Compounds and compositions that are bromodomain protein inhibitors

Abstract

The present invention relates to bromodomain inhibitors, and provides compositions and formulations containing such compounds, as well as methods of using and making such compounds.

Description

Technical Field

[0001] The present invention relates to compounds that can inhibit bromodomain proteins or modulate their activity in other ways, compositions and formulations containing such compounds, and methods of using and manufacturing such compounds.

Background Art

[0002] Examples of bromodomain (BRD) proteins that include the BET (bromodomain and extra-terminal domain) family are BRD2, BRD3, BRD4, and BRDT. Proteins of the BET family recognize the epigenetic code, acetylate lysine residues, and couple with histone proteins to alter chromatin structure and gene expression. While BRD2, BRD3, and BRD4 are widely expressed, BRDT is limited to germ cells. BET proteins are necessary for the regulation of gene transcription and the control of cell proliferation, but their roles do not overlap. BET proteins are associated with large protein complexes that regulate the transcription of many genes, such as RNA polymerase II (Pol II) and the positive transcription elongation factor (P-TEFb). The BRD2 and BRD4 proteins have been confirmed to be necessary for maintaining binding to chromosomes during mitosis and promoting the transcription of important genes (cyclin D and c-Myc) that initiate the cell cycle (Mochizuki, J Biol. Chem. 2008 283:9040-9048). The BRD4 protein, in combination with RNA polymerase II (Pol II) and the positive transcription elongation factor (P-TEFb), jointly promotes the transcription and expression of various genes related to cancer cell growth and apoptosis, such as c-Myc, cyclin, and the anti-apoptotic protein Bcl-2, and regulates the growth and proliferation of tumor cells (Jang et al., Mol. Cell 2005 19:523-534). The kinase activity of BRD4 may directly phosphorylate and activate RNA polymerase II (Devaiah et al., PNAS 2012 109:6927-6932). Cells lacking BRD4 show impaired cell cycle progression. It has been reported that BRD2 and BRD3 are associated with active transcription of histones and genes and can participate in promoting transcription elongation (Leroy et al., Mol. Cell. 2008 30:51-60). BET proteins, in addition to acetylated histones, selectively bind to acetylated transcription factors such as the RelA subunit of NF-kB and GATA1, and it has been demonstrated that they control the expression of genes involved in inflammation and hematopoietic differentiation by directly regulating the transcriptional activity of these proteins (Huang et al., Mol. Cell Biol. 2009 29:1375-1387; Lamonica Proc. Nat. Acad. Sci. 2011 108:E159-168).

[0003] BET proteins containing BRD4 have been identified as important mediators that alter gene expression profiles found in many diseases such as cancer, diabetes, obesity, atherosclerosis, cardiovascular diseases, kidney diseases, viral infections, etc. See Muller, S., et al., Expert Rev. Mol. Med., 13:e29 (2011); Zhou, M., et al., J. Virol., 83:1036-1044 (2009); Chung, C. W., et al., J. Med. Chem., 54:3827-3838 (2011). For example, Myc is involved in most human cancers, and BET proteins have been identified as regulators of c-Myc, and it has been shown that Myc transcription is reduced by inhibition of BET proteins (including BRD4).

[0004] Therefore, there is a strong demand for the development of compounds that can be used as bromodomain inhibitors. Specifically, the development of compounds that can be used as BET inhibitors is expected. Although several small-molecule BET inhibitors have been reported to be used in clinical studies, at present, there are no commercially available products. Therefore, in order to provide new options for clinical treatment drugs for BET-mediated diseases or illnesses, it is necessary to develop new small-molecule BET inhibitors.

Summary of the Invention

[0005] The present invention relates to a bromodomain inhibitor, particularly a compound that is a BRD4 inhibitor, and the use of such a compound in the treatment of BET-mediated diseases. The present invention first provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.

[0006]

Chemical Formula

[0007] Q is absent or selected from C 1-6 alkylene, -SO2- or -NH-, and the C 1-6 alkylene or -NH- is optionally substituted with halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0008] X is H, C 1-6 Alkyl, C 6-10 Aryl or C 5-10 Selected from heteroaryls, the C 1-6 Alkyl, C 6-10 Aryl or C 5-10 Heteroaryls can optionally be halogens, halogenated carbon 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkoxycarbonyl or C 1-6 Substituted with alkyl-SO2-;

[0009] Y is [ka] Here, ring A is a 5 or 6-membered ring containing 0, 1, 2, or 3 heteroatoms independently selected from N, O, or S, and ring B is phenyl, or C containing 1, 2, or 3 heteroatoms independently selected from N, O, or S. 5- It is a 6-heteroaryl;

[0010] R3 and R4 are either absent or, independently, H, halogen, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Selected from alkoxy, cyano, oxo, or -N(R5)-SO2-R6;

[0011] R5 and R6 are independently H and C 1-6 C substituted with alkyl or halogen 1-6 Selected from alkyl groups.

[0012] With respect to the compound represented by formula (I), the present invention provides the following preferred embodiments.

[0013] In some embodiments, R1 is H, C 1-4 Alkyl, phenyl, or C 5-6 Selected from heteroaryls, the C 1-4 Alkyl, phenyl, or C 5-6 Heteroaryls can optionally be C 1-6 Alkyl, -NH2, phenyl, or C 5-6 The heteroaryl is substituted, preferably comprising one, two, or three heteroatoms independently selected from nitrogen or sulfur.

[0014] In some specific embodiments, R1 is H, -CH3, [ka] That is the case.

[0015] In some embodiments, R1 is H, -CH3, [ka] That is the case.

[0016] In some embodiments, R2 is H or C 1-3 It is alkyl.

[0017] In some specific embodiments, R2 is H or -CH3.

[0018] In some specific embodiments, Q is absent or -CH2-, [ka] Selected from -NH- or -SO2-.

[0019] In some embodiments, X is H, C 1-3 Selected from alkyl or phenyl, the phenyl is unsubstituted or optionally a halogen, halogenated C 1-3Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkoxycarbonyl or C 1-3 It is substituted with alkyl-SO2-.

[0020] In some embodiments, X is H, C 1-3 Selected from alkyl or phenyl, the phenyl is either unsubstituted or optionally substituted with F, Cl, methyl, trifluoromethyl, methoxy, methylthio, methoxycarbonyl, or methyl-SO2-.

[0021] In some specific embodiments, X is -CH3, H, [ka] That is the case.

[0022] In some embodiments, Y is [ka] Selected from. During the ceremony, [ka] ∫ represents a double or single bond, and U, V, W, G, or Z are each independently selected from C or N. If G is N, R4 does not exist. If G is C, R4 is H or -N(R5)-SO2-R6, where R5 and R6 are independently H and C, respectively. 1-6 C substituted with alkyl or halogen 1-6 Alkyl is selected.

[0023] In some embodiments, Y is [ka] Selected from. During the ceremony, [ka] R3 represents a double or single bond, and U, W, or Z are each independently selected from C or N. R3 is H, halogen, hydroxyl, amino, or C 1-6 Alkyl, C 1-6 Selected from alkoxy, cyano, or oxo. R4 is H, or -N(R5)-SO2-R6, where R5 and R6 are independently H and C, respectively. 1-6 C substituted with alkyl or halogen 1-6 Selected from alkyl groups.

[0024] In some embodiments, R3 is H, C 1-6 Alkyl, C 1-6 It is alkoxy, cyano, or oxo.

[0025] In some embodiments, R3 is H, methyl, or oxo.

[0026] In some embodiments, R4 is -N(R5)-SO2-R6.

[0027] In some embodiments, R5 and R6 are independently H or C 1-6 Selected from alkyl groups.

[0028] In some embodiments, R5 and R6 are independently selected from H, methyl, or ethyl.

[0029] In some specific embodiments, Y is [ka] That is the case.

[0030] Preferably, Y is [ka] In this invention, Y is [ka] In this case, it not only maintains good activity but also possesses excellent PK properties.

[0031] The present invention further provides the following compounds or pharmaceutically acceptable salts thereof. Such compounds are 1) 4-(1-(4-chlorobenzyl)-2-methyl-1Himidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 2) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 3) 6-methyl-4-(2-methyl-1-(4-(methylthio)benzyl)-1H-imidazo[4,5-b]pyridine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 4) 6-methyl-4-(2-methyl-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 5) 4-(1-(3-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 6) 4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 7) 4-(1,2-dimethyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 8) 6-methyl-4-(2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 9) 4-((2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-imidazo[4,5-b]pyridine-1-yl)methyl)benzoate methyl ester; 10) 6-benzyl-4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3- c] Pyridine-7-one; 11) 6-Isobutyl-4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 12) 6-ethyl-4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 13) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-2-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 14) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-(thiazole-2-methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 15) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-(pyrazole-2-methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 16) 4-(1-(3-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-2-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 17) 4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-(pyridine-3-methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 18) 4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyrazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 19) 6-methyl-4-(2-methyl-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyrazine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 20) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 21) 4-(1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-imidazo[4,5-b]pyrazine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 22) 4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 23) 4-(1-(3-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 24) 4-(1-(2-fluoro-5-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 25) 4-(1-(3-fluoro-5-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 26) 4-(1-(2-fluoro-4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 27) 4-(1-(3-trifluoromethyl-4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2, 3-c]pyridine-7(6H)-one; 28) 4-(1-(3-fluoro-4-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 29) 4-(1-(3-chloro-4-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 30) 4-(1-(3-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 31) 4-(1-(2,4-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 32) 4-(1-(4-bromobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazin-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 33) 6-methyl-4-(2-methyl-1-(4-(methylsulfonyl)benzyl)-1H-imidazo[4,5-b]pyrazine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 34) 1-(4-chlorobenzyl)-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-one; 35) 4-(3-(1-(2,6-dichloro-3-fluorophenyl)ethyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 36) 4-(1-(2,6-dichlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 37) 4-(4-((4-chlorophenyl)amino)pyrido[2,3-d]pyrimidine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 38) 4-(1-(2,6-dichlorobenzyl)-2-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 39) 4-(1-(4-chlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 40) 4-(1-((4-chlorophenyl)sulfuryl)-1H-pyrrolo[2,3-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 41) N-(1-(4-chlorobenzyl-2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 42) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 43) N-(1-(4-methoxybenzyl-2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 44) N-(1-(1-(4-chlorophenyl)ethyl)-2-methyl-6-(6-methyl Tyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 45) N-(1-benzyl-2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 46) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 47) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 48) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 49) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2-fluoro-4-chlorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 50) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-(trifluoromethyl)-4-chlorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 51) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-fluoro-4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 52) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-chloro-4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 53) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 54) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2,4-difluorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 55) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(4-bromobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 56) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(4-(methylsulfonyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 57) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2-chloro-4-fluorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 58) N-(5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 59) N-(3-(2,4-difluoromethylbenzyl)-5-(6-methyl-7-o Xy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 60) N-(3-(1-(4-chlorophenyl)ethyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 61) N-(3-(2-fluoro-5-(trifluoromethyl)benzyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 62) N-(3-(3,5-difluorobenzyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 63) N-(5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(2-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 64) N-(3-(2,4-difluorobenzyl)-2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 65) N-(2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 66) N-(2-methyl-5-(6-methyl-7oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(2-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 67) N-(3-(3,5-difluorobenzyl)-2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; or 68) It is N-(3-(2,6-dimethylbenzyl)-2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide.

[0032] The present invention further provides crystalline form I of 6-methyl-4-(2-methyl-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyrazine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one (compound 19).

[0033] [ka] In some embodiments, the crystal form I has characteristic peaks in the powder X-ray diffraction spectrum with diffraction angles 2θ of 13.8±0.2°, 18.9±0.2°, and 26.0±0.2°.

[0034] In some embodiments, the crystal form I has characteristic peaks in the powder X-ray diffraction spectrum with diffraction angles 2θ of 6.2±0.2°, 13.8±0.2°, 18.9±0.2°, 19.5±0.2°, 26.0±0.2°, and 26.8±0.2°.

[0035] In some embodiments, the crystal form I has the powder X-ray diffraction spectrum shown in Figure 1.

[0036] The present invention summarizes the characteristic peaks in the powder X-ray diffraction spectrum of the aforementioned crystal form I, as shown in Table 1.

[0037] [Table 1]

[0038] In some embodiments, the crystal form I in the present invention can be identified by differential scanning calorimetry. In some embodiments, crystal form I has the differential scanning calorimetry curve shown in Figure 2. In the DSC curve, the endothermic peak of crystal form I is at approximately 288.9°C. The differential scanning calorimetry measurement is performed using TA instruments Q200 DSC (purge gas: nitrogen gas, flow rate: 40 mL / min, heating rate: 10°C / min).

[0039] In some embodiments, the crystal form I in the present invention is 1 It can be identified using 1H NMR. 1 The HNMR data is as follows: 1 HNMR(400MHz,DMSO)δ12.17(s,1H),8.94(s,1H),8.05(s,1H),7.75(d,J=8.0Hz,2H),7 .50(d,J=8.0Hz,2H),7.30(m,1H),6.77(m,1H),5.70(s,2H),3.65(s,3H),2.65(s,3H).

[0040] Preferably, the crystal form I has a purity of ≥ 85%.

[0041] Preferably, the crystal form I has a purity of ≥95%.

[0042] Preferably, the crystal form I has a purity of ≥99%.

[0043] Preferably, the crystal form I has a purity of ≥ 99.5%.

[0044] Preferably, the crystal form I is an anhydrous form.

[0045] Crystal form I provided by the present invention has good crystallinity, is non-hygroscopic, has good stability, and has acceptable oral bioavailability.

[0046] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above compounds and a pharmaceutically acceptable excipient, such as hydroxypropyl methylcellulose. In some pharmaceutical compositions, the weight ratio of the compound to the excipient is approximately 0.001 to 10.

[0047] The present invention further provides a method for treating a subject suffering from a disease or disorder of inhibitory response to a bromodomain-containing protein, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the bromodomain-containing protein is BRD4.

[0048] In some embodiments, the disease or disorder is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular disorders, renal disorders, viral infections, and obesity. In some embodiments, the disease or disorder is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes mellitus (including type 1 diabetes mellitus), and acute rejection during organ transplantation. In some embodiments, the disease or disorder is cancer, including hematological malignancies, lymphomas, multiple myeloma, leukemia, warts, cancer, or tumors (e.g., solid tumors). In some embodiments, the disease or disorder is a tumor or cancer of the colon, rectum, prostate (e.g., castrate-resistant prostate cancer), lung cancer (e.g., non-small cell lung cancer and / or small cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovaries, breast (e.g., basal or basal-like breast cancer and / or triple-negative breast cancer), skin (e.g., melanoma), or nervous system (including the brain, meninges, and central nervous system; neuroblastoma, glioblastoma, meningioma, and medulloblastoma). In some embodiments, the disease or disorder is a carcinoma. In certain embodiments, the disease or disorder is hepatocellular carcinoma. In some embodiments, the disease or disorder is lymphoma. In certain embodiments, the disease or disorder is B-cell lymphoma. In some embodiments, The disease or disorder is Burkitt lymphoma. In some embodiments, the disease or disorder is diffuse large B-cell lymphoma. In some embodiments, the disease or disorder is multiple myeloma. In some embodiments, the disease or disorder is chronic lymphocytic leukemia. In some embodiments, the disease or disorder is midline cardinoma (NUT). In some embodiments, the test subject is human.

[0049] In one embodiment, the compound is administered intravenously, intramuscularly, extraintestinally, nasally, or orally. In another embodiment, the compound is administered orally.

[0050] The present invention further provides a method for inhibiting a bromodomain protein, comprising contacting the bromodomain protein with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0051] The present invention further provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of pharmaceuticals for treating diseases or disorders of inhibitory response to bromodomain proteins.

[0052] The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapeutic purposes. Furthermore, it provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of subjects suffering from a disease or disorder of inhibitory response to a bromodomain-containing protein. Furthermore, it provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the above therapeutic method.

[0053] In this invention, unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups refer to fluorine, chlorine, and bromine.

[0054] In the present invention, unless otherwise specified, the term "alkyl" includes linear, branched, or cyclic saturated monovalent hydrocarbon groups. For example, alkyls 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 of alkyl 1-6 " is a linear or branched arrangement of 1, 2, 3, 4, 5, or 6 carbon atoms It refers to a group that contains an atom.

[0055] An alkoxy group refers to an oxyether formed from the linear, branched, or cyclic alkyl groups described above.

[0056] In the present invention, unless otherwise specified, the term "heteroaryl" refers to a stable monocyclic or bicyclic group, substituted or unsubstituted, having 5 to 10 ring atoms and including at least one aromatic ring, wherein the aromatic ring contains 1, 2, or 3 ring heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon atoms. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, and benzimidazole.

[0057] In the present invention, the term "composition" is intended to include products containing a specific amount of a specific component, and also includes any products obtained directly or indirectly from a specific amount of a specific component. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing said compounds are also included in the scope of the present invention. Furthermore, some compounds may exist in polymorphic crystalline forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.

[0058] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Typically, a prodrug refers to a functional derivative that can be readily converted in vivo to a desired compound. Therefore, the term “administration” in the therapeutic methods provided by the present invention includes administering the compounds disclosed in the present invention, or, although not explicitly disclosed, treating the respective diseases by conversion to the compounds disclosed in the present invention in vivo after administration to a test subject. Conventional methods for selecting and preparing appropriate prodrug derivatives are, for example, “Design of Prodrugs” (ed. H. Bundgaard). This is described in books such as (rd, Elsevier, 1985).

[0059] Clearly, the definition of any substituent or variable at a particular position within a molecule is independent of its position within the molecule. As will be readily apparent to those skilled in the art, substituents or substitutional forms of the compounds of the present invention can be selected by means of the prior art and by the methods of the present invention so as to provide chemically stable and readily synthesizable compounds.

[0060] The compounds of the present invention may contain one or more chiral centers, thereby allowing for the presence of diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure isolated enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0061] Formula (I) above does not specifically limit the stereostructure at any particular position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In synthetic processes for preparing such compounds, or processes employing racemization or epimerization methods known to those skilled in the art, the resulting product may be a mixture of stereoisomers.

[0062] Where tautomers of the compound represented by formula (I) exist, unless otherwise specified, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, as well as mixtures thereof.

[0063] The compound represented by formula (I) and its pharmaceutically acceptable salts are in solvate or polymorphic form. When in this state, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, similar solvents such as water, ethanol, propanol, and acetone can be used.

[0064] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid. If the compound provided by the present invention is an acid, its corresponding salt can be readily prepared from a pharmaceutically acceptable, non-toxic base (including inorganic and organic bases). Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valencies), ferric, ferrous, lithium, magnesium, manganese (high and low valencies), potassium, sodium, and zinc. Among these, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred. Non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary amines, secondary amines, and tertiary amines, and further include substituent-containing amines such as cyclic amines and naturally occurring substituent-containing amines and substituent-containing amines synthesized from them. Other pharmaceutically acceptable and non-toxic organic bases that can be derivatized into salts include ion exchange resins, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haramine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and ammonia butanetriol.

[0065] When the compound provided by the present invention is a base, the corresponding salt can be readily prepared from pharmaceutically acceptable, non-toxic acids (including inorganic and organic acids). Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharic acid, trifluoroacetic acid, tartaric acid, p-toluenesulfonic acid, and the like. Citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid are preferred. Formic acid and hydrochloric acid are more preferred. Since the compound represented by formula (I) is used as a pharmaceutical, it is preferable to use it in a substantially pure form, for example, with a purity of 60% or more, preferably 75% or more, and particularly preferably 98% or more (percentages are by weight).

[0066] The pharmaceutical compositions provided by the present invention comprise a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient, and any other therapeutic ingredient or excipient. In any particular case, the most appropriate method of administration of the active ingredient depends on the specific target to which it is administered, the nature of the target, and the severity of the disease, but the pharmaceutical compositions of the present invention include those suitable for oral administration, rectal administration, topical administration, and extraintestinal administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical compositions of the present invention exist as unit dosage forms known in the art and can be readily prepared by any preparation method known in the pharmaceutical field.

[0067] As described herein, new crystal forms can be identified by powder X-ray diffraction spectroscopy. However, those skilled in the art know that the peak intensity and / or peak state of powder X-ray diffraction may differ depending on experimental conditions such as diffraction test conditions and / or orientation priority. Furthermore, because the accuracy varies depending on the instrument, the 2θ measurement may differ. An error of approximately ±0.2° is present. However, because the relative intensity of the peaks depends more on the characteristics of the sample being measured, such as the size of the crystals in the sample, the crystal orientation, and the purity of the material being analyzed, than on the position of the peaks, a peak intensity deviation of approximately ±20% or more may be observed. Nevertheless, despite experimental errors, instrument errors, and orientation priority, those skilled in the art can obtain sufficient information from the XRD data provided herein to identify the crystal form.

[0068] In fact, according to conventional drug mixing techniques, the compound, prodrug, metabolite, or pharmaceutically acceptable salt represented by formula (I) of the present invention can be mixed with a drug carrier as an active ingredient to form a pharmaceutical composition. The pharmaceutical carrier can take various forms depending on the desired method of administration, e.g., orally or by injection (including intravenous injection). Thus, the pharmaceutical composition of the present invention can take the form of separate units suitable for oral administration, such as capsules, cachets, or tablets containing a predetermined amount of the active ingredient. Furthermore, the pharmaceutical composition of the present invention can take the form of a powder, granules, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be administered by controlled-release methods and / or delivery devices, in addition to the conventional dosage forms described above. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Such methods generally involve the step of binding the active ingredient to a carrier constituting one or more required components. The pharmaceutical composition is generally prepared by uniformly and tightly mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or a mixture of both. Furthermore, this product can be easily adjusted to the desired appearance.

[0069] Accordingly, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of the present invention also comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and one or more other compounds having therapeutic activity.

[0070] The pharmaceutical carrier used in the present invention may be, for example, a solid carrier, a liquid carrier, or a gaseous carrier. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing oral pharmaceutical formulations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, and colorants can be used in oral liquid formulations such as suspensions, elixirs, and solutions. Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants can be used in oral solid formulations such as powders, capsules, and tablets. For ease of administration, tablets and capsules using solid pharmaceutical carriers are preferred as oral formulations. Optionally, tablet coating can be performed using standard aqueous or non-aqueous formulation techniques.

[0071] Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compression or molding, optionally with one or more auxiliary components or excipients. Compressed tablets can be prepared by mixing the active ingredient, in a free-flowing form such as powder or granules, with a binder, lubricant, inert diluent, surfactant, or dispersant, and compressing it in a suitable machine. Molded tablets can be produced by impregnating the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding it in a suitable machine. Preferably, each tablet contains about 0.05 mg to 5 g of the active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of the active ingredient. For example, dosage forms used for oral administration to humans contain about 0.5 mg to about 5 g of the active ingredient, compounded with appropriately and conveniently measurable auxiliary substances accounting for about 5% to 95% of the total amount of the pharmaceutical composition. The unit dosage form generally contains about 1 mg to about 2 g, typically 25 mg. It contains 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg of the active ingredient.

[0072] The pharmaceutical composition suitable for extraintestinal administration provided by the present invention can be prepared by adding the active ingredient to water to form an aqueous solution or suspension. It may also contain a suitable surfactant such as hydroxypropylcellulose. A mixture of glycerin, liquid polyethylene glycol, and oil can also be provided as a dispersion. Furthermore, to prevent the growth of harmful microorganisms, the pharmaceutical composition of the present invention may contain a preservative.

[0073] The present invention provides a pharmaceutical composition suitable for injection, comprising a sterile aqueous solution or dispersion. Furthermore, the pharmaceutical composition may be prepared in the form of a sterile powder that can be used for the immediate preparation of a sterile injection solution or dispersion. In either case, the final injection must be sterile and flowable for easy injection. Furthermore, the pharmaceutical composition must be stable during preparation and storage. Therefore, storage that can protect against contamination by microorganisms such as bacteria and fungi is preferred. The carrier may be a solvent or dispersion medium, such as water, ethanol, polyols (glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, and suitable mixtures thereof.

[0074] The pharmaceutical compositions provided by the present invention may be in a form suitable for topical administration, such as an aerosol, emulsion, ointment, lotion, dusting, or other similar dosage form. Furthermore, the pharmaceutical compositions provided by the present invention may be in a form suitable for use in transdermal drug delivery devices. These can be manufactured by conventional processing methods using the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof. For example, the preparation of an emulsion or ointment involves adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above compound to prepare an emulsion or ointment with expected consistency.

[0075] The pharmaceutical compositions provided by the present invention can be prepared in a form suitable for rectal administration using a solid as a carrier. A preferred dosage form is a suppository of the mixture forming a unit dose. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be readily prepared by mixing the pharmaceutical composition with a softened or molten excipient, then cooling and molding.

[0076] The above-mentioned pharmaceutical formulations may, in addition to the carrier components, appropriately contain one or more additional auxiliary components as needed, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, and preservatives (including antioxidants). They may also contain osmolite as other excipients to adjust the isotonicity between the drug and blood. Pharmaceutical compositions containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or concentrate.

[0077] Generally, to treat the above symptoms or discomforts, the drug dose level is approximately 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, for inflammation, cancer, psoriasis, allergies / asthma, immune system disorders and discomforts, and central nervous system (CNS) disorders and discomforts, the effective therapeutic dose level is 0.01 mg / kg body weight to 50 mg / kg body weight per day, or 0.5 mg to 3.5 g per patient per day.

[0078] However, as those skilled in the art will understand, the specific dosage level for any particular patient depends on a variety of factors, including age, weight, overall health, sex, diet, administration time, route of administration, excretion rate, drug concomitant use, and the severity of the specific disease being treated. [Brief explanation of the drawing]

[0079] [Figure 1] This is the XRD spectrum of crystalline form I of compound 19. [Figure 2] This is the DSC curve for crystalline form I of compound 19. [Figure 3] These are the XRD comparative spectra of crystalline form I of compound 19 under different stability conditions. Of these, A is the XRD spectrum of crystalline form I at day 0; B is the XRD spectrum of crystalline form I after being dried at 80°C for 24 hours; C is the XRD spectrum of crystalline form I after being left at 25°C-60%RH for 10 days; and D is the XRD spectrum of crystalline form I after being left at 40°C-75%RH for 14 days. [Modes for carrying out the invention]

[0080] To facilitate understanding of the present invention, it will be described in detail in conjunction with the following examples; however, these are merely illustrative examples, and the scope of the present invention is not limited to these examples. Specific experimental methods not described in the examples are generally carried out according to conventional experimental methods.

[0081] Unless otherwise specified, all parts and percentages are calculated by weight, and all temperatures are in Celsius.

[0082] In the examples, the following abbreviations are used. AcOH: Acetic acid; (BPin)2: Bis(pinacolato)diborone; BRD4(D1): Bromodomain protein 4 (domain 1); BRD4(D2): Bromodomain protein 4 (domain 2); CDI: N,N'-carbonyldiimidazole; DCM: Dichloromethane; DIEA: N,N-diisopropylethylamine; DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DMSO: Dimethyl sulfoxide; EA: Ethyl acetate; EtOH: Ethanol; h: time; 1 HNMR: nuclear magnetic resonance; KAcO: Potassium acetate; LCMS: Liquid chromatography-mass spectrometry; LDA: Lithium diisopropylamide; Mel: Iodomethane; MeOH: methanol; min: minutes; NaBH4: Sodium borohydride; NaH: Sodium hydride; n-Hex: n-hexane; Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2.DCM:[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium; Pd(PPh3)2Cl2: Bis(triphenylphosphine) dichloride palladium; PE: Petroleum ether; POCl3: Phosphorus oxychloride; s: seconds; TEA: Triethylamine; TfOH: Trifluoromethanesulfonic acid; THF: Tetrahydrofuran; TLC: Thin-layer chromatography; TsCl:p-toluenesulfonyl chloride; XPhos:2-dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl.

[0083] Unless otherwise specified, the information and method parameters of the detection device used in the following examples are as follows:

[0084] [Table 2]

[0085] [Table 3]

[0086] Example 1 Synthesis of Compound 1, 4-(1-(4-chlorobenzyl)-2-methyl-1Himidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one [ka]

[0087] 1. Synthesis of compound 1M-11 5-bromo-2-methoxy-4-methyl-3-nitropyridine (3.90 g) was dissolved in DMF (250 mL), heated to 80°C, and N,N-dimethylformamide dimethylacetal (18 mL) was slowly added. The mixture was then heated to 95°C and reacted for 4 hours. The completion of the reaction was monitored by TLC, the solution was concentrated, water (1 L) was added, and the mixture was extracted three times with EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.50 g of crude compound 1M-11.

[0088] 2. Synthesis of compound 1M-12 Compound 1M-11 (3.50 g), iron powder (3.50 g), and ammonium chloride (3.50 g) were added to methanol (133 mL) and water (17.5 mL), and the mixture was refluxed for 7 hours. The completion of the reaction was monitored by TLC. The mixture was filtered while hot, the filter cake was washed twice with methanol, and the filtrates were combined and concentrated. The mixture was purified by column chromatography (PE:EA = 5:1) to obtain 2.26 g of crude compound 1M-12.

[0089] 3. Synthesis of compound 1M-13 Compound 1M-12 (2.26 g) was dissolved in THF (47 mL), protected with nitrogen, the temperature was lowered to 0°C, NaH (1.28 g) was added, and the mixture was heated to room temperature and reacted for 1 hour. The temperature was then lowered to 0°C, TsCl solution (2.50 g TsCl dissolved in 47 mL of THF) was added, and the mixture was reacted for 2 hours. The completion of the reaction was confirmed by TLC, and the mixture was quenched with ice water. The mixture was extracted three times with EA, the organic phases were combined, washed three times with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to obtain 3.80 g of crude compound 1M-13.

[0090] 4. Synthesis of compound 1M-14 Compound 1M-13 (3.80 g) was dissolved in ethanol (10 mL), and hydrogen bromide solution (40 mL, 40%) was added dropwise. The reaction was carried out at 90°C for 2 hours. The completion of the reaction was monitored by TLC, and after cooling to 0°C, a white solid precipitated. The solid was filtered and recovered, the filter cake was washed twice with water, and dried to obtain 3.60 g of crude compound 1M-14.

[0091] 5. Synthesis of compound 1M-15 Compound 1M-14 (3.60 g) was dissolved in dioxane (50 mL), cesium carbonate (3.94 g) and iodomethane (5.40 g) were added, and the mixture was stirred at room temperature. The completion of the reaction was monitored by TLC, the reaction solution was diluted with DCM (200 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was slurryed in a mixed solvent of n-Hex:EA=4:1 (V / V) (20 mL), and the solid was filtered and recovered to obtain 3.20 g of the pale yellow solid product.

[0092] 6. Synthesis of Compound 1-1 2,3-diamino-5-bromopyridine (4.03 g) and p-chlorobenzaldehyde (3.00 g) were dissolved in DCM (350 mL), acetic acid (10 mL) was added, and the mixture was stirred overnight at room temperature. The completion of the reaction was monitored by TLC, and Na2CO3 solution (100 mL) was added. The mixture was extracted twice with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 100:15) to obtain compound 1-1, a yellow solid of 3.75 g.

[0093] 7. Synthesis of Compounds 1-2 Compound 1-1 (3.75 g) was dissolved in methanol, the temperature was lowered in an ice bath, NaBH4 (2.30 g) was added, and the mixture was stirred overnight at room temperature. The completion of the reaction was monitored by TLC, the mixture was concentrated, 250 mL of water was added, and the mixture was extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-2 (3.65 g).

[0094] 8. Synthesis of Compounds 1-3 Compound 1-2 (3.65 g) was dissolved in acetic acid (150 mL), triethyl orthoacetate (7.52 g) was added, and the mixture was heated to 100 °C and reacted for 2 hours. The completion of the reaction was monitored by TLC, and the solution was concentrated. Na2CO3 solution (300 mL) was added, and the mixture was extracted twice with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 1:1 (V / V)) to obtain 2.73 g of compound 1-3, which was a yellow solid.

[0095] 9. Synthesis of Compounds 1-4 Compound 1-3 (1.00 g), hexamethylditine (1.17 g), and tetratriphenylphosphine palladium (0.69 g) were dissolved in toluene (25 mL), purged with nitrogen gas, heated to 115 °C for 2.5 hours, cooled, concentrated, and the crude product was purified by column chromatography (DCM:MeOH=100:2-100:3) to obtain 0.79 g of compound 1-4, which was a yellow solid.

[0096] 10. Synthesis of Compounds 1-5 Compounds 1-4 (0.33 g), 1M-15 (0.30 g), and Pd(PPh3)2Cl2 (0.06 mg) were dissolved in DMF (5 mL), protected with nitrogen gas, heated to 120 °C for 2 hours, cooled, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:3) to obtain 0.31 g of compound 1-5, which was a yellow solid.

[0097] 11. Synthesis of Compound 1 Compounds 1-5 (0.31 g) were dissolved in MeOH (10 mL) and DCM (5 mL), NaOH (0.30 g) was added, and the mixture was stirred overnight at room temperature. The completion of the reaction was monitored by TLC, the mixture was concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:2). 0.13 g of compound 1, a white solid, was obtained.

[0098] LCMS:[M+1] + = 404.2.

[0099] 1HNMR(400MHz,DMSO)δ12.17(s,1H),8.55(d,J=1.4Hz,1H),8.04(d,J=1.3Hz,1H),7.59-7.37(m ,3H),7.34(s,1H),7.21(d,J=8.2Hz,2H),6.29(s,1H),5.58(s,2H),3.58(s,3H),2.59(s,3H).

[0100] The method of the example is almost identical to that of Example 1. [ka] The examples in Table 4 below were prepared using the corresponding p-chlorobenzaldehyde derivative instead of (p-chlorobenzaldehyde). The corresponding p-chlorobenzaldehyde derivative, for example, [ka] These can all be obtained as commercially available products. The corresponding iodomethane derivatives, for example, [ka] These items are all available as commercially sold products.

[0101] [Table 4-1] [Table 4-2]

[0102] Example 18 Synthesis of Compound 18, 4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyrazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one [ka]

[0103] 1. Synthesis of compound 2M-1 Compound 1M-15 (6.00g), (BPin)2 (8.00g), XPhos (0.90g), Pd2(dba)3 (0.43g), and KAcO (3.40g) were dissolved in dioxane (90mL), protected with nitrogen gas, and stirred at 80°C for 4 hours. After cooling, the mixture was poured into a mixed solvent of EA (200mL) and saturated Na2CO3 (200mL), separated, the aqueous phase was extracted three times with EA, the organic phase was combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:30) to obtain 3.45g of compound 2M-1, a white solid.

[0104] 2. Synthesis of Compound 18-1 2-amino-3,5-dibromopyrazine (10.00 g), 4-chlorobenzylamine (16.90 g), and DIEA (25.54 g) were dissolved in DMSO (40 mL), heated to 120 °C, and stirred for 4 hours. After confirming the completion of the reaction by LC-MS, the mixture was cooled, cold water (200 mL) was added, and the mixture was extracted three times with DIEA. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 100:15-100:30) to obtain 13.91 g of compound 18-1, which was a yellow solid.

[0105] 3. Synthesis of Compound 18-2 Compound 18-1 (13.90 g), triethyl orthoacetate (35.96 g), and glacial acetic acid (200 mL) were mixed and reacted overnight at 100°C. The mixture was cooled, concentrated, diluted with EA, washed three times with saturated Na2CO3 solution, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 100:20-100:50) to obtain 12.05 g of compound 18-2, a pale yellow solid.

[0106] 4. Synthesis of Compound 18-4 Compound 18-2 (1.00g), 2M-1 (1.27g), and Pd(dppf)Cl2.DCM (0.25g) were dissolved in dioxane (20mL), K2CO3 (0.61g) and water (4mL) were added, the mixture was protected with nitrogen gas, and heated and stirred at 100°C overnight. After cooling, the mixture was poured into a mixed solvent of EA (50mL) and saturated Na2CO3 (50mL), separated, the aqueous phase was extracted three times with EA, the organic phase was combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The compound was concentrated. The crude product was purified by column chromatography (DCM:MeOH=100:2) to obtain 0.95 g of compound 18-4, which was a yellow solid.

[0107] 5. Synthesis of Compound 18 Compound 18-4 (0.95 g) was dissolved in MeOH (10 mL) and DCM (20 mL), NaOH (0.40 g) was added, and the mixture was stirred overnight at room temperature to concentrate. The crude solution was dissolved in 10 mL of DMF and added dropwise to saturated ammonium chloride solution (100 mL). The solid was filtered and recovered, the crude solution was slurryed with EA (10 mL), the solid was filtered and recovered, and the mixture was dried under reduced pressure to obtain 0.51 g of compound 18, a light brown solid.

[0108] LCMS:[M+1]+=405.8.

[0109] 1 HNMR (400MHz, DMSO) δ12.15(s,1H),8.93(s,1H),8.04(s,1H),7.58-7.13(m,5H),6.86(t,J=2.3Hz,1H),5.58(s,2H),3.64(s,3H),2.62(s,3H).

[0110] The method of the example is almost identical to that of Example 18. [ka] The examples in Table 5 below were prepared using the corresponding p-chlorobenzylamine derivative instead of (p-chlorobenzylamine). The corresponding p-chlorobenzylamine derivative, for example, [ka] These items are all available commercially.

[0111] [Table 5-1] [Table 5-2]

[0112] Example 34 Synthesis of Compound 34, 1-(4-chlorobenzyl)-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-one [ka]

[0113] 1. Synthesis of Compound 34-1 Compound 1-1 (4.43 g) was dissolved in CH3CN (25 mL), CDI (11.51 g) was added, and the mixture was stirred overnight at room temperature. The solid was collected by suction filtration, the filter cake was washed with n-hexane and dried to obtain 4.24 g of compound 34-1, which was a white solid.

[0114] 2. Synthesis of Compound 34-2 Compound 34-1 (1.00 g), hexamethyldisin (1.16 g), and tetratriphenylphosphine palladium (0.68 g) were dissolved in 1,4-dioxane (25 mL), protected with nitrogen gas, and stirred overnight at 100°C. After cooling and concentration, the crude product was purified by column chromatography (PE:EA = 100:25) to obtain 1.23 g of compound 34-2, an off-white solid.

[0115] 3. Synthesis of Compound 34-3 Compound 34-2 (0.35 g), compound 34-5 (0.31 g), and Pd(PPh3)2Cl2 (0.06 g) were added to DMF (5 mL) and dioxane (2.5 mL), protected with nitrogen gas, and reacted overnight at 100°C. After cooling, water (50 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated, and purified by column chromatography (DCM:MeOH = 100:3) to obtain 0.13 g of compound 34-3, an off-white solid.

[0116] 4. Synthesis of Compound 34 Compound 34-3 (0.21 g) was dissolved in MeOH (50 mL), NaOH (0.20 g) was added, and the mixture was stirred overnight at room temperature. Then, water (500 mL) and DCM (500 mL) were added to the reaction system, the solid was filtered and recovered, and the filter cake was dissolved in MeOH:DCM = 1:1 until clarified. The organic phases were combined and concentrated to obtain the product, compound 34, 0.06 g.

[0117] LCMS:[M+1]+=406.1.

[0118] 1 HNMR: (400MHz, DMSO) δ12.12 (s, 1H), 8.23-6.38 (m, 9H), 6.22 (t, J = 2.8Hz, 1H), 5.05 (s, 2H), 3.64 (s, 3H).

[0119] Example 35 Synthesis of Compound 35, 4-(3-(1-(2,6-dichloro-3-fluorophenyl)ethyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one [ka]

[0120] 1. Synthesis of Compound 35-1 5.00 g of 5-bromo-1H-pyrrolo[2,3-b]pyridine was dissolved in 100 mL of DMF, sodium hydride (1.82 g) was added at 0°C, and the mixture was heated to room temperature and reacted for 20 minutes. The temperature was then lowered to 0°C, benzenesulfonyl chloride (6.69 g) was added, and the mixture was heated to room temperature and reacted for 1 hour. 100 mL of saturated ammonium chloride solution was added to quench the mixture, and it was extracted three times with DCM. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 8.37 g of crude product.

[0121] 2. Synthesis of Compound 35-2 2-isopropylamine (4.20 g) was dissolved in THF (100 mL), protected with nitrogen, and the temperature was lowered to -78°C. n-butyllithium (16 mL) was added, and the reaction was carried out at low temperature for 60 min. Compound 35-1 (5.00 g) in THF (30 mL) solution was added. The reaction was carried out at -78°C for 60 min, iodomethane (6.31 g) was added, and the temperature was allowed to rise naturally to room temperature and the reaction was carried out for 2 hours. Saturated ammonium chloride solution (50 mL) was added to quench the mixture, concentrated it, extracted three times with EA, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 100:40) to obtain 4.52 g of a white solid product.

[0122] 3. Synthesis of Compound 35-3 Compound 35-2 (4.52 g) was dissolved in methanol (100 mL), sodium hydroxide (4.52 g) was added, and the mixture was stirred overnight at room temperature. Saturated ammonium chloride solution (50 mL) was added, the mixture was concentrated, extracted twice with EA, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2.80 g of crude product.

[0123] 4. Synthesis of Compound 35-4 Compound 35-3 (2.80 g) was dissolved in DCM (65 mL), protected with nitrogen, and trifluoromethanesulfonic acid (7.96 g) was added. A solution of 1-(2,6-dichloro-3-fluorophenyl)-ethanol (11.09 g) in DCM (20 mL) was added, and the mixture was reacted overnight at room temperature. The reaction was continued at 35 °C for 4 hours, saturated sodium carbonate solution (200 mL) was added, and the mixture was extracted three times with DCM (500 mL). The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurryed with EA (50 mL). The product was a white solid of 2.40 g.

[0124] 5. Synthesis of Compound 35-5 Compound 35-4 (0.10 g), 2M-1 (0.11 g), and Pd(dppf)Cl2 (0.02 g) were dissolved in DMF (2 mL), potassium carbonate (0.07 g) was added, the mixture was protected with nitrogen, and the mixture was reacted overnight at 115°C. After cooling and filtering, water (10 mL) was added to the filtrate, and it was extracted three times with DCM (10 mL). The mixture was washed three times with saturated saline (10 mL), and the solution was directly concentrated to obtain 0.21 g of brown oil, which was then used in the next reaction.

[0125] 6. Synthesis of Compound 35 Compound 35-5 (0.21 g) was dissolved in methanol (10 mL), sodium hydroxide (0.10 g) was added, and the mixture was stirred at 40°C for 4 hours. Saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted twice with DCM (50 mL). The mixture was washed twice with saturated brine, the organic phase was concentrated, and the mixture was purified by column chromatography (DCM:MeOH = 100:5) to obtain 0.07 g of product.

[0126] LCMS:[M+1]+=469.1.

[0127] 1 HNMR:(400MHz,DMSO)δ12.12(s,1H),11.42(s, 1H),8.24(d,J=1.9Hz,1H),7.83(d,J=1.7Hz,1H),7.50(dd,J=8.9,5.1Hz,1H),7.44-7.13(m,3 H),6.22-5.96(m,1H),5.22(q,J=7.2Hz,1H),3.58(s,3H),2.30(s,3H),1.87(d,J=7.5Hz,3H).

[0128] Example 36 Synthesis of Compound 36, 4-(1-(2,6-dichlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one [ka]

[0129] 1. Synthesis of Compound 36-1 5-bromo-2-methyl-3-nitropyrimidine (1.00 g) was dissolved in DMF (10 mL), N,N-dimethylformamide dimethylacetal (5 mL) was added, and the mixture was reacted at 100 °C for 1 hour. After cooling, saturated ammonium chloride solution (25 mL) was added to quench the mixture, and the mixture was extracted twice with EA (25 mL). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.45 g of crude product, which was then used directly in the next reaction.

[0130] 2. Synthesis of Compound 36-2 Compound 36-1 (1.45 g) and iron powder (2.38 g) were added to glacial acetic acid (50 mL), heated to 80°C and reacted for 5 hours, filtered while hot, washed the filter cake with EA, combined the filtrates and concentrated, added saturated Na2CO3 solution, filtered again, washed the filter cake with EA, separated the filtrate, took the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 100:50) to obtain 0.73 g of product.

[0131] 3. Synthesis of Compound 36-3 Compound 36-2 (0.70 g) was dissolved in DMF (25 mL), protected with nitrogen, and sodium hydride (0.19 g) was added at 0°C. The mixture was allowed to rise naturally to room temperature and stirred for 1 hour. 2,6-Dichlorobenzyl bromide (0.85 g) was added at 0°C, and the mixture was allowed to rise naturally to room temperature and reacted for 3 hours. 50 mL of ice water mixture was added to quench the reaction, and the mixture was extracted three times with EA. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was a yellow solid of 1.30 g.

[0132] 4. Synthesis of Compound 36-4 Compound 36-3 (0.40 g), Compound 2M-1 (0.48 g), and Pd(dppf)Cl2.DCM (0.10 g) were dissolved in dioxane (8 mL), and a solution of potassium carbonate (0.23 g) in water (1.5 mL) was added. The mixture was protected with nitrogen and stirred overnight at 100°C. Then, a mixed solution of EA (50 mL) and saturated Na2CO3 (50 mL) was added, the organic phase was collected, the aqueous phase was extracted three times with EA, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:2). The product was a brown solid of 0.50 g.

[0133] 5. Synthesis of Compound 36 Compound 36-4 (0.50 g) was dissolved in a mixed solution of MeOH / DCM = 10 mL:10 mL, sodium hydroxide (0.30 g) was added, and the mixture was stirred overnight at room temperature. The solution was concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:5) to obtain 0.21 g of a light brown solid.

[0134] LCMS:[M+1]+=423.1.

[0135] 1 HNMR:(400MHz,DMSO)δ12.17(s,1H),7.69-7.55(m,2H),7.52-7.23(m,6H),6.6 2(dd,J=3.3,0.7Hz,1H),6.30(dd,J=2.6,2.1Hz,1H),5.67(s,2H),3.61(s,3H).

[0136] Example 37 Synthesis of Compound 37, 4-(4-((4-chlorophenyl)amino)pyrido[2,3-d]pyrimidine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one [ka]

[0137] 1. Synthesis of Compound 37-1 3.00 g of 2-amino-5-bromonicotinic acid was dissolved in 15 mL of formamide, stirred at 160°C for 4 hours, 20 mL of formamide was added, and the reaction was continued at 160°C for another 6 hours. After cooling, the mixture was poured into 150 mL of water, and the solid was collected by filtration to obtain 2.20 g of a yellow solid.

[0138] 2. Synthesis of Compound 37-2 Compound 37-1 (0.40 g) was dissolved in phosphorus oxychloride (5 mL), triethylamine (0.5 mL) was added, and the mixture was reacted at 120 °C for 3 hours. The mixture was concentrated, toluene (20 mL) was added to the crude product, and the mixture was concentrated again. This process was repeated three times to obtain 0.60 g of a blackish-brown solid crude product, which was then used directly in the next reaction.

[0139] 3. Synthesis of Compound 37-3 Compound 37-2 (0.60 g) was dissolved in DCM (10 mL), p-chloroaniline (0.30 g) and triethylamine (1 mL) were added, the mixture was stirred at room temperature for 5 hours, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:5-100:10). The product was a reddish-brown solid of 0.70 g.

[0140] 5. Synthesis of Compound 37-4 Compound 37-3 (0.30 g), compound 2M-1 (0.38 g), and Pd(dppf)Cl2.DCM (0.07 g) were dissolved in dioxane, potassium carbonate (0.19 g) and water (1.5 mL) were added, the mixture was protected with nitrogen gas, and stirred overnight at 100°C. After cooling, EA (30 mL) and saturated Na2CO3 solution (30 mL) were added, and the mixture was separated. The aqueous phase was extracted three times with EA, the organic phase was combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 100:3), and the product was 0.29 g of yellow solid.

[0141] 6. Synthesis of Compound 37 Compound 37-4 (0.29 g) was dissolved in methanol (15 mL), sodium hydroxide (0.21 g) was added, and the mixture was stirred overnight at room temperature. The solution was concentrated and purified by column chromatography (DCM:MeOH=100:5), yielding 0.07 g of compound 37 as a yellow solid.

[0142] LCMS:[M+1]+=403.1.

[0143] 1 HNMR:(400MHz,DMSO)δ12.28(s,1H),8.76(s,1H),7.92(d,J=8.8Hz,2H),7.68(s,1H),7.6 1-7.53(m,2H),7.52-7.45(m,3H),7.43(t,J=2.8Hz,1H),6.67-6.53(m,1H),3.60(s,3H).

[0144] Example 38 Synthesis of Compound 38, 4-(1-(2,6-dichlorobenzyl)-2-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one [ka]

[0145] 1. Synthesis of Compound 38-1 5-Bromo-2-methyl-3-nitropyridine (1.00 g) and N,N-dimethylacetamidodimethylacetal (1.22 g) were dissolved in DMF (5 mL) and heated at 100°C for 1 hour. After cooling, the mixture was diluted with EA (300 mL), washed three times with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The product was a reddish-brown solid of 1.30 g.

[0146] 2. Synthesis of Compound 38-2 Compound 38-1 (1.30 g) and iron powder (3.00 g) were dissolved in glacial acetic acid (30 mL), stirred at 80°C for 90 min, cooled, poured into saturated Na2CO3 solution (200 mL), filtered through Celite, washed the filter cake with EA, extracted the filtrate three times with EA, combined the organic phases, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified the crude product by basic alumina column chromatography (PE:EA = 100:30-100:50). The product was 0.63 g of yellowish-brown solid.

[0147] 3. Synthesis of Compound 38-3 Compound 38-2 (0.53 g) was dissolved in DMF (25 mL), protected with nitrogen gas, the temperature was lowered to 0°C, sodium hydride (0.13 g) was added, the temperature was allowed to rise naturally to room temperature and stirred for 1 hour, the temperature was lowered to 0°C, 2,6-dichlorobenzyl bromide (0.60 g) was added, the temperature was allowed to rise naturally to room temperature and reacted for 2.5 hours, the mixture was quenched in ice water, extracted three times with EA, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (PE:EA = 100:10 to 100:30), and the product was 0.84 g of yellow solid.

[0148] 4. Synthesis of Compound 38-4 Compound 38-3 (0.20 g), compound 2M-1 (0.23 g) and Pd(dppf)Cl2.DCM (0.04 g) were dissolved in dioxane (5 mL), K2CO3 (0.11 g) and water (1 mL) were added, protected with nitrogen gas, and heated under reaction at 100 °C overnight. After cooling, EA (50 mL) and saturated Na2CO3 solution (50 mL) were added, the solution was mixed, separated, the aqueous phase was extracted 3 times with EA, the organic phases were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:3) to obtain 0.30 g of the crude product as a brown oil.

[0149] 5. Synthesis of Compound 38 Compound 38-4 (0.30 g) was added to methanol (15 mL), sodium hydroxide (0.20 g) was added, stirred at room temperature for 3 h, and purified by silica gel column chromatography (dry method) (DCM:MeOH = 100:2~100:3) to obtain 0.08 g of the product as a yellow solid.

[0150] LCMS: [M+1]+ = 437.1.

[0151] 1 HNMR: (400 MHz, DMSO) δ 12.13 (s, 1H), 8.42 (d, J = 1.8 Hz, 1H), 7.63 - 7.40 (m, 4H), 7.39 - 7.20 (m, 3H), 6.43 (s, 1H), 5.65 (s, 2H), 3.60 (s, 3H), 2.49 (s, 3H).

[0152] Example 39 Synthesis of Compound 39, 4-(1-(4-chlorobenzyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Chemical Structure

[0153] 1. Synthesis of Compound 39-1 6-Bromo-1H-pyrazolo[4,3-b]pyridine (1.00 g) was dissolved in DMF (30 mL), protected with nitrogen, sodium hydride (0.24 g) was added at 0 °C, the temperature was raised to room temperature and reacted for 1 h, p-chlorobenzyl chloride (0.90 g) was added at 0 °C, and the reaction was carried out overnight at room temperature. It was poured into ice water (100 mL) for quenching, extracted 3 times with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 100:4~100:20) to obtain 0.80 g of the product as a white solid.

[0154] 2. Synthesis of Compound 39-2 Compound 39-1 (0.30 g), 2M-1 (0.40 g) and Pd(dppf)Cl 2. DCM (0.08 g) was dissolved in dioxane (8 mL), potassium carbonate (0.19 g) and water (1.5 mL) were added, protected with nitrogen gas, and heated and stirred at 100 °C overnight. After cooling, it was poured into EA (100 mL) / saturated Na2CO3 solution (100 mL), separated, the aqueous phase was extracted 3 times with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 100:2.5) to obtain 0.52 g of the product as a yellow semi-solid.

[0155] 3. Synthesis of Compound 39 Compound 39-2 (0.52 g) was dissolved in methanol (10 mL) and DCM (10 mL), sodium hydroxide (0.12 g) was added, stirred at room temperature, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:2.5~100:3) to obtain 0.10 g of Compound 39 as a yellow solid.

[0156] LCMS: [M+1]+ = 390.1;

[0157] 1HNMR:(400MHz,DMSO)δ12.23(s,1H),8.78(d,J=1.8Hz,1H),8.43-8.20(m,2H),7.58(d, J=4.1Hz,1H),7.49-7.17(m,5H),6.57-6.21(m,1H),5.76(d,J=5.8Hz,2H),3.62(s,3H).

[0158] Example 40 Synthesis of Compound 40, 4-(1-((4-chlorophenyl)sulfuryl)-1H-pyrrolo[2,3-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one [ka]

[0159] 1. Synthesis of Compound 40-1 6-bromo-7-azaindole (1.00 g) was dissolved in DMF (15 mL), protected with nitrogen, sodium hydride (0.31 g) was added at 0°C, stirred at room temperature for 1 hour, p-chlorobenzenesulfonyl chloride (1.30 g) was added at 0°C, stirred at room temperature for 2 hours, quenched with ice water (50 mL), extracted three times with EA, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was a yellow solid of 1.30 g.

[0160] 2. Synthesis of Compound 40-2 Compound 40-1 (0.35 g), compound 2M-1 (0.49 g), and Pd(PPh3)4 (0.06 g) were dissolved in dioxane (7 mL), potassium carbonate (0.20 g) and water (7 mL) were added, the mixture was protected with nitrogen gas, and reacted overnight at 100 °C. After cooling, the mixture was poured into an EA (50 mL) / saturated Na2CO3 solution (50 mL), liquid-liquid separated, the aqueous phase was extracted three times with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH=100:3) to obtain a pale yellow solid of 0.35 g.

[0161] 3. Synthesis of Compound 40 Compound 40-2 (0.28 g) was dissolved in methanol (10 mL) and dichloromethane (10 mL), sodium hydroxide (0.07 g) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated, and the crude product was purified by column chromatography (DCM:MeOH=100:3). EA (10 mL) was added to the crude product to form a slurry, and the solid was collected by filtration. Product 0.04 g was obtained.

[0162] LCMS:[M+1]+=439.1;

[0163] 1 HNMR:(400MHz,DMSO)δ12.12(s,1H),8.11(ddd,J=14.8,8.4,5.5Hz,3H),7.96(s,1H),7.85(dd,J=1 6.1,6.2Hz,2H),7.71-7.52(m,2H),7.42(dt,J=4.9,2.7Hz,2H),6.85(d,J=4.0Hz,1H),3.65(s,3H).

[0164] Example 41 Synthesis of Compound 41, N-(1-(4-chlorobenzyl-2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide [ka]

[0165] 1. Synthesis of Compound 41-1 5-bromo-3-nitrobenzene-1,2-diamine (1.00 g) and acetylacetone (0.86 g) were dissolved in ethanol (20 mL), 5N hydrochloric acid (6 mL) was added, the mixture was stirred at 100 °C for 4 hours, cooled, concentrated, and the crude product was purified by column chromatography (PE:EA = 100:30) to obtain 0.90 g of the yellow solid product.

[0166] 2. Synthesis of Compound 41-2 Compound 41-1 (0.85 g) and potassium carbonate (0.92 g) were dissolved in acetonitrile (20 mL) and DMF (4 mL), p-chlorobenzyl chloride (0.98 g) was added, and the mixture was stirred at 60 °C overnight. After cooling, it was poured into 100 mL of water and extracted three times with EA. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 100:30) to obtain 1.04 g of a yellow solid.

[0167] 3. Synthesis of Compound 41-3 Compound 41-2 (0.50 g), Compound 2M-1 (0.56 g) and Pd(dppf)Cl2·DCM (0.11 g) were dissolved in dioxane (10 mL), potassium carbonate (0.27 g) and water (2 mL) were added, protected with nitrogen gas, and stirred at 90 °C overnight. After cooling, it was poured into 50 mL of water and extracted three times with EA. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:3) to obtain 0.83 g of a yellow solid.

[0168] 4. Synthesis of Compound 41-4 Compound 41-3 (0.80 g) was dissolved in THF (15 mL) and ethanol (15 mL), iron powder (0.37 g), ammonium chloride (0.14 g), and water (10 mL) were added, and the mixture was stirred at 90 °C overnight. Filtered while hot, the filter cake was rinsed three times with methanol, the filtrate was concentrated, saturated sodium carbonate solution (50 mL) was added, extracted three times with EA, the combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:4) to obtain 0.43 g of a dark yellow solid.

[0169] 5. Synthesis of Compound 41 Compound 41-4 (0.43 g) was dissolved in DCM (10 mL), triethylamine (0.31 g) and ethanesulfonyl chloride (0.19 g) were added, the mixture was stirred at room temperature for 2 hours, concentrated, dioxane (7.5 mL) and sodium hydroxide solution (10%, V / V, 2.5 mL) were added, the mixture was heated and stirred at 70 °C for 3 hours, cooled, poured into saturated ammonium chloride solution (100 mL), separated, the aqueous phase was extracted three times with EA, the organic phase was combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 100:3) to obtain 0.08 g of the yellow solid product.

[0170] LCMS:[M+1]+=511.1.

[0171] 1 HNMR(300MHz,DMSO)δ12.13(s,1H),9.65(s,1H),7.50-7.35(m,4H),7.35-7.30(m,2H),7.25-7.20(m ,2H),6.40(s,1H),5.55(s,2H),3.60(s,3H),3.35-3.20(m,2H)2.60-2.50(m,3H).1.45-1.20(m,3H).

[0172] In a method almost identical to that of Example 41, the Example [ka] The examples in Table 6 below were prepared using the corresponding p-chlorobenzyl chloride derivative instead of (p-chlorobenzyl chloride). The corresponding p-chlorobenzyl chloride derivative, for example, [ka] These items are all available commercially.

[0173] [Table 6-1] [Table 6-2] [Table 6-3]

[0174] Example 58 Synthesis of Compound 58, N-(5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide [ka]

[0175] 1. Synthesis of Compound 58-1 1M-15 (7.60g) and NaOH (1.60g) were dissolved in dioxane and water, and reacted at 80°C for 4 hours. After cooling, the mixture was poured into H2O, extracted three times by DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 90:10) to obtain 3.20g of a gray solid.

[0176] 2. Synthesis of Compound 58-2 Compound 58-1 (6.00 g), (Bpin)2 (8.00 g), SPhos (1.29 g), PdCl2(CH3CN)2 (0.68 g), and KOAc (3.40 g) were dissolved in dioxane, protected with nitrogen gas, and reacted at 80°C for 4 hours. After cooling, the mixture was poured into water, extracted three times with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 50:50) to obtain 3.20 g of gray solid.

[0177] 3. Synthesis of Compound 58-3 5,7-Dichloro-1H-imidazo[4,5-B]pyridine (1.88 g), p-trifluoromethylbenzyl chloride (1.94 g), and DIEA (1.56 g) were dissolved in DMF and reacted overnight at room temperature. The mixture was poured into water, extracted three times with DIEA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 50:50) to obtain 1.50 g of gray solid.

[0178] 4. Synthesis of Compound 58-4 58-3 (1.50 g) was placed in ammonia water and reacted overnight at 150°C. After cooling, it was filtered by suction, the filter cake was washed with water, and the solid was vacuum-dried to obtain 1.10 g of a white solid.

[0179] 5. Synthesis of Compound 58-5 58-4 (1.10 g) and TEA (1.70 g) were dissolved in DCM, and ethanesulfonyl chloride (0.86 g) was added dropwise. The mixture was reacted at room temperature for 2 hours. The mixture was poured into water, extracted three times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 30:70) to obtain 0.80 g of gray solid.

[0180] 6. Synthesis of Compound 58 58-2 (0.42g), 58-5 (0.27g), K2CO3 (0.41g), and Xphos-Pd-G2 (0.08g) were added to dioxane and water and reacted at 80°C for 4 hours. After cooling, the mixture was poured into water, extracted three times with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (MeOH:DCM = 10:90) to obtain 0.10g of a gray solid.

[0181] LCMS:[M+1]+=531.1.

[0182] 1HNMR(400MHz,DMSO)δ12.13(s,1H),10.61(s,1H),8.56(s,1H),7.75(d,J=10.1Hz,3H),7.67-7.53(m, 3H),7.32(t,J=2.8Hz,1H),6.73-6.54(m,1H),5.65(s,2H),3.72-3.53(m,5H),1.31(t,J=7.3Hz,3H).

[0183] Example 59 Synthesis of compound 59, N-(3-(2,4-difluoromethylbenzyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide [ka]

[0184] 1. Synthesis of Compound 59-1 5,7-Dichloro-1H-imidazo[4,5-B]pyridine (5.00 g), K2CO3 (11.00 g), and 2,4-difluorobenzyl chloride (6.50 g) were dissolved in DMF (50 mL) and stirred at room temperature for 8 hours. The reaction mixture was poured into ice water, filtered by suction, the filter cake was washed three times with water, and the crude product was purified by column chromatography (PE:EA = 70:30) to obtain 6.0 g of a white solid.

[0185] 2. Synthesis of Compound 59-2 59-1 (0.60 g) and ammonia (25 mL) were placed in a sealed tube and stirred overnight at 150°C. The mixture was poured into 100 mL of water, extracted three times with EA, the organic phases were combined, washed three times with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to obtain 0.30 g of a white solid.

[0186] 3. Synthesis of Compound 59-3 59-2 (0.15 g) and TEA (0.16 g) were dissolved in DCM (5 mL), and ethyl sulfonyl chloride (0.19 g) was slowly added dropwise at 0°C. After addition, the mixture was allowed to return to room temperature, and stirring was continued for 5 hours. Water was added to the reaction mixture, and the mixture was extracted three times with EA. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Flash-Prep-HPLC (H2O / CH3CN = 40%~45%) to obtain 0.10 g of a pale yellow solid.

[0187] 4. Synthesis of Compound 59 59-3 (0.10 g), 58-2 (0.07 g), Xphos-Pd-G2 (0.02 g), and K3PO4 (0.11 g) were dissolved in 5 mL of dioxane, 1 mL of water was added, and the mixture was heated to 80°C under a nitrogen atmosphere for 8 hours. After cooling, the mixture was diluted with water, extracted three times with EA, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 98:2) to obtain 0.06 g of a brown solid.

[0188] LCMS:[M+1]+=499.1.

[0189] 1 HNMR(400MHz,DMSO)δ12.12(d,J=17.8Hz,1H),8.46(s,1H),7.80(d,J=21.7Hz,1H),7.64-7.59(m,1H),7.55-7.42(m, 1H),7.39(t,J=2.8Hz,1H),7.36-6.97(m,3H),6.80-6.74(m,1H),5.56(s,2H),3.76-3.51(m,5H),1.38-1.25(m,3H).

[0190] Example 64 Synthesis of Compound 64, N-(3-(2,4-difluorobenzyl)-2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide [ka]

[0191] 1. Synthesis of Compound 64-1 1.08 g of 2-methyl-1H-imidazo[4,5-b]pyridine was dissolved in 15 mL of EA, 1.86 g of m-CPBA was added, the mixture was stirred overnight at room temperature, filtered by suction, the solid was washed with EA, and dried to obtain 1.05 g of a white solid.

[0192] 2. Synthesis of Compound 64-2 Dissolve 64-1 (1.05 g) in 10 ml of POCl3, react at 80°C for 15 min, heat to 120°C and react for 3 hours, pour into ice water, extract three times with EA, combine the organic phases, concentrate, and perform column chromatography (PE:EA = 50:50) to obtain 0.80 g of white solid.

[0193] 3. Synthesis of Compound 64-3 64-2 (0.80 g) was dissolved in 10 mL of EA, (1.25 g) m-CPBA was added, the mixture was stirred overnight at room temperature, filtered by suction, the filter cake was washed with EA and dried to obtain 0.70 g of a white solid.

[0194] 4. Synthesis of Compound 64-4 64-3 (0.70 g) was dissolved in 10 mL of DMF, 0.38 mL of methanesulfonyl chloride was added dropwise, the mixture was reacted at 80°C for 3 hours, poured into ice water, extracted three times with EA, the organic phases were combined and concentrated, and column chromatography (PE:EA = 50:50) was performed to obtain 0.60 g of a white solid.

[0195] 5. Synthesis of Compound 64-5 64-4 (0.70 g), 2,4-difluorobenzyl chloride (0.70 g), and K2CO3 (0.95 g) were dissolved in DMF and reacted overnight at room temperature. The mixture was poured into water, extracted three times with EA, washed three times with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 30:70) to obtain 0.65 g of yellow solid.

[0196] 6. Synthesis of Compound 64-6 64-5 (0.65 g) was placed in 10 mL of ammonia water and reacted overnight at 150°C. After cooling, it was filtered by suction, the filter cake was washed with water, and the solid was vacuum-dried to obtain 0.50 g of a white solid.

[0197] 7. Synthesis of Compound 64-7 Dissolve compound 64-6 (0.50 g) and TEA (0.49 g) in 10 mL of DCM. Ethanol chloride (0.42 g) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The mixture was poured into water, extracted three times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 30:70) to obtain 0.40 g of a white solid.

[0198] 8. Synthesis of Compound 64 Compounds 64-7 (0.40 g), 58-2 (0.27 g), K2CO3 (0.41 g), and Xphos-Pd-G2 (0.08 g) were added to dioxane and water and reacted at 80°C for 4 hours. After cooling, the mixture was poured into water, extracted three times with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (MeOH:DCM = 10:90) to obtain 0.1 g of gray solid.

[0199] LCMS:[M+1]+=513.1.

[0200] 1 HNMR(400MHz,DMSO)δ12.12(d,J=17.8Hz,1H),8.46(s,1H),7.64-7.59(m,1H),7.55-7.42(m,1H),7.39(t,J=2. 8Hz, 1H), 7.36-6.97 (m, 3H), 6.80-6.74 (m, 1H), 5.56 (s, 2H), 3.76-3.51 (m, 5H), 2.62 (s, 3H), 1.38-1.25 (m, 3H).

[0201] Using the corresponding intermediate or raw material in a manner very similar to that of Examples 58, 59, and 64, for example, [ka] Instead [ka] The compounds listed in Table 7 below were prepared using the following method.

[0202] [Table 7-1] [Table 7-2]

[0203] Example 69 Stability test of crystalline form I of compound 19 Table 2 shows the X-ray powder diffraction spectrum detection apparatus and method of the present invention.

[0204] The crystal form of the sample of compound 19 in crystal form I remained unchanged in all cases: when left to dry at 80°C for 24 hours, when left at 25°C-60%RH for 10 days, and when left at 40°C-75%RH for 14 days.

[0205] Figure 3 shows a comparison of the XRD values ​​of crystalline form I of compound 19 under different stability conditions. As can be seen, crystalline form I of compound 19 has good stability.

[0206] Example 70 Dynamic Moisture Adsorption (DVS) Measurement Table 3 shows the dynamic moisture adsorption detection device and method of the present invention.

[0207] The crystalline form A of compound II exhibits a weight change of approximately 0.1% within the range of 0%RH to 80%RH, does not absorb moisture, and is suitable for the preparation of solid dosage forms.

[0208] Comparative Example 1 [ka]

[0209] Synthesis of compound 1-M1 5-bromo-1,3-dimethyl-2-pyridone (0.50 g), bis(pinacolate)diborone (1.27 g), Pd(dppf)Cl2.DCM (0.20 g), potassium acetate (0.73 g), and 8 mL of 1,4-dioxane were mixed, protected with nitrogen gas, and reacted at 90°C for 3 hours. The mixture was poured into a mixture of 50 mL of ethyl acetate and 50 mL of saturated ammonium chloride solution, and the organic phase was collected by phase separation. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 100:20) to obtain 0.67 g of compound 1-M1 as an off-white solid.

[0210] Synthesis of Comparative Example 1-1 5-bromo-3-nitrophenyl-1,2-diamine (1.00 g), acetylacetone (0.86 g), 20 mL of ethanol, and hydrochloric acid (6 mL, 5 mol / L) were mixed and reacted by stirring at 100°C for 4 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (PE:EA = 100:30~100:45) to obtain 0.90 g of Comparative Example 1-1 as a yellow solid.

[0211] Synthesis of Comparative Examples 1-2 Compound 1-1 (0.85 g), p-chlorobenzyl chloride (0.70 g), potassium carbonate (0.92 g), 20 mL of acetonitrile, and 4 mL of DMF were mixed and reacted overnight at 60°C. After cooling, the mixture was poured into 100 mL of saturated sodium chloride solution, separated, the aqueous phase was extracted three times with ethyl acetate, the organic phase was combined, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 100:30~100:50) to obtain 1.04 g of Comparative Example 1-2 as a yellow solid.

[0212] Synthesis of Comparative Examples 1-3 Compound 1-2 (0.45g), Compound 1-M1 (0.29g), Pd(dppf)Cl2.DCM (0.10g), anhydrous potassium carbonate (0.24g), 10mL of 1,4-dioxane, and 2mL of water were mixed, protected with nitrogen gas, and stirred overnight at 90°C. After cooling, the mixture was poured into a mixed solution of 50mL of ethyl acetate and 50mL of saturated ammonium chloride solution, and the organic phase was separated to collect the organic phase. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:3) to obtain Comparative Example 1-3 (0.49g) as a brown solid.

[0213] Synthesis of Comparative Examples 1-4 Compound 1-3 (0.49 g), iron powder (0.33 g), ammonium chloride (0.13 g), 10 mL of tetrahydrofuran, 10 mL of ethanol, and 3 mL of water were mixed and reacted overnight at 90°C. The mixture was filtered through Celite, the filter cake was washed three times with methanol, the filtrate was concentrated, 50 mL of ethyl acetate and 50 mL of saturated sodium carbonate solution were added, the mixture was separated, the organic phase was collected, the aqueous phase was extracted three times with EA, the organic phases were combined, washed three times with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated to obtain Comparative Example 1-4 (0.30 g) as a dark brown solid crude product.

[0214] Synthesis of Comparative Example 1 Compound 1-4 (0.30 g) was dissolved in 10 mL of dichloromethane, triethylamine (0.31 g) was added, followed by ethanesulfonyl chloride (0.30 g). The mixture was stirred at room temperature for 2 hours and then concentrated. 7.5 mL of 1,4-dioxane and 2.5 mL of 10% aqueous sodium hydroxide solution were added, the mixture was stirred at 70°C for 3 hours, cooled, and 100 mL of saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:3) to obtain 0.08 g of Comparative Example 1 as a yellow solid. LCMS:[M+1]+=485.1.

[0215] Comparative Example 2 [ka]

[0216] Synthesis of Comparative Example 2-1 Comparative Example 1-1 (1.00 g) was dissolved in 15 mL of DMF, potassium carbonate (2.00 g) and 4-fluorochlorobenzyl (0.67 g) were added, the mixture was stirred overnight at room temperature, 50 mL of water was added, and the mixture was extracted three times with 50 mL of EA. The organic phases were combined, concentrated, and column chromatography (PE:EA = 50:50) was performed to obtain 0.80 g of Comparative Example 2-1 as a yellow solid.

[0217] Synthesis of Comparative Example 2-2 Comparative Example 2-1 (0.80 g) was dissolved in 10 mL of acetic acid, iron powder (0.60 g) was added, and the mixture was reacted at 60°C for 2 hours. After concentration, 100 mL of saturated sodium carbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. After concentration, column chromatography (PE:EA = 20:80) was performed to obtain Comparative Example 2-2 (0.60 g) as a yellow solid.

[0218] Synthesis of Comparative Example 2-3 Comparative Example 2-2 (0.60 g) and triethylamine (0.55 g) were dissolved in 10 mL of DCM, and methylsulfonyl chloride (0.31 g) was added dropwise, and the mixture was reacted at room temperature for 2 hours. Water ( 50 mL was poured in, extracted three times with 20 mL of dichloromethane, washed three times with 20 mL of saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. Purified by column chromatography (PE:EA = 30:70), 0.50 g of Comparative Example 2-3 was obtained as a yellow solid.

[0219] Synthesis of Comparative Example 2 Comparative Examples 2-3 (0.41g), 1-M1 (0.25g), K2CO3 (0.41g), and Pd(dppf)Cl2 (0.08g) were added to 10mL of dioxane and 2mL of water, and reacted at 80°C for 4h. After cooling, the mixture was poured into 30mL of water, extracted three times with 30mL of EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The solution was purified by column chromatography (MeOH:DCM=10:90) to obtain 40mg of Comparative Example 2 as a gray solid.

[0220] LCMS:[M+1]+=455.1

[0221] Pharmacology experiments Experimental Example 1: Inhibitory activity test of the compound of the present invention against BRD4(D1) and BRD4(D2) (IC) 50 ) The inhibitory activity of the compounds of the present invention against BRD4(D1) and BRD4(D2) was evaluated in vitro using (+)-JQ1 as a control compound.

[0222] BRD4(D1) and BRD4(D2) assays were performed in 384-well polystyrene plates. First, the test compounds were serially diluted with DMSO, and the test compound / DMSO mixture was transferred to the 384-well plate. The final concentration of DMSO in the assay was 0.1%. Twice the volume of the protein / peptide mixture was added to the 384-well plate, followed by twice the volume of the assay mixture, and the plate was shaken for 30 seconds. After incubating the plate at room temperature for 2 hours, the HTRF signal was read using EnVision.

[0223] In Excel, the data was fitted using mathematical formula (1) to obtain the suppression rate value.

[0224] Mathematical formula (1): Inhibition rate (%) = (Maximum value - Signal value) / (Maximum value - Minimum value) * 100 By fitting the data using mathematical formula (2) with GraphPad Prism 5.0 software, IC 50 Measurements were taken.

[0225] Mathematical formula (2): Y=Bottom +(Top-Bottom) / (1+10^((LogIC50-X) * (ChillSlope) (In mathematical formula (2), Y represents the percentage of inhibition, and X represents the concentration of the test compound.)

[0226] IC in experimental examples 50 The data is shown in the table below. In the table, A is IC 50 This indicates that it is <100nM, and B is IC. 50 This indicates that the current is between 100 and 300 nM, and that C is IC50 > 300 nM.

[0227] [Table 8-1] [Table 8-2]

[0228] Table 8 exemplifies the inhibitory activity of the compounds of the present invention against BRD4(D1) and BRD4(D2). As can be seen, the compounds of the present invention exhibit BRD4 inhibitory activity equivalent to or stronger than that of the positive control compound (+)-JQ1.

[0229] Experimental Example 2: Pharmacokinetic Study Male SD rats were sourced from Beijing Vital Lihua Experimental Animal Technology Co., Ltd. The rats were divided into groups of three, and each group received a single forced oral administration of a suspension of the test sample (5 mg / kg to 20 mg / kg). The animals were fasted overnight before the experiment, with a fasting period of 10 hours before administration to 4 hours after administration. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration. Blood was collected from the retinal venous plexus and placed in EDTA-K2 anticoagulation tubes. The samples were centrifuged at 4°C at 4000 rpm for 10 minutes, the plasma was transferred to a centrifuge tube, and the test compounds were extracted by protein precipitation. The extracts were analyzed by LC-MS / MS. Table 9 shows the PK data of the compounds in rats.

[0230] [Table 9]

[0231] The compounds provided in the present invention are preferably pharmaceutical compositions having multiple modes of administration. Most preferably, the pharmaceutical composition is administered orally. Such pharmaceutical compositions and the processes for preparing them are known in the art, for example, Remington: THE SCIENCE AND PRACTICE OF PHARMACY, A. Gennaro, et al., eds., 19 th This is described in ed., Mack Publishing Co., 1995. The compound represented by formula (I) is effective over a relatively wide dose range.

[0232] For example, the daily dose range is typically about 1 mg to about 200 mg (meaning the total daily dose), preferably 1 mg to 150 mg, and more preferably 1 mg to 50 mg. In some cases, dose levels below the lower limit of the above range may be sufficient. In other cases, higher doses are also possible. The above dose range does not limit the scope of protection of the present invention in any way. As those skilled in the art will understand, the actual dose of the compounds provided in the present invention is determined by a physician in accordance with relevant circumstances, including treatment conditions, choice of route of administration, the compound and complex actually administered, age, weight, individual patient response, and severity of the condition.

[0233] Although the present invention has been described in whole by its embodiments, various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the claims of the present invention.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R １ is selected from H, C １－６ alkyl, C １－６ alkoxy, C ６－１０ aryl or C ５－１０ heteroaryl, wherein said C １－６ alkyl or C １－６ alkoxy is optionally substituted with C １－６ alkyl, C ６－１０ aryl or C ５－１０ heteroaryl, and said C ６－１０ aryl or C ５－１０ heteroaryl is optionally substituted with C １－６ alkyl, and said C ５－１０ heteroaryl has 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ２ is H or C １－３ It is alkyl; Q does not exist, or C １－６ Alkylene, -SO ２ - or -NH- is selected, and the C １－６ Alkylene can optionally be C １－６ Substituted with alkyl; X is H, C １－６ Alkyl or C ６－１０ Selected from aryl, the C １－６ Alkyl or C ６－１０ Aryl can optionally be a halogen or halogenated C １－６ Alkyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkoxycarbonyl or C １－６ Alkyl-SO ２ Replaced by -; Y is, 【Chemistry 2】 Selected from, During the ceremony, 【Transformation 3】 represents a double or single bond, and U, W, or Z are each independently selected from C or N; R ３ H, halogen, hydroxy, amino, C １－６ Alkyl, C １－６ Selected from alkoxy or cyano; R ４ is H, or -N(R ５ ) - SO ２ -R ６ And here, R ５ and R ６ These are H and C, which are independent of each other. １－６ C substituted with alkyl or halogen １－６ A compound selected from alkyl groups.

2. R １ H, C １－４ Alkyl, phenyl, or C ５－６ Selected from heteroaryls, the C １－４ Alkyl is optionally C １－６ Alkyl, phenyl, or C ５－６ Substituted with heteroaryl, the phenyl or C ５－６ Heteroaryls can optionally be C １－６ The compound according to claim 1, characterized by being substituted with an alkyl group.

3. The compound according to claim 1 or 2, characterized in that the heteroaryl comprises one, two, or three heteroatoms independently selected from nitrogen or sulfur.

4. R １ H, -CH ３ , 【Chemistry 4】 A compound according to any one of claims 1 to 3, characterized in that it is the compound described above.

5. R １ H, -CH ３ , 【Transformation 5】 The compound according to any one of claims 1 to 4, characterized in that it is the compound described above.

6. R ２ is H, or -CH ３ A compound according to any one of claims 1 to 5, characterized in that it is the compound described above.

7. Q does not exist, or -CH ２ - 【Transformation 6】 -NH- or -SO ２ A compound according to any one of claims 1 to 6, characterized in that it is selected from -.

8. X is H, C １－３ Selected from alkyl or phenyl, the phenyl is unsubstituted or optionally a halogen, halogenated C １－３ Alkyl, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Alkoxycarbonyl or C １－３ Alkyl-SO ２ The compound according to any one of claims 1 to 7, characterized by being substituted with -.

9. X is H, C １－３ Selected from alkyl or phenyl, the phenyl is either unsubstituted or optionally F, Cl, methyl, trifluoromethyl, methoxy, methylthio, methoxycarbonyl, or methyl-SO ２ The compound according to any one of claims 1 to 8, characterized by being substituted with -.

10. X is -CH ３ , H, 【Transformation 7】 A compound according to any one of claims 1 to 9, characterized in that it is the compound described above.

11. R ３ H, C １－６ Alkyl, C １－６ A compound according to any one of claims 1 to 10, characterized by being an alkoxy or cyano compound.

12. R ３ The compound according to any one of claims 1 to 11, characterized in that is H or methyl.

13. R ４ ha-N(R ５ ) - SO ２ -R ６ A compound according to any one of claims 1 to 12, characterized in that it is the compound described above.

14. R ５ and R ６ These are, independently, H or C １－６ A compound according to any one of claims 1 to 13, characterized in that it is selected from alkyl groups.

15. R ５ and R ６ Each of these is independently selected from H, methyl, or ethyl. The compound according to any one of claims 1 to 14.

16. Y is 【Transformation 8】 A compound according to any one of claims 1 to 15, characterized in that it is the compound described above.

17. Y is 【Chemistry 9】 A compound according to any one of claims 1 to 16, characterized in that it is the compound described above.

18. 1) 4-(1-(4-chlorobenzyl)-2-methyl-1Himidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 2) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 3) 6-methyl-4-(2-methyl-1-(4-(methylthio)benzyl)-1H-imidazo[4,5-b]pyridine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 4) 6-methyl-4-(2-methyl-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 5) 4-(1-(3-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 6) 4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 7) 4-(1,2-dimethyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 8) 6-methyl-4-(2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 9) 4-((2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-imidazo[4,5-b]pyridine-1-yl)methyl)methyl benzoate; 10) 6-benzyl-4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 11) 6-Isobutyl-4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 12) 6-ethyl-4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 13) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-2-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 14) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-(thiazole-2-methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 15) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-(pyrazole-2-methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 16) 4-(1-(3-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-2-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 17) 4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-6-(pyridine-3-methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 18) 4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyrazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 19) 6-methyl-4-(2-methyl-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyrazine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 20) 4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 21) 4-(1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-imidazo[4,5-b]pyrazine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 22) 4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 23) 4-(1-(3-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 24) 4-(1-(2-fluoro-5-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2 ,3-c]pyridine-7(6H)-one; 25) 4-(1-(3-fluoro-5-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 26) 4-(1-(2-fluoro-4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 27) 4-(1-(3-trifluoromethyl-4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 28) 4-(1-(3-fluoro-4-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 29) 4-(1-(3-chloro-4-trifluoromethylbenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 30) 4-(1-(3-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 31) 4-(1-(2,4-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 32) 4-(1-(4-bromobenzyl)-2-methyl-1H-imidazo[4,5-b]piperazine-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 33) 6-methyl-4-(2-methyl-1-(4-(methylsulfonyl)benzyl)-1H-imidazo[4,5-b]pyrazine-6-yl)-1H-pyrrolo[2,3-c]pyridine-7(6H)-one; 34) 1-(4-chlorobenzyl)-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-one; 35) 4-(3-(1-(2,6-dichloro-3-fluorophenyl)ethyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 36) 4-(1-(2,6-dichlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 37) 4-(4-((4-chlorophenyl)amino)pyrido[2,3-d]pyrimidine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 38) 4-(1-(2,6-dichlorobenzyl)-2-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 39) 4-(1-(4-chlorobenzyl)-1H-pyrazolo[4,3-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 40) 4-(1-((4-chlorophenyl)sulfuryl)-1H-pyrrolo[2,3-b]pyridine-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one; 41) N-(1-(4-chlorobenzyl-2-methyl-6-(6-methyl-7-oxy -6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 42) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 43) N-(1-(4-methoxybenzyl-2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 44) N-(1-(1-(4-chlorophenyl)ethyl)-2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 45) N-(1-benzyl-2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 46) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 47) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 48) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 49) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2-fluoro-4-chlorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 50) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-(trifluoromethyl)-4-chlorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 51) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-fluoro-4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 52) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-chloro-4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 53) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 54) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2,4-difluorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 55) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(4-bromobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 56) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H- Pyrrolo[2,3-c]pyridin-4-yl)-1-(4-(methylsulfonyl)benzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 57) N-(2-methyl-6-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-(2-chloro-4-fluorobenzyl)-1H-benzo[d]imidazole-4-yl)ethanesulfonamide; 58) N-(5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 59) N-(3-(2,4-difluoromethylbenzyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 60) N-(3-(1-(4-chlorophenyl)ethyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 61) N-(3-(2-fluoro-5-(trifluoromethyl)benzyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 62) N-(3-(3,5-difluorobenzyl)-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 63) N-(5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(2-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 64) N-(3-(2,4-difluorobenzyl)-2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 65) N-(2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 66) N-(2-methyl-5-(6-methyl-7oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3-(2-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; 67) N-(3-(3,5-difluorobenzyl)-2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide; or 68) N-(3-(2,6-dimethylbenzyl)-2-methyl-5-(6-methyl-7-oxy-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl)ethanesulfonamide A compound, or a pharmaceutically acceptable salt thereof, characterized by being such.

19. A pharmaceutical composition comprising a therapeutically effective amount of any compound according to claim 1 to 18, and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition according to claim 19, characterized in that the weight ratio of the compound to the excipient is in the range of 0.001 to 10.

21. Use of the pharmaceutical composition according to claim 19 or 20, or the compound according to any one of claims 1 to 18, in the manufacture of a pharmaceutical product.

22. The use according to claim 21, characterized in that the pharmaceutical product is for the treatment or prevention of cancer, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, kidney diseases, viral infections and / or obesity.

23. The use according to claim 22, characterized in that the cancer is selected from B-cell acute lymphoblastic leukemia, Burkitt lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, follicular lymphoma, primary plasma cell leukemia, large cell neuroendocrine carcinoma, colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, melanoma, pancreatic cancer, brain tumor, or lung cancer.

24. The use according to claim 21, characterized in that the pharmaceutical product is used as a BET inhibitor.

25. The use according to claim 24, characterized in that the pharmaceutical product is used as a BRD4 inhibitor.

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