl; methoxy; -CH2OCH3; -CH2CH2OCH3 ; a 6 - membered} heteroaryl containing 1 or 2 heteroatoms selected from N or O; a 5-membered heterocycle containing 1 or 2 heteroatoms selected from N or O; a 6-membered heterocycle containing 1 or 2 heteroatoms selected from N or O; a 5-membered carbocycle; or a 6-membered carbocycle; and each _W is independently at each occurrence optionally unsubstituted or substituted with deuterium or -F.

In certain embodiments, wherein _W is selected from hydrogen, deuterium, -F _{, -CH3} , _-CD3 , _-CH2F , _{-CF2H , -CF3} , _-CH2CH3 , -CH2CD3 _{, -CH2CH2F} , _{-CH2CHF2 , -CH2CF3} , _{-CH2CH2CH3 , -CH2CH2CF3, -CH2CH2CD3, -CH(CH3)2 , -CH ( CF3 ) 2 , -CH ( CD3 ) 2 , methoxy , -CH2OCH3 , -CH2CH2OCH3 , or}

In certain embodiments, wherein W ₁ is selected from -C _1-6 alkyl substituted with F; or a 6-membered heterocyclic ring containing 1 heteroatom selected from O.

In certain embodiments, wherein W ₁ is selected from F-substituted -C _1-6 alkyl,

In certain embodiments, wherein W ₁ is selected from -CH ₂ CH ₂ CF ₃ or

In certain embodiments, wherein _W is selected from hydrogen; deuterium; -F; -Cl; -NH ₂ ; -CN; -OH; carboxyl; -C _1-3 alkyl; -C _1-3 alkoxy; phenyl; naphthyl; 5-membered heteroaryl, said 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-membered heteroaryl, said 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 7-membered heteroaryl, said 7-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 8-membered heteroaryl, said 8-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 9-membered heteroaryl, said 9-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 10-membered heteroaryl aryl, the 10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 3-membered heterocyclic ring, the 3-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; 4-membered heterocyclic ring, the 4-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; 5-membered heterocyclic ring, the 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-membered heterocyclic ring, the 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; 3-membered carbocyclic ring; 4-membered carbocyclic ring; 5-membered carbocyclic ring; or 6-membered carbocyclic ring; and each W ₂ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, and each of said substituents at each occurrence is selected from deuterium, halogen, _-NH2 , -CN, -OH, _-NO2 , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In certain embodiments, _W is selected from hydrogen; deuterium; phenyl; a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S; or a 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S; and each _W is independently, at each occurrence, optionally unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, and each of said substituents is, at each occurrence, selected from deuterium, -F, -Cl, _-Br , -NH, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In certain embodiments, wherein _W is selected from phenyl; a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S; or a 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S; and each _W is independently, at each occurrence, optionally unsubstituted or substituted with 1, 2, or 3 substituents, and each of said substituents is, at each occurrence, selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In certain embodiments, wherein W ₂ is selected from and each W ₂ is independently at each occurrence optionally substituted with 1, 2, or 3 substituents, and each of said substituents at each occurrence is selected from -F, -Cl, methyl, or methoxy.

In certain embodiments, wherein W ₂ is selected from or and each W ₂ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, or 3 substituents, and each of said substituents at each occurrence is selected from -F, -Cl, methyl, or methoxy.

In certain embodiments, wherein W ₂ is selected from and each W ₂ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, or 3 substituents, and each of said substituents at each occurrence is selected from -F, -Cl, methyl, or methoxy.

In certain embodiments, wherein W ₂ is selected from and each W ₂ is independently at each occurrence optionally unsubstituted or substituted with 1, 2, or 3 substituents, and each of said substituents at each occurrence is selected from -F, -Cl, methyl, or methoxy.

In certain embodiments, wherein W ₂ is independently selected from:

or

In certain embodiments, Z is selected from hydrogen, deuterium, -F, -Cl, -OH, -C _1-3 alkyl, or -C _1-3 alkoxy.

In certain embodiments, Z is selected from hydrogen, deuterium, -F, -Cl, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

In certain embodiments, wherein Z is selected from hydrogen or deuterium.

In certain embodiments, wherein Z is hydrogen.

In certain embodiments, wherein is selected from:

and each is independently at each occurrence optionally unsubstituted or substituted with 1, 2 or 3 substituents, and each of said substituents at each occurrence is selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In certain embodiments, wherein said is selected from:

and each is independently at each occurrence optionally unsubstituted or substituted with 1, 2 or 3 substituents, and each of said substituents at each occurrence is selected from -F, -Cl, methyl or methoxy.

In certain embodiments, wherein said A is independently selected from:

In certain embodiments, wherein

_R1 is _-C1-6 alkyl;

_R2 is

each R ₂₃ and R ₂₄ at each occurrence is -C _1-6 alkyl;

The A shown is

Each R ₃ and R ₄ , at each occurrence, is selected from -C _1-6 alkyl or -C _1-6 alkyl substituted with 1, 2, 3, 4, 5 or 6 deuterium;

W ₁ is selected from -F substituted -C _1-6 alkyl, or a 6-membered heterocyclic ring containing 1 heteroatom selected from O;

W ₂ is selected from phenyl; a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; or a 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and each W ₂ is independently at each occurrence optionally unsubstituted or substituted with 1, 2 or 3 substituents, and each of said substituents at each occurrence is selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

Z is selected from hydrogen or deuterium.

In certain embodiments, wherein,

_R1 is _-C1-3 alkyl;

each R ₂₃ and R ₂₄ at each occurrence is -C _1-3 alkyl;

each R ₃ and R ₄ at each occurrence is selected from -C _1-3 alkyl, or -C _1-3 alkyl substituted with 1, 2, 3, 4, 5, or 6 deuterium;

W ₁ is selected from -F substituted -C _1-6 alkyl,

_W is selected from and each _W is independently at each occurrence optionally unsubstituted or substituted with 1, 2 or 3 substituents, and each of said substituents is at each occurrence selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

Z is selected from hydrogen.

In certain embodiments, wherein,

_R1 is selected from methyl, ethyl, propyl or isopropyl;

each R ₂₃ or R ₂₄ at each occurrence is selected from methyl, ethyl, propyl or isopropyl;

each R ₃ and R ₄ at each occurrence is selected from methyl, ethyl, propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted propyl, or deuterium-substituted isopropyl;

W ₁ is selected from -CH ₂ CH ₂ CF ₃ or

W ₂ is selected from:

or

In certain embodiments, wherein,

R ₁ is methyl; R ₂ is; and each of R ₃ and R ₄ at each occurrence is independently selected from -CH ₃ or -CD ₃ .

In certain embodiments, wherein the compound is:

In certain embodiments, the compound is:

In certain embodiments, the compound is:

In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient. In certain embodiments, the weight ratio of the compound to the excipient is from about 0.0001 to about 10. In certain embodiments, the weight ratio of the compound to the excipient is from about 0.0005 to about 0.25.

In another aspect, the present invention provides a method for treating a patient suffering from a disease or condition associated with a bromodomain protein, the method comprising administering to the patient a therapeutically effective amount of at least one compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; or a pharmaceutical composition thereof. In certain embodiments, the disease or condition associated with a bromodomain protein is a solid tumor and/or a hematologic tumor. In certain embodiments, the solid tumor is selected from lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer, and/or ovarian cancer; and the hematologic tumor is selected from myeloma and/or leukemia. In certain embodiments, lung cancer includes non-small cell lung cancer and/or small cell lung cancer; gastrointestinal cancer includes esophageal cancer; leukemia includes acute myeloid leukemia (AML) and/or acute lymphocytic leukemia (ALL); and myeloma includes multiple myeloma.

In another aspect, the present invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; or a pharmaceutical composition for use in treating a disease or condition associated with a bromodomain protein. In certain embodiments, the disease or condition associated with a bromodomain protein is a solid tumor and/or a hematologic tumor. In certain embodiments, the solid tumor is selected from lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer, and/or ovarian cancer; and the hematologic tumor is selected from myeloma and/or leukemia. In certain embodiments, lung cancer includes non-small cell lung cancer and/or small cell lung cancer; gastrointestinal cancer includes esophageal cancer; leukemia includes acute myeloid leukemia (AML) and/or acute lymphocytic leukemia (ALL); and myeloma includes multiple myeloma.

In another aspect, the present invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; or a pharmaceutical composition thereof for use in the preparation of a medicament, wherein the medicament is used to treat a disease or condition associated with a bromodomain protein. In certain embodiments, the disease or condition associated with a bromodomain protein is a solid tumor and/or a hematologic tumor. In certain embodiments, the solid tumor is selected from lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer, and/or ovarian cancer; and the hematologic tumor is selected from myeloma and/or leukemia. In certain embodiments, lung cancer includes non-small cell lung cancer and/or small cell lung cancer; gastrointestinal cancer includes esophageal cancer; leukemia includes acute myeloid leukemia (AML) and/or acute lymphocytic leukemia (ALL); and myeloma includes multiple myeloma.

definition

Unless otherwise indicated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups include F, Cl and Br.

Unless otherwise indicated, the term "alkyl" as used herein includes saturated monovalent alkyl groups having a straight or branched chain. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and cyclohexyl. Similarly, C _1-6 in C _1-6 alkyl is defined as having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched arrangement.

The term "alkylene" refers to a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above, for example, methylene (i.e., _-CH2- ), ethylene (i.e., _-CH2 - _CH2- or -CH( _CH3 )-), and propylene (i.e., _-CH2 - _CH2 - _CH2- , -CH( _-CH2 - _CH3 ))-, or _-CH2 -CH( _CH3 )-).

The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, " _C2-6 alkenyl" contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a " _C2-6 alkynyl" group contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term "alkoxy" group is an oxygen ether formed from the aforementioned alkyl groups.

As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

As used herein, unless otherwise indicated, the term "heterocycle" refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is three to eight-membered and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably one, two, or three degrees of substitution.

Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxazepanyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazole.

Unless otherwise indicated, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. A heteroaryl group can be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group can have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl group can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can contain fused, spirocyclic, or bridged rings. For example, a bicyclic heteroaryl group is a polycyclic heteroaryl group. A bicyclic heteroaryl ring can contain 8 to 12 member atoms. A monocyclic heteroaryl ring can contain 5 to 8 member atoms (carbon atoms and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.

The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which a cycloalkyl group can be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "oxo" refers to an oxygen radical together with the carbon atom to which it is attached.

The term "carboxy" refers to the group C(O)OH.

As used herein, the term "composition" is intended to encompass products comprising specific ingredients in specific amounts, as well as any product resulting directly or indirectly from a combination of specific ingredients in specific amounts. Thus, pharmaceutical compositions containing a compound of the invention as an active ingredient and methods for preparing the compound of the invention are also part of the present invention. In addition, some crystalline forms of the compound may exist as polymorphs, and therefore these are intended to be included in the present invention. Additionally, some compounds may form solvates (i.e., hydrates) with water or common organic solvents, and these solvates are also included within the scope of the present invention.

The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts are generally those in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, saccharin, or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc salts.

The present invention includes within its scope prodrugs of the compounds of the present invention. Typically, such prodrugs are functional derivatives of compounds that are easily converted into the desired compound in vivo. Therefore, in the therapeutic methods of the present invention, the term "administering" should include the various conditions described for treating a specific disclosed compound, or a compound that may not be specifically disclosed, but is converted into a specific compound in vivo after administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definitions of substituents or variables at other positions in the molecule. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the invention to provide chemically stable compounds that can be readily synthesized by techniques known in the art and the methods illustrated herein.

The present invention includes that the compound may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all such possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The present invention includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the synthetic methods used to prepare these compounds, or during the use of racemization or epimerization methods known to those skilled in the art, the products of these methods may be mixtures of stereoisomers.

The term "stereoisomer" as used herein refers to isomers resulting from different spatial arrangements of atoms or groups of atoms in a molecule in the same order of interconnection, including configurational isomers and conformational isomers. Configurational isomers further include geometric isomers and optical isomers, and optical isomers primarily include enantiomers and diastereomers. The present invention includes all possible stereoisomers of the compound. In particular, when the carbon atom directly connected to W ₁ , W ₂ , or Z in Formula I is a chiral carbon, the present invention includes stereoisomers with an "R" configuration in Formula (I) and stereoisomers with an "S" configuration in Formula (I). For example, the stereoisomers included in the present invention include:

In formulas I-1, II-1, III-1, and IV-1, "R" indicates that when the carbon atom connected to W ₁ , W ₂ , and Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

In formulas I-2, II-2, III-2, and IV-2, "S" indicates that when the carbon atom connected to W ₁ , W ₂ , and Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

The present invention is intended to include all atomic isotopes present in the compounds of the present invention. Isotopes are atoms with the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as ^1H (hydrogen), ^2H (deuterium) and ^3H (tritium). They are also commonly represented as D (deuterium) and T (tritium). In this application, CD ₃ represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include ^13C and ^14C . Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents instead of non-labeled reagents.

Unless otherwise indicated, when tautomers of the compound of formula I exist, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as mixtures thereof.

When the compound of Formula I and its pharmaceutically acceptable salt exist in the form of a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent forming the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, etc. can be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including inorganic acids and organic acids. Since the compounds of Formula I are intended for pharmaceutical use, they are preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure, and particularly at least 98% pure (% is weight % by weight).

Pharmaceutical composition of the present invention comprises the compound (or its pharmaceutically acceptable salt) that formula I represents as active component, pharmaceutically acceptable carrier and optional other treatment composition or adjuvant.Although the most suitable approach in any given case will depend on specific host, and for the character and the order of severity of illness (using this active component for treating this illness), said composition includes the composition that is suitable for oral, rectal, local and parenteral (comprising subcutaneous, intramuscular and intravenous) administration.Pharmaceutical composition can exist with unit dosage form easily, and is prepared by any method known to pharmaceutical field.

In practice, according to conventional drug formulation technology, the compound represented by Formula I of the present invention or its prodrug or metabolite or its pharmaceutically acceptable salt can be combined into a close mixture as an active ingredient with a drug carrier. The carrier can take a variety of forms, depending on the formulation form required for the route of administration, such as oral or parenteral (including intravenous) route of administration. Therefore, the pharmaceutical composition of the present invention can exist as discrete units suitable for oral administration, such as capsules, cachets (cachets) or tablets each containing a predetermined amount of active ingredient. In addition, the composition can exist in the form of a powder, granular form, solution form, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion. In addition to the above-mentioned common dosage forms, the compound represented by Formula I or its pharmaceutically acceptable salt can also be administered by a controlled release device and/or a delivery device. The composition can be prepared by any pharmaceutical method. Typically, these methods include the step of combining the active ingredient with a carrier constituting one or more essential ingredients. Typically, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be easily shaped into the desired style.

Therefore, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compound or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition together with one or more other therapeutically active compounds.

The pharmaceutical carrier used can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavorings, preservatives, colorants, and the like can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, and the like can be used to form oral solid preparations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units in which solid pharmaceutical carriers are used due to their ease of administration. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent mixed with an appropriate and convenient amount of carrier material, which may comprise from about 0.05% to about 95% of the total composition. Dosage unit forms typically contain from about 0.01 mg to about 2 g of active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropylcellulose, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, preservatives can be included to prevent the harmful growth of microorganisms.

The pharmaceutical compositions of the present invention suitable for injection purposes include sterile aqueous solutions or dispersions. In addition, the composition can be in the form of a sterile powder for the temporary preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for injection. The pharmaceutical composition must be stable under manufacturing and storage conditions; therefore, it is preferably preserved under contamination by microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, a polyol (such as glycerol, propylene glycol and liquid polyethylene glycol), a vegetable oil and a suitable mixture thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, or the like. In addition, the compositions may be in a form suitable for transdermal application. Utilizing the compounds of Formula I of the present invention or pharmaceutically acceptable salts thereof, these formulations may be prepared by conventional processing methods. For example, a cream or ointment may be prepared by mixing a hydrophilic material and water with about 0.05 wt % to about 10 wt % of the compound to produce a cream or ointment of the desired consistency.

The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be easily formed by first mixing the composition with a softened or melted carrier, then cooling and molding in a mold.

Except above-mentioned carrier component, above-mentioned pharmaceutical preparation can suitably comprise one or more other carrier components, for example diluent, buffer, flavoring, adhesive, surfactant, thickening agent, lubricant, preservative (comprising antioxidant) etc.In addition, other adjuvants can be included so that preparation and the blood of expected recipient are isotonic.The composition containing compound shown in Formula I or its pharmaceutically acceptable salt also can be prepared into powder or liquid concentrate form.

Generally, dosage levels of about 0.001 mg/kg to about 150 mg/kg of body weight per day are useful for treating the above-mentioned conditions, or about 0.05 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies/asthma, diseases and disorders of the immune system, and diseases and disorders of the central nervous system (CNS) can be effectively treated by administering about 0.001 to 50 mg of the compound per kilogram of body weight per day, or about 0.05 mg to about 3.5 g per patient per day.

However, it will be understood that the specific dosage level for any particular patient will depend upon a variety of factors including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular condition being treated.

These and other aspects will become apparent from the following written description of the invention.

Preparation method

Those skilled in the art of organic synthesis can readily synthesize the compounds of the present invention using several methods described below, as well as synthetic methods well known in the art of synthetic organic chemistry, or variations thereof known to those skilled in the art. Preferred methods are not limited to those described below. The references cited herein are incorporated by reference in their entirety.

The synthetic method described below is intended to illustrate the present invention, rather than to limit the scope of the compounds claimed in its subject matter and these embodiments. When the starting compounds prepared are not described, they are commercially available or can be prepared similarly to known compounds or methods described herein. The materials described in the literature can be prepared according to disclosed synthetic methods. The compound of formula I can be prepared with reference to the method described in the following scheme. As shown here, the target compound is a product with the same structural formula as described in formula I. It should be understood that any compound of formula I can be prepared by selecting a reagent with appropriate substitution. Those skilled in the art can easily select solvent, temperature, pressure and other reaction conditions. According to standard methods for organic synthesis (T.W.Green and P.G.M.Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons) operate the protecting group. Use methods obvious to those skilled in the art to remove these groups at certain stages of compound synthesis.

Schemes 1-3 illustrate general synthetic routes to the compounds of the present invention, wherein substituents R ₁ , R ₂ , R ₃ , Y ₁ , Y ₂ , W ₁ , W ₂ , and Z are previously defined herein or are functional groups that can be converted to the desired final substituents. The substituent Hal is a halide, and L is a leaving group such as a halide ion or a hydroxyl group that can be readily converted to a triflate or tosylate. M is a suitable coupling ligand such as a boronic acid, a boronate ester, or a stannoyl.

As shown in Scheme 1, pyrazole 1 is subjected to Suzuki coupling with an aromatic heterocycle ₂ (e.g., 2,5-dibromo-3-nitropyridine) in THF/H ₂ O (5:1 by volume) using a suitable coupling catalyst (e.g., Pd(dppf)Cl 2 ) in the presence of a base (e.g., K ₃ PO ₄ ) to afford 3. Cadogan reductive cyclization of 3 in the presence of a phosphine reagent (e.g., 1,2-bis(diphenylphosphino)ethane (DPPE) or triethyl phosphate P(OEt) ₃ ) and a solvent (e.g., 1,2-dichlorobenzene or 1,2-dimethylbenzene) with heating affords tricyclic compound 4. Mitsunobu reaction of 4 with an alkylating agent 5 using triphenylphosphine and diisopropyl azodicarboxylate (DIAD) provides 7. 7 can also be generated by reacting 4 with an alkylating agent 6 under basic conditions (potassium carbonate), where L is a leaving group such as a halogen, methanesulfonate, or triflate. Coupling of 7 with 8 (where M is a suitable coupling ligand such as a boronic acid, boronate, or stannoic acid) via a Suzuki or Stille reaction can provide 9. In the case of a racemate of 9, chiral separation can provide an enantiomerically pure product. Further derivatization of _R1 and _R2 can provide additional compounds of the present invention. For example, when _R1 is a protecting group, further functionalization can be performed after deprotection; when _R2 is an ester, addition of a Grignard reagent or alkyllithium can produce a tertiary alcohol. The ester can also be hydrolyzed using, for example, potassium hydroxide to give the carboxylic acid, which can be further functionalized with the alkylamine; when _R is hydrogen, it can be replaced with a halogen (e.g., -Br) by a halogenation reaction using a reagent such as NBS and then further functionalized by a coupling reaction, such as the Buchwall, Mitszunobu, or Stille reaction.

Solution 1

As shown in Scheme 2, heteroaromatic compound 10 can be directly coupled with 7 (prepared as in Scheme 1) via palladium-mediated C-H activation to afford compound 9.

Option 2

Alternatively, heteroaromatic compound 10 can be deprotonated with a strong base such as n-BuLi and transmetallated to a zinc or tin reagent to give compound 8, which can be coupled with 7 (prepared as in Scheme 1) via a Negishi or Stille reaction in the presence of a suitable palladium catalyst to give compound 9. This is illustrated in Scheme 3.

Option 3

Example

The present invention will be further illustrated using the following examples, which should be understood to be illustrative only. Those skilled in the art will readily appreciate the essential characteristics of the present invention and, without departing from its spirit and scope, may make various modifications to adapt the present invention to various uses and conditions. Therefore, the present invention is not limited by the exemplary embodiments described below, but is defined by the appended claims.

The abbreviations are shown in Table 1 below:

Table 1

Preparation of intermediates

Unless otherwise stated, starting materials used in the preparation of intermediates and examples are commercially available.

Enantiomer a1 and enantiomer b1

(R)-(3-Fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol

((R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol)(“Enantiomer a1”)

and

(S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (“Enantiomer b1”)

Under _N₂ , three iodine crystals were added to a suspension of Mg (24.3 g, 1.00 mol) in THF (500 mL). Then, neat 4-bromotetrahydro-2H-pyran (100 g, 607 mmol) was added dropwise via a separate funnel, maintaining the internal temperature below 45°C. The reaction mixture was stirred at ambient temperature for another 2 hours. The reaction mixture was cooled to -30°C, and a solution of 3-fluoropicolinaldehyde (50.3 g, 402 mmol) in THF (300 mL) was added dropwise via a separate funnel, maintaining the internal temperature between -20°C and -30°C. After 1 hour, the reaction mixture was filtered through a thin pad of Celite. Saturated aqueous _NH₄Cl (100 mL) was added to the filtrate, and the two layers separated. The organic phase was _dried over anhydrous _Na₂SO₄ , collected by filtration, and washed with EtOAc (200 mL). The filtrate was concentrated on a rotary evaporator. The crude compound was purified using reverse phase chromatography eluting with 40%-50% MeCN/ _H2O to afford the racemic compound (52 g, 61% yield), which was separated by chiral preparative SFC to afford enantiomers a1, (R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (25.1 g, 29.6% yield) and (S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (25.3 g, 29.7%).

Enantiomer a1: LC-MS [M+H] ⁺ = 212. Chiral chromatography report: RT = 12.25 min (column: Chiralpak AY-H (ADHOCE-VC001) 0.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0 mL/min). Chiral chromatography report: RT = 14.023 min (column: YMC, Chiral ART-amylose-C Neo (5 μm, 250 × 4.6 mm; mobile phase: 90/10/0.1 hexane/EtOH/TFA; flow rate: 1.0 mL/min)). ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.42 (dd, J=3.20, 1.32Hz, 1H), 7.66 (ddd, J=9.8, 8.36, 1.12Hz, 1H), 7.35-7.42 (m, 1H), 5.23 ( d, J=6.52Hz, 1H), 4.52 (dd, J=7.32, 7.28Hz, 1H), 3.88 (dd, J=11.4, 2.92Hz, 1H), 3.75 (dd, J=11.2 , 3.02Hz, 1H), 3.26 (dt, J=12.0, 2.04Hz, 1H), 3.17 (dt, J=11.8, 2.24Hz, 1H), 2.01-2.12 (m, 1H), 1 .82 (dd, J=13.3, 1.52Hz, 1H), 1.24-1.38 (m, 1H), 1.12-1.24 (m, 1H), 1.00 (dd, J=12.9, 1.34, 1H).

Enantiomer b1: LC-MS [M+H] ⁺ = 212. Chiral chromatography report: RT = 13.57 min (column: Chiralpak AY-H (ADHOCE-VC001) 0.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0 mL/min). Chiral chromatography report: RT = 12.760 min (column: YMC, Chiral ART-amylose-C Neo (5 μm, 250 × 4.6 mm; mobile phase: 90/10/0.1 hexane/EtOH/TFA; flow rate: 1.0 mL/min)). ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.42 (dd, J=3.2, 1.35Hz, 1H), 7.66 (ddd, J=1.12, 8.4, 9.8Hz, 1H), 7.35-7.42 (m, 1H), 5.23 (d , J=6.48Hz, 1H), 4.52 (dd, J=7.32, 7.24Hz, 1H), 3.88 (dd, J=11.3, 2.96, 1H), 3.75 (dd, J=2.96, 1 1.2Hz, 1H), 3.26 (dt, J=12.0, 2.0Hz, 1H), 3.17 (dt, J=11.8, 2.24Hz, 1H), 2.01-2.12 (m, 1H), 1. 82 (dd, J=13.3, 1.52Hz, 1H), 1.24-1.38 (m, 1H), 1.12-1.24 (m, 1H), 1.00 (dd, J=12.9, 1.34, 1H).

Intermediate 3-Intermediate 17

The intermediates in Table 2 were prepared using the same method as the racemates of enantiomer a1 and enantiomer b1:

Table 2

Example 1

(S)-2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 1”)

(S)-2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 1”)

Step 1: Methyl 5-(5-bromo-3-nitropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate

To a THF solution (125 mL) of HBPin (26.4 _g , 0.21 mmol), dtbpy (1.06 g, 3.95 mmol), and (1,5-cyclooctadiene)-(methoxy)iridium(I) dimer (1.02 g, 1.54 mmol) was added methyl 1-methyl-1H-pyrazole-3-carboxylate (20.2 g, 0.14 mol) under N₂ at room temperature. The resulting solution was evacuated, filled with _N₂ , and this process was repeated three times. The reaction mixture was then refluxed under _N₂ for 12 hours. The reaction mixture was then concentrated under reduced pressure to give a red product. In a 1 L round-bottom flask, THF (500 mL), water (100 mL), _K₃PO₄ (65.13 g, 0.31 mol), and 2,5-dibromo-3-nitropyridine (47.1 g, 0.17 mol) were added to the _resulting crude product. The flask was evacuated and filled with _N2 , and the process was repeated three times, and then Pd(dppf) _Cl2 (11.3 g, 0.014 mmol) was added under _N2 . The mixture was refluxed under _N2 for 3 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc (500 mL). The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-30% EtOAc in hexane to obtain methyl 5-(5-bromo-3-nitropyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (27.6 g, 0.081 mol, 57% yield). LC-MS [M+H] ⁺ = 341.

Step 2: Methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

A mixture of 5-(5-bromo-3-nitropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (22.1 g, 0.065 mol) and DPPE (38.8 g, 0.088 mol) in 1,2-dichlorobenzene (250 mL) was heated to 150° C. and stirred under N ₂ for 4 hours. The reaction was then slowly cooled to room temperature. The solvent was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 30-50% EtOAC in hexane to give 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (3.98 g, 0.013 mol, 20% yield). LC-MS [M+H] ⁺ = 309.

Step 3: Methyl (S)-6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

A solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (207 mg, 0.67 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (169 mg, 0.88 mmol), and triphenylphosphine (446 mg, 1.70 mmol) in anhydrous THF (10 mL) was evacuated and backfilled with nitrogen three times. Diisopropyl azodicarboxylate (321 mg, 1.59 mmol) was added dropwise at room temperature, and the resulting solution was stirred for 2 hours. The reaction was then extracted with EtOAc (50 mL), washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-30% EtOAc in hexanes to give (S)-methyl 6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (315 mg, 97% yield). LC-MS [M+H] ⁺ = 483, 485.

Step 4: Methyl(S)-6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of (S)-6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (315 mg, 0.65 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (208 mg, 0.93 mmol), Pd(dppf) _Cl₂ (74 mg, 0.091 mmol) and _{K₃PO₄ (} 402 mg, 1.89 mmol). The mixture was evacuated and backfilled with nitrogen three times. The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). After separation, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-50% EtOAc in hexane to give (S)-6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (272 mg, 84% yield). LC-MS[M+H] ⁺ =500.

Step 5: (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Under _N₂ at -30°C, MeMgBr (1 M in THF, 5.0 mL, 5.03 mmol) was slowly added to a solution of (S)-methyl 6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (272 mg, 0.54 mmol) in anhydrous THF (10 mL) over 1 minute. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution and extracted with EtOAc (30 mL). The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-4% MeOH in DCM to give (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 1, 121 mg, 44% yield). LC-MS [M+H] ⁺ = 500. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.27 (d, J=1.5Hz, 1H), 7.75 (d, J=1.3Hz, 1H), 7.70 (d, J=7.6Hz, 2H), 7.31 (t, J=7.5Hz, 2H), 7.22 (t, J=7.3 Hz, 1H), 6.44 (d, J=11.2Hz, 1H), 5.77 (s, 1H), 4.13 (s, 3H), 3.85 (d, J=8.8Hz, 1H), 3.74 (d, J=8.7Hz, 1H), 3.47 (t, J=11.2Hz, 1H), 3.25 (dd, J=22.1, 11.0Hz, 2H), 2.34 (s, 3H), 2.15 (s, 3H), 1.79 (d, J=12.8Hz, 1H), 1.70 (s, 3H), 1.71 (s, 3H), 1.54 (qd, J=12.5, 4.2Hz, 1H), 1.37 (ddd, J=15.6, 12.6, 4.1Hz, 1H), 0.78 (d, J=12.6Hz, 1H).

Example 2

(S)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 2”)

(S)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 2”)

Step 1: (R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol ("Enantiomer a1") ((R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol ("Enantiomer a1")) and (S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol ("Enantiomer b1") ((S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol ("Enantiomer b1"))

To a suspension of magnesium (24.3 g, 1.00 mol) in THF (500 mL) were added three crystals of iodine, followed by the dropwise addition of neat 4-bromotetrahydro-2H-pyran (100 g, 607 mmol) under _N₂ , while the internal temperature was maintained below 45°C. The reaction mixture was stirred at ambient temperature for an additional 2 hours. The reaction mixture was cooled to -30°C, followed by the addition of a solution of 3-fluoropicolinaldehyde (50.3 g, 402 mmol) in THF (300 mL), while the internal temperature was maintained between -20°C and -30°C. After 1 hour, the reaction mixture was filtered through a thin layer of Celite. Saturated aqueous _NH₄Cl (100 mL) was added to the filtrate, and the two layers were separated. The organic phase was dried _over anhydrous _Na₂SO₄ and collected by filtration. The filtrate was concentrated on a rotary evaporator. The crude compound was purified using reverse phase chromatography eluting with 40%-50% MeCN in _H2O to afford the racemic compound (52 g, 61% yield), which was separated by chiral preparative SFC to afford enantiomer a1 of (R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (25.1 g, 29.6% yield) and enantiomer b1 of (S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (25.3 g, 29.7%).

Enantiomer a1: LC-MS [M+H] ⁺ = 212. Chiral chromatography report: RT = 12.25 min (column: Chiralpak AY-H (ADHOCE-VC001) 0.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0 mL/min). Chiral chromatography report: RT = 14.023 min (column: YMC, Chiral ART-amylose-C 0.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0 mL/min). Chiral chromatography report: RT = 14.023 min (column: YMC, ChiralART-amylose-CNeo (5 μm, 250×4.6 mm; mobile phase: 90/10/0.1 hexane/EtOH/TFA; flow rate: 1.0 mL/min)). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (dd, J = 3.20, 1.32 Hz, 1H), 7.66 (ddd, J = 9.8, 8.36, 1.12 Hz, 1H), 7.35-7.42 (m, 1H), 5.23 (d, J = 6.52 Hz, 1H). H), 4.52 (dd, J=7.32, 7.28Hz, 1H), 3.88 (dd, J=11.4, 2.92Hz, 1H), 3.75 (dd, J=11.2, 3.02Hz, 1H), 3.26 (dt, J=12.0, 2.04Hz, 1H), 3.17 (dt, J=11.8, 2.24Hz, 1H), 2.01-2.12 (m, 1H), 1.82 (dd, J=13.3, 1.52Hz, 1H), 1.24-1.38 (m, 1H), 1.12-1.24 (m, 1H), 1.00 (dd, J=12.9, 1.34, 1H).

Enantiomer b1: LC-MS [M+H] ⁺ = 212. Chiral chromatography report: RT = 13.57 minutes (column: Chiralpak AY-H (ADHOCE-VC001) 0.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0 mL/min). Chiral chromatography report: RT = 12.76 minutes (column: YMC, Chiral ART-amylose-C 0.46 × 25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0 mL/min). Chiral chromatography report: RT = 12.760 min (column: YMC, ChiralART-amylose-C Neo (5 μm, 250×4.6 mm; mobile phase: 90/10/0.1 hexane/EtOH/TFA; flow rate: 1.0 mL/min)). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (dd, J = 3.2, 1.35 Hz, 1H), 7.66 (ddd, J = 1.12, 8.4, 9.8 Hz, 1H), 7.35-7.42 (m, 1H), 5.23 (d, J = 6.48 Hz, 1H), 4.52 (dd, J = 7.32, 7.24 Hz, 1H), 3.88 (dd, J = 11.3, 2.96, 1H), 3.75 (dd, J = 2.96, 1 1.2Hz, 1H), 3.26 (dt, J=12.0, 2.0Hz, 1H), 3.17 (dt, J=11.8, 2.24Hz, 1H), 2.01-2.12 (m, 1H), 1. 82 (dd, J=13.3, 1.52Hz, 1H), 1.24-1.38 (m, 1H), 1.12-1.24 (m, 1H), 1.00 (dd, J=12.9, 1.34, 1H).

Step 2: (S)-Methyl 6-bromo-4-((3-flaoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

A solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step 2, 202 mg, 0.65 mmol), (R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (from enantiomer a1 in Step 1, 185 mg, 0.88 mmol), and triphenylphosphine (438 mg, 1.67 mmol) in anhydrous THF (10 mL) was evacuated and backfilled with nitrogen three times. A solution of diisopropyl azodicarboxylate (336 mg, 1.66 mmol) in THF (2 mL) was added dropwise at room temperature, and the resulting solution was stirred for 2 hours. The reaction was then extracted with EtOAc (50 mL), and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 0-35% EtOAc in hexanes to afford (S)-methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (317 mg, 92% yield). LC-MS [M+H] = 502.

Step 3: (S)-6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (

(S)-Methyl 6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate)

To a solution of (S)-methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from step 2, 317 mg, 0.63 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (207 mg, 0.93 mmol) and _{K3PO4 (} 386 mg, 1.82 mmol). The mixture was evacuated and backfilled with nitrogen three times, and then Pd(dppf) _Cl₂ (82 mg, 0.10 mmol) was added in one portion, and the resulting mixture was stirred under _N₂ at 80°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3×50 mL). After separation, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% EtOAc in MeOH to give (S)-methyl 6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (254 mg, 78% yield). LC-MS [M+H] ⁺ =519.

Step 4: (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

MeMgBr ( ₁ M in THF, 4.8 mL, 4.77 mmol) was slowly added to a solution of (S)-6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (from Step 3, 254 mg, 0.49 mmol) in anhydrous THF (10 mL) under N₂ at -30°C over 1 minute. After the addition was complete, the reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution and extracted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-4% MeOH in DCM to give (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 2, 93 mg, 37% yield). LC-MS [M+H] ⁺ = 519. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.54 (d, J=4.6Hz, 1H), 8.32 (d, J=1.6Hz, 1H), 8.10 (d, J=1.6Hz, 1H), 7.72 (t, J=8.9Hz, 1H), 7.47 (dt, J =8.5, 4.3Hz, 1H), 6.98 (d, J = 10.7Hz, 1H), 5.68 (s, 1H), 4.13 (s, 3H), 3.80 (d, J = 8.9Hz, 1H), 3.68 (d, J = 8. 6Hz, 1H), 3.28 (d, J=11.6Hz, 1H), 3.23-3.06 (m, 2H), 2.41 (s, 3H), 2.23 (s, 3H), 1.73 (s, 3H), 1.66-1.60 ( m, 1H), 1.57 (s, 3H), 1.51 (d, J=12.4Hz, 1H), 1.40 (ddd, J=24.2, 12.2, 4.2Hz, 1H), 0.50 (d, J=12.2Hz, 1H).

Example 3

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 3”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 3”)

Step 1: Methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step 2, 213 mg, 0.69 mmol), 4,4,4-trifluoro-1-phenylbutan-1-ol (Intermediate 8, 179 mg, 0.88 mmol), and triphenylphosphine (449 mg, 1.71 mmol) in anhydrous THF (10 mL) was added dropwise a solution of diisopropyl azodicarboxylate (350 mg, 1.73 mmol) in THF (2 mL) at room temperature. The resulting solution was stirred for 2 hours. The reaction mixture was then extracted with EtOAc (50 mL). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 0-35% EtOAc in hexanes to afford methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (314 mg, 92% yield). LC-MS [M+H] ⁺ = 495, 497.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (314 mg, 0.63 mmol) in DMF (10 mL) was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (521 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium (102 mg, 0.088 mmol), CuI (30 mg, 0.16 mmol), and TEA (221 mg, 2.00 mmol). The mixture was degassed under vacuum and backfilled with nitrogen three times, then stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3×50 mL). After separation, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (176 mg, 55% yield). LC-MS[M+H] ⁺ =512.

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Under _N₂ at -30°C, MeMgBr (1 M in THF, 3.2 mL, 3.20 mmol) was slowly added dropwise to a solution of methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (176 mg, 0.34 mmol) in anhydrous THF (10 mL) over 1 minute. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution and extracted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM to give 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 3, 94 mg, 53% yield). LC-MS [M+H] ⁺ = 512. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.40 (d, J=1.2Hz, 1H), 7.61 (s, 1H), 7.32 (d, J=4.2Hz, 4H), 7.25 (dd, J=8.3, 4.0Hz, 1H), 6.77 (t, J=8.0Hz, 1H), 5.77 (s, 1H), 4.1 9 (s, 3H), 3.73 (s, 3H), 2.80 (dd, J=16.2, 8.0Hz, 2H), 2.70-2.55 (m, 1H), 2.07 (s, 3H), 1.88-1.74 (m, 1H), 1.69 (s, 3H), 1.52 (s, 3H).

Example 4

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 4”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol("Compound 4”)

Step 1: Methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

A solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step 2, 221 mg, 0.71 mmol), 4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butan-1-ol (Intermediate 7, 215 mg, 0.97 mmol) and triphenylphosphine (471 mg, 1.80 mmol) in anhydrous THF (10 mL) was degassed under vacuum and backfilled with nitrogen three times. A solution of diisopropyl azodicarboxylate (353 mg, 1.75 mmol) in THF (3 mL) was added dropwise at room temperature and the resulting solution was stirred for 2 hours. The reaction was then extracted with EtOAc (50 mL). The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-40% EtOAc in hexanes to give methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (339 mg, 93% yield). LC-MS [M+H] ⁺ = 514, 516.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (339 mg, 0.66 mmol) in DMF (10 mL) was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (568 mg, 1.47 mmol), tetrakis(triphenylphosphine)palladium (130 mg, 0.11 mmol), CuI (26 mg, 0.14 mmol) and TEA (243 mg, 2.20 mmol). The mixture was degassed under vacuum and backfilled with nitrogen, and this process was repeated three times. The resulting mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. Using a 0-6% MeOH solution in DCM, the residue was purified by silica gel chromatography to give 6- (1,4-dimethyl-1H-1,2,3-triazol-5-yl) -1-methyl-4- (4,4,4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -1,4-dihydropyrazolo [3′, 4′: 4,5] pyrrolo [3,2-b] pyridine-3-carboxylic acid methyl ester (194 mg, 55% yield). LC-MS [M+H] ⁺ = 531.

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Under _N₂ at -30°C, MeMgBr (1 M in THF, 3.7 mL, 3.72 mmol) was slowly added to a solution of methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (194 mg, 0.37 mmol) in anhydrous THF (10 mL) over 1 minute. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution and extracted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM to give 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 4, 101 mg, 53% yield). LC-MS [M+H] ⁺ = 531. ¹ HNMR (400MHz, DMSO-d ₆ )δ8.55 (d, J=4.6Hz, 1H), 8.40 (d, J=1.6Hz, 1H), 7.76-7.66 (m, 1H), 7.58-7.47 (m, 2H), 7.09 (t, J=7.0Hz, 1H), 5.78 (s, 1H), 4.1 7 (s, 3H), 3.82 (s, 3H), 2.88-2.76 (m, 1H), 2.69-2.53 (m, 2H), 2.07 (s, 3H), 2.02-1.89 (m, 1H), 1.72 (s, 3H), 1.62-1.51 (m, 3H).

Example 5

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 5”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyr an-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 5”)

Step 1: Methyl 6-bromo-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described for the synthesis of methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate, 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Step 2, 237 mM in Example 1) was added. [0147] The intermediate 5 was converted from (1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (331 mg, 86% yield) to (3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (Intermediate 5, 249 mg, 1.20 mmol).

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

6-Bromo-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester was prepared by a procedure similar to that described for the synthesis of 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester. The ester (331 mg, 0.66 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (528 mg, 1.37 mmol) were converted to methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (217 mg, 64% yield). LC-MS [M+H] ⁺ = 515.

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure analogous to that described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1, 4-Dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (217 mg, 0.42 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 5, 115 mg, 53% yield). LC-MS [M+H] ⁺ = 515. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.54 (d, J=3.9Hz, 1H), 8.36 (d, J=1.2Hz, 1H), 7.89 (s, 1H), 7.57 (d, J=7.3Hz, 1H), 7.26 (dd, J=7.5, 4 .8Hz, 1H), 6.92 (d, J=10.4Hz, 1H), 5.97 (s, 1H), 4.16 (s, 3H), 3.85 (s, 3H), 3.80 (d, J=8.5Hz, 1H), 3.69 ( d, J=9.2Hz, 1H), 3.33 (s, 1H), 3.28 (s, 1H), 3.12 (t, J=11.5Hz, 1H), 2.25 (d, J=18.8Hz, 3H), 2.11 (s, 3H) , 1.72 (s, 3H), 1.67 (s, 1H), 1.66-1.60 (m, 1H), 1.57 (s, 3H), 1.44-1.31 (m, 1H), 0.46 (d, J=12.3Hz, 1H).

Example 6

(S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 6”)

(S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 6”)

Step 1: 5-bromo-2-(1-methyl-1H-pyrazol-5-yl)-3-nitropyridine

To a solution of 2,5- _dibromo -3-nitropyridine (34.4 g, 122 mmol) in THF (500 mL) and water (150 mL) was added (1-methyl-1H-pyrazol-5-yl)boronic acid (12.6 g, 99.7 mmol), Pd(dppf)Cl ₂ (8.38 g, 10.3 mmol) and K ₃ PO ₄ (42.3 g, 199.1 mmol) under N 2. The mixture was evacuated and backfilled with N ₂ , and the process was repeated three times. The resulting mixture was heated to reflux and stirred under N ₂ for 5 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 10-30% EtOAc in hexanes to give 5-bromo-2-(1-methyl-1H-pyrazol-5-yl)-3-nitropyridine (9.47 g, 33.5 mmol, 34% yield). LC-MS [M+H] ⁺ =283.

Step 2: 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

Under N ₂ , a mixture of 5-bromo-2-(1-methyl-1H-pyrazol-5-yl)-3-nitropyridine (9.47 g, 33.5 mmol) and DPPE (22.8 g, 57.3 mmol) in 1,2-dichlorobenzene (100 mL) was heated to 180 ° C and stirred for 4 hours. The reaction was then slowly cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 30-50% EtOAc in hexane to give 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (4.12 g, 16.4 mmol, 49% yield). LC-MS [M+H] ⁺ = 251.

Step 3: (S)-6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

To a solution of ₆ -bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (1.24 g, 4.96 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (2.52 g, 13.1 mmol), and triphenylphosphine (4.71 g, 18.0 mmol) in anhydrous THF (30 mL) was added diisopropyl azodicarboxylate (4.02 g, 19.9 mmol) under _N₂ at room temperature. The resulting solution was refluxed under N₂ for 2 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc (50 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30-50% EtOAc in hexanes to give (S)-6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (0.95 g, 2.23 mmol, 45%). LC-MS [M+H] ⁺ = 425.

Step 4: (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

To _a solution of (S)-6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (0.95 g, 2.23 mmol) in DMF (40 mL) was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (2.51 g, 6.50 mmol), tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol), CuI (0.18 g, 0.95 mmol) and TEA (1.02 g, 9.26 mmol) under N₂. The mixture was evacuated and backfilled with _N₂ , and the process was repeated three times. The resulting mixture was stirred at 85°C for 3 hours and then cooled to room temperature. The reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to afford (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (0.63 g, 1.43 mmol, 64% yield). LC-MS [M+H] ⁺ = 442.

Step 5: (S)-3-bromo-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

N-Bromosuccinimide (0.62 g, 3.48 mmol) was added in small batches to a solution of (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (0.63 g, 1.43 mmol) in THF (20 mL) and water (10 mL) at room temperature over 10 minutes. After addition, the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated NaHCO ₃ aqueous solution and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-3% MeOH in DCM to give the desired (S)-3-bromo-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (0.71 g, 1.36 mmol, 95%). LC-MS [M+H] ⁺ = 520.

Step 6: (S)-1-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one

To _a solution of (S)-3-bromo-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (0.71 g, 1.36 mmol) in 1,4-dioxane (20 mL) under N₂ was added tributyl(1-ethoxyvinyl)-stannane (1.08 g, 2.99 mmol), tetrakis(triphenylphosphine)palladium (0.27 g, 0.23 mmol), and cesium fluoride (0.71 g, 4.67 mmol). The mixture was evacuated and backfilled with _N₂ , and this process was repeated three times. The resulting mixture was refluxed for 20 hours. The solvent was then evaporated under reduced pressure to obtain a pale yellow substance.

To this mixture was added THF (10 mL) at room temperature, followed by 2N HCl (2 mL) and stirred for 2 hours. The reaction was then quenched with saturated aqueous _NaHCO₃ and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give the desired (S)-1-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (390 mg, 0.81 mmol, 60% yield). LC-MS [M+H] ⁺ = 484.

Step 7: (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

MeMgBr (1 M in THF, 10.0 mL, 10.0 mmol) was added dropwise to (S)-1-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (390 mg, 0.81 mmol) in THF (30 mL) at -30°C over 10 minutes. After the addition, the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous _NH4Cl solution and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM to give the desired (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (compound 6, 84 mg, 0.17 mmol, 44% yield). LC-MS [M+H] ⁺ = 500. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.35 (d, J=1.2Hz, 1H), 7.94 (s, 1H), 7.71 (d, J=7.6Hz, 2H), 7.26 (m, 3H), 6.46 (d, J=11.2Hz, 1H), 5.81 (s, 1H), 4.15 (s, 3H), 3.85 (s, 3H), 3.52-3.39 (m, 2H), 3.29-3.19 (m, 2H), 2.17 (s, 3H), 2.00 (m, 1H), 1.71 (d, J=13.2Hz, 4H), 1.23 (s, 6H).

Example 7

(S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 7”)

(S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl )methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 7”)

Step 1: (S)-Methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example ₁ , Step 2, 409 mg, 1.32 mmol), (R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (enantiomer a1 from Example 2, Step 1, 352 mg, 1.67 mmol), and triphenylphosphine (0.52 g, 1.98 mol) in anhydrous THF (30 mL) was added diisopropyl azodicarboxylate (0.49 g, 2.42 mmol) under _N₂ at room temperature. The resulting solution was refluxed under N₂ for 2 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc (50 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30-50% EtOAc in hexanes to give (S)-methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (442 mg, 0.88 mmol, 67%). LC-MS [M+H] ⁺ = 502.

Step 2: (S)-Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (“Compound 7-2”)

To _a solution of (S)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (442 mg, 0.88 mmol) in DMF (30 mL) under N₂ was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (680 mg, 1.76 mmol), tetrakis(triphenylphosphine)palladium (168 mg, 0.15 mmol), CuI (65 mg, 0.34 mmol) and TEA (0.92 g, 8.35 mmol). The mixture was evacuated and backfilled with _N₂ , and the process was repeated three times. The resulting mixture was stirred at 85°C for 3 hours and then cooled to room temperature. The reaction mixture was poured into water and extracted with EtOAc (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. Using a 0-5% MeOH solution in DCM, the residue was purified by silica gel chromatography to obtain (S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -4- ((3- fluoropyridin-2-yl) (tetrahydro -2H- pyrans -4- bases) methyl) -1- methyl -1,4- dihydropyrazolo [3 ', 4 ': 4,5] pyrrolo [3,2-b] pyridine -3- carboxylic acid methyl esters (compound 7-2, 201 mg, 0.38 mmol, 43% yield). LC-MS [M+H] ⁺ = 519.

Step 3: (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

(S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol was synthesized by a procedure analogous to that described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol. Methyl oxazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (0.20 g, 0.38 mmol) was converted to (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (compound 7, 38 mg, 0.073 mmol, 19% yield). LC-MS [M+H] ⁺ = 519.

¹ H NMR (600MHz, DMSO-d ₆ )δ8.50 (d, J=4.6Hz, 1H), 8.40 (d, J=1.6Hz, 1H), 8.27 (d, J=1.6Hz, 1H), 7.71 (t, J=9.3Hz, 1H), 7.45 (dt, J=8.5, 4. 3Hz, 1H), 6.99 (d, J=10.9Hz, 1H), 5.70 (s, 1H), 4.12 (s, 3H), 3.94 (s, 3H), 3.81-3.74 (m, 1H), 3.65 (dd, J=11.3, 2. 9Hz, 1H), 3.26 (dd, J=11.7, 9.9Hz, 1H), 3.22-3.15 (m, 1H), 3.09 (t, J=11.2Hz, 1H), 2.21 (5, 3H), 1.70 (s, 3H), 1.5 9 (ddd, J=25.2, 12.7, 4.6Hz, 1H), 1.53 (s, 3H), 1.44 (d, J=12.0Hz, 1H), 1.41-1.32 (m, 1H), 0.52 (d, J=12.5Hz, 1H).

Example 8

2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 8”)

2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 8”)

Step 1: Methyl 6-bromo-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described for the synthesis of methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate, 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step 2, 200 mg, 0 [00145] The product was purified by centrifugation at room temperature using a 4-[[(3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl]-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (210 mg, 0.42 mmol, 65%). LC-MS [M+H] ⁺ = 497.

Step 2: Methyl 6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To _a solution of methyl 6-bromo-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (210 mg, 0.42 mmol) in THF (20 mL) and water (5 mL) under N₂ was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (210 mg, 0.90 mmol), Pd(dppf) _Cl₂ (112 mg, 0.14 mmol) and _K₃PO₄ (428 _mg , 2.02 mmol). The mixture was evacuated and backfilled with _N₂ , and the process was repeated three times. The resulting mixture was heated to reflux and stirred under _N₂ for 5 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30-50% EtOAc in hexane to give 6- (3,5- dimethylisoxazol-4-yl) -1- methyl -4- ((3- methylpyridin-2-yl) (tetrahydro -2H- pyrans -4- yl) methyl) -1,4- dihydropyrazolo [3 ', 4 ': 4,5] pyrrolo [3,2-b] pyridine -3- carboxylic acid methyl esters (160 mg, 0.31 mmol, 73% yield). LC-MS [M+H] ⁺ = 515.

Step 3: 2-(6-(3,5-Dimethylisoxazol-4-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol was synthesized by a procedure analogous to that described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol. Methyl oxazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (160 mg, 0.31 mmol) was converted to 2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 8, 33 mg, 0.064 mmol, 21% yield). LC-MS [M+H] ⁺ = 515. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.56 (d, J=4.4Hz, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.56 (d, J=7.2Hz, 1H), 7.25 (m, 1H), 6 .90 (d, J=10.0Hz, 1H), 5.96 (s, 1H), 4.15 (s, 1H), 4.11 (d, J=6.0Hz, 3H), 3.80 (d, J=10.8H z, 1H), 3.69 (d, J=12.8Hz, 1H), 3.36 (s, 2H), 3.27-3.20 (m, 1H), 3.13 (m, 3H), 2.64 (t, J=1 .6, 1.6Hz, 3H), 2.31 (t, J=1.6, 1.6Hz, 3H), 2.19 (s, 2H), 2.12 (s, 1H), 1.74-1.62 (m, 6H).

Example 9

2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 9”)

2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 9”)

Step 1: Methyl 6-bromo-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described for the synthesis of methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate, 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Step 2, 2 in Example 1) was added. [00 mg, 0.65 mmol) and (tetrahydro-2H-pyran-4-yl)(o-tolyl)methanol (Intermediate 9, 191 mg, 0.93 mmol) were converted to methyl 6-bromo-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (280 mg, 0.56 mmol, 86%). LC-MS [M+H] ⁺ = 497.

Step 2: Methyl 6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To _a solution of methyl 6-bromo-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (280 mg, 0.56 mmol) in THF (20 mL) and water (5 mL) under N₂ was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (210 mg, 0.90 mmol), Pd(dppf) _Cl₂ (102 mg, 0.12 mmol) and _{K₃PO₄ (} 389 mg, 1.83 mmol). The mixture was evacuated and backfilled with _N₂ , and the process was repeated three times. The resulting mixture was heated to reflux and stirred under _N₂ for 5 hours. After being cooled to room temperature, reaction mixture is poured into water and extracted with EtOAc (100mL).Organic layer is washed with salt water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.Use 0-5% MeOH in DCM solution, by silica gel chromatography residue, obtain 6- (3,5- dimethylisoxazol-4-yl) -1- methyl -4- ((tetrahydro -2H- pyrans -4- bases) (o-tolyl) methyl) -1,4- dihydropyrazolo [3 ', 4 ': 4,5] pyrrolo [3,2-b] pyridine -3- carboxylic acid methyl esters (218mg, 0.42mmol, 75% yield).LC-MS [M+H] ⁺ =514.

Step 3: 2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following procedures analogous to those described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, 6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydro Methyl pyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (218 mg, 0.42 mmol) was converted to 2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (compound 9, 59 mg, 0.11 mmol, 26% yield). LC-MS [M+H] ⁺ = 514. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.24 (d, J=1.6Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.48 (s, 1H), 7.32 (t, J=7.2, 7.6Hz, 1H), 7.18 (t, J=7.6, 7.2Hz, 1H), 7.10 (d, J=15.2Hz, 1H), 6.79 (d, J=10.8Hz, 1H), 5.92 (s, 1H), 4.15 (s, 3H), 3.83 (d, J=11.6Hz, 1H), 3.72 (d, J=10.8Hz 1H), 3.45 (t, J=11.6Hz, 10.8Hz, 1H), 3.17 (t, J=11.2, 11.6Hz, 2H), 2.23 (s, 3H), 2 .04 (d, J=2.8Hz, 6H), 1.89-1.72 (m, 2H), 1.69 (d, J=9.2Hz, 6H), 1.51-1.31 (m, 2H).

Example 10

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 10”)

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 10")

Step 1: 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described for the synthesis of methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Step 2, 20 in Example 1) [00145] The product was purified by HPLC-MS/MS. The product was purified by HPLC-MS/MS. HPLC-MS/MS [00146] The product was purified by HPLC-MS/MS [00147] . The product was purified by HPLC-MS/MS [00148] . HPLC-MS/MS [ ⁰⁰¹⁴⁹ ...

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described for the synthesis of methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate, 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (277 [0266] The product was purified by centrifugation at room temperature using a 4-[ ^...

Step 3: 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure analogous to that described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol was added. Methyl oxazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (211 mg, 0.42 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(oxazol-4-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 10, 94 mg, 0.19 mmol, 45% yield). LC-MS [M+H] ⁺ = 503. ¹ HNMR (400MHz, DMSO-d ₆ )δ8.38(d, J=42.4Hz, 2H), 7.98(s, 1H), 6.72(s, 1H), 5.74(s, 1H), 4.16( s, 2H), 3.89 (s, 2H), 3.31 (s, 6H), 2.74 (s, 1H), 2.26 (s, 3H), 1.65 (s, 6H).

Example 11

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 11”)

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 11”)

Step 1: Methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described for the synthesis of methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate, methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 6, Step 2, 200 mg, 0.65 mmol) and 4,4,4-Trifluoro-1-(3-methylpyridin-2-yl)butan-1-ol (Intermediate 11, 202 mg, 1.48 mmol) and triphenylphosphine (387 mg, 1.48 mmol) were converted to methyl 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (257 mg, 0.50 mmol, 77%). LC-MS [M+H] ⁺ = 510.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described for the synthesis of methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-phenylbutyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate, 6-bromo-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (257 mmol) was added. [0147] The methyl group consisting of 1,4-dimethyl-1H-1,2,3-triazol-5-yl and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (788 mg, 2.04 mmol) was converted to methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (200 mg, 0.38 mmol, 76% yield). LC-MS [M+H] ⁺ = 527.

Step 3: 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure analogous to that described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol was added. Methyl oxazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (200 mg, 0.38 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-methylpyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 11, 89 mg, 0.17 mmol, 45% yield). LC-MS [M+H] ⁺ = 527. ¹ H NMR (400MHz, DMSO-d ₆ )8.53 (d, J=4.2Hz, 1H), 8.27 (s, 1H), 7.69 (s, 1H), 7.56 (d, J=7.6Hz, 1H), 7.25 (m, 1H), 6.95 (d, J=9.8Hz, 1H), 5.93 (s, 1H), 4.13 (s, 3H), 3.21 (s, 6H), 2.86 (s, 2H) 2.72 (s, 2H), 2.23 (s, 3H), 1.62 (d, J=9.4Hz, 6H).

Example 12

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 12”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyr an-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 12”)

Step 1: (2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol

At ambient temperature, 4-bromooxane (2.24g, 13.6mmol) is added dropwise to a THF (25mL) suspension of stirred magnesium (683mg, 29.1mmol) and crystallized iodine. The reaction mixture is stirred for 1 hour and then cooled in an ice-water bath. 2-methyloxazole-4-carboxaldehyde (1.00g, 9.00mmol) is added dropwise. The reaction mixture is then stirred overnight. The reaction mixture is quenched with saturated aqueous ammonium chloride solution (40mL) and diluted with ethyl acetate (100mL). The product is extracted into the organic phase and subsequently separated into layers. The aqueous layer is extracted with a second portion of ethyl acetate (50mL), and the combined organic phases are dried over sodium sulfate. Volatiles are removed under reduced pressure. The crude reaction is purified on a silica gel column to obtain (2-methyloxazole-4-yl) (tetrahydro-2H-pyran-4-yl) methanol (330mg, 1.67mmol, 19% yield). LC-MS: [M+H] ⁺ =198.

Step 2: Methyl 6-bromo-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl ₆ -bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (200 mg, 0.65 mmol), (2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol (Intermediate 12, 195 mg, 0.99 mmol), and triphenylphosphine (384 mg, 1.33 mmol) in anhydrous THF (20 mL) was added DIAD (289 mg, 1.43 mmol) under N₂ at 0°C. After addition, the reaction was heated to 28°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-50% EtOAc in hexanes to give methyl 6-bromo-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (404 mg, crude). LC-MS [M+H] ⁺ = 489.

Step 3: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (300 mg, 0.614 mmol) in DMF (10 mL) was added 1-methyl-4-(methyl)-5-(tributylstannyl)-1H-1,2,3-triazole (498 mg, 1.29 mmol), tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol), CuI (29 mg, 0.15 mmol) and TEA (203 mg, 1.842 mmol). The mixture was degassed and flushed with nitrogen three times and stirred at 110° C. for 16 hours. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC using 5% MeOH in DCM to give methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (85 mg, 27% yield). LC-MS: [M+H] ⁺ =505.

Step 4: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure analogous to that described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1 ,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (85 mg, 0.17 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 12, 15 mg, 18%). LC-MS: [M+H ⁺ ]=505. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.42 (d, J=3.2Hz, 2H), 8.09 (s, 1H), 6.36 (d, J=11.2Hz, 1H), 5.67 (s, 1H), 4.14 (s, 3H) , 4.02 (s, 3H), 3.82 (d, J = 8.1Hz, 1H), 3.66 (d, J = 8.5Hz, 1H), 3.17-3.04 (m, 1H), 2.97 (d, J =11.2Hz, 1H), 2.33(s, 3H), 2.31(s, 3H), 1.70(s, 3H), 1.66(s, 3H), 1.61(s, 1H), 1.40(dd , J=12.3, 3.8Hz, 1H), 1.26 (dd, J=15.1, 6.4Hz, 1H), 1.10 (s, 1H), 0.66 (d, J=12.5Hz, 1H).

Example 13

(S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 13”)

(S)-2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran -4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 13”)

Step 1: Methyl 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

To a solution of 1H-pyrazole-3-carboxylic acid methyl ester (20.1 g, 159 mmol) in THF (400 mL) in a three-necked round-bottom flask at room temperature was added NaH (8.20 g, 342 mmol). The resulting mixture was stirred under an _N atmosphere for 10 minutes. The reaction mixture was cooled to 0°C in an ice-water bath, and then SEMCl (29.1 g, 175 mmol) was added dropwise under an _N atmosphere. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous _NH4Cl and extracted with EtOAc (100 mL). After separation, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-10% EtOAc in hexane to obtain 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid methyl ester (29.3 g, 114 mmol, 71.7% yield). LC/MS [M+H] ⁺ =257.

Step 2: [5-Methoxycarbonyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid

At room temperature, to a THF (10 mL) solution of 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid methyl ester (29.10 g, 113.51 mmol) in a three-necked round-bottom flask, Dtbpy (113.51 mmol) and di(1,5-cyclooctadiene)dimethoxyiridium(I)dimer, 2.71 g, 4.07 mmol) were added. The mixture was evacuated and backfilled with N ₂ , and the process was repeated three times. HBin (38.10 g, 289.32 mmol) was added to the resulting mixture. The reaction mixture was then slowly warmed to 55° C. and continued to stir for 1 hour, then quenched with water (80 mL). The resulting mixture was concentrated under reduced pressure to give [5-methoxycarbonyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid (33.6 g, 98.6% yield), which was used in the next step without further purification. LC/MS [M+H] ⁺ =301.

Step 3: Methyl 5-(5-bromo-3-nitro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

Under _N₂ , a three-necked bottom flask was charged with [5-methoxycarbonyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid (37.51 g, 124.92 mmol), 2,5-dibromo-3-nitro-pyridine (38.7 g, 137 mmol), Pd(dppf) _Cl₂ (4.63 g, 6.24 mmol), _K₃PO₄ (57.5 g, 216 _mmol ), and THF (400 mL). The mixture was purged with a stream of _N₂ for 3 minutes, a condenser was attached, and then warmed to 38°C under a _N₂ atmosphere and stirred for 3 hours. The reaction mixture was cooled to room temperature, poured into water (300 mL), and extracted with EtOAc (3 x 200 mL). The collected organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The resulting residue was purified by silica gel chromatography eluting with 0-40% EtOAc in hexanes to give methyl 5-(5-bromo-3-nitro-2-pyridinyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (17.5 g, 30.6% yield). LC/MS [M+H] ⁺ = 458.

Step 4: Methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Under N ₂ , 5-(5-bromo-3-nitro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid methyl ester (15.0 g, 32.8 mmol), triethyl phosphite (10.5 g, 63.4 mmol) and 1,2-dichlorobenzene (160 mL) were added to a three-necked round-bottom flask. The mixture was purged with a stream of N ₂ for 3 minutes, a condenser was connected, and then warmed to 140 ° C and stirred for 2 hours under an N ₂ atmosphere. The reaction mixture was cooled to room temperature, then poured into water (200 mL) and extracted with EtOAc (3×150 mL). The collected organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 0-10% EtOAc in hexanes to afford methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (3.40 g, 24.3% yield). LC/MS [M+H] ⁺ = 426.

Step 5: (S)-Methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Under N ₂ , a three-necked round-bottom flask was charged with methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (2.01 g, 4.73 mmol), (R)-(3-fluoro-2-pyridyl)-tetrahydropyran-4-yl-methanol (enantiomer a1, 1.40 g, 6.63 mmol), 2-(diphenylphosphanyl)pyridine (3.47 g, 13.19 mmol) and THF (30 mL). The mixture was purged with a stream of N ₂ for 3 minutes, and then DTAD (3.04 g, 13.19 mmol) was added dropwise under N ₂ atmosphere. The reaction mixture was then slowly warmed to 32° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, poured into 4N HCl (30 mL) and extracted with EtOAC (2 × 60 mL). The collected organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using 0-20% EtOAc in hexane to give (S)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (3.02 g, 74% yield). LC/MS[M+H] ⁺ =619.

Step 6: (S)-Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate zol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxyla te)

Under _N₂ , 1,4-dimethyltriazole (312 mg, 3.21 mmol), (S)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (1.51 g, 2.38 mmol), bis(phenylphosphine)palladium(II) chloride (167 mg, 238 μmol), tetramethylammonium acetate (634 mg, 4.76 mmol) and DMF (15 mL) were added to a three-necked flask. The mixture was purged with a stream of _N₂ for 3 minutes, a condenser was attached, and then the mixture was warmed to 110° C. under _N₂ atmosphere and stirred for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAC (3×20 mL). The collected organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 0-75% EtOAc in hexane to give (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (700 mg, 48% yield). LC/MS[M+H] ⁺ =635.

Step 7: (S)-Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a vial was added (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (98 mg, 154 μmol), 0.8 mL of HCl (12N) and 0.8 mL of ethanol. The mixture was warmed to 75° C. and stirred for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography using a 5% MeOH solution in DCM as the developing solvent to give (S)-methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (62 mg, 80% yield). LC/MS [M+H] ⁺ = 505.

Step 8: (S)-2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

To a vial was added (S)-methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (62 mg, 0.123 mmol). The reaction mixture was cooled to 0°C in an ice-water bath, and then 1 mL of MeMgBr in _Et2O (3M) was added dropwise under _N2 . The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous _NH4Cl . The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography using 5% MeOH in DCM as the developing solvent to give (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 13, 34 mg, 54.8% yield). LC/MS [M+H] ⁺ = 505.

¹ H NMR (400MHz, MeOD) δ8.50 (s, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 7.56 (t, J=9.1Hz, 1H), 7.40 (dt, J =8.4, 4.3Hz, 1H), 7.15 (d, J = 10.1Hz, 1H), 4.02 (s, 3H), 3.91 (d, J = 11.2Hz, 1H), 3.79 (d, J = 8.1 Hz, 1H), 3.45 (d, J=22.8Hz, 1H), 3.25 (d, J=12.5Hz, 2H), 3.13 (s, 1H), 2.32 (s, 3H), 1.82 (d, J= 17.7Hz, 3H), 1.76 (dd, J=12.9, 4.1Hz, 1H), 1.70 (s, 3H), 1.60 (s, 2H), 0.71 (d, J=11.0Hz, 1H).

Example 14

(S)-2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-D3)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 14”)

(S)-2-(4-((3-Fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-d3)-6-(1-methyl-4-(methyl-d3) -1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound14”)

Step 1: (S)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester ((S)-Methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate)

To a three-necked round-bottom flask under _N2 was added 1-methyl-4-(methyl-D3)-1H-1,2,3-triazole (622 mg, 6.22 mmol), (S)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (from Example 13, Step 5, 1.42 g, 2.24 mmol), bis(triphenylphosphine)palladium(II) chloride (345 mg, 492 μmol), tetramethylammonium acetate (820 mg, 6.16 mmol) and DMF (15 mL). The mixture was purged with a stream of _N2 for 3 minutes, a condenser was attached, and then heated to 110°C under a _N2 atmosphere and stirred for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (3×20 mL). The collected organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained by silica gel chromatography eluting with 0-75% EtOAc in hexane gave (S)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (750 mg, 54% yield). LC-MS [M+H] ⁺ =638.

Step 2: (S)-Methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a vial was added (S)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (750 mg, 1.18 mol), 7 mL of HCl (12 N) and 7 mL of EtOH. The mixture was warmed to 75° C. and stirred for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative TLC using a 5% MeOH solution in DCM as the developing solvent to give (S)-methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (450 mg, 75% yield). LC-MS [M+H] ⁺ = 508.

Step 3: (S)-Methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-d3)-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of (S)-methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (601 mg, 1.18 mmol) in DMF (6 mL) in a vial was added _Cs2CO3 (1.16 g, 3.56 mmol) at room temperature, followed by the dropwise addition _{of CD3I} (215 mg, 1.48 mmol) under _N2 atmosphere. The reaction mixture was then slowly warmed to 60°C and stirred for 2 hours. The reaction mixture was quenched with 10 mL of HCl (1 N) and extracted with EtOAc (10 mL). After separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative TLC using 10% MeOH in DCM as the developing solvent to give (S)-methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-D3)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (150 mg, 24% yield). LC/MS [M+H] ⁺ = 525.

Step 4: (S)-2-(4-((3-Fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-D3)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol ((S)-2-(4-((3-Fluoropyridin-2-yl)( tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-d3)-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol)

To a vial was added (S)-methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-D3)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (148 mg, 0.282 mmol) and THF (10 mL). The reaction mixture was cooled to 0°C in an ice-water bath, and then 1.5 mL of MeMgBr (3 M in THF, 4.5 mmol) was added dropwise under _N2 . The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous _NH4Cl . The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase flash chromatography to afford (S)-2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-D3)-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 14, 93 mg, 63% yield). LC/MS [M+H] ⁺ = 525. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.52 (d, J=4.6Hz, 1H), 8.41 (d, J=1.7Hz, 1H), 8.29 (d, J=1.6Hz, 1H), 7.78-7.66 (m, 1H), 7.47 (dt, J=8.5, 4.3Hz, 1H), 7.01 (d, J=10.8Hz, 1H), 5.69 (s, 1H), 3.96 (s, 3H), 3.80 (d, J=9.6Hz, 1H), 3.67 (dd , J=11.0, 2.5Hz, 1H), 3.33-3.24 (m, 1H), 3.20 (d, J=11.1Hz, 1H), 3.12 (t, J=11.3Hz, 1H), 1.73 (s, 3H) , 1.68-1.59 (m, 1H), 1.56 (s, 3H), 1.47 (d, J=12.5Hz, 1H), 1.43-1.34 (m, 1H), 0.55 (d, J=12.5Hz, 1H).

Example 15

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N,N,1-trimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 15”)

6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-N,N,1-trimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 15”)

Step 1: Methyl 6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example ₁ , Step 2, 1.00 g, 3.23 mmol), phenyl(tetrahydro-2H-pyran-4-yl)methanol (933 mg, 4.85 mmol), and triphenylphosphine (1.29 g, 6.82 mmol) in anhydrous THF (60 mL) was added DIAD (600 mg, 2.97 mmol) at room temperature under N₂. The reaction was stirred for 3 hours. The reaction mixture was poured into water and extracted with EtOAc (400 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 5-30% EtOAc in hexanes to give methyl 6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (1.31 g, 83% yield). LC/MS [M+H]+ = 483, 485.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described in synthetic step 4 of Example 6, methyl 6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (1.95 g, 4.04 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (2.81 g, 7.27 mmol) were converted to methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (1.29 g, 2.59 mmol, 64% yield). LC-MS [M+H] ⁺ =500.

Step 3: 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid

To a solution of methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (148 mg, 0.30 mmol) in methanol (5 mL) and _H2O (2 mL) was added LiOH (74 mg, 3.09 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (10 mL), adjusted to pH = 7 with saturated aqueous _NaHCO3 solution and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid (143 mg, crude). LC-MS [M+H] ⁺ = 486.

Step 4: 6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carbonylchloride

To a solution of crude 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid (143 mg, 0.30 mmol) in DCM ( ₅ mL) was added SOCl₂ (2 mL). The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated under reduced pressure to afford crude 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carbonyl chloride (163 mg, crude).

Step 5: 6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-N,N,1-trimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of crude 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carbonyl chloride (54 mg, 0.10 mmol) in THF (3 mL) was added dimethylamine (126 mg, 2.53 mmol) and stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to afford 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N,N,1-trimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 15, 15 mg, 29% yield over three steps). LC-MS [M+H] ⁺ = 513.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.46 (s, 1H), 8.33 (s, 1H), 7.66 (s, 1H), 7.65 (s, 1H), 7.31-7.28 (m, 2H), 7.24-7.20 (m, 1H), 5.92 (d, J=10.8Hz, 1H), 4.25 ( s, 3H), 3.96 (s, 3H), 3.86-3.78 (m, 2H), 3.37-3.20 (m, 3H), 3.14 (s, 6H), 2.25 (s, 3H), 1.51-1.48 (m, 1H), 1.41-1.18 (m, 3H).

Example 16

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 16”)

6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 16”)

Step 1: 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of ammonia (25% in 1,4-dioxane, 5 mL) was added a solution of crude 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carbonyl chloride (from Example 15, Step 4, 52 mg, 0.10 mmol) in THF (3 mL). The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 16, 16 mg, 33% yield). LC-MS [M+H] ⁺ = 485;

¹ HNMR (400MHz, DMSO-d ₆ )δ8.44(s, 1H), 8.19(s, 1H), 7.80(s, 1H), 7.67(d, J=7.6Hz, 2H), 7.53(s, 1H), 7.31( t, J=7.6Hz, 2H), 7.22-7.20 (m, 1H), 6.92 (d, J=11.2Hz, 1H), 4.28 (s, 3H), 3.91 (s, 3H) ), 3.86 (d, J = 11.2Hz, 1H), 3.75 (d, J = 10.8Hz, 1H), 3.46-3.38 (m, 2H), 3.29-3.22 (m, 1H), 2.22 (s, 3H), 1.69 (d, J=12.4Hz, 1H), 1.40-1.23 (m, 2H), 1.03 (d, J=12.4Hz, 1H).

Example 17

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N,1-dimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 17”)

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N,1-dimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 17”)

Step 1: 6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-N,1-dimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of crude 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carbonyl chloride (from Example 15, Step 4, 55 mg, 0.10 mmol) in THF (3 mL) was added a solution of methylamine in THF (3 M, 3 mL). The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 12 mg of 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N,1-dimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 17, 11 mg, 24% yield over three steps). LC-MS [M+H] = 499.

¹ HNMR (400MHz, DMSO-d ₆ )δ8.44-8.41(m, 2H), 8.21(d, J＝1.2Hz, 1H), 7.67(d, J＝7.2Hz, 2H),, 7.31(t, J＝7.6Hz, 2H) , 7.22 (d, J=7.6Hz, 1H), 6.92 (d, J=11.2Hz, 1H), 4.28 (s, 3H), 3.91 (s, 3H), 3.86 (d, J=11.2H z, 1H), 3.75 (d, J=10.8Hz, 1H), 3.46-3.38 (m, J=8.2Hz, 2H), 3.29-3.22 (m, 1H), 2.89 (d, J=4 .8Hz, 3H), 2.22 (s, 3H), 1.69 (d, J=12.4Hz, 1H), 1.40-1.23 (m, 2H), 1.03 (d, J=12.8Hz, 1H).

Example 18

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-amine (“Compound 18”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-amine (“Compound 18”)

Step 1: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure analogous to that described in step 5 of the synthesis of Example 1, methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-carboxylate (from step 2 of Example 15, 125 mg, 0.250 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (94 mg, 75% yield). LC-MS [M+H] ⁺ =499.

Step 2: 3-(2-Azidopropan-2-yl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

To a solution of 2-(6-(1,4 _- dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (94 mg, 0.19 mmol) in DCM (3 mL) was added TMSN ₍ 62 mg, 0.54 mmol) at 0°C under N. The mixture was stirred at 0°C for 10 minutes and _BF.OEt (118 mg, 0.83 mmol) was added. The mixture was stirred at ambient temperature _for 2 days. The mixture was added to a saturated aqueous NaHCO solution ( ₅ mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried _{over Na2SO4} and concentrated under rotary vacuum to give 3-(2-azidopropan-2-yl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine (110 mg, crude).

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-amine

To a solution of crude 3-(2-azidopropan-2-yl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (110 mg, 0.19 mmol) in methanol (3 mL) was added wet Pd/C (20 mg, 18 w/w). The mixture was evacuated, backfilled with _H₂ , and the process was repeated three times. The resulting mixture was stirred at ambient temperature for 3 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-amine (Compound 18, 20 mg, 21% yield over two steps). LC-MS [M+H] ⁺ = 499.

¹ HNMR (400MHz, DMSO-d ₆ )δ9.08-8.48(br, J=10.2Hz, 2H), 8.39(s, 1H), 7.86(s, 1H), 7.62-7.60(m, 2H), 7.34-7.30(m, J＝6.5Hz, 2H), 7.26-7.22(m, J＝9.3Hz, 1H), 6.92(d, J＝11.2Hz, 1H), 4.19(s, 3H), 3.88-3.85(m, J=8.45Hz, 1H), 3.82 (s, 3H), 3.74-3.71 (m, 1H), 3.50-3.44 (m, 1H), 3.34-3.20 (m, J=7.5Hz, 2H) , 2.14 (s, 3H), 1.90-1.80 (m, J=7.3Hz, 1H), 1.71 (s, 6H), 1.60-1.43 (m, 2H), 0.80-0.78 (m, 1H).

Example 19

3-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)pentan-3-ol (“Compound 19”)

3-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)pentan-3-ol (“Compound 19”)

To a solution of methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 15, Step 2, 103 mg, 0.21 mmol) in THF (3 mL) was added EtMgBr (1 M in THF, 0.2 mL) and the mixture was stirred at ambient temperature for 1 hour. The mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated on a rotary vacuum evaporator. The residue was purified by preparative HPLC to give 3-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)pentan-3-ol (Compound 19, 38 mg, 34% yield). LC-MS [M+H] ⁺ = 528.

¹ HNMR (400MHz, DMSO-d ₆ )δ8.47(s, 1H), 8.23(s, 1H), 7.66(d, J=7.2Hz, 2H), 7.33(t, J=7.2Hz, 2H), 7.26-7.22( m, 1H), 6.53 (d, J=11.6Hz, 1H), 5.40-5.31 (m, 1H), 4.31 (s, 3H), 3.91 (s, 3H), 3.90-3.8 5(m, 1H), 3.77-3.74(m, 1H), 3.48-3.37(m, 2H), 3.29-3.23(m, 1H), 2.51(m, 4H), 2.21( s, 3H), 1.76-1.73 (m, 1H), 1.41 (t, J=6.8Hz, 6H), 1.37-1.25 (m, 2H), 1.07-1.04 (m, 1H).

Example 20

(S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid (“Compound 20”)

(S)-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid("Compound 20”)

To a solution of (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (from Example 7, Step 2, 36 mg, 0.069 mmol)) in MeOH (5 mL) and _H₂O (10 mL) was added LiOH (28 mg, 1.17 mmol). The resulting mixture was stirred at 25°C for 1 hour. The pH of the reaction mixture was adjusted to 1 with _CH₃COOH and extracted with EtOAc (10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid (compound 20, 8 mg, 0.016 mmol, 23% yield). LC-MS [M+H] ⁺ = 505.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.57 (d, J=4.5Hz, 1H), 8.48 (d, J=1.0Hz, 1H), 8.15 (s, 1H), 7.67 (t, J=9.0Hz, 1H), 7.47 (d t, J=8.3, 4.3Hz, 1H), 7.20 (d, J=8.8Hz, 1H), 4.31 (d, J=14.4Hz, 3H), 3.92 (s, 3H), 3.82 (d, J =9.6Hz, 1H), 3.72 (d, J = 9.9Hz, 1H), 3.37 (d, J = 10.5Hz, 2H), 3.22 (t, J = 11.3Hz, 1H), 2.18 (s , 3H), 1.63 (d, J=11.9Hz, 1H), 1.53-1.40 (m, 2H), 1.37-1.24 (m, 1H), 0.83 (d, J=12.1Hz, 1H).

Example 21

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 21”)

6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (“Compound 21”)

To _a solution of (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid (from Example 20, 100 mg, 0.20 mmol) in DMF (15 mL) was added HATU (68 mg, 0.18 mmol), NH ₄ Cl (48 mg, 0.90 mmol) and DIEA (72 mg, 0.56 mmol) under N 2. The mixture was evacuated and backfilled with N ₂ , and the process was repeated three times. The resulting mixture was stirred at 25° C. for 1.5 hours. The reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to afford (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 21, 10 mg, 0.020 mmol, 10% yield). LC-MS [M+H] ⁺ = 504.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.57 (d, J=4.6Hz, 1H), 8.47 (d, J=1.6Hz, 1H), 8.09 (d, J=1.6Hz, 1H), 7.75 (s, 1H), 7.66 (t, J=8.8Hz, 1H), 7.49 (s, 1H), 7.46 (dd, J=8.5, 4.3Hz, 1H), 7.37 (d, J=10.8Hz, 1H), 4.28 (s, 3H), 3.91 (s, 3H), 3.83 ( d, J=9.6Hz, 1H), 3.72 (d, J=11.6Hz, 1H), 3.38 (s, 2H), 3.21 (t, J=11.1Hz, 1H), 2.17 (s, 3H), 1.64 (d, J=1 2.3Hz, 1H), 1.49 (qd, J=12.4, 4.3Hz, 1H), 1.33 (ddd, J=15.9, 12.3, 4.2Hz, 1H), 0.78 (d, J=12.2Hz, 1H).

Example 22

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 22”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)m ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound twenty two")

Step 1: Methyl 6-bromo-1-methyl-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step ₂ , 400 mg, 1.29 mmol), (4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methanol (Intermediate 13, 600 mg, 2.89 mmol) and triphenylphosphine (850 mg, 3.24 mmol) in anhydrous THF (30 mL) was added DIAD (600 mg, 2.97 mmol) at room temperature under N₂. The mixture was stirred for 18 hours. The reaction mixture was poured into water and extracted with EtOAc (200 mL). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5-50% EtOAc in hexanes to give methyl 6-bromo-1-methyl-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (170 mg, 26.35% yield). LC-MS [M+H] ⁺ = 498,500.

Step 2: methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure similar to that described in Synthesis Step 2 of Example 3, a solution of methyl 6-bromo-1-methyl-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (170 mg, 0.34 mmol) in DMF (5 mL) and 1,4-dimethyl-5-(tributylstannyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (170 mg, 0.34 mmol) in DMF (5 mL) were prepared. H-1,2,3-triazole (274 mg, 0.71 mmol) was converted to methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (80 mg, 47.00% yield). LC/MS [M+H] ⁺ = 514.

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure similar to that described in synthetic step 3 of Example 3, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (130 mg, 0.26 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methylpyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 22, 20 mg). LC/MS [M+H] ⁺ =514.

Example 23

2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 23”)

2-(4-((3-Fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H -1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound twenty three")

Step 1: (S)-Methyl 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To _a solution of (S)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 7, Step 1, 200 mg, 0.40 mmol) in DMF (30 mL) was added 1-methyl-4-(methyl-D3)-5-(tributylstannyl)-1H-1,2,3-triazole (378 mg, 0.97 mmol), tetrakis(triphenylphosphine)palladium (148 mg, 0.13 mmol), CuI (40 mg, 0.21 mmol), and TEA (415 mg, 3.77 mmol) under _{N2. The mixture was evacuated and backfilled with N2} , and the process was repeated three times. The obtained mixture was stirred at 85 ° C for 3 hours and then cooled to room temperature. The reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. Using 0-5% MeOH in DCM solution, the residue was purified by silica gel chromatography to obtain (S) -4- ((3-fluoropyridin-2-yl) (tetrahydro -2H- pyrans -4- yl) methyl) -1- methyl -6- (1- methyl -4- (methyl -D3) -1H-1,2,3- triazole -5- yl) -1,4- dihydropyrazolo [3 ', 4 ': 4,5] pyrrolo [3,2-b] pyridine -3- carboxylic acid methyl esters (132 mg, 0.25 mmol, 63% yield). LC-MS [M+H] ⁺ = 522.

Step 2: (S)-2-(4-((3-Fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol ((S)-2-(4-((3-Fluoropyridin-2-yl)( tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol)

Following a procedure similar to that described in Synthesis Step 3 of Example 3, (S)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (132 mg, 0.25 mmol) was reacted with 4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (132 mg, 0.25 mmol) ) was converted to (S)-2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (compound 23, 51 mg, 0.098 mmol, 39% yield). LC-MS [M+H] ⁺ = 522.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.51(t, J=5.5Hz, 1H), 8.41 (d, J=1.4Hz, 1H), 8.29 (d, J=1.2Hz, 1H), 7.72 (t, J=9.2Hz, 1H), 7 .47 (dt, J=8.4, 4.3Hz, 1H), 7.01 (d, J=10.8Hz, 1H), 5.70 (s, 1H), 4.14 (s, 3H), 3.96 (s, 3H), 3.8 0 (d, J=9.4Hz, 1H), 3.67 (d, J=8.7Hz, 1H), 3.24 (dd, J=27.1, 11.1Hz, 2H), 3.12 (t, J=11.5Hz, 1H ), 1.73 (s, 3H), 1.62 (dd, J=12.5, 3.9Hz, 1H), 1.56 (s, 3H), 1.43 (m, 2H), 0.55 (d, J=12.4Hz, 1H).

Example 24

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 24”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)m ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound twenty four")

Step 1: Methyl 6-bromo-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure analogous to that described in Synthesis Step 1 of Example 3, methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step 2, 202 mg, 0.65 mmol) and (3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methanol (Intermediate 14, 184 mg, 0.87 mmol) were converted to methyl 6-bromo-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (259 mg, 0.52 mmol, 80% yield). LC-MS [M+H]+ = 502.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure similar to that described in Synthesis Step 2 of Example 3, 6-bromo-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (259 mg, 0.52 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1-yl)-3-carboxylate were reacted in DMF (30 mL). ,2,3-triazole (383 mg, 0.98 mmol) was converted to 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (178 mg, 0.34 mmol, 65% yield). LC-MS [M+H] ⁺ = 519.

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure similar to that described in Synthesis Step 3 of Example 3, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (178 mg, 0.34 mmol) was reacted with 1% paraformaldehyde to obtain 1% paraformaldehyde. ) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (compound 24, 63 mg, 0.13 mmol, 38% yield). LC-MS [M+H] ⁺ = 519.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.48 (d, J=4.7Hz, 2H), 8.41 (d, J=1.4Hz, 1H), 8.02 (t, J=5.8Hz, 1H), 7.92 (s, 1 H), 6.89 (d, J=11.1Hz, 1H), 5.77 (s, 1H), 4.15 (s, 3H), 3.86 (s, 3H), 3.74 (d, J=8.5 Hz, 1H), 3.41 (t, J=11.1Hz, 1H), 3.22 (m, 2H), 2.16 (s, 3H), 1.70 (s, 3H), 1.66 (d, J =13.6Hz, 2H), 1.58 (s, 3H), 1.46 (dd, J=20.5, 8.9Hz, 2H), 0.75 (d, J=12.8Hz, 1H).

Example 25

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 25”)

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl) methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 25”)

Step 1: Methyl 6-bromo-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step ₂ , 142 mg, 0.46 mmol), (4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methanol (Intermediate 16, 135 mg, 0.60 mmol) and triphenylphosphine (284 mg, 1.08 mmol) in anhydrous THF (30 mL) was added diisopropyl azodicarboxylate (243 mg, 1.20 mmol) at room temperature under N₂. The resulting solution was refluxed under _N₂ for 2 hours. After cooling to room temperature, the reaction mixture was poured into EtOAc (50 mL) and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30-50% EtOAc in hexanes to give methyl 6-bromo-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (200 mg, 0.39 mmol, 85% yield). LC-MS [M+H] ⁺ = 514.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure similar to that described in synthetic step 2 of Example 3, 6-bromo-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (169 mg, 0.33 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazol-1-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate were reacted with 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazol-1-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate to obtain a 1,4-dimethyl-5-(tributylstannyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate. The oxazole (318 mg, 0.82 mmol) was converted to methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (109 mg, 0.21 mmol, 64% yield). LC-MS [M+H]+ = 531.

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure similar to that described in Synthesis Step 3 of Example 3, methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (109 mg, 0.21 mmol) was added. 1) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-methoxypyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (compound 25, 9 mg, 0.017 mmol, 8% yield). LC-MS [M+H] ⁺ = 531.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.98 (s, 1H), 8.36 (m, 2H), 7.85 (s, 1H), 6.96 (d, J=5.5Hz, 1H), 6.66 (d, J=10. 9Hz, 1H), 5.58 (s, 1H), 4.14 (s, 3H), 3.84 (s, 1H), 3.79 (s, 3H), 3.72 (d, J=9.8Hz, 1H), 3.56 (s, 3H), 3.43 (t, J=11.4Hz, 1H), 3.17 (t, J=11.6Hz, 1H), 2.13 (s, 3H), 1.72 (s, 2H), 1.66 (s, 3H), 1.44 (dd, J=27.0, 8.9Hz, 2H), 0.63 (d, J=12.3Hz, 1H).

Example 26

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 26”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl) methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 26”)

Step 1: Methyl 6-bromo-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step ₂ , 290 mg, 0.94 mmol), (3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (Intermediate 17, 320 mg, 1.44 mmol) and triphenylphosphine (504 mg, 1.92 mmol) in anhydrous THF (20 mL) was added DIAD (417 mg, 2.06 mmol) at 25° C. under N 2. After addition, the reaction was heated to 40° C. for 2 h. Then, the mixture was stirred for 1 h. The reaction was slowly cooled to room temperature, the reaction mixture was poured into water, and extracted with EtOAc (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Using 60-70% acetonitrile aqueous solution, the residue was purified by C-18 chromatography to obtain 6-bromo-4-((3-methoxypyridin-2-yl) (tetrahydro-2H-pyrans-4-yl) methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (400 mg, 0.78 mmol, 83% yield). LC-MS[M+H] ⁺ =515.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure similar to that described in Synthesis Step 2 of Example 3, 6-bromo-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (125 mg, 0.24 mmol) and 1-methyl-4-(methyl)-5-(tributylstannyl)-1H-1 ,2,3-triazole (197 mg, 0.51 mmol) was converted to 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (120 mg, 93% yield). LC-MS: [M+H] ⁺ =531.

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following a procedure similar to that described in Synthesis Step 3 of Example 3, 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (120 mg, 0.2 3 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (compound 26, 56 mg, 47% yield). LC-MS: [M+H] ⁺ = 531.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.35 (d, J=1.4Hz, 1H), 8.25 (d, J=3.9Hz, 1H), 8.14 (d, J=1.3Hz, 1H), 7.43 (d, J=8.0Hz, 1H), 7.35 (dd, J=8 .3, 4.6Hz, 1H), 6.86 (d, J=10.7Hz, 1H), 5.49 (s, 1H), 4.14 (s, 3H), 3.91 (s, 3H), 3.77 (d, J=10.7Hz, 1H), 3.6 6 (s, 1H), 3.65 (s, 3H), 3.25 (dd, J=10.8, 3.3Hz, 1H), 3.09 (t, J=11.4Hz, 1H), 2.18 (s, 3H), 1.83-1.76 (m, 1H ), 1.75 (s, 3H), 1.65 (s, 3H), 1.49-1.39 (m, 1H), 1.24 (s, 1H), 0.85 (t, J=6.8Hz, 1H), 0.41 (d, J=12.3Hz, 1H).

Example 27

2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 27”)

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 27”)

Step 1: Methyl 6-bromo-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

[0146] Following a procedure analogous to that described in Synthesis Step 1 of Example 26, methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step 2, 200 mg, 0.65 mmol) and 1-(4-fluoro-2,6-dimethylphenyl)ethan-1-ol (Intermediate 15, 170 mg, 1.02 mmol) were converted to methyl 6-bromo-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (288 mg, 0.62 mmol, 96% yield). LC-MS [M+H] ⁺ = 460.

Step 2: Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

Following a procedure similar to that described in Synthesis Step 2 of Example 3, a solution of methyl 6-bromo-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (288 mg, 0.62 mmol) in DMF (10 mL) and 1-methyl-4-(methyl)-5-(tributylstannane) were added. [0366] The product was purified by HPLC-MS/MS. The product was purified by HPLC-MS/MS. HPLC-MS/MS [0367] The product was purified by HPLC-MS/MS [0368] . HPLC-MS/MS [0369] . The product was purified by HPLC-MS/MS ^[ 0369] . ...

Step 3: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

[0146] Following a procedure similar to that described in Synthesis Step 3 of Example 3, methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (100 mg, 0.21 mmol) was converted to 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 27, 27 mg, 27% yield). LC-MS [M+H] ⁺ = 476.

¹ HNMR (400MHz, DMSO-d ₆ )δ8.40(s, 1H), 7.48(s, 1H), 6.88(s, 2H), 6.84(s, 1H), 5.61(s, 1H), 4.18(s, 3H), 3.87( s, 3H), 3.33-3.28 (s, 6H), 2.11 (s, 3H), 2.03 (d, J=6.5Hz, 3H), 1.64 (s, 3H), 1.31 (s, 3H).

Example 28

(S)-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanesulfonamide (“Compound 28”)

(S)-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanesulfonamide(“Compound 28")

Step 1: (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-amine

To a solution of ammonia (25%, 6 mL) in DMSO (3 mL) were added (S)-3-bromo-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (Example 6, Step 5, 201 mg, 0.39 mmol), CuI (43 mg, 0.23 mmol), L-proline (35 mg, 0.30 mmol), and Cs ₂ CO ₃ (593 mg, 1.82 mmol). The mixture was stirred at 110° C. for 3 days. The mixture was poured into water (50 mL) and extracted with EtOAc (150 mL). The collected organic layers were washed with saturated brine (50 mL), dried over Na ₂ SO ₄ , and concentrated on a rotary vacuum evaporator. The residue was purified by silica gel column chromatography with DCM/MeOH (0%-5%) to afford (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-amine (70 mg, 39% yield). LC-MS [M+H] ⁺ = 457.

Step 2: (S)-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanesulfonamide

To a solution of (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-amine (20 mg, 0.044 mmol) and DMAP (4 mg, 0.033 mmol) in pyridine (1 mL) was added a solution of MsCl (17 mg, 0.15 mmol) in DCM (1 mL). The mixture was stirred at ambient temperature for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired (S)-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanesulfonamide (Compound 28, 2 mg, 8% yield). LC-MS [M+H] ⁺ = 535.

¹ HNMR (400MHz, CDCl ₃ )δ8.34 (s, 1H), 7.59 (s, 1H), 7.53-7.48 (m, J=6.9Hz, 2H), 7.33-7.29 (m, 3H), 6. 38 (s, 1H), 5.49 (d, J = 10.4, 1H), 4.31 (s, 3H), 4.02-3.89 (m, J = 9.8Hz, 2H), 3.88 ( s, 3H), 2.55-2.44 (m, J=11.3Hz, 2H), 3.33 (s, 3H), 3.15-3.09 (m, J=8.6Hz, 1H), 2.31 (s, 3H), 1.81-1.78 (m, J=7.9Hz, 1H), 1.57-1.50 (m, 1H), 1.39-1.25 (m, 2H).

Example 29

(S)-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)acetamide (“Compound 29”)

(S)-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)acetamide (“Compound 29”)

To a solution of (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridin-3-amine (from Example 28, Step 1, 21 mg, 0.046 mmol) and DMAP (4 mg, 0.033 mmol) in pyridine (1 mL) was added acetic anhydride ( ₁₅ mg, 0.15 mmol) in DCM (1 mL). The mixture was stirred at ambient temperature for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (60 mL). The combined organic layers were dried over _Na2SO4 and concentrated under vacuum. The residue was added to methanol (2 mL) and _K2CO3 (97 _mg ) and stirred at ambient temperature for 16 h. The mixture was added to EtOAc (20 mL) and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC to afford (S)-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)acetamide (Compound 29, 7 mg, 30% yield). LC-MS [M+H] ⁺ = 499.

Example 30

(R)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 30”)

(R)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl )methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 30”)

Step 1: (R)-Methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example ₁ , Step 2, 212 mg, 0.69 mmol), (S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (enantiomer b1 in Example 2, 176 mg, 0.83 mmol), and triphenylphosphine (381 mg, 1.45 mol) in anhydrous THF (20 mL) was added diisopropyl azodicarboxylate (297 mg, 1.47 mmol) under N₂ at room temperature. The resulting solution was refluxed under _N₂ for 2 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc (30 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel chromatography using 30-50% EtOAc in hexanes to give (R)-methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (287 mg, 0.57 mmol, 83%). LC-MS [M+H] ⁺ = 502.

Step 2: (R)-Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of (R)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (271 mg, 0.54 mmol) in DMF (20 mL) was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (417 mg, 1.08 mmol), tetrakis(triphenylphosphine)palladium (103 mg, 0.092 mmol), CuI (40 mg, 0.21 mmol) and TEA (0.56 g, 5.12 mmol). The mixture was evacuated and backfilled with _N2 , and the process was repeated three times. The resulting mixture was stirred at 85°C for 3 hours and then cooled to room temperature. The reaction solution was poured into water and extracted with EtOAc (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH in DCM to give (R)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (126 mg, 0.24 mmol, 45%). LC-MS [M+H] ⁺ = 519.

Step 3: (R)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Referring to the procedure described for the synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol, (R)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol was prepared. (R)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 30, 37 mg, 0.071 mmol, 31% yield) was synthesized from methyl 2-[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (118 mg, 0.23 mmol). LC-MS [M+H] ⁺ = 519.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.56-8.48 (m, 1H), 8.42 (d, J=1.8Hz, 1H), 8.29 (d, J=1.8Hz, 1H), 7.73 (ddd, J=10.0, 8.4, 1.2Hz, 1H), 7.47 (dt, J=8.5, 4.3Hz, 1H), 7.02 (d, J=10.9Hz, 1H), 5.71 (s, 1H), 4.15 (s, 3H), 3.97 (s, 3H), 3.80 (d, J=9.0Hz, 1H), 3.68 (d d, J=11.4, 2.8Hz, 1H), 3.28 (dd, J=11.4, 2.4Hz, 1H), 3.21 (d, J=11.2Hz, 1H), 3.13 (t, J=11.1Hz, 1H), 2.24 (s, 3H) , 1.74 (s, 3H), 1.69-1.60 (m, 1H), 1.57 (s, 3H), 1.48 (d, J=12.9Hz, 1H), 1.44-1.35 (m, 1H), 0.55 (d, J=12.1Hz, 1H).

Example 31

(R)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (“Compound 31”)

(R)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound 31")

Step 1: (R)-Methyl 6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

[0146] Following the same procedure as in Example 2, Step 2, 6-bromo-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (obtained from Example 1, Step 2, 195 mg, 0.627 mmol) and (S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (enantiomer b1 from Example 2, 180 mg, 0.856 mmol) were converted to (R)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (298 mg, 95% yield). LC-MS [M+H] ⁺ = 502.

Step 2: (R)-Methyl 6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

According to the same procedure as in Step 3 of Example 2, (R)-6-bromo-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (298 mg, 0.59 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- [0266] The product of (R)-6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (206 mg, 67% yield) was converted to (R)-6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (206 mg, 67% yield). LC-MS [M+H] ⁺ = 519.

Step 3: (R)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol

Following the same procedure as in Step 4 of Example 2, (R)-6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (206 mg, 0.397 mmol) was converted to (R)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol (Compound 31, 85 mg, 41% yield). LC-MS[M+H] ⁺ =519. ¹ HNMR (400MHz, DMSO-d ₆ )δ8.54 (d, J=4.6Hz, 1H), 8.32 (d, J=1.6Hz, 1H), 8.10 (d, J=1.5Hz, 1H), 7.72 (t, J=8.9Hz, 1H), 7.47 (dt, J=8.5, 4.3Hz, 1H), 6.98 (d, J=10.7Hz, 1H), 5.67 (s, 1H), 4.13 (s, 3H), 3.80 (d, J=9.1Hz, 1H), 3.68 (d, J= 8.9Hz, 1H), 3.30-3.17 (m, 2H), 3.11 (t, J=11.4Hz, 1H), 2.41 (s, 3H), 2.23 (s, 3H), 1.73 (s, 3H), 1.69-1. 60 (m, 1H), 1.57 (s, 3H), 1.51 (d, J=11.9Hz, 1H), 1.40 (dd, J=19.9, 11.5Hz, 1H), 0.51 (d, J=12.9Hz, 1H).

Example 32

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (“Compound 32”)

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine(“Compound 32”)

Step 1: Methyl 6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Example 1, Step ₂ , 1.00 g, 3.23 mmol), phenyl(tetrahydro-2H-pyran-4-yl)methanol (933 mg, 4.85 mmol) and triphenylphosphine (1.29 g, 6.82 mmol) in anhydrous THF (60 mL) was added DIAD (600 mg, 2.97 mmol) at room temperature under N₂. The reaction was stirred for 3 hours. The reaction mixture was poured into water and extracted with EtOAc (400 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 5-30% EtOAc in hexanes to give methyl 6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (1.31 g, 83.28% yield). LC-MS [M+H]+ = 483, 485.

Step 2: (6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanol

To a solution of methyl 6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (1.30 g, 2.69 mmol) in EtOH (20 mL) was added _NaBH₄ (540 mg, 14.27 mmol) and _CaCl₂ (374 mg, 3.36 mmol) at room temperature. The reaction was stirred for 3 hours. The reaction mixture was poured into water and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanol (1.05 g, 86.24% yield). LC-MS [M+H] ⁺ = 455, 457.

Step 3: 6-bromo-3-(bromomethyl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

To a solution of (6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanol (1.05 g, 2.32 mmol) in anhydrous DCM (40 mL) was added phosphorus tribromide (600 mg, 2.97 mmol) at room temperature. The reaction was stirred for 1 hour. The reaction mixture was poured into NaHCO ₃ (aq.) and extracted with DCM (400 mL). The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6-bromo-3-(bromomethyl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (1.12 g, 93.0% yield). LC-MS [M+H] ⁺ = 517, 519.

Step 4: 6-bromo-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

6-Bromo-3-(bromomethyl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (160 mg, 0.31 mmol), N-methylpiperazine (141 mg, 1.41 mmol), and _K₂CO₃ (140 mg, 1.01 mmol) were mixed in _DMF (10 mL) at room temperature. The reaction was stirred for 2 hours. The reaction was filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 2-10% MeOH in DCM to give 6-bromo-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (160 mg, 96.0% yield). LC-MS [M+H] ⁺ = 538, 540.

Step 5: 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

To _a solution of 6-bromo-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (160 mg, 0.30 mmol) in DMF (10 mL) was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (290 mg, 0.75 mmol), CuI (40 mg, 0.21 mmol), Pd(PPh ₃ ) ₄ (30 mg, 0.026 mmol), and TEA (120 mg, 1.09 mmol) under N 2. The mixture was purged with N ₂ for 2 minutes and stirred at 110° C. for 16 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc (100 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 10-60% EtOAc in hexanes to give 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (Compound 32, 20 mg). LC-MS [M+H] ⁺ = 554.

Example 33

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((methylsulfonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (“Compound 33”)

6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((methylsulfonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine(“Compound 33”)

Step 1: 6-bromo-1-methyl-3-((methylsulfonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

6-Bromo-3-(bromomethyl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (from Example 32, Step 3, 300 mg, 0.58 mmol) and sodium methanesulfinate (100 mg, 0.98 mmol) were stirred in a DMF (10 mL) solution at 60°C. The mixture was stirred for 2 hours. The mixture was cooled to room temperature. Poured into water and extracted with EtOAc (100 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 2-5% MeOH in DCM to give 6-bromo-1-methyl-3-((methylsulfonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (90 mg, 29.30% yield). LC-MS [M+H] ⁺ = 517, 519.

Step 2: 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((methylsulfonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

To _a solution of 6-bromo-1-methyl-3-((methylsulfonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (90 mg, 0.17 mmol) in dioxane (6 mL) was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (190 mg, 0.49 mmol), PdCl ₂ (PPh ₃ ) ₂ (20 mg, 0.028 mmol), and DIEA (100 mg, 0.77 mmol) under N 2. The mixture was purged with N ₂ for 2 minutes and stirred at 110° C. for 20 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc (100 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 20-60% EtOAc in hexanes to give 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((methylsulfonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (Compound 33, 45 mg, 49.57% yield). LC-MS [M+H] ⁺ = 534.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.44 (d, J=1.2Hz, 1H), 8.18 (s, 1H), 7.63 (d, J=7.4Hz, 2H), 7.32 (t, J=7.4Hz, 2H), 7.26 (t, J=7 .2Hz, 1H), 5.48 (d, J=10.9Hz, 1H), 4.85 (dd, J=31.6, 14.2Hz, 2H), 4.23 (s, 3H), 3.92 (s, 3H), 3.85 (d, J=9.1Hz, 1H), 3.73 (d, J=8.5Hz, 1H), 3.43 (t, J=11.0Hz, 1H), 3.26 (d, J=11.6Hz, 2H), 3.17 (s , 3H), 2.24 (d, J=12.7Hz, 3H), 1.64 (d, J=12.1Hz, 1H), 1.59-1.45 (m, 2H), 1.00 (d, J=12.2Hz, 1H).

Example 34

4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine (“Compound 34”)

4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine (“Compound 34”)

Step 1: 4-((6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine

6-Bromo-3-(bromomethyl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine (from Example 32, Step 3, 300 mg, 0.59 mmol), morpholine (100 mg, 1.15 mmol) and K ₂ CO ₃ (300 mg, 2.17 mmol) were combined in DMF (10 mL) at room temperature. The reaction was stirred for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 2-10% MeOH in DCM to afford 4-((6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine (120 mg, 39.00% yield). LC-MS [M+H] ⁺ = 524, 526.

Step 2: 4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine

To _a solution of 4-((6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine (120 mg, 0.23 mmol) in dioxane (6 mL) was added 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (185 mg, 0.48 mmol), PdCl₂(PPh₃ _{) ₂ (} 30 mg, 0.043 mmol), and DIEA (100 mg, 0.77 mmol) under N₂. The mixture was purged with _N₂ for 2 minutes and stirred at 110°C for 20 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc (100 mL). After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 20-60% EtOAc in hexanes to give 4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine (compound 34, 84 mg, 67.50% yield). LC-MS[M+H] ⁺ =541.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.39 (d, J=1.5Hz, 1H), 8.19 (s, 1H), 7.70 (d, J=7.4Hz, 2H), 7.32 (t, J=7.4Hz, 2H), 7.24 (t, J=7. 3Hz, 1H), 5.68 (d, J = 11.3Hz, 1H), 4.15 (s, 3H), 3.92 (s, 3H), 3.90 (s, 1H), 3.86 (d, J = 3.9Hz, 1H), 3 .82(d, J＝7.6Hz, 1H), 3.79(s, 1H), 3.71(d, J＝13.2Hz, 1H), 3.64(s, 4H), 3.47-3.33(m, 4H), 2.22( s, 3H), 1.63 (d, J=12.3Hz, 1H), 1.51 (d, J=11.8Hz, 1H), 1.42-1.33 (m, 1H), 1.14 (d, J=13.5Hz, 1H).

Example 35

N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)-N-(methylsulfonyl)acetamide (“Compound 35”)

N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)-N-(methylsulfonyl)acetamide("Compound 35”)

Step 1: N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)-N-(methylsulfonyl)acetamide

When compound N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methanesulfonamide (from Example 28, Step 2) was purified by preparative HPLC, 3 mg of N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)N-(methylsulfonyl)acetamide (Compound 35, 12% yield) was also obtained. LC-MS [M+H] ⁺ =577.

¹ HNMR (400MHz, CDCl ₃ )δ8.44(s, 1H), 7.53(s, 1H), 7.53-7.47(m, J=6.8Hz, 2H), 7.33-7.28(m, 3H), 5.4 7(d, J=10.4Hz, 1H), 4.30 (s, 3H), 4.02-3.89 (m, J=9.4Hz, 2H), 3.87 (s, 3H), 2.55 -2.44 (m, J=11.0Hz, 2H), 3.33 (s, 3H), 3.15-3.09 (m, J=10.3Hz, 1H), 2.43 (s, 3H) , 2.16 (s, 3H), 1.83-1.79 (m, J=7.1Hz, 1H), 1.55-1.50 (m, 1H), 1.35-1.22 (m, 2H).

Pharmacological testing

1. BRD4 (BD1) affinity test

The BRD4 (BD1) biochemical binding assay was performed by Sundia MediTech Co. Ltd using HTRF technology in 384-well white plates (OptiPlate-384, PerkinElmer).

Briefly, 20 nL of compound was transferred to a 384-well plate using a 550 liquid handler (Labcyte, USA), and 5 μL of BRD4 (BD1) (Reaction Biology Company, RD-11-157) solution or assay buffer was added to each well. After incubation at room temperature for 15 minutes, 5 μL of biotinylated H4-derived acetylated peptide (synthesized by GL Biochem (Shanghai) Ltd) and 10 μL of detection solution (Cisbio Assay) were added to each well. After incubation at room temperature for 1 hour, the HTRF signal was measured at 615 nm and 665 nm using an EnVision Multilabel Plate Reader (PerkinElmer, USA). The results were analyzed using a dual-wavelength signal ratio: intensity (665 nm) / intensity (615 nm). The inhibition rate of the compound was calculated according to the following formula: inhibition rate = (Max-Signal) / (Max-Min) × 100%. _IC50 values were fitted to the data using GraphPad Prism V5.0 software (San Diego, CA) and nonlinear regression analysis was performed using the equation, Y = bottom + (top - bottom)/(1 + 10^(( _LogIC50 - X) x slope), where Y represents inhibition rate and X represents compound concentration.

result:

The results of the BRD4 (BD1) affinity test are shown in Table 3 below:

Table 3. Results of BRD4 (BD1) affinity assay

It can be seen from Table 3 that the compounds of the present invention have very strong affinity with BRD4 (BD1).

2. Cell Proliferation Test

MTS assay protocol:

The effects of compounds on MV-4-11 cell proliferation were detected by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazole, inner salt) method. Briefly, MV-4-11 cells were cultured in IMDM (Iscove's Modified Dubecco's Medium) medium with 10% (v/v) FBS (fetal bovine serum) at a temperature of 37°C, 5% _CO2 and 95% humidity. Cells were collected in the logarithmic growth phase and counted using a hemocytometer. Cell viability was determined by trypan blue exclusion, and the cell viability was over 90%. The MV-4-11 cell concentration was adjusted to 1.2×10 ⁵ cells/mL using complete culture medium. Add 100 μL of cell suspension to a 96-well plate (three replicates for each concentration) to a final cell density of 1.2 × 10 ⁴ cells/well. The next day, dissolve the test compound in DMSO as a stock solution. Add 5 μL of the stock solution to 1 mL of culture medium, and add 25 μL of drug culture medium to the 96-well plate. After serial dilution with culture medium, the final concentrations of the compound are 0, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 nM. Incubate the drug for 3 days and then detect by MTS assay. Add PMS (phenaziniummethosulfate) solution to MTS solution (1:20). Then, add 20 μL of the MTS/PMS mixed solution to each well of the 96-well plate. Incubate the 96-well plate in an incubator for 1-4 hours. Measure the absorbance at 490 nm using a microplate spectrophotometer (Envision ^R , PeikinElmer). GraphPad 5.0 was used to fit the data and obtain _IC50 values.

result:

The results of the cell proliferation activity test are shown in Table 4 below:

Table 4. Results of cell proliferation activity test

It can be seen from Table 4 that the compound of the present invention has an excellent inhibitory effect on leukemia cells MV-4-11.

In addition, the compounds of the present invention also have a very good inhibitory effect on various cancer cells, including lung cancer cells, other leukemia cancer cells, myeloma cells, esophageal cancer cells, and ovarian cancer cells. Lung cancer cells include, but are not limited to, NCI-H526, NCI-H146, NCI-H820, DMS53, and NCI-H446 lung cancer cells; leukemia cells include, but are not limited to, NB4, JJN-3, Kasumi-1, OCI-AML3, and THP-1 leukemia cancer cells; myeloma cells include, but are not limited to, NCI-H929 and KMS-11 myeloma cancer cells; esophageal cancer cells include, but are not limited to, COLO-680N, KYSE-150, KYSE-270, KYSE-410, KYSE-70, OE19, T.Tn, and TE-1 esophageal cancer cells; and ovarian cancer cells include, but are not limited to, RMG-1 and OVCAR-4 ovarian cancer cells.

Claims (15)

1. A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from: 2. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3’,4’:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 3. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3’,4’:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 4. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3’,4’:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 5. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: 2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-D3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 6. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 7. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 8. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 9. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 10. The compound of claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: (S)-2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-(methyl-d3)-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 11. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound is: (R)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol. 12. A pharmaceutical composition comprising at least one compound according to any one of claims 1-11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient. 13. The use of any compound of claims 1-11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; or the use of the pharmaceutical composition of claim 12 in the preparation of a medicament for treating a disease or condition associated with a bromine domain protein, wherein the disease or condition is a solid tumor and/or a hematologic malignancy. 14. The use according to claim 13, wherein the solid tumor is selected from lung cancer, gastrointestinal tumors and ovarian cancer; and the hematologic malignancy is selected from myeloma and leukemia. 15. The use according to claim 14, wherein the lung cancer is selected from non-small cell lung cancer and small cell lung cancer; the digestive tract tumor is selected from esophageal cancer, colon cancer, rectal cancer and colorectal cancer; the leukemia is selected from acute myeloid leukemia and acute lymphoblastic leukemia; and the myeloma is multiple myeloma.