Fused five- and six-membered heterocyclic compound, and use thereof

Abstract

Provided are a fused five- and six-membered heterocyclic compound, and the use thereof. Specifically, provided are a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and the use thereof in a drug for treating and / or preventing SSTR2-associated diseases.

Description

Five-membered and six-membered heterocyclic compounds and uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims priority to Chinese Patent Application No. 2024107895976, filed on June 18, 2024, Chinese Patent Application No. 2024108089568, filed on June 20, 2024, and Chinese Patent Application No. 2024109333297, filed on July 11, 2024, the contents of all of which are incorporated by reference herein in their entirety as part of this application. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and relates to five-membered and six-membered heterocyclic compounds and uses thereof. BACKGROUND

[0004] Somatostatin (SST) is a polypeptide hormone that regulates neurotransmission in the brain and hormone secretion from endocrine cells in the anterior pituitary, pancreas, and gastrointestinal tract, and inhibits the secretion of growth hormone (GH). It also has inhibitory effects on cell proliferation, angiogenesis, and induction of apoptosis.

[0005] The biological activity of somatostatin is mediated by G protein-coupled somatostatin receptors (SSTRs) on the target cell membrane, of which there are five subtypes: SSTR1, SSTR2, SSTR2, SSTR3, SSTR4, and SSTR5. These are expressed in both normal tissues and tumors. Among them, SSTR2 is highly expressed in neuroendocrine tumors such as pancreatic neuroendocrine tumors. SST can directly or indirectly inhibit cell proliferation. After binding to somatostatin receptors (SSTRs), it inhibits DNA synthesis through cAMP, MAPK, PI3K, and other signaling pathways to exert an anti-tumor effect. The expression of SSTR2 is also associated with endocrine and metabolic diseases, such as acromegaly caused by excessive release of growth hormone. After binding to SSTRs, SST can inhibit the secretion of growth hormone (GH), thereby reducing the secretion of insulin-like growth factor-1 (IGF-1) and other growth-promoting factors by the liver.

[0006] Currently, somatostatin analogs such as octreotide and lanreotide have been approved for use in acromegaly and syndromes caused by neuroendocrine tumors such as carcinoid syndrome, which bind to somatostatin receptor subtype 2 (SSTR2) with high affinity. However, injections are the main method of administration in clinical practice, which is inconvenient to use. Therefore, there is a need to develop a small molecule SSTR2 agonist.

[0007] A small molecule non-peptide somatostatin type 2 (SSTR2) receptor agonist, paltusotine, is currently in clinical phase 3 trials, and can inhibit growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, and is developed for the treatment of acromegaly and neuroendocrine tumors. SUMMARY

[0008] The present application provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009] wherein,

[0010] Y is N or CR 2 ;

[0011] Z is S, CR 4 or NR 3 ;

[0012] W is C or N;

[0013] R 5 is absent, or selected from H, C1-C6alkyl, C1-C6alkoxy, C6-C 10 arylC1-C6alkyl, C3-C8cycloalkylC1-C6alkyl, 5-14 membered heteroarylC1-C6alkyl, 3-10 membered heterocyclylC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl; wherein said C1-C6alkyl, C1-C6alkoxy, C6-C 10 arylC1-C6alkyl, C3-C8cycloalkylC1-C6alkyl, 5-14 membered heteroarylC1-C6alkyl, 3-10 membered heterocyclylC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl is optionally substituted with one or more R g ;

[0014] said R g is selected from halogen, cyano, hydroxyl, nitro, amino, carboxyl, C1-C6alkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, C2-C6alkenyl, or C2-C6alkynyl;

[0015] B is selected from a chemical bond, -O-, -C(O)-, -NH-, or

[0016] wherein indicates that B is connected to R6 Location;

[0017] R d Selected from hydrogen or C1-C3 alkyl;

[0018] R 6 Selected from C3-C8 cycloalkyl, 3-12 membered heterocyclic C1-C6 alkyl, or 3-12 membered heterocyclic; R 6 Optionally by one or more R b replace;

[0019] Each R b They may be the same or different, and each is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -SR x -S(=O)R x -S(=O)2R x -S(=O)N(R) x (R) y -S(=O)2N(R) x (R) y ), -N(R y )S(=O)2R x -N(R) y )S(=O)R x , -C(=O)N(R x (R) y ), -N(R y )C(=O)R x -P(=O)(R x (R) y -OR x -C(O)R x -C(O)-OR x -N(R) x (R) y ), 3-10 membered heterocyclic groups, C3-C8 cycloalkyl groups, C6-C 10 Aryl or 5-14 heteroaryl groups;

[0020] R 7 Selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, or halo-C1-C6 alkoxy;

[0021] A is an optional location covered by 1-5 R's. e Substituted phenyl;

[0022] Each R ethe same or different and each independently selected from halogen, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, amino-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -SR x , -S(=O)R x , -S(=O)2R x , -S(=O)N(R x )(R y ), -S(=O)2N(R x )(R y ), -N(R y )S(=O)2R x , -N(R y )S(=O)R x , -C(=O)N(R x )(R y ), -N(R y )C(=O)R x , -P(=O)(R x )(R y ), -OR x , -C(=O)R x , -C(=O)-OR x , -N(R x )(R y ), 3-10 membered heterocyclyl, C3-C8-cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl;

[0023] R 1 is selected from cyano, C6-C 10 aryl, 5-14 membered heteroaryl, C3-C 10 cycloalkyl, 3-12 membered heterocyclyl, C6-C 10 arylaminoacyl or 5-14 membered heteroarylaminoacyl; wherein the C6-C 10 aryl, 5-14 membered heteroaryl, C3-C 10 cycloalkyl, 3-12 membered heterocyclyl, C6-C 10 arylaminoacyl or 5-14 membered heteroarylaminoacyl is each independently optionally substituted with one or more R c ;

[0024] each R c is the same or different and each independently selected from halogen, cyano, nitro, Ci-C6-alkyl, -SR x , -S(=O)R x , -S(=O)2R x , -S(=O)N(R x )(Ry ), -S(=O)2N(R x )(R y ), -N(R y )S(=O)2R x , -N(R y )S(=O)R x , -C(=O)N(R x )(R y ), -N(R y )C(=O)R x , -P(=O)(R x )(R y ), -OR x , -C(=O)R x , -C(=O)-OR x , -N(R x )(R y ), 3-10 membered heterocyclyl, C3-C8cycloalkyl, C6-C 10 aryl, or 5-14 membered heteroaryl; wherein each of said Ci-C6alkyl, 3-10 membered heterocyclyl, C3-C8cycloalkyl, C6-C 10 aryl, or 5-14 membered heteroaryl is independently optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, Ci-C3alkyl, or Ci-C3alkoxy;

[0025] R 2 is selected from hydrogen, halogen, cyano, amino, hydroxyl, Ci-C6alkyl, or C6-C 10 aryl; wherein said Ci-C6alkyl or C6-C 10 aryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, Ci-C6alkyl, Ci-C6alkoxy, halogenated Ci-C6alkyl, halogenated Ci-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-10 membered heterocyclyl, C3-C8cycloalkyl, C6-C 10 aryl, or 5-14 membered heteroaryl;

[0026] R 3 is absent, or is selected from hydrogen, Ci-C6alkyl, C6-C 10 aryloxy, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, or 5-14 membered heteroaryl; wherein each of said Ci-C6alkyl, C6-C 10 aryloxy, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, or 5-14 membered heteroaryl is independently optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, Ci-C6alkyl, Ci-C6alkoxy, halogenated Ci-C6alkyl, halogenated Ci-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-10 membered heterocyclyl, C3-C8cycloalkyl, C6-CArylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 aryl; wherein the C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 heteroaryl C1-C6 alkyl, (5-14 heteroaryl substituted C6-C 10 Aryl) C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C6-C 10 aryl carbonyl C1-C6 alkyl, C6-C 10 Arylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 Each aryl group is independently and optionally controlled by one or more R groups. a replace;

[0027] R 4 Selected from hydrogen, C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 heteroaryl C1-C6 alkyl, (5-14 heteroaryl substituted C6-C 10 Aryl) C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C6-C 10 aryl carbonyl C1-C6 alkyl, C6-C 10 Arylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 aryl; wherein the C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C6-C 10 aryl carbonyl C1-C6 alkyl, C6-C 10arylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, (5-14 membered heteroaryl substituted C6-C 10 Aryl) C1-C6 alkyl, 3-10 heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 Each aryl group is independently and optionally controlled by one or more R groups. a replace;

[0028] Each R a They may be the same or different, and each is independently selected from halogen, cyano, benzyloxy, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -SR x -S(=O)R x -S(=O)2R x -S(=O)N(R) x (R) y -S(=O)2N(R) x (R) y ), -N(R y )S(=O)2R x -N(R) y )S(=O)R x , -C(=O)N(R x (R) y ), -N(R y )C(=O)R x -P(=O)(R x (R) y -OR x -C(O)R x -C(O)-OR x -N(R) x (R) y ), C3-C8 cycloalkyl, 3-12 membered heterocyclic, C6-C 10 Aryl, 5-14 heteroaryl, C6-C 10 Aryl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-12 membered heterocyclic C1-C6 alkyl, C6-C 10 Aryloxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl; wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, C6-C 10Aryl, 5-14 heteroaryl, C6-C 10 Aryl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-12 membered heterocyclic C1-C6 alkyl, C6-C 10 Each of the aryloxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl groups is independently and optionally substituted by one or more groups selected from halogen, cyano, hydroxy, amino, nitro, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkoxy groups.

[0029] R x R y They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0030] The condition is that when W is N, Z is not S; and when R... 5 When it exists, Z is NR. 3 And R 3 It does not exist.

[0031] In some implementations, W is C.

[0032] In some implementations, Z is NR 3 .

[0033] In some implementations, at least one of Y, Z, and W is N or NR. 3 .

[0034] In some implementations, one, two, or three of Y, Z, and W are N or NR. 3 .

[0035] In some implementations, one or two of Y, Z, and W are N or NR. 3 .

[0036] In some implementations, Y is CR 2 Z represents S, and W represents C.

[0037] In some implementations, Y is N and Z is NR. 3 W is C.

[0038] In some embodiments, Y is CR 2 , Z is NR 3 , and W is C.

[0039] In some embodiments, Y is CR 2 , Z is CR 4 , and W is N.

[0040] In some embodiments, R 5 is selected from C6-C 10 aryl C1-C6 alkyl, 3-10 membered heterocyclyl C1-C6 alkyl, or 5-14 membered heteroaryl C1-C6 alkyl, said R 5 optionally substituted with one or more R g .

[0041] In some embodiments, R 5 is selected from phenyl C1-C6 alkyl, pyrazolyl C1-C6 alkyl, pyridinyl C1-C6 alkyl, or dihydropyrroloimidazolyl C1-C6 alkyl, said R 5 optionally substituted with one or more R g .

[0042] In some embodiments, R 5 is selected from phenyl C1-C3 alkyl, pyrazolyl C1-C3 alkyl, pyridinyl C1-C3 alkyl, or dihydropyrroloimidazolyl C1-C3 alkyl, said R 5 optionally substituted with one or more R g .

[0043] In some embodiments, R 5 is selected from , said R 5 optionally substituted with one or more R g .

[0044] In some embodiments, said R 5 is optionally substituted with 1, 2, or 3 R g .

[0045] In some embodiments, said R g is selected from halogen, cyano, hydroxyl, nitro, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, or halo C1-C6 alkoxy.

[0046] In some embodiments, said R g is selected from methyl.

[0047] In some embodiments, R 5 is selected from

[0048] In some embodiments, R 5 is selected from

[0049] In some embodiments, R 5 is absent.

[0050] In some embodiments, B is selected from a chemical bond.

[0051] In some embodiments, B is selected from -O- or -NH-.

[0052] In some embodiments, B is selected from

[0053] In some embodiments, R 6 is selected from C3-C8cycloalkyl, 3-12 membered heterocyclylCi-C6alkyl, or 3-12 membered heterocyclyl, said R 6 is optionally substituted with one or more R b .

[0054] In some embodiments, said R 6 is selected from C3-C8cycloalkyl, 3-8 membered monocyclic heterocyclyl, 6-10 membered fused heterocyclyl, 6-11 membered spiroheterocyclyl, 5-12 membered bridged heterocyclyl, 3-8 membered monocyclic heterocyclylCi-C6alkyl, 6-10 membered fused heterocyclylCi-C6alkyl, 6-11 membered spiroheterocyclylCi-C6alkyl, or 5-12 membered bridged heterocyclylCi-C6alkyl, said R 6 is optionally substituted with one or more R b .

[0055] In some embodiments, said R 6 is selected from C3-C8cycloalkyl, 3-8 membered nitrogen-containing monocyclic heterocyclyl, 6-10 membered nitrogen-containing fused heterocyclyl, 6-11 membered nitrogen-containing spiroheterocyclyl, 5-12 membered nitrogen-containing bridged heterocyclyl, 3-8 membered nitrogen-containing monocyclic heterocyclylCi-C6alkyl, 6-10 membered nitrogen-containing fused heterocyclylCi-C6alkyl, 6-11 membered nitrogen-containing spiroheterocyclylCi-C6alkyl, or 5-12 membered nitrogen-containing bridged heterocyclylCi-C6alkyl, said R 6 is optionally substituted with one or more R b .

[0056] In some embodiments, said R 6 is selected from C3-C8cycloalkyl, 3-8 membered nitrogen-containing monocyclic heterocyclyl, 6-10 membered nitrogen-containing fused heterocyclyl, 6-11 membered nitrogen-containing spiroheterocyclyl, or 5-12 membered nitrogen-containing bridged heterocyclyl, said R 6 is optionally substituted with one or more R b .

[0057] In some embodiments, said R6 C3-C8cycloalkyl, 4-7 membered nitrogen-containing monocyclic heterocyclyl, 6-10 membered nitrogen-containing fused heterocyclyl, 6-9 membered nitrogen-containing spiroheterocyclyl, or 6-9 membered nitrogen-containing bridged heterocyclyl, said R 6 optionally substituted with one or more R b substituents.

[0058] In some embodiments, the R 6 is selected from 4-7 membered nitrogen-containing monocyclic heterocyclyl, said R 6 optionally substituted with one or more R b substituents.

[0059] In some embodiments, the R 6 is selected from or cyclohexyl, said R 6 optionally substituted with one or more R b substituents.

[0060] In some embodiments, the R 6 is selected from or cyclohexyl, said R 6 optionally substituted with one or more R b substituents.

[0061] In some embodiments, the R 6 is optionally substituted with 1, 2, or 3 R b substituents.

[0062] In some embodiments, the R b are the same or different, and each is independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, amino, 3-10 membered heterocyclyl amine, C3-C8cycloalkyl amine, C6-C 10 aryl amine, 5-14 membered heteroaryl amine, aminoacyl, C1-C6alkylaminoacyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, C1-C6alkylamine, haloC1-C6alkylamine, hydroxyC1-C6alkyl, aminoC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 3-10 membered heterocyclyl, C3-C8cycloalkyl, C6-C 10 aryl, or 5-14 membered heteroaryl.

[0063] In some embodiments, the R b are selected from halogen, cyano, hydroxyl, amino, C1-C6alkylamine, 3-6 membered heterocyclyl amine, C3-C6cycloalkyl amine, C6-C 10arylaminyl, 5-7 membered heteroarylaminyl, carboxyl, aminoacyl, Ci-C6alkylaminoacyl, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloCi-C6alkoxy, haloCi-C6alkylaminyl, hydroxyCi-C6alkyl, aminoCi-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 3-6 membered heterocyclyl, or C3-C6cycloalkyl.

[0064] In some embodiments, the R b is selected from halo, cyano, hydroxyl, amino, Ci-C6alkylaminyl, carboxyl, aminoacyl, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloCi-C6alkoxy, haloCi-C6alkylaminyl, hydroxyCi-C6alkyl, or aminoCi-C6alkyl.

[0065] In some embodiments, the R b is selected from halo, cyano, hydroxyl, amino, carboxyl, aminoacyl, Ci-C6alkyl, Ci-C6alkoxy, or aminoCi-C6alkyl.

[0066] In some embodiments, the R b is selected from amino, -CH2NH2, carboxyl, methyl, methoxy, fluoro, hydroxyl, cyano, or aminoacyl.

[0067] In some embodiments, the R b is selected from amino.

[0068] In some embodiments, R 6 is selected from

[0069] In some embodiments, R 6 is selected from

[0070] In some embodiments, R 6 is selected from

[0071] In some embodiments, the R 7 is hydrogen.

[0072] In some embodiments, A is phenyl optionally substituted with 1, 2, or 3 R e substituents.

[0073] In some embodiments, A is selected from the group consisting of:

[0074] In some embodiments, R ethe same or different, and each is independently selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, hydroxyC1-C6alkyl, C1-C6alkylaminyl, aminocarbonyl, C1-C6alkylaminocarbonyl, C2-C6alkenyl, C2-C6alkynyl, 3-10 membered heterocyclyl, C3-C8cycloalkyl, C6-C10aryl, 5-14 membered heteroaryl, haloC3-C8cycloalkyl, haloC6-C10aryl, halo5-14 membered heteroaryl, and halo3-10 membered heterocyclyl. 10 aryl or 5-14 membered heteroaryl.

[0075] In some embodiments, R e are independently selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, hydroxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 3-7 membered heterocyclyl, C3-C6cycloalkyl, C6-C 10 aryl or 5-7 membered heteroaryl.

[0076] In some embodiments, R e are independently selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, or hydroxyC1-C6alkyl.

[0077] In some embodiments, R e are independently selected from halogen, cyano, C1-C6alkyl, or C1-C6alkoxy.

[0078] In some embodiments, R e are independently selected from fluorine, cyano, methyl, or methoxy.

[0079] In some embodiments, A is selected from the group consisting of:

[0080] In some embodiments, A is selected from

[0081] In some embodiments, A is selected from

[0082] In some embodiments, A is selected from

[0083] In some embodiments, the R 1 is selected from C6-C 10 aryl, 5-14 membered heteroaryl, 3-15 membered heterocyclyl, or C6-C 10 arylaminocarbonyl, the R 1optionally substituted with one or more R c substituents.

[0084] In some embodiments, the R 1 is selected from C6-C 10 aryl, 5-14 membered heteroaryl, 5-6 membered heterocyclyl, or C6-C 10 arylaminoacyl, the R 1 is optionally substituted with one or more R c substituents.

[0085] In some embodiments, the R 1 is selected from C6-C 10 aryl or 5-14 membered heteroaryl, the R 1 is optionally substituted with one or more R c substituents.

[0086] In some embodiments, the R 1 is selected from C6-C 10 aryl, 4-7 membered monocyclic heteroaryl, or 8-10 membered fused heteroaryl, the R 1 is optionally substituted with one or more R c substituents.

[0087] In some embodiments, the R 1 is selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazinonyl, benzodiazolyl, pyridinotriazinonyl, pyridinonyl, oxadiazinonyl, pyridinoimidazolyl, imidazopyridinyl, pyrazolopyridinyl, pyridinopyrazolyl, triazolopyridinyl, benzopyrazolyl, benzimidazinonyl, benzopyrrolyl, indolyl, benzopyridinyl, imidazolinyl, indolonyl, phenylaminoacyl, pyrrolyl, or naphthyl, the R 1 is optionally substituted with one or more R c substituents.

[0088] In some embodiments, the R 1 is selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazinonyl, benzodiazolyl, pyridinotriazinonyl, pyridinoimidazolyl, imidazopyridinyl, pyrazolopyridinyl, pyridinopyrazolyl, triazolopyridinyl, benzopyrazolyl, benzimidazinonyl, benzopyrrolyl, benzopyridinyl, indolonyl, pyrrolyl, or naphthyl, the R 1 is optionally substituted with one or more R c substituents.

[0089] In some embodiments, the R 1selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazinonyl, pyrazolopyridinyl, pyridopyrazolyl, triazolopyridinyl, benzopyrazolyl, benzimidazolonyl, benzopyrrolyl, indolonyl, pyrrolyl, or naphthyl, said R 1 optionally substituted with one or more R c substituents.

[0090] In some embodiments, said R 1 selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazinonyl, pyrazolopyridinyl, benzopyrazolyl, benzimidazolonyl, benzopyrrolyl, pyrrolyl, or indolonyl, said R 1 optionally substituted with one or more R c substituents.

[0091] In some embodiments, said R 1 selected from phenyl, said R 1 optionally substituted with one or more R c substituents.

[0092] In some embodiments, said R 1 selected from phenyl, said R 1 optionally substituted with one or more R c substituents.

[0093] In some embodiments, said R 1 selected from phenyl, said R 1 optionally substituted with one or more R c substituents.

[0094] In some embodiments, said R 1 selected from phenyl, said R 1 optionally substituted with one or more R c substituents.

[0095] In some embodiments, said R 1 selected from phenyl, said R 1 optionally substituted with one or more R c substituents.

[0096] In some embodiments, said R1 selected from phenyl or said R 1 is optionally substituted with one or more R c .

[0097] In some embodiments, said R 1 is optionally substituted with one, two, or three R c .

[0098] In some embodiments, said R c are the same or different, and each is independently selected from halogen, cyano, hydroxyl, amino, nitro, C1-C6alkyl, C1-C6alkoxy, aminoacyl, C1-C6alkylaminoacyl, C3-C6cycloalkyl, or C1-C6alkoxy-C(O)-; wherein each of said C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, or C1-C6alkoxy-C(O)- is independently optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, C1-C3alkyl, or C1-C3alkoxy.

[0099] In some embodiments, said R c are independently selected from halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, aminoacyl, C3-C6cycloalkyl, or C1-C6alkoxy-C(O)-; wherein each of said C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, or C1-C6alkoxy-C(O)- is independently optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, C1-C3alkyl, or C1-C3alkoxy.

[0100] In some embodiments, said R c are independently selected from halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoacyl, C3-C6cycloalkyl, or C1-C6alkoxy-C(O)-; wherein said C3-C6cycloalkyl is optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, C1-C3alkyl, or C1-C3alkoxy.

[0101] In some embodiments, said R c are independently selected from methyl, ethyl, n-propyl, isopropyl, hydroxyl, aminoacyl, fluoro, chloro, cyano, methoxy, -C(O)-OCH3, difluoromethyl, trifluoromethyl, difluoromethoxy, or cyclopropyl; wherein said cyclopropyl is optionally substituted with a group of halogen, cyano, or C1-C3alkyl.

[0102] In some embodiments, said R cIndependently selected from methyl, hydroxy, aminoacyl, fluorine, chlorine, cyano, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, the R... 1 Selected from the following group groups: phenyl,

[0103] In some implementations, the R 1 Selected from the following group groups:

[0104] In some implementations, the R 1 Selected from the following group groups:

[0105] In some implementations, the R 1 Selected from the following group groups:

[0106] In some implementation schemes, R 2 The group is selected from hydrogen or phenyl; the phenyl group is optionally substituted with one or more groups selected from halogen, cyano, hydroxy, amino, nitro or C1-C6 alkyl.

[0107] In some implementation schemes, R 2 Selected from hydrogen.

[0108] In some implementation schemes, R 3 It does not exist.

[0109] In some implementation schemes, R a They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, benzyloxy, nitro, carboxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 Aryl, 5-14 heteroaryl, C6-C 10 Aryl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-12 membered heterocyclic C1-C6 alkyl, C6-C 10 aryloxy C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, or C1-C6 alkylamide; wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, or C6-C 10aryl, 5-14 membered heteroaryl, C6-C 10 aryl, 5-14 membered heteroaryl, C6-C 10 each independently optionally substituted by one or more groups selected from halogen, cyano, hydroxy, amino, nitro, C1-C3alkyl, haloC1-C3alkyl, C1-C3alkoxy or haloC1-C3alkoxy.

[0110] In some embodiments, the R 3 selected from hydrogen, C1-C6alkyl, C6-C 10 aryl, 5-14 membered heteroaryl, C6-C 10 aryl, 5-14 membered heteroaryl, C6-C 3 optionally substituted by one or more R a substituents.

[0111] In some embodiments, the R 3 selected from hydrogen, C1-C6alkyl, C6-C 10 aryl, 5-14 membered heteroaryl, C6-C 10 aryl, 5-14 membered heteroaryl, C6-C 3 optionally substituted by one or more R a substituents.

[0112] In some embodiments, the R 3 selected from hydrogen, C6-C 10 aryl, 5-14 membered heteroaryl, C6-C 3 optionally substituted by one or more R a substituents.

[0113] In some embodiments, the R 3 is C6-C 10 aryl, 5-14 membered heteroaryl, C6-C 3 optionally substituted by one or more R a substituents.

[0114] In some embodiments, the R3 selected from hydrogen, Ci-C6alkyl, phenylCi-C6alkyl, cyclopropylCi-C6alkyl, pyrazolylCi-C6alkyl, triazolylCi-C6alkyl, pyrimidinylCi-C6alkyl, pyridinylCi-C6alkyl, dihydropyrroloimidazolylCi-C6alkyl, benzoylCi-C6alkyl, benzimidazolonylCi-C6alkyl, imidazolylCi-C6alkyl, or oxadiazolylCi-C6alkyl, said R 3 optionally substituted with one or more R a substituents.

[0115] In some embodiments, said R 3 selected from hydrogen, Ci-C6alkyl, phenylCi-C6alkyl, cyclopropylCi-C6alkyl, pyrazolylCi-C6alkyl, triazolylCi-C6alkyl, pyrimidinylCi-C6alkyl, pyridinylCi-C6alkyl, dihydropyrroloimidazolylCi-C6alkyl, or benzoylCi-C6alkyl, said R 3 optionally substituted with one or more R a substituents.

[0116] In some embodiments, said R 3 selected from hydrogen, phenylCi-C6alkyl, pyrazolylCi-C6alkyl, triazolylCi-C6alkyl, pyrimidinylCi-C6alkyl, pyridinylCi-C6alkyl, dihydropyrroloimidazolylCi-C6alkyl, or benzoylCi-C6alkyl, said R 3 optionally substituted with one or more R a substituents.

[0117] In some embodiments, said R 3 selected from phenylCi-C6alkyl, pyrimidinylCi-C6alkyl, or pyridinylCi-C6alkyl, said R 3 optionally substituted with one or more R a substituents.

[0118] In some embodiments, said R 3 selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl-CH2-, cyclopropane-CH2-, pyrazolyl-CH2-, phenyl-CH(CH3)-, cyclopropyl-CH(CH3)-, pyrazolyl-CH(CH3)-, triazolyl-(CH2)3-, pyrimidinyl-CH2-, pyrimidinyl-CH(CH3)-, pyridinyl-CH(CH3)-, imidazolyl-CH(CH3)-, oxadiazolyl-CH(CH3)-, dihydropyrroloimidazolyl-CH(CH3)-, phenyl-C(O)-CH2-, or benzimidazolonyl-CH2-CH2-, said R 3 optionally substituted with one or more R a substituents.

[0119] In some embodiments, said R 3 is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl-CH2-, cyclopropane-CH2-, pyrazolyl-CH2-, phenyl-CH(CH3)-, pyrazolyl-CH(CH3)-, triazolyl-(CH2)3-, pyrimidinyl-CH(CH3)-, pyridyl-CH(CH3)-, dihydropyrroloimidazolyl-CH(CH3)- or phenyl-C(O)-CH2-, said R 3 is optionally substituted with one or more R a substituents.

[0120] In some embodiments, said R 3 is selected from hydrogen, phenyl-CH2-, phenyl-CH(CH3)-, pyrazolyl-CH2-, phenyl-CH(CH3)-, pyrazolyl-CH(CH3)-, triazolyl-(CH2)3-, pyrimidinyl-CH(CH3)-, pyridyl-CH(CH3)-, dihydropyrroloimidazolyl-CH(CH3)- or phenyl-C(O)-CH2-, said R 3 is optionally substituted with one or more R a substituents.

[0121] In some embodiments, said R 3 is selected from phenyl-CH(CH3)-, pyrimidinyl-CH(CH3)- or pyridyl-CH(CH3)-, said R 3 is optionally substituted with one or more R a substituents.

[0122] In some embodiments, said R 3 is selected from hydrogen, methyl, ethyl, cyclopropane-CH2-, said R 3 is optionally substituted with one or more R a substituents.

[0123] In some embodiments, said R 3 is selected from hydrogen, methyl, cyclopropane-CH2-, said R 3 is optionally substituted with one or more R a substituents.

[0124] In some embodiments, said R 3 is selected from hydrogen, R 3 optionally substituted with one or more R a substituents.

[0125] In some embodiments, the R 3 is selected from R 3 optionally substituted with one or more R a substituents.

[0126] In some embodiments, the R 3 is selected from R 3 optionally substituted with one or more R a substituents;

[0127] each R h is the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, nitro, carboxyl, C1-C6alkyl, or C1-C6alkoxy; wherein the C1-C6alkyl or C1-C6alkoxy is optionally substituted with one or more groups selected from halogen, hydroxyl, amino, or C1-C6alkoxy.

[0128] In some embodiments, the R h is selected from hydrogen, halogen, C1-C6alkyl, or C1-C6alkoxy; wherein the C1-C6alkyl or C1-C6alkoxy is optionally substituted with one or more groups selected from halogen, hydroxyl, amino, or C1-C6alkoxy. In some embodiments, the R h is selected from hydrogen, halogen, C1-C3alkyl, or C1-C3alkoxy; wherein the C1-C3alkyl or C1-C3alkoxy is optionally substituted with one or more groups selected from halogen, hydroxyl, or C1-C3alkoxy.

[0129] In some embodiments, the R h is selected from fluorine, chlorine, methyl, hydroxymethyl, bromomethyl, methoxy, methoxymethyl, or trifluoromethyl.

[0130] In some embodiments, the R 3 is optionally substituted with 1, 2, or 3 R a substituents.

[0131] In some embodiments, the R a are the same or different, and each is independently selected from halogen, cyano, hydroxyl, amino, nitro, carboxyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, hydroxyC1-C6alkyl, aminoC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, C3-C8cycloalkenyl, 5-6 membered heteroaryl, C1-C6alkylcarbonyl, C1-C6alkoxycarbonyl, aminocarbonyl, or haloC1-C6alkoxycarbonyl. 10Aryl, 5-8 quinone heteroaryl, C6-C 10 aryl C1-C6 alkyl, 5-8 membered heteroaryl C1-C6 alkyl, 3-8 membered heterocyclic C1-C6 alkyl, or C3-C8 cycloalkyl C1-C6 alkyl; wherein the C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, or C6-C 10 Aryl, 5-8 quinone heteroaryl, C6-C 10 The aryl C1-C6 alkyl, 5-8-membered heteroaryl C1-C6 alkyl, 3-8-membered heterocyclic C1-C6 alkyl, or C3-C8 cycloalkyl C1-C6 alkyl groups are each optionally and independently substituted by one or more groups selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, or haloC1-C6 alkoxy groups.

[0132] In some implementations, the R a Selected from halogen, cyano, hydroxy, amino, nitro, carboxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, hydroxylated C1-C4 alkyl, C6-C 10 Aryl or C6-C 10 Aryl C1-C4 alkyl.

[0133] In some implementations, the R a It is selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, hydroxy C1-C4 alkyl, carboxyl, C1-C4 alkoxy or benzyl.

[0134] In some implementations, the R a Selected from methyl, fluorine, chlorine, hydroxyl, benzyl, bromine, -OCH3, -CH2OH, -CH2-OCH3, -CH2Br, trifluoromethyl or carboxyl.

[0135] In some implementations, the R a It is selected from methyl, hydroxyl, fluorine, chlorine, -OCH3, -CH2OH, -CH2-OCH3 or trifluoromethyl.

[0136] In some implementations, the R 3 Selected from hydrogen, methyl, ethyl, Cyclopropane-CH2-

[0137] In some implementations, the R 3 Selected from hydrogen, methyl, Cyclopropane-CH2-

[0138] In some implementations, the R 3 Selected from hydrogen,

[0139] In some implementations, the R 3 Selected from

[0140] In some implementations, the R 3 Selected from C6-C 10 arylsulfonyl, 5-14 heteroarylsulfonyl, (5-14 heteroaryl substituted C6-C) 10 aryl)sulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl or C1-C6 alkylaminosulfonyl, wherein R 3 Optionally by one or more R a replace.

[0141] In some implementations, the R 3 Selected from C6-C 10 arylsulfonyl, 4-7 membered monocyclic heteroarylsulfonyl, 6-10 membered fused heteroarylsulfonyl, (4-7 membered monocyclic heteroaryl substituted C6-C) 10 (aryl)sulfonyl, (6-10 fused aryl-substituted C6-C) 10 Aryl)sulfonyl, C3-C6 cycloalkylsulfonyl, 3-8 member monocyclic heterocyclic sulfonyl, 5-10 member fused heterocyclic sulfonyl, C1-C4 alkylsulfonyl or C1-C4 alkylaminosulfonyl, wherein R 3 Optionally by one or more R a replace.

[0142] In some implementations, the R 3 Selected from C6-C 10 arylsulfonyl, 5-6 membered monocyclic heteroarylsulfonyl, 8-10 membered fused heteroarylsulfonyl, (5-6 membered monocyclic heteroaryl substituted C6-C) 10 Aryl)sulfonyl, C3-C6 cycloalkylsulfonyl, 3-6 membered monocyclic heterocyclic sulfonyl, 8-10 membered fused heterocyclic sulfonyl, C1-C4 alkylsulfonyl or C1-C4 alkylaminosulfonyl, wherein R 3 Optionally by one or more R a replace.

[0143] In some implementations, the R 3 Selected from C6-C 10aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, (5-6 membered monocyclic heteroaryl substituted C6-C 10 aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, (5-6 membered monocyclic heteroaryl substituted C6-C 3 optionally substituted with one or more R a substituents.

[0144] In some embodiments, the R 3 is selected from C6-C 10 aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, (5-6 membered monocyclic heteroaryl substituted C6-C 10 aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, (5-6 membered monocyclic heteroaryl substituted C6-C 3 optionally substituted with one or more R a substituents.

[0145] In some embodiments, the R 3 is selected from phenylsulfonyl, pyrazolyl substituted phenylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, pyridylsulfonyl, furanyl sulfonyl, thienylsulfonyl, pyrrolylsulfonyl, triazolylsulfonyl, benzothiophenylsulfonyl, isoxazolylsulfonyl, dihydropyrroloimidazole sulfonyl, cyclopropylsulfonyl, methylsulfonyl, or dimethylaminosulfonyl, the R 3 optionally substituted with one or more R a substituents.

[0146] In some embodiments, the R 3 is selected from phenylsulfonyl, pyrazolyl substituted phenylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, pyridylsulfonyl, furanyl sulfonyl, thienylsulfonyl, pyrrolylsulfonyl, triazolylsulfonyl, benzothiophenylsulfonyl, benzofuranyl sulfonyl, dihydropyrroloimidazole sulfonyl, cyclopropylsulfonyl, or dimethylaminosulfonyl, the R 3 optionally substituted with one or more R a substituents.

[0147] In some embodiments, the R 3 is selected from phenylsulfonyl, pyrazolyl substituted phenylsulfonyl, thiazolylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridylsulfonyl, furanyl sulfonyl, thienylsulfonyl, pyrrolylsulfonyl, triazolylsulfonyl, benzothiophenylsulfonyl, benzofuranyl sulfonyl, or dihydropyrroloimidazole sulfonyl, the R 3 optionally substituted with one or more R a substituents.

[0148] In some embodiments, the R 3 is selected from phenylsulfonyl, pyrazolyl-substituted phenylsulfonyl, thiazolylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridylsulfonyl, furanyl- sulfonyl, pyrrolylsulfonyl, or triazolylsulfonyl, the R 3 is optionally substituted with one or more R a substituents.

[0149] In some embodiments, the R 3 is selected from the following groups: cyclopropylsulfonyl, methylsulfonyl, or dimethylaminosulfonyl, the R 3 is optionally substituted with one or more R a substituents.

[0150] In some embodiments, the R 3 is selected from the following groups: cyclopropylsulfonyl, or dimethylaminosulfonyl, the R 3 is optionally substituted with one or more R a substituents.

[0151] In some embodiments, the R 3 is selected from the following groups: the R 3 is optionally substituted with one or more R a substituents.

[0152] In some embodiments, the R 3 is selected from the following groups: the R 3 is optionally substituted with one or more R a substituents.

[0153] In some embodiments, the R 3 is optionally substituted with one, two, or three R a substituents.

[0154] In some embodiments, the R ahalo, cyano, hydroxyl, amino, nitro, carboxyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, hydroxyC1-C6alkyl, aminoC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C3-C8cycloalkyl, wherein each of said C2-C6alkenyl, C2-C6alkynyl, or C3-C8cycloalkyl is independently optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, or haloC1-C6alkoxy.

[0155] In some embodiments, the R a halogen, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, hydroxyl, or C3-C6cycloalkyl.

[0156] In some embodiments, the R a methyl, ethyl, isopropyl, tert-butyl, chloro, fluoro, bromo, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, or cyclopropyl.

[0157] In some embodiments, the R 3 selected from the following groups:

[0158] In some embodiments, the R 3 selected from the following groups:

[0159] In some embodiments, the R 3 selected from the following groups:

[0160] In some embodiments, the R 3 selected from the following groups:

[0161] In some embodiments, the R 3 C1-C6alkyl-C(O)-NH-NH-C(O)-, C3-C 10 C3-C12cycloalkyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl, or C6-C 10 R 3 optionally substituted with one or more R a substituents.

[0162] In some embodiments, the R3 C1-C6alkyl-C(O)-NH-NH-C(O)-, C3-C6cycloalkyl, 3-7 membered monocyclic heterocyclyl, 7-10 membered fused heterocyclyl, 5-7 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, or C6-C10aryl, said R 10 Cycloalkyl, 3-7 membered monocyclic heterocyclyl, 7-10 membered fused heterocyclyl, 5-7 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, or C6-C 10 Aryl, said R 3 Optionally substituted with one or more R a substituents.

[0163] In some embodiments, the R 3 C1-C6alkyl-C(O)-NH-NH-C(O)-, C3-C6cycloalkyl, 3-7 membered monocyclic heterocyclyl, 7-10 membered fused heterocyclyl, 5-7 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, or C6-C 10 Cycloalkyl, 3-7 membered monocyclic heterocyclyl, 7-10 membered fused heterocyclyl, 5-7 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, or C6-C 10 Aryl, said R 3 Optionally substituted with one or more R a substituents.

[0164] In some embodiments, the R 3 phenyl, cyclopropanyl, cyclobutanyl, CH3-C(O)-NH-NH-C(O)-, indanyl, tetrahydroindolyl, oxetanyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, triazolyl, thiazolyl, a-pyridonyl, β-pyridonyl, γ-pyridonyl, benzopyrazolyl, or pyrazolopyridinyl, said R 3 Optionally substituted with one or more R a substituents.

[0165] In some embodiments, the R 3 cyclopropanyl, cyclobutanyl, CH3-C(O)-NH-NH-C(O)-, indanyl, tetrahydroindolyl, oxetanyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, thiazolyl, or benzopyrazolyl, said R 3 Optionally substituted with one or more R a substituents.

[0166] In some embodiments, the R 3 CH3-C(O)-NH-NH-C(O)-, indanyl, tetrahydroindolyl, pyrazolyl, triazolyl, thiazolyl, or benzopyrazolyl, said R 3 Optionally substituted with one or more R a substituents.

[0167] In some embodiments, the R 3 phenyl, cyclopropanyl, cyclobutanyl, CH3-C(O)-NH-NH-C(O)-, said R 3 is optionally substituted with one or more R a .

[0168] In some embodiments, said R 3 is selected from the group consisting of cyclopropanyl, cyclobutanyl, CH3-C(O)-NH-NH-C(O)-, said R 3 is optionally substituted with one or more R a .

[0169] In some embodiments, said R 3 is selected from the group consisting of CH3-C(O)-NH-NH-C(O)-, said R 3 is optionally substituted with one or more R a .

[0170] In some embodiments, said R 3 is optionally substituted with 1, 2, or 3 R a .

[0171] In some embodiments, said R a is selected from halogen, cyano, hydroxyl, amino, benzyloxy, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, hydroxyC1-C6alkyl, C3-C6cycloalkylC1-C6alkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, or C1-C6alkylcarbonylamido; wherein each said C3-C6cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, C1-C3alkyl, haloC1-C3alkyl, C1-C3alkoxy, or haloC1-C3alkoxy.

[0172] In some embodiments, said R a is selected from C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, 3-6 membered heterocyclyl, or C1-C6alkylcarbonylamido; wherein said R a is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, cyano, or amino.

[0173] In some embodiments, said R a is selected from methyl, isopropyl, hydroxyisopropyl, cyclopropanyl, cyclopropane-CH2-, cyclopropanonyl, or acetylamido; wherein said R aoptionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, cyano, or amino.

[0174] In some embodiments, the R 3 selected from the group consisting of phenyl, cyclopropanyl, cyclobutanyl, CH3-C(O)-NH-NH-C(O)-,

[0175] In some embodiments, the R 3 selected from the group consisting of cyclopropanyl, cyclobutanyl, CH3-C(O)-NH-NH-C(O)-,

[0176] In some embodiments, the R 3 selected from the group consisting of CH3-C(O)-NH-NH-C(O)-,

[0177] In some embodiments, the R 3 selected from the group consisting of:

[0178] In some embodiments, the R 4 selected from 5-7 membered heteroaryl sulfonyl or C6-C 10 aryl sulfonyl, the R 4 optionally substituted with one or more R a substituents.

[0179] In some embodiments, the R 4 selected from pyrazole sulfonyl or phenyl sulfonyl, the R 4 optionally substituted with one or more R a substituents.

[0180] In some embodiments, the R 4 selected from the R 4 optionally substituted with one or more R a substituents.

[0181] In some embodiments, the R 4 optionally substituted with 1, 2, or 3 R a substituents.

[0182] In some embodiments, the R a selected from halogen, cyano, hydroxyl, amino, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, or haloC1-C6 alkoxy.

[0183] In some embodiments, the R a is selected from halogen, cyano, hydroxyl, amino, C1-C3alkyl, haloC1-C3alkyl, C1-C3alkoxy, or haloC1-C3alkoxy.

[0184] In some embodiments, the R 4 is selected from

[0185] In some embodiments, the R 4 is selected from

[0186] In some embodiments, the compound is according to Formula (I-1):

[0187] wherein R 1 , Y, Z, B, A, R 6 , R 7 are each defined as in Formula I.

[0188] In some embodiments, the compound is according to Formula (I-2):

[0189] wherein Z is CR 4 or N;

[0190] R 1 , Y, R 4 , B, A, R 6 , R 7 are each defined as in Formula I.

[0191] In some embodiments, the compound is according to Formula (II-1):

[0192] wherein R 1 , R 2 , R 3 , A, R 7 , R x , R y are each defined as in Formula I, and R 3 cannot be absent;

[0193] R 10 , R 11 are each independently selected from hydrogen, C1-C6alkyl, or C3-C8cycloalkyl; each of said C1-C6alkyl or C3-C8cycloalkyl is independently optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, amino, or C1-C6alkyl;

[0194] R 9a , R 9b , R9c R 9d R 9e R 9f R 9g R 9h are identical or different and each independently selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl, halogen-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cyano, amino-Ci-C6-alkyl, nitro, hydroxy-Ci-C6-alkyl, -SR x , -S(=O)R x , -S(=O)2R x , -S(=O)N(R x )(R y ), -S(=O)2N(R x )(R y ), -N(R y )S(=O)2R x , -N(R y )S(=O)R x , -C(=O)N(R x )(R y ), -N(R y )C(=O)R x , -P(=O)(R x )(R y ), -OR x , -C(=O)R x , -C(=O)-OR x , -N(R x )(R y ), 3-10 membered heterocyclyl, C6-C 10 aryl, 5-14 membered heteroaryl or C3-C6-cycloalkyl;

[0195] R 8 is selected from H or Ci-C6-alkyl;

[0196] or R 9a and R 9e together with the carbon atom to which they are attached form a bridge; or R 9a and R 9g together with the carbon atom to which they are attached form a bridge; or R 9c and R 9e together with the carbon atom to which they are attached form a bridge; or R 9c and R 9g together with the carbon atom to which they are attached form a bridge; said bridge having 1, 2, 3 or 4 CH2, wherein any of the CH2may optionally be replaced by O, S, NH; said bridge being optionally substituted with one or more R f ;

[0197] or R 9a and R 9b with the attached carbon atom, or R 9c and R 9d with the attached carbon atom, or R 9e and R 9f with the attached carbon atom or R 9g and R 9h with the attached carbon atom, together form a 3-8 membered cycloalkyl or 3-8 membered heterocyclyl, optionally substituted with one or more R f ;

[0198] or R 9a and R 11 with the attached atom or R 9h and R 10 with the attached atom together form a 4-7 membered heterocyclyl, optionally substituted with one or more R f ;

[0199] or R 9a and R 8 with the attached atom or R 9h and R 8 with the attached atom together form a 3-8 membered cycloalkyl or 3-8 membered heterocyclyl, optionally substituted with one or more R f ;

[0200] or R 8 and R 11 with the attached atom together form a 3-7 membered heterocyclyl, optionally substituted with one or more R f ;

[0201] each R f is the same or different, and each is independently selected from halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, cyano, amino, aminoacyl, carboxyl, nitro, hydroxyl, hydroxyC1-C6 alkyl, or aminoC1-C6 alkyl.

[0202] In some embodiments, R 2 is hydrogen.

[0203] In some embodiments, R 8 is hydrogen or methyl.

[0204] In some embodiments, R 8 is hydrogen.

[0205] In some embodiments, R 10 , R 11 each independently is hydrogen.

[0206] In some embodiments, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9g , R 9h are the same or different and each is independently selected from hydrogen, halogen, Ci-C6alkyl, haloCi-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, haloCi-C6alkoxy, cyano, amino, Ci-C6alkylaminyl, aminoCi-C6alkyl, nitro, hydroxyl, carboxyl, hydroxyCi-C6alkyl, or C3-C6cycloalkyl.

[0207] In some embodiments, the compound is according to Formula (II-2):

[0208] wherein, R 8 , R 10 , R 11 , R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9g , R 9h are each defined according to Formula II-1; R 1 , R 2 , R 4 , A, R 7 are defined according to Formula I.

[0209] In some embodiments, R 10 , R 11 are each independently hydrogen.

[0210] In some embodiments, the R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9g , R 9h are the same or different and each is independently selected from H, F, cyano, hydroxyl, carboxyl, methyl, methoxy, or aminoacyl.

[0211] In some embodiments, the compound according to Formula (II-1) or (II-2) wherein is selected from wherein, R 8 , R10 , R 11 each is defined as described for Formula II-1.

[0212] In some embodiments, the compound is of Formula (III):

[0213] wherein the R 1 is selected from phenyl, the R 1 is optionally substituted with one or more R c ;

[0214] n is 0, 1, 2, 3, 4, or 5;

[0215] the R c , R e , R 3 each is defined as described for Formula II-1.

[0216] In some embodiments, n is 0, 1, 2, or 3.

[0217] In some embodiments, n is 0, 1, or 2.

[0218] In some embodiments, n is 2.

[0219] In another aspect, the present application provides the following compounds, or a pharmaceutically acceptable salt thereof:

[0220] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is:

[0221] In some embodiments, the compound is selected from:

[0222] the isomer of the compound having a retention time of 8.13 min under the following conditions was resolved using preparative HPLC, with the following resolution method: Column: CHIRALPAK-IC 2*25 cm, 5 μm; Mobile Phase A: Cyclohexane (0.1% diethylamine), Mobile Phase B: Ethanol: Dichloromethane (1:1, v / v); Flow Rate: 20 mL / min; Isocratic 40% B; Wavelength: UV 254 / 220 nm; Column Temperature 25 °C;

[0223] the isomer of the compound having a retention time of 9.39 min under the following conditions was resolved using preparative HPLC, with the following resolution method: Column: CHIRALPAK-ID 3*25 cm, 5 μm; Mobile Phase A: n-Hexane (0.1% diethylamine), Mobile Phase B: Ethanol: Dichloromethane (1:1, v / v); Flow Rate: 40 mL / min; Isocratic 30% B; Detection Wavelength: UV 254 / 220 nm; Column Temperature: 25 °C;

[0224] the isomer of the compound having a retention time of 11.46 min under the following conditions was resolved using preparative HPLC, with the following resolution method: Column: CHIRALPAK-ID 3*25 cm, 5 μm; Mobile Phase A: n-Hexane (0.1% diethylamine), Mobile Phase B: Ethanol: Dichloromethane (1:1, v / v); Flow Rate: 40 mL / min; Isocratic 30% B; Detection Wavelength: UV 254 / 220 nm; Column Temperature: 25 °C;

[0225] the isomer of the compound having a retention time of 7.51 min under the following conditions was resolved using preparative HPLC, with the following resolution method: Column: CHIRALPAK-IA 2*25 cm, 5 μm; Mobile Phase A: n-Hexane (0.1% diethylamine), Mobile Phase B: Ethanol: Dichloromethane (1:1, v / v); Flow Rate: 20 mL / min; Isocratic 15% B; Detection Wavelength: UV 254 / 220 nm; Column Temperature: 25 °C;

[0226] the isomer of the compound having a retention time of 9.45 min under the following conditions was resolved using preparative HPLC, with the following resolution method: Column: CHIRALPAK-IA 2*25 cm, 5 μm; Mobile Phase A: n-Hexane (0.1% diethylamine), Mobile Phase B: Ethanol: Dichloromethane (1:1, v / v); Flow Rate: 20 mL / min; Isocratic 15% B; Detection Wavelength: UV 254 / 220 nm; Column Temperature: 25 °C; ​​​​the isomers of the compound of formula (I) are separated by preparative HPLC, the separation being carried out on a CHIRALPAK-IA 2*25 cm, 5 μm column using a mobile phase of n-hexane (0.1% diethylamine) and ethanol:dichloromethane (1 :1, v / v) at a flow rate of 20 mL / min, isocratic 15% B, with detection at UV 254 / 220 nm and a column temperature of 25 °C;

[0227] the compound having a retention time of 5.21 min under the following conditions the isomers of the compound of formula (I) are separated by preparative HPLC, the separation being carried out on a CHIRALPAK-IG 2*25 cm, 5 μm column using a mobile phase of n-hexane (0.1% diethylamine) and ethanol:dichloromethane (1 :1, v / v) at a flow rate of 20 mL / min, isocratic 40% B, with detection at UV 254 / 220 nm and a column temperature of 25 °C;

[0228] the compound having a retention time of 7.91 min under the following conditions the isomers of the compound of formula (I) are separated by preparative HPLC, the separation being carried out on a CHIRALPAK-IG 2*25 cm, 5 μm column using a mobile phase of n-hexane (0.1% diethylamine) and ethanol:dichloromethane (1 :1, v / v) at a flow rate of 20 mL / min, isocratic 40% B, with detection at UV 254 / 220 nm and a column temperature of 25 °C;

[0229] the compound having a retention time of 5.40 min under the following conditions the isomers of the compound of formula (I) are separated by preparative HPLC, the separation being carried out on a CHIRALPAK-ID 2*25 cm, 5 μm column using a mobile phase of methyl-tert-butyl ether (0.1% diethylamine) and ethanol at a flow rate of 20 mL / min, isocratic 10% B, with detection at UV 254 / 220 nm and a column temperature of 25 °C;

[0230] the compound having a retention time of 7.85 min under the following conditions the isomers of the compound of formula (I) are separated by preparative HPLC, the separation being carried out on a CHIRALPAK-ID 2*25 cm, 5 μm column using a mobile phase of methyl-tert-butyl ether (0.1% diethylamine) and ethanol at a flow rate of 20 mL / min, isocratic 10% B, with detection at UV 254 / 220 nm and a column temperature of 25 °C;

[0231] the compound having a retention time of 5.10 min under the following conditions the isomer of the compound having a retention time of 7.34 min under the following conditions, was separated by preparative HPLC with the following separation method: Column: Chiral NX(2) 5 pm, 250*30 mm; Mobile Phase A: Cyclohexane (10 mM NH3-MeOH), Mobile Phase B: Ethanol; Flow Rate: 40 mL / min; Isocratic 20% B; Detection Wavelength: UV 232 / 256 nm; Column Temperature: 25 °C;

[0232] the isomer of the compound having a retention time of 9.58 min under the following conditions, was separated by preparative HPLC with the following separation method: Column: CHIRALPAK ID, 3*25 cm, 5 pm; Mobile Phase A: Cyclohexane: Methyl-tert-Butyl Ether = 1 : 1 (v / v) (0.1% Diethylamine), Mobile Phase B: Methanol; Flow Rate: 40 mL / min; Isocratic 10% B; Detection Wavelength: UV 236 / 220 nm; Column Temperature: 25 °C; the isomer of the compound having a retention time of 16.83 min under the following conditions, was separated by preparative HPLC with the following separation method: Column: CHIRALPAK IE, 3*25 cm, 5 pm; Mobile Phase A: Methyl-tert-Butyl Ether (0.1% Diethylamine), Mobile Phase B: Methanol; Flow Rate: 40 mL / min; Isocratic 30% B; Detection Wavelength: UV 214 / 236 nm; Column Temperature: 25 °C.

[0233] the isomer of the compound having a retention time of 7.34 min under the following conditions, was separated by preparative HPLC with the following separation method: Column: Chiral NX(2) 5 pm, 250*30 mm; Mobile Phase A: Cyclohexane (10 mM NH3-MeOH), Mobile Phase B: Ethanol; Flow Rate: 40 mL / min; Isocratic 20% B; Detection Wavelength: UV 232 / 256 nm; Column Temperature: 25 °C;

[0234] the isomer of the compound having a retention time of 9.58 min under the following conditions, was separated by preparative HPLC with the following separation method: Column: CHIRALPAK ID, 3*25 cm, 5 pm; Mobile Phase A: Cyclohexane: Methyl-tert-Butyl Ether = 1 : 1 (v / v) (0.1% Diethylamine), Mobile Phase B: Methanol; Flow Rate: 40 mL / min; Isocratic 10% B; Detection Wavelength: UV 236 / 220 nm; Column Temperature: 25 °C; the isomer of the compound having a retention time of 16.83 min under the following conditions, was separated by preparative HPLC with the following separation method: Column: CHIRALPAK IE, 3*25 cm, 5 pm; Mobile Phase A: Methyl-tert-Butyl Ether (0.1% Diethylamine), Mobile Phase B: Methanol; Flow Rate: 40 mL / min; Isocratic 30% B; Detection Wavelength: UV 214 / 236 nm; Column Temperature: 25 °C.

[0235] The present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the first aspect or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0236] The medicaments of the present application can be administered by any suitable route or method, for example, by oral or parenteral administration. A therapeutically effective amount of a compound of the first aspect is from about 0.001 mg to 20 mg per Kg body weight per day, preferably from 0.01 mg to 10 mg per Kg body weight per day.

[0237] ​The third aspect of the present application provides use of the compound of the first aspect or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect in the manufacture of a medicament for treating and / or preventing a SSTR2 related disease.

[0238] The fourth aspect of the present application provides the compound of the first aspect or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect for use in treating and / or preventing a SSTR2 related disease.

[0239] The fifth aspect of the present application provides a method for treating a SSTR2 related disease, which comprises the step of administering to a patient in need thereof a therapeutically effective amount of the compound of the first aspect or a pharmaceutically acceptable salt thereof, or administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of the second aspect.

[0240] The sixth aspect of the present application provides the compound of the first aspect or the pharmaceutical composition of the present application for use in preventing and / or treating a SSTR2 related disease.

[0241] Examples of the SSTR2 related disease include, but are not limited to, peptic ulcer bleeding or acute pancreatitis.

[0242] The compound of the present application has agonistic effect on SSTR2, has high selectivity, and has good pharmacokinetic absorption, and has obviously better oral absorption effect.

[0243] Definitions

[0244] Unless otherwise indicated herein, the following terms used in this application have the following meanings. A particular term should not be construed as indefinite or unclear in the absence of a specific definition, but should be understood according to the ordinary meaning in the art.

[0245] The term "substituted" or "substituted with" means that any one or more hydrogen atoms on the specified atom are replaced with a substituent, provided that the valence of the specified atom is normal and the substituted compound is stable.

[0246] The term "optionally" or "optionally" means that the event or circumstance subsequently described can or can not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance. The "optionally substituted" described in the present application includes both "substituted" and "unsubstituted".

[0247] "one or more" herein refers to an integer of one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; further can be one, two, three, four or five; further can be one, two or three; but needs to meet the requirement of chemical valence.

[0248] When any variable (e.g., R) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other place in the compound.

[0249] The numerical ranges recited herein are inclusive of the integers within the given range. For example, "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C3-C6" means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0250] The term "membered" refers to the number of skeletal atoms or groups of atoms that make up a ring. For example, a group such as C=O, S(=O)2, or S(=O) has one skeletal atom, C, S, S, respectively, and is referred to as 1-membered. For example, "5-7 membered" means that the number of skeletal atoms or groups of atoms that make up a ring is 5, 6, or 7. For example, pyridine, piperidine is a six-membered ring, and thiazole and pyrrole are five-membered rings.

[0251] The term "chemical bond" refers to the strong force of attraction between two or more atoms (or ions) within a molecule or crystal, which binds them together, including covalent bond, ionic bond, metallic bond, coordinate bond, etc. Unless otherwise specified, the chemical bond in the compounds of the present application in free form is mostly covalent bond.

[0252] in which represents the point of attachment of the group to the rest of the molecule.

[0253] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or pharmaceutical agent to produce a desired result, without being toxic to the subject.

[0254] The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and non-toxicity of the free acids and bases of the particular compound. For example, salts of acids (including organic acids and inorganic acids) or salts of bases (including organic bases and inorganic bases) are meant.

[0255] The term "pharmaceutically acceptable carrier" refers to those carriers which do not cause an appreciable level of stimulation to the organism, and do not impair the biological activity and properties of the active compound. It includes, but is not limited to, diluents, disintegrants, binders, glidants, wetting agents.

[0256] The compounds of the present application exist in possible unsymmetrical centers and other chemical structures, and therefore the present application also includes these stereoisomers and mixtures thereof. Since the compounds of the present application (or their pharmaceutically acceptable salts) can exist in diastereomeric or enantiomeric forms or mixtures thereof. All optical isomers (e.g., enantiomeric and diastereomeric), racemic mixtures, diastereomeric mixtures, and other mixtures are within the scope of the present application. The compounds of the present application can be prepared using diastereomeric, enantiomeric, or racemic mixtures as starting materials. Optically active forms can be separated from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0257] A solid line A solid wedge Or a dashed wedge indicates a carbon-carbon bond of a compound of the present application. A bond to an asymmetric carbon atom is depicted as a solid line, indicating that all possible stereoisomers, e.g., enantiomeric, diastereomeric, or racemic mixtures are included. A bond to an asymmetric carbon atom is depicted as a solid wedge or a dashed wedge, indicating that the depicted stereoisomer, e.g., (R)- or (S)-enantiomer, is intended.

[0258] The term "tautomer" or "tautomeric forms" refers to different functional group isomers that are in a dynamic equilibrium and can rapidly interconvert. All tautomeric forms of the compounds of the present application are within the scope of the present application, either as individual isomers or mixtures thereof in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like.

[0259] The present application also includes isotopically-labelled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present application include isotopes of hydrogen, carbon, oxygen, nitrogen, sulfur, such as2H,3H,11C,13C,14C,15O,17O,18O,35S, and the like. Certain isotopically-labelled compounds of the present application (for example, those into which3H and14C are incorporated) are useful in compound and / or substrate tissue distribution assay methods. Deuterium, i.e.,2H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as15O,11C are useful in PET (positron emission tomography) studies for measuring substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples below, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent.

[0260] Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances, wherein deuterium substitution can be partial or complete, partial deuterium substitution refers to replacement of at least one hydrogen with at least one deuterium. Non-limiting examples of deuterated compounds include, but are not limited to: etc.

[0261] The present invention provides The present invention provides denotes an aromatic ring, which can have a double bond anywhere within the ring.

[0262] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which can be straight-chain or branched. For example, the term "Ci-C6alkyl" refers to alkyl groups containing 1 to 6 carbon atoms, non-limiting examples including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, i-hexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like. The term "Ci-C6alkyl" further can be "Ci-C4alkyl", "Ci-C3alkyl", Ci alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, C6alkyl.

[0263] The term "Ci-C6alkoxy" refers to "Ci-C6alkyl-O-", said "Ci-C6alkyl" being as previously defined. Non-limiting examples of said Ci-C6alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-l-butoxy, 2-methyl-l-butoxy, and the like. The "Ci-C6alkoxy" of the present invention further can be "Ci-C4alkoxy", "Ci-C3alkoxy".

[0264] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0265] The term "hydroxy" refers to the -OH group.

[0266] The term "amino" refers to the -NH2group.

[0267] The term "cyano" refers to a -CN group.

[0268] The term "nitro" refers to a -NO2 group.

[0269] The term "carbonyl" refers to an organic functional group (C=O) that consists of a carbon and an oxygen atom connected by a double bond.

[0270] The term "carboxyl" refers to -C(O)OH.

[0271] The term "haloCi-C6alkyl" or "haloCi-C6alkoxy" as used herein refers to an alkyl or alkoxy group substituted with one or more halogen atoms, wherein "halogen", "Ci-C6alkyl" or "Ci-C6alkoxy" are as defined above. Specific examples include, but are not limited to, difluoroethyl (-CH2CHF2, -CF2CH3, -CHFCH2F), trifluoroethyl (-CH2CF3, -CF2CH2F, -CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), and the like. The term "haloCi-C6alkyl" can further be "haloCi-C4alkyl", "haloCi-C3alkyl"; the term "haloCi-C6alkoxy" can further be "haloCi-C4alkoxy", "haloCi-C3alkoxy".

[0272] The term "hydroxyCi-C6alkyl" refers to an alkyl group substituted with one or more hydroxyl groups. Wherein "hydroxyl" or "Ci-C6alkyl" are as defined above. Specific examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like. The term "hydroxyCi-C6alkyl" can further be "hydroxyCi-C4alkyl", "hydroxyCi-C3alkyl".

[0273] The term "aminoCi-C6alkyl" refers to an alkyl group substituted with one or more amino groups. Wherein "amino" or "Ci-C6alkyl" are as defined above. Specific examples include, but are not limited to, -CH2NH2, -(CH2)2NH2, -CH(NH2)CH3, -CH(NH2)CH2NH2, -(CH2)3NH2. The term "aminoCi-C6alkyl" can further be "aminoCi-C4alkyl", "aminoCi-C3alkyl".

[0274] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond, wherein alkyl is as defined above. "C2-C6alkenyl" as used herein refers to alkenyl groups having from 2 to 6 carbon atoms. It can be a mono-olefin, a di-olefin, or a tri-olefin, non-limiting examples include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, and the like.

[0275] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, wherein the definition of alkyl is given above. Optionally containing at least one double bond, and which is attached to the rest of the molecule by a single bond. "C2-C6alkynyl" as used herein refers to an alkynyl group having 2 to 6 carbon atoms. Non-limiting examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0276] The term "cycloalkyl" refers to saturated, carbocyclic rings, including monocyclic, bicyclic or polycyclic fused, bridged or spiro rings. For example, the term "C3-C10cycloalkyl" refers to a cyclic alkyl group containing 3 to 10 ring carbon atoms, e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring atoms, which further can be C3-C8cycloalkyl, C3-C6cycloalkyl, non-limiting examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indane, and the like. 10 The term "cycloalkyl" refers to saturated, carbocyclic rings, including monocyclic, bicyclic or polycyclic fused, bridged or spiro rings. For example, the term "C3-C10cycloalkyl" refers to a cyclic alkyl group containing 3 to 10 ring carbon atoms, e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring atoms, which further can be C3-C8cycloalkyl, C3-C6cycloalkyl, non-limiting examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indane, and the like.

[0277] The term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic aromatic ring group having a conjugated pi-electron system. "C6-C10aryl" as used herein refers to an aryl group having 6 to 10 carbon atoms. Non-limiting examples of "C6-C10aryl" can include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. 10 The term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic aromatic ring group having a conjugated pi-electron system. "C6-C10aryl" as used herein refers to an aryl group having 6 to 10 carbon atoms. Non-limiting examples of "C6-C10aryl" can include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.

[0278] The term "aryloxy" refers to a monovalent functional group of the formula RO-, wherein R is aryl as defined above. "C6-C10aryloxy" as used herein refers to an aryloxy group having 6 to 10 carbon atoms. Non-limiting examples of "C6-C10aryloxy" include, but are not limited to, phenoxy, naphthoxy, and the like. 10 The term "aryloxy" refers to a monovalent functional group of the formula RO-, wherein R is aryl as defined above. "C6-C10aryloxy" as used herein refers to an aryloxy group having 6 to 10 carbon atoms. Non-limiting examples of "C6-C10aryloxy" include, but are not limited to, phenoxy, naphthoxy, and the like.

[0279] The term "heterocyclyl" refers to a saturated or partially saturated non-aromatic ring, at least one ring system containing one or more heteroatoms, which can be monocyclic, bicyclic fused, polycyclic fused, spiro, or bridged, i.e., containing monocyclic heterocyclyl, fused heterocyclyl, spiro heterocyclyl, or bridged heterocyclyl groups. "3-12 membered heterocyclyl" as used herein refers to a cyclic group containing 1, 2, 3, 4, or 5 heteroatoms and containing 3 to 12 (e.g., 5, 6, 5-7, 3-8, 5-12, 3-10, or 8-10) ring atoms, the heteroatoms selected from nitrogen, oxygen, sulfur. Wherein the nitrogen, carbon, or sulfur atoms in the heterocyclyl group can optionally be oxidized, e.g., the "-CH2-" group of the heterocyclyl group can optionally be oxidized, i.e., to form -C(=O)-; and the sulfur can optionally be oxidized, i.e., to form a sulfone or a sulfoxide. The heterocyclyl group as used herein further can be monocyclic heterocyclyl (e.g., 3-8 membered monocyclic heterocyclyl), spiro heterocyclyl (e.g., 5-12 membered spiro heterocyclyl), fused heterocyclyl (e.g., 5-12 membered fused heterocyclyl), and bridged heterocyclyl (e.g., 5-12 membered bridged heterocyclyl). The number of heteroatoms in the heterocyclyl group as used herein can be 1, 2, 3, 4, 5, or 6; further can be 1, 2, or 3 heteroatoms. The term "nitrogen-containing heterocyclyl" refers to a heterocyclyl group containing at least one nitrogen atom.

[0280] The term "monocyclic heterocyclyl" refers to a monocyclic radical containing at least one heteroatom selected from nitrogen, oxygen, sulfur. The heterocycle can be saturated or partially saturated. The "3-8 membered monocyclic heterocyclyl" of the present invention can further be "3-8 membered saturated monocyclic heterocyclyl" and "3-8 membered partially saturated monocyclic heterocyclyl". The "3-8 membered monocyclic heterocyclyl" is preferably "3-7 membered monocyclic heterocyclyl", "3-6 membered monocyclic heterocyclyl", "4-7 membered monocyclic heterocyclyl", "4-6 membered monocyclic heterocyclyl", "6-8 membered monocyclic heterocyclyl", "5-7 membered monocyclic heterocyclyl", "5-7 membered saturated monocyclic heterocyclyl", "5-7 membered partially saturated monocyclic heterocyclyl", "5-6 membered monocyclic heterocyclyl", "5-6 membered saturated monocyclic heterocyclyl", "5-6 membered partially saturated monocyclic heterocyclyl", "3-6 membered saturated monocyclic heterocyclyl", "5-6 membered saturated monocyclic heterocyclyl", "3-7 membered nitrogen-containing monocyclic heterocyclyl", "3-6 membered nitrogen-containing monocyclic heterocyclyl", "4-7 membered nitrogen-containing monocyclic heterocyclyl", "3-6 membered saturated nitrogen-containing monocyclic heterocyclyl", "5-6 membered nitrogen-containing monocyclic heterocyclyl", "5-6 membered saturated nitrogen-containing monocyclic heterocyclyl", "5-6 membered partially saturated nitrogen-containing monocyclic heterocyclyl", "6 membered saturated monocyclic heterocyclyl", "6 membered saturated nitrogen-containing monocyclic heterocyclyl", and the like. Non-limiting examples of the "3-8 membered monocyclic heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diaziridinyl, azetidinyl, oxetanyl, thietanyl, azepanyl, thiepanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxinyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl (pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl (pyrazolidin-2-yl, pyrazolidin-3-yl), 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl (piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), tetrahydropyridinyl, piperidonyl, tetrahydropyridonyl, dihydropiperidonyl, piperazinyl (2,5-piperazinyl), morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, and the like.

[0281] The term "spiroheterocyclyl" refers to a saturated or partially saturated ring structure containing 5 to 20 ring atoms formed by two or more cyclic structures sharing one ring atom with each other, which contains at least one heteroatom selected from nitrogen, oxygen, sulfur. The "6-14 membered spiroheterocyclyl" of the present invention can be further "9-14 membered spiroheterocyclyl", "7-12 membered spiroheterocyclyl", "9-14 membered spiroheterocyclyl", "9-14 membered nitrogen-containing spiroheterocyclyl", "7-12 membered nitrogen-containing spiroheterocyclyl", more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered single spiroheterocyclyl, more preferably 5-membered nitrogen-containing ring spiro 3-membered ring, 6-membered nitrogen-containing ring spiro 3-membered ring, 4-membered nitrogen-containing ring spiro 4-membered ring, 5-membered nitrogen-containing ring spiro 4-membered ring, 6-membered nitrogen-containing ring spiro 4-membered ring. Non-limiting examples of spiroheterocyclyl groups include, but are not limited to: etc.

[0282] The term "nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group containing at least one nitrogen atom.

[0283] The term "fused heterocyclyl" refers to a saturated or partially saturated ring structure containing 5 to 20 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, which contains at least one heteroatom selected from nitrogen, oxygen, sulfur. One of the rings in the fused ring can be aromatic, but the whole fused ring does not have aromaticity. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl. The "5-20 membered fused heterocyclyl" of the present invention can be further "6-14 membered fused heterocyclyl", "6-10 membered fused heterocyclyl", "8-10 membered fused heterocyclyl", "6-10 membered nitrogen-containing fused heterocyclyl", "8-10 membered nitrogen-containing fused heterocyclyl"; can be further "5-membered and 5-membered fused heterocyclyl" or "5-membered and 6-membered fused heterocyclyl"; can be further "5-membered nitrogen-containing ring fused 3-membered ring", "5-membered nitrogen-containing ring fused 4-membered ring", "5-membered nitrogen-containing ring fused 5-membered ring", "6-membered nitrogen-containing ring fused 3-membered ring", "6-membered nitrogen-containing ring fused 4-membered ring", "6-membered nitrogen-containing ring fused 5-membered ring", "6-membered nitrogen-containing ring fused 6-membered ring", "6-membered nitrogen-containing ring fused 5-membered ring". The "8-10 membered fused heterocyclyl" of the present invention includes "8-10 membered saturated fused heterocyclyl" and "8-10 membered partially saturated fused heterocyclyl". Non-limiting examples of fused heterocyclyl groups include, but are not limited to: etc.

[0284] The term "bridged heterocyclyl" refers to a saturated or partially saturated cyclic structure containing 5 to 14 ring atoms, which is formed by any two rings sharing two non-adjacent atoms, and which contains at least one heteroatom selected from nitrogen, oxygen, and sulfur. Depending on the number of rings, it can be a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. The "5-14 membered bridged heterocyclyl" of the present application can further be "5-12 membered bridged heterocyclyl", "7-10 membered bridged heterocyclyl", "7 membered bridged heterocyclyl", "8 membered bridged heterocyclyl", and the like, and can further be a 5-membered nitrogen-containing ring bridging a 4-membered ring, a 5-membered nitrogen-containing ring bridging a 5-membered ring, a 6-membered nitrogen-containing ring bridging a 4-membered ring, or a 6-membered nitrogen-containing ring bridging a 5-membered ring. Non-limiting examples of bridged heterocyclyl groups include, but are not limited to: etc.

[0285] The term "heteroaryl" refers to a monocyclic or fused polycyclic group having aromaticity, which contains at least one heteroatom selected from nitrogen, oxygen, sulfur, for example, containing 1, 2, or 3. The nitrogen, carbon, or sulfur atoms in the heteroaryl group can optionally be oxidized, as can the sulfur, i.e., to the sulfoxide or sulfone. The "5-14 membered heteroaryl" group of the present application further can be "5-12 membered heteroaryl," "5-10 membered heteroaryl," "5-9 membered heteroaryl," "5-6 membered heteroaryl," and still further can be 4-7 membered monocyclic heteroaryl (e.g., 4-, 5-, 6-, or 7-membered ring), 5-6 membered monocyclic heteroaryl, 6-14 membered fused heteroaryl, 6-10 membered fused heteroaryl, 8-10 membered fused heteroaryl, 6-9 membered fused heteroaryl. The number of heteroatoms in the heteroaryl group of the present application can be 1, 2, 3, 4, 5, or 6; further, the number of heteroatoms can be 1, 2, or 3. Non-limiting examples of heteroaryl groups include, but are not limited to: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (also known as tetrazolyl, e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-l,2,4-triazolyl, 1H-l,2,4-triazolyl, 1,2,3-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, pyridinonyl, oxadiazinonyl, indolonyl, and the like. The term "fused heteroaryl" can also include, but is not limited to, a monocyclic aromatic ring fused to a heteroaromatic ring to form a polycyclic group having aromaticity. The "8-10 membered fused heteroaryl" group of the present application refers to a fused heteroaromatic ring system having 8 to 10 ring atoms, non-limiting examples of which include, but are not limited to: imidazopyridinyl, pyridopyrimidinyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzopyrazolyl, benzimidazolonyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), and the like.

[0286] The term "aryl sulfonyl" refers to the group -S(O)2R, wherein R is aryl as defined above. The term "C6-C10 aryl sulfonyl" refers to the group -S(O)2R, wherein R is C6-C10 aryl as defined above. 10Non-limiting examples of "arylcarbonyl" groups include, but are not limited to, phenylcarbonyl.

[0287] The term "heteroarylcarbonyl" means a -C(O)R group where R is heteroaryl as defined above. The term "5-14 membered heteroarylcarbonyl" can further be "5-12 membered heteroarylcarbonyl", "5-10 membered heteroarylcarbonyl", and more further be 4-7 membered monocyclic heteroarylcarbonyl, 5-6 membered monocyclic heteroarylcarbonyl, 6-14 membered fused heteroarylcarbonyl, 6-10 membered fused heteroarylcarbonyl, 8-10 membered fused heteroarylcarbonyl. Non-limiting examples include, but are not limited to, pyrazolylcarbonyl, imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyridylcarbonyl, furanylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, benzothienylcarbonyl, isoxazolylcarbonyl, and the like.

[0288] The term "cycloalkylcarbonyl" means a -C(O)R group where R is cycloalkyl as defined above. The term "C3-C8 cycloalkylcarbonyl" can further be "C3-C6 cycloalkylcarbonyl". Non-limiting examples include, but are not limited to, cyclopropylcarbonyl, cyclobutylcarbonyl, and the like.

[0289] The term "alkylcarbonyl" means a -C(O)R group where R is alkyl as defined above. The term "C1-C6 alkylcarbonyl" can further be "C1-C4 alkylcarbonyl", "C1-C3 alkylcarbonyl". Non-limiting examples include, but are not limited to, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, and the like.

[0290] The term "alkylaminocarbonyl" means a -C(O)-N(R)2 group where R is alkyl as defined above. Non-limiting examples of the term "C1-C6 alkylaminocarbonyl" include, but are not limited to: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylisopropylaminocarbonyl.

[0291] The term "heterocyclylcarbonyl" means a -C(O)R group where R is heterocyclyl as defined above. The term "3-10 membered heterocyclylcarbonyl" can further be "3-8 membered monocyclic heterocyclylcarbonyl", "5-10 membered fused heterocyclylcarbonyl", "5-12 membered spiro heterocyclyl"; and more further be "3-6 membered monocyclic heterocyclylcarbonyl", "8-10 membered fused heterocyclylcarbonyl", "8-10 membered saturated fused heterocyclylcarbonyl", "8-10 membered partially saturated fused heterocyclylcarbonyl".

[0292] The term "alkylamino" refers to the -NHR radical, wherein R is alkyl as defined above. Non-limiting examples of the term "Ci-C6alkylamino" include, but are not limited to: methylamino, ethylamino, propylamino, or 2-propylamino.

[0293] The term "heterocyclylaminyl" refers to the -NHR radical, wherein R is heterocyclyl as defined above, for example, non-limiting examples of the term "3-6 membered heterocyclylaminyl" include, but are not limited to: pyrrol-2-amino, pyrrol-3-amino, piperidin-2-amino, piperidin-3-amino, piperidin-4-amino, piperazin-2-amino, dipyrryl-2-amino, and the like.

[0294] The term "aminoacyl" refers to the -C(O)NH2 radical.

[0295] The term "alkylaminoacyl" refers to the -C(O)NHR radical, wherein R is alkyl as defined above.

[0296] The term "arylaminocarbonyl" refers to the -C(O)NHR radical, wherein R is aryl as defined above.

[0297] The term "heteroarylaminocarbonyl" refers to the -C(O)NHR radical, wherein R is heteroaryl as defined above.

[0298] The term "alkylamido" denotes the -NHC(O)-R radical, wherein R is alkyl as defined above.

[0299] The term "C6-C 10 "aryl Ci-C6alkyl" refers to a Ci-C6alkyl radical substituted with an aryl radical, wherein Ci-C6alkyl and aryl are as defined above. 10 "aryl Ci-C6alkyl" refers to a Ci-C6alkyl radical substituted with an aryl radical, wherein Ci-C6alkyl and aryl are as defined above. 10 "aryl Ci-C6alkyl" refers to a Ci-C6alkyl radical substituted with an aryl radical, wherein Ci-C6alkyl and aryl are as defined above.

[0300] The term "C3-C8cycloalkyl Ci-C6alkyl" refers to a Ci-C6alkyl radical substituted with a C3-C8cycloalkyl radical, wherein Ci-C6alkyl and C3-C8cycloalkyl are as defined above.

[0301] The term "5-14 membered heteroaryl Ci-C6alkyl" refers to a Ci-C6alkyl radical substituted with a 5-14 membered heteroaryl radical, wherein Ci-C6alkyl and 5-14 membered heteroaryl are as defined above.

[0302] The term "3-10 membered heterocyclyl Ci-C6alkyl" refers to a Ci-C6alkyl radical substituted with a 3-10 membered heterocyclyl radical, wherein Ci-C6alkyl and 3-10 membered heterocyclyl are as defined above.

[0303] The term "arylcarbonyl" refers to the radical -C(O)R, wherein R is aryl as defined above. 10the group represented by -C(O)-.

[0304] The term "C6-C 10 The term "arylcarbonyl C1-C6alkyl" means a C1-C6alkyl group as defined above, wherein the C1-C6alkyl group is substituted by an arylcarbonyl group as defined above. 10 The term "arylcarbonyl C1-C6alkyl" means a C1-C6alkyl group as defined above, wherein the C1-C6alkyl group is substituted by an arylcarbonyl group as defined above. 10 The term "arylcarbonyl C1-C6alkyl" means a C1-C6alkyl group as defined above, wherein the C1-C6alkyl group is substituted by an arylcarbonyl group as defined above.

[0305] The term "C6-C 10 The term "aryloxy C1-C6alkyl" means a C1-C6alkyl group as defined above, wherein the C1-C6alkyl group is substituted by an aryloxy group as defined above. 10 The term "aryloxy C1-C6alkyl" means a C1-C6alkyl group as defined above, wherein the C1-C6alkyl group is substituted by an aryloxy group as defined above. 10 The term "aryloxy C1-C6alkyl" means a C1-C6alkyl group as defined above, wherein the C1-C6alkyl group is substituted by an aryloxy group as defined above.

[0306] The term "oxo" means "=O". DETAILED DESCRIPTION

[0307] The following illustrative examples and test examples serve to further illustrate the present application, but are not to be construed as limiting the scope thereof, and variations apparent to those skilled in the art are within the scope of the present application.

[0308] The compounds of the present application can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily made by one skilled in the art.

[0309] M: mol / L; nM means nmol / L; 1 H NMR: nuclear magnetic resonance hydrogen spectrum; MS (ESI): mass spectrum; DMSO-d6: deuterated dimethyl sulfoxide; Methanol-d4: deuterated methanol; CDCl3: deuterated chloroform; Ts: p-toluenesulfonyl; Bn: benzyl; Boc: tert-butoxycarbonyl; MOMO: methoxymethyl ether; SEM: (trimethylsilyl)ethoxymethyl; PMB: p-methoxybenzyl; Tf: trifluoromethanesulfonyl; HEX: cyclohexane; MTBE: methyl tert-butyl ether; DCM: dichloromethane; IPA: isopropanol; ACN: acetonitrile; MTBE: methyl tert-butyl ether; DEA: diethylamine; THP: 2-tetrahydropyranyl; EtOH: ethanol; DBAD: di-tert-butyl azodicarboxylate; PE: petroleum ether; EA: ethyl acetate; TFA: trifluoroacetic acid.

[0310] RT means retention time. "v / v" means volume ratio. UV means ultraviolet.

[0311] Preparation of intermediates

[0312] M1: tert-butyl (1-(3-bromo-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamate

[0313] a) 4,5-dichloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (M1-1)

[0314] Dissolve 4,5-dichloro-1H-pyrrolo[2,3-b]pyridine (5 g) in dichloromethane (50 mL), add 4-dimethylaminopyridine (1 g) and N,N-diisopropylethylamine (7 g), stir at room temperature, and pour in p-toluenesulfonyl chloride (6.1 g) during stirring. React at room temperature overnight. Quench the reaction with water, extract with dichloromethane, combine the organic phases, and concentrate to dryness to obtain the crude title compound M1-1 (9.1 g). MS (ESI, m / z): 340.99 [M+H] + .

[0315] b) tert-butyl (1-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (M1-2)

[0316] Dissolve the crude compound M1-1 (9.1 g) in N-methylpyrrolidone (50 mL), add N,N- diisopropylethylamine (10.4 g) and 4-tert-butoxycarbonylaminopiperidine (8.1 g), and react at 130 °C under nitrogen for 6 h. After the reaction is completed, extract with ethyl acetate and water, combine the organic phases, and concentrate to dryness to obtain the crude title compound M1-2 (13.6 g). MS (ESI, m / z): 505.2 [M+H] + .

[0317] c) tert-butyl (1-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (M1-3)

[0318] Add compound M1-2 (13.6 g) to a reaction flask, add methanol (50 mL) and water (10 mL), and raise the reaction temperature to 70 °C. While stirring, add an aqueous solution of sodium hydroxide (4.32 g) dropwise to the reaction. React for 1 h, and after the reaction is completed, directly concentrate the reaction liquid to dryness to obtain the crude title compound M1-3 (12.9 g). MS (ESI, m / z): 351.2 [M+H] + .

[0319] d) tert-butyl (1-(3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (M1-4)

[0320] Compound M1-3 (11.9 g) was dissolved in N,N-dimethylformamide (50 mL) under nitrogen, and stirred at room temperature. A solution of N-bromosuccinimide (5 g) in N,N-dimethylformamide was added dropwise to the reaction solution. After 30 min, saturated aqueous sodium sulfite was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic layers were combined and concentrated to give a solid, which was purified by column chromatography to obtain the title compound M1-4 (4.8 g).

[0321] e) tert-Butyl (1-(3-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamate (M1)

[0322] Compound M1-4 (3.6 g) was dissolved in dichloromethane (10 mL), and 4-dimethylaminopyridine (90 mg) and N,N-diisopropylethylamine (2.3 g) were added thereto. The mixture was stirred at room temperature, and p-toluenesulfonyl chloride (1.8 g) was added dropwise thereto during the stirring. After completion of the reaction, the reaction solution was extracted with water and dichloromethane. The organic layers were combined and concentrated to give a solid, which was purified by column chromatography to obtain the title compound M1 (3 g). MS (ESI, m / z): 583.1 [M+H] + .

[0323] M2: 2-(Methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0324] a) 3-Bromo-2-(methoxymethoxy)benzonitrile (M2-1)

[0325] 3-Bromo-2-hydroxybenzonitrile (25 g) was dissolved in N,N-dimethylformamide (300 mL), and potassium carbonate (35 g) was added thereto. The mixture was cooled to 0°C, and bromomethyl methyl ether (32 g) was slowly added dropwise thereto. The mixture was stirred at room temperature overnight, and the reaction solution was quenched with water. The organic layer was extracted with ethyl acetate, dried, and concentrated to give a solid, which was purified to obtain the title compound M2-1 (29 g).

[0326] b) 2-(Methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (M2)

[0327] Compound M2-1 (29 g) was dissolved in dioxane (300 mL), and 4,4,4',4',5,5',5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (33.46 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (4.9 g), and potassium acetate (23.5 g) were added thereto. The mixture was stirred at 100°C for 5 hours under nitrogen. The reaction solution was filtered, concentrated, and purified to obtain the title compound M2 (29 g). 1H NMR (400 MHz, DMSO-d6) δ 7.93 (ddd, J = 9.5, 7.6, 1.8 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 5.19 (s, 2H), 3.57 (s, 3H), 1.31 (s, 12H).

[0328] M3: tert-butyl (1-(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5- difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate

[0329] a) tert-butyl (1-(5-chloro-3-(3-cyano-2-(methoxymethoxy)phenyl)-1- toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (M3-1)

[0330] Compound M1 (1.2 g), 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (1.2 g), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (153 mg), cesium carbonate (2.1 g) were dissolved in 30 mL of 1,4-dioxane, 3 mL of water was added, and the mixture was stirred at 80 °C for 3 hours under nitrogen. After the reaction was completed, the reaction solution was filtered using celite, and the filtrate was concentrated to give a sand, which was purified by column chromatography to obtain the title compound M3-1 (1.09 g). MS (ESI, m / z): 666.2 [M+H] + .

[0331] b) tert-butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)- 1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (M3-2)

[0332] Compound M3-1 (1.09 g), 3,5-difluorophenylboronic acid (776 mg), bis[ditert- butyl-(4-dimethylaminophenyl)phosphine]palladium dichloride (116 mg), cesium carbonate (1.6 g) were dissolved in 25 mL of 1,4-dioxane, and the mixture was stirred at 100 °C for 3 hours under nitrogen. After the reaction was completed, the reaction solution was filtered using celite, and the filtrate was concentrated to give a sand, which was purified by column chromatography to obtain the title compound M3-2 (1 g). MS (ESI, m / z): 744.2 [M+H] + .

[0333] c) (1-(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (M3)

[0334] Compound M3-2 (1 g) was dissolved in methanol (10 mL), 1 mL of water was added, and the reaction was warmed to 70 °C. A solution of sodium hydroxide (214 mg) in water was added dropwise, and the reaction was stirred for 30 minutes. The reaction was concentrated to dryness and purified by column chromatography to give 600 mg of the title compound M3. MS (ESI, m / z): 590.2 [M+H] + .

[0335] Example 1: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl)-2-hydroxybenzonitrile (Compound 1)

[0336] Compound M3-2 (600 mg) was dissolved in 1,4-dioxane (5 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 5 mL) was added to the reaction. The reaction was stirred at room temperature for 2 hours, concentrated to dryness, and purified by reverse-phase high-performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 32% B to 52% B in 10 minutes; wavelength: UV 254 nm; RT (min): 9.210; column temperature: 25 °C) to give the title compound 1 (300 mg). MS (ESI, m / z): 599.8 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.11 - 8.03 (m, 2H), 7.97 (s, 1H), 7.73 (s, 1H), 7.51 - 7.41 (m, 3H), 7.36 - 7.23 (m, 2H), 7.06 - 6.98 (m, 2H), 6.75 (t, J = 7.6 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.60 - 2.51 (m, 1H), 2.38 (s, 3H), 2.36 - 2.27 (m, 2H), 1.28 - 1.20 (m, 2H), 0.60 - 0.45 (m, 2H).

[0337] Example 2: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl)-2-hydroxybenzonitrile

[0338] a) tert-Butyl (1-(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (M3)

[0339] To the reaction bottle was added compound M3-2 (80 mg), methanol (2 mL), water (0.5 mL), the reaction temperature was raised to 70 °C, and a sodium hydroxide (100 mg) aqueous solution was added dropwise to the reaction while stirring. After 1 hour, the reaction was completed, and the reaction solution was directly concentrated to dryness to obtain the title compound M3 (130 mg).

[0340] b) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- hydroxybenzonitrile (Compound 2)

[0341] Compound M3 was dissolved in a dioxane solution (2 mL), and a hydrochloric acid dioxane solution (4.0 mol / L, 2 mL) was added. After stirring for 2 hours, the reaction solution was concentrated to dryness to obtain a crude product, which was purified by reverse-phase high-performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 15% B to 35% B in 10 minutes; wavelength: UV 254 nm; RT (min): 9.092, column temperature: 25 °C) to obtain the title compound 2 (11.2 mg). MS (ESI, m / z): 446.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.48-8.25 (m, 1H), 7.88 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 6.8 Hz, 2H), 7.25 (s, 1H), 7.01 (d, J = 7.2 Hz, 2H), 6.90 (d, J = 7.8 Hz, 1H), 2.90 (d, J = 11.9 Hz, 2H), 2.40 (d, J = 11.9 Hz, 3H), 1.25 (d, J = 8.8 Hz, 2H), 0.64-0.43 (m, 2H).

[0342] Example 3: 2-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin- 3-yl)-6-fluorophenol

[0343] a) tert-Butyl (l-(5-chloro-3-(3-fluoro-2-methylphenyl)-l-tosyl-lH-pyrrolo[2,3- b]pyridin-4-yl)piperidin-4-yl)carbamate (3a)

[0344] Compound Ml (50 mg), 2-(3-fluoro-2-methoxyphenyl)-4,4,5-5-tetramethyl-l,3,2- dioxaborolane (17 mg), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (5 mg), cesium carbonate (110 mg) were dissolved in 5 mL of 1,4-dioxane, and the reaction was carried out at 80 °C for 3 hours under nitrogen. After the reaction was completed, the reaction solution was filtered using celite, and the filtrate was concentrated to dryness and purified by column chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain the title compound 3a (35 mg).

[0345] b) tert-Butyl (l-(5-(3,5-difluorophenyl)-3-(3-fluoro-2-methoxyphenyl)-l-tosyl-lH- pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (3b)

[0346] Compound 3a (40 mg), 3,5-difluorophenylboronic acid (11 mg), bis[ditert-butyl-(4- dimethylaminophenyl)phosphine]palladium dichloride (5 mg), cesium carbonate (78 mg) were dissolved in 5 mL of 1,4-dioxane, and the reaction was carried out at 100 °C for 3 hours under nitrogen. After the reaction was completed, the reaction solution was filtered using celite, and the filtrate was concentrated to dryness and purified by column chromatography (petroleum ether / ethyl acetate = 3: 1) to obtain the title compound 3b (41 mg).

[0347] c) 2-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin- 3-yl)-6-fluorophenol (Compound 3)

[0348] Compound 3b was dissolved in dichloromethane solution (2 mL), and the system was placed in an ice bath, and boron tribromide (1.0 mL) was added. After stirring for 2 hours, the reaction solution was concentrated to dryness to obtain a crude product, which was purified by reverse phase high performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm * 250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 35% B to 55% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.621; column temperature: 25 °C) to obtain the title compound 3 (9 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 8.0 Hz, 2H), 7.98 (s, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.27 (t, J = 9.3 Hz, 1H), 7.18 (t, J = 9.5 Hz, 1H), 7.04 (t, J = 5.7 Hz, 3H), 6.90 - 6.80 (m, 1H), 2.81 (d, J = 12.0 Hz, 2H), 2.38 (s, 3H), 2.35 - 2.19 (m, 3H), 1.22 - 1.10 (m, 2H), 0.41 (d, J = 11.7 Hz, 2H). MS (ESI, m / z): 592.8 [M+H] + .

[0349] Example 4: 3-(4-(4-aminopiperidin-1-yl)-1-(1-cyclopropylethyl)-5-(3,5- difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0350] a) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-1-(1- cyclopropylethyl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamate (4a)

[0351] Compound M3 (40 mg), 1-cyclopropylethanol (11.69 mg), triphenylphosphine (35.59 mg) and di-tert-butyl azodicarboxylate (31.24 mg) were dissolved in tetrahydrofuran at 0 °C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give the title compound 4a (25 mg). MS (ESI+): 658.25 (M+H) + .

[0352] b) 3-(4-(4-aminopiperidin-1-yl)-1-(1-cyclopropylethyl)-5-(3,5-difluorophenyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 4)

[0353] Compound 4a (20 mg), methanol (1 mL) and hydrochloric acid in 1,4-dioxane (4.0 mol / L, 1 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC (column: Sunfire C18 5 pm, 30 mm*150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 3% B to 22% B in 10 min; wavelength: UV 254 nm / 220 nm; RT (min): 8.65; column temperature: 40 °C) to give the formate salt of the title compound 4 (1.9 mg). 1 H NMR = (400 MHz, DMSO-d6, ppm) δ 8.27 (s, 2H), 8.06 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.30 (dd, J = 10.5, 8.2 Hz, 1H), 7.14 (dt, J = 7.9, 3.9 Hz, 2H), 6.95 (t, J = 7.6 Hz, 1H), 4.78 (dd, J = 9.7, 6.5 Hz, 1H), 3.14 - 3.05 (m, 3H), 2.44 (s, 2H), 1.73 (dq, J = 9.4, 4.6, 4.1 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 11.3 Hz, 2H), 0.69 (tt, J = 9.8, 5.4 Hz, 3H), 0.52 (dt, J = 9.6, 4.7 Hz, 1H), 0.43 (dt, J = 8.7, 4.2 Hz, 1H), 0.33 (dq, J = 9.8, 4.9 Hz, 1H). 19 F NMR = (376 MHz, DMSO-d6, ppm) δ -109.69. MS (ESI+): 513.95 (M+H) + .

[0354] Example 5: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(p-tolyl)ethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0355] a) tert-Butyl (1-(3-bromo-5-chloro-1-(1-(p-tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamate (5a)

[0356] Compound M1-4 (400 mg) was dissolved in tetrahydrofuran (8 mL), 1-(p- tolyl)ethan-1-ol (140 mg) and triphenylphosphine (317 mg) were added, and the mixture was cooled to 0 °C. Diisopropyl azodicarboxylate (245 mg) in tetrahydrofuran (3 mL) was added dropwise slowly. The reaction was stirred at 0 °C for 1 h. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give a residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound 5a (200 mg).

[0357] b) tert-Butyl (1-(5-chloro-3-(3-cyano-2-(methoxymethoxy)phenyl)-1-(1-(p- tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (5b)

[0358] Compound 5a (150 mg), 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (158 mg), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (45 mg), and cesium carbonate (267 mg) were dissolved in dioxane (5 mL). The mixture was stirred at 100 °C for 5 h under nitrogen. The reaction was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound 5b (80 mg).

[0359] c) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-(1-(p- tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (5c)

[0360] Compound 5b (80 mg), (3,5-difluorophenyl)boronic acid (40 mg), dichlorobis-(4- dimethylaminophenyl) palladium(II) (18 mg), and cesium carbonate (124 mg) were dissolved in dioxane (5 mL). The mixture was stirred at 90 °C for 3 h under nitrogen. The reaction was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound 5c (50 mg).

[0361] d) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(p-tolyl)ethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 5)

[0362] Compound 5c (50 mg) was dissolved in dioxane (3 mL), and 4N hydrochloric acid in dioxane (3 mL) was added. The reaction was stirred at room temperature for 2 hours, concentrated to dryness, and the residue was purified by preparative HPLC (column: X-Bridge Prep C 18 10 pm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 37% B to 57% B in 10 minutes; wavelength: UV 254 nm; RT (min): 8.278, column temperature: 25 °C) to isolate the title compound 5 (6 mg). 1 H NMR (400 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.50 - 7.40 (m, 3H), 7.26 - 7.24 (d, J = 8.0 Hz, 2H), 7.14 - 7.12 (d, J = 8.0 Hz, 2H), 7.02 - 6.86 (m, 4H), 6.22 - 6.16 (q, J = 7.2 Hz, 1H), 3.12 - 3.07 (m, 2H), 2.63 - 2.47 (m, 3H), 2.29 (s, 3H), 1.93 - 1.90 (d, J = 7.2 Hz, 3H), 1.46 - 1.43 (d, J = 11.9 Hz, 2H), 0.76 - 0.65 (tt, J = 12.2, 6.1 Hz, 2H). MS (ESI, m / z): 563.9 [M+H] + .

[0363] e) 5A / 5B

[0364] Compound 5 was purified by chiral prep (column: CHIRALPAK AD-3 4.6*50 mm, 3 pm, 19 mm*250 mm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isocratic: 10% B in 7 minutes; wavelength: UV 254 nm; column temperature: 25 °C) to isolate compound isomers 5A (RT = 5.29 min) and 5B (RT = 4.08 min).

[0365] 5A: 1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.60 - 7.51 (m, 1H), 7.48 - 7.39 (m, 1H), 7.34 - 7.29 (m, 2H), 7.29 - 7.21 (m, 1H), 7.18 - 7.10 (m, 2H), 7.06 - 6.98 (m, 2H), 6.97 - 6.89 (m, 1H), 6.19 - 6.09 (m, 1H), 2.96 - 2.84 (m, 2H), 2.47 - 2.29 (m, 3H), 2.25 (s, 3H), 1.91 - 1.73 (m, 3H), 1.30 - 1.20 (m, 2H), 0.70 - 0.33 (tt, J=12.2, 6.1 Hz, 2H). MS (ESI, m / z): 564.60 [M+H] + .

[0366] 5B: 1 H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.90 - 7.60 (m, 1H), 7.52 - 7.43 (m, 1H), 7.40 - 7.21 (m, 4H), 7.19 - 7.10 (m, 2H), 7.08 - 6.94 (m, 2H), 6.72- 6.78 (m, 1H), 6.20 - 6.08 (m, 1H), 2.93 - 2.82 (m, 2H), 2.42 - 2.39 (m, 1H), 2.35 - 2.30 (m, 2H), 2.25 (s, 3H), 1.91 - 1.80 (m, 3H), 1.25 - 1.15 (m, 2H), 0.64 - 0.36 (m, 2H). MS (ESI, m / z): 564.60 [M+H] + .

[0367] Example 6: 3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0368] a) tert-Butyl (l-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (6a)

[0369] A solution of compound M3 (40 mg), benzenesulfonyl chloride (14.32 mg), 4-dimethylaminopyridine (0.83 mg) and N,N-diisopropylethylamine (26.3 mg) in dichloromethane (4.0 mL) was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1, v / v) to give the title compound 6a (40 mg).

[0370] b) 3-(4-(4-amino piperidin-1-yl)-5-(3,5-difluorophenyl)-1-(phenylsulfonyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 6)

[0371] A solution of compound 6a (30 mg) and hydrochloric acid in 1,4-dioxane (4.0 M, 0.75 mL) in methanol (0.75 ml) was stirred at room temperature for 1 hour. The crude product (40 mg) was purified by preparative HPLC under the following conditions (column: Kinetex 5 pm EVO C 18 , 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HC03), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 53% B in 8 minutes; wavelength: UV 254 nm / 221 nm; RT (min): 7.4, column temperature: 25 °C) to give the title compound 6 (10.0 mg). 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.18 (dd, J = 7.7, 1.8 Hz, 2H), 7.94 (d, J = 1.6 Hz, 1H), 7.75 (t, J = 7.4 Hz, 1H), 7.70 - 7.61 (m, 3H), 7.33 (s, 1H), 7.26 (t, J = 9.7 Hz, 1H), 7.16 (s, 1H), 7.03 - 6.50 (d,, 2H), 6.42 (s, 1H), 2.83 (d, J = 12.2 Hz, 2H), 2.50 (S, 1H), 2.40 (d, J = 11.8 Hz, 2H), 1.20 (d, J = 12.0 Hz, 2H), 0.60 (s, 2H). MS (ESI, m / z): 585.9 [M+H] + .

[0372] Example 7: 1-(5-(3,5-difluorophenyl)-1- toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0373] The by-product from Example 1 (tert-butyl (1-(5-(3,5-difluorophenyl)-1- toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate) was dissolved in dioxane solution (2 mL), hydrochloric acid in dioxane solution (4.0 M, 2 ml) was added, stirred for 2 h, the reaction was concentrated to dryness to give the crude product, which was purified by preparative separation to give compound 7 (15.2 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.94 (m, 3H), 7.80 (d, J = 4.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.1 Hz, 3H), 6.93 (d, J = 4.1 Hz, 1H), 3.37 (d, J = 12.4 Hz, 2H), 2.96 (t, J = 12.0 Hz, 3H), 2.36 (s, 3H), 1.76 (s, 2H), 1.34 (s, 2H). MS (ESI+): 482.9 (M+H) + .

[0374] Example 8: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((2- methoxyphenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0375] a) tert-butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-((2- methoxyphenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (8a)

[0376] M3 (60 mg) was dissolved in N,N-dimethylformamide (10 mL) under nitrogen condition, sodium hydride (5 mg) was added, stirred for 30 minutes at 0 °C, 2-methoxybenzenesulfonyl chloride (25 mg) was added. Extracted with water and ethyl acetate, combined the organic phase, washed with water, the organic phase was concentrated to dryness to give the crude product of title compound 8a.

[0377] b) 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((2-methoxyphenyl)sulfonyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (compound 8)

[0378] The crude product of compound 8a was dissolved in dichloromethane (6 mL), trifluoroacetic acid in dichloromethane (1 :5, 6 mL) was added, stirred for 2 hours, the reaction was concentrated to dryness to give the crude product, which was purified by preparative reverse phase high performance liquid chromatography (column: X-Bridge Prep C18 OBD, 10 x 50 mm, 5 pm; mobile phase: acetonitrile and water with 0.1% formic acid; method: 10-90% acetonitrile and water with 0.1% formic acid; flow rate: 10 mL / min).18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 30% B to 60% B in 10 min; wavelength: UV 254 nm; RT (min): 7.28, column temperature: 25 °C) to give the title compound 8 (18.7 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (dd, J = 8.1, 1.8 Hz, 1H), 7.80 (s, 1H), 7.70 (ddd, J = 8.8, 7.5, 1.8 Hz, 1H), 7.63 (s, 1H), 7.41 (dd, J = 7.8, 1.9 Hz, 1H), 7.28 - 7.16 (m, 4H), 7.02 - 6.97 (m, 2H), 6.60 (d, J = 7.6 Hz, 1H), 3.73 (s, 3H), 2.83 (d, J = 12.2 Hz, 2H), 2.71 (s, 1H), 2.36 (t, J = 11.6 Hz, 2H), 1.23 (d, J = 11.6 Hz, 2H), 0.60 (d, J = 12.3 Hz, 2H). MS (ESI, m / z): 615.8 [M+H] + .

[0379] Table 1 Compounds were prepared by modifying the preparation method of the above examples by changing some of the starting materials.

[0380] Example 34: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-methyl-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0381] a) (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-(1-methyl-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (34a)

[0382] Compound M3 (40 mg) was dissolved in N,N-dimethylformamide (5 mL), (1- methyl-1H-pyrazol-4-yl)boronic acid (13 mg), 4,4-di-tert-butylbipyridine (20 mg), copper trifluoromethanesulfonate (30 mg) and pyridine (53 mg) were added, and the reaction was allowed to proceed at 80 °C under an oxygen atmosphere for 24 hours. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound 34a (30 mg).

[0383] b) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 34)

[0384] Compound 34a (30 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and concentrated to dryness. The resulting residue was purified by reverse phase high performance liquid chromatography (column: X-Bridge Prep C 18 10μm OBD, 19mm*250mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 25% B to 55% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.02, column temperature: 25 °C) to give the formate salt of the title compound 34 (6 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.01 - 7.97 (d, J = 18.4 Hz, 2H), 7.77 (s, 1H), 7.46 - 7.44 (dd, J = 7.6, 1.8 Hz, 1H), 7.34 - 7.31 (dd, J = 7.6, 1.8 Hz, 1H), 7.28 - 7.26 (tt, J = 9.6, 2.4 Hz, 1H), 7.25 - 7.23 (dd, J = 8.0 Hz, 1H), 7.04 - 7.01 (dt, J = 8.4, 3.4 Hz, 2H), 6.69 - 6.73 (t, J = 7.6 Hz, 1H), 3.92 (s, 3H), 2.92 - 2.89 (d, J = 12.0 Hz, 2H), 2.47 - 2.38 (q, J = 11.2, 3.2 Hz, 3H), 1.26 - 1.23 (d, J = 11.6 Hz, 2H), 0.60 - 0.57 (d, J = 11.6 Hz, 2H). MS (ESI, m / z): 526.3 [M+H] + .

[0385] Example 35: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((6- methylpyridin-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-hydroxybenzyl cyanide

[0386] a) tert-butyl (1-(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-((6- methylpyridin-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (35a)

[0387] Into a 25 mL vial was added N,N-dimethylformamide (5 mL), compound M3 (44 mg), sodium hydride (10 mg) at 10 °C, 5 min later added 5-methylpyridine-2-sulfonyl chloride (31 mg), under nitrogen protection, the reaction was carried out at 20 °C for 0.5 h. The reaction was stopped, the reaction solution was extracted with ethyl acetate (20 mL), water (20 mL), the organic phase was distilled to dryness under reduced pressure to give the title compound 35a (74 mg) which was used directly in the next step.

[0388] b) 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H- pyrrolo[2,3-b]pyridin-3-yl]-2-hydroxybenzyl cyanide (compound 35)

[0389] Into a 25 mL vial was added dichloromethane (2 mL), compound 35a (60 mg), hydrochloric acid (4 M, 2 mL), the reaction was carried out at 20 °C for 1 h. The reaction was stopped, the reaction solution was distilled to dryness under reduced pressure, the residue was column chromatographed with DCM / methanol = 10:1 to give the title product 25 mg, the product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 10% B to 50% B in 10 min; wavelength: UV 254 nm; RT (min): 9.895, column temperature: 25 °C) to give the hydrochloride salt of the title compound 35 (10 mg). 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.46 (dd, J = 8.3, 2.5 Hz, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.67 - 7.61 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 7.6, 1.8 Hz, 1H), 7.32 (tt, J = 9.4, 2.4 Hz, 1H), 7.11 - 6.97 (m, 3H), 2.85 (d, J = 12.0 Hz, 2H), 2.58 (s, 4H), 2.30 (t, J = 11.3 Hz, 2H), 1.32 (d, J = 11.6 Hz, 2H), 0.43 (d, J = 12.2 Hz, 2H). MS (ESI, m / z): 601.2 [M+H] + .

[0390] Example 36: 3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0391] a) 1-(5-methylpyridin-2-yl)ethan-1-ol (36a)

[0392] Into a 50 mL three-necked flask was placed 5-methylpyridine-2-carboxaldehyde (500 mg) and tetrahydrofuran (20 mL) at room temperature. To the reaction was added methyl magnesium bromide (984.36 mg) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water (20 mL). The organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound 36a (400 mg).

[0393] b) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (36b)

[0394] To a 40 mL vial was added compound 36a (37.22 mg) and compound M3 (80 mg), triphenylphosphine (71.17 mg) at room temperature. To the above mixture was added dropwise a solution of di-tert-butyl azodicarboxylate (62.48 mg) in tetrahydrofuran (5 mL) at 0 °C over a period of 5 minutes. The resulting mixture was stirred at 0 °C for another 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography plate (petroleum ether / ethyl acetate = 2:1) to give the title compound 36b (50 mg).

[0395] c) 36A / 36B

[0396] To a 8 mL vial was added compound 36b (45 mg), methanol (2 mL) and a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4.0 mol / L) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge BEH C 18 OBD Prep Column, 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 50% B in 10 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 6.52 / 7.92, column temperature: 25 °C) to give compound 36 (8.1 mg) as a crude product.

[0397] The crude product was then purified by chiral HPLC under the following conditions (column: CHIRALPAK-ID 3*25 cm, 5 pm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol:dichloromethane (1:1, v / v); flow rate: 40 mL / min; isocratic 30% B; wavelength: UV 254 / 220 nm; sample solvent: EtOH; column temperature: 25 °C) to give compound isomers 36A (RT = 9.39 min, 3.1 mg) and 36B (RT = 11.46 min, 2.4 mg) by resolution.

[0398] 36A: 1H NMR: (400 MHz, DMSO-d6, ppm) δ 8.39 (d, J = 2.3 Hz, 1H), 7.89 (s, 1H), 7.60 (d, J = 3.1 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.24 (t, J = 9.3 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.04 - 6.97 (m, 2H), 6.87 - 6.74 (m, 1H), 6.21 (q, J = 7.1 Hz, 1H), 2.89 (t, J = 12.8 Hz, 2H), 2.48 - 2.44 (m, 1H), 2.40 - 2.33 (m, 2H), 2.26 (s, 3H), 1.86 (d, J = 7.2 Hz, 3H), 1.24 - 1.18 (m, 2H), 0.65 - 0.38 (m, 2H). MS (ESI, m / z): 565.20 [M+H] + .

[0399] 36B: 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.2 Hz, 1H), 7.87 (s, 1H), 7.62 - 7.48 (m, 2H), 7.42 (dd, J = 7.8, 1.9 Hz, 1H), 7.35 - 7.18 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.99 (h, J = 4.5 Hz, 2H), 6.69 (t, J = 7.6 Hz, 1H), 6.20 (q, J = 7.1 Hz, 1H), 2.97 - 2.83 (m, 2H), 2.48 - 2.33 (m, 3H), 2.25 (s, 3H), 1.85 (d, J = 7.2 Hz, 3H), 1.21 (m, 2H), 0.70 - 0.45 (m, 2H). MS (ESI, m / z): 565.35 [M+H] + .

[0400] Example 37: 3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-(l-(l-methyl-lH- pyrazol-3-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0401] a) (l-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-(l-(l-methyl-lH- pyrazol-3-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (37a)

[0402] Compound M3 (80 mg) was dissolved in tetrahydrofuran, 1-(1-methylpyrazol-3- yl)ethanol (25.67 mg), triphenylphosphine (71.17 mg) were added, the mixture was stirred under nitrogen at 0 °C for 5 min. (E)-N-([(tert-butoxy)carbonyl]imino(tert- butoxy)methanamide (62.48 mg) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was concentrated to dryness. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1:1 (v / v)) to give the title compound 37a (43 mg).

[0403] b) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(1-methyl-1H-pyrazol-3- yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 37)

[0404] Compound 37a (33 mg) was dissolved in methanol (1 mL), hydrogen chloride in 1,4-dioxane (4 mol / L, 1 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction was concentrated to dryness to give the crude product. The crude product was purified by preparative HPLC under the following conditions (column: YMC Triart C 18 ExRs 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 50% B in 10 min; wavelength: UV 254 nm / 220 nm; column temperature: 25 °C; RT (min): 3.62 / 8.77) to give compound 37 (8.1 mg).

[0405] The product was then purified by preparative chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SC 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: methanol:dichloromethane (1:1, v / v); flow rate: 20 mL / min; isocratic 25% B; wavelength: UV 254 / 220 nm; column temperature: 25 °C; sample solvent: methanol); resolution gave compound isomers 37A (RT = 15.27 min, 0.7 mg) and 37B (RT = 17.54 min, 0.3 mg).

[0406] 37A: 1H NMR: (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 7.8, 1.7 Hz, 1H), 7.48 (s, 1H), 7.40 (dd, J = 7.5, 1.8 Hz, 1H), 7.33 - 7.23 (m, 1H), 7.07 - 6.99 (m, 2H), 6.98 - 6.91 (m, 1H), 6.27 (d, J = 2.2 Hz, 1H), 6.22 (q, J = 7.3 Hz, 1H), 3.79 (s, 3H), 2.96 - 2.82 (m, 2H), 2.44 - 2.29 (m, 3H), 1.80 (d, J = 7.2 Hz, 3H), 1.39 - 1.26 (m, 2H), 0.60 - 0.36 (m, 2H). MS (ESI, m / z): 554.35 [M+H] + .

[0407] 37B: 1 H NMR: (400 MHz, DMSO-d6): δ 7.94 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 7.7, 1.8 Hz, 1H), 7.44 (s, 1H), 7.35 (dd, J = 7.5, 1.8 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.05 - 6.97 (m, 2H), 6.88 - 6.81 (m, 1H), 6.26 (d, J = 2.2 Hz, 1H), 6.22 (q, J = 7.1 Hz, 1H), 3.79 (s, 3H), 2.89 (s, 2H), 2.44 - 2.28 (m, 3H), 1.79 (d, J = 7.1 Hz, 3H), 1.26 - 1.15 (m, 2H), 0.65 - 0.38 (m, 2H). MS (ESI, m / z): 554.15 [M+H] + .

[0408] Example 38: (3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-(2-methyl-2H- indazol-7-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0409] a) (l-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-(2-methyl-2H- indazol-7-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (38a)

[0410] A 250 mL flask was charged with compound M3 (77 mg), 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (201 mg), pyridine (31 mg), copper trifluoromethanesulfonate (47 mg), 4,4-ditert-butyldipyrridine (70 mg), N,N-dimethylformamide (5 mL), purged with argon, and fitted with a drying tube. The reaction was stirred at 80 °C for 3 h. The reaction was quenched with water (50 mL) and ethyl acetate (50 mL). The organic phase was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (PE / EA = 2:1) to give the title compound 38a (80 mg).

[0411] b) (3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(2-methyl-2H-indazol-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 38)

[0412] A 25 mL flask was charged with 1,4-dioxane (4 mL), compound 38a (80 mg), hydrochloric acid in 1,4-dioxane (2 mL, 4 mol / L), and stirred at 20 °C for 2 h. The reaction was quenched and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give the title compound 38 (32 mg). 1 H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.90 - 7.80 (m, 2H), 7.73 (s, 1H), 7.66 (dd, J = 7.2, 0.9 Hz, 1H), 7.56 (ddd, J = 13.5, 7.7, 1.8 Hz, 2H), 7.28 (dd, J = 8.4, 7.2 Hz, 1H), 7.07 - 6.92 (m, 4H), 4.20 (s, 3H), 3.15 (d, J = 11.9 Hz, 2H), 2.56 (t, J = 11.8 Hz, 3H), 1.47 (d, J = 12.1 Hz, 2H), 0.67 (dd, J = 11.9, 3.8 Hz, 2H). MS (ESI, m / z): 576.3 [M+H] + .

[0413] Example 39: 3-(1-((4-(1H-Pyrazol-1-yl)phenyl)sulfonyl)-4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0414] a) tert-Butyl 1-(1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-3-(3-cyano-2- (methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin- 4-yl)carbamate (39a)

[0415] Compound M3 (60 mg) was dissolved in N,N-dimethylformamide (10 mL) under nitrogen, sodium hydride (5 mg) was added, stirred at 0 °C for 30 min, 4-(1H-pyrazol-1- yl)benzenesulfonyl chloride (25 mg) was added. Extracted with water and ethyl acetate, combined the organic phase, washed with water, the organic phase was concentrated to dryness to give the crude title compound 39a.

[0416] b) 3-(1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-4-(4-aminopiperidin-1-yl)-5-(3,5- difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 39)

[0417] The crude compound 39a was dissolved in dichloromethane (6 mL), trifluoroacetic acid in dichloromethane (1 :5, 6 mL) was added, stirred for 2 h, the reaction was concentrated to dryness to give the crude product, which was purified by reverse phase high performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 20% B to 60% B in 10 min; wavelength: UV 254 nm; RT (min): 8.90, column temperature: 25 °C) to give the title compound 39 (15.1 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 2.7 Hz, 1H), 8.30 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 8.9 Hz, 2H), 7.96 (s, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.70 (s, 1H), 7.37 (dd, J = 7.8, 1.9 Hz, 1H), 7.26 (tt, J = 9.4, 2.4 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.65 - 6.60 (m, 1H), 6.51 (t, J = 7.4 Hz, 1H), 2.83 (d, J = 12.3 Hz, 2H), 2.41 - 2.31 (m, 3H), 1.22 (d, J = 12.0 Hz, 2H), 0.61 (d, J = 11.8 Hz, 2H). MS (ESI, m / z): 651.8 [M+H] +.

[0418] Example 40: 3-(4-(4-aminopiperidin-1-yl)-1-(benzofuran-2-ylsulfonyl)-5-(3,5- difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0419] Reference to the preparation method of Example 8, replace 2-methoxybenzenesulfonyl chloride in step a) with benzofuran-2-sulfonyl chloride, to prepare the title compound 40 crude, the crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 10 pm OBD, 19 mm*250 mm; mobile phase A: water (0.1% formic acid, mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 25% B to 65% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.60, column temperature: 25 °C) to give the formate salt of the title compound 40 (13.1 mg).

[0420] 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.93 - 7.86 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.71 - 7.64 (m, 3H), 7.63 - 7.54 (m, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.30 (tt, J = 9.4, 2.3 Hz, 1H), 7.10 - 7.00 (m, 3H), 2.86 (d, J = 11.9 Hz, 2H), 2.58 (s, 1H), 2.30 (t, J = 11.6 Hz, 2H), 1.33 (d, J = 11.7 Hz, 2H), 0.43 (d, J = 13.9 Hz, 2H). MS (ESI, m / z): 313.4 (M / 2+H).

[0421] Example 41: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((1,2-dimethyl-1H- imidazol-4-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0422] a) (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-((1,2-dimethyl-1H- imidazol-4-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (41a)

[0423] Prepared according to the procedure of Example 8, Step a) replacing 2-methylbenzenesulfonyl chloride in Step a) with 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride to give Compound 41a (50 mg).

[0424] b) 3-(4-(4-amino piperidin-1-yl)-5-(3,5-difluorophenyl)-1-((1,2-dimethyl-1H- imidazol-4-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 41)

[0425] Prepared according to the procedure of Example 6, Step b) replacing Compound 6a in Step b) with Compound 41a to give Compound 41 crude product which was purified by preparative HPLC (Column: YMC Triart C18 ExRs 5 μm, 30 mm*150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 44% B in 8 minutes; Wavelength: UV 254 nm / 220 nm; RT (min): 7.1, Column temperature: 25 °C) to give Compound 41 (17.8 mg). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.25 (s, 1H), 7.89 (d, J = 5.4 Hz, 1H), 7.53 (d, J = 4.0 Hz, 1H), 7.32 (s, 1H), 7.29 - 7.22 (m, 1H), 7.15 (s, 1H), 7.03 (d, J = 7.3 Hz, 2H), 6.43 (s, 1H), 3.62 (s, 3H), 2.84 (d, J = 11.9 Hz, 2H), 2.47 (s, 1H), 2.43 - 2.38 (m, 2H), 2.25 (s, 3H), 1.26 - 1.17 (m, 2H), 0.67 - 0.51 (m, 2H). MS (ESI, m / z): 604.15 [M+H] + .

[0426] Example 42: 3-(4-(4-amino piperidin-1-yl)-5-(3,5-difluorophenyl)-1-(2-methyl-2H- indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0427] a) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-(2- methyl-2H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (42a)

[0428] To a reaction flask was added compound M3 (40 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (70 mg), copper trifluoromethanesulfonate (38 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (18 mg), pyridine (54 mg), N,N-dimethylformamide (5 mL), a drying tube was inserted into the reaction flask, and the reaction was stirred at 60 °C for 4 h. After the reaction was completed, the reaction mixture was extracted with water and ethyl acetate, the organic phases were combined and washed with water, and the organic phase was concentrated to dryness to give the title compound 42a.

[0429] b) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(2-methyl-2H-indazol-5-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 42)

[0430] To compound 42a was added hydrochloric acid in dioxane (4 M, 4 mL), and the reaction was stirred for 2 h. The reaction mixture was concentrated to dryness to give a crude product, which was purified by reverse-phase high performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 25% B to 45% B in 10 min; wavelength: UV 254 nm; RT (min): 7.59, column temperature: 25 °C) to give the title compound 42 (6.09 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.09 - 8.04 (m, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.76 - 7.68 (m, 2H), 7.52 - 7.46 (m, 1H), 7.44 - 7.39 (m, 1H), 7.31 - 7.23 (m, 1H), 7.08 - 7.00 (m, 2H), 6.84 - 6.74 (m, 1H), 4.21 (s, 3H), 2.98 - 2.88 (m, 2H), 2.45 - 2.33 (m, 3H), 1.29 - 1.18 (m, 2H), 0.61 - 0.47 (m, 2H). MS (ESI, m / z): 572.8 [M+H] + .

[0431] Example 43: 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((1-isopropyl-1H- pyrazol-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0432] a) 1 -isopropyl- 1 H-pyrazole-3-sulfonyl chloride (43a)

[0433] To a 100 mL three-necked flask, was added 1 -isopropylpyrazol-3-amine (500 mg) and acetonitrile (35.8 mL) at -10 °C. A solution of hydrochloric acid (7 mL, 36% wt in water) in water (1.6 mL) was added. The resulting mixture was then stirred at -15 °C for 0.75 h. A solution of sodium nitrite (330.71 mg, 4.8 mmol) in water (c = 0.4 mL / mmol) was then added slowly.

[0434] To the reaction mixture was added acetic acid (3.6 mL), copper chloride dihydrate (340.48 mg) and cuprous chloride (19.77 mg) at -30 °C. The mixture was then sparged with sulphur dioxide gas at -30 °C for 0.25 h. The mixture was stirred at 0 °C for 1 h. The mixture was then poured into ice water and the resulting mixture was extracted with dichloromethane (3*50 mL). The organic layers were combined, washed with saturated brine (1*50 mL) and dried over anhydrous sodium sulphate. After filtration, it was concentrated to dryness and the residue was column chromatographed (petroleum ether / ethyl acetate = 9:1) to give the title compound 43a (180 mg).

[0435] b) (1 -(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)- 1 -(( 1 -isopropyl- 1 H-pyrazol-3-yl)sulfonyl)- 1 H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamic acid tert-butyl ester (43b)

[0436] Referring to the preparation method of Example 6, compound 43b (180 mg) was prepared by replacing the benzenesulfonyl chloride in step a) with compound 43a.

[0437] c) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((1-isopropyl-1H-pyrazol-3- yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 43)

[0438] Prepared according to the procedure of Example 6, substituting compound 43b for compound 6a in step b), to give the title compound 43 as a crude product which was purified by preparative HPLC (column: Kinetex 5 pm EVO C18, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 7.02; column temperature: 25 °C) to give compound 43 (48 mg). 1 H NMR: (400 MHz, DMSO-d6) d 8.05 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.32 - 7.22 (m, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 7.05 - 7.00 (m, 2H), 6.43 (s, 1H), 4.59 (p, J = 6.6 Hz, 1H), 2.85 (d, J = 12.3 Hz, 2H), 2.44 (s, 1H), 2.41 - 2.36 (m, 2H), 1.40 (d, J = 6.7 Hz, 6H), 1.26 - 1.17 (m, 2H), 0.65 - 0.56 (m, 2H). MS (ESI, m / z): 618.20 [M+H] + .

[0439] Example 44: 1-(5-(3,5-difluorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-1- toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0440] a) (1-(5-chloro-3-(3-methyl-1H-pyrazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3- b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (44a)

[0441] Compound M1 (40 mg) and 5-methyl-2H-pyrazol-3-ylboronic acid (12.94 mg) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL), [1,1'- bis(di-tert-butylphosphino)ferrocene]dichloropalladium (4.46 mg) and potassium phosphate (29.08 mg) were added, and the reaction was carried out at 80 °C under nitrogen for 2 hours. The reaction was concentrated to dryness and column chromatography (petroleum ether / ethyl acetate = 3:1) gave the title compound 44a (50 mg).

[0442] MS (ESI, m / z): 582.8 [M+H] + .

[0443] b) tert-Butyl (1-(5-(3,5-difluorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-1- toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (44b)

[0444] Compound 44a (50 mg), (3,5-difluorophenyl)boronic acid (40.5 mg) were dissolved in 1,4-dioxane (2.0 mL) and water (0.4 mL), [1,1'-bis(ditert- butylphosphine)ferrocene]dichloropalladium (5.57 mg) and potassium phosphate (36.28 mg) were added, and the reaction was stirred at 100 °C for 2 hours under nitrogen. The reaction was concentrated to dryness and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound 44b (25 mg). MS (ESI, m / z): 663.55 [M+H] + .

[0445] c) 1-(5-(3,5-Difluorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-1- toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 44)

[0446] To a solution of compound 44b (18 mg) in 1,4-dioxane (0.5 mL) was added hydrochloric acid in ethyl acetate (4 mol / L, 0.5 mL) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated to dryness to give a crude product, which was purified by preparative HPLC under the following conditions (column: Sunfire C 18 , 5 μm, 30 mm*150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 43% B in 8 minutes; wavelength: UV 254 nm / 221 nm; RT (min): 6.83, column temperature: 25 °C) to give the title compound 44 (3.8 mg). 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.34 (s, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.98 (s, 1H), 7.77 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.29 (t, J = 9.7 Hz, 1H), 7.08 (d, J = 6.8 Hz, 2H), 6.18 (s, 1H), 2.89 (d, J = 12.2 Hz, 2H), 2.46 (s, 3H), 2.39 (d, J = 15.4 Hz, 3H), 2.27 (s, 3H), 1.27 (t, J = 13.8 Hz, 2H), 0.76 (d, J = 11.4 Hz, 2H). MS (ESI, m / z): 562.9 [M+H] + .

[0447] Example 45: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-methyl-1H-1,2,3- triazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0448] a) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-(1-methyl- 1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (45a)

[0449] Compound M3 (50 mg) was dissolved in xylene (5 mL), 4-bromo-1-methyl-1H-1,2,3- triazole (28 mg), N,N'-dimethylethylenediamine (6 mg), cuprous iodide (4 mg) and potassium phosphate (54 mg) were added. Nitrogen was replaced, stirred at 100 °C for 5 hours. The reaction was quenched with water, extracted with ethyl acetate, the organic phase was dried, concentrated, purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound 45a (40 mg).

[0450] b) 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-methyl-1H-1,2,3-triazol-4- yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 45)

[0451] Compound 45a (40 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 2 hours, concentrated to dryness, the crude was purified by reverse phase high performance liquid chromatography (column: X-Bridge Prep C 1810 pm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 15% B to 45% B in 10 min; wavelength: UV 254 nm; RT (min): 8.533, column temperature: 25 °C) to give the formate salt of the title compound 45 (18.8 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.46-7.43 (dd, J = 7.7, 1.9 Hz, 1H), 7.34-7.32 (dd, J = 8.0 Hz, 1H), 7.29-7.28 (tt, J = 4.0 Hz, 1H), 7.08-7.01 (m, 2H), 6.71-6.68 (t, J = 12.0 Hz, 1H), 4.17 (s, 3H), 2.94-2.91 (d, J = 12.0 Hz, 2H), 2.45-2.40 (m, 3H), 1.29-1.26 (d, J = 12.0 Hz, 2H), 0.64-0.61 (d, J = 12.0 Hz, 2H). MS (ESI, m / z): 527.2 [M+H] + .

[0452] Example 46: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyrimidin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0453] Reference to the preparation method of Example 36, replace 5-methylpyridine-2- carboxaldehyde in step a) with 5-methylpyrimidine-2-carboxaldehyde, to prepare compound 46 crude product, the crude product was purified by preparative HPLC under the following conditions (column: XBridge BEH Shield RP18 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 48% B in 10 min; wavelength: UV 254 nm / 220 nm; column temperature: 25 °C; RT (min): 8.92) to prepare compound 46 (42 mg).

[0454] Compound 46 was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK-IC 2*25 cm, 5 pm; mobile phase A: HEX (0.1% DEA), mobile phase B: EtOH:DCM (1 : 1, v / v) flow rate: 20 mL / min; isocratic 40% B; wavelength: UV 254 / 220 nm; column temperature: 25 °C; sample solvent: methanol; resolution of compound isomers 46A (RT = 8.13 min, 12.6 mg) and 46B (RT = 11.47 min, 11.9 mg).

[0455] 46A: 1 H NMR: (400 MHz, DMSO-d6) δ 8.70 - 8.55 (m, 2H), 7.92 - 7.74 (m, 1H), 7.57 - 7.51 (m, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.27 - 7.17 (m, 1H), 7.02 - 6.93 (m, 2H), 6.79 - 6.63 (m, 1H), 6.29 (q, J = 7.2 Hz, 1H), 2.96 - 2.79 (m, 2H), 2.46 - 2.35 (m, 2H), 2.35 - 2.29 (m, 1H), 2.25 (s, 3H), 1.87 (d, J = 7.2 Hz, 3H), 1.23 - 1.10 (m, 2H), 0.68 - 0.34 (m, 2H). MS (ESI, m / z): 566.55 [M+H] + .

[0456] 46B: 1H NMR: (400 MHz, DMSO): δ 8.67 - 8.60 (m, 2H), 7.86 (s, 1H), 7.57 (s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.28 - 7.18 (m, 1H), 7.04 - 6.95 (m, 2H), 6.80 - 6.69 (m, 1H), 6.29 (q, J = 7.2 Hz, 1H), 2.96 - 2.78 (m, 2H), 2.46 - 2.35 (m, 2H), 2.34 - 2.31 (m, 1H), 2.25 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H), 1.22 - 1.11 (m, 2H), 0.69 - 0.40 (m, 2H). MS (ESI, m / z): 566.60 [M+H] + .

[0457] Example 47: N'-acetyl-4-(4-aminopiperidin-l-yl)-3-(3-cyano-2-hydroxyphenyl)-5- (3,5-difluorophenyl)-lH-pyrrolo[2,3-b]pyridine-l-carbohydrazide

[0458] a) tert-Butyl (l-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-(5- methyl-l,3,4-oxadiazol-2-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (Compound 47a)

[0459] Compound M3 (50 mg) was added to a reaction tube under nitrogen, followed by 2-bromo-5-methyl-l,3,4-oxadiazole (25 mg), 2-dicyclohexylphosphino-2',6'- diisopropoxy-l,l'-biphenyl (6 mg), tris(dibenzylideneacetone)dipalladium (15.2 mg), cesium carbonate (110 mg), dioxane (2 mL) and stirred at 100 °C for 3 hours. Extracted with water and ethyl acetate, combined the organic phase and washed with water, the organic phase was concentrated to dryness and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1 (v / v)) to give the title compound 47a (54 mg).

[0460] b) N'-acetyl-4-(4-aminopiperidin-l-yl)-3-(3-cyano-2-hydroxyphenyl)-5-(3,5- difluorophenyl)-lH-pyrrolo[2,3-b]pyridine-l-carbohydrazide (Compound 47)

[0461] Compound 47a (54 mg) was dissolved in dichloromethane (6 mL), hydrochloric acid in dioxane (4.0 mol / L, 2 mL) was added, stirred for 2 hours, the reaction solution was concentrated to dryness to give a crude product, which was purified by reverse phase high performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 15% B to 35% B in 10 minutes; wavelength: UV 254 nm; RT (min): 8.63, column temperature: 25 °C) to give the title compound 47 (12.5 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.44 - 7.36 (m, 1H), 7.26 (dd, J = 8.4, 6.3 Hz, 2H), 7.12 - 7.03 (m, 2H), 6.60 (t, J = 7.5 Hz, 1H), 2.90 (d, J = 12.2 Hz, 2H), 2.55 (s, 1H), 2.42 (t, J = 11.6 Hz, 2H), 1.95 (s, 3H), 1.25 (d, J = 11.7 Hz, 2H), 0.63 (d, J = 11.9 Hz, 2H). MS (ESI, m / z): 545.8 [M+H] + .

[0462] Example 48: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((2,5- dimethylfuran-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0463] (1-(3-bromo-5-chloro-1-((2,5-dimethylfuran-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)piperidin-4-yl)carbamic acid tert-butyl ester (Compound 48a)

[0464] To a vial was added compound M1-4 (150 mg), 2,5-dimethylfuran-3-sulfonyl chloride (101.9 mg), 4-dimethylaminopyridine (4.26 mg), N,N-diisopropylethylamine (135.34 mg), dichloromethane (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was concentrated to dryness and column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound 48a (125 mg).

[0465] b) (1-(5-chloro-3-(3-cyano-2-(methoxymethoxy)phenyl)-1-((2,5-dimethylfuran-3- yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (Compound 48b)

[0466] To a vial was added compound 48a (150 mg), 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (110.47 mg), potassium phosphate (162.19 mg), 1,4-dioxane (10 mL), water (2 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (20.75 mg), and the mixture was heated to 80 °C under nitrogen for 4 h. After the reaction was completed, the reaction solution was concentrated to dryness, and column chromatography (petroleum ether / ethyl acetate = 2:1) gave the title compound 48b (125 mg).

[0467] c) tert-Butyl (1-(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-((2,5-dimethylfuran-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (Compound 48c)

[0468] To a reaction vial was added compound 48b (105 mg), 3,5-difluorobenzoic acid (37.11 mg), tris(dibenzylideneacetone)dipalladium (14.35 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14.94 mg), potassium phosphate (66.51 mg), 1,4-dioxane (10 mL), and water (2 mL). The mixture was heated to 90 °C under nitrogen for 2 h. The reaction solution was concentrated to dryness, and column chromatography (petroleum ether / ethyl acetate = 2:1) gave the title compound 48c (80 mg).

[0469] d) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((2,5-dimethylfuran-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 48)

[0470] Reference Example 6 was prepared according to the preparation method of Reference Example 6, substituting compound 48c for compound 6a of step b) to give the title compound 48 as a crude product, which was purified by preparative HPLC under the following conditions (column: YMC Triart C18 ExRs 5 µm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 42% B to 62% B in 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 6.47; column temperature: 40 °C) to give the title compound 48 (42.7 mg). 1H NMR: (400 MHz, DMSO-d6, ppm) δ 7.94 (s, 1H), 7.56 (s, 1H), 7.32 (dd, J = 7.6, 1.9 Hz, 1H), 7.25 (tt, J = 9.5, 2.4 Hz, 1H), 7.17-7.11 (m, 1H), 7.05 (h, J = 4.5 Hz, 2H), 6.46 (d, J = 1.3 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 2.89-2.77 (m, 2H), 2.66 (s, 3H), 2.47 (s, 1H), 2.44-2.36 (m 2H), 2.19 (s, 3H), 1.27-1.14 (m, 2H), 0.69-0.50 (m 2H). MS (ESI, m / z): 603.80 [M+H] + .

[0471] Example 49: 3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-((l,5- dimethyl-lH-pyrazol-3-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0472] Reference to the preparation method of Example 43, replace 1-isopropylpyrazol-3-amine in step a) with 1,5-dimethyl-lH-pyrazol-3-amine, to prepare compound 49 crude product, the crude product was purified by preparative HPLC under the following conditions (column: Xselect CSHTM Prep C18 5 μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 40% B in 10 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 7.15, column temperature: 25 °C) to prepare formate salt of compound 49 (7.0 mg). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.26-8.12 (m, 1H), 7.89 (s, 1H), 7.52 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.26-7.13 (m, 2H), 6.97 (d, J = 7.1 Hz, 2H), 6.81 (s, 1H), 6.63-6.49 (m, 1H), 3.72 (s, 3H), 2.79 (d, J = 12.2 Hz, 2H), 2.41-2.38 (m, 1H), 2.34-2.27 (m, 2H), 2.21 (s, 3H), 1.23-1.14 (m, 2H), 0.58-0.44 (m, 2H). MS (ESI, m / z): 604.20 [M+H]+ .

[0473] Example 50: 3-(4-(4-aminopiperidin-1-yl)-1-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,5- difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0474] a) (1-(3-cyano-2-(methoxymethoxy)phenyl)-1-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,5- difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (50a)

[0475] Compound M3 (50 mg) was dissolved in N,N-dimethylformamide (2 mL) under nitrogen, 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg), copper acetate (40 mg), pyridine (20 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (60 mg) were added successively, and the mixture was stirred at 60 °C for 3 h. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was combined and washed with water. The organic phase was concentrated to dryness, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 50a (31 mg).

[0476] b) 3-(4-(4-aminopiperidin-1-yl)-1-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,5-difluorophenyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (compound 50)

[0477] The crude compound 50a was dissolved in dichloromethane (6 mL), and a solution of trifluoroacetic acid in dichloromethane (1:5, 6 mL) was added. The mixture was stirred at room temperature for 2 h, and the reaction mixture was concentrated to dryness to give a crude product. The crude product was purified by reverse-phase high-performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 15% B to 55% B in 10 min; wavelength: UV 254 nm; RT (min): 8.18; column temperature: 25 °C) to give the title compound 50 (9.6 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.48 (dd, J = 7.7, 1.8 Hz, 1H), 7.35 (dd, J = 7.4, 1.8 Hz, 1H), 7.30 - 7.22 (m, 1H), 7.03 (d, J = 5.7 Hz, 2H), 6.78 (t, J = 7.6 Hz, 1H), 3.82 (tt, J = 7.4, 3.9 Hz, 1H), 2.97 - 2.87 (m, 2H), 2.42 (d, J = 11.6 Hz, 3H), 1.27 (d, J = 11.8 Hz, 2H), 1.13 - 1.06 (m, 2H), 1.05 - 0.96 (m, 2H), 0.65 - 0.51 (m, 2H). MS (ESI, m / z): 552.8 [M+H] + .

[0478] Example 51: 5-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l- toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-imidazole-2-carbonitrile

[0479] a) 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (51a)

[0480] To a 40 mL vial was added 4-bromo-3H-imidazole (1 g) in THF (10 mL) and sodium hydride (0.49 g) at 0 °C. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 0.5 h. Then 2-(trimethylsilyl)ethoxymethyl chloride (1.70 g) was added to the reaction. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched by adding water / ice (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with brine (1*30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5: 1) to afford the title compound 51a (1.2 g). MS (ESI, m / z): 277 [M+H] + .

[0481] b) 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carboxaldehyde (51b)

[0482] Compound 51a (670 mg) was dissolved in tetrahydrofuran (20.1 mL) and lithium diisopropylamide (310.68 mg) was added dropwise. The reaction was stirred at -78 °C under nitrogen atmosphere for 0.5 h, then N,N-dimethylformamide (353.3 mg) was added dropwise at room temperature. The solution was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water at room temperature. The aqueous layer was extracted with ethyl acetate (10*3 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to afford the title compound 51b (300 mg).

[0483] MS (ESI, m / z): 305 [M+H] + .

[0484] c) (E) 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carbaldehyde oxime (51c)

[0485] Compound 51b (290 mg) and hydroxylamine hydrochloride (72.62 mg), pyridine (0.5 mL) were mixed and stirred at room temperature under air atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude compound 51c (320 mg) was used directly in the next step without further purification. MS (ESI, m / z): 320 [M+H] + .

[0486] d) 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carbonitrile (51d)

[0487] Compound 51c (300 mg) and triethylamine (94.8 mg), 1,4-butyne diacid dimethyl ester (266.2 mg), acetonitrile (9.0 mL) were mixed and stirred at room temperature under air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (20:1) to afford the title compound 51d (210 mg). 1 H NMR: (400 MHz, Chloroform-d, ppm) δ 7.22 (s, 1H), 5.41 (s, 2H), 3.64-3.44 (m, 2H), 0.99-0.89 (m, 2H), 0.00 (s, 9H).

[0488] e) (l-(5-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3- b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (51e)

[0489] A mixture of compound Ml (350 mg) and potassium acetate (176.48 mg), tetrakis triphenylphosphine palladium (69.26 mg), 4,4,5,5-tetramethyl-2-(4,4,5,-5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborinane (456.62 mg), 1,4-dioxane (10 mL) was stirred at 80 °C under nitrogen atmosphere overnight. The precipitated solid was collected by filtration. The crude product of compound 51e was used directly in the next step without further purification. MS (ESI, m / z): 631 [M+H] + .

[0490] f) tert-Butyl (l-(5-chloro-3-(2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)-l- toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (51f)

[0491] A solution of compound 51e (350 mg) and compound 51d (58.68 mg), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (14.21 mg), potassium phosphate (123.63 mg) in 1,4-dioxane (17.5 mL) / water (3.5 mL) was stirred at 100 °C under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3: 1) to give the title compound 51f (230 mg). MS (ESI, m / z): 726 [M+H] + .

[0492] g) tert-Butyl (l-(3-(2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)-5-(3,5- difluorophenyl)-l-toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (51g)

[0493] A mixture of compound 51f (220 mg) and 3,5-difluorophenylboronic acid (9.33 mg), tris(dibenzylideneacetone)dipalladium (3.61 mg), 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (3.75 mg), potassium phosphate (25 mg), 1,4-dioxane (5 mL) and water (1 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: (column, C18; mobile phase, aqueous acetonitrile (10 mmol / L ammonium bicarbonate), 10% to 100% gradient in 20 min; detector, UV 254 nm) to afford the title compound 51g (27 mg). MS (ESI, m / z): 804 [M+H] + .

[0494] h) 5-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l- toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-imidazole-2-carbonitrile (Compound 51)

[0495] A mixture of compound 51g (14 mg) in trifluoroacetic acid (0.33 mL) / dichloromethane (1 mL) was stirred at room temperature under air atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 28% B to 58% B in 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 6.93) to afford the title compound 51 (3.8 mg). 1 H NMR: (400 MHz, DMSO-d6, ppm) d 8.03 (d, J = 8.2 Hz, 2H), 7.97 (s, 1H), 7.62 (s, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.29 - 7.21 (m, 1H), 7.15 - 7.00 (m, 3H), 2.94 - 2.70 (m, 2H), 2.58 - 2.53 (m, 3H), 2.36 (s, 3H), 1.44 - 1.32 (m, 2H), 0.96 - 0.77 (m, 2H). MS (ESI, m / z): 574.20 [M+H] + .

[0496] Example 52: 1-(3-(6,7-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0497] a) tert-Butyl (1-(3-(6,7-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (52a)

[0498] tert-Butyl (1-(5-(3,5-difluorophenyl)-3-formyl-1-(1-(5-methylpyridin-2-yl)ethyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (130 mg) and 3,4-difluoro-benzene-1,2- diamine (45 mg) were dissolved in acetic acid solution (5 ml), 50 mg copper acetate was added, stirred at room temperature for 12 hours, extracted with water and dichloromethane, the organic phase was combined and concentrated to give a sand, column chromatography to give the title compound 52a (90 mg). MS (ESI+): 698.27 (M+H) + .

[0499] b) 1-(3-(6,7-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 52)

[0500] Compound 52a (60 mg) was dissolved in dioxane (5 ml), 2 ml of 4.0 M hydrochloric acid was added. Stirred at room temperature for 3 hours to give compound 52 (4.8 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.58 (dd, J = 8.1, 2.3 Hz, 1H), 7.41 (s, 1H), 7.29 (dt, J = 9.2, 2.4 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 5.9 Hz, 2H), 6.28 (d, J = 7.2 Hz, 1H), 3.01 (s, 3H), 2.75 - 2.56 (m, 2H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.35 (d, J = 6.5 Hz, 2H), 0.84 (s, 2H). MS (ESI+): 600.3 (M+H) +.

[0501] Example 53: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(2-oxo-2-(p-tolyl)ethyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0502] a) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-(2-oxo-2-(p- tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (53a)

[0503] To a reaction flask was added compound M3 (40 mg), potassium carbonate (10 mg), N,N- dimethylformamide (3 mL), stirred for 10 minutes at room temperature, added 2-bromo-1-(p- tolyl)ethan-1-one (12 mg), and reacted for 4 hours. After completion of the reaction, the reaction solution was extracted with water and ethyl acetate, the organic layers were combined and washed with water, and the organic layer was concentrated to dryness to obtain the crude title compound 53a.

[0504] b) 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(2-oxo-2-(p-tolyl)ethyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 53)

[0505] To the crude compound 53a was added a hydrochloric acid solution in dioxane (4 M, 2 mL), stirred for 2 hours, and the reaction solution was concentrated to dryness to obtain a crude product, which was purified by reverse phase high performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 30% B to 60% B in 10 minutes; wavelength: UV 254 nm; RT (min): 5.72, column temperature: 25°C) to obtain the title compound 53 (1.39 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 8.0 Hz, 2H), 7.82 (s, 1H), 7.47 - 7.38 (m, 4H), 7.31 (m, 1H), 7.23 (m, 1H), 7.06 - 6.98 (m, 2H), 6.71 (t, J = 7.6 Hz, 1H), 5.87 (s, 2H), 2.93 (m, 2H), 2.43 (m, 6H), 1.25 (m, 2H), 0.63 (m, 2H). MS (ESI, m / z): 578.3 [M+H] +.

[0506] Example 54: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(5-methyl-2,3- dihydro-1H-inden-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0507] a) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-(5- methyl-2,3-dihydro-1H-inden-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamate (54a)

[0508] Compound M3 (50 mg) was dissolved in toluene (5 mL), 5-methyl-2,3-dihydro-1H- inden-1-ol (25 mg), cyano methylene tributyl phosphonium (31 mg) were added. Nitrogen was purged, stirred at 130 °C for 5 hours. The reaction was quenched with water, extracted with ethyl acetate, the organic phase was dried to give the crude title compound 54a (50 mg).

[0509] b) 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(5-methyl-2,3-dihydro-1H- inden-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 54)

[0510] Compound 54a (50 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 2 hours, concentrated to dryness, the crude was purified by reverse phase high performance liquid chromatography (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 35% B to 75% B in 10 minutes; wavelength: UV 254 nm; RT (min): 6.75, column temperature: 25 °C) to give the formate salt of the title compound 54 (11 mg). 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.95 (s, 1H), 7.44-7.42 (dd, J = 8.0, 1.8 Hz, 1H), 7.35-7.32 (dd, J = 12.0 Hz, 1H), 7.18 (s, 1H), 7.03-6.97 (m, 5H), 6.92 (s, 1H), 6.82-6.78 (m, 1H), 6.46-6.42 (t, J = 16.0 Hz, 1H), 3.19-3.11 (m, 3H), 3.03-2.95 (m, 1H), 2.79-2.70 (m, 1H), 2.61-2.48 (m, 3H), 2.34-2.24 (m, 4H), 1.45-1.42 (d, J = 12.0 Hz, 2H), 0.77-0.65 (m, 2H). MS (ESI, m / z): 576.3 [M+H] + .

[0511] Example 55: 2-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l- toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-imidazole-5-carbonitrile

[0512] a) l-((2-(Trimethylsilyl)ethoxy)methyl)-lH-imidazole-5-carbonitrile (55a)

[0513] To a solution of lH-imidazole-5-carbonitrile (1.5 g) in tetrahydrofuran (40 mL) was added sodium hydride (1.61 g) at 0 °C under nitrogen atmosphere for 2 h, then 2-(trimethylsilyl)ethoxymethyl chloride (4.03 g) was added portion wise at 0 °C. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layer was washed with water (3 x 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3: 1) to afford the title compound 55a (1.4 g). MS (ESI, m / z): 224.10 [M+H] + .

[0514] b) 2-Bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-5-carbonitrile (55b)

[0515] To N-bromosuccinimide (525.94 mg) and compound 55a (600 mg) was added carbon tetrachloride (6 mL), azobisisobutyronitrile (44.11 mg) was added dropwise at 60 °C under nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1, v / v) to give the title compound 55b (400 mg). MS (ESI, m / z): 303.85 [M+H] + .

[0516] Referring to Example 51, replace 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazole-2-carbonitrile in step f) with compound 55b to give compound 55 crude product (30 mg), which was purified by preparative HPLC under the following conditions (column: XBridge BEH Shield RP 185 µm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 63% B in 8 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 6.68, column temperature: 25 °C) to give compound 55 (4.6 mg). 1 H NMR (400 MHz, DMSO-d6, ppm) 8.11-8.06 (m, 3H), 8.03-8.00 (m, 2H), 7.45 (d, J = 8.16 Hz, 2H), 7.31-7.27 (m, 1H), 7.10-7.08 (m, 2H), 2.84-2.81 (m, 2H), 2.37-2.33 (m, 6H), 1.26-1.24 (m, 2H), 0.62-0.58 (m, 2H). MS (ESI, m / z): 574.15 [M+H] + .

[0517] Example 56: 3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-((6,7-dihydro-5H- pyrrolo[l,2-a]imidazol-2-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0518] a) 2-iodo-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (56a)

[0519] Into a 250 mL round bottom flask was placed 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole (1.4 g), N-iodosuccinimide (3.2 g), acetonitrile (150 mL) at 0 °C. The mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium thiosulfate solution at room temperature. The mixture was extracted with ethyl acetate. The combined organic layers were dried and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8: 1) to give the title compound 56a (30 mg).

[0520] b) 2-(benzylthio)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (56b)

[0521] Into a vial was placed compound 56a (310 mg), benzyl mercaptan (246.77 mg), tris(dibenzylideneacetone)dipalladium (60.65 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (76.64 mg), N,N-diisopropylethylamine (427.99 mg), 1,4-dioxane (10 mL) and water (2 mL) at room temperature. The mixture was stirred at 100 °C under nitrogen overnight. The reaction was concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6: 1) to give the title compound 56b (200 mg).

[0522] 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76.64 mg), N,N- diisopropylethylamine (427.99 mg), 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 100 °C under nitrogen overnight. The reaction was concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6: 1) to give the title compound 56b (200 mg).

[0523] c) 6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-2-sulfonyl chloride (56c)

[0524] Into a vial was placed compound 56b (180 mg), 1,3-dichloro-5,5-dimethylimidazolidine- 2,4-dione (123 mg), acetonitrile (1.6 mL), acetic acid (0.4 mL) and water (0.8 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6: 1) to give the title compound 56c (50 mg).

[0525] d) (l-(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-((6,7- dihydro-5H-pyrrolo[l,2-a]imidazol-2-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin- 4-yl)carbamic acid tert-butyl ester (56d)

[0526] To a vial was added compound 56c (10.51 mg), compound M3 (30 mg), N,N- diisopropylethylamine (19.73 mg), 4-dimethylaminopyridine (0.62 mg) and dichloromethane (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The residue was purified by preparative thin layer chromatography plate (petroleum ether / ethyl acetate = 2:1) to give the title compound 56d (30 mg).

[0527] e) 3-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-((6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-2-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 56)

[0528] To a vial was added compound 56d (30 mg), hydrogen chloride in 1,4-dioxane (2 mL) and methanol (2 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: YMC Triart C 18 ExRs 5 μm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 24% B to 54% B in 8 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 6.02, column temperature: 25 °C) to give the title compound 56 (13.3 mg). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 7.99 (s, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.32-7.24 (m, 1H), 7.21 (s, 1H), 7.07-7.02 (m, 2H), 6.47 (s, 1H), 4.25 (t, J = 7.3 Hz, 2H), 2.85-2.80 (m, 4H), 2.60-2.53 (m, 2H), 2.45-2.34 (m, 3H), 1.30-1.17 (m, 2H), 0.70-0.50 (m, 2H). MS (ESI, m / z): 616.05 [M+H] + .

[0529] Example 57: 3-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-((2-methyl-2H-l,2,3- triazol-4-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0530] 4-(benzylsulfanyl)-2H-1,2,3-triazole (57a)

[0531] A solution of sodium 2H-1,2,3-triazole-4-thiol (5 g) and benzyl bromide (7.64 g) in ethanol (40 mL) was stirred at 0 °C under air overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (3 x 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with methyl tert-butyl ether / isohexane (1 :1) (10 mL). The precipitated solid was collected by filtration and washed with ethyl acetate (3 x 5 mL) to give the title compound 57a (7.2 g).

[0532] 4-(benzylsulfanyl)-2-methyl-2H-1,2,3-triazole (57b)

[0533] To a stirred solution of potassium carbonate (8.67 g) and compound 57a (4 g) in N,N-dimethylformamide (30 mL) was added iodomethane (3.27 g) dropwise at room temperature under air. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (3 x 10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give compound 57b (1.1 g).

[0534] 2-methyl-2H-1,2,3-triazole-4-sulfonic acid chloride (57c)

[0535] To a sealed tube was added compound 57b (100 mg), acetonitrile (2 mL), acetic acid (0.4 mL) and water (1 mL) at room temperature. Then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (143.96 mg) was added at 0 °C. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (5 x 6 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (4:1) to give the title compound 57c (28 mg).

[0536] d) tert-butyl (1-(3-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (57d)

[0537] To a sealed tube at room temperature was added compound 57c (12.32 mg), dichloromethane (1 mL), compound M3 (40 mg), N,N-diisopropylethylamine (26.3 mg) and 4-dimethylaminopyridine (0.83 mg). The mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography plate (petroleum ether / ethyl acetate = 2:1) to give the title compound 57d (34 mg).

[0538] e) 3-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-((2-methyl-2H-l,2,3- triazol-4-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 57)

[0539] To a sealed tube at room temperature was added compound 57d (30 mg), dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC under the following conditions (column: Kinetex 5 pm EVO C 18 , 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 13% B to 43% B in 8 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 7.18, column temperature: 25 °C) to give the title compound 57 (7.2 mg). 1 H NMR (400 MHz, DMSO-d6, ppm) 8.65 (s, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.34-7.28 (m, 1H), 7.27-7.25 (m, 1H), 7.20-7.19 (m, 1H), 7.05-7.03 (m, 2H), 6.43 (s, 1H), 4.26 (s, 3H), 2.68 (d, J = 12.28 Hz, 2H), 2.45-2.32 (m, 3H), 1.24-1.22 (m, 2H), 0.64-0.61 (m, 2H). MS (ESI, m / z): 591.15 [M+H] + .

[0540] Example 58: 3-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-((l-methyl-lH-l,2,3- triazol-4-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0541] a) 1 -Methyl- 1H- 1,2,3-triazole-4-sulfonyl chloride (58a)

[0542] To a sealed tube was added 4-(benzylsulfanyl)-l-methyl-l,2,3-triazole (100 mg), acetic acid (2 mL), water (1 mL) at room temperature. Then N-chlorosuccinimide (260.19 mg) was added at 0 °C. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (5 x 6 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (4: 1) to give the title compound 58a (40 mg).

[0543] b) (l-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-((l-methyl-lH- 1,2,3-triazol-4-yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (58b)

[0544] To a sealed tube was added compound 58a (12.32 mg), dichloromethane (1 mg), compound M3 (40 mg), N,N-diisopropylethylamine (26.3 mg) and 4-dimethylaminopyridine (0.83 mg). The mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography plate (petroleum ether / ethyl acetate = 2: 1) to give the title compound 58b (50 mg).

[0545] c) 3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-((l-methyl-lH-l,2,3-triazol-4- yl)sulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 58)

[0546] To a sealed tube was added compound 58b (45 mg), dichloromethane (3 mL) and trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product (45 mg) was purified by preparative HPLC under the following conditions (Column: Kinetex 5 pm EVO C 18 , 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 13% B to 43% B in 8 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 8.07, column temperature: 25 °C) to give the title compound 58 (9.0 mg). 1HNMR: (400 MHz, DMSO-d6) 9.22 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.34-7.28 (m, 1H), 7.27-7.24 (m, 1H), 7.20-7.18 (m, 1H), 7.06-7.03 (m, 2H), 6.45-6.44 (m, 1H), 4.13 (s, 3H), 2.87-2.79 (m, 2H), 2.52-2.33 (m, 3H), 1.24-1.21 (m, 2H), 0.63-0.61 (m, 2H). MS (ESI, m / z): 591.10 [M+H] + .

[0547] Example 59: 3-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-(2-methyl- 4,5,6,7-tetrahydro-2H-indazol-7-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2- hydroxybenzonitrile

[0548] a) 1 -Methyl-4-vinyl- 1 H-pyrazole-3-carboxylic acid methyl ester (59a)

[0549] A solution of 4-bromo-l-methylpyrazole-3-carboxylic acid methyl ester (5 g), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (4.56 g) [l,l'-bis(diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (1.86 g) and potassium phosphate (14.54 g) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 100 °C under nitrogen for 3 h. The resulting mixture was extracted with ethyl acetate (3 x 20 mL) and dried over anhydrous sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to afford the title compound 59a (4.0 g).

[0550] b) 1 -Methyl-4-vinyl- 1 H-pyrazole-3-carboxylic acid methyl ester (59a)

[0551] A solution of diisobutylaluminium hydride (6.85 g) and morpholine (4.19 g) in tetrahydrofuran (40.0 mL) was stirred at 0 °C under nitrogen for 0.5 h. To the above mixture was added compound 59a (2 g) drop wise at 0 °C over a period of 2 min. The resulting mixture was stirred at room temperature for another 2 h. The mixture was acidified to pH 5 with concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL) and dried over anhydrous sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to afford the title compound 59b (520 mg).

[0552] c) 1 -(1 -Methyl-4-vinyl-1 H-pyrazol-3-yl)but-3-en-1 -ol (59c)

[0553] A solution of compound 59b (400 mg) in tetrahydrofuran (40.0 mL) was stirred at 0 °C under nitrogen. To the above mixture was added allylmagnesium bromide (3.53 mL) dropwise at 0 °C over 3 min. The resulting mixture was stirred at 0 °C for another 20 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (5:1 ) to give the title compound 59c (320 mg).

[0554] d) 2-Methyl-6,7-dihydro-2H-indazol-7-ol (59d)

[0555] A solution of compound 59c (500 mg) and phenylmethylenebis(tricyclohexylphosphine)dichlororuthenium (234.8 mg) in 1,2-dichloroethane (25.0 mL) was stirred at 80 °C under nitrogen overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 :1, v / v) to give the title compound 59d (240 mg).

[0556] e) 2-Methyl-4,5,6,7-tetrahydro-2H-indazol-7-ol (59e)

[0557] A solution of compound 59d (170 mg) and palladium on carbon (16.86 mg) in ethyl acetate (5.1 mL) and dichloromethane (0.85 mL) was stirred at room temperature under hydrogen for 3 h. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3 x 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 :1, v / v) to give the title compound 59e (150 mg).

[0558] f) tert-Butyl (1 -(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1 -(2- methyl-4,5,6,7-tetrahydro-2H-indazol-7-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamate (59f)

[0559] Compound 59e (80 mg) was dissolved in tetrahydrofuran (2.67 mL), compound M3 (154.97 mg) and triphenylphosphine (137.87 mg) were added and the mixture was treated with di-tert-butyl azodicarboxylate (121.03 mg) at room temperature under nitrogen atmosphere. The mixture was stirred at 70 °C under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1, v / v) to give the title compound 59f (18 mg).

[0560] g) 3-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-(2-methyl-4,5,6,7- tetrahydro-2H-indazol-7-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 59)

[0561] Compound 59f (17 mg) was dissolved in dichloromethane (0.6 mL) and trifluoroacetic acid (0.2 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated to dryness. The crude product (20 mg) was purified by preparative HPLC under the following conditions (column: XBridge BEH Shield RP18 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 33% B to 56% B in 10 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 8.48; column temperature: 25 °C) to give the title compound 59 (3.3 mg). 1 H NMR: (400 MHz, DMSO-d6) d 7.95 (s, 1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.27 (dd, J = 18.9, 9.6 Hz, 2H), 7.10 - 6.99 (m, 2H), 6.90 (s, 1H), 6.79 (s, 1H), 6.05 (t, J = 5.7 Hz, 1H), 3.74 (s, 3H), 2.90 (d, J = 11.9 Hz, 2H), 2.67 (p, J = 1.9 Hz, 1H), 2.37 (s, 2H), 2.33 (p, J = 1.9 Hz, 2H), 2.16 (d, 2H), 1.78 (d, J = 18.5 Hz, 2H), 1.18 (d, J = 14.4 Hz, 2H), 0.58 (d, J = 11.7 Hz, 1H), 0.46 (d, J = 10.5 Hz, 1H). MS (ESI, m / z): 580.20 [M+H] + .

[0562] h) Compound 59 was resolved by preparative chiral HPLC under the following conditions (preparative chiral column: CHIRALPAK-IC 2*25 cm, 5 pm; mobile phase A: HEX (0.1% DEA), mobile phase B: MeOH:DCM (1 : 1, v / v); flow rate: 20 mL / min; isocratic 35% B; wavelength: 254 / 220 nm; sample solvent: methanol; column temperature: 25 °C) to give compound isomers 59A (RT = 11.97 min, 21.1 mg) and 59B (RT = 13.65 min, 22.1 mg).

[0563] 59A: 1 H NMR (400 MHz, DMSO-d6, ppm) δ 7.94 (s, 1H), 7.50 (s, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.27 (dd, J = 10.3, 8.1 Hz, 2H), 7.04 (d, J = 6.7 Hz, 2H), 6.91 (d, J = 7.1 Hz, 1H), 6.75 (s, 1H), 6.04 (t, J = 5.6 Hz, 1H), 3.74 (s, 3H), 2.92 (t, J = 11.8 Hz, 2H), 2.67 (p, J = 1.9 Hz, 1H), 2.63 (s, 1H), 2.33 (p, J = 1.9 Hz, 3H), 2.15 (s, 2H), 1.76 (d, 2H), 1.21 (d, J = 14.1 Hz, 2H), 0.59 (d, J = 11.5 Hz, 1H), 0.47 (d, J = 12.0 Hz, 1H). 19 F NMR (376 MHz, DMSO-d6, ppm) δ -110.18. MS (ESI+): 580.20 (M+H) + .

[0564] 59B: 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.96 (s, 1H), 7.49 (d, J = 11.1 Hz, 2H), 7.36 - 7.23 (m, 2H), 7.04 (d, J = 6.7 Hz, 2H), 6.91 (s, 1H), 6.84 (s, 1H), 6.05 (t, J = 5.8 Hz, 1H), 3.74 (s, 3H), 2.90 (d, J = 11.9 Hz, 2H), 2.67 (p, J = 1.9 Hz, 1H), 2.47 (d, 1H), 2.37 (d, 1H), 2.33 (p, J = 1.9 Hz, 2H), 2.16 (d, 2H), 1.78 (d, J = 18.5 Hz, 2H), 1.18 (d, J = 14.4 Hz, 2H), 0.58 (d, J = 11.7 Hz, 1H), 0.46 (d, J = 10.5 Hz, 1H). 19 F NMR (376 MHz, DMSO-d6, ppm) δ -110.07. MS (ESI+): 580.15 (M+H) + .

[0565] Example 60: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((1-methyl-1H- pyrrol-3-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0566] a) N-methyl-pyrrole-3-sulfonic acid sodium salt (60a)

[0567] N-methylpyrrole (5 g), sulfur trioxide pyridine (10.79 g) and 1,2-dichloroethane (150 mL) were added into a 250 mL three-necked round-bottom flask at room temperature. The resulting mixture was stirred at 85 °C under nitrogen atmosphere for 24 hours. The mixture was cooled to room temperature. The top layer of the reaction mixture was removed by decantation, and sodium hydroxide (4.93 g, 1 mol / L aqueous solution) was added into the residue in turn. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The aqueous phase was concentrated under reduced pressure. The crude product was used directly in the next step without further purification to give the title compound 60a.

[0568] b) N-methyl-pyrrole-3-sulfonyl chloride (60b)

[0569] To a sealed tube was added compound 60a (2.0 g), phosphorus pentachloride (3.41 g) in dichloromethane (50 mL). The mixture was stirred at 40 °C overnight. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 : 1, v / v) to afford the title compound 60b (330 mg).

[0570] c) (1 -(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1 -((1 - methyl-pyrrol-3-yl)sulfonyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (60c)

[0571] To a sealed tube was added compound 60b (9.14 mg) and compound M3 (30 mg) in dichloromethane (1 mL) and N,N-diisopropylethylamine (19.73 mg) and 4-dimethylaminopyridine (0.62 mg) was added at room temperature. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate 1 : 1, v / v) to afford the title compound 60c (34 mg).

[0572] d) 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-((1-methyl-pyrrol-3- yl)sulfonyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (compound 60)

[0573] To a sealed tube was added compound 60c (30 mg, 0.016 mmol) and trifluoroacetic acid (1.0 mL) / dichloromethane (3.0 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC under the following conditions (column: XBridge BEH Shield RP18, 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 20% B to 50% B in 10 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 8.65, column temperature: 25 °C) to afford the title compound 60 (5.1 mg). 1H NMR: (400 MHz, DMSO-d6, ppm) 7.98 (s, 1H), 7.76-7.75 (m, 1H), 7.54 (s, 1H), 7.37-7.36 (m, 1H), 7.30-7.25 (m, 1H), 7.21-7.19 (m, 1H), 7.05-7.03 (m, 2H), 6.87-6.86 (m, 1H), 6.61-6.60 (m, 1H), 6.52 (s, 1H), 3.66 (s, 3H), 2.85-2.82 (m, 2H), 2.39-2.32 (m, 3H), 1.23-1.20 (m, 2H), 0.59-0.57 (m, 2H). MS (ESI, m / z): 589.20 [M+H] + .

[0574] Example 61: 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-amine

[0575] tert-Butyl 2-(1-benzyl-4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-(3,5- difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-1H-benzo[d]imidazole-1-carboxylate (compound 197e, 200 mg) was dissolved in dichloromethane (10 mL), palladium dichloride (2 mL) was added, stirred under hydrogen condition for 16 hours, the reaction solution was filtered and concentrated to dryness to obtain a crude product, which was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C 18 10 μm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5% B to 25% B in 10 minutes; wavelength: UV 254 nm; RT (min): 8.75, column temperature: 25 °C) to obtain the title compound 61 (3.9 mg). 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.92 (s, 1H), 7.64 - 7.56 (m, 2H), 7.32 - 7.26 (m, 1H), 7.15 - 7.09 (m, 2H), 3.04 - 2.98 (m, 2H), 2.70 - 2.58 (m, 3H), 1.36 (d, J = 12.5 Hz, 2H), 0.95 - 0.82 (m, 2H). MS (ESI, m / z): 480.9 [M+H] + .

[0576] Example 62: 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0577] a) 4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (62a)

[0578] Compound 62a (1.2 g) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (256 mg) was added, stirred at 25 °C for 30 min, 2-(1-chloroethyl)-5- methylpyridine (992 mg) was added, stirred at 20 °C for 3 h under nitrogen. The reaction mixture was concentrated to dryness, extracted with ethyl acetate and water, the organic phase was washed with saturated sodium chloride solution, dried, concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1) to give the title compound 62a (1.2 g).

[0579] b) 4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (62b)

[0580] N-methyl-N-phenylformamide (1.33 g) was dissolved in dichloromethane (30 mL), oxalyl chloride (1.24 g) was added, stirred at 25 °C for 30 min, compound 62a (1 g) was added, stirred at 20 °C for 16 h. The reaction mixture was concentrated to dryness, slurry with a mixture of petroleum ether: ethyl acetate = 10:1 (v / v), filtered to give the crude product of the title compound 62b, which was used directly in the next step.

[0581] c) 2-(4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6- difluoro-1H-benzo[d]imidazole (62c)

[0582] Compound 62b (1.0 g) was dissolved in acetic acid (10 mL), 4,5-difluorobenzene-1,2- diamine (0.65 g) was added, stirred at 120 °C for 1 h. The reaction mixture was concentrated to dryness to give the title compound 62c, which was used directly in the next step.

[0583] d) tert-Butyl 1-(5-chloro-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (62d)

[0584] Compound 62c (1 g) was dissolved in N-methylpyrrolidone (10 mL), tert-butyl piperidin-4-ylcarbamate (0.84 g), N,N-diisopropylethylamine (0.85 g) were added, and the mixture was stirred under nitrogen at 160°C for 8 hours by microwave. The reaction solution was concentrated to dryness, extracted with ethyl acetate and water, and the organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain the title compound 62d (0.8 g).

[0585] e) tert-Butyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-chloro-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-lH- benzo[d]imidazole-l-carboxylate (62e)

[0586] Compound 62d (200 mg) was dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (84 mg), N,N-diisopropylethylamine (125 mg), 4-dimethylaminopyridine (4 mg) were added, and the mixture was stirred under nitrogen at 20°C for 1 hour. The reaction solution was concentrated to dryness, extracted with ethyl acetate and water, and the organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4:1 (v / v)) to obtain the title compound 62e (200 mg).

[0587] f) tert-Butyl 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-(3,5- difluorophenyl)-l-(l-(5-methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)- 5,6-difluoro-lH-benzo[d]imidazole-l-carboxylate (62f)

[0588] Compound 62e (200 mg) was dissolved in dioxane (10 mL), (3,5-difluorophenyl)boronic acid (66 mg), cesium carbonate (270 mg), dichlorobis-(4- dimethylaminophenyl) palladium(II) (20 mg) were added, and the mixture was stirred under nitrogen at 100°C for 3 hours. The reaction solution was concentrated to dryness, extracted with ethyl acetate and water, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain the title compound 62f (130 mg).

[0589] g) 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 62)

[0590] Compound 62f (130 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, stirred for 2 hours, the reaction was concentrated to dryness to give a crude product, which was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C 18 10 pm OBD, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 50% B in 10 min; wavelength: UV 254 nm; RT (min): 7.59, column temperature: 25 °C) to give the title compound 62 as a crude product. 1 H NMR (400 MHz, DMSO-d6) d 8.38 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.63 - 7.55 (m, 3H), 7.28 (tt, J = 9.3, 2.4 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 3.00 (td, J = 8.5, 4.1 Hz, 2H), 2.65 - 2.54 (m, 2H), 2.37 - 2.29 (m, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.30 (d, J = 12.1 Hz, 2H), 0.79 (dtd, J = 23.3, 11.4, 7.7 Hz, 2H). MS (ESI, m / z): 599.8 [M+H] + .

[0591] Compound 62 crude product (50 mg) was purified by preparative-chiral HPLC under the following conditions (column: CHIRALPAK-IA 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% (v / v) DEA), mobile phase B: ethanol:dichloromethane (1:1, v / v); flow rate: 20 mL / min; isocratic 15% B; wavelength: UV 254 / 220 nm; sample solvent: EtOH; column temperature: 25 °C) to give compound isomers 62A (RT = 7.51 min, 15.5 mg) and 62B (RT = 9.45 min, 16.7 mg) upon resolution.

[0592] 62A: 1H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.58 (m, 3H), 7.29 (tt, J = 9.5, 2.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.17 - 7.02 (m, 2H), 6.28 (q, J = 7.2 Hz, 1H), 2.99 (t, J = 10.4 Hz, 2H), 2.55 (d, J = 13.4 Hz, 2H), 2.26 (s, 4H), 1.91 (d, J = 7.1 Hz, 3H), 1.26 (d, J = 13.2 Hz, 2H), 0.87 - 0.47 (m, 2H). MS (ESI, m / z): 599.90 [M+H] + .

[0593] 62B: 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.58 (m, 3H), 7.29 (tt, J = 9.4, 2.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 - 6.99 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 2.99 (t, J = 10.6 Hz, 2H), 2.63 - 2.52 (m, 2H), 2.26 (s, 4H), 1.91 (d, J = 7.2 Hz, 3H), 1.26 (t, J = 10.0 Hz, 2H), 0.74 (dddd, J = 27.2, 23.1, 15.9, 5.6 Hz, 2H). MS (ESI, m / z): 599.90 [M+H] + .

[0594] Example 63: 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)-7-((l-methyl-lH- pyrazol-3-yl)sulfonyl)pyrrolo[l,2-b]pyridazin-5-yl)-2-hydroxybenzonitrile

[0595] a) 2-(3,5-difluorophenyl)acetaldehyde (63a)

[0596] A mixture of 2-(3,5-difluorophenyl)ethanol (4 g) and Dys-Martin oxidant (12.87 g) in dichloromethane (160.0 mL) was stirred at room temperature in air for 3 hours. The reaction was quenched by adding water (20 mL) at 0 °C. The aqueous layer was extracted with dichloromethane (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (10:1) to give the title compound 63a (3.5 g).

[0597] b) 1-[(Z)-[2-(3,5-difluorophenyl)ethylidene]amino]pyrrole-2-carboxylic acid methyl ester (63b)

[0598] A mixture of compound 63a (3.5 g) and methyl 1-aminopyrrole-2-carboxylate (3.14 g, 22.417 mmol) was stirred overnight at 140 °C under a nitrogen atmosphere to obtain the crude product of title compound 63b. The crude product mixture was used directly in the next step without further purification.

[0599] c) 3-(3,5-difluorophenyl)pyrrolo[1,2-b]pyridazine-4-ol (63c)

[0600] A mixture of compound 63b (7.3 g) and potassium tert-butoxide (2.94 g) in ethanol (146.01 mL) was stirred at 90 °C in air for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: C 18 Column; mobile phase, mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 10% B to 50% B over 10 min; detector, UV 254 nm, yielded title compound 63c (510 mg). MS (ESI, m / z): 247 [M+H] + .

[0601] d) 3-(3,5-difluorophenyl)pyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (63d)

[0602] A mixture of compound 63c (400 mg), N,N-diisopropylethylamine (629.92 mg), trifluoromethanesulfonic anhydride (916.69 mg), and 4-dimethylaminopyridine (19.85 mg) in dichloromethane (7 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (20:1) to give the title compound 63d (470 mg). MS (ESI, m / z): 379 [M+H] + .

[0603] e) N-(1-[3-(3,5-difluorophenyl)pyrrolo[1,2-b]pyridazin-4-yl]piperidin-4-yl)carbamic acid tert-butyl ester (63e)

[0604] A mixture of compound 63d (320 mg) and tert-butyl piperidin-4-ylcarbamate (338.86 mg), N,N-diisopropylethylamine (328.01 mg) in acetonitrile (16.0 mL) was stirred at 80 °C under air atmosphere for 8 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (10:1) to give the title compound 63e (270 mg). MS (ESI, m / z): 429 [M+H] + .

[0605] f) N-(1-[3-(3,5-difluorophenyl)-7-iodopyrrolo[1,2-b]pyridazin-4-yl]piperidin-4-yl)carbamic acid tert-butyl ester (63f)

[0606] A mixture of compound 63e (260 mg) and N-iodosuccinimide (163.82 mg) in tetrahydrofuran (13.0 mL) was stirred at room temperature under nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (10:1) to give the title compound 63f (280 mg).

[0607] g) N-(1-[3-(3,5-difluorophenyl)-7-(1-methylpyrazol-3-ylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]piperidin-4-yl)carbamic acid tert-butyl ester (63g)

[0608] A mixture of compound 63f (260 mg) and sodium 1-methylpyrazole-3-sulfinate (78.86 mg), L-proline (10.8 mg), copper iodide (17.86 mg) in dimethyl sulfoxide (6.5 mL) was stirred at 90 °C under nitrogen for 3 hours. The residue was purified by reverse phase flash chromatography with the following conditions: Column: XBridge® C18 OBD®; Mobile Phase A: Water (10 mmol / L ammonium bicarbonate), Mobile Phase B: Acetonitrile, Gradient: 10% B to 100% B in 15 minutes; Detector, UV 254 nm to give the title compound 63g (120 mg). 18 .

[0609] h) N-(1-[5-bromo-3-(3,5-difluorophenyl)-7-(1-methylpyrazol-3-ylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]piperidin-4-yl)carbamic acid tert-butyl ester (63h)

[0610] A solution of 63 g (100 mg) of the compound and N-bromosuccinimide (31.08 mg) in tetrahydrofuran (3 mL) was stirred for 1 hour at room temperature under air. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: C 18 Column; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 10% B to 100% B over 15 min; detector, UV 254 nm, yielded the title compound 63 h (70 mg). MS (ESI, m / z): 651 [M+H] + .

[0611] i)N-(1-(5-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)-7-(1-methylpyrazol-3-ylsulfonyl)pyrrolo[1,2-b]pyridazine-4-ylpiperidin-4-yl)tert-butyl carbamate (63i)

[0612] A mixture of compound 63h (50 mg) and 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzylnitrile (33.28 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.62 mg), and potassium phosphate (48.87 mg) in 1,4-dioxane (1.25 mL) / water (0.25 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: C 18 Column; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 10% B to 100% B over 10 min; detector, UV 254 nm, yielded title compound 63i (47 mg). MS (ESI, m / z): 734 [M+H] + .

[0613] j) 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-7-(1-methylpyrazol-3-ylsulfonyl)pyrrolo[1,2-b]pyridazin-5-yl]-2-hydroxybenzyl nitrile (Compound 63)

[0614] The mixture of compound 63i (42 mg) in trifluoroacetic acid (0.5 mL) and dichloromethane (1.5 mL) was stirred at room temperature under air for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions (column: Xselect CSH™ Prep C...). 185 pm 30*150 mm OBD; column temperature: 25 °C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 13% B to 31% B in 7 min; wavelength: UV 254 nm / 220 nm; RT (min): 6.02) to give the title compound 63 (5 mg). 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.07 - 7.95 (m, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.36 - 7.26 (m, 2H), 7.25 - 7.13 (m, 1H), 7.12 - 6.99 (m, 2H), 6.96 (d, J = 2.3 Hz, 1H), 6.65 - 6.52 (m, 1H), 3.89 (s, 3H), 2.95 - 2.76 (m, 2H), 2.42 - 2.35 (m, 2H), 2.35 - 2.30 (m, 1H), 1.22 - 1.10 (m, 2H), 0.58 - 0.40 (m, 2H). 19 F NMR: (376 MHz, DMSO-d6, ppm) δ -109.2. MS (ESI, m / z): 590.20 [M+H] + .

[0615] Example 64: (S)-5-(4-(4-aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-(l-(p- tolyl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-imidazole-2-carbonitrile

[0616] a) 3-bromo-4,5-dichloro-lH-pyrrolo[2,3-b]pyridine (64a)

[0617] To a 40 mL vial was added 4,5-dichloro-lH-pyrrolo[2,3-b]pyridine (10 g) and N,N- dimethylformamide (150.0 mL) at room temperature. N-bromosuccinimide (10.47 g) was dissolved in N,N-dimethylformamide (4 mL) and added to the reaction at 0 °C. The resulting mixture was stirred at room temperature for 1 h. LCMS indicated the desired product. The reaction was quenched by the addition of water / ice (200 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. The precipitated solid was collected by filtration and washed with water (3 x 100 mL). The resulting solid was dried by lyophilization. The crude compound 64a was used directly in the next step without further purification. MS (ESI, m / z): 265 [M+H] + .

[0618] b) 3-bromo-4,5-dichloro-1-(1-(p-tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridine (64b)

[0619] To a 250 mL three necked round bottom flask was added compound 64a (6 g) and tetrahydrofuran (120 mL) at room temperature. (R)-1-(p-tolyl)ethan-1-ol (3.69 g) and triphenylphosphine (11.1 g) were added at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 0.5 h. Di-tert-butyl azodicarboxylate (10.39 g) in tetrahydrofuran (20 mL) was added at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 2 h. LCMS indicated the desired product. The reaction was quenched by the addition of water (80 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3*80 mL). The combined organic layers were washed with brine (1*80 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to afford the title compound 64b (9.5 g). MS (ESI, m / z): 384 [M+H] + .

[0620] c) tert-butyl (1-(3-bromo-5-chloro-1-(1-(p-tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamate (64c)

[0621] To a 40 mL vial was added compound 64b (4.2 g), tert-butyl piperidin-4-ylcarbamate (6.57 g), N-methyl pyrrolidinone (25 mL) and N,N-diisopropylethylamine (4.24 g) at room temperature. The resulting mixture was stirred at 170 °C for 5 h. The mixture was cooled to room temperature. The reaction was quenched by the addition of water / ice (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with brine (3*20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (4:1) to afford the title compound 64c (2.8 g). MS (ESI, m / z): 548 [M+H] + .

[0622] d) tert-butyl (1-(5-chloro-3-(2-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1-(1-(p- tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (64d)

[0623] A solution of compound 64c (750 mg), potassium phosphate (871.65 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (111.51 mg) and (2-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)boronic acid (548.56 mg) was added to 1,4-dioxane (23.4 mL) and water (4.7 mL) and stirred at 80 °C under nitrogen atmosphere for 2 h. The mixture was stirred at 80 °C under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (0%~20%) to give the title compound 64d (150 mg). MS (ESI, m / z): 690 [M+H] + .

[0624] e) (1-(3-(2-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-5-(3,5- difluorophenyl)-1-(1-(p-tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl) carbamic acid tert-butyl ester (64e)

[0625] A solution of compound 64d (100 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (13.81 mg), tris(dibenzylideneacetone)dipalladium (13.26 26 mg) and potassium phosphate (92.24 mg) and 3.5-difluorophenylboronic acid (68.62 mg) was added to 1,4-dioxane (6.25 mL) and water (1.25 mL) and stirred at 100 °C under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (0%~100%) to give compound 64e (60 mg). MS (ESI, m / z): 768 [M+H] + .

[0626] f) (S)-5-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(p-tolyl)ethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)-1H-imidazole-2-carbonitrile (Compound 64)

[0627] Compound 64e (40 mg) and trifluoroacetic acid (0.3 mL) were added to dichloromethane (0.9 mL), the mixture was stirred at room temperature under air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure to give compound 64 crude product. The crude product was purified by preparative HPLC under the following conditions (column: XBridge BEH Shield RP18 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 42% B to 58% B, 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 6.53; column temperature: 25 °C) to give title compound 64 (5.5 mg). 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 7.91 (s, 1H), 7.63 (s, 1H), 7.29-7.18 (m, 3H), 7.12 (d, J = 7.5 Hz, 3H), 7.10-7.01 (m, 2H), 6.16 (q, J = 7.1 Hz, 1H), 2.95-2.85 (m, 2H), 2.60 (d, J = 11.1 Hz, 1H), 2.48-2.41 (m, 2H), 2.25 (s, 3H), 1.85 (d, J = 7.2 Hz, 3H), 1.34 (d, J = 11.6 Hz, 2H), 0.88-0.69 m, 2H). MS (ESI, m / z): 538.2 [M+H] + .

[0628] Example 65: 3-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile

[0629] a) 2-(1-chloroethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (65a)

[0630] To a 40 mL vial was added 1-(5H,6H,7H pyrrolo[1,2-a]imidazol-2-ylethan-1-ol (100 mg), dichloromethane (3 mL) and dichlorosulfoxide (0.6 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The crude product of compound 65a was used directly in the next step without further purification.

[0631] b) (l-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-(l-(5,6,7- trihydro-pyrrolo[l,2-a]imidazol-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)carbamic acid tert-butyl ester (65b)

[0632] To a 20 mL vial was added compound M3 (60 mg), N,N-dimethylformamide (2 mL) and sodium hydride (7.33 mg) at 0 °C. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 0.5 h. Compound 65a (115.76 mg) was added to the reaction system at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. The reaction was quenched by the addition of water / ice (5 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 :2) to afford the title compound 65b (45 mg). MS (ESI, m / z): 724.00 [M+H] + .

[0633] c) 3-[4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-7-(l-(5,6,7-trihydro- pyrrolo[l,2-a]imidazol-2-yl)ethyl)pyrrolo[2,3-b]pyridin-3-yl]-2-hydroxybenzonitrile (Compound 65)

[0634] To a 20 mL round bottom flask was added compound 65b (20 mg), methanol (1 mL) and hydrogen chloride in 1,4-dioxane (4 M, 1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (22 mg) was purified by preparative HPLC under the following conditions (column: YMC Triart C18 Ex Rs 5 μm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 35% B to 48% B in 8 minutes; wavelength: UV 254 nm / 220 nm; RT (min): 5.92, column temperature: 40 °C) to afford the title compound 65 (4.2 mg). 1H NMR =: (400 MHz, DMSO-d6, ppm) δ 7.91 (s, 1H), 7.40 (d, J = 11.4 Hz, 2H), 7.24 (dd, J = 12.7, 7.5 Hz, 2H), 7.04 (s, 1H), 7.03 - 6.97 (m, 2H), 6.72 - 6.64 (m, 1H), 6.07 (q, J = 6.9 Hz, 1H), 3.88 (t, J = 7.1 Hz, 2H), 2.90 - 2.84 (m, 2H), 2.71 - 2.65 (m, 2H), 2.50 - 2.34 (m, 2H), 2.35 - 2.27 (m, 2H), 1.73 (d, J = 7.0 Hz, 3H), 1.22 - 1.12 (m, 3H), 0.62 - 0.42 (m, 2H). 19 F NMR: (376 MHz, DMSO-d6, ppm) δ -110.25. MS (ESI, m / z): 580.4 [M+H] + .

[0635] Example 66: 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1- toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0636] a) 4,5-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (66a)

[0637] 4,5-Dichloro-3a,4-dihydro-1H-pyrrolo[2,3-b]pyridine (500 mg) was dissolved in N,N- dimethylformamide (10 mL), sodium hydride (128 mg) was added, stirred at 25 °C for 30 min, 2- (trimethylsilyl)ethoxymethyl chloride (534 mg) was added, stirred at 20 °C for 3 hours under nitrogen protection. The reaction solution was concentrated to dryness, extracted with ethyl acetate and water, the organic phase was washed with saturated sodium chloride solution, dried, concentrated to dryness to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1) to give the title compound 66a (500 mg).

[0638] b) 4,5-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3- carboxaldehyde (66b)

[0639] N-methyl-N-phenylformamide (643 mg) was dissolved in dichloromethane (30 mL), oxalyl chloride (600 mg) was added, stirred at 25 °C for 30 min, compound 66a (500 mg) was added, stirred at 20 °C for 16 h. The reaction solution was concentrated to dryness, slurry with a mixture of petroleum ether: ethyl acetate = 10: 1), filtered to give compound 66b as a crude product, which was used directly in the next step.

[0640] c) 4,5-dichloro-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (66c)

[0641] Compound 66b (300 mg) was dissolved in dioxane (2 mL), 4 M hydrochloric acid dioxane solution (10 mL) was added, stirred for 16 h. The reaction solution was concentrated to dryness to give the title compound 66c, which was used directly in the next step.

[0642] d) 4,5-dichloro-l-methylsulfanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (66d)

[0643] Compound 66c (10 mL) was added with p-toluenesulfonyl chloride (266 mg), N,N-diisopropylethylamine (454 mg), 4-dimethylaminopyridine (14 mg), stirred at 20 °C for 1 h under nitrogen protection. The reaction solution was concentrated to dryness, extracted with ethyl acetate and water, the organic phase was washed with saturated sodium chloride solution, dried, concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1) to give the title compound 66d (220 mg).

[0644] e) 2-(4,5-dichloro-l-methylsulfanyl-lH-pyrrolo[2,3-b]pyridine-3-yl)-5,6-difluoro-lH- benzo[d]imidazole (66e)

[0645] Compound 66d (220 mg) was dissolved in acetic acid (10 mL), 4,5-difluorobenzene-l,2-diamine (171 mg) was added, stirred at 120 °C for 1 h. The reaction solution was concentrated to dryness to give the title compound 66e, which was used directly in the next step.

[0646] f) tert-butyl (l-(5-chloro-3-(5,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-methylsulfanyl- lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (66f)

[0647] Compound 66e (170 mg) was dissolved in N-methylpyrrolidone (10 mL), and tert-butyl piperidin-4-ylcarbamate (138 mg), N,N-diisopropylethylamine (134 mg) were added. The mixture was stirred at 160°C for 8 hours under microwave irradiation. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 66f (130 mg).

[0648] g) tert-Butyl 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-chloro-l- toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-lH-benzo[d]imidazole-l- carboxylate (66g)

[0649] Compound 66f (130 mg) was dissolved in dichloromethane (10 mL), and di-tert- butyl dicarbonate (51 mg), N,N-diisopropylethylamine (77 mg), and 4-dimethylaminopyridine (2 mg) were added. The mixture was stirred at 20°C for 1 hour under nitrogen atmosphere. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1) to give the title compound 66g (150 mg).

[0650] h) tert-Butyl 2-(4-(((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-(3,5- difluorophenyl)-l-toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-lH- benzo[d]imidazole-l-carboxylate (66h)

[0651] Compound 66g (150 mg) was dissolved in dioxane (10 mL), and 3,5-difluorophenylboronic acid (47 mg), cesium carbonate (195 mg), dichlorobis-(4- dimethylaminophenyl) palladium(II) (14 mg) were added. The mixture was stirred at 100°C for 3 hours under nitrogen atmosphere. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 1 (v / v)) to give the title compound 66h (90 mg).

[0652] i) 1-(3-(5,6-Difluoro-lH-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-l- toluenesulfonyl-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 66)

[0653] Compound 66h (130 mg) was dissolved in dioxane (2 mL), 4M hydrochloric acid in dioxane (10 mL) was added, stirred for 2 hours, the reaction solution was concentrated to dryness to give a crude product, which was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C 18 10pm OBD, 19mm*250mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 26% B to 46% B in 10 min; wavelength: UV 254 nm; RT (min): 8.82, column temperature: 25 °C) to give the title compound 66 (18.2 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.22 (s, 1H), 8.10 (d, J = 8.2 Hz, 2H), 8.06 (s, 1H), 7.69 - 7.60 (m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.33 - 7.25 (m, 1H), 7.14 - 7.07 (m, 2H), 2.96 - 2.88 (m, 2H), 2.48 - 2.41 (m, 3H), 2.38 (s, 3H), 1.24 - 1.15 (m, 2H), 0.65 - 0.54 (m, 2H). MS (ESI, m / z): 634.7 [M+H] + .

[0654] Example 67: (S)-5-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(p- tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-imidazole-2-carboxamide

[0655] Prepared according to the procedure of Example 64 to give a crude product of compound 64, which was purified by preparative HPLC under the following conditions (column: YMC Triart C18 ExRs 5pm, 30mm*150mm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 67% B in 9 min; wavelength: UV 254 nm / 220 nm; RT (min): 3.0, column temperature: 25 °C) to give a crude product of compound 64 (12.3 mg).

[0656] The crude compound 64 (12.3 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK-ID 2*25 cm, 5 pm; mobile phase A: HEX (0.1% formic acid), mobile phase B: (0.3% methanesulfonic acid) MeOH:DCM (1:1, v / v); flow rate: 20 mL / min; isocratic 70% B; wavelength: UV 254 / 220 nm; RT (min): 22.68; sample solvent: methanol; column temperature: 25 °C) to give compound 64 solution. The compound 64 solution was concentrated to give the crude compound 67. The crude compound 67 (20 mg) was purified by preparative HPLC under the following conditions (column: XBridge BEH Shield RP18 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 44% B to 62% B in 9 min; wavelength: UV 254 nm / 220 nm; RT (min): 6.13, column temperature: 25 °C) to give the title compound 67 (1.2 mg). LCMS: (ESI, m / z): 556.20 [M+H] + .

[0657] Example 68: 1-(3-(1H-Benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0658] a) 1-(3-(1H-Benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2- yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (68a)

[0659] The 4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3- carboxaldehyde (500 mg) was dissolved in acetic acid (10 mL), and benzene-1,2- diamine (242 mg) was added. The reaction was stirred at 120 °C open for 1 h. The reaction was concentrated to dryness to give the title compound 68a, which was used directly in the next step.

[0660] b) (1-(3-(1H-Benzo[d]imidazol-2-yl)-5-chloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (68b)

[0661] Compound 68a (200 mg) was dissolved in N-methylpyrrolidone (10 mL), and tert-butyl piperidin-4-ylcarbamate (189 mg), N,N-diisopropylethylamine (185 mg) were added. The mixture was stirred at 160°C for 1 hour under microwave irradiation. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 68b (150 mg).

[0662] c) tert-Butyl 2-(4-(4-(((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-chloro-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-benzo[d]imidazole-l-carboxylate (68c)

[0663] Compound 68b (150 mg) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (105 mg), N,N-diisopropylethylamine (94 mg), and 4-dimethylaminopyridine (3 mg) were added. The mixture was stirred at 20°C for 1 hour under nitrogen. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4:1) to give the title compound 68c (150 mg).

[0664] d) tert-Butyl 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-(3,5-difluorophenyl)-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-benzo[d]imidazole-l-carboxylate (68d)

[0665] Compound 68c (120 mg) was dissolved in dioxane (10 mL), and (3,5-difluorophenyl)boronic acid (41 mg), cesium carbonate (170 mg), dichlorobis-(4-dimethylaminophenyl) palladium(II) (12 mg) were added. The mixture was stirred at 100°C for 3 hours under nitrogen. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 68d (80 mg).

[0666] e) 1-(3-(lH-Benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-l-(l-(5-methylpyridin-2- yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 68)

[0667] Compound 68d (80 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, stirred for 2 h, the reaction was concentrated to dryness to give a crude product, which was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5% B to 45% B in 10 min; wavelength: UV 254 nm; RT (min): 7.06, column temperature: 25 °C) to give title compound 68 (39 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.38 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.61 - 7.51 (m, 3H), 7.32 - 7.25 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.14 - 7.09 (m, 2H), 6.29 (q, J = 7.1 Hz, 1H), 3.06 - 2.97 (m, 2H), 2.75 - 2.60 (m, 2H), 2.40 - 2.30 (m, 1H), 2.26 (s, 3H), 1.92 (d, J = 7.1 Hz, 3H), 1.41 - 1.26 (m, 2H), 1.00 - 0.79 (m, 2H). MS (ESI, m / z): 563.9 [M+H] + .

[0668] f) 68A / 68B

[0669] The product of compound 68 (38.2 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK-ID 2*25 cm, 5 pm; mobile phase A: HEX (0.1% DEA), mobile phase B: ethanol: dichloromethane (1 : 1, v / v); flow rate: 20 mL / min; isocratic 30% B; wavelength: UV 254 / 220 nm sample solvent: methanol; to give compound isomers 68A (RT = 7.16 min, 10.65 mg) and 68B (RT = 10.13 min, 11.27 mg) upon resolution.

[0670] 68A: 1H NMR: (400 MHz, DMSO-d6, ppm): 8.42 - 8.33 (m, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.58 (dd, J = 8.2, 2.3 Hz, 3H), 7.33 - 7.25 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.20 - 7.05 (m, 4H), 6.29 (q, J = 7.1 Hz, 1H), 3.07 - 2.95 (m, 2H), 2.69 - 2.55 (m, 2H), 2.26 (s, 4H), 1.92 (d, J = 7.2 Hz, 3H), 1.25 (t, J = 8.3 Hz, 2H), 0.92 - 0.61 (m, 2H). MS (ESI, m / z): 563.95 [M+H] + .

[0671] 68B: 1 H NMR: (400 MHz, DMSO-d6, ppm): 8.42 - 8.33 (m, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.58 (dd, J = 8.2, 2.3 Hz, 3H), 7.33 - 7.25 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.20 - 7.05 (m, 4H), 6.29 (q, J = 7.1 Hz, 1H), 3.07 - 2.95 (m, 2H), 2.69 - 2.55 (m, 2H), 2.26 (s, 4H), 1.92 (d, J = 7.2 Hz, 3H), 1.25 (t, J = 8.3 Hz, 2H), 0.92 - 0.61 (m, 2H). MS (ESI, m / z): 563.95 [M+H] + .

[0672] Example 69: 1-(5-(3,5-difluorophenyl)-3-(5-fluoro-6-methoxy-1H-benzo[d]imidazol-2-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0673] Referring to Example 68, replacing benzene-1,2-diamine with 4-fluoro-5- methoxybenzene-1,2-diamine gives Compound 69 crude product.

[0674] The crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5% B to 45% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.73, column temperature: 25 °C) to give compound 69. 1 H NMR (400 MHz, DMSO-d6) d 8.41 - 8.35 (m, 2H), 8.09 (s, 1H), 7.97 (s, 1H), 7.58 (dd, J = 8.1, 2.2 Hz, 1H), 7.40 (d, J = 11.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.28 (q, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.03 - 2.96 (m, 2H), 2.70 - 2.58 (m, 2H), 2.39 - 2.32 (m, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.39 - 1.29 (m, 2H), 0.94 - 0.79 (m, 2H). MS (ESI, m / z): 611.7 [M+H] + .

[0675] Compound 69 (90 mg) was resolved by preparative chiral HPLC under the following conditions (column: CHIRALPAK-IE 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% DEA), mobile phase B: methanol:dichloromethane (1 : 1, v / v); flow rate: 20 mL / min; isocratic 40% B; wavelength: UV 254 / 220 nm; sample solvent: methanol; column temperature: 25 °C) to give compound isomer 69A (RT = 10.85 min, 26.3 mg) and 69B (RT = 15.29 min, 27.1 mg).

[0676] 69A: 1H NMR =: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.61 - 7.54 (m, 2H), 7.40 (d, J = 12.1 Hz, 1H), 7.34 - 7.23 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 - 6.99 (m, 2H), 6.27 (m, 1H), 3.86 (s, 3H), 2.99 (t, J = 10.2 Hz, 2H), 2.57 (d, J = 11.3 Hz, 2H), 2.44 - 2.30 (m, 1H), 2.26 (s, 3H),, 1.91 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 12.1 Hz, 2H),, 0.75 (m, 2H). MS (ESI, m / z): 612.20 [M+H] + .

[0677] 69B: 1 H NMR =: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.61 - 7.54 (m, 2H), 7.40 (d, J = 12.1 Hz, 1H), 7.34 - 7.23 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 - 6.99 (m, 2H), 6.27 (m, 1H), 3.86 (s, 3H), 2.99 (t, J = 10.2 Hz, 2H), 2.57 (d, J = 11.3 Hz, 2H), 2.44 - 2.30 (m, 1H), 2.26 (s, 3H),, 1.91 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 12.1 Hz, 2H),, 0.75 (m, 2H). MS (ESI, m / z): 612.20 [M+H] + .

[0678] Example 70: (3-(4-(4-aminopiperidin-l-yl)-l-(l-(l-chloro-3-hydroxypropan-2-yl)-lH- pyrazol-4-yl)-5-(3,5-difluorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzyl) cyano carbamate

[0679] a) (l-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-l-(l-(oxetan-3-yl)-lH- pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (70a)

[0680] Compound M3 (50 mg) was dissolved in N,N-dimethylformamide (2 ml) under nitrogen, 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg), copper acetate (34 mg), pyridine (62 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (22 mg) were added successively, and the mixture was stirred at 60°C for 3 hours. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was combined and washed with water, and the organic phase was concentrated to dryness, and column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) was performed to give the title compound 70a (41 mg).

[0681] b) (3-(4-(4-Aminopiperidin-1-yl)-1-(1-(1-chloro-3-hydroxypropan-2-yl)-1H-pyrazol-4-yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxybenzonitrile (Compound 70)

[0682] Compound 70a was dissolved in dioxane (2 mL), hydrochloric acid in dioxane (4.0 M, 2 ml) was added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated to dryness to give a crude product, which was purified by reverse phase high performance liquid chromatography (X-Bridge Prep C18 OBD 10 μm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 20% B to 40% B in 10 minutes; wavelength: UV 254 nm; RT (min): 8.43, column temperature: 25°C) to give the title compound 70 (2.3 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.27 (t, J = 9.5 Hz, 1H), 7.04 (d, J = 7.2 Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H), 4.59 (dd, J = 8.4, 4.9 Hz, 1H), 4.14 - 4.00 (m, 2H), 3.82 (d, J = 6.3 Hz, 2H), 2.93 (d, J = 12.0 Hz, 2H), 2.41 (t, J = 11.6 Hz, 3H), 1.33 (d, J = 11.7 Hz, 2H), 0.57 (d, J = 12.3 Hz, 2H). MS (ESI+): 603.8 (M+H) + .

[0683] Example 71: 1-(5-(3,5-difluorophenyl)-3-(6-methyl-1H-benzo[d]imidazol-2-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0684] Referring to Example 68, compound 71 was prepared by replacing 4-methylaniline with phen-1,2-diamine.

[0685] The crude product was purified by preparative HPLC (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 40% B in 10 min; wavelength: UV 254 nm; RT (min): 6.98, column temperature: 25 °C) to give compound 71 (39 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.35 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.58 (dd, J = 8.0, 2.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.31 - 7.24 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 - 7.09 (m, 2H), 6.99 (dd, J = 8.2, 1.5 Hz, 1H), 6.28 (q, J = 7.1 Hz, 1H), 3.06 - 2.96 (m, 2H), 2.86 - 2.61 (m, 3H), 2.42 (s, 3H), 2.26 (s, 3H), 1.91 (d, J = 7.1 Hz, 3H), 1.36 (d, J = 11.2 Hz, 2H), 1.06 - 0.85 (m, 2H). MS (ESI, m / z): 577.9 [M+H] + .

[0686] Example 72: 1-(5-(3,5-difluorophenyl)-3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0687] a) 2-(4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-6- fluoro-1H-benzo[d]imidazole (72a)

[0688] Dissolve 4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3- carboxaldehyde (0.4 g) in acetic acid (10 ml), add 4-fluoro-1,2-diaminobenzene (170 mg), and react at 120 °C for 3 hours. Concentrate the reaction mixture to dryness, wash with saturated sodium bicarbonate solution, extract with ethyl acetate, and concentrate the organic phase to dryness to give the title compound 72a (500 mg). LCMS (ESI, m / z): 440.1 [M+H] + .

[0689] b) tert-Butyl 1-(5-chloro-3-(5-fluoro-1H-benzo[d]imidazol-2-yl)-1-(1-(5-methylpyridin-2- yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (72b)

[0690] Dissolve compound 72a (10 ml) in dichloromethane (5 ml), add N,N-diisopropylethylamine (200 mg), 4-dimethylaminopyridine (10 mg), and di-tert-butyl dicarbonate (360 mg), and stir at 20 °C for 2 hours. Quench the reaction with water, extract with ethyl acetate, and concentrate the organic phase to dryness. Purify the crude product by column chromatography (PE:EA = 5:1) to give the title compound 72b (300 mg). LCMS (ESI, m / z): 604.3 [M+H] + .

[0691] c) tert-Butyl 2-(4-(4-(((tert-butoxy carbonyl)amino)piperidin-1-yl)-5-chloro-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-1H-benzo[d]imidazole-1- carboxylate (72c)

[0692] Dissolve compound 72b (500 mg) in dichloromethane (5 ml), add N,N-diisopropylethylamine (200 mg), 4-dimethylaminopyridine (10 mg), and di-tert-butyl dicarbonate (360 mg), and stir at 20 °C for 2 hours. Quench the reaction with water, extract with ethyl acetate, and concentrate the organic phase to dryness. Purify the crude product by column chromatography (PE:EA = 5:1) to give the title compound 72c (300 mg). LCMS (ESI, m / z): 704.27 [M+H] + .

[0693] d) tert-Butyl 2-(4-((tert-butoxy carbonyl)amino)piperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1- (5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-1H-benzo[d]imidazole-1- carboxylate (72d)

[0694] Compound 72c (300 mg) was dissolved in dioxane (10 ml), (3,5-difluorophenyl)boronic acid (100 mg), dichlorobis-(4-dimethylaminophenyl) palladium(II) (26 mg) and cesium carbonate (280 mg) were added, and the mixture was stirred at 100 °C for 3 hours under nitrogen. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness and the crude product was purified by column chromatography (PE:EA = 4:1) to give the title compound 72d (140 mg). LCMS (ESI, m / z): 782.36 [M+H] + .

[0695] e) 1-(5-(3,5-difluorophenyl)-3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 72)

[0696] Compound 72d (140 mg) was dissolved in dioxane (5 ml), and hydrochloric acid dioxane solution (5 ml) was added. The reaction was stirred at room temperature for 2 hours and concentrated to dryness to give the crude product. The crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 13% B to 33% B in 10 minutes; wavelength: UV 254 nm; RT (min): 8.04, column temperature: 25 °C) to give the title compound 72 (41.75 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.41 - 8.32 (m, 2H), 8.17 (s, 1H), 7.99 (s, 1H), 7.57 (ddd, J = 11.6, 8.4, 3.6 Hz, 2H), 7.37 (dd, J = 9.6, 2.4 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.16 - 7.09 (m, 2H), 7.02 (ddd, J = 11.2, 8.8, 2.4 Hz, 1H), 6.29 (q, J = 7.2 Hz, 1H), 3.07 - 2.98 (m, 2H), 2.72 (dt, J = 34.6, 11.6 Hz, 2H), 2.41 (s, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.40 (d, J = 11.6 Hz, 2H), 1.09 - 0.91 (m, 2H). LCMS (ESI, m / z): 581.9 [M+H] + .

[0697] Compound 72 (30 mg) was purified by preparative chiral HPLC under the following conditions: (column: CHIRALPAK-ID 2*25 cm, 5 pm; mobile phase A: MTBE (0.1% DEA), mobile phase B: EtOH; flow rate: 20 mL / min; isocratic 10% B; wavelength: UV 254 / 220 nm; sample solvent: EtOH; column temperature: 25 °C) to give compound isomers 72A (RT = 5.40 min, 14.3 mg) and 72B (RT = 7.85 min, 10.8 mg).

[0698] 72A: 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.58 (dd, J = 8.2, 2.3 Hz, 1H), 7.52 (s, 1H), 7.40 - 7.30 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.11 (tq, J = 6.7, 4.5, 3.4 Hz, 2H), 7.05 - 6.95 (m, 1H), 6.28 (q, J = 7.1 Hz, 1H), 3.16 - 2.91 (m, 2H), 2.60 (s, 2H), 2.26 (s, 3H), 2.24 (d, J = 3.7 Hz, 1H), 1.91 (d, J = 7.2 Hz, 3H), 1.32 - 1.21 (m, 2H), 0.87 - 0.63 (m, 2H). LCMS (ESI, m / z): 582.25 [M+H] + .

[0699] 72B: 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.41 - 8.35 (m, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.61 - 7.56 (m, 1H), 7.52 (s, 1H), 7.40 - 7.30 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.05 - 6.95 (m, 1H), 6.28 (q, J = 7.1 Hz, 1H), 3.00 (t, J = 10.5 Hz, 2H), 2.63 - 2.51 (m, 2H), 2.26 (s, 3H), 2.24 - 2.17 (m, 1H), 1.91 (d, J = 7.1 Hz, 3H), 1.26 (d, J = 12.0 Hz, 2H), 0.87 - 0.58 (m, 2H). LCMS (ESI, m / z): 582.20 [M+H] + .

[0700] Example 73: tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-1-(1- cyclopropyl-1H-pyrazol-3-yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin- 4-yl)carbamate

[0701] a) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-1-(1-cyclopropyl-1H-pyrazol-3- yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (73a)

[0702] Compound M3 (50 mg) was dissolved in xylene (5 ml), 3-bromo-1-cyclopropyl-1H- pyrazole (31 mg), N,N'-dimethylethylenediamine (6 mg), cuprous iodide (4 mg) and potassium phosphate (54 mg) were added. Nitrogen was purged, stirred at 100 °C for 5 hours. The reaction was quenched with water, extracted with ethyl acetate, the organic phase was dried, concentrated and purified to give the title compound 73a (50 mg).

[0703] b) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-1-(1-cyclopropyl-1H-pyrazol-3- yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (compound 73)

[0704] Compound 73a (50 mg) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for 2 hours, concentrated and the crude was purified by reverse phase high performance liquid chromatography (X-Bridge Prep C18 OBD 10 μm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 28% B to 48% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.51, column temperature: 25 °C) to give the title compound 73 (2.8 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.48 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (dd, J = 7.6, 2.0 Hz, 1H), 7.26 (tt, J = 9.6, 2.4 Hz, 1H), 7.04 (h, J = 4.8 Hz, 2H), 6.97 (d, J = 2.4 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 3.75 (dq, J = 7.2, 3.6 Hz, 2H), 2.90 (d, J = 12.0 Hz, 2H), 2.50 - 2.40 (t, J = 11.6 Hz, 4H), 1.30 - 1.22 (m, 2H), 1.09 (dd, J = 5.2, 2.4 Hz, 2H), 0.98 (td, J = 7.6, 4.8 Hz, 2H), 0.57 (d, J = 11.6 Hz, 2H). MS (ESI+): 552.3 (M+H) + .

[0705] Example 74: 1-(5-(3,5-difluorophenyl)-3-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0706] Referring to Example 68, replacing benzene-1,2-diamine with 4,5-dimethylbenzene-1,2- diamine, compound 74 crude was prepared.

[0707] The crude product (80 mg) was purified by preparative HPLC under the following conditions (column: CHIRALPAK-ID 2*25 cm, 5 pm; mobile phase A: methyl tert-butyl ether (0.1% DEA), mobile phase B: ethanol; flow rate: 20 mL / min; isocratic 10% B; wavelength: 254 / 220 nm; sample solvent: methanol; resolution to compound isomers 74A (RT = 6.69 min, 29.5 mg) and 74B (RT = 9.25 min, 28.5 mg).

[0708] 74A: 1H NMR: (400 MHz, DMSO-d6, ppm) δ 12.32 (d, J = 47.6 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.57 (dd, J = 8.1, 2.2 Hz, 1H), 7.37 (s, 1H), 7.33 - 7.16 (m, 3H), 7.17 - 7.04 (m, 2H), 6.27 (q, J = 7.1 Hz, 1H), 3.05-2.90 (m, 2H), 2.64 - 2.53 (m, 2H), 2.31 (s, 6H), 2.26 (s, 3H), 2.18 (dd, J = 10.0, 4.2 Hz, 1H), 1.91 (d, J = 7.1 Hz, 3H), 1.26 - 1.07 (m, 2H), 0.93 - 0.59 (m, 2H). MS (ESI, m / z): 592.30 [M+H] + .

[0709] 74B: 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 12.32 (d, J = 48.2 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.57 (dd, J = 8.1, 2.3 Hz, 1H), 7.47 - 7.16 (m, 4H), 7.16 - 7.03 (m, 2H), 6.27 (q, J = 7.1 Hz, 1H), 3.05-2.92 (m, 2H), 2.65-2.53 (m, 2H), 2.31 (s, 6H), 2.26 (s, 3H), 2.22 - 2.13 (m, 1H), 1.91 (d, J = 7.0 Hz, 3H), 1.35 - 1.09 (m, 2H), 0.88-0.63 (m, 2H). MS (ESI, m / z): 592.35 [M+H] + .

[0710] Example 75: 1-(5-(3,5-difluorophenyl)-3-(2-methyl-2H-indazol-5-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0711] a) tert-Butyl 1-(5-chloro-3-(2-methyl-2H-indazol-5-yl)-1-(1-(5-methylpyridin-2- yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (75a)

[0712] Dissolve tert-butyl (1-(3-bromo-5-chloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (100 mg) in dioxane (5 mL), add (2-methyl-2H-indazol-5-yl)boronic acid (35 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (15 mg) and cesium carbonate (120 mg), replace with nitrogen, stir at 80 °C for 5 hours. Filter the reaction mixture, concentrate to dryness, and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) to give the title compound 75a (80 mg). MS (ESI, m / z): 600.3 [M+H] + .

[0713] b) tert-butyl (1-(5-(3,5-difluorophenyl)-3-(2-methyl-2H-indazol-5-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (75b)

[0714] Dissolve compound 75a (80 mg) in dioxane (10 ml), add (3,5-difluorophenyl)boronic acid (30 mg), bis[ditert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) dichloride (8 mg) and cesium carbonate (60 mg), stir at 100 °C for 2 hours. Filter the reaction mixture, concentrate to dryness, and purify the crude product by column chromatography (PE:EA = 4:1) to give the title compound 75b (70 mg).

[0715] c) 1-(5-(3,5-difluorophenyl)-3-(2-methyl-2H-indazol-5-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (compound 75)

[0716] Dissolve compound 75b (70 mg) in dichloromethane (6 mL), add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours, concentrate to dryness, and purify the crude product by preparative HPLC under the following conditions (column: X-Bridge Prep C 18 OBD 10 μm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 25% B to 45% B in 10 minutes; wavelength: UV 254 nm; RT (min): 8.08, column temperature: 25 °C) to give the formate salt of compound 75 (42.2 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.0 Hz, 1H), 8.33 (s, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.59 - 7.54 (m, 3H), 7.32 (dd, J = 8.8, 1.6 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H), 4.19 (s, 3H), 3.06 (t, J = 13.2 Hz, 2H), 2.40 (m, 3H), 2.26 (s, 3H), 1.89 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 11.2 Hz, 2H), 0.95 - 0.72 (m, 2H). MS (ESI, m / z): 578.3 [M+H] + .

[0717] Example 76: tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5- difluorophenyl)-1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)piperidin-4-yl)carbamate

[0718] a) tert-Butyl (1-(3-cyano-2-(methoxymethoxy)phenyl)-5-(3,5-difluorophenyl)-1-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (76a)

[0719] Compound M3 (50 mg) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2-one (23.92 mg), copper acetate (3.08 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (12.91 mg) were mixed at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (PE / EA 1:1, v / v) to give compound 76a (38 mg).

[0720] b) 3-(4-(4-Aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-hydroxybenzonitrile (Compound 76)

[0721] To a solution of compound 76a (28 mg) in methanol (1.7 mL), hydrochloric acid in 1,4-dioxane (4 mol / L, 1.7 mL) was added and stirred at room temperature under air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Sunfire C18 5 pm, 30 mm*150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 30% B in 8 min; wavelength: UV 254 nm / 220 nm; column temperature: 25 °C; RT (min): 7.57) to give formate salt of compound 76 (12.5 mg). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.29 (s, 1H), 8.16 (d, J = 2.9 Hz, 1H), 7.95 (s, 1H), 7.86 (dd, J = 9.6, 2.9 Hz, 1H), 7.66 (s, 1H), 7.53 (dd, J = 7.7, 1.8 Hz, 1H), 7.42 (dd, J = 7.4, 1.8 Hz, 1H), 7.32 - 7.22 (m, 1H), 7.08 - 6.97 (m, 2H), 6.92 - 6.78 (m, 1H), 6.55 (d, J = 9.7 Hz, 1H), 3.51 (s, 3H), 2.95 - 2.86 (m, 2H), 2.46 - 2.30 (m, 3H), 1.38 - 1.18 (m, 2H), 0.63 - 0.41 (m, 2H).19F NMR (376 MHz, DMSO-d6, ppm) δ -109.8. MS (ESI+): 553.15 (M+H) + .

[0722] Example 77: 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5- methylphenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- amine

[0723] a) 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-1H-benzo[d]imidazole-1- carboxylic acid tert-butyl ester (77a)

[0724] Tert-butyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-chloro-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-lH- benzo[d]imidazole-l-carboxylate (140 mg) was dissolved in dioxane (10 mL) and water (0.25 mL), (3-methyl-5-fluorophenyl)boronic acid (94 mg), bis[ditert-butyl-(4- dimethylaminophenyl)phosphine]palladium(II) dichloride (15 mg) and cesium carbonate (120 mg) were added, nitrogen was purged, stirred at 100 °C for 3 hours. The reaction was filtered, concentrated to dryness, prepared and column chromatography (petroleum ether: ethyl acetate = 1: 1 (v / v)) to give the title compound 77a (70 mg).

[0725] b) 1-(3-(5,6-Difluoro-lH-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 77)

[0726] Compound 77a (80 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 2 hours, concentrated to dryness and prepared to give the title compound 77 (25.4 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.32 (m, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.68 - 7.52 (m, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 - 6.95 (m, 3H), 6.28 (q, J = 7.2 Hz, 1H), 3.00 (s, 2H), 2.58 (dd, J = 24.4, 11.6 Hz, 2H), 2.38 (s, 4H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.32 (d, J = 12.4 Hz, 2H), 0.84 (d, J = 12.8 Hz, 2H). MS (ESI, m / z): 596.3 [M+H] + .

[0727] c) 77A / 77B

[0728] Compound 77 crude product (40 mg) was purified by preparative chiral HPLC under the following conditions: (Column: CHIRALPAK-IG 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% DEA), mobile phase B: ethanol: dichloromethane (1 : 1, v / v); flow rate: 20 mL / min; isocratic 25% B; wavelength: UV 254 / 220 nm; sample solvent: ethanol; resolution gave compound isomers 77A (RT = 9.72 min, 14.4 mg) and 77B (RT = 14.54 min, 17.7 mg).

[0729] 77A: 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.59 (d, J = 2.7 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.14 - 7.04 (m, 1H), 7.02 - 6.91 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 3.07 - 2.92 (m, 2H), 2.58 (dt, J = 6.4, 3.1 Hz, 1H), 2.54 (s, 1H), 2.43 - 2.40 (m, 3H), 2.37 (s, 3H), 2.26 (s, 1H), 1.91 (d, J = 7.2 Hz, 3H), 1.31 - 1.18 (m, 2H), 0.74 (dt, J = 24.8, 12.7 Hz, 2H). MS (ESI, m / z): 596.15 [M+H] + .

[0730] 77B: 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.61 - 7.58 (m, 1H), 7.57 - 7.52 (m, 2H), 7.22 (d, J = 7.9 Hz, 1H), 7.10 - 7.03 (m, 1H), 7.03 - 6.94 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 2.98 (t, J = 11.7 Hz, 2H), 2.57 (s, 1H), 2.54 (s, 1H), 2.46 - 2.39 (m, 3H), 2.37 (s, 3H), 2.26 (s, 1H), 1.91 (d, J = 7.2 Hz, 3H), 1.32 - 1.18 (m, 2H), 0.87 - 0.63 (m, 2H). MS (ESI, m / z): 596.00 [M+H] + .

[0731] Example 78: 1-(5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-3-(5,6,7- trifluoro-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)amine

[0732] Referring to Example 68, replace benzene-1,2-diamine with 3,4,5-trifluorobenzene-1,2- diamine to prepare compound 78 crude.

[0733] The crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 20% B to 50% B in 10 min; wavelength: UV 254 nm; RT (min): 7.00, column temperature: 25 °C) to give compound 78 (111.4 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.38 (d, J = 2.1 Hz, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.58 (dd, J = 8.0, 2.3 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.29 (tt, J = 9.4, 2.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.11 (h, J = 4.5 Hz, 2H), 6.28 (q, J = 7.1 Hz, 1H), 3.02 (d, J = 17.7 Hz, 2H), 2.74 - 2.53 (m, 3H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.36 (d, J = 12.0 Hz, 2H), 0.81 (ddd, J = 28.0, 11.8, 3.7 Hz, 2H). MS (ESI, m / z): 617.2 [M+H] + .

[0734] Compound 78 was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK-IA 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% DEA), mobile phase B: ethanol: dichloromethane (1:1, v / v); flow rate: 20 mL / min; isocratic 15% B; wavelength: 254 / 220 nm; sample solvent: ethanol; column temperature: 25 °C) to give compound isomers 78A (RT = 7.89 min, 34.5 mg) and 78B (RT = 9.70 min, 34.5 mg) as a mixture of diastereomers.

[0735] 78A: 1H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (dd, J = 2.2, 1.1 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.58 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H), 7.45 (ddd, J = 10.0, 6.2, 1.7 Hz, 1H), 7.29 (tt, J = 9.5, 2.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 3.05 - 2.92 (m, 2H), 2.70 - 2.57 (m, 1H), 2.55 (s, 1H), 2.35 - 2.28 (m, 1H), 2.26 (s, 3H), 1.92 (d, J = 7.2 Hz, 3H), 1.27 (d, J = 12.4 Hz, 2H), 0.79 - 0.56 (m, 2H). MS (ESI, m / z): 618.10 [M+H] + .

[0736] 78B: 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (dd, J = 2.2, 1.1 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.58 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H), 7.45 (ddd, J = 10.0, 6.2, 1.7 Hz, 1H), 7.29 (tt, J = 9.5, 2.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 3.05 - 2.92 (m, 2H), 2.70 - 2.57 (m, 1H), 2.55 (s, 1H), 2.35 - 2.28 (m, 1H), 2.26 (s, 3H), 1.92 (d, J = 7.2 Hz, 3H), 1.27 (d, J = 12.4 Hz, 2H), 0.79 - 0.56 (m, 2H). MS (ESI, m / z): 618.10 [M+H] + .

[0737] Example 79: 5-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2- yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-imidazole-2-carbonitrile

[0738] Reference to the preparation method of Example 64, (R)-1-(p-tolyl)ethan-1-ol in step b) was replaced by 1-(5-methylpyridin-2-yl)ethan-1-ol to obtain compound 79a (90 mg), compound 79a (45 mg) and trifluoroacetic acid (1 ml), dichloromethane (3 mL) were mixed, stirred at room temperature for 2 hours under air atmosphere. The resulting mixture was concentrated under reduced pressure to prepare compound 79 crude product. The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: YMC Triart C18 ExRs 5 μm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 67% B in 9 min; wavelength: UV 254 nm / 220 nm; RT (min): 3.00, column temperature: 25 °C) to obtain compound 79. 1 H NMR (400 MHz, DMSO-d6, ppm) 8.38 (s, 1H), 7.89 (s, 1H), 7.58-7.54 (m, 2H), 7.25-7.21 (m, 1H), 7.12-7.05 (m, 4H), 6.22-6.18 (m, 1H), 2.98-2.90 (m, 3H), 2.67 (s, 2H), 2.25 (s, 3H), 2.00 (d, J = 4.84 Hz, 3H), 1.34-1.23 (m, 2H), 1.17-0.84 (m, 2H).19F NMR (376 MHz, DMSO-d6, ppm) δ -110.47. LCMS (ESI, m / z): 539.15 [M+H] + .

[0739] Reference to the preparation method of Example 64, (R)-1-(p-tolyl)ethan-1-ol in step b) was replaced by (R)-1-(5-methylpyridin-2-yl)ethan-1-ol to obtain compound 79A crude product. The crude product (30 mg) was purified by preparative HPLC under the following conditions (column: XBridge BEH Shield RP18 5 μm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 58% B in 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 5.82, column temperature: 25 °C) to obtain compound isomer 79A (2.7 mg). 1H NMR (400 MHz, DMSO-d6, ppm) 8.38 (s, 1H), 7.89 (s, 1H), 7.58-7.54 (m, 2H), 7.25-7.21 (m, 1H), 7.12-7.05 (m, 4H), 6.22-6.18 (m, 1H), 2.98-2.90 (m, 3H), 2.67 (s, 2H), 2.25 (s, 3H), 2.00 (d, J = 4.84 Hz, 3H), 1.34-1.23 (m, 2H), 1.17-0.84 (m, 2H). 19 F NMR (376 MHz, DMSO-d6, ppm) δ -110.47. LCMS (ESI, m / z): 539.15 [M+H] + .

[0740] Example 80: 1-(3-(5,7-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0741] Referring to Example 68, replacing phen-1,2-diamine with 3,5-difluorobenzen-1,2-diamine, compound 80 crude was obtained.

[0742] The crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 45% B in 10 min; wavelength: UV 254 nm; RT (min): 7.81, column temperature: 25 °C). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.58 (dd, J = 8.1, 2.3 Hz, 1H), 7.40 - 7.18 (m, 3H), 7.16 - 6.99 (m, 3H), 6.29 (q, J = 7.1 Hz, 1H), 3.09 - 2.94 (m, 2H), 2.81 - 2.58 (m, 2H), 2.48 - 2.37 (m, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.42 - 1.31 (m, 2H), 0.87 (dd, J = 23.9, 11.5 Hz, 2H). MS (ESI, m / z): 599.8 [M+H] + .

[0743] Compound 80 (55 mg) was purified by chiral HPLC under the following conditions (column: CHIRALPAK-CHIRALPAK-IG 2*25 cm, 5 pm; column temperature: 25; mobile phase A: n-hexane (0.1% DEA), mobile phase B: ethanol: dichloromethane (1 : 1, v / v); flow rate: 20 mL / min; isocratic 40% B; wavelength: UV 254 / 220 nm; sample solvent: methanol; resolution to give compound isomers 80A (RT = 4.60 min, 13.9 mg) and 80B (RT = 8.91 min, 12.6 mg).

[0744] 80A: 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.60 - 7.56 (m, 1H), 7.29 (ddd, J = 9.5, 7.1, 2.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.13 - 7.08 (m, 2H), 7.04 (td, J = 10.6, 2.2 Hz, 1H), 6.28 (q, J = 7.1 Hz, 1H), 2.99 (q, J = 7.2, 4.1 Hz, 2H), 2.68 - 2.53 (m, 2H), 2.33 (t, J = 1.9 Hz, 1H), 2.26 (s, 3H), 1.92 (d, J = 7.2 Hz, 3H), 1.27 (d, J = 12.6 Hz, 2H), 0.71 (dd, J = 26.2, 12.2 Hz, 2H). MS (ESI, m / z): 600.20 [M+H] + .

[0745] 80B: 1H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.33 - 7.26 (m, 1H), 7.25 - 7.16 (m, 2H), 7.14 - 7.07 (m, 2H), 7.02 (dd, J = 10.6, 2.4 Hz, 1H), 6.31 - 6.24 (m, 1H), 2.99 (s, 2H), 2.68 - 2.52 (m, 2H), 2.26 (d, J = 3.1 Hz, 3H), 2.22 (s, 1H), 1.92 (dd, J = 7.4, 3.3 Hz, 3H), 1.25 (d, J = 12.3 Hz, 2H), 0.68 (dd, J = 27.6, 12.4 Hz, 2H). MS (ESI, m / z): 600.20 [M+H] + .

[0746] Example 81: 1-(3-(5,7-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5- methylphenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- yl)amine

[0747] Referring to Example 68, the crude product of compound 81 was obtained by replacing benzene-1,2-diamine in step a) with 3,5-difluorobenzene-1,2-diamine and replacing 2,4-difluorobenzoic acid in step d) with (3-fluoro-5-methylphenyl)boronic acid.

[0748] The crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 22% B to 42% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.10, column temperature: 25 °C). 1H NMR (400 MHz, DMSO-d6) δ 8.41 - 8.33 (m, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.58 (dd, J = 8.1, 2.3 Hz, 1H), 7.42 (d, J = 5.0 Hz, 2H), 7.32 - 7.20 (m, 2H), 7.09 - 6.92 (m, 2H), 6.29 (d, J = 7.1 Hz, 1H), 3.03 (d, J = 11.6 Hz, 2H), 2.77 - 2.58 (m, 2H), 2.41 - 2.29 (m, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.1 Hz, 3H), 1.39 (d, J = 11.6 Hz, 2H), 0.92 (dd, J = 24.8, 12.4 Hz, 2H). MS (ESI, m / z): 595.8 [M+H] + .

[0749] Compound 81 (70 mg) was purified by preparative HPLC under the following conditions (column: CHIRALPAK-IG 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% DEA), mobile phase B: ethanol: dichloromethane (1:1, v / v); flow rate: 20 mL / min; isocratic 40% B; wavelength: 254 / 220 nm; column temperature 25 °C) to give compound isomers 81A (RT = 4.97 min, 14.4 mg) and 81B (RT = 9.73 min, 12.0 mg) by resolution.

[0750] 81A: 1 H NMR (400 MHz, DMSO-d6, ppm): δ 8.38 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.58 (dd, J = 8.1, 2.3 Hz, 1H), 7.30 - 7.15 (m, 2H), 7.11 - 7.03 (m, 2H), 7.02-6.94 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 2.97 (d, J = 10.8 Hz, 2H), 2.66 (s, 1H), 2.37 (s, 3H), 2.26 (s, 3H), 2.21 (s, 2H), 1.92 (d, J = 7.1 Hz, 3H), 1.26 (d, J = 12.8 Hz, 2H), 0.77-0.59 (m, 2H). MS (ESI, m / z): 596.00 [M+H] + .

[0751] 81B: 1H NMR: (400MHz, DMSO-d6, ppm): δ8.38(s,1H),8.20(s,1H),7.95(s,1H),7.58(dd, J=8.1,2.3Hz,1H),7.30–7.15(m,2H),7.11–7.03(m,2H),7.02-6.94(m,2H),6.2 8(q,J=7.1Hz,1H),2.97(d,J=10.8Hz,2H),2.66(s,1H),2.37(s,3H),2.26(s,3H ), 2.21 (s, 2H), 1.92 (d, J = 7.1Hz, 3H), 1.26 (d, J = 12.8Hz, 2H), 0.77-0.59 (m, 2H). MS(ESI, m / z): 596.15 [M+H] + .

[0752] Example 82: 1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-4-amine

[0753] a) 1-(5-chloro-3-carboxyl-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)amino

[0754] tert-butyl carbamate (82a)

[0755] 300 mg of 4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde was dissolved in 20 mL of N-methylpyrrolidone, followed by the addition of 235 mg of piperidine-4-ylcarbamate and 230 mg of N,N-diisopropylethylamine. The mixture was stirred at 160 °C for 4 hours. The mixture was extracted with water and ethyl acetate, and the organic phases were combined and washed with water. The organic phase was concentrated to dryness and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give crude compound 82a (523 mg), which was used directly in the next step. MS (ESI, m / z): 497.22 [M+H] + .

[0756] b) 1-(5-(3,5-difluorophenyl)-3-formyl-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)

[0757] Piperidin-4-yl)tert-butyl carbamate (82b)

[0758] Compound 82a (0.2 g), 3,5-difluorophenylboronic acid (0.25 g), bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium dichloride (10 mg), and cesium carbonate (1.3 g) dissolved in 5 mL of 1,4-dioxane were added to a reaction flask. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 3 hours. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography to obtain compound 82b (50 mg). MS (ESI, m / z): 576.27 [M+H] + .

[0759] c)(1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-

[0760] 1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)tert-butyl carbamate (82c)

[0761] Compound 82b (130 mg) and 4-chlorophenyl-1,2-diamine (16 mg) were dissolved in acetic acid solution (5 mL), and 50 mg of copper acetate was added. After stirring at room temperature for 12 hours, the mixture was extracted with water and dichloromethane. The organic phases were combined, concentrated, and subjected to column chromatography to give the title compound 82c (120 mg). MS (ESI, m / z): 698.27 [M+H] + .

[0762] d)1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-

[0763] Pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (compound 82)

[0764] Compound 82c (120 mg) was dissolved in dioxane (5 mL), and 2 mL of 4.0 M hydrochloric acid was added. The mixture was stirred at room temperature for 3 hours, and the reaction solution was concentrated to dryness. The crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18OBD 10 μm, 19 mm * 250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 40% B over 10 minutes; wavelength: UV 254 nm; RT (min): 8.55, column temperature: 25 °C) to obtain compound 82 (83 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.64 - 7.52 (m, 3H), 7.32 - 7.16 (m, 3H), 7.12 (d, J = 5.9 Hz, 2H), 6.28 (q, J = 7.1 Hz, 1H), 3.02 (d, J = 8.6 Hz, 2H), 2.77 - 2.59 (m, 2H), 2.43 (d, J = 10.9 Hz, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.44 - 1.29 (m, 2H), 0.98 (d, J = 6.4 Hz, 2H). MS (ESI, m / z): 597.80 [M+H] + .

[0765] e) 82A / 82B

[0766] Compound 82 crude (50 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK-IG 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% DEA), mobile phase B: ethanol: dichloromethane (1 : 1, v / v); flow rate: 20 mL / min; isocratic 40% B; wavelength: UV 254 / 220 nm; sample solvent: methanol; column temperature: 25 °C) to give compound isomers 82A (RT = 5.20 min, 18.4 mg) and 82B (RT = 7.88 min, 18.2 mg).

[0767] 82A: 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.1 Hz, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.62 - 7.55 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.15 - 7.07 (m, 2H), 6.28 (d, J = 7.1 Hz, 1H), 3.30 (s, 1H), 3.00 (s, 2H), 2.69 - 2.52 (m, 1H), 2.33 - 2.30 (m, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.37 - 1.22 (m, 2H), 0.82 (s, 2H). MS (ESI, m / z): 598.15 [M+H] + .

[0768] 82B: 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.62 - 7.55 (m, 2H), 7.59 - 7.50 (m, 1H), 7.32 - 7.26 (m, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.19 (dd, J = 8.5, 2.1 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.28 (q, J = 7.1 Hz, 1H), 3.30 (s, 1H), 3.00 (s, 2H), 2.64 - 2.53 (m, 1H), 2.26 (s, 3H), 2.25 - 2.21 (m, 1H), 1.91 (d, J = 7.1 Hz, 3H), 1.26 (d, J = 13.2 Hz, 2H), 0.73 (dd, J = 25.2, 11.9 Hz, 2H). MS (ESI, m / z): 598.15 [M+H] + .

[0769] Example 83: 1-(5-(3,5-difluorophenyl)-3-(4-fluoro-6-methoxy-1H- benzo[d]imidazol-2-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)piperidin-4-amine

[0770] Referring to Example 68, the crude product of compound 83 was obtained by replacing benzene-1,2-diamine with 3-fluoro-5-methoxybenzene-1,2-diamine.

[0771] The crude product was purified by preparative HPLC (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 40% B in 10 min; wavelength: UV 254 nm; RT (min): 8.55, column temperature: 25 °C). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.4 Hz, 2H), 8.14 (s, 1H), 7.98 (s, 1H), 7.58 (dd, J = 8.0, 2.4 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.84 (s, 1H), 6.67 (dd, J = 12.4, 2.4 Hz, 1H), 6.28 (q, J = 7.2 Hz, 1H), 3.79 (s, 3H), 2.99 (s, 2H), 2.33 - 2.32 (m, 2H), 2.26 (s, 3H), 2.20 - 2.12 (m, 1H) 1.91 (d, J = 7.2 Hz, 3H), 1.35 - 1.29 (m, 2H), 0.88 - 0.82 (m, 2H). MS (ESI, m / z): 611.8 [M+H] + .

[0772] Referring to Example 68, replacing benzene-1,2-diamine with 3-fluoro-5- methoxybenzene-1,2-diamine, compound 83a was obtained.

[0773] Compound 83a (190 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK-IA 2*25 cm, 5 pm; mobile phase A: HEX (0.1% DEA), mobile phase B: EtOH:DCM (1:1, v / v); flow rate: 20 mL / min; isocratic 5% B; wavelength: UV 254 / 220 nm; sample solvent: methanol; column temperature: 25 °C) to give compound isomer compound 83Ab (RT = 8.477 min, 70 mg) and 83Bb (RT = 10.82 min, 70 mg).

[0774] A solution of compound 83Ab (70 mg) in DCM (1 mL) was treated with TFA (0.3 mL) at room temperature for 30 min. The desired product could be detected by LCMS. The crude product (60 mg) was purified by prep-HPLC under the following conditions (column: XBridge BEH Shield RP18 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 64% B in 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 5.22, column temperature: 25 °C) to give compound 83A (12.4 mg).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.41-8.36 (m, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.61-7.55 (m, 1H), 7.29 (tt, J = 9.5, 2.3 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.15-7.06 (m, 2H), 6.83 (s, 1H), 6.67 (dd, J = 12.4, 2.1 Hz, 1H), 6.28 (q, J = 7.1 Hz, 1H), 3.79 (s, 3H), 3.06-2.91 (m, 2H), 2.82-2.54 (m, 2H), 2.26 (s, 3H), 2.21-2.07 (m, 1H), 1.92 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 12.3 Hz, 2H), 0.82-0.59 (m, 3H). LCMS (ESI, m / z): 612.00 [M+H] + .

[0775] A solution of compound 83Bb (70 mg) in DCM (1 mL) was treated with TFA (0.3 mL) at room temperature for 30 min. The desired product could be detected by LCMS. The crude product (60 mg) was purified by prep-HPLC under the following conditions (column: XBridge BEH Shield RP18 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 60% B in 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 5.38, column temperature: 25 °C) to give compound 83B (28 mg). 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.41 - 8.36 (m, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.61 - 7.55 (m, 1H), 7.29 (tt, J = 9.5, 2.3 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.83 (s, 1H), 6.67 (dd, J = 12.4, 2.1 Hz, 1H), 6.28 (q, J = 7.1 Hz, 1H), 3.79 (s, 3H), 3.06 - 2.91 (m, 2H), 2.82 - 2.54 (m, 2H), 2.26 (s, 3H), 2.21 - 2.07 (m, 1H), 1.92 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 12.3 Hz, 2H), 0.82 - 0.59 (m, 3H). LCMS (ESI, m / z): 612.00 [M+H] + .

[0776] Example 84: (S)-1-(5-(3,5-difluorophenyl)-3-(5-fluoro-1H-indazol-6-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0777] a) 6-bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (84a)

[0778] To a stirred solution of 6-bromo-5-fluoro-1H-indazole (500 mg) in dichloromethane (10 mL) was added dihydropyran (586.80 mg), 4-methylbenzene-1-sulfonic acid hydrate (44.23 mg) at 25 °C and stirred for 17 h. The progress of reaction was monitored by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to get crude product which was further purified by column chromatography (EA / PE: gradient 5-20%) to afford the title compound 84a (750 mg).

[0779] b) (5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)boronic acid (84b)

[0780] To a solution of compound 84a (500 mg) in tetrahydrofuran (10 mL) was added dropwise n-butyllithium (2.5 M in n-hexane) (128.49 mg) at -78 °C under N2atmosphere. The reaction mixture was stirred at -78 °C for 30 min. Then trimethyl borate (416.83 mg) in tetrahydrofuran (2 mL) was added dropwise and the mixture was stirred for another 10 h. The reaction was quenched with MeOH and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: (column: C18 silica gel; mobile phase: acetonitrile / water, 10% to 100% gradient in 10 min; detector: UV 254 nm) to give the title compound 84b (200 mg).

[0781] c) (S)-tert-Butyl 1-(5-(3,5-difluorophenyl)-3-(5-fluoro-1H-indazol-6-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (84c)

[0782] To a solution of (S)-tert-butyl 1-(3-chloro-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (100 mg) and compound 84b (90.73 mg) in 1,4-dioxane (3 mL) and water (0.3 mL) was added potassium phosphate (109.40) and

[0783] [1,1’-Bis(ditert-butylphosphine)ferrocene]dichloropalladium (11.20 mg). After stirring at 100 °C for 17 h under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EA (3:1) to give the title compound 84c (50 mg).

[0784] d) (S)-1-(5-(3,5-difluorophenyl)-3-(5-fluoro-1H-indazol-6-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (compound 84)

[0785] To a stirred solution of compound 84c (40 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 25 °C and stirred for 30 min. The progress of the reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0786] The crude product was purified by preparative high performance liquid chromatography (column: CHIRALPAK IE, 3*25 cm, 5 μm; mobile phase A: Hex: MTBE = 1:1 (v / v) (0.5% 2M NH3-MeOH), mobile phase B: MeOH; flow rate: 40 mL / min; column temperature: 25 °C; isocratic 5% B; wavelength: 216 / 234 nm; RT (min): 16.91; sample solvent: methanol to give compound 84 (12.9 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 2.2 Hz, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.59 - 7.46 (m, 3H), 7.29 - 7.19 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H), 2.84 (t, J = 12.5 Hz, 2H), 2.33 (m, 2H), 2.26 (s, 3H), 2.12 - 1.99 (m, 1H), 1.98 - 1.82 (m, 3H), 1.05 - 0.92 (m, 2H), 0.20 (m, 2H). (ES, m / z): 582.30 [M+H] + .

[0787] Example 85: 1-(5-(3,5-difluorophenyl)-3-(1H-indazol-5-yl)-1-(1-(5-methylpyridin-2- yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0788] a) (1-(tert-butoxycarbonyl)-1H-indazol-5-yl)boronic acid (85a)

[0789] (1H-indazol-5-yl)boronic acid (300 mg) was dissolved in dichloromethane (10 mL), p-dimethylaminopyridine (40 mg), N,N-diisopropylethylamine (400 mg) and di-tert-butyl dicarbonate (400 mg) were added, stirred at 20 °C for 12 hours. The reaction solution was extracted with water (20 ml) and dichloromethane (20 ml*3), the organic phase was concentrated to dryness to give the title compound 85a (350 mg).

[0790] b) tert-butyl 5-(4-(4-(((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-chloro-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indazole-1-carboxylate (85b)

[0791] Tert-butyl (l-(3-bromo-5-chloro-l-(l-(5-methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3- b]pyridin-4-yl)piperidin-4-yl)carbamate (150 mg) was dissolved in dioxane (10 mL), compound 85a (135 mg), cesium carbonate (170 mg) and [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride (21 mg) were added. Nitrogen was purged, stirred at 80 °C for 5 hours. The reaction was filtered, concentrated to dryness, purified by column chromatography (PE:EA = 4: 1) to give the title compound 85b (150 mg). MS (ESI, m / z): 686.2 [M+H] + .

[0792] c) Tert-butyl 5-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-(3,5-difluorophenyl)- l-(l-(5-methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-indazole-l-carboxylate (85c)

[0793] Compound 85b (150 mg) was dissolved in dioxane (10 mL) and water (0.25 mL), (3,5-difluorophenyl)boronic acid (70 mg), bis[ditert-butyl-(4-dimethylaminophenyl)phosphine] palladium(II) dichloride (16 mg) and cesium carbonate (150 mg) were added, nitrogen was purged, stirred at 100 °C for 3 hours. The reaction was filtered, concentrated to dryness, dried, purified by column chromatography (petroleum ether: ethyl acetate = 1: 1 (v / v)) to give the title compound 85c (100 mg).

[0794] d) 1-(5-(3,5-Difluorophenyl)-3-(lH-indazol-5-yl)-l-(l-(5-methylpyridin-2-yl)ethyl)-lH- pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 85)

[0795] Compound 85c (100 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 2 hours, concentrated to dryness, the crude was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 μm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 45% B in 10 minutes; wavelength: UV 254 nm; RT (min): 9.33, column temperature: 25 °C) to give the title compound 85 (29.37 mg). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.62 (s, 1H), 7.60 - 7.53 (m, 2H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 7.25 (tt, J = 9.6, 2.4 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H), 2.98 (t, J = 12.4 Hz, 2H), 2.45 - 2.38 (m, 1H), 2.33 (d, J = 10.8 Hz, 2H), 2.25 (s, 3H), 1.89 (d, J = 7.2 Hz, 3H), 1.14 (t, J = 12.4 Hz, 2H), 0.76 - 0.62 (m, 1H), 0.55 (d, J = 12.0 Hz, 1H). MS (ESI, m / z): 564.20 [M+H] + .

[0796] Compound 85 (172 mg) crude product was purified by preparative HPLC under the following conditions (column: CHIRALPAK IG, 3*25 cm, 10 pm; mobile phase A: Hex (10 mM NH3-MeOH), mobile phase B: EtOH; flow rate: 50 mL / min; isocratic 10% B; wavelength: 230 / 254 nm; column temperature: 25 °C; sample solvent: methanol); resolution gave compound isomers 85A (RT = 45.00 min, 74.9 mg) and 85B (RT = 53.00 min, 71.2 mg).

[0797] 85A: 1 NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.62 (s, 1H), 7.59 - 7.46 (m, 2H), 7.41 (dd, J = 8.5, 1.6 Hz, 1H), 7.31 - 7.19 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H), 3.12 - 2.92 (m, 2H), 2.50-2.30 (m, 3H), 2.25 (s, 3H), 1.88 (d, J = 7.1 Hz, 3H), 1.26 (t, J = 6.2 Hz, 2H), 0.99 - 0.82 (m, 2H). LCMS (ES, m / z): 564.30 [M+H] +

[0798] 85B: 1 HNMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.62 (s, 1H), 7.59 - 7.46 (m, 2H), 7.41 (dd, J = 8.5, 1.6 Hz, 1H), 7.31 - 7.19 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H), 3.12 - 2.92 (m, 2H), 2.49-2.28 (m, 3H), 2.25 (s, 3H), 1.88 (m, 3H), 1.26 (m, 2H), 0.99 - 0.82 (m, 2H). LCMS (ES, m / z): 564.25 [M+H] +

[0799] Example 86: 1-(5-(3,5-difluorophenyl)-3-(1H-indazol-6-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0800] Referring to Example 85, replace (1H-indazol-5-yl)boronic acid with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole to obtain crude compound 86.

[0801] The crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 20% B to 50% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.469, column temperature: 25 °C) to obtain compound 86 (36.28 mg). 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.31 - 7.18 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.07 (h, J = 4.5, 4.1 Hz, 2H), 6.24 (q, J = 7.1 Hz, 1H), 2.99 (t, J = 12.6 Hz, 2H), 2.46 - 2.40 (m, 1H), 2.39 - 2.29 (m, 2H), 2.25 (s, 3H), 1.90 (d, J = 7.2 Hz, 3H), 1.16 (t, J = 12.5 Hz, 2H), 0.71 (td, J = 13.1, 9.0 Hz, 1H), 0.56 (dd, J = 12.8, 8.8 Hz, 1H). MS (ESI, m / z): 564.2 [M+H] + .

[0802] Compound 86 (152 mg) was purified by preparative HPLC under the following conditions (Column: Lux 5u Cellulose-2, 30*250mm, 5.0um; Mobile Phase A: Hex (10mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Isocratic 40% B; Wavelength: 208 / 236 nm; Column temperature: 25 °C; 11.3; Sample Solvent: EtOH; Resolved to give compound isomers 86A (RT = 8.60 min, 49.9 mg) and 86B (RT = 11.30 min, 50.7 mg).

[0803] 86A: 1HNMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.62 - 7.49 (m, 2H), 7.33 - 7.20 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H),, 2.97 (t, J = 12.9 Hz, 2H), 2.39 (dd, J = 26.5, 12.9 Hz, 2H), 2.25 (s, 4H), 1.90 (d, J = 7.3 Hz, 3H),, 1.13 (d, J = 14.0 Hz, 2H),, 0.64 (d, J = 11.7 Hz, 1H), 0.50 (s, 1H). LCMS (ES, m / z): 564.25 [M+H] + .

[0804] 86B: HNMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 1.1 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.62 - 7.49 (m, 2H), 7.33 - 7.20 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H),, 2.97 (t, J = 12.9 Hz, 2H), 2.39 (dd, J = 26.5, 12.9 Hz, 2H), 2.25 (s, 4H), 1.90 (d, J = 7.3 Hz, 3H),, 1.13 (d, J = 14.0 Hz, 2H),, 0.64 (d, J = 11.7 Hz, 1H), 0.50 (s, 1H). LCMS (ES, m / z): 564.25 [M+H] + .

[0805] Example 87: 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5- methoxyphenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4- amine

[0806] Referring to Example 68, replacing step a) phenyl-1,2-diamine with 4,5-difluoro- phenyl-1,2-diamine and step d) 3,5-difluorophenylboronic acid with (3-fluoro-5- methoxyphenyl)boronic acid gives compound 87 crude product.

[0807] The crude product was purified by preparative HPLC under the following conditions (column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 39% B to 59% B in 10 min; wavelength: UV 254 nm / 220 nm; RT (min): 6.43; column temperature: 25 °C) to give compound 87 (4.8 mg).

[0808] Compound 87 (15.0 mg) was resolved by preparative chiral HPLC under the following conditions (column: CHIRALPAK-IG 2*25 cm, 5 pm; mobile phase A: n-hexane (0.1% DEA), mobile phase B: EtOH:DCM (1:1, v / v); and flow rate: 20 mL / min; isocratic 40% B; wavelength: UV 254 / 220 nm; sample solvent: methanol; column temperature: 25 °C) to give compound isomers 87A (RT = 5.21 min, 4.8 mg) and 87B (RT = 7.91 min, 4.4 mg).

[0809] 87A: 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.61-7.59 (m, 1H), 7.59-7.54 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 6.91-6.83 (m, 1H), 6.81-6.71 (m, 2H), 6.28 (q, J = 7.0 Hz, 1H), 3.81 (d, J = 3.3 Hz, 3H), 3.04 (d, J = 11.8 Hz, 2H), 2.71-2.57 (m, 2H), 2.56 (s, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.1 Hz, 3H), 1.27 (t, J = 13.3 Hz, 2H), 0.83-0.63 (m, 2H). MS (ESI, m / z): 612.20 [M+H] + .

[0810] 87B: 1H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.58 (dd, J = 7.8, 2.7 Hz, 3H), 7.22 (d, J = 8.0 Hz, 1H), 6.87 (dt, J = 11.2, 2.4 Hz, 1H), 6.81 - 6.71 (m, 2H), 6.27 (q, J = 7.1 Hz, 1H), 3.80 (s, 3H), 3.02 (t, J = 11.5 Hz, 2H), 2.68 - 2.53 (m, 2H), 2.29 (s, 1H), 2.26 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.32 - 1.21 (m, 2H), 0.84 - 0.66 (m, 2H). MS (ESI, m / z): 612.20 [M+H] + .

[0811] Example 88: 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- (methoxymethyl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0812] a) tert-Butyl (1-(3-(5,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5-(methoxymethyl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (88a)

[0813] Tert-butyl (1-(3-(5,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (0.140 g), 2-(1-chloroethyl)-5-(methoxymethyl)pyridine (0.100 g), sodium hydride (0.080), water (2 mL) were dissolved in N,N-dimethylformamide (5 mL) and reacted at 50 °C for 3 hours under nitrogen protection. Then quenched with water, extracted with ethyl acetate, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the title compound 88a (100 mg).

[0814] b) 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- (methoxymethyl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (88b)

[0815] Compound 88a (0.100 g) was dissolved in trifluoroacetic acid (5 mL) and stirred at 20 °C for 1 h under anhydrous and oxygen-free nitrogen atmosphere. Then it was concentrated to dryness under reduced pressure to give the title compound 88b, which was used directly for the next step.

[0816] c) 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- (methoxymethyl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 88)

[0817] Compound 88b was dissolved in methanol (10 mL) and stirred with potassium carbonate (590 mg) for 1 h, then filtered. The organic phase was concentrated to dryness, and the crude product was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 20% B to 50% B in 10 min; wavelength: UV 254 nm; RT (min): 7.18, column temperature: 25 °C) (petroleum ether: ethyl acetate = 1:1) to give the title compound 88 (23 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.49 (d, J = 2.1 Hz, 2H), 8.20 (s, 1H), 7.98 (s, 1H), 7.78 - 7.54 (m, 3H), 7.30 (dd, J = 16.2, 8.6 Hz, 2H), 7.20 - 7.02 (m, 2H), 6.32 (q, J = 7.1 Hz, 1H), 4.41 (s, 2H), 3.28 (s, 3H), 3.00 (d, J = 10.5 Hz, 2H), 2.66 (d, J = 12.3 Hz, 1H), 2.58 (d, J = 11.8 Hz, 1H), 2.36 (d, J = 14.7 Hz, 1H), 1.94 (d, J = 7.2 Hz, 3H), 1.42 - 1.28 (m, 2H), 0.85 (dt, J = 20.9, 7.7 Hz, 2H). MS (ESI, m / z): 630.20 [M+H] + .

[0818] Example 89: l-(3-(5,6-difluoro-lH-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)- lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0819] a) 4,5-Dichloro-l-(l-(p-tolyl)ethyl)-lH-pyrrolo[2,3-b]pyridine (89a)

[0820] Compound 89a (600 mg) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (280 mg) was added, and the mixture was stirred at 20 °C for 1 hour under nitrogen. l-(l-Bromoethyl)-4-methylbenzene (490 mg) was added, and the mixture was stirred at 20 °C for 2 hours under nitrogen. The reaction mixture was concentrated to dryness, extracted with ethyl acetate and water, and the organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 1 (v / v)) to give the title compound 89a (600 mg).

[0821] b) 4,5-Dichloro-l-(l-(p-tolyl)ethyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (89b)

[0822] Compound 89a (600 mg) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (280 mg) was added, and the mixture was stirred at 20 °C for 1 hour under nitrogen. l-(l-Bromoethyl)-4-methylbenzene (490 mg) was added, and the mixture was stirred at 20 °C for 2 hours under nitrogen. The reaction mixture was concentrated to dryness, extracted with ethyl acetate and water, and the organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 1 (v / v)) to give the title compound 89a (600 mg).

[0823] c) 2-(4,5-Dichloro-l-(l-(p-tolyl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro- lH-benzo[d]imidazole (89c)

[0824] Compound 89b (500 mg) was dissolved in acetic acid (10 mL), and 4,5-difluorobenzene- 1,2-diamine (242 mg) was added, and the mixture was stirred at 120 °C for 1 hour with open air. The reaction mixture was concentrated to dryness to give the title compound 89c, which was used directly in the next step.

[0825] d) (l-(5-chloro-3-(5,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-(l-(p-tolyl)ethyl)- lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (89d)

[0826] Compound 89c (400 mg) was dissolved in N-methylpyrrolidone (10 mL), and tert-butyl piperidin-4-ylcarbamate (349 mg), N,N-diisopropylethylamine (341 mg) were added. The mixture was stirred at 160°C under microwave irradiation for 1 hour. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 89d (300 mg).

[0827] e) tert-Butyl 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-chloro-l-(l-(p- tolyl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-lH-benzo[d]imidazole-l- carboxylate (89e)

[0828] Compound 89d (300 mg) was dissolved in dichloromethane (10 mL), and di-tert- butyl dicarbonate (223 mg), N,N-diisopropylethylamine (266 mg), and 4-dimethylaminopyridine (8 mg) were added. The mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4:1) to give the title compound 89e (300 mg).

[0829] f) tert-Butyl 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-(3,5-difluorophenyl)- l-(l-(p-tolyl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-lH-benzo[d]imidazole-l- carboxylate (89f)

[0830] Compound 89e (300 mg) was dissolved in dioxane (10 mL), and (3,5-difluorophenyl)boronic acid (129 mg), cesium carbonate (399 mg), dichlorobis-(4- dimethylaminophenyl) palladium(II) (29 mg) were added. The mixture was stirred at 100°C under nitrogen for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 89f (200 mg).

[0831] g) 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(p- tolyl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 89)

[0832] Compound 89f (200 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, stirred for 2 hours, the reaction was concentrated to dryness to get crude, which was purified by preparative HPLC under the following conditions (column: X-Bridge Prep C18 OBD 10 pm, 19 mm*250 mm; mobile phase A: water (0.1% formic acid, mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 20% B to 50% B in 10 minutes; wavelength: UV 254 nm; RT (min): 7.18, column temperature: 25 °C) to give the title compound 89 (79.3 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.18 (s, 1H), 8.00 (s, 1H), 7.59 (dd, J = 10.5, 7.8 Hz, 2H), 7.34 - 7.25 (m, 3H), 7.13 (dd, J = 9.7, 6.9 Hz, 4H), 6.22 (q, J = 7.1 Hz, 1H), 3.05 - 2.94 (m, 2H), 2.69 - 2.52 (m, 2H), 2.39 - 2.32 (m, 1H), 2.25 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H), 1.37 - 1.26 (m, 2H), 0.92 - 0.72 (m, 2H). MS (ESI, m / z): 598.8 [M+H] + .

[0833] Example 90: 6-(4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-2-one

[0834] a) 4,5-dichloro-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (90a)

[0835] To a stirred solution of compound 90a (2 g) in N-methyl pyrrolidine (20 mL) was added tert-butyl piperidin-4-ylcarbamate (3.92 g) at room temperature under nitrogen. The resulting mixture was stirred at 170 °C for 5 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 : 1) to afford the title compound 90b (1 g). MS (ESI, m / z): 470 [M+H] + .

[0836] b) tert-Butyl 1 -(5-chloro- 1 -( 1 -(5-methylpyridin-2-yl)ethyl)- 1 H-pyrrolo[2,3- b]pyridin-4-yl)piperidin-4-yl)carbamate (90b)

[0837] To a stirred solution of compound 90a (2 g) in N-methyl pyrrolidine (20 mL) was added tert-butyl piperidin-4-ylcarbamate (3.92 g) at room temperature under nitrogen. The resulting mixture was stirred at 170 °C for 5 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 : 1) to afford the title compound 90b (1 g). MS (ESI, m / z): 470 [M+H] + .

[0838] c) tert-Butyl 1 -(5-(3,5-difluorophenyl)- 1 -( 1 -(5-methylpyridin-2-yl)ethyl)- 1 H-pyrrolo[2,3- b]pyridin-4-yl)piperidin-4-yl)carbamate (90c)

[0839] To a stirred solution of compound 90b (800 mg), 3,5-difluorophenylboronic acid (806.33 mg) in 1,4-dioxane (10 mL) and water (2 mL), potassium phosphate (1083.88 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (81.14 mg) and tris(dibenzylideneacetone)dipalladium (155.87 mg) were added under nitrogen at room temperature. The resulting mixture was stirred at 100 °C overnight. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1, v / v) to give the title compound 90c (1 g). MS (ESI, m / z): 548 [M+H] + .

[0840] d) tert-Butyl (1-(3-chloro-5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (90d)

[0841] Compound 90c (800 mg) was dissolved in N,N-dimethylformamide (10 mL) and N-chlorosuccinimide (348.85 mg) was added and the reaction was allowed to proceed at room temperature for 24 h. The desired product was detected by LCMS. The reaction was quenched with water at 0 °C. It was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride (2 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: C18 column; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 10% B to 50% B in 10 min; detector, UV 254 nm to give the title compound 90d (300 mg). MS (ESI, m / z): 582 [M+H] + .

[0842] e) tert-Butyl 1-(5-(3,5-difluorophenyl)-1-(1-(5-methylpyridin-2-yl)ethyl)-3-(2-oxoindol-6-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (90e)

[0843] To a stirred solution of compound 90d (50 mg), 6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l, 3-dihydroindol-2-one (22.26 mg), 4-dioxane (1 mL) and water (0.2 mL) was added 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl (4.09 mg), potassium phosphate (36.47 mg, 0.172 mmol, 2 eq) and tris(dibenzylideneacetone)dipalladium (15.73 mg) under nitrogen at 100 °C overnight. LCMS can detect the desired product. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: C18 column; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 10% B to 50% B in 10 min; detector, UV 254 nm, to give compound 90e (40 mg). MS (ESI, m / z): 679 [M+H] + .

[0844] f) 6-(4-(4-Aminopiperidin-l-yl)-5-(3,5-difluorophenyl)-l-(l-(5-methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)indolin-2-one (Compound 90)

[0845] Compound 90e (80 mg) and trifluoroacetic acid (0.6 mL) were dissolved in dichloromethane (2 mL), the mixture was stirred at room temperature under air atmosphere for 30 min. LCMS can detect the desired product. The resulting mixture was concentrated under vacuum. The crude product (40 mg) was purified by Prep HPLC with the following conditions (column: Xselect CSHTM Prep C18 5 μm 30*150 mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 37% B in 8 min; wavelength: UV 254 nm / 220 nm; RT (min): 6.22; column temperature: 25 °C) to give compound 90 (15.3 mg). 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 7.87 (s, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.30-7.27 (m, 1H), 7.25-7.22 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.09-7.03 (m, 2H), 7.01 (s, 1H), 6.92 (s, 1H), 6.21 (m, 1H), 3.53 (s, 2H), 3.03 (m, 2H), 2.63 (m, 1H), 2.50 (m, 2H), 2.27 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H), 1.37 (s, 2H), 0.85-0.72 (m, 2H). MS (ESI, m / z): 579.00 [M+H] + .

[0846] Compound 90 (14.3 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IA, 2*25 cm, 5 pm; mobile phase A: Hex (0.1% DEA), mobile phase B: EtOH:DCM (1:1, v / v); flow rate: 20 mL / min; isocratic 40% B; wavelength: UV 254 / 220 nm; column temperature: 25 °C) to give compound isomers 90A (RT = 6.45 min, 6.2 mg) and 90B (RT = 12.29 min, 4.1 mg) by resolution.

[0847] 90A: 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 7.87 (s, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.30-7.27 (m, 1H), 7.25-7.22 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.09-7.03 (m, 2H), 7.01 (s, 1H), 6.92 (s, 1H), 6.21 (m, 1H), 3.53 (s, 2H), 3.03 (m, 2H), 2.63 (m, 1H), 2.50 (m, 2H), 2.27 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H), 1.37 (s, 2H), 0.85-0.72 (m, 2H). LCMS (ESI, m / z): 579.05 [M+H] + .

[0848] 90B: 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.2 Hz, 1H), 7.87 (s, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.30-7.27 (m, 1H), 7.25-7.22 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.09-7.03 (m, 2H), 7.01 (s, 1H), 6.92 (s, 1H), 6.21 (m, 1H), 3.53 (s, 2H), 3.03 (m, 2H), 2.63 (m, 1H), 2.50 (m, 2H),, 2.27 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H), 1.37 (s, 2H), 0.85-0.72 (m, 2H). LCMS (ESI, m / z): 579.05 [M+H] + .

[0849] Example 91: 5-(4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorobenzonitrile

[0850] a) tert-Butyl 1-(5-(3-cyano-4-fluorophenyl)-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (91a)

[0851] tert-Butyl 1-(5-chloro-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-(1-(5-methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (60 mg), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (71.49 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (9.2 mg), potassium phosphate (61.42 mg), tris(dibenzylideneacetone)dipalladium (8.83 mg) were dissolved in 1,4-dioxane (0.9 mL) and water (0.3 mL) and stirred at 100 °C under nitrogen overnight. The desired product was detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol (0-10%) to give the title compound 91a (61 mg). LCMS (ESI, m / z): 707 [M+H] + .

[0852] b) 5-(4-(4-aminopiperidin-l-yl)-3-(5,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-(l-(5- methylpyridin-2-yl)ethyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorobenzonitrile (Compound 91)

[0853] To a stirred solution of compound 91a (61 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. The resulting mixture was stirred at room temperature for another 1 h. LCMS can detect the desired product. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm*150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 35% B to 50% B in 8 min; Wavelength: UV 254 nm / 220 nm; RT (min): 6.30; Column Temperature: 25 °C) to give the title compound 91 (28.9 mg). LCMS (ESI, m / z): 607.25 [M+H] + .

[0854] 91A / 91B

[0855] The compound 91 crude (28.9 mg) was purified by chiral HPLC (Column: CHIRALPAK-IC 2*25 cm, 5 pm; Mobile Phase A: HEX (0.1% DEA), Mobile Phase B: EtOH:DCM (1:1, v / v); Flow Rate: 20 mL / min; Isocratic 40% B; Wavelength: UV 254 / 220 nm; Sample Solvent: Methanol; Column Temperature: 25 °C) to give compound isomers 91A (RT = 6.76 min, 8.6 mg) and 91B (RT = 9.58 min, 7.6 mg) as a racemate.

[0856] 91A: 1H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.98 - 7.92 (m, 2H), 7.75 (ddd, J = 7.8, 5.3, 2.3 Hz, 1H), 7.60 (dd, J = 7.5, 5.0 Hz, 2H), 7.56 (d, J = 9.7 Hz, 2H), 7.23 (dd, J = 8.0, 2.1 Hz, 1H), 6.28 (dd, J = 7.1, 2.1 Hz, 1H), 2.95 (d, J = 12.9 Hz, 2H), 2.68 - 2.66 (m, 1H), 2.33 (q, J = 1.8 Hz, 1H), 2.26 (d, J = 2.0 Hz, 3H), 2.21 (d, J = 10.1 Hz, 1H), 1.91 (dd, J = 7.1, 2.0 Hz, 3H), 1.23 (d, J = 11.4 Hz, 2H), 0.67 (dd, J = 26.1, 12.5 Hz, 2H). LCMS (ESI, m / z): 607.25 [M+H] + .

[0857] 91B: 1 H NMR: (400 MHz, DMSO-d6, ppm) δ 8.38 (q, J = 1.0 Hz, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.94 (dd, J = 6.3, 2.3 Hz, 1H), 7.75 (ddd, J = 8.7, 5.3, 2.3 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.59 - 7.57 (m, 1H), 7.57 - 7.54 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 6.28 (q, J = 7.1 Hz, 1H), 2.93 (t, J = 5.4 Hz, 2H), 2.68 - 2.66 (m, 1H) 2.33 (p, J = 1.9 Hz, 1H), 2.26 (s, 3H), 2.21 (d, J = 6.8 Hz, 1H), 1.91 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 11.5 Hz, 2H), 0.67 (dd, J = 25.9, 12.1 Hz, 2H). LCMS (ESI, m / z): 607.25 [M+H] + .

[0858] Example 92: 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methoxypyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0859] a) 1 -(5-methoxypyridin-2-yl)ethan-1 -ol (92a)

[0860] Dissolve 1 -(5-methoxypyridin-2-yl)ethan-1 -one (1 g) in methanol (10 mL), add sodium borohydride (500 mg), stir at 20 °C for 2 h under nitrogen. Spin down the reaction, extract with ethyl acetate and water, wash the organic phase with saturated sodium chloride solution, dry, spin down to give a crude product. Purify the crude product by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 :1 (v / v)) to give the title compound 92a (820 mg).

[0861] b) 4,5-dichloro-1 -(1 -(5-methoxypyridin-2-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridine (92b)

[0862] Dissolve 4,5-dichloro-1 H-pyrrolo[2,3-b]pyridine (500 mg) in xylene (10 mL), add cyanomethylene tri-n-butylphosphonium (1.94 g) and compound 92a (819 mg), stir at 20 °C for 2 h under nitrogen. Spin down the reaction, extract with ethyl acetate and water, wash the organic phase with saturated sodium chloride solution, dry, spin down to give a crude product. Purify the crude product by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 :1 (v / v)) to give the title compound 92b (600 mg).

[0863] c) 4,5-dichloro-1 -(1 -(5-methoxypyridin-2-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridine-3- carboxaldehyde (92c)

[0864] Dissolve N-methyl-N-phenylformamide (800 mg) in dichloromethane (10 mL), add oxalyl chloride (750 mg), stir at 20 °C for 1 h under nitrogen. Add compound 92b (600 mg), stir at 20 °C for 16 h under nitrogen. Spin down the reaction, extract with ethyl acetate and water, wash the organic phase with saturated sodium chloride solution, dry, concentrate to give a crude product. Purify the crude product by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 :1 (v / v)) to give the title compound 92c (500 mg).

[0865] d) 2-(4,5-dichloro-1 -(1 -(5-methoxypyridin-2-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)- 5,6-difluoro-1 H-benzo[d]imidazole (92d)

[0866] Dissolve compound 92c (500 mg) in acetic acid (10 mL), add 4,5-difluorobenzene-1,2- diamine (242 mg), stir at 120 °C for 1 h open to the air. Concentrate the reaction to dryness to give the title compound 92d which is used directly in the next step.

[0867] e) tert-Butyl 1 -(5-chloro-3-(5,6-difluoro-1 H-benzo[d]imidazol-2-yl)-1 -(1 -(5- methoxypyridin-2-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)carbamate (92e)

[0868] Compound 92d (400 mg) was dissolved in N-methylpyrrolidone (10 mL), tert- butyl piperidin-4-ylcarbamate (349 mg), N,N-diisopropylethylamine (341 mg) were added, and the mixture was stirred at 160 °C under microwave irradiation for 1 h. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 : 1 (v / v)) to give the title compound 92e (300 mg).

[0869] f) tert-Butyl 2-(4-(4-(((tert-butoxycarbonyl)amino)piperidin-1 -yl)-5-chloro-1 -(1 -(5- methoxypyridin-2-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-1 H- benzo[d]imidazole-1 -carboxylate (92f)

[0870] Compound 92e (300 mg) was dissolved in dichloromethane (10 mL), di-tert- butyl dicarbonate (223 mg), N,N-diisopropylethylamine (266 mg), and 4-dimethylaminopyridine (8 mg) were added, and the mixture was stirred at 20 °C for 1 h under nitrogen. The reaction solution was concentrated to dryness, and extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to dryness to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1) to give the title compound 92f (300 mg).

[0871] g) tert-Butyl 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-1 -yl)-5-(3,5-difluorophenyl)- 1 -(1 -(5-methoxypyridin-2-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-1 H- benzo[d]imidazole-1 -carboxylate (92g)

[0872] tert-Butyl 2-(4-(4-((tert-butoxycarbonyl)amino)piperidin-1 -yl)-5-(3,5-difluorophenyl)- 1 -(1 -(5-methoxypyridin-2-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-difluoro-1 H- benzo[d]imidazole-1 -carboxylate (92g)

[0873] Compound 92f (300 mg) was dissolved in dioxane (10 mL), (3,5-difluorophenyl)boronic acid (129 mg), cesium carbonate (399 mg), dichlorobis-(4-dimethylaminophenyl) palladium (29 mg), stirred at 100 °C for 3 h under nitrogen protection. The reaction solution was concentrated to dryness, extracted with ethyl acetate and water, the organic phase was washed with saturated sodium chloride solution, dried, concentrated to dryness to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 92g (200 mg).

[0874] h) 1-(3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3,5-difluorophenyl)-1-(1-(5- methoxypyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine (Compound 92)

[0875] Compound 92g (200 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 ml) was added, stirred for 2 h, the reaction solution was concentrated to dryness to give the crude product, which was purified by preparative separation to give the title compound 92 (48.2 mg).1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 2.8 Hz, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.59 (dd, J = 10.4, 7.8 Hz, 2H), 7.38 - 7.25 (m, 3H), 7.15 - 7.07 (m, 2H), 6.33 - 6.25 (m, 1H), 3.80 (s, 3H), 3.04 - 2.94 (m, 2H), 2.70 - 2.54 (m, 2H), 2.39 - 2.34 (m, 1H), 1.90 (d, J = 7.1 Hz, 3H), 1.39 - 1.28 (m, 2H), 0.93 - 0.76 (m, 2H). LCMS (ESI, m / z): 615.8 [M+H] + .

[0876] Example 93: 1-(5-(3,5-difluorophenyl)-3-(7-fluoro-5-methyl-1H-benzo[d]imidazol-2-yl)-1-(1-(5- methylpyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-amine

[0877] Referring to Example 68...

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, Y is N or CR 2 ; Z represents S and CR. 4 or NR 3 ; W is either C or N; R 5 It does not exist, or is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic; wherein the C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group optionally bound by one or more R g replace; The R g Selected from halogen, cyano, hydroxy, nitro, amino, carboxyl, C1-C6 alkyl, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkyl, haloC1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl; B is selected from chemical bonds, -O-, -C(O)-, -NH- or in This indicates that B is chemically bonded to R. 6 Location; R d Selected from hydrogen or C1-C3 alkyl; R 6 Selected from C3-C8 cycloalkyl, 3-12 membered heterocyclic C1-C6 alkyl, or 3-12 membered heterocyclic; R 6 Optionally by one or more R b replace; Each R b They may be the same or different, and each is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -SR x -S(=O)R x -S(=O)2R x -S(=O)N(R) x (R) y -S(=O)2N(R) x (R) y ), -N(R y )S(=O)2R x -N(R) y )S(=O)R x , -C(=O)N(R x (R) y ), -N(R y )C(=O)R x -P(=O)(R x (R) y -OR x -C(O)R x -C(O)-OR x -N(R) x (R) y ), 3-10 membered heterocyclic groups, C3-C8 cycloalkyl groups, C6-C 10 Aryl or 5-14 heteroaryl groups; R 7 Selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, or halo-C1-C6 alkoxy; A is an optional location covered by 1-5 R's. e Substituted phenyl; Each R e They may be the same or different, and each is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -SR x -S(=O)R x -S(=O)2R x -S(=O)N(R) x (R) y -S(=O)2N(R) x (R) y ), -N(R y )S(=O)2R x -N(R) y )S(=O)R x , -C(=O)N(R x (R) y ), -N(R y )C(=O)R x -P(=O)(R x (R) y -OR x -C(=O)R x -C(=O)-OR x -N(R) x (R) y ), 3-10 membered heterocyclic groups, C3-C8 cycloalkyl groups, C6-C 10 Aryl or 5-14 heteroaryl groups; R 1 Selected from cyano, C6-C 10 Aryl, 5-14 heteroaryl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, C6-C 10 Arylaminoacyl or 5-14 heteroarylaminoacyl; wherein the C6-C 10 Aryl, 5-14 heteroaryl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, C6-C 10 The aryl aminoacyl group or the 5-14 heteroaryl aminoacyl group is independently and optionally surrounded by one or more R c replace; Each R c They may be the same or different, and each is independently selected from halogen, cyano, nitro, C1-C6 alkyl, -SR x -S(=O)R x -S(=O)2R x -S(=O)N(R) x (R) y -S(=O)2N(R) x (R) y ), -N(R y )S(=O)2R x -N(R) y )S(=O)R x , -C(=O)N(R x (R) y ), -N(R y )C(=O)R x -P(=O)(R x (R) y -OR x -C(=O)R x -C(=O)-OR x -N(R) x (R) y ), 3-10 membered heterocyclic groups, C3-C8 cycloalkyl groups, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, nitro, C1-C3 alkyl or C1-C3 alkoxy; R 2 Selected from hydrogen, halogen, cyano, amino, hydroxyl, C1-C6 alkyl or C6-C 10 Aryl; wherein the C1-C6 alkyl or C6-C 10 The aryl group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C8 cycloalkyl, C6-C 10 Substitution of aryl or 5-14 heteroaryl groups; R 3 It does not exist, or is selected from hydrogen, C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 heteroaryl C1-C6 alkyl, (5-14 heteroaryl substituted C6-C 10 Aryl) C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C6-C 10 aryl carbonyl C1-C6 alkyl, C6-C 10 Arylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 aryl; wherein the C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 heteroaryl C1-C6 alkyl, (5-14 heteroaryl substituted C6-C 10 Aryl) C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C6-C 10 aryl carbonyl C1-C6 alkyl, C6-C 10 Arylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 Each aryl group is independently and optionally controlled by one or more R groups. a replace; R 4 Selected from hydrogen, C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 heteroaryl C1-C6 alkyl, (5-14 heteroaryl substituted C6-C 10 Aryl) C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C6-C 10 aryl carbonyl C1-C6 alkyl, C6-C 10 Arylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 aryl; wherein the C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl, C6-C 10 aryl carbonyl C1-C6 alkyl, C6-C 10 arylsulfonyl, 5-14 membered heteroarylsulfonyl, C3-C8 cycloalkylsulfonyl, (5-14 membered heteroaryl substituted C6-C 10 Aryl) C1-C6 alkyl, 3-10 heterocyclic sulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 Each aryl group is independently and optionally controlled by one or more R groups. a replace; Each R a They may be the same or different, and each is independently selected from halogen, cyano, benzyloxy, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -SR x -S(=O)R x -S(=O)2R x -S(=O)N(R) x (R) y -S(=O)2N(R) x (R) y ), -N(R y )S(=O)2R x -N(R) y )S(=O)R x , -C(=O)N(R x (R) y ), -N(R y )C(=O)R x -P(=O)(R x (R) y -OR x -C(O)R x -C(O)-OR x -N(R) x (R) y ), C3-C8 cycloalkyl, 3-12 membered heterocyclic, C6-C 10 Aryl, 5-14 heteroaryl, C6-C 10 Aryl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-12 membered heterocyclic C1-C6 alkyl, C6-C 10 Aryloxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl; wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-14 heteroaryl, C6-C 10 Aryl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-12 membered heterocyclic C1-C6 alkyl, C6-C 10 Each of the aryloxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl groups is independently and optionally substituted by one or more groups selected from halogen, cyano, hydroxy, amino, nitro, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkoxy groups. R x R y They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. The condition is that when W is N, Z is not S; and when R... 5 When it exists, Z is NR. 3 And R 3 It does not exist. According to claim 1, the compound or a pharmaceutically acceptable salt thereof, wherein W is C, Or Z is NR 3 ; Or at least one of Y, Z, and W is N or NR. 3 Preferably, one, two, or three of Y, Z, and W are N or NR. 3 More preferably, one or two of Y, Z, and W are N or NR. 3 ; Or, Y is CR 2 Z represents S, and W represents C; Alternatively, Y is N and Z is NR. 3 W is C; Or, Y is CR 2 Z is NR 3 W is C; Or, Y is CR 2 Z is CR 4 , W is N. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from C3-C8 cycloalkyl, 3-12 membered heterocyclic C1-C6 alkyl, or 3-12 membered heterocyclic, wherein R 6 Optionally by one or more R b replace; Preferably, R 6 The R group is selected from C3-C8 cycloalkyl, 3-8 member monocyclic heterocyclic, 6-10 member fused heterocyclic, 6-11 member spirocyclic, 5-12 member bridged heterocyclic, 3-8 member monocyclic heterocyclic C1-C6 alkyl, 6-10 member fused heterocyclic C1-C6 alkyl, 6-11 member spirocyclic C1-C6 alkyl, or 5-12 member bridged heterocyclic C1-C6 alkyl. 6 Optionally by one or more R b replace; More preferably, R 6 Selected from C3-C8 cycloalkyl, 3-8 member nitrogen-containing monocyclic heterocyclic group, 6-10 member nitrogen-containing fused heterocyclic group, 6-11 member nitrogen-containing spirocyclic group, 5-12 member nitrogen-containing bridged heterocyclic group, 3-8 member nitrogen-containing monocyclic heterocyclic group C1-C6 alkyl, 6-10 member nitrogen-containing fused heterocyclic group C1-C6 alkyl, 6-11 member nitrogen-containing spirocyclic group C1-C6 alkyl, or 5-12 member nitrogen-containing bridged heterocyclic group C1-C6 alkyl, wherein R 6 Optionally by one or more R b replace; More preferably, R 6 The R group is selected from C3-C8 cycloalkyl groups, 3-8 member nitrogen-containing monocyclic heterocyclic groups, 6-10 member nitrogen-containing fused heterocyclic groups, 6-11 member nitrogen-containing spirocyclic groups, or 5-12 member nitrogen-containing bridged heterocyclic groups. 6 Optionally by one or more R b replace; More preferably, R 6 Selected from C3-C8 cycloalkyl, 4-7 member nitrogen-containing monocyclic heterocyclic groups, 6-10 member nitrogen-containing fused heterocyclic groups, 6-9 member nitrogen-containing spirocyclic groups, or 6-9 member nitrogen-containing bridged heterocyclic groups, wherein R 6 Optionally by one or more R b replace; More preferably, R 6 Selected from 4-7 member nitrogen-containing monocyclic heterocyclic groups, wherein R 6 Optionally by one or more R b replace; More preferably, R 6 Selected from Or cyclohexyl, the R 6 Optionally by one or more R b replace; More preferably, R 6 Selected from Or cyclohexyl, the R 6 Optionally by one or more R b replace; More preferably, R 6 Optionally by 1, 2 or 3 R b replace; More preferably, R b They may be the same or different, and each is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, 3-10 membered heterocyclic amine, C3-C8 cycloalkylamine, C6-C 10 Arylamino, 5-14 membered heteroarylamino, aminoacyl, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 alkylamino, halo-C1-C6 alkylamino, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Aryl or 5-14 heteroaryl compounds. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein A is optionally surrounded by one, two or three Rs. e Substituted phenyl; Preferably, A is selected from the following group: Preferably, R e They may be the same or different, and each is independently selected from halogen, cyano, nitro, hydroxy, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylamino, aminoacyl, C1-C6 alkylaminoacyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 Aryl or 5-14 heteroaryl compounds. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C6-C 10 Aryl, 5-14 membered heteroaryl, 3-15 membered heterocyclic or C6-C 10 arylaminoyl, the R 1 Optionally by one or more R c replace; Preferably, R 1 Selected from C6-C 10 Aryl, 5-14 membered heteroaryl, 5-6 membered heterocyclic or C6-C 10 arylaminoyl, the R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from C6-C 10 Aryl or 5-14 heteroaryl, wherein R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from C6-C 10 aryl, 4-7 membered monocyclic heteroaryl, or 8-10 membered fused heteroaryl, wherein R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazolinone, benzodicyclopentyl, pyridinyltriazolone, pyridinone, oxadiazolone, pyridinylimidazolyl, imidazopyridyl, pyridopyridyl, pyridopyridyl, triazolopyridyl, benzopyrazolyl, benzimidazolone, benzopyrrole, indole, benzopyridyl, imidazolinyl, indoleone, phenylaminoyl, pyrrole, or naphthyl, wherein R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazolinone, benzodicyclopentyl, pyridinium triazolone, pyridinium imidazolyl, imidazopyridyl, pyridopyridyl, pyridopyrazolyl, triazolopyridyl, benzopyrazolyl, benzimidazolone, benzopyrroleyl, benzopyridyl, indoloneyl, pyrroleyl, or naphthyl, wherein R 1 Optionally by one or more R c replace; More preferably, R 1 The R group is selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazolidinonel, pyrazolopyridyl, pyridopyrazolyl, triazolopyridyl, benzopyrazolyl, benzimidazolonel, benzopyrroleyl, indoleonel, pyrroleyl, or naphthyl. 1 Optionally by one or more R c replace; More preferably, R 1 The R group is selected from phenyl, imidazolyl, pyrazolyl, benzimidazolyl, benzothiazolidinonel, pyrazolopyridyl, benzopyrazolyl, benzimidazolonel, benzopyrroleyl, pyrroleyl, or indolonel. 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl, The R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl, The R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl, The R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl, The R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl, The R 1 Optionally by one or more R c replace; More preferably, R 1 Selected from phenyl or The R 1 Optionally by one or more R c replace; More preferably, R 1 Optionally by 1, 2 or 3 R c replace; More preferably, R c The groups are either the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, aminoacyl, C1-C6 alkylaminoacyl, C3-C6 cycloalkyl or C1-C6 alkoxy-C(O)-; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 alkoxy-C(O)- is each optionally independently substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, nitro, C1-C3 alkyl or C1-C3 alkoxy. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R 3 It does not exist; Or, R 3 Selected from hydrogen, C1-C6 alkyl, C6-C 10 aryl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, 5-14 membered heteroaryl C1-C6 alkyl, 3-10 membered heterocyclic C1-C6 alkyl or C6-C 10 aryl carbonyl C1-C6 alkyl, wherein R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from hydrogen, C1-C6 alkyl, C6-C 10 Aryl C1-C6 alkyl, C3-C6 cycloalkyl C1-C6 alkyl, 5-9 membered heteroaryl C1-C6 alkyl, 3-8 membered monocyclic heterocyclic C1-C6 alkyl, 8-10 membered fused heterocyclic C1-C6 alkyl or C6-C 10 aryl carbonyl C1-C6 alkyl, wherein R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from hydrogen, C6-C 10 aryl C1-C6 alkyl, C3-C6 cycloalkyl C1-C6 alkyl, 5-6 membered heteroaryl C1-C6 alkyl, 3-8 membered monocyclic heterocyclic C1-C6 alkyl, or 8-10 membered fused heterocyclic C1-C6 alkyl, wherein R 3 Optionally by one or more R a replace; Preferably, R 3 For C6-C 10 aryl C1-C6 alkyl, 5-6-membered heteroaryl C1-C6 alkyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, C1-C6 alkyl, phenyl C1-C6 alkyl, cyclopropyl C1-C6 alkyl, pyrazolyl C1-C6 alkyl, triazolyl C1-C6 alkyl, pyrimidinyl C1-C6 alkyl, pyridinyl C1-C6 alkyl, dihydropyrrolizimidazolyl C1-C6 alkyl, benzoyl C1-C6 alkyl, benzimidazolone C1-C6 alkyl, imidazolyl C1-C6 alkyl, or oxadiazolyl C1-C6 alkyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, C1-C6 alkyl, phenyl C1-C6 alkyl, cyclopropyl C1-C6 alkyl, pyrazolyl C1-C6 alkyl, triazolyl C1-C6 alkyl, pyrimidinyl C1-C6 alkyl, pyridinyl C1-C6 alkyl, dihydropyrrolidinazole C1-C6 alkyl, or benzoyl C1-C6 alkyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 The R is selected from hydrogen, phenyl C1-C6 alkyl, pyrazolyl C1-C6 alkyl, triazolyl C1-C6 alkyl, pyrimidinyl C1-C6 alkyl, pyridinyl C1-C6 alkyl, dihydropyrrolidinazole C1-C6 alkyl, or benzoyl C1-C6 alkyl. 3 Optionally by one or more R a replace; More preferably, R 3 Selected from phenyl C1-C6 alkyl, pyrimidinyl C1-C6 alkyl, or pyridinyl C1-C6 alkyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl-CH2-, cyclopropane-CH2-, pyrazolyl-CH2-, phenyl-CH(CH3)-, cyclopropyl-CH(CH3)-, pyrazolyl-CH(CH3)-, triazolyl-(CH2)3-, pyrimidinyl-CH2-, pyrimidinyl-CH(CH3)-, pyridinyl-CH(CH3)-, imidazole-CH(CH3)-, oxadiazolyl-CH(CH3)-, dihydropyrroloimidazolyl-CH(CH3)-, phenyl-C(O)-CH2- or benzimidazolone-CH2-CH2-, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl-CH2-, cyclopropane-CH2-, pyrazolyl-CH2-, phenyl-CH(CH3)-, pyrazolyl-CH(CH3)-, triazolyl-(CH2)3-, pyrimidinyl-CH(CH3)-, pyridyl-CH(CH3)-, dihydropyrrolizimidazolyl-CH(CH3)-, or phenyl-C(O)-CH2-, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, phenyl-CH2-, phenyl-CH(CH3)-, pyrazolyl-CH2-, phenyl-CH(CH3)-, pyrazolyl-CH(CH3)-, triazolyl-(CH2)3-, pyrimidinyl-CH(CH3)-, pyridyl-CH(CH3)-, dihydropyrroloimidazoleyl-CH(CH3)- or phenyl-C(O)-CH2-, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from phenyl-CH(CH3)-, pyrimidinyl-CH(CH3)-, or pyridinyl-CH(CH3)-, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, methyl, ethyl, Cyclopropane-CH2- The R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, methyl, Cyclopropane-CH2- The R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from hydrogen, The R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from The R 3 Optionally by one or more R a replace; More preferably, R 3 Optionally by 1, 2 or 3 R a replace; More preferably, R a They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, carboxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl, 5-8 quinone heteroaryl, C6-C 10 aryl C1-C6 alkyl, 5-8 membered heteroaryl C1-C6 alkyl, 3-8 membered heterocyclic C1-C6 alkyl, or C3-C8 cycloalkyl C1-C6 alkyl; wherein the C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, or C6-C 10 Aryl, 5-8 quinone heteroaryl, C6-C 10 Each of the aryl C1-C6 alkyl, 5-8-membered heteroaryl C1-C6 alkyl, 3-8-membered heterocyclic C1-C6 alkyl, or C3-C8 cycloalkyl C1-C6 alkyl groups is independently and optionally substituted by one or more groups selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, or haloC1-C6 alkoxy groups; Or, R 3 Selected from C6-C 10 arylsulfonyl, 5-14 heteroarylsulfonyl, (5-14 heteroaryl substituted C6-C) 10 aryl)sulfonyl, C3-C8 cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C1-C6 alkylsulfonyl or C1-C6 alkylaminosulfonyl, wherein R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from C6-C 10 arylsulfonyl, 4-7 membered monocyclic heteroarylsulfonyl, 6-10 membered fused heteroarylsulfonyl, (4-7 membered monocyclic heteroaryl substituted C6-C) 10 (aryl)sulfonyl, (6-10 fused aryl-substituted C6-C) 10 Aryl)sulfonyl, C3-C6 cycloalkylsulfonyl, 3-8 member monocyclic heterocyclic sulfonyl, 5-10 member fused heterocyclic sulfonyl, C1-C4 alkylsulfonyl or C1-C4 alkylaminosulfonyl, wherein R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from C6-C 10 arylsulfonyl, 5-6 membered monocyclic heteroarylsulfonyl, 8-10 membered fused heteroarylsulfonyl, (5-6 membered monocyclic heteroaryl substituted C6-C) 10 Aryl)sulfonyl, C3-C6 cycloalkylsulfonyl, 3-6 membered monocyclic heterocyclic sulfonyl, 8-10 membered fused heterocyclic sulfonyl, C1-C4 alkylsulfonyl or C1-C4 alkylaminosulfonyl, wherein R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from C6-C 10 arylsulfonyl, 5-6 membered monocyclic heteroarylsulfonyl, 8-10 membered fused heteroarylsulfonyl, (5-6 membered monocyclic heteroaryl substituted C6-C) 10 Aryl)sulfonyl, C3-C6 cycloalkylsulfonyl, 3-6 member monocyclic heterocyclic sulfonyl or 8-10 member fused heterocyclic sulfonyl, wherein R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from C6-C 10 arylsulfonyl, (5-6 membered monocyclic heteroaryl substituted C6-C) 10 aryl)sulfonyl or 5-6 membered monocyclic heteroarylsulfonyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 The R group is selected from phenylsulfonyl, pyrazolyl-substituted phenylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, pyridylsulfonyl, furanylsulfonyl, thiopheneylsulfonyl, pyrrololylsulfonyl, triazolylsulfonyl, benzothiopheneylsulfonyl, isoxazolylsulfonyl, dihydropyrroloimidazolylsulfonyl, cyclopropylsulfonyl, methylsulfonyl, or dimethylaminosulfonyl. 3 Optionally by one or more R a replace; More preferably, R 3 The R group is selected from phenylsulfonyl, pyrazolyl-substituted phenylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, pyridylsulfonyl, furanylsulfonyl, thienylsulfonyl, pyrrololylsulfonyl, triazolylsulfonyl, benzothienylsulfonyl, benzofuranylsulfonyl, dihydropyrroloimidazolylsulfonyl, cyclopropylsulfonyl, or dimethylaminosulfonyl. 3 Optionally by one or more R a replace; More preferably, R 3 The R group is selected from phenylsulfonyl, pyrazolyl-substituted phenylsulfonyl, thiazolylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridylsulfonyl, furanylsulfonyl, thiopheneylsulfonyl, pyrrololylsulfonyl, triazolylsulfonyl, benzothiopheneylsulfonyl, benzofuranylsulfonyl, or dihydropyrroloimidazolylsulfonyl, 3 Optionally by one or more R a replace; More preferably, R 3 The R group is selected from phenylsulfonyl, pyrazolyl-substituted phenylsulfonyl, thiazolylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridylsulfonyl, furanylsulfonyl, pyrroleylsulfonyl, or triazolylsulfonyl, wherein the R group is... 3 Optionally by one or more R a replace; More preferably, R 3 Selected from the following groups: Cyclopropylsulfonyl, methylsulfonyl, or dimethylaminosulfonyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from the following groups: Cyclopropylsulfonyl or dimethylaminosulfonyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from the following groups: The R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from the following groups: The R 3 Optionally by one or more R a replace; More preferably, R a The group is selected from halogen, cyano, hydroxy, amino, nitro, carboxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl, wherein each of the C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl groups is independently and optionally substituted by one or more groups selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkoxy; Or, R 3 Selected from C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C6-C 10 Aryl, the R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 3-7 member monocyclic heterocyclic, 7-10 member fused heterocyclic, 5-7 member monocyclic heteroaryl, 8-10 member fused heteroaryl or C6-C 10 Aryl, the R 3 Optionally by one or more R a replace; Preferably, R 3 Selected from C1-C6 alkyl-C(O)-NH-NH-C(O)-, C3-C 10 Cycloalkyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, benzo5-6-membered heteroaryl, 5-6-membered heteroaryl-5-6-membered heteroaryl or C6-C 10 Aryl, the R 3 Optionally by one or more R a replace; More preferably, R 3 The R is selected from phenyl, cyclopropane, cyclobutane, CH3-C(O)-NH-NH-C(O)-, indanyl, tetrahydroindolyl, 1,4,5,6-tetrahydrocyclopentadienylpyrazolyl, oxacyclobutane, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, triazolyl, thiazolyl, α-pyridoneyl, β-pyridoneyl, γ-pyridoneyl, benzopyrazolyl, or pyrazolopyridinyl. 3 Optionally by one or more R a replace; More preferably, R 3 The R group is selected from cyclopropane, cyclobutane, CH3-C(O)-NH-NH-C(O)-, indanyl, tetrahydroindolyl, oxacyclobutane, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, thiazolyl, or benzopyrazolyl, wherein the R group is selected from cyclopropane, cyclobutane, CH3-C(O)-NH-NH-C(O)-, indaneyl, tetrahydroindolyl, oxacyclobutane, oxacyclobutane, thiazolyl, or benzopyrazolyl. 3 Optionally by one or more R a replace; More preferably, R 3 Selected from CH3-C(O)-NH-NH-C(O)-, indanyl, tetrahydroindolyl, pyrazolyl, triazolyl, thiazolyl, or benzopyrazolyl, wherein R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from the following groups: phenyl, cyclopropane, cyclobutane, CH3-C(O)-NH-NH-C(O)-, The R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from the following groups: cyclopropane, cyclobutane, CH3-C(O)-NH-NH-C(O)-, The R 3 Optionally by one or more R a replace; More preferably, R 3 Selected from the following group: CH3-C(O)-NH-NH-C(O)-, The R 3 Optionally by one or more R a replace; More preferably, R a The group is selected from halogen, cyano, hydroxy, amino, benzyloxy, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group or C1-C6 alkylamide group; each of the C3-C6 cycloalkyl or 3-6 membered heterocyclic group is optionally substituted independently by one or more groups selected from halogen, cyano, hydroxy, amino, nitro, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from 5-7-membered heteroarylsulfonyl or C6-C 10 arylsulfonyl, the R 4 Optionally by one or more R a replace; Preferably, R 4 Selected from pyrazole sulfonyl or phenyl sulfonyl, wherein R 4 Optionally by one or more R a replace; More preferably, R 4 Selected from The R 4 Optionally by one or more R a replace; More preferably, R 4 Optionally by 1, 2 or 3 R a replace; More preferably, the R a Selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkoxy; Preferably, R a It is selected from halogen, cyano, hydroxy, amino, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein the compound is as shown in formula I-1: in, R 1 Y, Z, B, A, R 6 R 7 Each customization is as described in Equation I; Alternatively, the compound may be represented as shown in Formula I-2: Where Z is CR 4 Or N; R 1 Y, R 4 B, A, R 6 R 7 Each customization is as described in Equation I; Alternatively, the compound may be represented as shown in Formula II-1: Among them, R 1 R 2 R 3 A, R 7 R x R y Each custom expression is as described in Equation I, and R 3 It cannot be non-existent; R 10 R 11 Each group is independently selected from hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; each of the C1-C6 alkyl or C3-C8 cycloalkyl groups is optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, or C1-C6 alkyl. R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h They may be the same or different, and each is independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amino C1-C6 alkyl, nitro, hydroxy C1-C6 alkyl, -SR x -S(=O)R x -S(=O)2R x -S(=O)N(R) x (R) y -S(=O)2N(R) x (R) y ), -N(R y )S(=O)2R x -N(R) y )S(=O)R x , -C(=O)N(R x (R) y ), -N(R y )C(=O)R x -P(=O)(R x (R) y -OR x -C(=O)R x -C(=O)-OR x -N(R) x (R) y ), 3-10 membered heterocyclic groups, C6-C 10 Aryl, 5-14 membered heteroaryl or C3-C6 cycloalkyl; R 8 Selected from H or C1-C6 alkyl groups; Or R 9a and R 9e Together with the attached carbon atom, they form a bridge; or R 9a and R 9g Together with the attached carbon atom, they form a bridge; or R 9c and R 9e Together with the attached carbon atom, they form a bridge; or R 9c and R 9g Together with the attached carbon atom, they form a bridge; the bridge has one, two, three, or four CH2 atoms, any one of which may be optionally replaced by O, S, or NH; the bridge may optionally be connected by one or more R atoms. f replace; Or R 9a and R 9b With the attached carbon atom, or R 9c and R 9d With the attached carbon atom, or R 9e and R 9f With the attached carbon atom or R 9g and R 9h Together with the attached carbon atom, it forms a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R... f replace; Or R 9a and R 11 With the attached atom or R 9h and R 10 Together with the attached atoms, they form a 4-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; Or R 9a and R 8 With the attached atom or R 9h and R 8 Together with the attached atoms, it forms a 3-8 membered cycloalkyl or 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R f replace; Or R 8 and R 11 Together with the attached atoms, they form a 3-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; Each R f They may be the same or different, and each is independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, aminoacyl, carboxyl, nitro, hydroxy, hydroxy C1-C6 alkyl or amino C1-C6 alkyl. Alternatively, the compound may be represented as shown in Formula II-2: Among them, R 8 R 10 R 11 R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h Each custom expression is as described in Equation II-1; R 1 R 2 R 4 A, R 7 The definition is as described in Equation I; Preferably, the Selected from Among them, R 8 R 10 R 11 Each definition is as described in Equation II-1; Alternatively, the compound may be as shown in formula (III): Wherein, the R 1 Selected from phenyl, The R 1 Optionally by one or more R c replace; n is 0, 1, 2, 3, 4, or 5; the R c R e R 3 Each definition is as described in Equation II-1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: Preferably, the compound or a pharmaceutically acceptable salt thereof is: A pharmaceutical composition comprising the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 10 in the preparation of a medicament for treating and / or preventing SSTR2-related diseases. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10, is used for the treatment and / or prevention of SSTR2-related diseases, preferably selected from peptic ulcer bleeding or acute pancreatitis. A method for treating and / or preventing SSTR2-related diseases, the method comprising administering to a desired patient a therapeutically effective amount of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or administering to a desired patient a therapeutically effective amount of the pharmaceutical composition of claim 10.

Images