ROCK inhibitors, their production methods and uses

Abstract

The present invention relates to a ROCK inhibitor represented by formula (I), and its preparation method and use. It has excellent ROCK inhibitory activity, particularly exhibits relatively good selective inhibition of ROCK2 kinase, and has relatively good safety and metabolic stability, and high bioavailability. Its preparation method is simple and it is easy to purify, so it has good application prospects. [Formula 1] JPEG2023534259000170.jpg25169

Description

Detailed Description of the Invention

[0001] This application claims priority to two prior applications entitled "ROCK inhibitors and their preparation and use," filed with the State Intellectual Property Office of China on July 14, 2020, and January 11, 2021, bearing application numbers 202010676711.6 and 202110040185.9, respectively. The entire contents of these two prior applications are incorporated herein by reference.

[0002] [Technical Field] The present invention relates to the field of pharmaceutical technology, particularly to a ROCK inhibitor and its preparation method and use.

[0003] [Background technology] Idiopathic interstitial pulmonary fibrosis (IPF) is a chronic, diffuse interstitial lung disease of unknown etiology that evolves from common interstitial pneumonia, although histopathological and radiological findings often resemble common interstitial pneumonia. Due to its complex pathogenesis and irreversible progression, early diagnosis is difficult. Even once diagnosed, patient survival rates decline significantly over time, with a 3-year survival rate of 50% and a 5-year survival rate of only 20%, lower than the survival rates of many cancers (e.g., leukemia, breast cancer, colon cancer, uterine tumors, renal cancer, etc.). IPF has often been referred to as a "cancer that isn't cancer." Currently, there are no proven, highly effective treatments for IPF. Recent randomized controlled clinical trials have shown that drugs such as pirfenidone and nintedanib are suitable for use in accordance with the current clinical situation in China. However, treatment with nintedanib is only recommended for IPF patients with mild to moderate pulmonary dysfunction. Further study is needed to determine whether nintedanib is effective in treating IPF patients with severe pulmonary dysfunction, as well as the course of drug administration.

[0004] Rho GTPases, discovered in 1985, belong to the Ras superfamily and share 25% homology with Ras. The Rho GTPases currently found in mammalian histiocytes include Rho (A, B, C), Rac (1, 2, 3), Cdc42 (Cdc42Hs / G25K, TC10, Tcl), Rho D, Rho G, Chp (1, 2), Rnd (Rho E / Rnd3, Rnd1 / Rho6, Rnd2 / Rho7), Rho H / TTF, Rif, Wrch1, and Rho BTB (1, 2). Among these, Rho (A, B, C) is one of the most prominent members of the Rho GTPase family. ROCK (Rho-associated protein kinase), also known as Rho kinase, is a serine / threonine protein kinase with a molecular weight of approximately 160 kD. It is the downstream target effector molecule of Rho, the function of which has been most thoroughly characterized. ROCK includes subtypes ROCK1 (ROKβ, p160-ROCK) and ROCK2 (ROKα). The two subtypes share 65% amino acid sequence identity and high similarity in their kinase domains (92% identity). ROCK is distributed throughout the body; ROCK1 is more highly expressed in non-neuronal tissues (blood, small intestine, thymus, etc.), whereas ROCK2 is more highly expressed in the brain, heart, and colon.

[0005] ROCK is involved in the development of various cardiovascular and cerebrovascular diseases, including hypertension, atherosclerosis, ischemic stroke, heart disease, diabetic nephropathy, eye diseases, tumors, nerve damage diseases, radiation injury, and autoimmune diseases. For example, the Rho / ROCK signaling pathway is involved in the activation of NAD(P)H oxidase, inducing oxidative stress, cardiac microvascular injury, and C-reactive protein-induced atherosclerotic thrombosis; high glucose activation of the Rho / ROCK pathway induces the expression of visfatin and type I procollagen in cardiac fibroblasts, leading to their hyperproliferation and diabetic cardiomyopathy; activation of the Rho / ROCK signaling pathway regulates the NF-κB signaling pathway, upregulating inflammatory genes and inducing the development of diabetic nephropathy; the Rho / ROCK signaling pathway affects cancer cell metastasis by altering membrane permeability; and spinal cord injury, inducing Rho activation, induces growth cone atrophy, impairing axon regeneration, and inducing the inhibitory effect of chondroitin sulfate proteoglycans on neuronal growth.

[0006] The Rho / ROCK signaling pathway is also involved in the initiation and development of fibrosis. Activation of the Rho / ROCK signaling pathway can enhance the severity of ischemic myocardial fibrosis, and Rho and ROCK expression is significantly elevated in cardiac tissue from rats with acute myocardial fibrosis. Activation of the Rho / ROCK signaling pathway can induce actin phosphorylation and lead to cellular fibrosis. Both in vivo and in vitro experimental results demonstrate that physiological and pathological cardiopulmonary damage caused by long-term radiation exposure is linked to fibrosis mediated by the Rho / ROCK pathway. Ionizing radiation-induced endothelial adhesion fibronectin and focal adhesion formation, reduced endothelial cell migration, and endothelial dysfunction are linked to actin cytoskeleton reorganization and stress fiber formation induced by activation of the Rho / ROCK signaling pathway.

[0007] Lung injury in IPF primarily targets alveolar epithelial cells (ACEs), whose death triggers wound-healing responses, including activation of innate immunity, vascular leakage and extravascular coagulation, fibroblast recruitment, proliferation, and activation, extracellular matrix synthesis and cross-linking, alveolar collapse, and epithelial cell regeneration. ROCK signaling can fundamentally regulate the behavior of these cells, particularly epithelial cells, endothelial cells, and fibroblasts, involved in the healing response. The pivotal role of ROCK in these responses further suggests the potential for the treatment of pulmonary fibrosis with ROCK inhibitors.

[0008] Currently, no drugs are commercially available that treat many diseases, including fibrosis, via the ROCK inhibitory pathway. The development of new drugs requires the thorough optimization of the chemical and biological properties of lead compounds. Furthermore, the compounds must possess desirable pharmacokinetic and pharmacodynamic characteristics. This painstaking development process typically requires extensive testing. The process of identifying the optimal compound often requires the preparation of thousands of structurally similar compounds. Therefore, improving ROCK kinase inhibitors and developing new scaffolds with ROCK1 and / or ROCK2 kinase inhibitory activity is of positive significance for the treatment of the above diseases.

[0009] Summary of the Invention In order to overcome the problems in the prior art, the present invention provides a compound represented by the following formula (I), a racemate, a stereoisomer, a tautomer, an isotope-labeled compound, a nitrogen oxide, a solvate, a crystalline polymorph, a metabolite, an ester, a pharmaceutically acceptable salt, or a prodrug thereof:

[0010] [ka]

[0011] Among them, Ring A is the following group: a 3- to 20-membered heterocyclyl group, or a 5- to 20-membered heteroaryl group, unsubstituted or optionally substituted with one, two or more Rc; Ring B may be any of the following groups: C, unsubstituted or optionally substituted with one, two or more Rd: 3-20 Cycloalkyl groups, 3-20 membered heterocyclyl groups, C 6-20 an aryl group, or a 5- to 20-membered heteroaryl group; The ring A and the ring B form a parallel ring with W and V as connecting sites; Rc and Rd are the same or different and are selected from the group consisting of halogen, amino, hydroxyl, formyl, unsubstituted or optionally substituted with one, two or more Rs groups: 1-20 Alkyl group, C 1-20 are independently selected from alkoxy groups; W and V are each independently C or N, and W and V are not both N; X is -C(=O)-; Y is OH, chemical bond, C 1-20 Alkoxy group, C 1-20 Alkyl group, -NH- or -N(C 1-20 alkyl group)-, -NH(C 1-20 alkyl group), -NH(C 1-20 alkoxy group); 1-20 Alkoxy group, C 1-20 Alkyl groups and -N(C 1-20 alkyl group)-, -NH(C 1-20 alkyl group), -NH(C 1-20 C in "alkoxy group" 1-20 Alkoxy group, C 1-20 The alkyl group may be unsubstituted or optionally substituted with one, two or more Rs;

[0012] [ka]

[0013] may or may not be present; However, Y is OH, C 1-20 Alkoxy group, C 1-20 Alkyl group, -NH(C 1-20 alkyl group), -NH(C 1-20alkoxy group),

[0014] [ka]

[0015] does not exist; If Y is a chemical bond,

[0016] [ka]

[0017] is unsubstituted or optionally substituted by one, two or more Ra groups: a 3- to 20-membered heterocyclyl group, a 5- to 20-membered heteroaryl group, C 3-20 Cycloalkyl group, or C 6-20 selected from aryl groups; Y is -NH- or -N(C 1-20 alkyl group)-,

[0018] [ka]

[0019] is unsubstituted or optionally substituted by one, two or more Rb groups: 1-20 Alkyl group, 3-20 membered heterocyclyl group, 5-20 membered heteroaryl group, C 3-20 Cycloalkyl group, or C 6-20 selected from aryl groups; The Ra and Rb may be the same or different and may be halogen, CN, or C1- unsubstituted or optionally substituted with one, two or more Rs. 20 independently selected from an alkyl group, OH, a 5- to 20-membered heteroaryl group, and a halogenated 5- to 20-membered heteroaryl group; Ring D is a group selected from the group: C, unsubstituted or optionally substituted with one, two or more Re. 3-20 Cycloalkyl groups, 3-20 membered heterocyclyl groups, C 6-20an aryl group or a 5- to 20-membered heteroaryl group, and said ring A is connected to ring D via an N atom; Re is selected from the group consisting of halogen, CN, OH, unsubstituted or optionally substituted with one, two or more Rs: 1-20 Alkyl group, C 3-20 Cycloalkyl groups, C 1-20 Alkoxy group, C 6-20 selected from an aryl group, a 3- to 20-membered heterocyclyl group, or a 5- to 20-membered heteroaryl group; Or when there are at least two Re substitutions in ring D, the two adjacent Re are C together with the D ring atoms of the connecting chain. 3-20 form a cycloalkyl group or a 3- to 20-membered heterocyclyl group or a 3- to 20-membered heteroaryl group; The Rs is a halogen, CN, OH, C 1-20 Alkyl group, C 1-20 Alkoxy group, C 6-20 It is selected from an aryl group or a 5- to 20-membered heteroaryl group.

[0020] Z is -NH-; Ring E may be any of the following groups: C, unsubstituted or optionally substituted with one, two or more Rf groups: 6-20 an aryl group, or a 5- to 20-membered heteroaryl group; Rf is halogen, CN, OH, or one of the following groups: C1-C, unsubstituted or optionally substituted with one, two or more Rg groups: 20 Alkyl group, C 6-20 selected from an aryl group, or a 5- to 20-membered heteroaryl group; Rg is a halogen, CN, OH, C1-C optionally substituted with one, two or more halogens. 20 It is selected from an alkyl group, an -O-5-20 membered heteroaryl group, said -O-5-20 membered heteroaryl group being optionally substituted with -C(O)-NH2.

[0021] According to an embodiment of the present invention, W is selected from N or C; V is selected from C; X is -C(=O)-; Y is OH, chemical bond, C 1-6 Alkoxy group, C 1-6 Alkyl group, -NH- or -N(C 1-6 alkyl group)-, -NH(C 1-6 alkyl group), -NH(C 1-6 alkoxy group); 1-6 Alkoxy group, C 1-6 Alkyl groups and -N(C 1-6 alkyl group)-, -NH(C 1-6 alkyl group), -NH(C 1-6 C in "alkoxy group" 1-6 Alkoxy group, C 1-6 The alkyl group may be unsubstituted or optionally substituted with one, two or more Rs; The Rs is a halogen, CN, OH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-12 It is selected from an aryl group or a 5-12 membered heteroaryl group.

[0022] According to an embodiment of the present invention, If Y is a chemical bond,

[0023] [ka]

[0024] is selected from the following groups: a 3- to 6-membered heterocyclyl group or a 5- to 12-membered heteroaryl group, unsubstituted or optionally substituted with one, two or more Ra; wherein Ra is F, Cl, CN, OH or C optionally substituted with one, two or more halogens. 1-6 selected from alkyl groups; Y is -NH- or -N(C 1-6 alkyl group)-,

[0025] [ka]

[0026] is the following group unsubstituted or optionally substituted with one, two or more Rb: 3-6 Cycloalkyl groups, C 1-6 selected from an alkyl group, a 3- to 6-membered heterocyclyl group, or a 5- to 12-membered heteroaryl group; Rb is selected from F, Cl, CN, OH, F- or Cl-substituted 5-12 membered heteroaryl groups; In one embodiment, when Y is a chemical bond, said X is

[0027] [ka]

[0028] connected to a heteroatom of a 3-6 membered heterocyclyl group represented by Ring A is the following group: a 3- to 6-membered heterocyclyl group, or a 5- to 12-membered heteroaryl group, unsubstituted or optionally substituted with one, two or more Rc; Ring B may be any of the following groups: a 3- to 6-membered heterocyclyl group, C 6-12 an aryl group or a 5-12 membered heteroaryl group; The ring A and the ring B form a parallel ring with the W and the V as connecting sites; Rc and Rd are the same or different and may be F, Cl, an amino group, a hydroxyl group, a formyl group, or C 1-6 alkyl groups, 1-6 The alkyl group is unsubstituted or optionally substituted with one, two or more halogens; The ring D may be any of the following groups: C, unsubstituted or optionally substituted with one, two or more Re. 6-12 an aryl group or a 5-12 membered heteroaryl group, and said ring A is connected to ring D via an N atom; Re is selected from the group consisting of halogen, CN, OH, unsubstituted or optionally substituted with one, two or more Rs: 1-6 Alkyl group, C 3-6Cycloalkyl groups, C 1-6 Alkoxy group, C 6-12 selected from an aryl group, a 3- to 6-membered heterocyclyl group, or a 5- to 12-membered heteroaryl group; Or when there are at least two Re substitutions in ring D, the two adjacent Re are C together with the D ring atoms of the connecting chain. 3-6 form a cycloalkyl group or a 3- to 6-membered heterocyclyl group or a 5- to 12-membered heteroaryl group; The Rs is a halogen, CN, OH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-12 selected from an aryl group or a 5-12 membered heteroaryl group; Z is -NH-; The ring E is unsubstituted or optionally substituted with one, two or more Rf. 6-12 an aryl group, or a 5-12 membered heteroaryl group; Rf is F, Cl, or the following group unsubstituted or optionally substituted with one, two or more Rg: 6-12 selected from an aryl group, or a 5-12 membered heteroaryl group; Rg is selected from F, Cl, -O-5-12 membered heteroaryl group, said -O-5-12 membered heteroaryl group optionally substituted with -C(O)-NH2.

[0029] According to a preferred embodiment of the present invention, W is selected from N or C; V is selected from C; X is -C(=O)-; Y is OH, a chemical bond, -NH- or -N(methyl)-, provided that when Y is OH:

[0030] [ka]

[0031] does not exist; If Y is a chemical bond,

[0032] [ka]

[0033] is selected from the following groups: azetidine unsubstituted or substituted with one, two or more F; azetidine unsubstituted or substituted with one, two or more CN; azetidine unsubstituted or substituted with one, two or more CF2; azetidine unsubstituted or substituted with one, two or more CF3; azacyclopentane unsubstituted or substituted with F and / or OH; When Y is -NH- or -N(methyl)-,

[0034] [ka]

[0035] is selected from the following groups: cyclobutane unsubstituted or substituted with one, two or more F; isopropyl; pyridazinyl; azetidine unsubstituted or substituted with one, two or more CN; azacyclopentane substituted with F and / or OH; ethyl unsubstituted or substituted with one, two or more F; -N-chloropyridine-piperidinyl; pyridinyl unsubstituted or substituted with one, two or more F; In one embodiment, when Y is a chemical bond, said X is

[0036] [ka]

[0037] connected to a heteroatom of a heterocyclyl group represented by: In one embodiment,

[0038] [ka]

[0039] is absent, Y is a methyl group, an ethyl group, a propyl group, a butyl group, -CH2CF3, -NH-CH2CF3, -NHCH2(CH2)2, -OCH2CF3, -OCH2CH3; According to an embodiment of the present invention, the rings A and B form the following parallel rings:

[0040] [ka]

[0041] According to an embodiment of the present invention, the ring D is selected from the group below, unsubstituted or optionally substituted with one, two or more Re:

[0042] [ka]

[0043] is; where Re is as defined above.

[0044] The ring D may further include

[0045] [ka]

[0046] can be chosen from; According to an embodiment of the present invention, Z is -NH-; According to an embodiment of the present invention, The ring E is

[0047] [ka]

[0048] is; According to an embodiment of the present invention,

[0049] [ka]

[0050] is selected from the following structures:

[0051] [ka]

[0052] According to an embodiment of the present invention, the Re is selected from halogen, CF3, CN, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CHF2, CNCH2-, propylene oxide, oxetane, and oxolane; or, when there are at least two Re substitutions in the ring D, two adjacent Re are C together with the D ring atom of the connecting chain. 5-6 forming a cycloalkyl group or a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, such as a cyclopentane group, an oxolane group, an oxacyclohexane group, or a pyrrolyl group; In some embodiments, the present invention provides a compound represented by the following formula (II), a racemate, stereoisomer, tautomer, isotopically labeled form, nitroxide, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof:

[0053] [ka]

[0054] wherein W is selected from N or C; Double lines, including solid and dashed lines, represent single or double bonds; X1, X3, and X5 are each independently selected from N or C, and X1, X3, and X5 are not simultaneously N; X2, X4 are selected from C or a chemical bond; X3 is selected from N or C; Y1 is selected from N, O or S; Y2 is selected from C, N or a chemical bond; Y3 is selected from N or C; Y2 and Y3 cannot be N at the same time; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; The remaining groups are as defined above.

[0055] In some embodiments, the present invention provides a compound represented by the following formula (III), a racemate, stereoisomer, tautomer, isotopically labeled compound, nitroxide, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof:

[0056] [ka]

[0057] wherein W is selected from N or C; Double lines, including solid and dashed lines, represent single or double bonds; Y2 and Y3 are each independently C or N, and Y2 and Y3 are not both N; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; The remaining groups are as defined above.

[0058] In some embodiments, the present invention provides a compound represented by the following formula (IV), a racemate, stereoisomer, tautomer, isotopically labeled form, nitroxide, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof:

[0059] [ka]

[0060] wherein W is selected from N or C; Y2 is selected from N or C; Double lines, including solid and dashed lines, represent single or double bonds; Y is a chemical bond, -NH- or -N(C 1-6 alkyl group)-, -NH(C 1-6 alkyl group); The above “-N(C 1-6 alkyl group)-, -NH(C 1-6 C in "Alkyl group" 1-6 Alkyl The group is unsubstituted or optionally substituted with one, two or more halogens; If Y is a chemical bond,

[0061] [ka]

[0062] is the group:

[0063] [ka]

[0064] Selected from; Y is -NH- or -N(C 1-6 alkyl group)-,

[0065] [ka]

[0066] is the group:

[0067] [ka]

[0068] Selected from; Y is -N H (C 1-6 alkyl group),

[0069] [ka]

[0070] does not exist; The Rc and Rd are the same or different, and C 1-6 are independently selected from alkyl groups; Re is selected from the group consisting of halogen, CN, OH, unsubstituted or optionally substituted with one, two or more Rs: 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 6-12 selected from an aryl group, a 3- to 6-membered heterocyclyl group, or a 5- to 12-membered heteroaryl group; Or, when there are at least two Re, the two adjacent Re are C together with the ring atoms of the bonding chain. 3-6 form a cycloalkyl group or a 3- to 6-membered heterocyclyl group or a 5- to 12-membered heteroaryl group; The Rs is a halogen, CN, OH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-12 It is selected from an aryl group or a 5-12 membered heteroaryl group.

[0071] Rf 1 , Rf 2 are identical or different and are independently selected from Rf as defined above, preferably independently selected from halogen, CN, OH; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q' is independently 0, 1 or 2 at each occurrence.

[0072] In some embodiments, the present invention provides a compound, its racemate, stereoisomer, tautomer, isotopically labeled form, nitroxide, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof, of which

[0073] [ka]

[0074] is preferably the following group:

[0075] [ka]

[0076] is.

[0077] In some embodiments, the present invention provides a compound represented by the following formula (V), a racemate, stereoisomer, tautomer, isotopically labeled form, nitroxide, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof:

[0078] [ka]

[0079] Among them,

[0080] [ka]

[0081] is the group:

[0082] [ka]

[0083] Selected from; Rc and Rd are homologous or different, C 1-6are independently selected from alkyl groups; Re is selected from the group consisting of halogen, CN, OH, unsubstituted or optionally substituted with one, two or more Rs: 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 6-12 selected from an aryl group, a 3- to 6-membered heterocyclyl group, or a 5- to 12-membered heteroaryl group; Or when there are at least two Re, the two adjacent Re are C together with the ring atoms of the bonding chain. 3-6 form a cycloalkyl group or a 3- to 6-membered heterocyclyl group or a 5- to 12-membered heteroaryl group; The Rs is a halogen, CN, OH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-12 It is selected from an aryl group or a 5-12 membered heteroaryl group.

[0084] Rf 1 , Rf 2 are identical or different and are independently selected from Rf as defined above, preferably independently selected from halogen, CN, OH; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q' is independently 0, 1 or 2 at each occurrence.

[0085] According to a preferred embodiment of the present invention, In formula (I),

[0086] [ka]

[0087] is selected from the following structures:

[0088] [ka]

[0089] X is -C(=O)-; If Y is a chemical bond,

[0090] [ka]

[0091] is the group:

[0092] [ka]

[0093] Selected from; Y is -NH- or -N(C 1-20 alkyl group)-,

[0094] [ka]

[0095] is selected from the group:

[0096] [ka]

[0097] or

[0098] [ka]

[0099] is absent, then Y is -NH-CH2CF3; Ring D is selected from the following structures:

[0100] [ka]

[0101] Z is -NH-; Ring E is selected from the following structures:

[0102] [ka]

[0103] According to a preferred embodiment of the present invention, In formula (I),

[0104] [ka]

[0105] is selected from the following structures:

[0106] [ka]

[0107] X is -C(=O)-; If Y is a chemical bond,

[0108] [ka]

[0109] is the group:

[0110] [ka]

[0111] Selected from Y is -NH- or -N(C 1-20 alkyl group)-,

[0112] [ka]

[0113] is selected from the group:

[0114] [ka]

[0115] or

[0116] [ka]

[0117] is absent, then Y is -OCH2CF3; Ring D is selected from the following structures:

[0118] [ka]

[0119] Z is -NH-; Ring E is selected from the following structures:

[0120] [ka]

[0121] As an example, in the compound represented by the formula (I), its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, the compound of formula (I) may be selected from the following structures:

[0122] [Table 1] JPEG0007772771000052.jpg229169JPEG0007772771000053.jpg192169JPEG0007772771000054.jpg223169 JPEG0007772771000055.jpg216169JPEG0007772771000056.jpg229169JPEG0007772771000057.jpg229169 JPEG0007772771000058.jpg190169JPEG0007772771000059.jpg190169JPEG0007772771000060.jpg190169 JPEG0007772771000061.jpg229169JPEG0007772771000062.jpg223169JPEG0007772771000063.jpg177169

[0123] The present invention further provides a method for preparing a compound of formula (I), comprising at least one of the following aspects:

[0124] [ka]

[0125] A compound represented by formula (I-1) is reacted with a compound represented by formula (I-2) to obtain a compound represented by formula (I); Among them, ring A, ring B, ring D,

[0126] [ka]

[0127] Rings E, W, V, X, Y, and Z have the above definitions; L is selected from leaving groups such as halogens.

[0128] The present invention further provides intermediate compounds for producing the compounds of formula (I) of the present invention, including formula (I-1), formula (I-2), and the like.

[0129] In a preferred embodiment, formula (I-1) is selected from the following structures:

[0130] [ka]

[0131] Formula (I-2) is selected from the following structures:

[0132] [ka]

[0133] wherein each group is as defined above.

[0134] More preferably, the formula (I-1) is selected from the following structures:

[0135] [ka]

[0136] More preferably, the formula (I-2) can be selected from the following structures:

[0137] [ka]

[0138] In some embodiments, the present invention further provides an intermediate compound for preparing a compound of formula (I) of the present invention, the intermediate being:

[0139] [ka]

[0140] can be selected from.

[0141] It should be understood by those skilled in the art that the compound of formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, or isotopically labeled compound can be used as a raw material or intermediate to prepare a prodrug or pharmaceutically acceptable salt of the compound of formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, or isotopically labeled compound. Thus, the present invention further provides the use of the compound of formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, or isotopically labeled compound in the preparation of a prodrug or pharmaceutically acceptable salt of the compound of formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, or isotopically labeled compound.

[0142] The present invention further provides the following compounds:

[0143] [ka]

[0144] The present invention further provides the use of at least one of the compounds of formula (I), a racemate, stereoisomer, tautomer, nitroxide, isotopically labeled form, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof, in the manufacture of a pharmaceutical agent that is an inhibitor of protein kinase.

[0145] In particular, said pharmaceutical agent has the function of modulating Rho-kinase.

[0146] The pharmaceutical preparation can be used for the prevention or treatment of one or more diseases caused by overexpression or overactivation of ROCK, such as cardiovascular and cerebrovascular diseases, nervous system diseases, fibrosis, eye diseases, tumors, arterial thrombosis, radiation injury, respiratory diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte accumulation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, renal dialysis (epithelial stability), glomerulosclerosis, and neuronal degenerative inflammation.

[0147] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula (I), a racemate, stereoisomer, tautomer, nitroxide, isotopic label, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof.

[0148] Preferably, the pharmaceutical composition may optionally contain pharmaceutically acceptable auxiliary materials such as carriers, excipients, etc. Illustratively, the auxiliary materials may be at least one selected from disintegrants, glidants, lubricants, diluents or fillers, adhesives, and colorants.

[0149] The pharmaceutical composition of the present invention has the function of regulating Rho-kinase and can be used for the prevention or treatment of one or more diseases caused by overexpression or excessive activation of ROCK, such as cardiovascular and cerebrovascular diseases, nervous system diseases, fibrosis, eye diseases, tumors, arterial thrombosis, radiation injury, respiratory system diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte accumulation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, renal dialysis (epithelial stability), glomerulosclerosis, and neuronal degeneration and inflammation.

[0150] The present invention further provides a method for modulating Rho-kinase function, comprising administering to an individual in need thereof an effective amount of the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitroxide, isotope-labeled form, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug, or the pharmaceutical composition. The method can be used to prevent or treat one or more diseases caused by overexpression or overactivation of ROCK.

[0151] The present invention further provides a method for preventing or treating one or more diseases caused by high expression of ROCK or excessive activation of ROCK, which comprises administering to an individual in need thereof an effective amount of the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope-labeled compound, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition. Examples of such diseases include cardiovascular and cerebrovascular diseases, nervous system diseases, fibrosis, eye diseases, tumors, arterial thrombosis, radiation injury, respiratory diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte accumulation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, kidney dialysis (epithelial stability), glomerulosclerosis, and neuronal degeneration and inflammation.

[0152] In another aspect, the present application provides compounds of formula (I) for use in modulating Rho-kinase function, comprising administering to an individual in need thereof an effective amount of one or more compounds of the present invention, or a pharmaceutical composition comprising said compounds.

[0153] In yet another aspect, the present application provides a compound of formula (I), for use in the prevention or treatment of one or more diseases caused by high expression of ROCK or excessive activation of ROCK, comprising administering to an individual in need thereof an effective amount of the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label, solvate, crystalline polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition. Examples of such diseases include cardiovascular and cerebrovascular diseases, nervous system diseases, fibrosis, eye diseases, tumors, arterial thrombosis, radiation injury, respiratory diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte accumulation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, kidney dialysis (epithelial stability), glomerulosclerosis, and neuronal degeneration and inflammation.

[0154] [Definitions and explanations of terms] Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application include illustrative definitions, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., and may be arbitrarily combined or linked with each other. The group definitions and compound structures after such combinations and linkages shall fall within the scope described in the specification of this application.

[0155] In the specification and claims of this application

[0156] [ka]

[0157] When labeled as such, the part represents the connection site.

[0158] In the specification and claims of this application, "more than" means three or more than three. The term "halogen" refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I can be described as "halogen" herein.

[0159] The term “C 1-20 "Alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms, preferably C 1-6 It should be understood that the term "C" is an alkyl group. 1-12 The term "alkyl group" should be understood to denote a linear or branched saturated monovalent hydrocarbon group, preferably having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or isomers thereof.

[0160] The term “C 1-20 "Alkoxy group" is -OC 1-20 Represents an alkyl group, of which C 1-20 The alkyl group has the definition given above. 1-6 an alkoxy group.

[0161] The term “C 3-20 "Cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3-6 The term "C" should be understood to mean a "cycloalkyl group." 3-6A "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. 3-6 The cycloalkyl group may be a monocyclic hydrocarbon group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0162] The term "3- to 20-membered heterocyclyl group" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5 heteroatoms independently selected from N, O, and S, preferably a "3- to 6-membered heterocyclyl group." The term "3- to 6-membered heterocyclyl group" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3, heteroatoms selected from N, O, and S. The heterocyclyl group may be attached to the remainder of the molecule at any one of the carbon atoms or at the nitrogen atom, if present. In particular, the heterocyclyl group may include, but is not limited to, a four-membered ring such as azetidinyl or oxetanyl; a five-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or pyrrolinyl; or a six-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. According to the present invention, the heterocyclyl group is non-aromatic.

[0163] The term “C 6-20 "Aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-12 The term "C" should be understood to mean "aryl group." 6-12 An "aryl group" is preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, or 12 carbon atoms ("C 6-12 aryl groups"), in particular rings having 6 carbon atoms ("C6 aryl groups"), such as phenyl or biphenyl, or rings having 9 carbon atoms ("C9 aryl groups"), such as indanyl or indenyl, or rings having 10 carbon atoms ("C 10aryl group"), for example a tetrahydronaphthyl group, a dihydronaphthyl group or a naphthyl group.

[0164] The term "5-20 membered heteroaryl group" should be understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5-12 membered heteroaryl groups". The term "5-12 membered heteroaryl group" should be understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. In particular, heteroaryl groups include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, as well as their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, and isoindolyl. or a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, and the like, and benzo derivatives thereof, for example, a quinolyl group, a quinazolinyl group, an isoquinolyl group, or an azocinyl group, an indolizinyl group, a purinyl group, and the like, and benzo derivatives thereof; or a cinnolinyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a naphthyridinyl group, a pteridinyl group, a carbazolyl group, an acridinyl group, a phenazinyl group, a phenothiazinyl group, a phenoxazinyl group, or the like.

[0165] Unless otherwise specified, a heterocyclyl, heteroaryl, or heteroarylene group includes all possible isomeric forms thereof, for example, positional isomers thereof. Thus, as some illustrative and non-limiting examples, a pyridinyl or pyridylidene group includes pyridinyl-2-yl, pyridylidene-2-yl, pyridinyl-3-yl, pyridylidene-3-yl, pyridinyl-4-yl, and pyridylidene-4-yl, and a thienyl or thenylidene group includes thienyl-2-yl, thenylidene-2-yl, thienyl-3-yl, and thenylidene-3-yl.

[0166] In addition, in the definition of the above group, the numerical range, for example, C 1-20 , 3-20, C 6-20 or numerical ranges such as 5-20 represent the endpoints of the range and any integers at both ends, but are not limited to including only the endpoints.

[0167] Unless otherwise specified, the term "leaving group" as used herein shall refer to a charged or uncharged atom or group that is eliminated during a substitution or replacement reaction. Suitable examples include, but are not limited to, H, F, Br, Cl, I, methanesulfonate groups, toluenesulfonate groups, etc.

[0168] In any of the methods for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in textbooks and reference books in the field. The protecting groups can be removed at a convenient subsequent stage by methods known in the art. Those skilled in the art will recognize that, depending on the specific protecting group, other reagents can be used for this deprotection step, including, but not limited to, Pd / C, Pd(OH)2, PdCl2, Pd(OAc)2 / Et3SiH, Raney nickel, an appropriately selected acid, an appropriately selected base, fluoride, and the like.

[0169] The target compound can be isolated by known methods, for example, by extraction, filtration or column chromatography.

[0170] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Therefore, these compounds may exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or can be used in synthesis in this form. In the case of racemic amines, the non-enantiomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline and N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic resolution of enantiomers is also commonly achieved using optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives, or chirally derivatized methacrylate polymers, immobilized on silica gel). Suitable eluents for this purpose are water or alcohol-containing solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0171] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because the nitrogen must have an available lone pair of electrons to be oxidized to an oxide; however, those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. Methods for preparing these N-oxides have been widely described and compiled in the literature.

[0172] Pharmaceutically acceptable salts may be, for example, acid addition salts of the compounds of the invention which have a nitrogen atom in the chain or ring and which are sufficiently basic, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, and nitric acid, or hydrogen sulfate salts, or with acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfate, 3-phenylpropionic ... benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, Acid addition salts formed with organic acids such as methylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-glucose acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, and thiocyanic acid.

[0173] Further suitable pharmaceutically acceptable salts of compounds of the present invention that are sufficiently acidic are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts formed with organic bases that provide physiologically acceptable cations, such as salts formed with sodium ions, potassium ions, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, and 1-amino-2,3,4-butanetriol. By way of example, the pharmaceutically acceptable salts include salts formed from a -COOH group with sodium ions, potassium ions, calcium ions, magnesium ions, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, and 1-amino-2,3,4-butanetriol.

[0174] Furthermore, basic nitrogen-containing groups can be converted to quaternary ammonium salts using reagents such as lower alkyl halides such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long-chain halides such as chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl groups; and aralkyl halides such as bromides of benzyl and phenethyl groups. Examples of pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, hydrogensulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates, and meglumine salts.

[0175] Since the compound of the present invention may have multiple salt-forming sites, the "pharmaceutically acceptable salt" includes not only salts formed at one salt-forming site in the compound of the present invention, but also salts formed at two, three, or all of the salt-forming sites. Therefore, in the "pharmaceutically acceptable salt," the molar ratio of the compound of formula (I) to the acid ion (anion) or base cation necessary for salt formation can vary within a wide range, and may be, for example, 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0176] According to the present invention, pharmaceutically acceptable anions include those selected from anions formed by ionizing inorganic or organic acids. The "inorganic acids" include, but are not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, and nitric acid. The "organic acids" include, but are not limited to, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethacin, thiazolinone ... Examples of suitable carboxylic acids include, but are not limited to, benzosulfonic acid, dodecylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-glucose acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0177] The term "tautomer" refers to a functional isomer resulting from the rapid shift of an atom between two positions within a molecule. The compounds of the present invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Proton-shift tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and isolating a single tautomer usually produces a mixture whose physicochemical properties match those of the mixture of compounds. The position of the equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0178] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound described in the present invention to achieve the desired application (including, but not limited to, the treatment of diseases defined below). A therapeutically effective amount can vary depending on the desired application (in vitro or in vivo), the subject and condition being treated, such as the subject's weight and age, the severity of the condition, and the method of administration, and can be easily determined by one skilled in the art. The specific dosage will vary depending on the particular compound selected, the method of administration used, whether or not it is administered in combination with other compounds, the time schedule of administration, the tissue to which it is administered, and the physical delivery system used.

[0179] The term "auxiliary material" refers to pharmaceutically acceptable inactive ingredients. Examples of types of excipients include, but are not limited to, adhesives, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, etc. Excipients can improve the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression. Typical examples of pharmaceutically acceptable carriers suitable for the above formulations include sugars such as lactose, sucrose, mannitol, and sorbitol; starches such as corn starch, tapioca starch, and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate, calcium sulfate, polyvinylpyrrolidone, polyvinyl alcohol; stearic acid, alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; nonionic, cationic, and anionic surfactants; glycol polymers; fatty alcohols; grain hydrolyzed solids; and other non-toxic, compatible fillers, adhesives, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, and other auxiliary materials commonly used in pharmaceutical formulations.

[0180] The beneficial effects of the present invention include: The compounds provided by the present invention have excellent ROCK inhibitory activity, particularly exhibiting relatively good selective inhibition of ROCK2 kinase. Furthermore, the compounds of the present invention have relatively good safety and metabolic stability, and are highly bioavailable. Finally, the compounds of the present invention are easy to prepare and purify, so they have good application prospects.

[0181] [Mode for Carrying Out the Invention] The compounds of the general formula of the present invention and their preparation methods and applications will be described in more detail below with reference to specific examples. The following examples are merely for illustrative purposes and are not to be construed as limiting the scope of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention. Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0182] Nouns and representative reagents The nouns used in the specific experimental descriptions below represent the following reagents (unless otherwise stated): DMF: N,N-dimethylformamide; DCM: dichloromethane; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; DIEA: N,N-diisopropylethylamine; THF: tetrahydrofuran; DME: ethylene glycol dimethyl ether; CDI: N,N'-carbonyldiimidazole; MsCl: methylsulfonyl chloride; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DMSO: dimethyl sulfoxide; EA: ethyl acetate; MeOH: methanol; EtOH: ethanol; MeCN: acetonitrile Nitriles; NCS: N-chlorosuccinimide; n-BuOH: n-butanol; DCE: 1,2-dichloroethane; NMAC: N,N-dimethylacetamide; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride; IPA: isopropyl alcohol; mCPBA: m-chloroperbenzoic acid; nBuLi: n-butyllithium; NMP: N-methylpyrrolidone; TFA: trifluoroacetic acid; t-BuOK: potassium tert-butoxide; t-BuOMe: methyl tert-butyl ether; xantphos: 5-bis(diphenylphosphino)-9,9-dimethyloxaanthracene; DHP: 3,4-dihydro-2H-pyran.

[0183] <Manufacturing Example> Intermediate 1 Preparation of 3,3-difluoro-N-methylcyclobutan-1-amine hydrochloride (M001)

[0184] [ka]

[0185] (1) Preparation of compound (3,3-difluorocyclobutane)aminoformate tert-butyl (M001-1) 3,3-Difluorocyclobutan-1-amine (1.00 g, 9.34 mmol) was dissolved in a mixture of methanol (10 mL) and saturated aqueous sodium carbonate (10 mL), and di-tert-butyl dicarbonate (2.45 g, 11.20 mmol) was added to the mixture at room temperature. The reaction mixture was stirred overnight at room temperature. The product precipitated from the mixture. After filtration, the filter cake was spun dry to obtain 1.35 g of crude white solid product (3,3-difluorocyclobutane) tert-butyl aminoformate in 70.2% yield.

[0186] 1 H NMR (301 MHz, CD3OD) δ 3.89 (m, 1H), 2.93 - 2.74 (m, 2H), 2.58 - 2.38 (m, 2H), 1.42 (s, 9H).

[0187] (2) Preparation of compound (3,3-difluorocyclobutane)(methyl)aminoformate tert-butyl ester (M001-2) Under nitrogen gas protection, tert-butyl (3,3-difluorocyclobutane)aminoformate (900 mg, 4.34 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). The mixture was cooled to 0 °C, and sodium hydride (60%, 208 mg, 5.21 mmol) was added in several portions. The mixture was stirred at room temperature for 0.5 h. Methyl iodide (1.23 g, 8.69 mmol) was added dropwise in an ice-water bath, and the reaction was stirred overnight at room temperature. The mixture was quenched by slowly adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.10 g of crude tert-butyl (3,3-difluorocyclobutane)(methyl)aminoformate as a pale yellow solid.

[0188] 1 H NMR (301 MHz, CD3OD) δ 4.35 - 4.27 (m, 1H), 2.82 (s, 3H), 2.75 (dt, J = 15.5, 8.5 Hz, 4H), 1.45 (s, 9H).

[0189] Tert-butyl (3,3-difluorocyclobutane)(methyl)aminoformate (1.10 g, crude product) was dissolved in dichloromethane (10 mL), and a solution of hydrogen chloride in ethanol (33%, 3 mL) was added. The mixture was stirred at room temperature overnight. Concentration under reduced pressure gave 800 mg of a tan solid. The product was 3,3-difluoro-N-methylcyclobutan-1-amine hydrochloride, and the crude product was overweight. LC-MS [M+H] + : 122.1.

[0190] Intermediate 2 Preparation of tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (M002)

[0191] [ka]

[0192] 1) Preparation of tert-butyl 4-(4-nitrophenyl)-1H-pyrazolyl-1-formate (M002-1) (4-(4,4,5 ,5 - Tetra tert-Butyl (methyl-1,3,2-dioxaborolan-2-yl)pyrazolyl-1-yl)formate (58.8 g, 0.2 mol), 1-bromo-4-nitrobenzene (20 g, 0.1 mol), anhydrous potassium carbonate (41.5 g, 0.3 mol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (7.3 g, 10 mmol) were added to 1,4-dioxane:water (30:1) (207 mL) and purged with nitrogen gas three times. The mixture was stirred in an oil bath at 100 °C for 5 h. TLC confirmed the completion of the reaction, and the reaction was stopped and filtered under reduced pressure. The filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give 16 g of a yellow solid in 46% yield. MS (M+1-100) + =190.05, and the hydrogen spectrum indicated product M002-1.

[0193] 2) Preparation of tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (M002) Tert-butyl 4-(4-nitrophenyl)-1H-pyrazolyl-1-formate (16 g, 55.3 mol) was dissolved in methanol (160 mL), palladium on carbon (3.2 g) was added, a hydrogen balloon was attached, and the hydrogen gas was replaced. The reaction was allowed to proceed at 45°C for 16 h. After TLC showed the completion of the reaction, diatomaceous earth was added and the mixture was filtered under reduced pressure. The filtrate was concentrated to give a yellow crude product, which was then purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 9.6 g of a pale white solid, with a yield of 60%. MS (M+1) + =260.15.

[0194] Intermediate 3 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)aniline (M003)

[0195] [ka]

[0196] 1) Preparation of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl (M003-1) 4 5 g (34.02 mmol) of 1-bromopyrazolyl was dissolved in 25 ml of 3,4-dihydro-2H-pyran, and 387.9 mg (3.4 mmol) of trifluoroacetic acid was slowly added dropwise. After the addition was complete, the mixture was heated to 80°C and reacted overnight. A sample was taken and sent to LCMS monitoring. A large amount of product was generated from the raw material. Workup: After adjusting the pH to approximately 8 with saturated aqueous NaHCO3, 20 ml of EA was added and extracted three times. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to obtain a yellow oil, which was directly used in the next reaction. LC-MS [M+H] + =233.00.

[0197] 2) Preparation of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)aniline (M003) 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl (7.86 g, 34.01 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Pd(dppf)Cl2 (8.94 g, 40.81 mmol), potassium carbonate (9.4 g, 68.02 mmol), and Pd(dppf)Cl2 (2.49 g, 3.4 mmol) were dissolved in dioxane / water (70 mL / 10 mL) and heated at 80 °C overnight under nitrogen gas protection. A sample was taken and sent to LCMS to confirm the reaction of the raw materials. After the reaction was complete, ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography to obtain 5 g of an ink-green solid in 60% yield. LC-MS [M + H] + =244.15.

[0198] Intermediate 4 Preparation of tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (M004), N-(4-(1H-pyrazolyl-4-yl)phenyl)-2-chloropyrimidin-4-amine (M004')

[0199] [ka]

[0200] 1) Preparation of compound tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylic acid ester (M004): tert-Butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-carboxylate (5.64 g, 21.69 mmol) and 2,4-dichloropyrimidine (4.85 g, 1.44 mmol) were dissolved in N,N-dimethylformamide (90 mL). N,N-diisopropylethylamine (8.39 g, 65.07 mmol) was added and the mixture was incubated at 80°C for 8 hours under nitrogen gas protection. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 50:1 to 5:1) to give 4.40 g of a pale yellow solid in 54% yield. LC-MS [M+H] + :371.7.

[0201] 2) Preparation of N-(4-(1H-pyrazolyl-4-yl)phenyl)-2-chloropyrimidin-4-amine (M004') tert-Butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate was dissolved in anhydrous dichloromethane, and a solution of hydrogen chloride in ethanol (33%) was added. The mixture was stirred at room temperature for 2 hours. Concentration under reduced pressure gave N-(4-(1H-pyrazolyl-4-yl)phenyl)-2-chloropyrimidin-4-amine. MS (M +1) + = 272.4.

[0202] Example 1, Preparation of Compound 1 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001)

[0203] [ka]

[0204] 1.1 Preparation of compound ethyl 3-(3-nitropyridin-4-yl)-2-carbonylpropionate (L001-1) Under nitrogen gas protection, 4-methyl-3-nitropyridine (10.0 g, 72.0 mmol) was dissolved in diethyl oxalate (50 mL). DBU (12.7 g, 83.0 mmol) was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was quenched by adding ice water (30.0 g). The pH was adjusted to 4-5 with 1N dilute hydrochloric acid, filtered, and the filter cake was washed with ethyl acetate (100 ml*2). After drying in an oven, 18.0 g of a red solid was obtained. The crude product was directly used in the next step. LC-MS [M+H] + :239.1.

[0205] 1.2 Preparation of compound ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L001-2) Under nitrogen gas protection, ethyl 3-(3-nitropyridin-4-yl)-2-carbonylpropionate (17.0 g, 70.0 mmol) was dissolved in anhydrous dichloromethane (200 mL). Palladium on carbon (3.4 g) was added to the reaction mixture and allowed to stand overnight at room temperature. The filtrate was filtered and concentrated under reduced pressure. After concentration, the mixture was separated by silica gel column chromatography (PE / EA = 1 / 1) to give 6.0 g of a yellow oily liquid. The yield for the two steps was 43.8%. LC-MS [M + H] + : 191.1.

[0206] 1.3 Preparation of compound 1-tert-butoxycarbonyl-pyrrolo[2,3-c]pyridine-2-carboxylate ethyl (L001-3) Under nitrogen gas protection, ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate (6.0 g, 31.5 mmol) was dissolved in anhydrous dichloromethane (50 mL). Boc anhydride (7.6 g, 34.7 mmol) and DMAP (384 mg, 3.2 mmol) were added to the reaction mixture and stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 7.5 g of a yellow oily liquid. The yield was 82.4%, and LC-MS [M+H] + : 291.0.

[0207] 1.4 Preparation of compound ethyl 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L001-4) Under nitrogen gas protection, ethyl 1-tert-butoxycarbonyl-pyrrolo[2,3-c]pyridine-2-carboxylate (7.2 g, 24.7 mmol) was dissolved in anhydrous DMF (50 mL). Benzyl bromide (4.2 g, 24.7 mmol) was added and the mixture was incubated at 80 °C for 4 hours. The mixture was concentrated under reduced pressure. The resulting solid was dissolved in ethanol (50 mL). Sodium borohydride (934 mg, 24.7 mmol) was added to the reaction mixture and the mixture was incubated at room temperature for 3 hours. The mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give 3.5 g of a yellow oily liquid in 49.8% yield. LC-MS [M+H] + : 285.1.

[0208] 1.5 Preparation of compound ethyl 6-tert-butoxycarbonyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L001-5) Ethyl 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (3.5 g, 12.3 mmol) was dissolved in methanol (40 mL), Boc anhydride (4.0 g, 18.5 mmol) and palladium on carbon (700 mg) were added, and the mixture was left overnight at room temperature under a hydrogen gas atmosphere. The mixture was filtered and concentrated, and separated by silica gel column chromatography (PE / EA = 5 / 1) to give 1.8 g of a yellow oily liquid in 50.0% yield. MS [M / 2 + H] + =295.1.

[0209] 1.6 Preparation of compound ethyl 6-tert-butoxycarbonyl-1-methyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L001-6) Under nitrogen gas protection, ethyl 6-tert-butoxycarbonyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.8 g, 6.1 mmol) was dissolved in tetrahydrofuran (20 mL). The temperature was lowered to 0 °C, and sodium hydride (364 mg, 9.1 mmol, 60%) was added to the reaction mixture. The mixture was stirred at this temperature for 30 min. Methyl iodide (1.7 g, 12.2 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 2 h. The mixture was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (30 mL), combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.8 g of a yellow oily liquid (crude product). LC-MS [M+H] + : 308.9.

[0210] 1.7 Preparation of compound ethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L001-7) 6-tert-butoxycarbonyl- 1-Methyl- Ethyl 4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.8 g, 5.8 mmol) was dissolved in anhydrous dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the mixture was allowed to react at room temperature for 3 hours. After concentration under reduced pressure, saturated sodium bicarbonate solution was slowly added dropwise to adjust the pH to 8-9, and the mixture was extracted with dichloromethane (20 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to give 900 mg of a yellow oily liquid. The yield of the two steps was 71%, and LC-MS [M + H] + : 209.1.

[0211] 1.8 Preparation of compound ethyl 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L001-8) tert-Butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (1342 mg, 3.6 mmol) was dissolved in n-butanol (10 mL). Ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (500 mg, 2.4 mmol) and DIEA (930 mg, 7.2 mmol) were added to the reaction mixture, which was then heated to 120 °C and reacted overnight. The mixture was quenched with water (40 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give 900 mg of a yellow oily liquid in 84.5% yield. LC-MS [M+H] + : 444.1.

[0212] 1.9 Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) Ethyl 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (800 mg, 1.5 mmol) was dissolved in tetrahydrofuran / methanol / water (3 / 1 / 1, 10 mL total), sodium hydroxide (292 mg, 7.3 mmol) was added, the mixture was heated to 50°C, and reacted for 1 hour. After concentration under reduced pressure, the pH was adjusted to 5-6 with 1 N dilute hydrochloric acid, and the mixture was concentrated under reduced pressure to obtain 1.0 g of a white solid, which is the crude product and contains sodium chloride. LC-MS [M+H] + : 416.0.

[0213] Example 2, Preparation of Compound 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (L002)

[0214] [ka]

[0215] 2.1 Preparation of compound imidazo[1,2-a]pyrazine-2-carboxylate ethyl (L002-1) Pyrazin-2-amine (3.5 g, 36.82 mmol) and ethyl 3-bromo-2-carbonylpropionate (7.0 g, 44.18 mmol) were dissolved in ethylene glycol dimethyl ether (60 mL) and heated at 60 °C overnight. The mixture was cooled to room temperature, filtered, and the filter cake was collected. Ethanol (40 mL) was added and the mixture was heated at 80 °C for 3 hours. After concentration under reduced pressure, saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 1:1) to give 1.15 g of a yellow oily product in 16.4% yield. LC-MS [M+H] + : 192.0.

[0216] 2.2 Preparation of compound ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (L002-2) Ethyl imidazo[1,2-a]pyrazine-2-carboxylate (1.1 g, 5.75 mmol) was dissolved in anhydrous methanol (30 mL), palladium-carbon catalyst (10%, 600 mg) was added, and the mixture was stirred overnight at room temperature under a stream of hydrogen gas. After filtration, the filtrate was rotary evaporated to give 800 mg of ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate as a tan oil in 71.2% yield. LC-MS [M+H] + : 196.0.

[0217] 2.3 Preparation of compound ethyl 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (L002-3) Ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (310 mg, 1.59 mmol), tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (589 mg, 1.59 mmol), and N,N-diisopropylethylamine (570 mg, 4.42 mmol) were dissolved in n-butanol (5 mL) and stirred at 120 °C for 5 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (dichloromethane:methanol=5:1) to obtain 430 mg of brown oily crude product, ethyl 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate. The yield was 62.9%. LC-MS [M+H] + : 431.1.

[0218] 2.4 Preparation of compound 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (L002) Ethyl 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (430 mg, 1.00 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (126 mg, 3.00 mmol) was added and the reaction was stirred at room temperature overnight. The acid was adjusted to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The grey solid product 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid was obtained in an amount of 350 mg, with a yield of 87.1%. LC-MS [M+H] + : 403.0.

[0219] Example 3, Preparation of compound (5-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L003)

[0220] [ka]

[0221] 3.1 Preparation of compound 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazolyl-3,5-dicarboxylate dimethyl (L003-1) Dimethyl 1H-pyrazolyl-3,5-dicarboxylate (5.00 g, 27.10 mmol) was added to anhydrous N,N-dimethylformamide (60 mL), potassium carbonate (5.61 g, 40.60 mmol) was added, and under nitrogen gas protection in an ice-water bath, tert-butyl (2-bromoethyl)carbamate (6.64 g, 29.80 mmol) was added, and the mixture was stirred at room temperature for 3 h. Water (100 mL) was added for dilution, and a large amount of solid precipitated. This was suction filtered, and the filter cake was washed with water (50 mL). The solid was collected and dried to give 8.70 g of crude product, a white solid with a purity of 70%. The yield was 68%. MS [M + H] + =350.2.

[0222] 3.2 Preparation of compound 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-(methoxycarbonyl)-1H-pyrazolyl-5-carboxylic acid (L003-2) Dimethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazolyl-3,5-dicarboxylate (5.60 g, 17.10 mmol) was dissolved in dichloromethane (30 mL) and methanol (30 mL). Potassium hydroxide methanol solution (2.2 M, 5.4 mL, 11.9 mmol) was added dropwise and the mixture was allowed to react at room temperature for 1 h. Water (60 mL) was added for dilution, and the mixture was back-extracted with dichloromethane (50 mL x 2). The aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (1 N) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.20 g of crude product as a white solid in 78% yield. MS [M + H] + = 336.2.

[0223] 3.3 Preparation of compound methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(hydroxymethyl)-1H-pyrazolyl-3-carboxylate (L003-3) 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-3-(methoxycarbonyl)-1H-pyrazolyl-5-carboxylic acid (2.00 g, 6.30 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), N,N'-carbonyldiimidazole (2.04 g, 12.6 mmol) (CDI) was added, and the mixture was stirred at 45 °C for 1 h. Sodium borohydride (957 mg, 25.20 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated ammonium chloride solution (20 mL), diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (petroleum ether:ethyl acetate = 3:1) to give 400 mg of a colorless, clear oily liquid in 21% yield. MS [M + H] + = 322.1.

[0224] 3.4 The compound 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(((methanesulfonyl) Oxy Preparation of methyl)-1H-pyrazolyl-3-carboxylate (L003-4) Methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(hydroxymethyl)-1H-pyrazolyl-3-carboxylate (400 mg, 1.33 mmol) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (201 mg, 2.00 mmol) was added, and methylsulfonyl chloride (182 mg, 1.59 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1.5 h. The mixture was quenched with saturated sodium bicarbonate (5 mL), diluted with water (10 mL), and extracted with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 420 mg of a colorless, transparent oily liquid. The crude product was obtained in an 83% yield. MS (M −99) + = 278.1.

[0225] 3.5 Preparation of compound methyl 5-tert-butoxycarbonyl-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-2-carboxylate (L003-5) 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(((methanesulfonyl) Oxy Methyl)-1H-pyrazolyl-3-carboxylate (420 mg, 1.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Sodium hydride (76 mg, 1.89 mmol, 60%) was added under nitrogen gas protection at 0 °C and stirred at room temperature for 1.5 h. After the reaction was completed, the mixture was quenched with saturated ammonium chloride (10 mL), diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give 200 mg of a colorless, transparent oil in 64% yield. MS [M + H] + = 282.2.

[0226] 3.6 Preparation of compound 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (L003-6) Methyl 5-tert-butoxycarbonyl-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-2-carboxylate (200 mg, 0.71 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Aqueous sodium hydroxide solution (2 N, 1.4 mL, 2.80 mmol) was added dropwise and the mixture was allowed to react at room temperature for 1 h. The mixture was diluted with water (5 mL) and back-extracted with ethyl acetate (5 mL x 2). The aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 130 mg of crude product as a white solid in 68% yield. MS (M +1) + = 268.2.

[0227] 3.7 Preparation of compound tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (L003-7) 5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (130 mg, 0.49 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), and 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (205 mg, 0.54 mmol), N,N-diisopropylethylamine (255 mg, 1.96 mmol), and 3,3-difluorotrimethyllideneimide hydrochloride (70 mg, 0.54 mmol) were added, followed by stirring at room temperature for 2 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column purification (petroleum ether: ethyl acetate = 3:1) to obtain 110 mg of a white solid, with a yield of 65%. MS (M +1) + = 343.2.

[0228] 3.8 Preparation of compound (3,3-difluoroazetidin-1-yl)(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl ketone (L003-8) 2-(3,3-Difluoroazetidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate tert-butyl ester (110 mg, 0.32 mmol) was dissolved in anhydrous dichloromethane (3 mL), and a solution of hydrogen chloride in ethanol (33%, 1 mL) was added. The mixture was stirred at room temperature for 2 h. Concentration under reduced pressure gave 90 mg of the crude product as a white solid. MS (M +1) + = 242.9.

[0229] 3.9 Preparation of compound (5-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L003) (3,3-Difluoroazetidin-1-yl)(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl ketone hydrochloride (90 mg, 0.32 mmol) was dissolved in n-butanol (3 mL), and tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (119 mg, 0.32 mmol) and N,N-diisopropylethylamine (255 mg, 1.96 mmol) were added. The mixture was refluxed overnight, diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to give 19.6 mg of a white solid. The two-step yield was 12%. MS (M +1) + = 478.2.

[0230] 1 H NMR (400 MHz, DMSO) δ 12.91 (brs, 1H), 9.42 (s, 1H), 8.08-7.96 (m, 3H), 7.63-7.58(m, 4H), 6.68 (s, 1H), 6.15 (d, J = 5.7 Hz, 1H), 4.97 (s, 2H), 4.85 (t, J = 12.4 Hz, 2H), 4.44 (t, J = 12.4 Hz, 2H), 4.25 (s, 4H).

[0231] Example 4, Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L004)

[0232] [ka]

[0233] 4.1 Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L004) 6-(4-((4-(1H-Pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (150 mg, 0.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (185 mg, 1.44 mmol), 3,3-difluorocyclobutan-1-amine hydrochloride (57 mg, 0.40 mmol), and 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (150 mg, 0.40 mmol) were added. The mixture was reacted under nitrogen gas protection at room temperature for 4 hours. After the reaction was completed, the reaction mixture was quenched by adding water (15 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column using dichloromethane:methanol (20:1) as the eluent to give 40.8 mg of a white solid, with a yield of 22%. MS [M + H] + =504.9.

[0234] 1H NMR (400 MHz, MeOD) δ 7.93 (brs, 2H), 7.88 (d, J = 6.0 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 6.63 (s, 1H), 6.09 (d, J = 6.0 Hz, 1H), 4.77 (s, 2H), 4.28 -4.22 (m, 1H), 4.02 - 3.96 (m, 2H), 3.80(s, 3H), 2.95-2.87 (m, 2H), 2.65-2.62 (m ,4H).

[0235] Example 5, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L005)

[0236] [ka]

[0237] 3,3-Difluoroazetidine (67 mg, 0.7 mmol) was dissolved in DMF (10 mL) and 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (200 mg, 0.5 mmol), HATU (547 mg, 1.4 mmol), and DIEA (186 mg, 1.4 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified to give 60 mg of a white solid. LC-MS [M+H] + : 490.7.

[0238] 1H NMR (400 MHz, MeOD) δ 7.96 (s, 2H), 7.90 (d, J = 6.1 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 6.48 (s, 1H), 6.15 (d, J = 6.1 Hz, 1H), 4.82 (s, 2H), 4.64-4.52 (m, 4H), 4.03 (t, J = 5.7 Hz, 2H), 3.83 (s, 3H), 2.69 (t, J = 5.5 Hz, 2H).

[0239] Example 6, Preparation of compound (6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L006)

[0240] [ka]

[0241] 6.1 Preparation of Compound N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (L006-1) Under nitrogen gas protection, 2,4-dichloropyrimidine (1.48 g, 10.0 mmol) and 1H-indazol-5-amine (1.33 g, 10.0 mmol) were dissolved in absolute ethanol (10 mL), triethylamine (1.01 g, 10.0 mmol) was added, and the mixture was heated to reflux and reacted for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with 20 mL of water, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and rotary evaporated to give 1.30 g (53% yield) of a pink solid, N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine. MS [M+H] + =246.0.

[0242] 6.2 Preparation of compound 6-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L006-2) Ethyl 6-tert-butoxycarbonyl-1-methyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (4.0 g, 12.9 mmol) was dissolved in methanol (40 mL), sodium hydroxide solution (38.7 mL, 1 N) was added, and the mixture was allowed to react at 50 °C for 2 hours. The pH was adjusted to 5-6 with dilute hydrochloric acid (1 N), extracted with ethyl acetate (50 mL*3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to give 3.2 g of a purple oil. LC-MS [M+H] + : 281.1.

[0243] 6.3 Preparation of compound tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (L006-3): 6-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (2.4 g, 8.5 mmol) was dissolved in anhydrous DMF (20 mL). 3,3-Difluoroazetidine hydrochloride (1.2 g, 12.8 mmol), HATU (4.9 g, 12.8 mmol), and DIEA (3.3 g, 25.6 mmol) were added and reacted at room temperature for 1 hour. The mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. 2.5 g of a yellow oil was obtained by silica gel column chromatography (PE / EA = 3 / 1). The yield was 83.3%. LC-MS [M+H] + : 355.8.

[0244] 6.4 Preparation of compound (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L006-4): tert-Butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (1.8 g, 5.8 mmol) was dissolved in absolute ethanol (20 mL), and ethanolic hydrochloric acid (5 mL, mass fraction 33%) was added. The mixture was allowed to react at room temperature for 3 hours. After vacuum rotary evaporation and concentration, 2.0 g of a yellow solid was obtained. LC-MS [M+H] + : 256.0.

[0245] 6.5 Preparation of compound (6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L006) (3,3-Difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (50 mg, 0.20 mmol) and N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (73.7 mg, 0.30 mmol) were dissolved in n-butanol (1.0 mL), diisopropylethylamine (53 mg, 0.41 mmol) was added, and the mixture was reacted at 120 °C for 15 hours. After the reaction was complete, the mixture was cooled to room temperature, rotary dried under reduced pressure, and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:5) to obtain 20 mg of a white solid in 22% yield. MS [M + H] + =485.0.

[0246] 1H NMR (400 MHz, DMSO) δ 12.97 (s, 1H), 9.28 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.44 (dd, J = 8.9, 1.6 Hz, 1H), 6.46 (s, 1H), 6.06 (d, J = 5.8 Hz, 1H), 4.80 (s, 2H), 4.62-4.48 (m, 4H), 3.97 (t, J = 5.6 Hz, 2H), 3.76 (s, 3H) , 2.56 (t, J = 5.5 Hz, 2H).

[0247] Example 7, Preparation of compound 2-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)pyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (L007)

[0248] [ka]

[0249] 7.1 Preparation of compound 2-(4-amino-2-fluorophenoxy)nicotinamide (L007-1): 2-Chloronicotinamide (3.00 g, 19.16 mmol) and 4-amino-2-fluorophenol (2.43 g, 19.16 mmol) were dissolved in anhydrous dimethyl sulfoxide (50 mL), cesium carbonate (18.68 g, 57.48 mmol) was added, and the mixture was stirred at 100 °C for 12 h. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL * 8). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by silica gel column (dichloromethane:methanol = 10:1) to give 1.60 g of brown solid product, 2-(4-amino-2-fluorophenoxy)nicotinamide, in 34% yield. LC-MS [M+H] +: 248.1.

[0250] 7.2 Preparation of compound 2-(4-((2-chloropyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (L007-2): 2-(4-amino-2-fluorophenoxy)nicotinamide (300 mg, 1.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and 2,4-dichloropyrimidine (180 mg, 1.21 mmol) and N,N-diisopropylethylamine (470 mg, 3.63 mmol) were added. The mixture was heated to 80 °C and reacted for 3 h. The reaction was quenched by adding water (30 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 1:1) to obtain 150 mg of a pale yellow solid product, 2-(4-((2-chloropyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide, in 31% yield.

[0251] 7.3 Preparation of compound 2-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)pyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (L007): 2-(4-((2-chloropyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (85 mg, 0.24 mmol) was dissolved in n-butanol (3 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone hydrochloride (60 mg, 0.24 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) were added to the system. The system was heated to 120°C and stirred for 4 h. After detecting the completion of the reaction, the reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and rotary evaporated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 12.1 mg of white solid product 2-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)pyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide, with a yield of 8.8%. LC-MS [M+H] + : 579.0.

[0252] 1 H NMR (301 MHz, DMSO) δ 9.58 (s, 1H), 8.23 ​​- 8.13 (m, 2H), 8.05 - 7.98 (m, 1H), 7.92 (d, J = 13.6 Hz, 1H), 7.82 (s, 2H), 7.38 - 7.29 (m, 2H), 7.26 - 7.20 (m, 1H), 6.44 (s, 1H), 6.09 (d, J = 5.7 Hz, 1H), 4.78 (s, 2H), 4.53 (t, J=7.1 Hz, 4H), 3.99-3.92 (m, 2H), 3.70 (s, 3H), 2.58-2.50 (m, 2H).

[0253] Example 8, Preparation of Compound 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (L008)

[0254] [ka]

[0255] 7-(4-((4-(1H-Pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (L002) (100 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (5 mL). HATU (140 mg, 0.37 mmol), 3,3-difluorocyclobutan-1-amine hydrochloride (53 mg, 0.37 mmol), and N,N-diisopropylethylamine (160 mg, 1.25 mmol) were added and stirred overnight at room temperature under nitrogen gas protection. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (15 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (dichloromethane:methanol=10:1), the collected product was concentrated and freeze-dried to give 24.7 mg of white solid product 7-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide, yield 20.1%. LC-MS [M+H] + : 492.0.

[0256] 1H NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 9.41 (s, 1H), 8.49 (d, J = 7.7 Hz, 1H), 8.20 - 7.85 (m, 3H), 7.66 - 7.56 (m, 5H), 6.14 (d, J = 5.8 Hz, 1H), 4.91 (s, 2H), 4.30 - 4.25 (m, 1H), 4.20 - 4.08 (m, 4H), 2.87 - 2.77 (m, 4H).

[0257] Example 9, Preparation of Compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-N-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L009)

[0258] [ka]

[0259] 6-(4-((4-(1H-Pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (150 mg, 0.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (185 mg, 1.44 mmol), isopropylamine (57 mg, 0.40 mmol), and 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (24 mg, 0.40 mmol) were added. The mixture was allowed to react at room temperature for 4 hours under nitrogen gas protection. After the reaction was completed, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified to give 30.7 mg of a white solid in 18% yield. MS [M+H] + = 457.2.

[0260] 1 H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 9.31 (s, 1H), 8.01 (s, 2H), 7.96 (d, J = 5.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.58 - 7.55 (m, 3H), 6.62 (s, 1H), 6.07 (d, J = 5.8 Hz, 1H), 4.76 (s, 2H), 4.05 - 3.98 (m, 3H), 3.78 (s, 3H), 2.54 - 2.52 (m, 2H), 1.10 (d, J = 6.6 Hz, 6H).

[0261] Example 10, Preparation of compound 1-(6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L010)

[0262] [ka]

[0263] 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (150 mg, 0.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (185 mg, 1.44 mmol), 3-cyanoazetidine hydrochloride (47 mg, 0.40 mmol), and 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (150 mg, 0.40 mmol) were added. The mixture was allowed to react at room temperature for 4 hours under nitrogen gas protection. After the reaction was completed, the reaction mixture was quenched by adding water (15 mL) and extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column using dichloromethane:methanol (20:1) as the eluent to give 58.6 mg of a white solid, with a yield of 34%. MS [M+H] + =479.9.

[0264] 1 H NMR (400 MHz, MeOD) δ 7.92 (brs, 2H), 7.87 (d, J = 6.0, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 6.38 (s, 1H), 6.09 (d, J = 6.0 Hz, 1H), 4.75 (s, 2H), 4.60 - 4.28 (m, 4H), 4.00 - 3.96 (m, 2H), 3.77 (s, 3H), 3.75 - 3.68 (m, 1H), 2.66 - 2.60 (m, 2H).

[0265] Example 11, Preparation of compound (2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L011)

[0266] [ka]

[0267] 11.1 Preparation of compound (3,3-difluoroazetidin-1-yl)(1H-indazol-5-yl)methyl ketone (L011-1) 1H-Indazole-5-carboxylic acid (1.50 g, 9.26 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). 3,3-Difluorotrimethyllidenimide hydrochloride (1.31 g, 10.18 mmol), 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.86 g, 10.18 mmol), and N,N-diisopropylethylamine (4.78 g, 37.04 mmol) were added and stirred at room temperature for 4 h. Water (50 mL) was added for dilution, followed by extraction with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA) to give 1.40 g of a white solid in 63% yield. LC-MS [M+H] + : 237.9.

[0268] 11.2 Preparation of compound N-(4-bromophenyl)-2-chloropyrimidin-4-amine (L011-2) 2,4-Dichloropyrimidine (500 mg, 3.38 mmol) was dissolved in acetonitrile (5 mL), 4-bromoaniline (577 mg, 3.38 mmol) and N,N-diisopropylethylamine (872 mg, 6.76 mmol) were added, and the mixture was heated to reflux and reacted for 24 hours. After concentration under reduced pressure, the crude product was separated by silica gel column chromatography (PE / EA = 2 / 1) to obtain 800 mg of a white solid in 83% yield. LC-MS [M + H] + : 283.9.

[0269] 11.3 Preparation of compound (2-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L011-3) N-(4-Bromophenyl)-2-chloropyrimidin-4-amine (800 mg, 2.82 mmol) was dissolved in acetonitrile (5 mL), and (3,3-difluoroazetidin-1-yl)(1H-indazol-5-yl)methyl ketone (735 mg, 3.10 mmol) and acetic acid (0.1 mL) were added. The mixture was stirred at 140 °C for 1 h in a microwave oven. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA) to give 250 mg of a colorless oily liquid as compound L011-3 in 18% yield. LC-MS [M+H] + : 484.8.

[0270] 11.4 Preparation of compound (2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L011) Under nitrogen gas protection, (2-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (250 mg, 0.51 mmol) was dissolved in dioxane (6 mL) and water (1 mL), and the solution was added with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolyl-1-carboxylate (180 mg, 0.61 mmol), potassium carbonate (140 mg, 10.2 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride(II) (37 mg, 0.051 mmol) and stirred at 80 °C for 3 h. The mixture was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (10 mL*3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and purified to give 23 mg of a white solid. The yield was 10%. LC-MS [M+H] + : =472.8.

[0271] 1 H NMR (400 MHz, DMSO) δ 12.93 (s, 1H), 10.16 (s, 1H), 9.31 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 8.30 (s, 1H), 8.19 (s,1H), 7.94 (s,1H),7.83-7.76 (m, 3H), 7.68 (d, J = 8.6 Hz, 2H), 7.63 (dd, J = 9.2, 1.5 Hz, 1H), 6.86 (d, J = 5.9 Hz, 1H), 4.72 (brs, 4H).

[0272] Example 12, Preparation of Compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-N-(pyridazin-4-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L012)

[0273] [ka]

[0274] Pyridazin-4-amine (34 mg, 0.36 mmol) was dissolved in DMF (4 mL) and 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (100 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and DIEA (93 mg, 0.72 mmol) were added. The mixture was reacted at room temperature for 2 hours under nitrogen gas protection. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified to give 2 mg of a white solid.

[0275] LC-MS [M+H] + :492.7.

[0276] 1 H NMR (400 MHz, DMSO) δ 12.98 (s, 1H), 10.23 (s, 1H), 9.47 (s, 1H), 9.35 (s, 1H), 8.99 (d, J = 5.8 Hz, 1H), 8.34 (s, 1H), 8.08 - 7.94 (m, 3H), 7.66 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H), 6.09 (d, J = 6.0 Hz, 1H), 4.85 (s, 2H), 4.05 - 3.97 (m, 2H), 3.85 (s, 3H), 3.54 - 3.46 (m, 2H).

[0277] Example 13, Preparation of compound 2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (L013)

[0278] [ka]

[0279] 13.1 Preparation of Compound 1H-Pyrrolo-2,4-dicarboxylate Diethyl (L013-1) Under nitrogen gas protection, ethyl 2-isocyanatoacetate (5.0 g, 44.2 mmol) was dissolved in methyl tert-butyl ether (50 mL). Ethyl propiolate (4.3 g, 44.2 mmol) was added to the reaction mixture. Potassium tert-butoxide (6.9 g, 61.9 mmol) was added to the reaction mixture in an ice-salt bath. The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was quenched with water (50 mL) and extracted with methyl tert-butyl ether (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give 2.5 g of a yellow oily liquid in 26.9% yield. LC-MS [M+H] + : 212.0.

[0280] 13.2 Preparation of compound 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrolo-2,4-dicarboxylate diethyl (L013-2) Under hydrogen gas protection, diethyl 1H-pyrrolo-2,4-dicarboxylate (2.5 g, 11.8 mmol) was dissolved in anhydrous DMSO (20 mL), tert-butyl (2-bromoethyl)carbamate (7.9 g, 35.4 mmol), and potassium carbonate (4.9 g, 35.4 mmol) were added, and the mixture was stirred at 80 °C overnight. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 2.0 g of a yellow oily liquid in 47.9% yield. LC-MS [M + Na] + : 376.9.

[0281] 13.3 Preparation of compound 1-(2-aminoethyl)-1H-pyrrolo-2,4-dicarboxylate diethyl ester (L013-3) Under nitrogen gas protection, 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrolo-2,4-dicarboxylate diethyl ester (2.0 g, 5.6 mmol) was dissolved in absolute ethanol (10 mL), and 33% hydrogen chloride ethanol solution (5 mL) was added and stirred at room temperature for 2 hours. After concentration, 2.2 g of a yellow oily liquid was obtained, and the crude product was used directly in the next reaction. LC-MS [M+H] + :255.1.

[0282] 13.4 Preparation of the compound ethyl 1-carbonyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (L013-4) Under nitrogen gas protection, diethyl 1-(2-aminoethyl)-1H-pyrrolo-2,4-dicarboxylate (1.5 g, 5.9 mmol) was dissolved in absolute ethanol (15 mL), potassium carbonate (4.1 g, 29.5 mmol) was added, and the reaction mixture was refluxed for 12 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give 600 mg of a colorless oily liquid in 48.9% yield. LC-MS [M+H] + : 209.1.

[0283] 13.5 Preparation of compound ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (L013-5) Under hydrogen gas protection, ethyl 1-carbonyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (600 mg, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and borane (12.4 mL, 12.4 mmol) was added, followed by stirring at 80°C for 3 hours. The mixture was cooled to room temperature and quenched by the slow dropwise addition of methanol (2 mL). After stirring for 20 minutes, 1 N dilute hydrochloric acid (20 mL) was slowly added dropwise and stirred for 20 minutes. Water (10 mL) was added and extracted with ethyl acetate (20 mL). The aqueous phase was adjusted to pH 9 with 1 N NaOH solution and extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 200 mg of a colorless oil. The yield was 33.1%. MS [M / 2 +H]+ = 195.1.

[0284] 13.6 Preparation of compound ethyl 2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (L013-6) Under nitrogen gas protection, ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (200 mg, 1.0 mmol) was dissolved in n-butanol (5 mL), tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (408 mg, 1.1 mmol), and DIEA (400 mg, 3.1 mmol) were added, and the mixture was stirred at 120 °C for 12 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure. The crude product was purified on a silica gel column (DCM / MeOH=20 / 1) to give 200 mg of a pale yellow solid in 46.5% yield. LC-MS [M+H] + : 430.1.

[0285] 13.7 Preparation of the compound 2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (L013) Ethyl 2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (200 mg, 0.5 mmol) was dissolved in methanol / water / tetrahydrofuran (1 / 1 / 3 = 10 mL), lithium hydroxide (100 mg, 2.5 mmol) was added, and the mixture was allowed to react at room temperature overnight. After concentration under reduced pressure, the pH was adjusted to 5-6 with 1 N dilute hydrochloric acid, and the mixture was concentrated under reduced pressure to give 400 mg of a yellow solid, which was the crude product. LC-MS [M + H] + : 402.0.

[0286] Example 14, Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-N,1-dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L014)

[0287] [ka]

[0288] 6-(4-((4-(1H-Pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (200 mg, 0.71 mmol) was dissolved in N,N-dimethylformamide (6 mL). HATU (274 mg, 0.72 mmol), 3,3-difluoro-N-methylcyclobutan-1-amine hydrochloride (M001) (87 mg, 0.72 mmol), and N,N-diisopropylethylamine (248 mg, 1.92 mmol) were added and stirred at room temperature overnight. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (dichloromethane:ethyl acetate=1:1), collected and freeze-dried to give 24.4 mg of white solid product 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-N,1-dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, yield 9.8%. LC-MS [M+H] + : 519.1.

[0289] 1 H NMR (400 MHz, DMSO) δ 12.85 (brs, 1H), 10.20 (brs, 1H)8.05 (s, 2H), 7.94 (d, J = 6.5 Hz, 1H), 7.64 (s, 4H), 6.28 - 6.24 (m, 2H), 4.83 (s, 2H), 4.70 - 4.60 (m, 1H), 4.02 - 3.96 (m, 2H), 3.58 (s, 3H), 3.00 (s, 3H), 2.95 - 2.80 (m, 4H), 2.66 - 2.60 (m, 2H).

[0290] Example 16, Preparation of compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone

[0291] [ka]

[0292] 16.1 Preparation of compound N-(4-bromo-3-fluorophenyl)-2-chloropyrimidin-4-amine (L016-1): Under nitrogen gas protection, 2,4-dichloropyrimidine (1000 mg, 6.7 mmol) was dissolved in n-butanol (5 mL), 4-bromo-3-fluoroaniline (1274 mg, 6.7 mmol), and DIEA (2601 mg, 20.1 mmol) were added, and the mixture was heated to 120 °C and reacted for 8 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 600 mg of a yellow solid in 29.6% yield. LC-MS [M+H] + : 301.9 / 303.9.

[0293] 16.2 Preparation of compound (6-(4-((4-bromo-3-fluorophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L016-2): N-(4-Bromo-3-fluorophenyl)-2-chloropyrimidin-4-amine (500 mg, 1.6 mmol) was dissolved in n-butanol (5 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (421 mg, 1.6 mmol) and DIEA (639 mg, 4.9 mmol) were added. The mixture was heated to 120 °C and reacted for 8 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 450 mg of a yellow solid. LC-MS [M + H] + : 520.7.

[0294] 16.3 Preparation of compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L016-3): (6-(4-((4-Bromo-3-fluorophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (500 mg, 0.9 mmol) was dissolved in 1,4-dioxane (10 mL). tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolyl-1-carboxylate (366 mg, 1.4 mmol), Pd(dppf)Cl2 (70 mg, 0.09 mmol), and potassium acetate (282 mg, 2.9 mmol) were added, and the mixture was reacted at 80 °C for 12 hours under nitrogen gas protection. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by wet silica gel column chromatography (PE / EA = 5 / 1) to give 500 mg of a brown oily liquid. MS [M + H] + =569.2.

[0295] 16.4 Preparation of compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L016-4): (3,3-Difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (500 mg, 0.9 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 4-bromo- 3Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl (426 mg, 1.4 mmol), Pd(PPh3)4 (111 mg, 0.09 mmol), and potassium carbonate (398 mg, 2.9 mmol) were added, and the mixture was reacted at 90 °C for 4 hours under nitrogen gas protection. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA = 1 / 1) to obtain 100 mg of a yellow oily liquid. MS [M + H] + =657.0.

[0296] 16.5 The compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L01 6) Manufactured by: (3,3-Difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (150 mg, 0.2 mmol) was dissolved in ethanol (5 mL), and a solution of hydrochloric acid in ethanol (2 mL, mass fraction 33%) was added. The mixture was allowed to react at room temperature for 2 hours under nitrogen gas protection. The mixture was concentrated under reduced pressure, and after concentration, 7.6 mg of a white solid was obtained by purification and isolation. MS [M + H] + =527.0.

[0297] MS [M + H] +=527.0. 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 9.63 (s, 1H), 8.03 (d, J = 5.7 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.51 (t, J = 8.6 Hz, 1H), 7.34 (d, J = 6.9 Hz, 1H), 6.47 (s, 1H), 6.12 (d, J = 5.7 Hz, 1H), 4.81 (s, 2H), 4.65-4.65 (m, 4H), 3.99 (t, J = 5.6 Hz, 2H), 3.77 (s, 3H), 2.61-2.55 (m, 2H).

[0298] Example 17, Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L017)

[0299] [ka]

[0300] 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (70 mg, 0.17 mmol) was dissolved in nitrogen, nitrogen-dimethylformamide (5 mL), and 2,2,2-trifluoroethane-1-amine (25 mg, 0.25 mmol), 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ester (96 mg, 0.25 mmol), and nitrogen, nitrogen-diisopropylethylamine (110 mg, 0.84 mmol) were added sequentially, and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (15 mL*3), the organic phases were combined, washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by silica gel column (4 g, dichloromethane:methanol=20:1) and then freeze-dried to obtain a white solid product. Compound titled as 6.7 mg was obtained, with a yield of 5.39%. LC-MS [M+H] + : 497.0.

[0301] 1 H NMR (301 MHz, CD3OD) δ 8.00 (s, 2H), 7.92 (d, J = 5.9 Hz, 1H), 7.74 - 7.56 (m, 4H), 6.72 (s, 1H), 6.20 (d, J = 6.1 Hz, 1H), 4.85 (s, 2H), 4.03 (dd, J = 18.8, 9.1 Hz, 4H), 3.88 (s, 3H), 2.72 (s, 2H).

[0302] Example 19, Preparation of compound (3,3-difluoroazetidin-1-yl)(6-(4-(4-(3-fluoro-1H-pyrazolyl-4-yl)benzyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L019)

[0303] [ka]

[0304] 19.1 Preparation of compound (6-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L019-1): N-(4-bromophenyl)-2-chloropyrimidin-4-amine (150 mg, 0.5 mmol) was dissolved in n-butanol (5 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (127 mg, 0.5 mmol) and DIEA (129 mg, 1 mmol) were added. The mixture was heated to 120 °C and reacted for 8 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 500 mg of a yellow solid. LC-MS [M + H] + : 503.0.

[0305] 19.2 Preparation of compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L019-2): (6-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (200 mg, 0.4 mmol) was dissolved in 1,4-dioxane (10 mL). tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolyl-1-carboxylate (152 mg, 0.6 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), and potassium acetate (78 mg, 0.8 mmol) were added, and the mixture was reacted at 80 °C for 12 hours under nitrogen gas protection. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by wet silica gel column chromatography (PE / EA = 5 / 1) to give 200 mg of a brown oily liquid. MS [M + H] + =551.2.

[0306] 19.3 Preparation of compound (3,3-difluoroazetidin-1-yl)(6-(4-((4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L019-3): (3,3-Difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (200 mg, 0.4 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 4-bromo- 3Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl (177 mg, 0.6 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol), and potassium carbonate (110 mg, 0.8 mmol) were added, and the mixture was reacted at 90 °C for 4 hours under nitrogen gas protection. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA = 5 / 1) to obtain 100 mg of a yellow oily liquid. MS [M + H] + =639.0. 19.4 Preparation of the compound (3,3-difluoroazetidin-1-yl)(6-(4-(4-(3-fluoro-1H-pyrazolyl-4-yl)benzyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L019): (3,3-Difluoroazetidin-1-yl)(6-(4-((4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (100 mg, 0.2 mmol) was dissolved in ethanol (5 mL), and a solution of hydrochloric acid in ethanol (2 mL, mass fraction 33%) was added. The mixture was allowed to react at room temperature for 2 hours under nitrogen gas protection. The mixture was concentrated under reduced pressure, and after concentration, 3.5 mg of a white solid was obtained by purification and isolation. MS [M + H] + =509.0.

[0307] 1H NMR (400 MHz, MeOD) δ 7.95 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 7.1 Hz, 1H), 7.64 (s, 4H), 6.49 (s, 1H), 6.34 (d, J = 7.0 Hz, 1H), 4.84 (s, 1H), 4.65-4.48 (m, 4H), 4.06-3.98 (m, 2H), 3.80 (s, 3H), 2.75 (t, J = 5.5 Hz, 2H).

[0308] Example 20, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L020)

[0309] [ka]

[0310] 20.1 Preparation of compound ethyl 4-formyl-1H-pyrrolo-2-carboxylate (L020-1): Ethyl pyrrole-2-carboxylate (6.9 g, 49.6 mmol) and aluminum trichloride (13.2 g, 99.2 mmol) were added to 1,2-dichloroethane-nitromethane (1:1, 100 mL). The temperature was lowered to -20 °C, and dichloro(methoxy)methane (11.4 g, 99.2 mmol) was added dropwise. The mixture was stirred for 1 hour and then allowed to stand at -20 °C overnight. The reaction mixture was poured into 100 mL of ice water, the organic phase was separated, and the aqueous layer was extracted with DCM (3 x 100 mL), washed with aqueous ammonia (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (petroleum ether:ethyl acetate = 1:1) to give 5.0 g of a yellow solid, ethyl 4-formyl-1H-pyrrolo-2-carboxylate, in 54% yield. MS: [M+H] + =168.0.

[0311] 20.2 Preparation of compound ethyl 4-((dimethylamino)methyl)-1H-pyrrolo-2-carboxylate (L020-2): At room temperature, 4-formyl-1H-pyrrolo-2-carboxylic acid ethyl A mixture of (5.0 g, 29.9 mmol) and dimethylamine (2 N in THF, 0.45 mL) in MeOH (3 mL) was added in portions with sodium triacetoxyborohydride (381.5 mg, 1.8 mmol). The mixture was stirred for 16 h, concentrated under reduced pressure, washed with water (100 mL), extracted with DCM (3 x 50 mL), adjusted to pH 12 with NaCO, and extracted with DCM (3 x 50 mL) to give 4.3 g of a colorless oily liquid, ethyl 4-((dimethylamino)methyl)-1H-pyrrolo-2-carboxylate. MS: [M+H] + =197.1.

[0312] 20.3 Preparation of compound 1-(5-(ethoxycarbonyl)-1H-pyrrolo-3-yl)-N,N,N-trimethylcarboxamide (L020-3): Ethyl 4-((dimethylamino)methyl)-1H-pyrrolo-2-carboxylate (4.3 g, 21.9 mmol) was dissolved in 80 mL of THF:DCM (1:1) at room temperature, methyl iodide (15.5 g, 11.0 mmol) was added, and the mixture was stirred for 15 hours. The mixture was concentrated under reduced pressure, and ethyl acetate was added. The mixture was stirred for 1 hour and then suction filtered to obtain 4.7 g of a white solid, 1-(5-(ethoxycarbonyl)-1H-pyrrolo-3-yl)-N,N,N-trimethylcarboxamide, in a 63% yield. MS: [M+H] + =211.0.

[0313] 20.4 Preparation of compound ethyl 4-(cyanomethyl)-1H-pyrrolo-2-carboxylate (L020-4): 1-(5-(Ethoxycarbonyl)-1H-pyrrolo-3-yl)-N,N,N-trimethylcarboxamide (4.67 g, 13.8 mmol) was added to ethanol (30 mL), and NaCN (2.6 g, 53.1 mmol) was added. The mixture was heated to 78 °C and refluxed for 15 h. The mixture was concentrated under reduced pressure, washed with water (20 mL), extracted with ethyl acetate (3 x 20 mL), and the organic phase was concentrated. The crude product was purified by column chromatography on silica gel (dichloromethane:methanol = 20:1) to give 2.0 g of ethyl 4-(cyanomethyl)-1H-pyrrolo-2-carboxylate as a colorless oil in 81% yield. MS: [M+H] + =179.0.

[0314] 20.5 Preparation of compound ethyl 4-(2-cyanopropan-2-yl)-1-methyl-1H-pyrrolo-2-carboxylate (L020-5): Under nitrogen gas protection, ethyl 4-(cyanomethyl)-1H-pyrrolo-2-carboxylate (300 mg, 1.68 mmol) was added to N,N-dimethylformamide (5 mL) and cooled to -50 °C. Sodium hydride (336.0 g, 8.4 mmol) was added, followed by dropwise addition of methyl iodide (1.19 g, 8.4 mmol). After stirring for 0.5 h, the reaction was warmed to -5 °C and stirred for 3 h. Saturated NH4Cl (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL), concentrated, and the crude product was chromatographed on a silica gel column (PE: EtOAc = 10:1) to give 250 mg of a colorless oily liquid, ethyl 4-(2-cyanopropan-2-yl)-1-methyl-1H-pyrrolo-2-carboxylate, in 67% yield. MS: [M+H] + =221.0.

[0315] 20.6 Preparation of compound ethyl 4-(1-amino-2-methylpropan-2-yl)-1-methyl-1H-pyrrolo-2-carboxylate (L020-6): Ethyl 4-(1-cyano-1-methylethyl)-1-methylpyrrole-2-carboxylate (50 mg, 0.23 mmol) was added to formic acid (2 mL), Ni (0.3 mL) was added, and the mixture was heated to 100 °C and stirred for 2 h. After returning to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 50 mg of a colorless oily liquid, ethyl 4-(1-amino-2-methylpropan-2-yl)-1-methyl-1H-pyrrolo-2-carboxylate. MS: [M+H] + =225.0.

[0316] 20.7 Preparation of compound ethyl 1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L020-7): Ethyl 4-(1-amino-2-methylpropan-2-yl)-1-methyl-1H-pyrrolo-2-carboxylate (50 mg, 0.22 mmol) and trifluoroacetic acid (50.17 mg, 0.44 mmol) were added to dichloromethane (1 mL) at room temperature, followed by the addition of aqueous formaldehyde (13 mg, 0.45 mmol). The mixture was stirred for 4 hours and concentrated under reduced pressure to give 50 mg of a colorless oily liquid, ethyl 1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate. MS: [M+H] + =237.0.

[0317] 20.8 Preparation of compound 6-(tert-butoxycarbonyl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L020-8): Ethyl 1,4,4-trimethyl-5H,6H,7H-pyrrolo[2,3-c]pyridine-2-carboxylate (50 mg, 0.21 mmol) was dissolved in methanol (2 mL) at room temperature, and 5 mL of lithium hydroxide (1 N, dissolved in water) was added and stirred for 20 hours. Concentrated under reduced pressure, BocO (137.5 mg, 0.63 mmol) was added and stirred for 12 hours. Extracted with ethyl acetate (2 × 2 mL), the mixture was adjusted to pH 5 with hydrochloric acid, extracted with DCM (3 × 5 mL), and concentrated under reduced pressure to give 70 mg of 6-(tert-butoxycarbonyl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid as a colorless oil. MS: [M+Na] + =331.0.

[0318] 20.9 Preparation of compound tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1,4,4-trimethyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate (L020-9): At room temperature, 6-(tert-butyl-1'{3}-oxy)-1,4,4-trimethyl-5H,7H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (70 mg, 0.23 mmol), 3,3-difluoroazetidine (44.50 mg, 0.345 mmol), and HATU (131.2) were added to 1,2-dichloroethane (3 mL), and DIEA (89.2 mg, 0.7 mmol) was added. The mixture was stirred for 15 hours. Upon completion of the reaction, the mixture was washed with water (5 mL), extracted with ethyl acetate (3x5 mL), concentrated under reduced pressure, and purified by thin-layer chromatography (petroleum ether / ethyl acetate) = (1:1). 35 mg of tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1,4,4-trimethyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate was obtained as a colorless oily liquid in a yield of 49%. MS: [M+H] + =384.0.

[0319] 20.10 Preparation of compound (3,3-difluoroazetidin-1-yl)(1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L020-10): At room temperature, tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1,4,4-trimethyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate (35 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), 1 mL of HCl (4 N, dissolved in 1,4-dioxane) was added, the mixture was stirred for 1 hour, and concentrated under reduced pressure to give 30 mg of (3,3-difluoroazetidin-1-yl)(1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone as a white solid. MS: [M+H] + =284.0.

[0320] 20.11 Preparation of (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L020): Under nitrogen gas protection, (3,3-difluoroazetidin-1-yl)(1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (30 mg, 0.11 mmol) and N-(4-(1H-pyrazolyl-4-yl)phenyl)-2-chloropyrimidin-4-amine (61.52 mg, 0.165 mmol) were dissolved in n-butanol (0.5 mL), DIEA (71.08 mg, 0.55 mmol) was added, the mixture was heated to 120 °C, stirred for 5 hours, concentrated under reduced pressure, and purified by high performance liquid chromatography to give product 6.5. mg of (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone was obtained as a white solid, 12% yield. MS: [M+H] + =519.31.

[0321] 1 H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 8.26 (s, 1H), 8.02 (s, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 6.60 (s, 1H), 6.07 (d, J = 5.7 Hz, 1H), 4.74 (s, 2H), 4.58 (s, 4H), 3.76 (d, J = 3.4 Hz, 5H), 1.18 (s, 6H).

[0322] Compounds L015 and L022 were produced in accordance with the methods described in Examples 2 and 8 above.

[0323] Compound L018 was produced in accordance with the method described in Example 20 above.

[0324] Compounds L021, L023 and L024 were produced in accordance with the methods described in Examples 1, 4, 5, 9, 10, 12 and 14 above.

[0325] Characterization data for each compound is shown in the table below:

[0326] [Table 2]

[0327] Example 25, Preparation of compound (2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L025)

[0328] [ka]

[0329] Under nitrogen gas protection, the crude product 2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (L013) (200 mg) was dissolved in DMF (10 mL). 3,3-Difluorotrimethyllidenimide hydrochloride (39 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), and DIEA (129 mg, 1.0 mmol) were added and reacted at room temperature for 2 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to give 15 mg of a white solid.

[0330] LC-MS [M+H] + : 476.9.

[0331] 1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 8.04 (brs, 2H), 7.96 (d, J = 6.3 Hz, 1H), 7.75-7.57 (m, 4H), 7.32 (s, 1H), 6.30 (s, 1H), 6.24 (s, 1H), 4.86 (s, 2H), 4.71-4.41 (m, 4H), 4.17-4.05 (m, 4H).

[0332] Example 26, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-methoxypyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L026)

[0333] [ka]

[0334] 26.1 Preparation of compound N-(4-(1H-pyrazolyl-4-yl)phenyl)-2-chloro-5-methoxypyrimidin-4-amine (L026-1) 2,4-Dichloro-5-methoxypyrimidine (300 mg, 1.68 mmol) was dissolved in isopropanol (5 mL), and tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-carboxylate (436 mg, 1.68 mmol) and N,N-diisopropylethylamine (1.30 g, 10.08 mmol) were added. The mixture was stirred at 120 °C for 16 h under nitrogen gas protection. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (DCM / MeOH = 20 / 1) to give 450 mg of a white solid in 88% yield. LC-MS [M + H] + : 301.9.

[0335] 26.2 Preparation of the compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-methoxypyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone N-(4-(1H-pyrazolyl-4-yl)phenyl)-2-chloro-5-methoxypyrimidin-4-amine (100 mg, 0.33 mmol) was dissolved in isopropanol (0.5 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone hydrochloride (116 mg, 0.40 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) were added. The mixture was heated to 140°C in a microwave oven under nitrogen gas protection and reacted for 2 hours. After the reaction was completed, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 26.2 mg of a white solid in 15% yield. LC-MS [M + H] + : 520.9.

[0336] 1 H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 8.72 (s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.83-7.78 (m, 3H), 7.56 (d, J = 8.7 Hz, 2H), 6.45 (s, 1H), 4.71 (s, 2H), 4.65-4.48 (m, 4H), 3.89 (t, J = 5.5 Hz, 2H), 3.82 (s, 3H), 3.75 (s, 3H), 2.58-2.52 (m, 2H).

[0337] Example 27, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L027)

[0338] [ka]

[0339] 27.1 Preparation of compound tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L027-1): tert-Butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-carboxylate (M002) (1.8 g, 6.9 mmol) was dissolved in ethanol (20 mL), and 2,4-dichloro-5-fluoropyrimidine (2.3 g, 13.8 mmol) and DIEA (3.6 g, 27.6 mmol) were added sequentially. The reaction mixture was stirred at 40 °C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched by adding water (20 mL), extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified on a silica gel column (PE / EA = 3 / 1) to give 2.3 g of brown solid product in 85.2% yield. LC-MS [M+H] + : 389.9.

[0340] 27.2 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L027): tert-Butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (1.6 g, 12.3 mmol) was dissolved in n-butanol (16 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone hydrochloride (784 mg, 3.1 mmol) and DIEA (1.2 g, 3.1 mmol) were added to the system, followed by stirring at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature and quenched with water (20 mL), extracted with ethyl acetate (20 mL * 3), and the combined organic phases were washed with saturated brine (20 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was chromatographed on a silica gel column (DCM / MeOH = 20 / 1) and then lyophilized to give 600 mg of a white solid. LC-MS [M+H] + : 508.7.

[0341] 1 H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 9.34 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 3.7 Hz, 1H), 7.91 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 6.46 (s, 1H), 4.73 (s, 2H), 4.56 (s, 4H), 3.92 (t, J = 5.5 Hz, 2H), 3.74 (s, 3H), 2.55 (t, J = 5.2 Hz, 2H).

[0342] Example 28, Preparation of compound (2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L028)

[0343] [ka]

[0344] 28.1 Preparation of compound tert-butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (L028-1) 2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (300 mg, 1.08 mmol) was dissolved in nitrogen, nitrogen-dimethylformamide (10 mL), and 3,3-difluoroazetidine (210 mg, 1.62 mmol), 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ester (615 mg, 1.62 mmol), and nitrogen, nitrogen-diisopropylethylamine (557 mg, 4.32 mmol) were added sequentially, followed by stirring at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (15 mL*3), the combined organic phases were washed with saturated brine (30 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified on a silica gel column (4 g, petroleum ether:ethyl acetate=3:1) to obtain 350 mg of white solid product, tert-butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, in a yield of 91.80%. LC-MS [M+H] + : 375.0.

[0345] 28.2 Preparation of compound (3,3-difluoroazetidin-1-yl)(1,2,3,4-tetrahydroisoquinolin-7-yl)methyl ketone hydrochloride (L028-2) tert-Butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.85 mmol) was dissolved in dichloromethane (3 mL). A 33% solution of hydrochloric acid in dioxane (1 mL) was added to the mixture and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was spun to dryness to obtain 270 mg of crude brown solid product (3,3-difluoroazetidin-1-yl)(1,2,3,4-tetrahydroisoquinolin-7-yl)methyl ketone hydrochloride, which was used directly in the next reaction. LC-MS [M+H] + : 253.0.

[0346] 28.3 Preparation of the compound (2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L028) (3,3-Difluoroazetidin-1-yl)(1,2,3,4-tetrahydroisoquinolin-7-yl)methyl ketone hydrochloride (100 mg, 0.27 mmol) was dissolved in n-butanol (5 mL), and tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (81 mg, 0.32 mmol) and N,N-diisopropylethylamine (105 mg, 0.81 mmol) were added, followed by reaction at room temperature (120°C) overnight. After the reaction was completed, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (15 mL*3), and the combined organic phases were washed with saturated brine (30 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified on a silica gel column (4 g, dichloromethane:methanol=20:1) and then lyophilized to give a white solid product (2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(3,3-difluoroazetidin-1-yl)methyl ketone 32.6 mg, 24.74% yield. LC-MS [M+H] + : 488.0.

[0347] 1 H NMR (301 MHz, DMSO) δ 12.84 (s, 1H), 9.38 (s, 1H), 8.16 - 7.91 (m, 3H), 7.66 (d, J = 8.7 Hz, 2H), 7.62 - 7.52 (m, 3H), 7.49 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 6.07 (d, J = 5.8 Hz, 1H), 4.90 (s, 2H), 4.78 (s, 2H), 4.47 (s, 2H), 3.98 (t, J = 5.7 Hz, 2H), 2.92 (t, J = 5.4 Hz, 2H).

[0348] Example 30, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L030)

[0349] [ka]

[0350] 30.1 Preparation of compound tert-butyl 4-(4-((2,6-difluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L030-1) tert-Butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-carboxylate (500 mg, 1.93 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and 2,4,6-trifluoropyrimidine (258 mg, 1.93 mmol) and N,N-diisopropylethylamine (747 mg, 5.79 mmol) were added sequentially, followed by stirring at 0°C overnight. After the reaction was completed, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (15 mL*3), the combined organic phases were washed with saturated brine (30 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified on a silica gel column (4 g, petroleum ether:ethyl acetate=3:1) to obtain 200 mg of white solid product, tert-butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, in a yield of 27.70%. LC-MS [M+H] + : 374.0.

[0351] 30.2 Preparation of compound tert-butyl 4-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-6-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L030-2) tert-Butyl 4-(4-((2,6-difluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (120 mg, 0.32 mmol) was dissolved in acetonitrile (5 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone hydrochloride (140 mg, 0.48 mmol) and N,N-diisopropylethylamine (156 mg, 1.21 mmol) were added to the system and stirred at 50 °C overnight. After the reaction was completed, the reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL*3), and the combined organic phases were washed with saturated brine (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified on a silica gel column (4 g, dichloromethane:methanol=20:1) and then lyophilized to obtain 130 mg of white solid product, tert-butyl 4-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-6-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate, with a yield of 66.71%. LC-MS [M+H] + : 609.0.

[0352] 30.3 Preparation of the compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L030) tert-Butyl 4-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-6-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (130 mg, 0.21 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added to the system, followed by stirring at room temperature overnight. After the reaction was completed, the system was spun down and the crude product was purified using a Gemini-C18 150 x 21.2 mm, 5 μm column (flow rate: ACN-HO (0.1% FA), gradient: 20-35). The product was then lyophilized to give 81.9 mg of a white solid product (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone, a yield of 76.19%. LC-MS [M+H] + : 509.0.

[0353] 1 H NMR (301 MHz, DMSO) δ 9.58 (s, 1H), 8.01 (s, 2H), 7.57 (s, 4H), 6.46 (s, 1H), 5.62 (s, 1H), 4.76 (s, 2H), 4.55 (t, J = 11.6 Hz, 4H), 3.94 (s, 2H), 3.75 (s, 3H), 2.56 (s, 2H).

[0354] Example 31, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L031)

[0355] [ka]

[0356] 31.1 Preparation of compound 2-chloro-N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)phenyl)-7,8-dihydro-5H-pyran[4,3-d]pyrimidin-4-amine (L031-1): 2,4-Dichloro-7,8-dihydro-5H-pyrano[4,3-D]pyrimidine (150 mg, 0.732 mmol) and 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)aniline (178 mg, 0.732 mmol) were dissolved in n-butanol (10 mL), DIPEA (189 mg, 1.464 mmol) was added, and the atmosphere was purged with N2 three times. The reaction was stirred at 110 °C for 48 h. When LCMS showed the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE / EA = 3:1 to 1:3) to give 140 mg of a tan solid. LC-MS: [M+H] + =412.15.

[0357] 31.2 Preparation of compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)phenyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L031-2): L031-1 (140 mg, 0.341 mmol), (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (104 mg, 0.409 mmol), Pd(dba) (31 mg, 0.034 mmol), Xantsphos (39 mg, 0.068 mmol), and CsCO (222 mg, 0.682 mmol) were weighed, 1,4-dioxane was added, the atmosphere was purged with N, and the reaction was allowed to proceed overnight at 90 °C. When LCMS showed the reaction was complete, the reaction mixture was cooled to room temperature, and the 1,4-dioxane was removed by rotary evaporation. The mixture was diluted with HO (30 mL) and extracted three times with EA (50 mL). The EA phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified using a silica gel column (DCM / MeOH=20:1) to give 44 mg of a yellow solid product. LC-MS: [M+H] + =631.25.

[0358] 31.3 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L031): L031-2 (39 mg, 0.063 mmol) and acidic resin (40 mg) were weighed into a 25 mL round-bottom flask, and methanol (8 mL) and 4 M HCl / dioxane (0.4 mL) were added. The mixture was allowed to react at room temperature for 1 h. When LCMS showed the reaction was complete, the pH was adjusted to 8 with triethylamine and the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified and separated by prep-HPLC. After lyophilization, a white solid product (2.0 mg, purity 95.573%) was obtained. LC-MS: [M+H] + =547.25.

[0359] 1H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.60 (d, J = 9.4 Hz, 2H), 6.46 (s, 1H), 4.74 (s, 1H), 4.56 (d, J = 10.3 Hz, 3H), 3.91 (t, J = 5.5 Hz, 2H), 3.70 (s, 1H), 2.71 (s, 1H), 2.57 (s, 1H).

[0360] Example 32, Preparation of compound 2,2,2-trifluoroethyl 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ester (L032)

[0361] [ka]

[0362] 32.1 Preparation of compound 6-tert-butyl 2-(2,2,2-trifluoroethyl)1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-2,6(7H)-dicarboxylate (L032-1) 6-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (90 mg, 0.32 mmol) was dissolved in anhydrous dichloromethane (5 mL), and 2,2,2-trifluoroethanol (38 mg, 0.38 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.38 mmol), and 4-dimethylaminopyridine (47 mg, 0.38 mmol) were added. The mixture was stirred at room temperature for 4 h under nitrogen gas protection, diluted with water (10 mL), extracted with dichloromethane (5 mL*2), and the combined organic phases were washed with dilute hydrochloric acid (1 N) (5 mL*2), saturated sodium bicarbonate (5 mL*2), and saturated brine (10 mL*2). mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA=20 / 1) to obtain 90 mg of a colorless oily liquid in 77% yield. LC-MS [M+H] + : 362.9.

[0363] 32.2 Preparation of compound 2,2,2-trifluoroethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L032-2) 6-tert-Butyl 2-(2,2,2-trifluoroethyl) 1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-2,6(7H)-dicarboxylate (90 mg, 0.25 mmol) was dissolved in anhydrous dichloromethane (3 mL), and hydrochloric acid in dioxane (1 mL) was added. The mixture was reacted at room temperature under nitrogen gas protection for 2 hours. After the reaction was completed, the mixture was concentrated to give 80 mg of the crude product as a pale yellow solid. LC-MS [M+H] + : 262.8.

[0364] 32.3 Preparation of compound 2,2,2-trifluoroethyl 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ester (L032) The crude product, 2,2,2-trifluoroethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate hydrochloride (80 mg, 0.25 mmol) was dissolved in n-butanol (2 mL), and N,N-diisopropylethylamine (97 mg, 0.75 mmol) and N-(4-(1H-pyrazolyl-4-yl)phenyl)-2-chloropyrimidin-4-amine (94 mg, 0.33 mmol) were added. The mixture was heated to 120 °C under nitrogen gas protection and reacted for 4 hours. After the reaction was complete, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give 47.9 mg of a white solid. The two-step yield was 38%. LC-MS [M+H] + : 497.8.

[0365] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.08 (s, 2H), 7.96 (d, J = 6.9 Hz, 2H), 7.72-7.60 (m, 4H), 6.85 (s, 1H), 6.34 (d, J = 6.8 Hz, 1H), 4.95-4.82 (m, 4H), 4.03-3.93 (m, 2H), 3.80 (s, 3H), 2.72-2.63 (m, 2H).

[0366] Example 34, Preparation of compound 4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)pyrimidine-5-carbonitrile (L034)

[0367] [ka]

[0368] 34.1 Preparation of the compound 2-(methylthio)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (L034-1) 4-Chloro-2-(methylthio)pyrimidine-5-carbonitrile (300 mg, 1.62 mmol) was dissolved in n-butanol (4 mL), and 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)aniline (468 mg, 1.62 mmol) and N,N-diisopropylethylamine (418 mg, 3.24 mmol) were added. The mixture was reacted at 90 °C for 4 h under nitrogen gas protection. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA = 5 / 1) to obtain 540 mg of a white solid in 76% yield. LC-MS [M+H] + : 438.9.

[0369] Among these, 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)aniline (M005) was produced by reference to the production method for L038-1 described in Example 38 below.

[0370] 34.2 Preparation of compound 2-(methylsulfonyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (L034-2) 2-(Methylthio)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (200 mg, 0.46 mmol) was dissolved in anhydrous dichloromethane (5 mL), m-chloroperoxybenzoic acid (280 mg, 1.38 mmol) was added, and the mixture was reacted at room temperature for 2 hours under nitrogen gas protection. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate solution (10 mL) until the aqueous phase reached a pH of approximately 10. The mixture was extracted with dichloromethane (10 mL * 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA = 3 / 1) to obtain 110 mg of a white solid in 51% yield. LC-MS [M+H] + : 471.2.

[0371] 34.3 Preparation of compound 2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (L034-3) 2-(Methylsulfonyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (110 mg, 0.23 mmol) was dissolved in n-butanol (3 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone hydrochloride (80 mg, 0.28 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol) were added. The mixture was reacted at 120 °C for 4 hours under nitrogen gas protection. After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL*2), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA=5 / 1) to give 100 mg of a yellow solid in 65% yield. LC-MS [M+H] + : 645.8.

[0372] 34.4 Preparation of the compound 4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)pyrimidine-5-carbonitrile (L034) 2-(2-(3,3-Difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (100 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid in 1,4-dioxane (1 mL) was added. The mixture was reacted at room temperature for 2 hours under nitrogen gas protection. After the reaction was completed, the mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL*2). The aqueous phase was adjusted to a pH of about 10 with sodium hydroxide (2 N). The mixture was extracted with dichloromethane (5 mL*2). The organic phases were combined and the mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give 43 mg of a white solid, with a yield of 55%. LC-MS [M+H] + : 515.8.

[0373] 1 H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 8.38 (s, 1H), 7.92 (s, 2H), 7.60 - 7.49 (m, 4H), 6.39 (s, 1H), 4.79 (s, 2H), 4.50 (t, J = 12.5 Hz, 4H), 3.99 (t, J = 5.8 Hz, 2H), 3.69 (s, 3H), 2.56 (t, J = 5.6 Hz, 2H).

[0374] Example 35, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L035)

[0375] [ka]

[0376] 35.1 Preparation of compound tert-butyl 4-(4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L035-1) 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (100 mg, 0.46 mmol) was dissolved in n-butanol (2 mL) and N,N-diisopropylethylamine (118 mg, 0.92 mmol) was added. Under nitrogen gas protection, the temperature was lowered to -20 °C, and tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-carboxylate (143 mg, 0.55 mmol) was slowly added to the reaction mixture. The mixture was stirred for 1 h, then warmed to room temperature and stirred for 5 h. After the reaction was complete, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA = 8 / 1) to obtain 120 mg of a white solid (including isomers). LC-MS [M+H] + : 439.8.

[0377] 35.2 Preparation of the compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L035) tert-Butyl 4-(4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (including isomers) (120 mg, 0.27 mmol) was dissolved in n-butanol (2 mL), and N,N-diisopropylethylamine (106 mg, 0.82 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone carbonate (94 mg, 0.33 mmol) were added. The mixture was heated to 120 °C under nitrogen gas protection and reacted for 4 hours. After the reaction was complete, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give 30.2 mg of a white solid, with a two-step yield of 20%. LC-MS [M+H] + : 558.9.

[0378] 1 H NMR (400 MHz, DMSO) δ 12.93 (s, 1H), 8.61 (d, J = 29.9 Hz, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.51 (s, 2H), 6.45 (s, 1H), 4.90-4.65 (m, 2H), 4.60-4.42 (m, 4H), 4.12-3.80 (m, 2H), 3.76 - 3.50 (m, 3H), 2.56-2.52 (m, 2H).

[0379] Example 36, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L036)

[0380] [ka]

[0381] 36.1 Preparation of compound tert-butyl 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-formate (L036-1): 2,4-Dichloro-1,3,5-triazine (120 mg, 0.80 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (219 mg, 0.84 mmol) were added to ethanol (3 mL), followed by diisopropylethylamine (517 mg, 4.0 mmol), and the mixture was stirred at 70 °C for 5 h. When the mass detector detected the completion of the reaction, the mixture was suction filtered to give 100 mg of tert-butyl 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-formate as a white solid, with a yield of 31.43%. MS (M+H) + =372.7.

[0382] 36.2 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L036): tert-Butyl 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-formate (50 mg, 0.13 mmol) and 3,3-difluoro-1-((1-methyl-4H,5H,6H,7H-pyrrolo(2,3-c)pyridin-2-yl)carbonyl)azetidine (34 mg, 0.13 mmol) were added to n-butanol (2 mL), followed by diisopropylethylamine (86 mg, 0.7 mmol). The mixture was heated at 120 °C for 5 min. The mixture was stirred for 1 hour. When the mass detector detected the completion of the reaction, 24.2 mg of a white solid (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone was obtained, for a yield of 36.55%. MS (M+H) + =492.2.

[0383] 1 H NMR (400 MHz, DMSO) δ 12.89 (s, 1H), 9.74 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.76 - 7.67 (m, J = 8.6 Hz, 2H), 7.61 - 7.51 (m, 2H), 6.49 (s, 1H), 4.86 (s, 2H), 4.57 (s, 4H), 4.03 (t, J = 5.5 Hz, 2H), 3.82 - 3.71 (m, J = 14.8 Hz, 3H), 2.63 - 2.56 (m, 2H).

[0384] Example 37, Preparation of compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L037)

[0385] [ka]

[0386] 37.1 Preparation of compound tert-butyl 4-(4-(((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)-1H-pyrazolyl-1-formate (L037-1): 3,5,6-Trichloro-1,2,4-triazine (205 mg, 1.4 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (353 mg, 1.4 mmol) were added to ethanol (5 mL), followed by diisopropylethylamine (350 mg, 2.7 mmol) and stirring at room temperature for 1 h. When the reaction was complete as detected by a mass detector, the mixture was concentrated to give 600 mg of tert-butyl 4-(4-(((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)-1H-pyrazolyl-1-formate, which was the crude product. MS (M+H) + =406.8.

[0387] 37.2 Preparation of compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L037-2): tert-Butyl 4-(4-(((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)-1H-pyrazolyl-1-formate (400 mg, 0.98 mmol) and 3,3-difluoro-1-((1-methyl-4H,5H,6H,7H-pyrrolo(2,3-c)pyridin-2-yl)carbonyl)azetidine (286 mg, 0.98 mmol) were added to n-butanol (10 mL), followed by diisopropylethylamine (633 mg, 4.9 mmol). The mixture was heated at 120 °C for 2 h. The mixture was stirred for 1 hour. When the mass detector detected the completion of the reaction, an aliquot was taken and purified to give 127.7 mg of a white solid (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone. MS (M+H) + =526.0.

[0388] 37.3 Preparation of compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L037): (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (the product of the previous step) was dissolved in methanol (10 mL), palladium carbon (50 mg) was added, and the mixture was stirred uniformly. Then, triethylamine (1 mL) was added, a hydrogen balloon was attached, hydrogen gas was replaced, and the mixture was stirred at room temperature for 10 hours. When the completion of the reaction was detected, the mixture was suction filtered, and the filtrate was concentrated to obtain 36.6 mg of white solid (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone, MS (M+H) + =491.8.

[0389] 1 HNMR (400 MHz, ) δ 12.88 (s, 1H), 9.96 (s, 1H), 8.22 - 7.87 (m, 3H), 7.71 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 6.48 (s, 1H), 4.86 (s, 2H), 4.57 (s, 4H), 4.01 (s, 2H), 3.78 (s, 3H), 2.60 (t, J = 5.4 Hz, 2H).

[0390] Example 38, Preparation of compound (6-(5-chloro-4-((4-(3-fluoro-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L038)

[0391] [ka]

[0392] 38.1 Preparation of compound 4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)aniline (L038-1): 4-Bromo-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl (500 mg, 1.70 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (446 mg, 2.04 mmol), potassium carbonate (73 mg, 0.38 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (124 mg, 0.17 mmol) were added. Under nitrogen gas protection, the mixture was heated to 90 °C and stirred for 4 h. The mixture was filtered, diluted with water (10 mL), extracted with ethyl acetate (10 mL*2), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA=5 / 1). mg of white solid was obtained, yield 57%. LC-MS [M+H] + : 307.8.

[0393] 38.2 Preparation of compound 2,5-dichloro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)pyrimidin-4-amine (L038-2): 4-(5-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)aniline (70 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 2,4,5-trichloropyrimidine (63 mg, 0.34 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol) were added. The mixture was incubated at room temperature under nitrogen gas protection for 5 hours. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA = 4 / 1) to give 90 mg of a yellow solid in 86% yield. LC-MS [M+H] + : 453.8.

[0394] 38.3 Preparation of compound (6-(5-chloro-4-((4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L038-3): 2,5-Dichloro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)pyrimidin-4-amine (90 mg, 0.19 mmol) was dissolved in n-butanol (2 mL), and N,N-diisopropylethylamine (73 mg, 0.57 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone hydrochloride (66 mg, 0.23 mmol) were added. The mixture was heated to 120 ° C. under nitrogen gas protection and reacted for 4 hours. After the reaction was complete, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA = 2 / 1) to obtain 110 mg of a white solid in 86% yield. LC-MS [M+H] + : 672.8.

[0395] 38.4 Preparation of compound (6-(5-chloro-4-((4-(3-fluoro-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L038): (6-(5-chloro-4-((4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (110 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added to the reaction mixture. The mixture was reacted at room temperature for 2 hours under nitrogen gas protection. After the reaction was complete, the mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL * 2). The aqueous phase was adjusted to pH 10 with 2N sodium hydroxide solution and extracted with dichloromethane (5 mL * 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give 45.3 mg of a white solid in 52% yield. LC-MS [M+H] + : 542.8.

[0396] 1 H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.86 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 6.45 (s, 1H), 4.72 (s, 2H), 4.68-4.48 (s, 4H), 3.98-3.90 (m, 2H), 3.71 (s, 3H), 2.55-2.53 (m, 2H).

[0397] Example 39, Preparation of compound (3-(difluoromethyl)azetidin-1-yl)(6-(5-fluoro-4-((4-(3-fluoro-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L039)

[0398] [ka]

[0399] 39.1 Preparation of compound tert-butyl 2-(3-(difluoromethyl)azetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (L039-1): 6-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (300 mg, 1.07 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and 3-(difluoromethyl)azetidine hydrochloride (183 mg, 1.28 mmol), 2-(7-benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (487 mg, 1.28 mmol), and N,N-diisopropylethylamine (414 mg, 3.21 mmol) were added. The mixture was stirred at room temperature under nitrogen gas protection for 4 h, diluted with water (10 mL), extracted with ethyl acetate (10 mL*2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA=3 / 1) to give 280 mg of a colorless oily liquid was obtained, with a yield of 71%. LC-MS [M+H] + : 369.9.

[0400] 39.2 Preparation of compound (3-(difluoromethyl)azetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L039-2): tert-Butyl 2-(3-(difluoromethyl)azetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (280 mg, 0.75 mmol) was dissolved in anhydrous dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature under nitrogen gas protection for 2 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL * 2). The aqueous phase was adjusted to pH 10 with aqueous sodium hydroxide (2 N), extracted with dichloromethane (10 mL * 2). The organic phases were combined and concentrated to give 160 mg of crude product as a yellow solid. LC-MS [M+H] + : 269.8.

[0401] 39.3 Preparation of compound 2-chloro-5-fluoro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)pyrimidin-4-amine (L039-3): 4-(5-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)aniline (80 mg, 0.26 mmol) was dissolved in absolute ethanol (3 mL), and N,N-diisopropylethylamine (100 mg, 0.78 mmol) and 2,4-dichloro-5-fluoropyrimidine (86 mg, 0.52 mmol) were added. The mixture was heated to 40 °C under nitrogen gas protection and reacted for 2 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a silica gel column (PE / EA = 3 / 1) to obtain 100 mg of a white solid in 88% yield. LC-MS [M+H] + : 438.2.

[0402] 39.4 Preparation of the compound (3-(difluoromethyl)azetidin-1-yl)(6-(5-fluoro-4-((4-(3-fluoro-1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L039): 2-Chloro-5-fluoro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-4-yl)phenyl)pyrimidin-4-amine (100 mg, 0.22 mmol) was dissolved in n-butanol (3 mL), and N,N-diisopropylethylamine (85 mg, 0.66 mmol) and (3-(difluoromethyl)azetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (71 mg, 0.26 mmol) were added to the reaction mixture, and the mixture was heated to 120 ° C. under nitrogen gas protection and reacted for 12 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give 10.9 mg of a white solid in 10% yield. LC-MS [M+H] + : 541.2.

[0403] NMR (400 MHz, ) DMSO δ 12.51 (s, 1H), 9.36 (s, 1H), 8.10 (t, J = 2.0 Hz, 1H), 8.03 (d, J = 3.7 Hz, 1H), 7.75 (d, J = 1.9 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 6.44 (d, J = 4.4 Hz, 0.25H), 6.33 (s, 1H), 6.29 (d, J = 4.3 Hz, 0.5H), 6.15 (d, J = 4.4 Hz, 0.25H), 4.68 (s, 2H), 4.35 - 4.00 (m, 4H), 3.87 (t, J = 5.6 Hz, 2H), 3.69 (s, 3H), 3.15 - 3.04 (m, 1H), 2.53 - 2.46 (m, 2H).

[0404] Example 40, Compound (6-(5-fluoro-4-((2-fluoro-4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl) (3 ,3 - J Preparation of fluoroazetidin-1-yl)methyl ketone (L040)

[0405] [ka]

[0406] 40.1 Preparation of compound 4-(3-fluoro-4-nitrophenyl)-1H-pyrazolyl (L040-1): 4-Bromo-2-fluoro-1-nitrobenzene (4.0 g, 18.18 mmol), tert-butyl (4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)pyrazolyl-1-yl)formate (8.02 g, 27.27 mmol), Pd(dppf)Cl2 (1.99 g, 2.732 mmol), and K2CO3 (7.54 g, 54.55 mol) were weighed and added to 1,4-dioxane (90 mL) and water (9 mL). The mixture was purged with nitrogen and heated to 100 °C for 3 h. When TLC showed the reaction was complete, the reaction mixture was cooled, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (PE / EA = 20 / 1 to 3 / 1). 2.3 g of a yellow solid powder was obtained.

[0407] 40.2 Preparation of compound tert-butyl 4-(4-amino-3-fluorophenyl)-1H-pyrazolyl-1-carboxylate (L040-2): L040-1 (500 mg, 2.41 mmol) and Pd / C (150 mg) were weighed and added to 5 mL of methanol. The mixture was purged with hydrogen gas and heated to 40 °C for 2 hours. LCMS indicated the completion of the reaction. After filtration, the solvent was removed by rotary evaporation to obtain 320 mg of a yellow oily liquid. LC-MS: [M+H] + =278.30.

[0408] 40.3 Preparation of compound tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-fluorophenyl)-1H-pyrazolyl-1-carboxylate (L040-3): 2,4-Dichloro-5-fluoropyrimidine (390 mg, 2.37 mmol) and L040-2 (540 mg, 1.95 mmol) were weighed into a 50 mL eggplant-shaped flask, dissolved in n-butanol, and then DIEA (1.01 g, 7.8 mmol) was added. The mixture was heated to 120 °C and reacted for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1), followed by further silica gel column chromatography (pure DCM) to obtain 70 mg of a yellow solid product. LC-MS: [M+H] + =308.04.

[0409] 40.4 The compound (6-(5-fluoro-4-((2-fluoro-4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl) (3 ,3 - J Preparation of fluoroazetidin-1-yl)methyl ketone (L040): L040-3 (70 mg, 0.23 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (70 mg, 0.27 mmol) were weighed into a 35 mL sealed tube, dissolved in n-butanol (2 mL), and DIEA (119 mg, 0.92 mmol) was added. The mixture was allowed to react at 120 °C overnight. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified and separated by prep-HPLC in a HO / ACN system. After lyophilization, a white solid product (7.2 mg, purity 95.736%) was obtained. LC-MS: [M+H] + =527.10.

[0410] 1H-NMR (400 MHz, dmso) δ 8.97 (d, J = 0.6 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.31 (d, J = 0.6 Hz, 1H), 7.52 (dd, J = 12.8, 1.8 Hz, 1H), 7.34 (dd, J = 8.2, 1.9 Hz, 1H), 6.79 (dd, J = 9.5, 8.3 Hz, 1H), 6.48 (s, 1H), 5.25 (s, 2H), 4.83 (s, 2H), 4.54 (t, J = 11.8 Hz, 4H), 4.06 (t, J = 5.3 Hz, 2H), 3.78 (s, 3H), 2.60 (t, J = 5.3 Hz, 2H), 2.05 (s, 1H).

[0411] Example 41, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L041)

[0412] [ka]

[0413] 41.1 Preparation of compound tert-butyl 4-(4-((2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L041-1): 2,4-Dichloro-6-trifluoromethylpyrimidine (100 mg, 0.46 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (119.52 mg, 0.46 mmol) were weighed into a 5 mL sample flask and dissolved in 1 mL of n-butanol. DIEA (297.8 mg, 1.15 mmol) was added and the mixture was stirred at 70 °C for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give 233 mg of crude product as a pale yellow solid. LC-MS: [M+H] + =440.10.

[0414] 41.2 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L041): L041-1 (200 mg, 0.454 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (116 mg, 0.454 mmol) were weighed into a 25 mL eggplant-shaped flask, dissolved in 5 mL of n-butanol, and then DIEA (294 mg, 2.27 mmol) was added and stirred at 120 °C for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give the crude product. After lyophilization, the crude product was obtained as a white solid (56.1 mg, purity 96.192%). LC-MS: [M+H] + =559.15.

[0415] 1H NMR (600 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.82 (s, 1H), 8.33 - 7.81 (m, 1H), 7.64 (dd, J = 28.2, 8.0 Hz, 2H), 6.48 (s, 1H), 6.43 (s, 1H), 4.82 (s, 1H), 4.56 (s, 2H), 4.01 (t, J = 5.0 Hz, 1H), 3.77 (s, 2H), 2.59 (s, 1H).

[0416] Example 43, Preparation of compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-methoxy-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L043)

[0417] [ka]

[0418] (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (300 mg, 0.570 mmol) was weighed into a 35 mL sealed tube and dissolved in methanol (10 mL). Sodium methoxide (308 mg, 5.703 mmol) was added and the reaction was carried out at 100 °C for 11 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified and separated by prep-HPLC in a HO / ACN system and lyophilized to give a white solid product (15.0 mg, purity 97.816%). LC-MS: [M+H] + =522.20.

[0419] 1H NMR (400 MHz, DMSO-d) δ 9.46 (s, 1H), 8.14 (s, 1H), 8.05 (s, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.63 (dd, J = 8.6, 1.7 Hz, 2H), 6.46 (s, 1H), 4.72 (s, 2H), 4.56 (t, J = 11.8 Hz, 4H), 4.01 (s, 3H), 3.89 (t, J = 5.5 Hz, 2H), 3.76 (s, 3H), 2.58 (s, 2H).

[0420] Example 45, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L045)

[0421] [ka]

[0422] 45.1 Preparation of compound 6-(tert-butyl)2-ethyl 1-(difluoromethyl)-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylic acid (L045-1): 6-(tert-butyl)2-ethyl 1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylic acid (2.0 g, 6.8 mmol) and diethyl bromofluoromethylphosphonate (2.7 g, 10.2 mmol) were weighed into a 100 mL eggplant-shaped flask and dissolved in acetonitrile (20 mL). KF (1.2 g, 20.4 mmol) was added and the mixture was allowed to react at room temperature for 16 h. When TLC showed the reaction was complete, the reaction was stopped, filtered under reduced pressure, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 10:1-4:1) to yield 800 mg of an approximately white solid product. LC-MS: [2M+H] +=689.30.

[0423] 45.2 Preparation of compound tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1-(difluoromethyl)-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate (L045-2): L045-1 (720 mg, 2.0 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in THF (20 mL) and water (4 mL). Solid NaOH (0.4 g, 10 mmol) was added and the mixture was allowed to react at room temperature for 4 h. When LCMS showed the reaction was complete, the pH was adjusted to 5-6 with acetic acid in an ice bath, the solid was filtered, and the filtrate was rotary evaporated to give the product. DCM (20 mL) was added to dissolve the product, and DIEA (1 mL, 6.0 mmol), HATU (1.5 g, 4.0 mmol), and 3,3-difluorotrimethylideneimide (389 mg, 3.0 mmol) were added. The mixture was allowed to react at room temperature for 3 h. When LCMS showed the reaction of the raw materials was complete, the reaction was stopped, filtered under reduced pressure, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1) to give 900 mg of a pale yellow solid product. LC-MS: [M+H-56] + =336.05.

[0424] 45.3 Preparation of compound (3,3-difluoroazetidin-1-yl)(1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L045-3): L045-2 (900 mg, 2.3 mmol) was weighed into a 50 mL eggplant flask, dissolved in methanol (20 mL), and then 20 mL of 4M HCl in 1,4-dioxane was added. The mixture was allowed to react at room temperature for 5 h. When LCMS showed the reaction was complete, the solvent was evaporated and the HCl was removed by DCM stripping to give 700 mg of the hydrochloride salt of L045-3 as a yellow solid product. LC-MS: [M+H] + =292.05.

[0425] 45.4 Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L045): tert-Butyl 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-formate (100 mg, 0.268 mmol) and L045-03 (78 mg, 0.268 mmol) were weighed into a 25 mL eggplant-shaped flask, and 2 mL of n-butanol was added to dissolve them. DIEA (173 mg, 1.34 mmol) was added and the mixture was stirred at 120 °C for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give the crude product. After lyophilization, a white solid product (70.4 mg, purity 98.524%) was obtained. LC-MS: [M+H] + =528.15.

[0426] 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.74 (s, 1H), 8.40 - 7.74 (m, 2H), 7.68 (s, 1H), 7.52 (dd, J = 31.2, 7.6 Hz, 1H), 6.72 (s, 1H), 5.06 (s, 1H), 4.62 (s, 2H), 4.06 (t, J = 5.6 Hz, 1H), 2.60 (s, 1H).

[0427] Example 46, Preparation of compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L046)

[0428] [ka]

[0429] 46.1 Preparation of compound tert-butyl 4-(4-isothiocyanatophenyl)-1H-pyrazolyl-1-carboxylate (L046-1) tert-Butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (M002) (520 mg, 2.005 mmol) was weighed and dissolved in tetrahydrofuran (10 mL). CS2 (1.522 g, 20.050 mmol) and NaH (200 mg, 5.013 mmol) were added and the mixture was allowed to react overnight at 50 °C. When LCMS showed the reaction of the starting materials was complete, Boc2O (437 mg, 2.005 mmol) and DMAP (25 mg, 0.205 mmol) were added to the reaction mixture, and the mixture was allowed to react at room temperature for 5 hours. When LCMS showed the reaction was complete, the mixture was diluted with an appropriate amount of water and extracted with EA (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA=8:1) to give 650 mg of tert-butyl 4-(4-isothiocyanatophenyl)-1H-pyrazolyl-1-carboxylate as a pale yellow solid. LC-MS: [M+H] + =302.05.

[0430] 46.2 Preparation of the compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbonyl chloride (L046-2) (3,3-Difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (500 mg, 1.961 mmol) and DIEA (2.529 g, 19.610 mmol) were weighed into a 50 mL eggplant-shaped flask and dissolved in DCM (10 mL). The mixture was stirred at room temperature for 10 minutes, and then a DCM solution of solid triphosgene (1.741 g, 5.883 mmol) was added dropwise in an ice bath. After the addition was complete, the mixture was allowed to react at room temperature for 5 hours. LCMS indicated the reaction was complete. The mixture was diluted with water and extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1 g of crude product as a tan oil. LC-MS: [M+H] + =318.00.

[0431] 46.3 Preparation of the compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbohydrazide (L046-3) in DMSO L046-2 (1.0 g, 3.147 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in DMSO (10 mL). Hydrazine hydrate (1.6 g, 31.474 mmol) was slowly added dropwise in an ice bath. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. LCMS indicated the completion of the reaction. 10 mL of L046-3 DMSO solution was obtained, and the solution was pale yellow. LC-MS: [M+H] + =314.10.

[0432] 46.4 Preparation of compound tert-butyl 2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-6-carbonyl)hydrazine-1-carboxylate (L046-4) To the 10 mL of DMSO solution obtained in the previous step, 10 mL of water, THF (10 mL), K2CO3 (2 g), and Boc2O (5 mL) were added and the mixture was allowed to react at room temperature overnight. LCMS showed the reaction was complete. The mixture was diluted with an appropriate amount of water and extracted with EA (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:2) to give 380 mg of an approximately white solid product. LC-MS: [M+H] + =414.20.

[0433] 46.5 Preparation of compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbohydrazide (L046-3) L046-4 (380 mg, 0.921 mmol) was weighed into a 50 mL eggplant-shaped flask, dissolved in DCM (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was allowed to react at room temperature for 1 hour. LCMS showed the reaction was complete. Concentration under reduced pressure gave 380 mg of crude product, which was a pale yellow oil. LC-MS: [M+H] + =314.15.

[0434] 46.6 Preparation of compound tert-butyl 4-(4-(2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-6-carbonyl)hydrazine-1-thiaamino)phenyl)-1H-pyrazolyl-1-carboxylate (L046-5) The crude L046-3 (300 mg, 0.958 mmol) was weighed into a 50 mL eggplant-shaped flask, DIEA (248 mg, 1.916 mmol) was added, and dichloromethane (10 mL) was added to dissolve the mixture. The mixture was stirred at room temperature for 10 minutes, and a dichloromethane solution of L046-1 (288 mg, 0.958 mmol) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 1:1-1:3) to obtain 360 mg of a pale yellow solid product. LC-MS: [M+H] + =615.15.

[0435] 46.7 Preparation of compound tert-butyl 4-(4-((5-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,4-oxadiazol-2-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L046-6) L046-5 (360 mg, 0.586 mmol) was weighed into a 50 mL eggplant-shaped flask, EDCI (1.122 g, 5.856 mmol) was added, and NMP (20 mL) was added to dissolve the mixture. The mixture was stirred at 60 °C for 5 h. LCMS showed the reaction was complete. The mixture was diluted with an appropriate amount of water and extracted with EA (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1-10:1) to give 280 mg of a pale yellow solid product.

[0436] 46.8 Preparation of the compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L046) L046-6 (260 mg, 0.448 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in DCM (16 mL). Trifluoroacetic acid (4 mL) was added and the reaction was allowed to proceed at room temperature for 2 h. LCMS indicated the reaction was complete. The solvent was concentrated under reduced pressure, and the residue was diluted with water. The pH was adjusted to 9 with saturated NaHCO3, and the mixture was extracted with EA (50 mL x 3). The organic phase was collected to obtain the crude product, which was purified and separated by prep-HPLC. After lyophilization, a white solid (28.0 mg, purity 98.641%) was obtained. LC-MS: [M+H] + =481.15.

[0437] 1 H-NMR (400 MHz, DMSO-d) δ 10.07 (s, 1H), 7.94 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 6.47 (s, 1H), 4.55 (s, 1H), 4.47 (s, 1H), 3.70 (s, 1H), 3.59 (t, J = 5.6 Hz, 1H), 2.62 (t, J = 5.5 Hz, 1H).

[0438] Example 47, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L047)

[0439] [ka]

[0440] tert-Butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (190 mg, 0.49 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in n-BuOH (10 mL). DIEA (0.40 mL, 2.45 mmol) and L045-3 hydrochloride (192 mg, 0.59 mmol) were added and the mixture was reacted at 120 °C for 16 h. When TLC showed the completion of the reaction, the reaction was stopped. The solvent was concentrated under reduced pressure, and the mixture was washed with water (50 mL x 3). The mixture was then extracted with EA (50 mL x 3). The organic phase was collected to obtain the crude product. The crude product was purified and separated by prep-HPLC. After lyophilization, a white solid product (38.0 mg, purity 98.251%) was obtained. LC-MS: [M+H] + =545.15.

[0441] 1 H NMR (400 MHz, dmso) δ 12.83 (s, 1H), 9.33 (s, 1H), 8.36 (s, 0H), 8.21 (s, 1H), 8.04 (t, J = 13.2 Hz, 3H), 7.75 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 6.69 (s, 1H), 4.97 (s, 2H), 4.62 (s, 4H), 3.94 (t, J = 5.6 Hz, 2H), 2.58 (t, J = 5.1 Hz, 2H).

[0442] Example 48, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-ethyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L048)

[0443] [ka]

[0444] 48.1 Preparation of compound 2,4-dichloro-6-ethyl-1,3,5-triazine (L048-1): 2,4,6-Trichloro-1,3,5-triazine (1.84 g, 10.0 mmol) was dissolved in 20 mL of DCM and cooled to -10 °C in a dry ice / acetonitrile bath. 11.0 mmol of ethylmagnesium bromide solution was added dropwise. After the addition was complete, the mixture was allowed to react at low temperature for 0.5 h. After the mixture was allowed to warm to room temperature, the reaction was quenched with ammonium chloride. The mixture was extracted with EA / water, dried over anhydrous sodium sulfate, and then rotary evaporated to give 1.4 g of the product as a yellow solid, which was used directly in the next reaction. LC-MS: [M+H] + =178.00.

[0445] 48.2 Preparation of compound tert-butyl 4-(4-((4-chloro-6-ethyl-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L048-2): 2,4-Dichloro-6-ethyl-1,3,5-triazine (534 mg, 3.0 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (932 mg, 3.6 mmol) were weighed into a 50 mL eggplant-shaped flask, dissolved in 30 mL of ethanol, and then DIEA (1.5 mL, 9.0 mmol) was added. The mixture was stirred at 60 °C overnight until TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and extracted with EA / water. The crude product was purified by silica gel column chromatography (PE:EA = 4:1) to give 1.4 g of a yellow solid. LC-MS: [M+H] + =401.10.

[0446] 48.3 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-ethyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L048): L048-2 (400.87 mg, 1 mmol) and 3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (255.27 mg, 1 mmol) were weighed into a 25 mL one-neck flask and dissolved in 5 mL of n-butanol. DIEA (646.2 mg, 5 mmol) was added and the mixture was stirred at 120 °C for 3 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give the crude product. After lyophilization, the crude product was obtained as a white solid (135 mg, purity 97.309%). LC-MS: [M+H] + =520.20.

[0447] 1 H-NMR (400 MHz, DMSO-d) δ 12.87 (s, 1H), 9.62 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.48 (s, 1H), 4.86 (d, J = 11.9 Hz, 1H), 4.56 (t, J = 11.3 Hz, 2H), 4.04 (s, 1H), 3.77 (d, J = 9.9 Hz, 1H), 2.64 - 2.52 (m, 2H), 1.23 (t, J = 7.6 Hz, 2H).

[0448] Example 50, Preparation of compound 1-(6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L050)

[0449] [ka]

[0450] 50.1 Preparation of compound tert-butyl 4-(4-((4-chloro-6-methyl-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L050-1) 2,4-Dichloro-6-methyl-1,3,5-triazine (150 mg, 0.915 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (237 mg, 0.915 mmol) were weighed into a 25 mL one-neck flask, dissolved in 5 mL of n-butanol, and then DIEA (591 mg, 4.573 mmol) was added and stirred at 70 °C for 3 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give 350 mg of crude product as a pale yellow solid. LC-MS: [M+H] + =387.10.

[0451] 50.2 Preparation of compound ethyl 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L050-2) L050-1 (300 mg, 0.776 mmol) and ethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (162 mg, 0.776 mmol) were weighed into a 25 mL one-neck flask, dissolved in 5 mL of n-butanol, and then DIEA (502 mg, 3.88 mmol) was added. The mixture was stirred at 130 °C for 6 hours, and LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give 1.46 g of crude product as a pale yellow solid. LC-MS: [M+H] + =459.20.

[0452] 50.3 Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L050-3) L050-2 (1.36 g, 2.966 mmol), NaOH (356 mg, 8.898 mmol), and MeOH / HO (12 mL / 3 mL) were weighed into a 50 mL eggplant-shaped flask and stirred at 55 °C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give 600 g of crude product as a pale yellow solid. LC-MS: [M+H] + =387.15.

[0453] 50.4 Preparation of the compound 1-(6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L050) L050-3 (200 mg, 0.465 mmol), 3-acetonitrilecyclobutylamine hydrochloride (83 mg, 0.697 mmol), and HATU (354 mg, 0.93 mmol) were weighed into a 25 mL eggplant-shaped flask, dissolved in 3 mL of DCM, and then DIEA (181 mg, 1.395 mmol) was added and stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction mixture was extracted twice with DCM / HO. The organic phase was separated, dried, and concentrated to give the crude product. The crude product was lyophilized to give a white solid (15.8 mg, purity 98.055%). LC-MS: [M+H] + =495.15.

[0454] 1H NMR (400 MHz, DMSO-d) δ 12.81 (s, 1H), 9.63 (s, 1H), 8.01 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 6.39 (s, 1H), 4.84 (s, 1H), 4.35 (d, J = 40.3 Hz, 2H), 4.02 (t, J = 5.3 Hz, 1H), 3.85 - 3.78 (m, 1H), 3.75 (d, J = 10.7 Hz, 1H), 2.57 (s, 1H), 2.27 (s, 1H).

[0455] Example 51, Preparation of compound 2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,5-triazin-2-yl)acetonitrile (L051)

[0456] [ka]

[0457] 51.1 Preparation of compound (6-(4,6-dichloro-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L051-1): 2,4,6-Trichloro-1,3,5-triazine (184 mg, 1.0 mmol) was dissolved in 4 mL of acetonitrile, and 248 mg (3.0 mmol) of sodium bicarbonate was added. 292 mg (1.0 mmol) of (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone hydrochloride was added in portions. After the addition, the mixture was allowed to react at room temperature for 3 h. LCMS showed the product as the major peak. The reaction mixture was extracted with EA / water system, dried, and rotary evaporated to give 400 mg of a yellow solid, which was directly used in the next step. LC-MS: [M+H] + =403.05.

[0458] 51.2 Preparation of compound tert-butyl 2-(4-chloro-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c)]pyridin-6-yl)-1,3,5-triazin-2-yl)-2-cyanoacetate (L051-2): A 25 mL reaction flask was charged with L051-1 (320 mg, 0.8 mmol) and 3 mL of tetrahydrofuran, and the mixture was stirred at room temperature. A separate 25 mL reaction flask was charged with tert-butyl cyanoacetate (128 mg, 0.88 mmol) and 3 mL of tetrahydrofuran. 40 mg of NaH was added in portions in an ice bath, and the mixture was allowed to react at room temperature for 30 min. The mixture was then added dropwise to the tetrahydrofuran solution of L051-1. After the addition was complete, the mixture was allowed to react at room temperature for 4.0 h. LCMS indicated the completion of the reaction. The reaction was quenched with ammonium chloride, extracted with EA / water, dried, and spun to dryness to obtain 400 mg of the crude product, a yellow solid, which was directly used in the next step. LC-MS: [M+H] + =508.15.

[0459] 51.3 Preparation of compound 2-(4-chloro-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,5-triazin-2-yl)acetonitrile (L051-3): L051-2 (400 mg, 0.79 mmol) was weighed and dissolved in 4 mL of dichloromethane. 1 mL of trifluoroacetic acid was added. After the addition, the reaction was allowed to proceed at room temperature for 2 hours, and LCMS showed the reaction was complete. Treatment: The reaction mixture was diluted with 20 mL of dichloromethane, neutralized with sodium bicarbonate, extracted with dichloromethane / water, dried, concentrated, and purified using a column to give 200 mg of a white solid product. LC-MS: [M+H] + =408.10.

[0460] 51.4 Preparation of compound 2-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,5-triazin-2-yl)acetonitrile (L051): L051-3 (180 mg, 0.44 mmol), tert-butyl 4-(4-aminophenyl)-1H-pyrazolyl-1-formate (148 mg, 0.57 mmol), KF (38 mg, 0.66 mmol), and DIEA (170 mg, 1.32 mmol) were weighed into a reaction flask, and n-butanol (3 mL) was added to dissolve the mixture. The reaction was then allowed to proceed at 90 °C overnight. LCMS indicated the completion of the reaction. After concentration under reduced pressure, the mixture was extracted with EA / water system, and the crude product was obtained by rotary evaporation and concentration. The crude product was purified and lyophilized to give a white solid product (68.0 mg, purity 98.924%). LC-MS: [M+H] + =531.25.

[0461] 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.85 (s, 1H), 7.98 (d, J = 88.1 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.53 (s, 2H), 6.46 (d, J = 4.1 Hz, 1H), 4.85 (d, J = 10.2 Hz, 2H), 4.53 (s, 4H), 4.02 (s, 4H), 3.73 (d, J = 19.2 Hz, 3H), 2.55 (s, 2H).

[0462] Example 52, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-(oxetan-3-yl)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L052)

[0463] [ka]

[0464] 52.1 Preparation of compound 2,4-dichloro-6-(oxetan-3-yl)-1,3,5-triazine (L052-1): 3-Bromooxetane (411 mg, 3.0 mmol) was placed in 4 mL of tetrahydrofuran, cooled to -78°C in a dry ice / ethyl acetate bath, and 3.0 mmol of n-butyllithium solution was added dropwise. After the addition was complete, the mixture was allowed to react at low temperature for 30 minutes.

[0465] 2,4,6-Trichloro-1,3,5-triazine (607 mg, 3.3 mmol) was weighed into a separate reaction flask, and 6.0 mL of tetrahydrofuran was added. The mixture was cooled to -78 °C in a dry ice / ethyl acetate bath, and the 3-bromooxetane solution was added dropwise. After the addition was complete, the mixture was allowed to react at low temperature for 30 minutes, then allowed to warm to room temperature and stirred for 1 hour. LCMS indicated approximately 50% product. The reaction mixture was quenched with ammonium chloride, extracted with EA / water, dried, and rotary evaporated to give 500 mg of a yellow solid, which was directly used in the next step. LC-MS: [M+H] + =206.00.

[0466] 52.2 Preparation of compound tert-butyl 4-(4-((4-chloro-6-(oxetan-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L052-2): 2,4-Dichloro-6-(oxetan-3-yl)-1,3,5-triazine (206 mg, 1.0 mmol) and M002 (260 mg, 1.0 mmol) were weighed into a 50 mL eggplant-shaped flask, dissolved in ethanol, and then DIEA (390 mg, 3.0 mmol) was added and stirred at 50 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and extracted with EA / water to give 400 mg of crude product as a yellow solid, which was directly used in the next step. LC-MS: [M+H] + =429.15.

[0467] 52.3 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6-(oxetan-3-yl)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L052): tert-Butyl 4-(4-((4-chloro-6-(oxetan-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (400 mg, 0.93 mmol), L006-4 hydrochloride (298 mg, 1.02 mmol), and DIEA (360 mg, 2.79 mmol) were weighed into a reaction flask, and n-butanol (5 mL) was added to dissolve the mixture. The reaction was carried out at 100 °C overnight. LCMS showed the completion of the reaction. After concentration under reduced pressure, the mixture was extracted with EA / water system, and then rotary dried and concentrated to obtain the crude product. The crude product was purified and freeze-dried to obtain a white solid product (68.0 mg, purity 96.727%). LC-MS: [M+H] + =548.20.

[0468] Example 53, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6,7-dihydro-5H-cyclopentadiene[d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L053)

[0469] [ka]

[0470] 53.1 Preparation of compound 2-chloro-N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (L053-1): 2,4-Dichloro-6,7-dihydro-5H-cyclopentadi[d]pyrimidine (189.04 mg, 1 mmol) and 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)aniline (243.31 mg, 1 mmol) were weighed into a 25 mL eggplant-shaped flask, and 5 mL of n-butanol was added to dissolve the mixture. DIEA (646.2 mg, 5 mmol) was then added and the mixture was stirred at 100 °C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, concentrated, and then purified by silica gel column chromatography (PE / EA=4 / 1) to obtain 176 mg of a pale yellow solid. LC-MS: [M+H] + =396.15.

[0471] 53.2 Preparation of the compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)phenyl)amino)-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L053-2): L053-1 (150 mg, 0.379 mmol), (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (110 mg, 0.379 mmol), Pd2dba3 (69.4 mg, 0.0758 mmol), xantphos (43.8 mg, 0.0758 mmol), and Cs2CO3 (246 mg, 0.758 mmol) were weighed into a 25 mL one-neck flask and dissolved in 5 mL of dioxane. The atmosphere was purged with nitrogen gas three times, and the mixture was stirred at 100 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, concentrated, and then purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 100 mg of a pale yellow solid product. LC-MS: [M+H] + =615.25.

[0472] 53.3 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-6,7-dihydro-5H-cyclopentadiene[d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L053): L053-2 (100 mg, 0.163 mmol), acidic resin (20 mg), and HCl / dioxane solution (0.4 mL) were weighed into a 25 mL eggplant-shaped flask, and 3 mL of methanol was added to dissolve the mixture. The mixture was then stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was filtered and concentrated to obtain the crude product. The crude product was purified and lyophilized to obtain a white solid product (5 mg, purity 98.148%). LC-MS: [M+H] + =531.20.

[0473] 1 H NMR (400 MHz, DMSO-d) δ 12.85 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 6.45 (s, 1H), 4.76 (s, 2H), 4.55 (t, J = 11.8 Hz, 4H), 3.94 (t, J = 5.6 Hz, 2H), 3.75 (s, 3H), 2.75 - 2.67 (m, 4H), 2.54 (d, J = 5.5 Hz, 2H), 2.01 - 1.96 (m, 2H).

[0474] Example 56, Preparation of compound 1-(6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L056)

[0475] [ka]

[0476] 56.1 Preparation of compound ethyl 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L056-1): tert-Butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (450 mg, 1.154 mmol) and ethyl 1-methyl-1,4,5,7-tetrahydro-612-pyrrolo[2,3-c]pyridine-2-carboxylate (240 mg, 1.154 mmol) were weighed into a 50 mL one-neck flask, and 6 mL of n-butanol was added to dissolve the mixture. DIEA (746 mg, 5.770 mmol) was added and the mixture was stirred at 140 °C for 4 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, concentrated, and then purified by silica gel column chromatography (PE / EA = 5 / 1) to give 406 mg of a pale yellow solid. LC-MS: [M+H] + =462.15.

[0477] 56.2 Preparation of compound 6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L056-2): L056-1 (406 mg, 0.880 mmol), NaOH (352 mg, 8.80 mmol), and MeOH / HO (5 mL / 5 mL) were weighed into a 50 mL one-neck flask and stirred at 155 °C for 12 hours. LCMS showed the reaction was complete. The reaction was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give 140 mg of crude product as a pale yellow solid. LC-MS: [M+H] + =434.15.

[0478] 56.3 Preparation of compound 1-(6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L056): L056-2 (140 mg, 0.323 mmol), 3-acetonitrilecyclobutylamine hydrochloride (58 mg, 0.484 mmol), and HATU (246 mg, 0.646 mmol) were weighed into a 25 mL eggplant-shaped flask, dissolved in 3 mL of DCM, and then DIEA (126 mg, 0.969 mmol) was added and stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction mixture was extracted twice with DCM / HO. The organic phase was separated, dried, and concentrated to give the crude product. After lyophilization, a white solid product (22.4 mg, purity 99.220%) was obtained. LC-MS: [M+H] + =498.25.

[0479] 1 H NMR (400 MHz, DMSO-d) δ 12.83 (s, 1H), 9.31 (s, 1H), 8.05 (d, J = 3.7 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.61 - 7.55 (m, 1H), 6.37 (s, 1H), 4.72 (s, 1H), 4.34 (d, J = 41.2 Hz, 2H), 3.91 (t, J = 5.6 Hz, 1H), 3.80 (tt, J = 9.2, 6.1 Hz, 1H), 3.73 (s, 1H), 2.55 (t, J = 5.3 Hz, 1H).

[0480] Example 57, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L057)

[0481] [ka]

[0482] 57.1 Preparation of compound 2-chloro-N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (L057-1): 2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine (400 mg, 2.128 mmol) and 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)aniline (518 mg, 2.128 mmol) were weighed into a 50 mL eggplant-shaped flask, dissolved in 10 mL of n-butanol, and then DIEA (1375 mg, 10.64 mmol) was added and stirred at 40 °C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, concentrated, and then purified by silica gel column chromatography (PE / EA = 4 / 1) to give 579 mg of a pale yellow solid. LC-MS: [M+H] + =395.15.

[0483] 57.2 Preparation of the compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl-4-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (L057-2): L057-1 (360 mg, 0.912 mmol), (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (265 mg, 0.912 mmol), Pd2dba3 (168 mg, 0.1824 mmol), dit-Bu-xphos (78 mg, 0.1824 mmol), and t-BuONa (176 mg, 1.824 mmol) were weighed into a 50 mL one-neck flask, dissolved in 10 mL of dioxane, and the mixture was purged with nitrogen gas three times and stirred at 100 °C for 18 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, concentrated, and then purified by silica gel column chromatography (PE / EA = 3 / 1) to give 83.6 mg of a pale yellow solid. LC-MS: [M+H] + =614.25.

[0484] 57.3 Preparation of the compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L057): L057-2 (80 mg, 0.130 mmol), acidic resin (100 mg), and HCl / dioxane solution (0.1 mL) were weighed into a 25 mL eggplant-shaped flask, dissolved in 3 mL of methanol, and stirred at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered and concentrated to obtain the crude product, which was then freeze-dried to give a white solid (3 mg, purity 98.796%). LC-MS: [M+H] + =530.15.

[0485] 1H-NMR (400 MHz, DMSO-d) δ 12.91 (s, 1H), 9.70 (s, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.49 (dd, J = 2.3, 1.7 Hz, 1H), 7.02 (dd, J = 4.4, 1.5 Hz, 1H), 6.51 (dd, J = 4.4, 2.5 Hz, 1H), 6.46 (s, 1H), 4.67 (s, 1H), 4.63 - 4.45 (m, 2H), 3.88 (t, J = 5.5 Hz, 1H), 3.76 (s, 1H), 2.59 (t, J = 5.4 Hz, 1H).

[0486] Example 58, Preparation of compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,4-thiadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L058)

[0487] [ka]

[0488] 58.1 Preparation of the compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbothiohydrazide (L058-1) (3,3-Difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (400 mg, 1.568 mmol) and KOH (176 mg, 3.137 mmol) were weighed into a 100 mL eggplant-shaped flask and dissolved in ethanol. An ethanol solution of CS2 (238 mg, 3.137 mmol) was added dropwise in an ice bath. After the addition was complete, the mixture was incubated at 10 °C for 5 h. A mixed solution of chloroacetic acid (298 mg, 3.137 mmol) and KOH (176 mg, 3.137 mmol) was added, followed by overnight incubation at room temperature. Upon completion of the reaction, hydrazine hydrate (784 mg, 15.683 mmol) was added to the reaction mixture and incubated at 65 °C for 4 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (50 mL x 3). The organic phase was collected to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 50:1-20:1) to give 350 mg of an approximately white solid product. LC-MS: [M+H] + =330.05.

[0489] 58.2 Preparation of compound tert-butyl 4-(4-(2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-6-carbothioacyl)hydrazine-1-carbothioamido)phenyl)-1H-pyrazolyl-1-carboxylate (L058-2) L058-1 (330 mg, 1.001 mmol) was weighed into a 100 mL eggplant-shaped flask, DIEA (258 mg, 2.002 mmol) was added, and dichloromethane (10 mL) was added to dissolve the mixture. The mixture was stirred at room temperature for 10 minutes, and a dichloromethane solution of L046-1 (241 mg, 0.801 mmol) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 150 mg of a yellow solid product. LC-MS: [M+H] + =631.15.

[0490] 58.3 Preparation of compound tert-butyl 4-(4-((5-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,4-thiadiazol-2-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (L058-3) L058-2 (100 mg, 0.156 mmol) was weighed into a 50 mL eggplant-shaped flask, EDCI (303 mg, 1.561 mmol) was added, and NMP (10 mL) was added to dissolve the mixture. The mixture was stirred at 50 °C for 5 hours. LCMS showed the reaction was complete. The mixture was diluted with an appropriate amount of water and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1-20:1) to obtain 80 mg of a yellow oily product. LC-MS: [M+H] + =597.20.

[0491] 58.4 Preparation of the compound (6-(5-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-1,3,4-thiadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L058) L058-3 (80 mg, 0.134 mmol) was weighed into a 25 mL eggplant-shaped flask and dissolved in DCM (6 mL). Trifluoroacetic acid (2 mL) was added and the reaction was allowed to proceed at room temperature for 1 h. LCMS indicated the reaction was complete. The solvent was concentrated under reduced pressure, and the residue was diluted with water. The pH was adjusted to 9 with saturated NaHCO3, and the mixture was extracted with EA (20 mL x 3). The organic phase was collected to obtain the crude product, which was purified and separated by prep-HPLC. After lyophilization, a white solid (11.0 mg, purity 98.435%) was obtained. LC-MS: [M+H] + =497.10.

[0492] 1 H NMR (400 MHz, DMSO-d) δ 12.83 (s, 1H), 9.81 (s, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.50 (td, J = 8.9, 2.2 Hz, 2H), 6.48 (s, 1H), 4.54 (d, J = 13.2 Hz, 2H), 3.73 (s, 1H), 3.61 (t, J = 5.7 Hz, 1H), 2.65 (dt, J = 11.1, 3.7 Hz, 1H).

[0493] Example 59, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoropyrrolidin-1-yl)methyl ketone (L059)

[0494] [ka]

[0495] 59.1 Preparation of compound tert-butyl 3-chloro-2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate (L059-1): tert-Butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (810 mg, 2.279 mmol) and NCS (304 mg, 2.279 mmol) were weighed into a 50 mL one-neck flask, 10 mL of MeCN was added, and the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete, with a product yield of 20%. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated. After concentration, the mixture was purified by silica gel column chromatography (PE / EA = 4 / 1) to give 200 mg of a pale yellow solid. LC-MS: [M+H] + =390.10.

[0496] 59.2 Preparation of compound (3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methyl ketone (L059-2): L059-1 (200 mg, 0.513 mmol), HCl / dioxane solution (5 mL), and DCM (2 mL) were weighed into a 50 mL one-neck flask and stirred at room temperature for 2 hours. LCMS showed the reaction was complete, with a product yield of 20%. The reaction mixture was concentrated and extracted twice with EA / HO. The organic phase was separated, dried, and concentrated to give 177.6 mg of crude product as a pale yellow solid. LC-MS: [M+H] + =290.05.

[0497] 59.3 Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoropyrrolidin-1-yl)methyl ketone (L059): L059-2 (145 mg, 0.445 mmol) and tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (174 mg, 0.445 mmol) were weighed into a 25 mL eggplant-shaped flask, and 3 mL of n-butanol was added to dissolve the mixture. DIEA (288 mg, 2.225 mmol) was added and the mixture was stirred at 120 °C for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to give the crude product. After lyophilization, a white solid (33 mg, purity 97.663%) was obtained. LC-MS: [M+H] + =543.15.

[0498] 1 H NMR (400 MHz, DMSO-d) δ 12.89 (s, 1H), 9.34 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 3.7 Hz, 1H), 7.90 (s, 1H), 7.77 - 7.72 (m, 1H), 7.62 - 7.57 (m, 1H), 4.74 (s, 1H), 4.52 (t, J = 11.9 Hz, 2H), 3.93 (t, J = 5.6 Hz, 1H), 3.59 (s, 2H), 2.52 (d, J = 1.9 Hz, 1H).

[0499] Example 60, Preparation of compound (6-(4-((4-(1H-pyrazolyl-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-(difluoromethyl)azetidin-1-yl)methyl ketone (L060)

[0500] [ka]

[0501] (3-(Difluoromethyl)azetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl ketone (55 mg, 0.20 mmol) was dissolved in n-butanol (2 mL), N,N-diisopropylethylamine (77 mg, 0.60 mmol) and tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazolyl-1-carboxylate (89 mg, 0.24 mmol) were added, and the mixture was heated to 120 °C under nitrogen gas protection and reacted for 4 hours. After the reaction was completed, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give 44.5 mg of a white solid. The two-step yield was 36%. LC-MS [M+H] + : 504.9.

[0502] 1 H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 9.31 (s, 1H), 8.01 (s, 2H), 7.96 (d, J = 5.7 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 6.48 (d, J = 4.3 Hz, 0.25H), 6.38 (s, 1H), 6.34 (d, J = 4.3 Hz, 0.5H), 6.20 (d, J = 4.4 Hz, 0.25H), 6.07 (d, J = 5.7 Hz, 1H), 4.79 (s, 2H), 4.65-4.05(m ,4H),3.98 (t, J = 5.5 Hz, 2H), 3.76 (s, 3H), 3.19 - 3.09 (m, 1H), 2.55 (t, J = 6.6 Hz, 2H).

[0503] Compound L029 was produced in accordance with the method described in Example 28 above.

[0504] Compound L033 was produced in accordance with the method described in Example 39 above.

[0505] Compound L042 was produced in accordance with the method described in Example 41 above.

[0506] Compound L044 was produced in accordance with the method described in Example 36 above.

[0507] Compound L049 was produced in accordance with the method described in Example 48 above.

[0508] Compound L054 was produced in accordance with the method described in Example 53 above.

[0509] Compound L055 was produced in accordance with the method described in Example 11 above.

[0510] Referring to the corresponding synthesis methods in the above examples, the characteristic data of each synthesized compound are as shown in the table below:

[0511] [Table 3]

[0512] <Biological activity test> In some embodiments, the compounds of the present invention have been tested by conventional methods in the art and found to inhibit kinases in vitro and / or in vivo, particularly ROCK1 and / or ROCK2 kinases. Furthermore, the compounds of the present invention have been found to have relatively low cytotoxicity and relatively good pharmacokinetic properties, and experiments have revealed that the compounds of the present invention have more suitable metabolic stability and potential for drug discovery.

[0513] 1. In Vitro Assessment of ROCK2 Kinase Activity ROCK2 activity was screened using a 96-well (Cisbio) time-resolved fluorescence assay. ROCK2 activity was detected using the following assay buffer: 5 mM MgCl2 (Sigma), 1 mM DTT (Sigma), and 1X kinase buffer. 7.5 μL of ROCK2 kinase (Invitrogen, PV3759) was diluted with kinase buffer to a final concentration of 0.4 ng / μL and added to a 96-microwell plate. 0.25 μL of the compound to be assayed was then added, adjusted to 1% DMSO (volume fraction), and incubated at room temperature for 0.5 h. To initiate the reaction, ATP (Aladin) and the substrate STK-substrate 2-biotin were mixed together in kinase buffer, and 7.5 μL of the mixture was added to the microwell plate to a final concentration of 6.739 μM and 1 μM, respectively, and incubated at room temperature for 2 h. 5 mL of detection buffer was mixed with the STK antibody-Cryptate, and an appropriate volume was then mixed with an equal volume of streptavidin-XL665. The reaction was stopped by adding 10 μL of this mixture to the microwell plate. After approximately 1 hour of incubation, the plate was read using a Molecular Devices Spectra Max i3x multifunction microplate reader. The kinase buffer, STK-substrate 2-biotin, detection buffer, STK antibody-Cryptate, and streptavidin-XL665 were all obtained from the HTRF KinEASE-STK kit (Cisbio, 1000 tests, 61GSTXLA).

[0514] 2. In Vitro Assessment of ROCK1 Kinase Selectivity ROCK1 activity was detected using a 96-well (Cisbio) time-resolved fluorimetric assay. ROCK1 assays were performed in the following assay buffer: 5 mM MgCl2 (Sigma), 1 mM DTT (Sigma), and 1X kinase buffer. 7.5 μL of ROCK1 kinase (Invitrogen) diluted with kinase buffer was added to a 96-microwell plate to a final concentration of 0.4 ng / μL. Then, 0.25 μL of the compound to be assayed was added, adjusted to 1% DMSO, and incubated at room temperature for 0.5 h. To initiate the reaction, ATP (Aladin) and the substrate STK-substrate 2-biotin were mixed together in kinase buffer, and 7.5 μL of the mixture was added to the microwell plate to a final concentration of 3.53 μM and 1 μM, respectively, and incubated at room temperature for 2 h. 5 mL of detection buffer was mixed with the STK antibody-Cryptate, and an appropriate volume was then mixed with an equal volume of streptavidin-XL665. The reaction was stopped by adding 10 μL of the mixture. After approximately 1 h of incubation, the plate was read using a Molecular Devices SpectraMax i3x multifunction microplate reader. The kinase buffer, STK-substrate 2-biotin, detection buffer, STK antibody-Cryptate, and streptavidin-XL665 were all obtained from the HTRF KinEASE-STK kit (Cisbio, 1000 tests, 61GSTXLA).

[0515] Example 61 The compounds according to the examples of the present invention were subjected to the in vitro kinase activity evaluation experiment to confirm the inhibitory activity of each compound against ROCK1 / 2. All of the compounds of the present invention showed relatively good activity, and the IC of one compound against two types of kinases was 50 The IC of a compound against two kinases is less than 10 μM. 50 ≤50 nM (activity level A) and IC of a compound against two kinases 50 >50 nM and ≤500 nM (activity level B), and the IC of a compound against two kinases 50>500 nM and ≤4.5 μM (activity level C), and IC of a compound against two kinases 50 >4.5 μM (activity level D).

[0516] Among them, the IC of representative compounds 50 Values ​​are reported in Table 1 below: Notes: (A: ≦50 nM; B: >50 nM and ≦500 nM; C: >500 nM and ≦4.5 μM; D: >4.5 μM; ND: Not detected)

[0517] [Table 4] JPEG0007772771000127.jpg231169JPEG0007772771000128.jpg33169

[0518] Example 62 In vitro cytotoxicity test of compounds of the present invention The in vitro cytotoxicity test of the compounds of this invention was performed using the CCK-8 assay in HepG2 cells. Logarithmic phase HepG2 cells (Kita Bio) were harvested, the cell suspension concentration was adjusted, and 50,000 cells / well were plated in a 96-well cell culture plate. The cells were incubated overnight in a cell culture incubator at 5% CO₂ and 37°C. After the cells reached 80-90% confluence, the liquid was replaced and the compound or solvent (DMSO) to be measured at each concentration gradient was added. The mixture was then incubated in a cell incubator at 5% CO₂ and 37°C for 48 hours. After treatment, the medium in the plate was discarded and washed twice with PBS. 100 μL of CCK-8 working solution (Biyuntian Biotechnology) was added to each well and incubated at 37°C in the dark for 1.5 hours. The OD was measured using a microplate reader. 450nm Detect the absorbance of each well at CC of each compound. 50 is analyzed and calculated.

[0519] As a result of carrying out the above experiments on the compounds according to the examples of the present invention, it was found that all the compounds of the present invention have relatively good safety and CC 50The CC of a preferred compound is >10 μM. 50 >30 μM, preferably CC 50 The CC of a representative compound was found to be >50 μM. 50 are shown in Table 2 below.

[0520] [Table 5]

[0521] Example 63 In vitro metabolic stability test of the compounds of the present invention The in vitro metabolic stability of the compounds of the present invention was measured using various liver microsome incubation methods. An appropriate amount of test compound was added to a liver microsome reaction system (1 mg / mL liver microsomal protein, 25 U / mL glucose 6-phosphate dehydrogenase, 1 mM NADP, 6 mM D-glucose 6-phosphate, 5 mM MgCl2) and incubated in a water bath at 37°C to initiate the reaction. At each time point, 100 μL of the reaction mixture was added to a centrifuge tube containing 400 μL of an internal standard working solution (containing 200 ng / mL dexamethasone, diclofenac, tolbutamide, and labetalol in acetonitrile) pre-cooled to 0°C. The reaction was terminated by centrifugation at 10,000 g for 10 min at 4°C. The supernatant was then analyzed and measured by LC-MS to obtain the in vitro metabolic half-lives of the test compounds in various liver microsomes. The T obtained by the above method was 1 / 2 are shown in Table 3.

[0522] [Table 6]

[0523] The above test was carried out on the compounds according to the examples of the present invention, and it was found that the compounds of the present invention have relatively good metabolic stability in humans, rats, and mice, and have T 1 / 2 Preferably, the T in human liver microsomes is >30 min.1 / 2 The inventors have further conducted comparative experiments with the ROCK inhibitor KD-025, which is currently in clinical trials, and have found that the in vitro stability of the preferred compounds of the present invention is superior to that of KD-025.

[0524] Example 64 Pharmacokinetic study of the compounds of the present invention in mice SPF mice (Beijing SPF Biotechnology Co., Ltd.) were acclimatized and then fasted overnight (water was not restricted). 1 The compound of the present invention is administered at a dose of 100 mg / kg. After administration, the plasma of the mice is collected at predetermined time points, and the concentration of the compound in the plasma is detected by LC-MS / MS (AB SCIEX Qtrap4500). Statistical analysis is performed, and the PK parameters of each compound are calculated (WinNonlin V5.2, Pharsight), which shows the pharmacokinetic properties of the compound of the present invention in mice.

[0525] As a result of carrying out the above-mentioned experiments on the compounds of the examples of the present invention, it is found that the compounds of the present invention all have relatively good pharmacokinetic properties in mice, and can achieve relatively high in vivo exposure and relatively high oral bioavailability at relatively low doses, with some compounds having oral bioavailability of >30%, and some compounds having oral bioavailability of >50%.The following Table 4 shows the experimental data of representative compounds.

[0526] [Table 7]

[0527] In the description herein, the reference terms "one embodiment," "some embodiments," "example," "specific example," or "some examples" mean that the specific feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In the description herein, the descriptive expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine different embodiments or examples and features of different embodiments or examples described herein without mutually contradicting each other.

[0528] Although the embodiments of the present invention have been shown and described above, the above embodiments are illustrative and should not be understood as limiting the present invention, and it will be understood that those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound represented by the following formula (III), a racemate, a stereoisomer, a tautomer, an isotope-labeled compound, a solvate, a crystalline polymorph, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 wherein W is C or N; Double lines, including solid and dashed lines, represent single or double bonds; Y 2 and Y 3 are each independently C or N, and Y 2 and Y 3 are not both N; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; Y is a chemical bond, -NH-, -N(C 1-6 alkyl group)- or -NH(C 1-6 alkyl group), wherein the C 1-6 alkyl group in the "-N(C 1-6 alkyl group)- or -NH(C 1-6 alkyl group)" is unsubstituted or optionally substituted with one, two or more halogens; If Y is a chemical bond, 【Chemistry 2】 is selected from the following groups: azetidine unsubstituted or substituted with one, two or more F; azetidine unsubstituted or substituted with one, two or more CN; azetidine unsubstituted or substituted with one, two or more CF2; azetidine unsubstituted or substituted with one, two or more CF3; azacyclopentane unsubstituted or substituted with F and / or OH; when Y is -NH- or -N(C 1-6 alkyl group)-, the C 1-6 alkyl group in -N(C 1-6 alkyl group) is unsubstituted or optionally substituted with one, two or more halogens; 【Transformation 3】 is selected from the following groups: cyclobutane unsubstituted or substituted with one, two or more F; isopropyl; pyridazinyl; azetidine unsubstituted or substituted with one, two or more CN; azacyclopentane substituted with F and / or OH; ethyl unsubstituted or substituted with one, two or more F; -N-chloropyridine-piperidinyl; pyridinyl unsubstituted or substituted with one, two or more F; when Y is -NH(C 1-6 alkyl group), the C 1-6 alkyl group in -NH(C 1-6 alkyl group) is unsubstituted or optionally substituted with one, two or more halogens; 【Chemistry 4】 does not exist; Rc and Rd are the same or different and are independently selected from C 1-6 alkyl groups; Re is selected from halogen, CN, OH, the following groups unsubstituted or optionally substituted by one, two or more Rs: a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group, a C 6-12 aryl group, a 3-6 membered heterocyclyl group or a 5-12 membered heteroaryl group; or when there are at least two Re, two adjacent Re together with the ring atoms of the connecting chain form a C 3-6 cycloalkyl group, a 3-6 membered heterocyclyl group, or a 5-12 membered heteroaryl group; Rs is selected from halogen, CN, OH, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 6-12 aryl group or a 5-12 membered heteroaryl group; 【Transformation 5】 teeth, 【Transformation 6】 and wherein Rf 1 and Rf 2 are the same or different and are independently selected from halogen, CN, and OH; and q' is independently 0, 1, or 2. 【Request Item 2】 【Chemistry 7】 is the following group unsubstituted or optionally substituted with one, two or more Re: 【Transformation 8】 is; Re is selected from the group consisting of halogen, CN, OH, unsubstituted or optionally substituted with one, two or more Rs, and the following groups: 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 6-12 selected from an aryl group, a 3- to 6-membered heterocyclyl group, or a 5- to 12-membered heteroaryl group; A compound represented by formula (III) according to claim 1, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof.

3. When Y is a chemical bond, the carbonyl group in formula (III) is 【Chemistry 9】 is connected to a heteroatom of a heterocyclyl group represented by A compound represented by formula (III) according to claim 1 or 2, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof. 【Request Item 4】 【Chemistry 10】 is the following group: 【Chemistry 11】 is; 【Chemistry 12】 is the following group: 【Chemistry 13】 is; 【Chemistry 14】 teeth, 【Chemistry 15】 That is, A compound represented by formula (III) according to any one of claims 1 to 3, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof.

5. The formula (III) may further be selected from the following formula (IV): 【Chemistry 16】 wherein Y is a chemical bond, -NH- or -N(C 1-6 alkyl group)-, -NH(C 1-6 alkyl group); Said “-N(C 1-6 alkyl group)-, -NH(C 1-6 C in alkyl group 1-6 The alkyl group is unsubstituted or optionally substituted with one, two or more halogens; If Y is a chemical bond, 【Chemistry 17】 is the following group: [Chemistry 18] Selected from: When Y is -NH- or -N(methyl group)-, the methyl group in the "-N(methyl group)-" is unsubstituted or optionally substituted with one, two or more halogens; 【Chemistry 19】 is the following group: 【Chemistry 20】 Selected from: When Y is -NH (methyl group), the methyl group in the "-NH (methyl group)-" is unsubstituted or optionally substituted with one, two or more halogens; 【Chemistry 21】 does not exist; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; A compound represented by formula (III) according to any one of claims 1 to 4, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof.

6. The formula (III) may further be selected from the following formula (V): 【Chemistry 22】 Among them, 【Chemistry 23】 is the following group: 【Chemistry 24】 Selected from A compound represented by formula (III) according to any one of claims 1 to 4, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof.

7. The compound is selected from the following structures: 【Chemistry 25】 【change】 【change】 【change】 【change】 A compound represented by formula (III) according to claim 1, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof. 【Request Item 8】 【Chemistry 26】 The method comprises the step of reacting a compound represented by formula (III-1) with a compound represented by formula (III-2) to obtain a compound represented by formula (III); wherein L is a halogen; A method for producing the compound represented by formula (III) according to any one of claims 1 to 7, or a racemate, stereoisomer, tautomer, isotope-labeled product, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof.

9. Selected from the following structures: 【Chemistry 27】 An intermediate for producing the compound of formula (III) according to any one of claims 1 to 7.

10. Selected from the following structures: 【Chemistry 28】 10. The intermediate of claim 9.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (III) described in any one of claims 1 to 7, or a racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 11, characterized in that the pharmaceutical composition contains an auxiliary material selected from at least one of a disintegrant, a glidant, a lubricant, a diluent, a filler, an adhesive, and a colorant.

13. Use of a compound of formula (III) according to any one of claims 1 to 7, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical agent for modulating Rho-kinase.

14. Use of a compound represented by formula (III) according to any one of claims 1 to 7, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the prevention or treatment of one or more diseases caused by high expression of ROCK or excessive activation of ROCK.

15. The use according to claim 14, characterized in that the disease is one of the following: cardiovascular and cerebrovascular diseases, nervous system diseases, fibrosis, eye diseases, tumors, arterial thrombosis, radiation injury, respiratory system diseases, and autoimmune diseases.

16. The use according to claim 14, characterized in that the disease is one of the following: atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration, nerve damage disease, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte accumulation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, COPD, renal dialysis, glomerulosclerosis and neuronal degenerative inflammation.

17. The use described in claim 14, characterized in that the disease is idiopathic pulmonary fibrosis.

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