Tricyclic compounds

Abstract

The present invention discloses tricyclic compounds as bromodomain and extra-terminal (BET) inhibitors, as shown in Formula III, their synthesis and their use for treating diseases. More specifically, the present invention discloses fused heterocyclic derivatives useful as BET inhibitors, methods for preparing these compounds and methods for treating diseases and conditions in which inhibition of one or more BET bromodomains provides a benefit.

Description

[0001] This application is a divisional application of Chinese patent application 201980041760.8, filed on April 26, 2019, with the invention name “Tricyclic Compounds”. Technical Field

[0002] The present invention relates to certain novel tricyclic compounds (Formula I) as 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 as BET inhibitors, methods for preparing these compounds, and methods for treating diseases or conditions where inhibition of one or more BET bromodomains provides benefits. Background Art

[0003] Several physiological processes may contribute to epigenetic regulation, including DNA methylation, noncoding RNA-mediated scaffolding and complex formation, and histone modifications. Histone modifications are processes associated with the post-translational covalent modification of histones, which significantly influence 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. Enzymes that regulate lysine acetylation in histones are called "writers" or histone acetyltransferases (HATs), and enzymes that regulate lysine deacetylation in histones are called "erasers" or histone deacetylases (HDACs). Bromodomains (BRDs), "readers" of epigenetic marks, specifically recognize g-N-acetyllysine (Kac) residues on histone tails.

[0004] BRD is a conserved 110 amino acid structural domain composed of four α-helices (αZ, αA, αB and αC), which contains a left-hand bundle (S. Mujtaba, L. Zeng, MM Zhou, Oncogene, 2007 (26), 5521-5527). The α-helices are connected together by two loop regions (ZA and BC) and form a surface that interacts with acetylated lysine in nucleosomal histones (C. Dhalluin, JE. Carlson, L. Zeng et al, Nature, 1999 (399), 491-496). Based on structural / sequence similarity, there are 46 known bromodomain-containing proteins from humans, which span 8 families. Among them, bromodomains and extra-terminal domains (BET) recognize acetylated lysine residues in histones H3 and H4. The BET family, including four members, BRD2, BRD3, BRD4 and BRDT, shares two N-terminal bromodomains and an additional C-terminal domain (ET), showing a high degree of sequence conservation. It is reported that along actively transcribed genes, BRD2 and BRD3 bind to histones and may be involved in promoting transcriptional elongation (Leroy et al., Mol. Cell 200830 (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 RNA polymerase regulation of transcription and increasing transcriptional output (Hargreaves et al., Cell, 2009138 (1): 1294145). Unlike the other three BET proteins that are ubiquitously expressed, BRDT expression is usually testis-specific (MH 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 leads to the recruitment of BET proteins to the enhancer and promoter regions of genes for active transcription. Thus, 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, USA 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.

[0005] It is believed that BET proteins mainly mediate their role in disease pathogenesis and progression by localizing to super enhancers (SEs) of pathology-related genes and driving their expression (MA 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; WA 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 (JM Shahni 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. It is desirable to generate additional BET inhibitors with improved properties over existing BET inhibitors, e.g., improved activity, safety, pharmacokinetics, and / or pharmacodynamics. Summary of the invention

[0006] In one aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0007]

[0008] in,

[0009] X 1 Selected from O, S, SO, SO 2 or NR 1 ;

[0010] R 1 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 1l ;-COR 11 ;-CONR 11 R 12 ;-POR 11 R 12 ;-C 5-6 Aryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-6 Heteroaryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 3-8 Heterocyclic; or -C 3-8 carbon ring; and each R 1 is optionally substituted, independently at each occurrence, with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently 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 Carbon ring;

[0011] Each R 11 and R 12 is independently selected at each occurrence from hydrogen, deuterium, -OH, -NH 2 、-CN、-C 1-6 Alkyl, -C 1-6 Alkoxy, -C 5-6 Aryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-6 Heteroaryl; -C1-6 Alkylene-C 3-8 Carbocyclic; or -C 3-8 carbon ring; and each R 11 and R 12 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence 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, carboxyl, -SO 2 (C 1-6 Alkyl) or -C 3-8 Carbon ring; or

[0012] R 11 and R 12 Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered heterocyclic ring, and each of said heterocyclic rings may further contain 1, 2, 3 or 4 atoms selected from N, O, S, SO or SO 2 wherein each heterocycle is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each substituent 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 ; containing 1 or 2 -C heteroatoms selected from N, O or S 3-6 Heterocyclic ring; or -C substituted by deuterium 1-6 alkyl;

[0013] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium, halogen, -NH 2 , -C 1-6 Alkoxy or -C 1-6 Alkyl; or

[0014] R 13and R 14 Together with the carbon atoms to which they are commonly attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic rings is independently and 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, -NH 2 、-CN、-C 1-6 Alkyl or -C 1-6 Alkoxy;

[0015] R 2 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 5-6 Aryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-6 Heteroaryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 3-8 Heterocyclic ring; or C 3-8 carbon ring; and each R 2is independently at each occurrence 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 Carbon ring;

[0016] Each R 21 and R 22 is independently selected at each occurrence from hydrogen; deuterium; -OH; NH 2 ;-CN;-C 1-6 Alkyl; -C 1-6 Alkoxy; -C 5-6 Aryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-6 Heteroaryl; -C 1-6 Alkylene-C 3-8 Carbocyclic; or -C 3-8 carbon ring; and each R 21 and R 22 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence 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, carboxyl, -SO 2 (C 1-6 Alkyl) or -C 3-8 Carbon ring; or

[0017] R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, and each of the heterocyclic rings may further contain 1, 2, 3 or 4 radicals selected from N, O, S, SO or SO 2 wherein each heterocycle is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each substituent 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 ; containing 1 or 2 -C heteroatoms selected from N, O or S 3-6 Heterocyclic ring; or -C substituted by deuterium 1-6 alkyl;

[0018] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium, halogen, -NH 2 , -C 1-6 Alkoxy or -C 1-6 Alkyl; or

[0019] R 23 and R 24 Together with the carbon atoms to which they are commonly attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic rings is independently and 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, -NH 2 、-CN、-C 1-6 Alkyl or -C 1-6 Alkoxy;

[0020] A is selected from

[0021] Y 1 Select N or CRY 1 ;

[0022] Y 2 Selected from O, S, CR Y1 R Y2 or NR Y2 ;

[0023] Each R Y1 and R Y2 is independently selected at each occurrence from hydrogen, deuterium, halogen, -OH, NH 2 、-CN、-C 1-6 Alkyl or -C 1-6 Alkoxy;

[0024] Each R 3 and R 4 is independently selected at each occurrence from hydrogen, deuterium, halogen, -CN, -SOR 5 、-SO 2 R 5 、-SO2 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 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence selected from deuterium, halogen, -OH, -NH 2 、-CN、-C 1-6 Alkyl or -C 1-6 Alkoxy;

[0025] Each R 5 and R 6 is independently selected at each occurrence from hydrogen; deuterium; -OH; -NH 2 ;-CN;-C 1-6 Alkyl; -C 1-6 Alkoxy; -C 5-6 Aryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-6 Heteroaryl; -C 1-6 Alkylene-C 3-8 Carbocyclic; or -C 3-8 carbon ring; and each R 5 and R 6 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence 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, carboxyl, -SO 2 (C 1-6 Alkyl) or -C 3-8 Carbon ring; or

[0026] R 5 and R 6 Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered heterocyclic ring, and each of the heterocyclic rings may further contain 1, 2, 3 or 4 atoms selected from N, O, S, SO or SO 2wherein each heterocycle is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each substituent 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 ; containing 1 or 2 -C heteroatoms selected from N, O or S 3-6 Heterocyclic ring; or -C substituted by deuterium 1-6 alkyl;

[0027] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0028] W 1 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; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-10 Heteroaryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 3-8 Heterocyclic; or -C 3-8 carbon ring; and each W 1 is independently at each occurrence optionally unsubstituted or substituted;

[0029] W 2 Selected from hydrogen; deuterium; halogen; -NH 2 ;-CN;-OH;-NO 2 ; Carboxyl; -C 1-6 Alkyl; -C 1-6 Alkoxy; -C 5-10 Aryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-10Heteroaryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 3-8 Heterocyclic; or -C 3-8 carbon ring; and each W 2 is independently at each occurrence optionally unsubstituted or substituted with a substituent;

[0030] Z is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, carboxyl, -C 1-6 Alkyl or -C 1-6 Alkoxy.

[0031] In certain embodiments, the compound is represented by Formula I-1:

[0032]

[0033] In formula I-1, "R" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

[0034] In certain embodiments, the compound is represented by Formula I-2:

[0035]

[0036] In formula I-2, "S" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

[0037] In certain embodiments, the compound is represented by Formula II:

[0038]

[0039] In certain embodiments, the compound is represented by Formula II-1:

[0040]

[0041] In formula II-1, "R" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

[0042] In certain embodiments, the compound is represented by Formula II-2:

[0043]

[0044] In formula II-2, "S" represents1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

[0045] In certain embodiments, the compound is represented by Formula III:

[0046]

[0047] In certain embodiments, the compound is represented by formula III-1:

[0048]

[0049] In formula III-1, "R" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

[0050] In certain embodiments, the compound is represented by formula III-2:

[0051]

[0052] In formula III-2, "S" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

[0053] In certain embodiments, the compound is represented by Formula IV:

[0054]

[0055] In certain embodiments, the compound is represented by Formula IV-1:

[0056]

[0057] In formula IV-1, "R" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

[0058] In certain embodiments, the compound is represented by formula IV-2:

[0059]

[0060] In formula IV-2, "S" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

[0061] In certain embodiments, wherein R 1 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 ; containing 1, 2, 3 or 4 selected from N, O, S or SO 2 Heteroatom -C 5-6 Heteroaryl; containing 1, 2, 3 or 4 selected from N, O, S or SO 2 Heteroatom -C 3-8 Heterocyclic; or -C 3-8 carbon ring; 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 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), -N(C 1-6 alkyl) 2 or -C 3-8 Carbon ring;

[0062] Each R 11 and R 12 is independently selected at each occurrence from hydrogen, deuterium, -C 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 Carbocyclic or -C 3-8 carbon ring; and each R 11 and R 12 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence 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 -C3-8 Carbon ring; or

[0063] R 11 and R 12 Together with the nitrogen atom to which they are commonly attached, they form a 4-6 membered heterocyclic ring, and each of the heterocyclic rings may further contain 1, 2 or 3 atoms selected from N, O, S or SO 2 wherein each heterocycle is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each substituent 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 ; containing 1, or 2 -C selected from N, O or S heteroatoms 3-6 Heterocyclic ring; or deuterium-substituted -C 1-6 alkyl;

[0064] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium or -C 1-6 Alkyl; or

[0065] R 13 and R 14 Together with the carbon atoms to which they are commonly attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic rings is independently optionally substituted or substituted with 1, 2, 3 or 4 substituents at each occurrence, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH 2 、-CN、-C 1-6 Alkyl or -C 1-6 Alkoxy;

[0066] n is selected from 0, 1, 2 or 3.

[0067] In certain embodiments, wherein R 1 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, the-C 5-6 The heteroaryl group contains 1, 2, 3 or 4 atoms selected from N, O, S or SO 2 Heteroatom; -C 3-6 Heterocyclic, the-C 3-6 The heterocyclic ring contains 1, 2, 3 or 4 atoms selected from N, O, S or SO 2 heteroatom; or -C 3-6 carbon ring; and each R 1 is optionally substituted, independently at each occurrence, with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently 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 Carbon ring;

[0068] 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 Carbocyclic, or -C 3-6 carbon ring, and each R 11 and R 12 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, -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 Carbon ring; or

[0069] R 11 and R 12Together with the nitrogen atom to which they are all attached, they form a 4-6 membered heterocyclic ring, and each of said heterocyclic rings may further contain 1, 2 or 3 atoms selected from N, O or SO 2 wherein each heterocycle 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, the-C 4-6 The heterocycle contains 1 heteroatom selected from N or O; or -C substituted by deuterium 1-3 alkyl;

[0070] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium or -C 1-3 Alkyl; or

[0071] R 13 and R 14 Together with the carbon atoms to which they are all attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic rings is independently optionally substituted with 1, 2, 3 or 4 substituents, and each of the substituents is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH 2 、-CN、-C 1-3 Alkyl or -C 1-3 Alkoxy;

[0072] n is selected from 0, 1, 2 or 3.

[0073] In certain embodiments, wherein R 1 Selected from hydrogen; deuterium; -SOR 11 ;-SO 2 R 11 ;-SO 2 NR 11 R 12 ; Methyl; Ethyl; Propyl; Isopropyl; -COOR 11 ;-COR11 ;-CONR 11 R 12 ;-POR 11 R 12 ; 5-membered heteroaryl, the 5-membered heteroaryl contains 1, 2 or 3 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 selected from N, O, S or SO 2 A 4-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O, S or SO 2 A 5-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O, S or SO 2 heteroatom; 6-membered heterocyclic ring, the 6-membered heterocyclic ring contains 1, 2 or 3 selected from N, O, S or SO 2 heteroatom; 3-membered carbocyclic ring; 4-membered carbocyclic ring; 5-membered carbocyclic ring; or 6-membered carbocyclic ring; and each R 1 is optionally substituted, independently at each occurrence, with 1, 2, 3, 4, 5 or 6 substituents, each of which 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 )、-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 carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring;

[0074] Each R 11 and R 12is 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 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, -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, -8O 2 CH 3 、-SO 2 CH 2 CH 3 、-SO 2 CH 2 CH 2 CH 3 、-SO 2 CH(CH 3 ) 2 , 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring; or

[0075] R 11 and R 12 Together with the nitrogen atom to which they are all attached, they form a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, and each of the heterocyclic rings may further contain 1 or 2 atoms selected from N, O or SO 2wherein each heterocycle 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;

[0076] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

[0077] R 13 and R 14 Together with the carbon atoms to which they are all attached, they 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 is independently and optionally unsubstituted or substituted by 1, 2, 3 or 4 substituents at each occurrence, and each of the substituents is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

[0078] n is selected from 0, 1, 2 or 3.

[0079] In certain embodiments, wherein R 1 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 contains 1, 2 or 3 selected from N, O, S or SO 2 heteroatom; 6-membered heterocyclic ring, the 6-membered heterocyclic ring contains 1, 2 or 3 selected from N, O, S or SO 2 heteroatom; or a 3-membered carbocyclic ring; and each R 1is optionally substituted, independently at each occurrence, with 1, 2, 3, 4, 5 or 6 substituents, each of which 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;

[0080] Each R 11 or R 12 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -methylene-3-membered carbocyclic ring or 3-membered carbocyclic ring; and each R 11 or R 12 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, -NH 2 、-NH(CH 3 )、-N(CH 3 ) 2 , methyl, methoxy, -SO 2 CH 3 or a 3-membered carbocyclic ring; or

[0081] R 11 and R 12 Together with the nitrogen atom to which they are both attached, they form a heterocyclic ring selected from The heterocycle is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, and each of the substituents is independently selected 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. -CHD2 or -CD 3 ;

[0082] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

[0083] R 13 and R 14 Together with the carbon atoms to which they are both attached, they 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 is independently selected at each occurrence from deuterium, -OH, methyl, ethyl, propyl or isopropyl;

[0084] n is selected from 0 or 1.

[0085] In certain embodiments, wherein R 1 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 、-S0 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 CH3 )、-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(CD3 ) 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 ,

[0086] In certain embodiments, wherein R 1 Selected from -SO 2 R 11 , -C 1-6 alkyl, or -C 3-8 carbon ring; and each R 1 is optionally substituted independently at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently selected from deuterium, halogen, -OH, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NH2 、-NH(C 1-6 Alkyl) or -N(C 1-6 alkyl) 2 ;

[0087] R 11 Selected from hydrogen, deuterium or -C 1-6 alkyl;

[0088] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium or -C 1-6 alkyl;

[0089] n is selected from 0, 1, 2, 3, 4, 5 or 6.

[0090] In certain embodiments, wherein R 1 Selected from -SO 2 R 11 , -C 1-3 alkyl, or -C 3-6 carbon ring; and each R 1 is optionally substituted independently at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, each of which 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 ;

[0091] R 11 Selected from hydrogen, deuterium or -C 1-3 alkyl;

[0092] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium or -C 1-3 alkyl;

[0093] n is selected from 0, 1, 2 or 3.

[0094] In certain embodiments, wherein R 1 Selected from -SO 2 R 11 , methyl, ethyl, propyl, isopropyl, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring or 6-membered carbocyclic ring; and each R 1is optionally substituted, independently at each occurrence, with 1, 2, 3, 4, 5 or 6 substituents, each of which 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 )、-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 );

[0095] R 11 is selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl;

[0096] Each R 13 and R 14 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl;

[0097] n is selected from 0, 1, 2 or 3.

[0098] In certain embodiments, wherein R 1 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 、-CH2 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 ,

[0099] 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 CH2 N(CH 3 ) 2 、-CH 2 CF 3 、-CH(CH 3 ) 2 ,

[0100] In certain embodiments, wherein R 1 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 ,

[0101] In certain embodiments, wherein R 1 Yes-C 1-6 alkyl.

[0102] In certain embodiments, wherein R 1 Yes-C 1-3 alkyl.

[0103] In certain embodiments, wherein R 1 Selected from methyl, ethyl, propyl or isopropyl.

[0104] In certain embodiments, wherein R 1 It's methyl.

[0105] In certain embodiments, wherein R 2 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; -COOR21 ;-COR 21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO 2 R 22 ;-POR 21 R 22 ; containing 1, 2, 3 or 4 selected from N, O, S or SO 2 Heteroatom -C 5-6 Heteroaryl; containing 1, 2, 3 or 4 selected from N, O, S or SO 2 Heteroatom -C 3-8 Heterocyclic; or -C 3-8 carbon ring; 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 at each occurrence is independently selected from deuterium, halogen, -OH, -C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-8 Carbon ring;

[0106] Each R 21 and R 22 is independently selected at each occurrence from hydrogen, deuterium, -C 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 Carbocyclic or -C 3-8 carbon ring; and each R 21 and R 22 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence 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 Carbon ring; or

[0107] R 21 and R 22 Together with the nitrogen atom to which they are commonly attached, they form a 4-6 membered heterocyclic ring, each of which may further contain 1, 2 or 3 atoms selected from N, O, S or SO 2wherein each heterocycle is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each substituent 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 ; containing 1 or 2 -C heteroatoms selected from N, O or S 3-6 Heterocyclic ring; or -C substituted by deuterium 1-6 alkyl;

[0108] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium or -C 1-6 Alkyl; or

[0109] R 23 and R 24 Together with the carbon atoms to which they are commonly attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic rings is independently optionally substituted with 1, 2, 3 or 4 substituents at each occurrence, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH 2 、-CN、-C 1-6 Alkyl or -C 1-6 Alkoxy;

[0110] n is selected from 0, 1, 2, 3, 4, 5 or 6. In certain embodiments, wherein R 2 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 ;-COR21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO 2 R 22 ;-POR 21 R 22 ; containing 1, 2, 3 or 4 selected from N, O, S or SO 2 Heteroatom -C 5-6 Heteroaryl; containing 1, 2, 3 or 4 selected from N, O, S or SO 2 Heteroatom -C 3-6 Heterocyclic; or -C 3-6 carbon ring; and each R 2 is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence selected from deuterium, -F, -Cl, -Br, -OH, -C 1-3 Alkyl, -C 1-3 Alkoxy or -C 3-6 Carbon ring;

[0111] 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 Carbocyclic or -C 3-6 carbon ring; 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, each of which is independently at each occurrence selected 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 Carbon ring; or

[0112] R 21 and R 22 Together with the nitrogen atom to which they are attached, they 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, and each of the heterocycles 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; -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 ; containing 1 -C selected from N or O heteroatom 4-6 Heterocyclic ring; or -C substituted by deuterium 1-3 alkyl;

[0113] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium or -C 1-3 Alkyl; or

[0114] R 23 and R 24 Together with the carbon atoms to which they are commonly attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic rings is independently optionally substituted with 1, 2, 3 or 4 substituents at each occurrence, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH 2 、-CN、-C 1-3 Alkyl or -C 1-6 Alkoxy;

[0115] n is selected from 0, 1, 2 or 3.

[0116] In certain embodiments, wherein R 2 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; Propylene; -COOR 21 ;-COR21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO 2 R 22 ;-POR 21 R 22 ; containing 1, 2 or 3 selected from N, O, S or SO 2 5-membered heteroaryl containing 1, 2 or 3 atoms selected from N, O, S or SO 2 6-membered heteroaryl containing 1, 2 or 3 atoms selected from N, O, S or SO 2 3-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O, S or SO 2 4-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O, S or SO 2 5-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O, S or SO 2 a 6-membered heterocyclic ring containing a heteroatom; a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; or a 6-membered carbocyclic ring; and each R 2 is, independently at each occurrence, optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently selected at each occurrence from deuterium, -F, -Cl, -Br, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring or 6-membered carbocyclic ring;

[0117] Each R 21 or R 22 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 21 or R 22 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently at each occurrence selected from deuterium, -F, -Cl, -Br, -OH, -CN, -NH 2 、-NH(CH 3 )、-NH(CH 2 CH 3 )、-NH(CH 2 CH 2 CH3 ), -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, -8O 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

[0118] R 21 and R 22 Together with the nitrogen atom to which they are commonly connected, they 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 atoms selected from N, O, or SO 2 wherein each heterocycle 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, 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 CH3 ) 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;

[0119] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl;

[0120] or

[0121] R 23 and R 24Together with the carbon atoms to which they are commonly attached, they 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 the carbocyclic rings is independently and optionally substituted with 1, 2, 3 or 4 substituents at each occurrence, and each of the substituents is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

[0122] n is selected from 0, 1, 2 or 3.

[0123] In certain embodiments, wherein R 2 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 ; containing 1, 2 or 3 selected from N, O, S or SO 2 5-membered heteroaryl containing 1, 2 or 3 atoms selected from N, O, S or SO 2 a 6-membered heterocyclic ring containing a heteroatom; or a 3-membered carbon ring; and each R 2 is, independently at each occurrence, optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which, at each occurrence, is independently selected from deuterium, -F, -Cl, -Br, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or a 3-membered carbocyclic ring;

[0124] Each R 21 and R 22 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -methylene-3-membered carbocyclic ring or 3-membered carbocyclic ring; and each R2 1 and R22 is optionally substituted, independently at each occurrence, with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH 2 、-NH(CH 3 )、-N(CH 3 ) 2 , methyl, methoxy, -SO 2 CH 3 or a 3-membered carbocyclic ring: or

[0125] R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a heterocyclic ring selected from Each heterocycle is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each substituent is independently 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 ;

[0126] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

[0127] R 23 and R 24 Together with the carbon atom to which they are commonly attached, they form a 3-membered carbocyclic ring, and the carbocyclic ring is independently optionally substituted with 1, 2, 3 or 4 substituents, and each of the substituents is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

[0128] n is selected from 0 or 1.

[0129] In certain embodiments, where 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 2CH 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(CD3 )、-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 ,

[0130] 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 2CHF 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 CF3 、 -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(CH2 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 2CH 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 ,

[0131] In certain embodiments, wherein R 2 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 carbon ring; and each R 2 is optionally substituted independently at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently selected from deuterium, halogen, -OH, -C 1-6 Alkyl or -C 1-6 Alkoxy;

[0132] Each R 21or R 22 is independently selected at each occurrence from hydrogen, deuterium or -C 1-6 Alkyl; or

[0133] R 21 and R 22 Together with the nitrogen atom to which they are all attached, they form a 4-6 membered heterocyclic ring, each of which may further contain 1, 2 or 3 atoms selected from N, O, S, or SO 2 wherein each heterocycle is independently selected from deuterium, oxo, -C 1-6 Alkyl; -NH(C 1-6 or -C 3-6 Heterocyclic, the-C 3-6 The heterocycle contains 1 or 2 heteroatoms selected from N or O;

[0134] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium or -C 1-6 Alkyl; or

[0135] R 23 and R 24 Together with the carbon atoms to which they are all attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic 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, -OH or -C 1-6 alkyl;

[0136] n is selected from 0, 1, 2, 3, 4, 5 or 6.

[0137] In certain embodiments, wherein R 2 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 21R 22 , or -C 3-6 carbon ring; and each R 2 is optionally substituted independently at each occurrence with 1, 2, 3, 4, 5, or 6 substituents, each of which is independently selected from deuterium, halogen, -OH, -C 1-3 Alkyl or -C 1-3 Alkoxy;

[0138] Each R 21 or R 22 is independently selected at each occurrence from hydrogen, deuterium or -C 1-3 Alkyl; or

[0139] R 21 and R 22 Together with the nitrogen atom to which they are all attached, they 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 may be independently optionally substituted or substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of which may be independently selected from deuterium, oxo, -C 1-3 Alkyl, -NH(C 1-3 alkyl), or -C 4-6 Heterocyclic, the-C 4-6 The heterocycle contains 1 heteroatom selected from N, or O;

[0140] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium or -C 1-3 Alkyl; or

[0141] R 23 and R 24 Together with the carbon atoms to which they are all attached, they form a 3-6 membered carbocyclic ring, and each of the carbocyclic 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, -OH or -C 1-3 alkyl;

[0142] n is selected from 0, 1, 2 or 3.

[0143] In certain embodiments, wherein R 2 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 at each occurrence;

[0144] Each R 21 or R 22 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl, or isopropyl; or

[0145] R 21 and R 22 Together with the nitrogen atom to which they are all attached, they form a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each of which may further contain 1 heteroatom selected from N or O at each occurrence, and each of which may be independently optionally substituted or substituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of which 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 ,

[0146] Each R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

[0147] R 23 and R 24Together with the carbon atoms to which they are all attached, they form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, and each of said carbocyclic rings is independently optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium, -OH, methyl, ethyl, propyl or isopropyl;

[0148] n is selected from 0, 1, 2 or 3.

[0149] In certain embodiments, wherein R 2 Selected from hydrogen, deuterium, -F, -Cl, -Br, -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 , -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(CH3 ) 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 2、-P(O)H(CH 3 )、-P(O)(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 ,or

[0150] In certain embodiments, wherein R 2 Selected from hydrogen, deuterium, -F, -Cl, -Br, -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 , -SO 2 CH 3 、-SO 2 CD3 、-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、-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 CH2 CH 3 、-NHSO 2 CH 2 CH 2 CH 3 、-NHSO 2 CH(CH 3 ) 2 、-P(O)H 2 、-P(O)H(CH 3 )、-P(O)(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 or

[0151] In certain embodiments, wherein R 2 Selected from hydrogen, -Cl, -Br, -NH 2 , -SO 2 CH 3 、-SO 2 NH 2 、-SO 2 NHCH 3 、-SO 2 N(CH 3 ) 2 、-CH 3 , -COOH, -COOCH 3 、-CONH 2 、-CONHCH 3 、-CON(CH 3 ) 2 、-NHCOCH 3 、-NHSO 2 CH 3 、-PO(CH 3 ) 2 or

[0152] In certain embodiments, wherein R 2Selected from hydrogen, -Cl, -Br, -NH 2 , -8O 2 CH 3 、-SO 2 NH 2 、-SO 2 NHCH 3 、-SO 2 N(CH 3 ) 2 、-CH 3 , -COOCH 3 、-CONH 2 、-CONHCH 3 、-CON(CH 3 ) 2 、-NHCOCH 3 、-NHSO 2 CH 3 、-PO(CH 3 ) 2 or

[0153] In certain embodiments, wherein R 2 yes

[0154] Each R 23 and R 24 -C in each occurrence 1-6 alkyl.

[0155] In certain embodiments, each R 23 and R 24 -C in each occurrence 1-3 alkyl.

[0156] In certain embodiments, each R 23 and R 24 is selected at each occurrence from methyl, ethyl, propyl or isopropyl.

[0157] In certain embodiments, wherein R 2 yes

[0158] In certain embodiments, A is

[0159] In certain embodiments, A is

[0160] In certain embodiments, each R 3 and R 4is independently selected at each occurrence 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 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, halogen or -OH;

[0161] Each R 5 and R 6 is independently selected at each occurrence from deuterium; -C 1-3 Alkyl; -C 5-6 Aryl; containing 1, 2, 3 or 4 selected from N, O, S, SO or SO 2 Heteroatom -C 5-6 heteroaryl; or -C 3-6 carbon ring, and each R 5 and R 6 is optionally substituted, independently at each occurrence, with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently selected from deuterium, halogen, -C 1-3 Alkyl or -C 1-3 Alkoxy;

[0162] In certain embodiments, each R 3 and R 4 is independently selected at each occurrence from hydrogen, deuterium, -F, -Cl, -Br, -CN, -SOR 5 、-SO 2 R 5 、-SO 2 NH 2 、-SO 2 NHR5 、-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 is independently at each occurrence optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently selected at each occurrence from deuterium, -F, -Cl, -Br or -OH;

[0163] Each R 5 and R 6 is independently selected at each occurrence from deuterium; methyl; ethyl; propyl; isopropyl; phenyl; containing 1, 2, 3 or 4 atoms selected from N, O, S, SO or SO 2 5-membered heteroaryl containing 1, 2, 3 or 4 atoms selected from N, O, S, SO or SO 2 6-membered heteroaryl containing a heteroatom; 3-membered carbocyclic ring; 4-membered carbocyclic ring; 5-membered carbocyclic ring; or 6-membered carbocyclic ring; and each R 5 and R 6 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,

[0164] -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

[0165] In certain embodiments, each R 3 and R 4 is independently selected at each occurrence from hydrogen, deuterium, -F, -Cl, -Br, -CN, -SOCH 3 、-SOCH 2 CH 3 、-SOCH 2 CH 2 CH 3 、-SOCH(CH 3 ) 2 、-SO 2 CH 3 、-SO 2 CH2 CH 3 、-SO 2 CH 2 CH 2 CH 3 、-SO 2 CH(CH 3 ) 2 、-SO 2 NH 2 、-SO 2 NHCH 3 、-SO 2 NHCH 2 CH 3 、-SO 2 NHCH 2 CH 2 CH 3 、-SO 2 NHCH(CH 3 ) 2 、-SO 2 N(CH 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 、-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 CH3 、-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 ; and each R 3 and R 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.

[0166] In certain embodiments, each R 3 and R 4 is independently selected at each occurrence from hydrogen, deuterium, -F, -Cl, -Br, -CN, -SOCH 3 、-SOCD 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 NH 2 、-SO 2 NHCH 3 、-SO 2 NHCD 3 、-SO 2 NHCH 2 CH 3 、-SO 2 NHCH 2 CH 2 CH 3 、-SO 2 NHCH(CH 3 ) 2 、-SO 2 N(CH 3 ) 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 .

[0167] In certain embodiments, each R 3 and R 4 In each occurrence, independently selected from -C 1-3 Alkyl, -CONH 2 ,-CONHR 5 or-CONR 5 R 6 ; and each R 3 and R 4 is optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents independently at each occurrence, and each of said substituents is independently selected at each occurrence from deuterium or halogen;

[0168] Each R 5 and R 6 In each occurrence, independently selected from -C 1-3 Alkyl or -C 3-6 carbon ring, and each R 5 and R 6 is optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is independently selected from deuterium, halogen or -C 1-3 alkyl.

[0169] In certain embodiments, each R 3 and R 4 is independently selected at each occurrence from methyl, ethyl, propyl, isopropyl, -CONH 2 ,-CONHR 5 or-CONR 5 R 6 ; and each R 3 and R 4 is optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, independently at each occurrence, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl or -Br;

[0170] Each R 5 and R 6 is independently selected at each occurrence from methyl, ethyl, propyl, isopropyl, a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, or a 6-membered carbocycle, and each R 5 and R 6 is optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents, independently at each occurrence, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, -Br, methyl, ethyl, propyl or isopropyl.

[0171] In certain embodiments, 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 optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents independently at each occurrence, and each of said substituents is independently selected at each occurrence from deuterium, -F or methyl.

[0172] In certain embodiments, each R 3 or R 4 is independently selected at each occurrence from -CH 3 、-CD 3 、-CH 2 CH 3 、-CD 2 CD 3 、-CH 2 CH2 CH 3 、-CH 2 CH 2 CD 3 、-CH(CH 3 ) 2 、-CH(CD 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 ) or -CON(CH 2 CH 2 CH 3 ) 2 .

[0173] In certain embodiments, each R 3 or R 4 is independently selected at each occurrence from -CH 3 、-CD 3 、-CONH 2 、-CONHCH 3 、-CONHCH 2 CH 3 ,

[0174] In certain embodiments, each R 3 and R 4 In each occurrence, independently selected from -C 1-3 Alkyl, and the -C 1-3 Alkyl 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.

[0175] In certain embodiments, each R 3 and R 4 is independently selected at each occurrence from methyl, ethyl, propyl or isopropyl; and each R 3 and R 4 is optionally unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents, independently at each occurrence, and each of said substituents is independently selected at each occurrence from deuterium, -F, -Cl, or -Br.

[0176] In certain embodiments, each R 3 and R 4 is independently selected at each occurrence from methyl, ethyl, propyl or isopropyl; and each R 3 and R 4 is optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents independently at each occurrence, and each of said substituents at each occurrence is independently selected from deuterium or -F.

[0177] In certain embodiments, each R 3 and R 4 is independently selected at each occurrence from -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 or -CH(CD 3 ) 2 .

[0178] In certain embodiments, each R3 and R 4 Select -C at each occurrence 1-3 Alkyl, or -C substituted by 1, 2, 3, 4, 5 or 6 deuterium 1-3 alkyl.

[0179] In certain embodiments, each R 3 and R 4 and is selected at each occurrence from methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, or deuterated isopropyl.

[0180] In certain embodiments, wherein said A is selected from

[0181] In certain embodiments, wherein said A is independently selected from

[0182] In certain embodiments, wherein W 1 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 contains 1, 2 or 3 heteroatoms selected from N and O; 6-membered heteroaryl, the 6-membered heteroaryl contains 1, 2 or 3 heteroatoms selected from N and O; 3-membered heterocyclic ring, the 3-membered heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N and O; 4-membered heterocyclic ring, the 4-membered heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N and O; 5-membered heterocyclic ring, the 5-membered heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N and O; 6-membered heterocyclic ring, the 6-membered heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N and 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, each of which is selected from deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 , carboxyl, -C 1-3 Alkyl or -C 1-3 Alkoxy.

[0183] In certain embodiments, wherein W 1 Selected from hydrogen; deuterium; -F; -Cl; -NH 2 ; -CN; -OH; methyl; ethyl; propyl; isopropyl; Methoxy; Ethoxy; Propoxy; Isopropoxy; -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 1 is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 substituents, each of which is selected from deuterium, -F, -Cl, -NH 2 , -CN, -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

[0184] In certain embodiments, wherein W 1 is selected from hydrogen; deuterium; -F; methyl; ethyl; propyl; isopropyl; Methoxy; -CH 2 OCH 3 ; -CH 2 CH 2 OCH 3 ; 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 1 Each occurrence is independently optionally unsubstituted or substituted with deuterium or -F.

[0185] In certain embodiments, wherein W 1 Selected from hydrogen, deuterium, -F, -CH 3 、-CD 3 、-CH 2 F, -CF 2 H, -CF 3 、-CH 2 CH 3 、-CH 2 CD 3 、-CH 2 CH2 F, -CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 3 、-CH 2 CH 2 CF 3 、-CH 2 CH 2 CD 3 、-CH(CH 3 ) 2 、-CH(CF 3 ) 2 、-CH(CD 3 ) 2 , Methoxy, -CH 2 OCH 3 、-CH 2 CH 2 OCH 3 , or

[0186] In certain embodiments, wherein W 1 Selected from F substituted -C 1-6 or a 6-membered heterocyclic ring containing 1 heteroatom selected from O.

[0187] In certain embodiments, wherein W 1 Selected from F substituted -C 1-6 alkyl,

[0188] In certain embodiments, wherein W 1 Selected from -CH 2 CH 2 CF 3 or

[0189] In certain embodiments, wherein W 2 Selected from hydrogen; deuterium; -F; -Cl; -NH 2 ;-CN;-OH; carboxyl;-C 1-3 Alkyl; -C 1-3alkoxy; phenyl; naphthyl; 5-membered heteroaryl, the 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-membered heteroaryl, the 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 7-membered heteroaryl, the 7-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 8-membered heteroaryl, the 8-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 9-membered heteroaryl, the 9-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 10-membered heteroaryl wherein the 10-membered heteroaryl group contains 1, 2 or 3 heteroatoms selected from N, O or S; a 3-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; a 4-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; a 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; a 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; or a 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, each of which is selected from deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

[0190] In certain embodiments, wherein W 2 is selected from hydrogen; deuterium; phenyl; a 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S; or a 6-membered heteroaryl group 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, 3, 4 or 5 substituents, and each of said substituents at each occurrence is selected from deuterium, -F, -Cl, -Br, -NH 2 , -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

[0191] In certain embodiments, wherein W 2 phenyl; 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; or 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.

[0192] In certain embodiments, wherein W 2 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.

[0193] In certain embodiments, wherein W 2 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.

[0194] In certain embodiments, wherein W 2 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.

[0195] In certain embodiments, wherein W 2 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.

[0196] In certain embodiments, wherein W 2 Independently selected from:

[0197]

[0198] or

[0199] In certain embodiments, wherein Z is selected from hydrogen, deuterium, -F, -Cl, -OH, -C 1-3 Alkyl or -C 1-3 Alkoxy.

[0200] In certain embodiments, Z is selected from hydrogen, deuterium, -F, -Cl, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0201] In certain embodiments, wherein Z is selected from hydrogen or deuterium.

[0202] In certain embodiments, wherein Z is hydrogen.

[0203] In certain embodiments, wherein Selected from:

[0204]

[0205]

[0206] 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.

[0207] In certain embodiments, wherein said Selected from:

[0208]

[0209] 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.

[0210] In certain embodiments, wherein said A is independently selected from:

[0211]

[0212] In certain embodiments, wherein

[0213] R 1 Yes-C 1-6 alkyl;

[0214] R 2 yes

[0215] Each R 23 and R 24 -C in each occurrence 1-6 alkyl;

[0216] The A shown is

[0217] Each R 3 and R 4 Select -C at each occurrence 1-6 Alkyl or -C substituted by 1, 2, 3, 4, 5 or 6 deuterium1-6 alkyl;

[0218] W 1 Selected from -F substituted -C 1-6 Alkyl, or a 6-membered heterocyclic ring containing 1 heteroatom selected from O;

[0219] W 2 phenyl; 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; or 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;

[0220] Z is selected from hydrogen or deuterium.

[0221] In certain embodiments, wherein,

[0222] R 1 Yes-C 1.3 alkyl;

[0223] Each R 23 and R 24 -C in each occurrence 1-3 alkyl;

[0224] Each R 3 and R 4 Select -C at each occurrence 1-3 Alkyl, or -C substituted by 1, 2, 3, 4, 5 or 6 deuterium 1-3 alkyl;

[0225] W 1 Selected from -F substituted -C 1-6 alkyl,

[0226] W 2 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, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

[0227] Z is selected from hydrogen.

[0228] In certain embodiments, wherein,

[0229] R 1is selected from methyl, ethyl, propyl or isopropyl;

[0230] Each R 23 or R 24 is selected at each occurrence from methyl, ethyl, propyl or isopropyl;

[0231] Each R 3 and R 4 is selected at each occurrence from methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl or deuterated isopropyl;

[0232] W 1 Selected from -CH 2 CH 2 CF 3 or

[0233] W 2 Selected from:

[0234]

[0235] or

[0236] In certain embodiments, wherein,

[0237] R 1 is methyl; R 2 yes Each R 3 and R 4 is independently selected at each occurrence from -CH 3 or -CD 3 .

[0238] In certain embodiments, wherein the compound is:

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] In certain embodiments, the compound is:

[0251]

[0252]

[0253]

[0254] In certain embodiments, the compound is:

[0255]

[0256] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as described above, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0257] In certain embodiments, the weight ratio of the compound to the excipient is about 0.0001 to about 10. In certain embodiments, the weight ratio of the compound to the excipient is about 0.0005 to about 0.25.

[0258] In another aspect, the present invention provides a method for treating 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 the pharmaceutical composition. In certain embodiments, the disease or condition associated with a bromodomain protein is a solid tumor and / or a blood tumor. In certain embodiments, the solid tumor is selected from lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer and / or ovarian cancer; the blood 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); myeloma includes multiple myeloma.

[0259] On the other hand, the present invention provides the compound of formula I, its pharmaceutically acceptable salt, or its stereoisomer; or the pharmaceutical composition 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 blood tumor. In certain embodiments, the solid tumor is selected from lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer and / or ovarian cancer; the blood 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); myeloma includes multiple myeloma.

[0260] In another aspect, the present invention provides the compound of formula I, its pharmaceutically acceptable salt, or its stereoisomer; or the use of the pharmaceutical composition in the preparation of a drug, wherein the drug 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 blood tumor. In certain embodiments, the solid tumor is selected from lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer and / or ovarian cancer; the blood 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); myeloma includes multiple myeloma.

[0261] definition

[0262] Unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups include F, Cl and Br.

[0263] Unless otherwise specified, the term "alkyl" as used herein includes saturated monovalent alkyl groups having straight or branched chains. 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 C in the alkyl group 1-6 It is defined as having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched arrangement.

[0264] The term "alkylene" refers to a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, a methylene group (i.e., -CH 2-), ethylene (i.e. -CH 2 -CH 2 - or -CH(CH 3 )-) and propylene (i.e. -CH 2 -CH 2 -CH 2 -、-CH(-CH 2 -CH 3 ))-or-CH 2 -CH(CH 3 )-).

[0265] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. 2-6 "Alkenyl" contains 2 to 6 carbon atoms. Alkenyl includes, but is not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0266] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. 2-6 "Alkynyl" contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0267] The term "alkoxy" group is an oxygen ether formed from the aforementioned alkyl groups.

[0268] Unless otherwise indicated, the term "aryl" as used herein 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.

[0269] Unless otherwise indicated, the term "heterocycle" as used herein 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 members 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.

[0270] Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepanyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazole.

[0271] Unless otherwise indicated, the term "heteroaryl" as used herein means an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl can have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can contain fused, spiro or bridged rings, for example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings can contain 8 to 12 member atoms. Monocyclic heteroaryl rings 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.

[0272] 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.

[0273] The term "oxo" refers to an oxygen atom and a carbon atom to which it is attached. Group.

[0274] The term "carboxy" refers to the group C(O)OH.

[0275] As used herein, the term "composition" is intended to encompass products comprising specific ingredients in specific amounts, as well as any product produced directly or indirectly by a combination of specific ingredients in specific amounts. Therefore, pharmaceutical compositions containing the compounds of the invention as active ingredients and methods for preparing the compounds of the invention are also part of the present invention. In addition, some crystalline forms of the compounds may exist as polymorphs, and therefore these are intended to be included in the present invention. In addition, 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.

[0276] The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, the 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 in the form of protonated basic nitrogen 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.

[0277] 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 desired compounds in vivo. Therefore, in the therapeutic methods of the present invention, the term "administration" should include various conditions described by the treatment of specific disclosed compounds, or compounds that may not be specifically disclosed, but are converted into specific compounds in vivo after being administered to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described in, for example, "Prodrug Design" ("Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.).

[0278] 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 and can be readily synthesized by techniques known in the art and the methods illustrated herein.

[0279] 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 these possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0280] 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. In the course of synthetic methods for preparing these compounds, or in the course of using racemization or epimerization methods known to those skilled in the art, the products of these methods may be mixtures of stereoisomers.

[0281] The "stereoisomers" of the present invention refer to isomers caused by the same order of connection of atoms or atomic groups in the molecule but different spatial arrangements, including configurational isomers and conformational isomers, wherein configurational isomers include geometrical isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The present invention includes all possible stereoisomers of the compound, in particular, when the W in Formula I is 1 , W 2 When the carbon atom directly connected to Z is a chiral carbon, the present invention includes the following: The stereoisomers of the "R" configuration, and the Stereoisomers of the "S" configuration, for example, the stereoisomers included in the present invention include:

[0282]

[0283]

[0284] In formula I-1, II-1, III-1, and IV-1, "R" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration.

[0285] In formula I-2, II-2, III-2, and IV-2, "S" represents 1 , W 2 When the carbon atom connected to Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

[0286] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes are atoms having 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 by 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). They are also often expressed 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 13 C and 14 C. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.

[0287] Unless otherwise indicated, when tautomers of the compound of formula I exist, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0288] When the compound of formula I and its pharmaceutically acceptable salt exist in the form of 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.

[0289] 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 used for pharmaceutical purposes, they are preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% is weight % by weight)).

[0290] The pharmaceutical composition of the present invention comprises the compound (or its pharmaceutically acceptable salt) of Formula I representative as active ingredient, pharmaceutically acceptable carrier and optional other therapeutic ingredients or adjuvant. Although the most suitable approach in any given case will depend on specific host, and for the nature and severity of illness (using the active ingredient for treating the illness), the composition includes compositions suitable for oral, rectal, local and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical composition can exist in unit dosage form conveniently, and is prepared by any method known to the pharmaceutical field.

[0291] In practice, according to conventional drug formulation techniques, 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 with a drug carrier as an active ingredient. 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 or tablets each containing a predetermined amount of active ingredients. In addition, the composition can exist in the form of a powder, a granular form, a solution form, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or an oil-in-water 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. Generally, these methods include a step of combining the active ingredient with a carrier constituting one or more essential ingredients. Generally, 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 conveniently formed into a desired style.

[0292] 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 of Formula I or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition together with one or more other therapeutically active compounds.

[0293] The pharmaceutical carrier used can be, for example, solid, liquid or gas. Examples of solid carriers include lactose, gypsum, 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 the preparation of compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, colorants, etc. can be used to form oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants can be used to form oral solid preparations such as powders, capsules and tablets. Tablets and capsules are preferred oral dosage units due to ease of administration, in which solid pharmaceutical carriers are used. Optionally, tablets can be coated by standard aqueous or non-aqueous techniques.

[0294] Tablets containing the compositions of the present invention may be prepared by compression or molding, optionally containing one or more auxiliary ingredients or adjuvants. Compressed tablets may 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 may be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. 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 account for 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.

[0295] 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 harmful growth of microorganisms.

[0296] The pharmaceutical composition of the present invention suitable for injection purposes includes sterile aqueous solutions or dispersions. In addition, the composition can be in the form of sterile powders 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 the contamination of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0297] The pharmaceutical composition of the present invention can be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, etc. In addition, the composition can be in a form suitable for transdermal devices. Using the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05wt% to about 10wt% of the compound to produce a cream or ointment with a desired consistency.

[0298] Pharmaceutical compositions 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.

[0299] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparation can suitably include one or more other carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants) or the like. In addition, other adjuvants can be included to make the preparation isotonic with the blood of the intended recipient. The composition containing the compound shown in Formula I or its pharmaceutically acceptable salt can also be prepared into powder or liquid concentrate form.

[0300] Typically, dosage levels of about 0.001 mg / kg to about 150 mg / kg of body weight per day are useful for treating the above 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, 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.

[0301] However, it should be understood that the specific dosage level for any particular patient will depend on 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 disease being treated.

[0302] These and other aspects will become apparent from the following written description of the invention.

[0303] Preparation method

[0304] Those skilled in the art of organic synthesis can use several methods described below and synthetic methods well known in the field of organic synthetic chemistry or variations of the above methods known to those skilled in the art to synthesize the compounds of the present invention well. Preferred methods are not limited to the methods described below. The documents cited herein are incorporated by reference in their entirety.

[0305] 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 the 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. Solvents, temperature, pressure and other reaction conditions can be easily selected by those skilled in the art. Protective groups are operated according to standard methods for organic synthesis (TW Green and PGM Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at certain stages of compound synthesis using methods obvious to those skilled in the art.

[0306] The general synthetic routes to the compounds shown in the present invention are described in Schemes 1-3, wherein R 1 , R 2 , R 3 , Y 1 , Y 2 , W 1 , W 2 Substituents such as, and Z are previously defined herein or are functional groups that can be converted to the desired final substituent. The substituent Hal is a halide, L is a leaving group such as a halide ion or a hydroxyl group that can be easily converted to a triflate or tosylate. M is a suitable coupling ligand such as a boronic acid, a boric ester or a stannoyl.

[0307] As shown in Scheme 1, using a suitable coupling catalyst (e.g., Pd(dppf)Cl 2 ), in alkali (such as K 3 PO 4 ) in the presence of pyrazole 1 and aromatic heterocycle 2 (e.g. 2,5-dibromo-3-nitropyridine) in THF / H 2 O (volume ratio of 5:1) to obtain 3. In the presence of a phosphine reagent (such as 1,2-bis(diphenylphosphino)ethane (DPPE) or triethyl phosphate P(OEt) 3 ) and a solvent (such as 1,2-dichlorobenzene or 1,2-dimethylbenzene) and heating, Cadogan reductive cyclization of 3 can give the tricyclic compound 4. Mitsunobu reaction of 4 with alkylating agent 5 using triphenylphosphine and diisopropyl azodicarboxylate (DIAD) provides 7. 7 can also be produced by reaction of 4 with alkylating agent 6 under basic conditions (potassium carbonate), where L is a leaving group such as a halogen, mesylate or triflate. Coupling of 7 with 8 (wherein M is a suitable coupling ligand such as boronic acid, boric ester or stannoyl) by Suzuki or Stille reaction can give 9. In the case where 9 is a racemate, chiral separation can provide enantiomerically pure products. R 1 and R 2 Further derivatization of can provide additional compounds of the invention. For example, when R 1 When it is a protecting group, it can be further functionalized after deprotection; when R 2 When it is an ester, the addition of a Grignard reagent or an alkyl lithium can produce a tertiary alcohol. The ester can also be hydrolyzed using, for example, potassium hydroxide to give a carboxylic acid, which can be further functionalized with an alkylamine; when R 2 When hydrogen, it can be replaced with a halogen (eg, -Br) by halogenation using reagents such as NBS, and then further functionalized by coupling reactions such as the Buchwall, Mitszunobu, or Stille reactions.

[0308] Solution 1

[0309]

[0310] As shown in Scheme 2, heteroaromatic compound 10 can be coupled directly with 7 (prepared as in Scheme 1) via palladium-mediated C-H activation to afford compound 9.

[0311] Solution 2

[0312]

[0313] 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.

[0314] Solution 3

[0315] Example

[0316] The present invention is further illustrated using the following examples, which should be understood to be for illustration only. Those skilled in the art can undoubtedly determine the essential features of the present invention, and, without departing from its spirit and scope, can make multiple 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.

[0317] The abbreviations are shown in Table 1 below:

[0318] Table 1

[0319]

[0320]

[0321] Preparation of intermediates

[0322] Unless otherwise stated, starting materials used in the preparation of the intermediates and examples are commercially available.

[0323] Enantiomer a1 and enantiomer b1

[0324] (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 ((S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol) (“enantiomer b1”)

[0325]

[0326] In N 2To a suspension of Mg (24.3 g, 1.00 mol) in THF (500 mL) was added three iodine crystals, and then neat 4-bromotetrahydro-2H-pyran (100 g, 607 mmol) was added dropwise through another funnel, during which the internal temperature was controlled below 45°C. The reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was cooled to -30°C, and then a solution of 3-fluoropyridinecarboxaldehyde (50.3 g, 402 mmol) in THF (300 mL) was added dropwise through another funnel, during which the internal temperature was maintained between -20°C and -30°C. After 1 hour, the reaction mixture was filtered through a thin celite pad. Saturated NH 4 Cl (100 mL) aqueous solution, separated into two layers. The organic phase was washed with anhydrous Na 2 SO 4 The filtrate was concentrated on a rotary evaporator. The crude compound was purified by reverse phase chromatography using 40%-50% MeCN / H 2 O was used for elution to give a racemic compound (52 g, 61% yield), which was separated by chiral preparative SFC to give enantiomers a1, (R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (25.1 g, yield 29.6%) and (S)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (25.3 g, 29.7%).

[0327] Enantiomer a1: LC-MS [M+H] + =212. Chiral chromatography report: RT=12.25min (column: ChiralpakAY-H (ADHOCE-VC001) 0.46×25cm; mobile phase: 90 / 10 / 0.1 hexane / EtOH / DEA; flow rate: 1.0mL / min). Chiral chromatography report: RT=14.023min (column: YMC, ChiralART-amylose-C Neo (5μm, 250×4.6mm; mobile phase: 90 / 10 / 0.1 hexane / EtOH / TFA; flow rate: 1.0mL / 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).

[0328] Enantiomer b1: LC-MS [M+H] + =212. Chiral chromatography report: RT=13.57min (column: Chiralpak AY-H (ADHOCE-VC001) 0.46×25cm; mobile phase: 90 / 10 / 0.1 hexane / EtOH / DEA; flow rate: 1.0mL / min). Chiral chromatography report: RT=12.760min (column: YMC, Chiral ART-amylose-CNeo (5μm, 250×4.6mm; mobile phase: 90 / 10 / 0.1 hexane / EtOH / TFA; flow rate: 1.0mL / 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).

[0329] Intermediate 3-Intermediate 17

[0330] The intermediates in Table 2 were prepared using the same method as the racemates of enantiomer a1 and enantiomer b1:

[0331] Table 2

[0332]

[0333]

[0334] Example 1

[0335] (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”)

[0336] (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”)

[0337]

[0338] Step 1: Methyl 5-(5-bromo-3-nitropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate

[0339] In N 2 , 1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (20.2 g, 0.14 mol) was added 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) at room temperature. The resulting solution was evacuated and filled with N 2 This process was repeated three times, and then the reaction mixture was heated to N 2 The mixture was refluxed for 12 hours. The reaction mixture was then concentrated under reduced pressure to obtain a red object. THF (500 mL), water (100 mL), K3 PO 4 (65.13 g, 0.31 mol) and 2,5-dibromo-3-nitropyridine (47.1 g, 0.17 mol). The flask was evacuated and filled with N 2 , and repeat the process three times, then 2 Pd(dppf)Cl 2 (11-3 g, 0.014 mmol). The mixture was stirred under N 2 The mixture was refluxed for 3 hours at room temperature. 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 give 5-(5-bromo-3-nitropyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (27.6 g, 0.081 mol, 57% yield). LC-MS [M+H] + =341.

[0340] Step 2: Methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

[0341] A mixture of methyl 5-(5-bromo-3-nitropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (22.1 g, 0.065 mol), DPPE (38.8 g, 0.088 mol) in 1,2-dichlorobenzene (250 mL) was heated to 150° C. under N 2 The reaction mixture was stirred for 4 hours at 4 °C. The reaction mixture 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 methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (3.98 g, 0.013 mol, 20% yield). LC-MS [M+H] + =309.

[0342] 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

[0343] 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, and this process was repeated 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)-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-carboxylic acid methyl ester (315 mg, 97% yield). LC-MS [M+H] + =483,485.

[0344] 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

[0345] 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)Cl 2 (74 mg, 0.091 mmol) and K 3 PO 4 (402 mg, 1.89 mmol). The mixture was evacuated and backfilled with nitrogen, and this process was repeated 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 hexanes 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.

[0346] 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

[0347] In N 2MeMgBr (1M in THF, 5.0 mL, 5.03 mmol) was slowly added to a solution of (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, 0.54 mmol) in anhydrous THF (10 mL) at -30°C over 1 minute. After the addition was complete, the reaction was warmed to room temperature and stirred for 2 hours. The mixture was heated to room temperature with saturated NH 4 The reaction was quenched with Cl aqueous 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).

[0348] Example 2

[0349] (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”)

[0350] (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")

[0351]

[0352] 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")

[0353]

[0354] To a suspension of magnesium (24.3 g, 1.00 mol) in THF (500 mL) were added three crystals of iodine, and then heated to 40 °C under N 2 Neat 4-bromotetrahydro-2H-pyran (100 g, 607 mmol) was added dropwise at 45 ° C., during which the internal temperature was controlled below 45 ° C. The reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was cooled to -30 ° C., and then a solution of 3-fluoropyridinecarboxaldehyde (50.3 g, 402 mmol) in THF (300 mL) was added, during which the internal temperature was maintained between -20 ° C and -30 ° C. After 1 hour, the reaction mixture was filtered through thin celite. Saturated NH 4 Cl aqueous solution (100 mL) was added and separated into two layers. The organic phase was washed with anhydrous Na 2 SO 4The filtrate was concentrated on a rotary evaporator. The crude compound was purified by reverse phase chromatography using 40%-50% MeCN in H 2 O was used for elution to give a racemic compound (52 g, 61% yield), which was separated by chiral preparative SFC to give 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%).

[0355] Enantiomer a1: LC-MS [M+H] + =212. Chiral chromatography report: RT=12.25 minutes (column: ChiralpakAY-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, 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).

[0356] Enantiomer b1: LC-MS [M+H] +=212. Chiral chromatography report: RT=13.57 minutes (column: ChiralpakAY-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, 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).

[0357] Step 2: (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

[0358] A solution of 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, 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, and this process was repeated 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 reactant 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 resulting residue was purified by silica gel chromatography eluting with 0-35% EtOAc in hexanes to give (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 (317 mg, 92% yield). LC-MS [M+H] + =502.

[0359] Step 3: (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

[0360] 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 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 K 3 PO4 (386 mg, 1.82 mmol). The mixture was evacuated and backfilled with nitrogen three times, and then Pd(dppf)Cl was added in one portion. 2 (82 mg, 0.10 mmol), and the resulting mixture was stirred under N 2 , 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 0-5% EtOAc in MeOH to give (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 (254 mg, 78% yield). LC-MS [M+H] + =519.

[0361] 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

[0362] In N 2 MeMgBr (1M 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) at -30°C over 1 minute. After the addition was complete, the reaction was warmed to room temperature and stirred for 2 hours. The mixture was heated to room temperature with saturated NH 4The reaction was quenched with Cl aqueous solution and extracted with EtOAc (30 mL). The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-4% MeOH in DCM solution 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).

[0363] Example 3

[0364] 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”)

[0365] 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”)

[0366]

[0367] 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

[0368] To a solution of 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (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 a solution of diisopropyl azodicarboxylate (350 mg, 1.73 mmol) in THF (2 mL) 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, 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 give 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.

[0369] 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

[0370] To a solution of 6-bromo-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 (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, and the process was repeated three times before stirring 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 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 (176 mg, 55% yield). LC-MS [M+H] + =512.

[0371] 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

[0372] In N 2, MeMgBr (1M 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) at -30°C over 1 minute. After the addition was complete, the reaction was warmed to room temperature and stirred for 2 hours. Saturated NH 4 The reaction was quenched with Cl aqueous solution and extracted with EtOAc (30 mL). The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM solution 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 (400 MHz, 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).

[0373] Example 4

[0374] 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”)

[0375] 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")

[0376]

[0377] 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

[0378] A solution of 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (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, and the process was repeated 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 reactants were 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.

[0379] 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

[0380] To a solution of 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-carboxylic acid methyl ester (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 the 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. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM 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.

[0381] 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

[0382] In N 2 MeMgBr (1M 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) at -30°C over 1 minute. After the addition was complete, the reaction was warmed to room temperature and stirred for 2 hours. The mixture was heated to room temperature with saturated NH 4 The reaction was quenched with Cl aqueous solution. And extracted with EtOAc (30mL). The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 0-6% MeOH in DCM solution 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, 101mg, 53% yield). LC-MS[M+H] + =531. 1 HNMR (400 MHz, 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).

[0383] Example 5

[0384] 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”)

[0385] 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”)

[0386]

[0387] 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

[0388] 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. g, 0.77 mmol), (3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (Intermediate 5, 249 mg, 1.20 mmol) was converted to 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 (331 mg, 86% yield). LC-MS [M+H] + =498,500.

[0389] 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

[0390] 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 following 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 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, 64% yield). LC-MS [M+H] + =515.

[0391] 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

[0392] 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).

[0393] Example 6

[0394] (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”)

[0395] (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”)

[0396]

[0397] Step 1: 5-bromo-2-(1-methyl-1H-pyrazol-5-yl)-3-nitropyridine

[0398] In N 2 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). The mixture was evacuated and heated to 40 ℃ for 2 h. 2 The resulting mixture was heated to reflux and heated to N 2 The product was stirred for 5 hours at 4 °C. 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 hexane 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.

[0399] Step 2: 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

[0400] In N 2A 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.

[0401] 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

[0402] In N 2 , diisopropyl azodicarboxylate (4.02 g, 19.9 mmol) was added 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) at room temperature. The resulting solution was stirred at N 2 Reflux 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 hexane 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.

[0403] 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

[0404] In N 2 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). The mixture was evacuated and heated to 40 ℃ with N 2 Backfill, 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 (100mL). 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 (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.

[0405] 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

[0406] N-Bromosuccinimide (0.62 g, 3.48 mmol) was added in small portions 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 mixture was heated to 40°C with saturated NaHCO 3 The reaction was quenched with 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.

[0407] 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

[0408] In N 2 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) 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 heated with N 2 The mixture was refluxed for 20 hours and the solvent was then evaporated under reduced pressure to obtain a pale yellow substance.

[0409] To the mixture was added THF (10 mL) and then 2N HCl (2 mL) at room temperature, followed by stirring for 2 hours. 3 The reaction was quenched with aqueous solution 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- pyrans -4-yl) methyl) -1,4- dihydropyrazolo [3', 4': 4,5] pyrrolo [3,2-b] pyridin-3-yl) ethyl -1- ketone (390 mg, 0.81 mmol, 60% yield). LC-MS [M+H] + =484.

[0410] 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

[0411] MeMgBr (1M 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 addition, the reaction was stirred at room temperature for 2 hours. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with Cl aqueous solution and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The DCM solution of 0-6% MeOH was used and the residue was purified by silica gel chromatography to obtain the desired (S) -2- (6- (1,4-dimethyl -1H-1,2,3- triazole -5- bases) -1- methyl -4- (phenyl (tetrahydro -2H- pyrans -4- bases) 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 (400 MHz, 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).

[0412] Example 7

[0413] (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”)

[0414] (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”)

[0415]

[0416] 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

[0417] In N 2To a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from step 2 of Example 1, 409 mg, 1.32 mmol), (R)-(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (enantiomer a1 in step 1 of Example 2, 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) at room temperature. The resulting solution was stirred at N 2 Reflux for 2 hours. After cooling to room temperature, the reaction mixture was 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 (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, 67%). LC-MS[M+H] + =502.

[0418] 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”)

[0419] In N 2To 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) were 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 heated to 40 ℃ for 1 hr. 2 Backfill, 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 (50mL). 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) -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 (compound 7-2, 201mg, 0.38mmol, 43% yield). LC-MS [M + H] + =519.

[0420] 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

[0421] (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 prepared by 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. 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.

[0422] 1 H NMR (600 MHz, 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 (s, 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).

[0423] Example 8

[0424] 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”)

[0425] 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”)

[0426]

[0427] 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

[0428] 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, 0.05% ethyl acetate) was added. .65mmol) and (3-methylpyridin-2-yl)(tetrahydro-2H-pyran+4-yl)methanol (Intermediate 5, 184mg, 0.89mmol) were converted to 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 (210mg, 0.42mmol, 65%). LC-MS [M+H] + =497.

[0429] 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

[0430] In N 2 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) 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)Cl 2 (112 mg, 0.14 mmol) and K 3 PO 4 (428 mg, 2.02 mmol). The mixture was evacuated and heated to 400 °C with N 2 The resulting mixture was heated to reflux and heated to N 2 The product was stirred for 5 hours at room temperature. 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-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (160 mg, 0.31 mmol, 73% yield). LC-MS[M+H] + =515.

[0431] 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

[0432] 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 prepared by 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. 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).

[0433] Example 9

[0434] 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”)

[0435] 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”)

[0436]

[0437] 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

[0438] 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. 00mg, 0.65mmol) and (tetrahydro-2H-pyran-4-yl)(o-tolyl)methanol (Intermediate 9, 191mg, 0.93mmol) were converted to 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-carboxylic acid methyl ester (280mg, 0.56mmol, 86%). LC-MS [M+H] + =497.

[0439] 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

[0440] In N 2 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) 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)Cl 2 (102 mg, 0.12 mmol) and K 3 PO 4 (389 mg, 1.83 mmol). The mixture was evacuated and heated to 400 °C with N 2 The resulting mixture was heated to reflux and heated to N 2The product was stirred for 5 hours at room temperature. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (100 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 a 0-5% MeOH solution in DCM to give 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-carboxylic acid methyl ester (218 mg, 0.42 mmol, 75% yield). LC-MS[M+H] + =514.

[0441] 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

[0442] 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-(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 (400 MHz, 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).

[0443] Example 10

[0444] 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”)

[0445] 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")

[0446]

[0447] 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

[0448] 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, 20 in Example 1) was added. 0 mg, 0.65 mmol) and 4,4,4-trifluoro-1-(oxazol-4-yl)butan-1-ol (Intermediate 10, 280 mg, 1v43 mmol) were converted to 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-carboxylic acid methyl ester (277 mg, 0.57 mmol, 87%). LC-MS [M+H] + =486.

[0449] 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

[0450] 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-carboxylic acid methyl ester (277) was prepared by a procedure analogous 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. mg, 0.57 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (485 mg, 1.26 mmol) were converted to 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-carboxylic acid methyl ester (211 mg, 0.42 mmol, 73% yield). LC-MS [M+H] + =442.

[0451] 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

[0452] 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 prepared by 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. 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 H NMR (400 MHz, 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).

[0453] Embodiment 11

[0454] 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”)

[0455] 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”)

[0456]

[0457] 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

[0458] 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 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.

[0459] 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

[0460] 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-carboxylic acid methyl ester (257) was prepared by following a procedure analogous 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. 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (788 mg, 2.04 mmol) was converted to 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-carboxylic acid methyl ester (200 mg, 0.38 mmol, 76%) yield). LC-MS [M+H] + =527.

[0461] 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

[0462] 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 prepared by 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. 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 (400 MHz, 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).

[0463] Example 12

[0464] 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”)

[0465] 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”)

[0466]

[0467] Step 1: (2-methyloxazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol

[0468] At ambient temperature, 4-bromooxane (2.24g, 13.6mmol) was added dropwise to a stirred suspension of magnesium (683mg, 29.1mmol) and crystallized iodine in THF (25mL). The reaction mixture was stirred for 1 hour and then cooled in an ice-water bath. 2-methyloxazole-4-carboxaldehyde (1.00g, 9.00mmol) was added dropwise. The reaction mixture was then stirred overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (40mL) and diluted with ethyl acetate (100mL). The product was extracted into the organic phase and then separated into layers. The water layer was extracted with a second portion of ethyl acetate (50mL), and the combined organic phases were dried over sodium sulfate. Volatiles were removed under reduced pressure. The crude reaction was 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.

[0469] 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

[0470] In N2 , DIAD (289 mg, 1.43 mmol) was added to a solution of 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (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) 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.

[0471] 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

[0472] 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 with 5% MeOH in DCM to give 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, 27% yield). LC-MS: [M+H] + =505.

[0473] 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

[0474] 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, 0v17 mmol) was converted into 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).

[0475] Embodiment 13

[0476] (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”)

[0477] (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”)

[0478]

[0479] Step 1: Methyl 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0480] 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 was added NaH (8.20 g, 342 mmol) at room temperature. 2 The reaction mixture was cooled to 0°C in an ice-water bath and then stirred under N 2 SEMCl (29.1 g, 175 mmol) was added dropwise under a 3% CO atmosphere. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours. 4 The reaction was quenched with aqueous Cl solution 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 give methyl 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (29.3 g, 114 mmol, 71.7% yield). LC / MS [M+H] + =257.

[0481] Step 2: [5-Methoxycarbonyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid

[0482] To a solution of methyl 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (29.10 g, 113.51 mmol) in THF (10 mL) in a three-necked round-bottom flask at room temperature were added Dtbpy (113.51 mmol) and di(1,5-cyclooctadiene)-(methoxy)iridium(I)dimer (2.71 g, 4.07 mmol). The mixture was evacuated and heated to 40 ℃ for 1 h. 2 The mixture was backfilled 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, and 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 directly in the next step without further purification. LC / MS [M+H] + =301.

[0483] Step 3: Methyl 5-(5-bromo-3-nitro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0484] In N 2 In a three-necked flask, [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)Cl 2 (4.63 g, 6.24 mmol), K 3 PO 4 (57.5 g, 216 mmol) and THF (400 mL). The mixture was washed with N 2 Purge with air flow for 3 minutes, connect the condenser, and then 2The mixture was heated to 38°C under an atmosphere and stirred for 3 hours. The reaction mixture was cooled to room temperature, poured into water (300 mL) and extracted with EtOAc (3×200 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 hexane to give 5-(5-bromo-3-nitro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid methyl ester (17.5 g, 30.6% yield). LC / MS[M+H] + =458.

[0485] Step 4: Methyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate

[0486] In N 2 Under 40 ℃, 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. 2 Purge with air flow for 3 minutes, connect the condenser, and then 2 The mixture was heated to 140°C under an atmosphere and stirred for 2 hours. The reaction mixture was cooled to room temperature, 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 residue was purified by silica gel chromatography eluting with 0-10% EtOAc in hexane to give 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (3.40 g, 24.3% yield). LC / MS[M+H] + =426.

[0487] 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

[0488] In N 2 Under 40 ℃, 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (2.01 g, 4.73 mmol), (R)-(3-fluoro-2-pyridyl)-tetrahydropyran-4-yl-methanol (enantiomer a1, 1.40 g, 6.63 mmol), 2-(diphenylphosphinyl)pyridine (3.47 g, 13.19 mmol) and THF (30 mL) were added to a three-necked round-bottom flask. The mixture was heated with N 2 The air flow was purged for 3 minutes, and then N 2 DTAD (3.04 g, 13.19 mmol) was added dropwise under 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 residue was purified by silica gel chromatography eluting with 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-carboxylic acid methyl ester (3.02 g, 74% yield). LC / MS[M+H] + =619.

[0489] Step 6: (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 ((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)

[0490] In N 2 Under 40 ℃, 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 washed with N 2 Purge with air flow for 3 minutes, connect the condenser, and then 2 The mixture was heated to 110°C under an 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 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.

[0491] 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

[0492] 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 HCl (12N) and 0.8 mL 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 5% MeOH in DCM as a developing solvent 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)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (62 mg, 80% yield). LC / MS [M+H] + =505.

[0493] 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

[0494] 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 heated to 40° C. under N 2 1 mL of Et 2 O (3M) in MeMgBr. The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour. 4 The reaction was quenched with aqueous Cl solution. The reaction mixture was concentrated under reduced pressure. The 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.

[0495] 1H 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).

[0496] Embodiment 14

[0497] (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”)

[0498] (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”)

[0499]

[0500] 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)

[0501] In N 2 To a three-necked round-bottom flask were 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 washed with N 2 Purge with air flow for 3 minutes, connect the condenser, and then 2 The mixture was heated to 110°C under an 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 eluting with 0-75% EtOAc in hexane was purified by silica gel chromatography to give (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.

[0502] 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

[0503] 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 HCl (12 N) and 7 mL 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 5% MeOH in DCM as the developing solvent to give (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)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (450 mg, 75% yield). LC-MS [M+H] + =508.

[0504] 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

[0505] 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 Cs 2 CO 3 (1.16 g, 3.56 mmol), then in N 2 Add CD under atmosphere 3 I (215mg, 1.48mmol). The reaction mixture was then slowly warmed to 60°C and continued to stir for 2 hours. The reaction was quenched with 10mL HCl (1N) and extracted with EtOAc (10mL). 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 a 10% MeOH solution in DCM as a developing solvent to give (S) -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- carboxylic acid methyl ester (150mg, 24% yield). LC / MS [M+H] + =525.

[0506] 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 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)

[0507] 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 heated under N 2 1.5 mL of MeMgBr (3 M in THF, 4.5 mmol) was added dropwise under a 4% CO atmosphere. The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour. 4 The reaction was quenched with aqueous Cl solution. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase flash chromatography to give (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).

[0508] Embodiment 15

[0509] 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”)

[0510] 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”)

[0511]

[0512] 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

[0513] At room temperature and N 2 DIAD (600 mg, 2.97 mmol) was added to a solution of 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (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) under reduced pressure. The reaction system 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.

[0514] 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

[0515] Following a procedure analogous to that described in synthetic step 4 of Example 6, 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-carboxylic acid methyl ester (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 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 methyl ester (1.29 g, 2.59 mmol, 64% yield). LC-MS [M+H] + =500.

[0516] 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

[0517] 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 H 2 O (2 mL) was added with LiOH (74 mg, 3.09 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was poured into water (10 mL) and washed with saturated NaHCO 3The aqueous solution was adjusted to pH=7 and extracted with EtOAc (2×50 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.

[0518] 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

[0519] 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 SOCl 2 (2 mL). The reaction mixture was stirred at ambient temperature for 4 hours. The mixture 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-carbonyl chloride (163 mg, crude).

[0520] 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

[0521] 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 then 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)-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, three-step yield 29%). LC-MS [M+H] + =513.

[0522] 1 H NMR (400 MHz, 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).

[0523] Example 16

[0524] 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”)

[0525] 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”)

[0526]

[0527] 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

[0528] 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;

[0529] 1 HNMR (400 MHz, 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 = 10.8Hzz, 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).

[0530] Embodiment 17

[0531] 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”)

[0532] 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 (“Compound17”)

[0533]

[0534] 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

[0535] 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 give 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.

[0536] 1 HNMR (400 MHz, 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).

[0537] Embodiment 18

[0538] 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”)

[0539] 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”)

[0540]

[0541] 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

[0542] Following a procedure similar to that described in Synthesis Step 5 of Example 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-carboxylic acid methyl ester (from Example 15, Step 2, 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.

[0543] 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

[0544] At 0°C and N 2To 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 3 (62 mg, 0.54 mmol). The mixture was stirred at 0°C for 10 minutes and BF 3 .OET 2 (118 mg, 0.83 mmol). The mixture was stirred at ambient temperature for 2 days. The mixture was added to saturated NaHCO 3 The combined organic layers were washed with Na 2 SO 4 Drying and concentration under rotary vacuum gave 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).

[0545] 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

[0546] 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 and backfilled with H 2and 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, two-step yield 21%). LC-MS [M+H] + =499.

[0547] 1 HNMR (400 MHz, 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).

[0548] Embodiment 19

[0549] 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”)

[0550] 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”)

[0551]

[0552] 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 washed with Na 2 SO 4 Dry and concentrate 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.

[0553] 1 HNMR (400 MHz, 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).

[0554] Embodiment 20

[0555] (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”)

[0556] (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”)

[0557]

[0558] 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 H 2 O (10 mL) solution was added with LiOH (28 mg, 1.17 mmol). The resulting mixture was stirred at 25 °C for 1 hour. 3 The pH of the reaction mixture was adjusted to 1 by COOH 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.

[0559] 1 H NMR (400 MHz, 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).

[0560] Embodiment 21

[0561] 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”)

[0562] 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”)

[0563]

[0564] In N 2 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). The mixture was evacuated and heated with N2 Backfill, 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 (100mL). 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-carboxamide (Compound 21, 10 mg, 0.020 mmol, 10% yield). LC-MS [M+H] + =504.

[0565] 1 H NMR (400 MHz, 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).

[0566] Embodiment 22

[0567] 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”)

[0568] 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")

[0569]

[0570] 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

[0571] At room temperature, N 2 To a solution of 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (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). 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.

[0572] 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

[0573] According to the 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 H-1,2,3-triazole (274 mg, 0.71 mmol) was converted to 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 (80 mg, 47.00% yield). LC / MS [M+H] + =514.

[0574] 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

[0575] 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]pyridin-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.

[0576] Embodiment 23

[0577] 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”)

[0578] 2-(4-((3-Fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H -1,2,3-triaxol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propan-2-ol(“Compound twenty three")

[0579]

[0580] 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

[0581] In N 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 (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). The mixture was evacuated and heated to 40 ℃ with N 2 Backfill, 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 (100mL). 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)-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 (132mg, 0.25mmol, 63% yield). LC-MS[M+H] + =522.

[0582] 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)

[0583] 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 added. ) 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.

[0584] 1 H NMR (400 MHz, 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).

[0585] Embodiment 24

[0586] 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”)

[0587] 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")

[0588]

[0589] 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

[0590] 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 Step 2 of Example 1, 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.

[0591] 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

[0592] 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 (500 mg, 0.52 mmol) were added to a molten-dryl-hydrogen sulfoxide (1% ethanol, 0.2% sodium hydroxide) (2% sodium hydroxide, 0.2% sodium hydroxide) (1 ... , 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.

[0593] 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

[0594] 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 added. ) 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.

[0595] 1 H NMR (400 MHz, 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).

[0596] Embodiment 25

[0597] 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”)

[0598] 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”)

[0599]

[0600] 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

[0601] At room temperature, N 2 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). 2 Under 30-50% EtOAc in hexane solution, the residue was purified by silica gel chromatography to give 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 (200 mg, 0.39 mmol, 85% yield). LC-MS[M+H] + =514.

[0602] 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

[0603] According to the procedure similar to that described in the 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-triazine were reacted with 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazine. The oxazole (318 mg, 0.82 mmol) was converted to 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-carboxylic acid methyl ester (109 mg, 0.21 mmol, 64% yield). LC-MS [M+H] + =531.

[0604] 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

[0605] According to the method similar to that described in the synthesis step 3 of Example 3, 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-carboxylic acid methyl ester (109 mg, 0.21 mmol) was added to the mixture. l) 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.

[0606] 1 H NMR (400 MHz, 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).

[0607] Embodiment 26

[0608] 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”)

[0609] 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”)

[0610]

[0611] 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

[0612] At 25°C, N 2 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). After addition, the reaction was heated to 40° C. for 2 hours. Then, the mixture was heated to 40° C. for 2 hours. 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-pyran-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.

[0613] 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

[0614] According to the procedure similar to that described in the synthetic 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.

[0615] 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

[0616] According to the method similar to that described in the 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 3mmol) was converted into 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]pyrro[3,2-b]pyridin-3-yl)propan-2-ol (Compound 26, 56 mg, 47% yield). LC-MS: [M+H] + =531.

[0617] 1 H NMR (400 MHz, 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).

[0618] Embodiment 27

[0619] 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”)

[0620] 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”)

[0621]

[0622] 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

[0623] 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 Step 2 of Example 1, 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.

[0624] 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

[0625] 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. 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-carboxylic acid methyl ester (100 mg, 34% yield). LC-MS [M+H] + =476.

[0626] 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

[0627] 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)+4-(1-(4-fluoro-2,6-dimethylphenyl)ethyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (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.

[0628] 1 HNMR (400 MHz, 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).

[0629] Embodiment 28

[0630] (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”)

[0631] (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”)

[0632]

[0633] 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

[0634] 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 layer was washed with saturated brine (50 mL) and washed with Na2SO 4 Dry and concentrate on a rotary vacuum evaporator. The residue was purified by silica gel column chromatography with DCM / MeOH (0%-5%) to give (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.

[0635] 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

[0636] 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 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with Na 2 SO 4 Dry and concentrate 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.

[0637] 1 HNMR (400 MHz, 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).

[0638] Embodiment 29

[0639] (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”)

[0640] (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”)

[0641]

[0642] 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 a solution of 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 washed with Na 2 SO 4The residue was added to methanol (2 mL) and K 2 CO 3 (97 mg) and stirred at ambient temperature for 16 hours. 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 give (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.

[0643] Embodiment 30

[0644] (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”)

[0645] (R)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fiuoropyridin-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”)

[0646]

[0647] 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

[0648] In N 2 , diisopropyl azodicarboxylate (297 mg, 1.47 mmol) was added to a solution of methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (from Step 2 of Example 1, 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), triphenylphosphine (381 mg, 1.45 mol) in anhydrous THF (20 mL) at room temperature. The resulting solution was stirred at N 2 The mixture was refluxed for 2 hours, cooled to room temperature, and the reaction mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The residue was purified by silica gel chromatography using 30-50% EtOAc in hexane to give (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 (287 mg, 0.57 mmol, 83%). LC-MS [M+H] + =502.

[0649] 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

[0650] 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-carboxylic acid methyl ester (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 heated to 40 ℃ for 1 hr. 2 Backfill, 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 (30mL). 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 solution 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-carboxylic acid methyl ester (126mg, 0.24mmol, 45%). LC-MS[M+H] + =519.

[0651] 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

[0652] Referring to the procedure described in 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. [3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (118 mg, 0.23 mmol) was used to synthesize (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). LC-MS [M+H] + =519.

[0653] 1 H NMR (400 MHz, 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).

[0654] Embodiment 31

[0655] (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”)

[0656] (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”)

[0657]

[0658] 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

[0659] Following the same procedure as in Step 2 of Example 2, methyl 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylate (obtained from Step 2 of Example 1, 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 methyl (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 (298 mg, 95% yield). LC-MS [M+H] + =502.

[0660] 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

[0661] 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- The resulting mixture was converted into (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).

[0662] LC-MS [M+H] + =519.

[0663] 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

[0664] According to 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 into (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 (400 MHz, 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).

[0665] Embodiment 32

[0666] 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”)

[0667] 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”)

[0668]

[0669] 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

[0670] At room temperature, N 2 To a solution of 6-bromo-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxylic acid methyl ester (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). The reaction system 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.

[0671] 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

[0672] 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 NaBH 4 (540 mg, 14.27 mmol) and CaCl 2 (374 mg, 3.36 mmol). The reaction system 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.

[0673] 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

[0674] Phosphorus tribromide (600 mg, 2.97 mmol) was added 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) at room temperature. The reaction system was stirred for 1 hour. The reaction mixture was poured into NaHCO 3 (aqueous solution) and extracted with DCM (400 mL). The 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.

[0675] 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

[0676] 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 K 2 CO 3 (140 mg, 1.01 mmol) was mixed in DMF (10 mL). The reaction system was stirred for 2 hours. The reaction system 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-methylpiperazine-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.

[0677] 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

[0678] In N 2 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). The mixture was washed with N 2 Purge for 2 minutes and stir 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 hexane to give 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-3-((4-methylpiperazine-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.

[0679] Embodiment 33

[0680] 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”)

[0681] 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”)

[0682]

[0683] Step 1: 6-bromo-1-methyl-3-((methylsuffonyl)methyl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine

[0684] At 60°C, 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 (Sodium methanesulphinate, 100 mg, 0.98 mmol) were stirred in a DMF (10 mL) solution. 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.

[0685] 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

[0686] In N 2 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). The mixture was washed with N 2Purge for 2 minutes and stir 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, eluted with 20-60% EtOAc in hexane 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.

[0687] 1 H NMR (400 MHz, 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).

[0688] Embodiment 34

[0689] 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”)

[0690] 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”)

[0691]

[0692] 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

[0693] 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 were stirred at room temperature. 2 CO 3 (300 mg, 2.17 mmol) was mixed in DMF (10 mL). The reaction system was stirred for 2 hours. The reaction system was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 2-10% MeOH in DCM to give 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.

[0694] 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

[0695] In N 2 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), PdCl 2 (PPh 3 ) 2 (30 mg, 0.043 mmol) and DIEA (100 mg, 0.77 mmol). The mixture was washed with N 2 Purge for 2 minutes and stir at 110 ° C for 20 hours. The reaction mixture was cooled to room temperature. Pour into water and extract 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, eluted with 20-60% EtOAc in hexane 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.

[0696] 1 H NMR (400 MHz, 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).

[0697] Embodiment 35

[0698] 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”)

[0699] 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”)

[0700]

[0701] 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

[0702] 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 step 2 of Example 28) 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.

[0703] 1 HNMR (400 MHz, 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).

[0704] Pharmacological tests

[0705] 1. BRD4 (BD1) affinity test

[0706] The BRD4 (BD1) biochemical binding assay was performed by Sundia MediTech Co. Ltd using HTRF technology in 384-well white plates (OptiPlate-384, PerkinElmer).

[0707] In short, through 550 liquid handler (Labcyte, USA) transferred 20nL of compound to 384-well plate, and then 5μL 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, 5μL of biotinylated H4-derived acetylated peptide (synthesized by GL Biochem (Shanghai) Ltd) and 10μL of detection solution (Cisbio Assay) were added to each well. After incubation at room temperature for 1 hour, HTRF signals were measured at 615nm and 665nm using EnVision Multilabel PlateReader (PerkinElmer, USA). The results were analyzed using dual-wavelength signal ratio: intensity (665nm) / intensity (615nm). The inhibition rate of the compound was calculated according to the following formula: inhibition rate = (Max-Signal) / (Max-Min)×100%. IC was fitted using the data in GrphaPad Prism V5.0 software (San Diego, CA). 50 Values ​​were analyzed by nonlinear regression using the equation, Y = bottom + (top - bottom) / (1 + 10^((LogIC 50 -X)×slope), where Y represents the inhibition rate and X represents the concentration of the compound.

[0708] result:

[0709] The results of the BRD4 (BD1) affinity test are shown in Table 3 below:

[0710] Table 3. Results of BRD4 (BD1) affinity assay

[0711]

[0712]

[0713] It can be seen from Table 3 that the compounds of the present invention have a very strong affinity with BRD4 (BD1).

[0714] 2. Cell Proliferation Test

[0715] MTS assay protocol:

[0716] 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-tetrazolyl, inner salt) method. Briefly, the cells were cultured at 37°C and 5% CO 2 MV-4-11 cells were cultured in IMDM (Iscove's Modified Dubecco's Medium) with 10% (v / v) FBS (fetal bovine serum) at 4 °C and 95% humidity. Cells were collected during the logarithmic growth phase and counted using a hemocytometer. Cell viability was determined by trypan blue exclusion, and the cell survival rate was over 90%. The MV-4-11 cell concentration was adjusted to 1.2×10 5 Add 100 μL of cell suspension to a 96-well plate (three replicate wells for each concentration), and the final cell density is 1.2×10 4 cells / well. The next day, the test compound was dissolved in DMSO as a stock solution. 5 μL of the stock solution was added to 1 mL of culture medium, and 25 μL of drug culture medium was added to a 96-well plate. After serial dilution with culture medium, the final concentrations of the compound were 0, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 nM. The drug was incubated for 3 days and then detected by the MTS method. PMS (phenaziniummethosulfate) solution was added to the MTS solution (1:20). Then 20 μL of the MTS / PMS mixed solution was added to each well of the 96-well plate. The 96-well plate was incubated in an incubator for 1-4 hours. A microplate spectrophotometer (Envision R , PeikinElmer) measured the absorbance at 490 nm. GraphPad 5.0 was used to fit the data and obtain IC 50 value.

[0717] result:

[0718] The results of the cell proliferation activity test are shown in Table 4 below:

[0719] Table 4. Results of cell proliferation activity test

[0720]

[0721] It can be seen from Table 4 that the compounds of the present invention have excellent inhibitory effects on leukemia cells MV-4-11.

[0722] In addition, the compounds of the present invention also have very good inhibitory effects on a variety of cancer cells such as lung cancer cells, other leukemia cancer cells, myeloma cells, esophageal cancer cells and ovarian cancer cells. Among them, lung cancer cells include but are not limited to NCI-H526, NCI-H146, NCI-H820, DMS53, NCI-H446 and other lung cancer cells; leukemia cells include but are not limited to NB4, JJN-3, Kasumi-1, OCI-AML3, THP-1 and other leukemia cancer cells; myeloma cells include but are not limited to NCI-H929, KMS-11 and other 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, TE-1 and other esophageal cancer cells; ovarian cancer cells include but are not limited to RMG-I, OVCAR-4 and other ovarian cancer cells.

Claims

1. A compound of formula III, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof: Wherein R1 is selected from hydrogen, deuterium or -C 1-6 Alkyl; and the -C 1-6 The alkyl group is optionally unsubstituted or substituted with 1, 2 or 3 substituents, each of which is deuterium; R2 is selected from -COOR 21 or -C 1-6 Alkyl, and the -C 1-6 The alkyl group is substituted with 1 substituent, which is -NH2; R 21 Selected from hydrogen, deuterium or -C 1-6 Alkyl; or R 23 and R 24 is independently selected at each occurrence from hydrogen, deuterium or -C 1-6 alkyl; n is selected from 0; A is Each R3 and R4 at each occurrence is independently selected from hydrogen, deuterium or -C 1-3 Alkyl; and the -C 1-3 Alkyl is optionally unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents independently at each occurrence, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -OH; W1 Selected from -C 1-6 alkyl; 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 W1 is independently optionally substituted or substituted by 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of the substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -C 1-3 Alkyl or -C 1-3 Alkoxy; W2 is selected from phenyl; 5-membered heteroaryl, the 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-membered heteroaryl, the 6-membered heteroaryl 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; and each W2 is independently optionally substituted with 1, 2, 3, 4 or 5 substituents at each occurrence, and each of the substituents is selected from deuterium, halogen, -NH2, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy at each occurrence; Z is selected from hydrogen or deuterium.

2. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein the compound is of formula III-1 or III-2: In formula III-1, "R" means that when the carbon atom connected to W1, W2 and Z is a chiral carbon, the absolute configuration of the chiral carbon is R configuration; In formula III-2, "S" means that when the carbon atom connected to W1, W2 and Z is a chiral carbon, the absolute configuration of the chiral carbon is S configuration.

3. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein R1 is selected from hydrogen, deuterium, -CH3 or -CD3.

4. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein R2 is 5. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein: Each R3 and R4 is independently -C at each occurrence 1-3 Alkyl; and the -C 1-3 Alkyl, 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 or halogen.

6. The compound of formula III according to claim 5, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein each R3 and R4 at each occurrence is selected from -C 1-3 Alkyl, or -C substituted by 1, 2, 3, 4, 5 or 6 deuterium 1-3 alkyl.

7. The compound of formula III according to claim 6, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein each R3 and R4 at each occurrence is selected from methyl, or methyl substituted by deuterium.

8. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein said A is independently selected from:

9. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein: W1 is selected from -C 1-6 Alkyl, or a 6-membered heterocyclic ring containing 1 heteroatom selected from O; W2 is selected from phenyl; 5-membered heteroaryl, the 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; or 6-membered heteroaryl, the 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and each W2 is independently optionally substituted or substituted with 1, 2 or 3 substituents at each occurrence, and each of the substituents is selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy at each occurrence; Z is selected from hydrogen or deuterium.

10. The compound of formula III according to claim 9, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein: W1 is selected from -CH2CH2CF3 or W2 is independently selected from: Z is hydrogen.

11. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein: The Selected from: And each Independently at each occurrence is optionally unsubstituted or substituted with 1, 2 or 3 substituents, and each of said substituents at each occurrence is selected from -F, methyl or methoxy.

12. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein: R1 is -C 1-6 alkyl; R2 is Each R 23 and R 24 -C in each occurrence 1-6 alkyl; The A is Each of R3 and R4, at each occurrence, is selected from -C 1-3 alkyl, or 1, 2, 3, 4, 5 or 6 deuterium-substituted -C 1-3 alkyl; W1 is selected from -F substituted -C 1-6 Alkyl; or a 6-membered heterocyclic ring containing 1 heteroatom selected from O; W2 is selected from phenyl; 5-membered heteroaryl, the 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; or 6-membered heteroaryl, the 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and each W2 is independently optionally substituted or substituted with 1, 2 or 3 substituents at each occurrence, and each of the substituents is selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy at each occurrence; Z is selected from hydrogen or deuterium.

13. The compound of formula III according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, wherein: R1 is selected from methyl; Each R 23 or R 24 is selected at each occurrence from methyl; each R3 and R4 at each occurrence is selected from methyl or methyl substituted with deuterium; W1 is selected from -CH2CH2CF3 or W2 is selected from:

14. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, wherein the compound is:

15. A pharmaceutical composition comprising at least one compound of formula III according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a compound according to claim 14, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and at least one pharmaceutically acceptable excipient.

16. Use of the compound of any one of claims 1 to 13, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, the compound of claim 14, its pharmaceutically acceptable salt, its stereoisomer or its tautomer, or the pharmaceutical composition of claim 15 in the preparation of a medicament, wherein the medicament is used to treat acute myeloid leukemia associated with bromodomain proteins.

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