A (1H-indazol-5-yl)amino-2-pyridine derivative and its use

Abstract

The application belongs to the technical field of medicine, and particularly relates to a (1H-indazole-5-yl)amino-2-pyridine derivative and application thereof. The application relates to a compound shown in the formula (I) or a pharmaceutically acceptable salt thereof, wherein A, L, X, R1 and R2 are as described in the specification. The compound has strong ROCK2 inhibitory activity in vitro, and can be used for treating ROCK2 related diseases, such as tumors or fibrosis.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a (1H-indazol-5-yl)amino-2-pyridine derivative and application thereof. BACKGROUND

[0002] ROCK (Rho-associated protein kinase) is also known as Rho kinase, belongs to serine / threonine protein kinase, is the downstream effector of small GTPase Rho with the most detailed functional research. ROCK widely participates in a series of biological processes such as cell mitosis, cytoskeleton remodeling, smooth muscle cell contraction, nerve regeneration, tumor cell infiltration, regulation of cell apoptosis, etc. by regulating the reorganization of cell actin cytoskeleton. A large number of studies have shown that ROCK is closely related to the occurrence and development of eye diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, tumors and fibrosis and other diseases.

[0003] At present, a variety of ROCK inhibitors have been developed at home and abroad. According to the different structures of kinase hinge binding region, the existing ROCK inhibitors can be roughly divided into isoquinoline, 4-aminopyridine, biaryl and indazole. The structural characteristics of isoquinoline ROCK inhibitors is that there is an isoquinoline structure and a homopiperazine ring, both of which are connected by a sulfonyl group. The representative drugs are Fasudil and Ripasudil (WO2020177291, US2008064681), which are used for the treatment of amyotrophic lateral sclerosis and glaucoma respectively. The 4-aminopyridine compound has a benzene ring or a cyclohexane structure at the center of the molecule, and has a side chain at the 4-position of the cyclohexane. The representative drug is Netarsudil (WO2017086941) for the treatment of open-angle glaucoma. The structural characteristics of biaryl ROCK inhibitors is that there is a small molecule heterocycle containing nitrogen at the end, which is connected by an amide bond or a urea structure to an aromatic ring serving as a hydrophobic ring to stabilize the conformation of the compound. The representative drug is disclosed in the invention patent WO2011130740.

[0004] Indazole compounds are a new class of ROCK inhibitors, which have attracted extensive attention from researchers in recent years due to their high selectivity for the ROCK2 subtype. The representative drug Belumosudil was approved for the treatment of chronic graft-versus-host disease in 2021, and also has good effects on the treatment of fibrotic diseases. However, due to its insufficient inhibitory potency, it has not made significant progress in other disease treatment areas. The technologies disclosed in the invention patents US201314136359, CA2922312, WO2024118556, CN116891460, CN114504574, etc. are all ROCK inhibitors containing an indazole structure. In addition to the indazole as the protein hinge binding region, the molecular terminal is combined with different aromatic groups and protein hydrophobic pockets, and the linker in the middle is amide, urea, aromatic ring or simple aliphatic ring. However, most of them lack specific therapeutic effects on tumors or fibrosis. So far, no ROCK inhibitor for the treatment of tumors or fibrosis has been approved. SUMMARY

[0005] In view of the problems in the background art, the present application provides a (1H-indazol-5-yl)amino-2-pyridine derivative and its application.

[0006] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0007] A (1H-indazol-5-yl)amino-2-pyridine derivative, the derivative is a compound represented by the general formula (I) and its pharmaceutically acceptable salt,

[0008]

[0009] In the formula:

[0010] L is

[0011] R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or (CH2) 2- p is independently 0, 1, 2 or 3; p NR3R4;

[0012] R5 is halogen, hydroxyl, amino, cyano or carboxyl;

[0013] R5 is halogen, hydroxyl, amino, cyano or carboxyl;

[0014] R3and R4are the same or different, each independently selected from the group consisting of hydrogen, (C1-C6)alkyl unsubstituted or substituted with at least one R6which is the same or different, and (C3-C8)cycloalkyl; or R3and R4together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group containing at least one heteroatom, said heterocyclyl group being optionally substituted with 0-3 independent hydroxy, (C1-C6)alkyl unsubstituted or substituted with at least one R6which is the same or different, (C1-C6)alkoxy, or (C1-C6)alkoxycarbonyl;

[0015] R6is halogen, amino, hydroxy, cyano, or (C3-C6)cycloalkyl;

[0016] A is a 4-7 membered heterocyclyl group, said heterocyclyl group containing 1-3 heteroatoms optionally selected from N, O, and S;

[0017] X is selected from

[0018] R2is selected from (C1-C6)alkyl unsubstituted or substituted with at least one R5which is the same or different, (C3-C6)cycloalkyl, 4-6 membered heterocyclyl, aryl unsubstituted or substituted with at least one R7which is the same or different;

[0019] R7is halogen, hydroxy, nitro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C1-C6)alkylamino.

[0020] Preferably, the derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, wherein:

[0021] L is

[0022] R1is (C1-C6)alkyl unsubstituted or substituted with at least one R5which is the same or different, (C3-C8)cycloalkyl, (C2-C6)alkenyl, or (CH2) p NR3R4;

[0023] R5is halogen, hydroxy, amino, cyano, or carboxyl;

[0024] wherein p is independently 0, 1, 2, or 3;

[0025] R3and R4are the same or different, each independently selected from the group consisting of hydrogen, (C1-C6)alkyl unsubstituted or substituted with at least one R6which is the same or different, and (C3-C6)cycloalkyl; or R3and R4together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group containing at least one heteroatom, said heterocyclyl group being optionally substituted with 0-3 independent hydroxy, (C1-C6)alkyl unsubstituted or substituted with at least one R6which is the same or different, (C1-C6)alkoxy, or (C1-C6)alkoxycarbonyl;

[0026] R6is halogen, amino, hydroxy, cyano or (C3-C6)cycloalkyl;

[0027] A is a 4-7 membered heterocyclyl, which contains 1-3 heteroatoms, optionally from N or O;

[0028] X is selected from the group consisting of ;

[0029] R2is selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, 4-6 membered heterocyclyl, aryl, unsubstituted or substituted by at least one identical or different R7;

[0030] R7is halogen, hydroxy, nitro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)alkylamino.

[0031] Further preferred, the derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, wherein

[0032] L is

[0033] R1is (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl or (CH2) p NR3R4;

[0034] R5is halogen, hydroxy, amino, cyano or carboxyl;

[0035] wherein p is independently 1, 2 or 3

[0036] R3and R4are identical or different and independently selected from the group consisting of hydrogen, (C1-C4)alkyl and (C3-C6)cycloalkyl, unsubstituted or substituted by at least one identical or different R6; or R3and R4together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl containing at least one heteroatom, which is optionally substituted by 0-1 independent hydroxy, (C1-C3)alkyl, (C1-C3)alkyl unsubstituted or substituted by at least one identical or different R6, (C1-C3)alkoxycarbonyl;

[0037] R6is amino, hydroxy or (C3-C6)cycloalkyl;

[0038] A is a 5-6 membered heterocyclyl, which contains 1-2 heteroatoms, optionally from N or O;

[0039] X is selected from the group consisting of ;

[0040] R2is selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, 4-piperidinyl, aryl unsubstituted or substituted with at least one R7which is the same or different;

[0041] R7is halogen, hydroxy, nitro, cyano, (C1-C4)alkyl or (C1-C4)alkylamino.

[0042] Still further preferred, the derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, wherein:

[0043] L is

[0044] R1is (C1-C4)alkyl, (C2-C4)alkenyl or CH2NR3R4;

[0045] R3and R4are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl unsubstituted or substituted with at least one R6which is the same or different, and (C3-C6)cycloalkyl; or R3and R4together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl ring containing at least one heteroatom, said heterocyclyl ring being optionally substituted with 0-1 substituents independently selected from hydroxy, (C1-C3)alkyl, (C1-C3)alkyl unsubstituted or substituted with at least one R6which is the same or different, and methoxycarbonyl;

[0046] R6is hydroxy or cyclopropyl;

[0047] A is

[0048] X is selected from ; and pharmaceutically acceptable salts thereof.

[0049] R2is selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, 4-piperidinyl, aryl unsubstituted or substituted with at least one R7which is the same or different;

[0050] R7is halogen, (C1-C4)alkyl or (C1-C4)alkylamino.

[0051] Still further preferred, the derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, wherein:

[0052] L is

[0053] R1is methyl, t-butyl, ethenyl,

[0054]

[0055] X is selected from one of the following:

[0056] A is

[0057] R2 is

[0058] most preferably, the derivative is the following compound and pharmaceutically acceptable salts thereof,

[0059] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0060] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0061] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0062] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0063] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0064] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0065] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0066] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0067] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l-yl]pyridin-3-yl}-2- morpholinoacetamide;

[0068] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-methylbenzoyl)piperazin-l-yl]pyridin-3- yl}-2-[(2-hydroxyethyl)amino]acetamide;

[0069] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-methylbenzoyl)piperazin-l-yl]pyridin-3- yl}-2-(4-hydroxypiperidin-l-yl)acetamide;

[0070] N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-methylbenzoyl)piperazin-l-yl]pyridin-3- yl}-2-[4-(2-hydroxyethyl)piperazin-l-yl]acetamide;

[0071] (S)-{l-[6-[(lH-indazol-5-yl)amino]-3-(methylsulfonamido)pyridin-2-yl]pyrrolidin-2- yl}methyl[4-(dimethylamino)phenyl]carbamate;

[0072] (S)-{l-[6-[(lH-indazol-5-yl)amino]-3-[2-(pyrrolidin-l-yl)acetamido]pyridin-2-yl]pyrrolidin- 2-yl}methyl{4-(dimethylamino)phenyl}carbamate;

[0073] (S)-{l-[6-[(lH-indazol-5-yl)amino]-3-[2-(dimethylamino)acetamido]pyridin-2-yl]pyrrolidin- 2-yl}methyl[4-(dimethylamino)phenyl]carbamate;

[0074] (S)-{l-[6-[(lH-indazol-5-yl)amino]-3-[2-(4-methylpiperazin-l-yl)acetamido]pyridin-2- yl]pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate;

[0075] (S)-{l-[6-[(lH-indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetamido}pyridin-2- yl]pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate;

[0076] (S)-{l-[6-[(lH-indazol-5-yl)amino]-3-{2-[(2-hydroxyethyl)amino]acetamido}pyridin-2- yl]pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate;

[0077] (S)-{l-[6-[(lH-indazol-5-yl)amino]-3-acrylamidopyridin-2-yl]pyrrolidin-2-yl}p-tolylcarbamate;

[0078] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0079] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0080] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0081] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0082] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0083] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0084] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0085] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0086] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0087] (S)-{1 -[6-[(1 H-indol-5-yl)amino]-3-(2-oxoazepan-1 -yl)acetylamino]pyridin-2-yl}- methylpiperidin-4-ylcarbamate;

[0088] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0089] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0090] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0091] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0092] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0093] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0094] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0095] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0096] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0097] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methylisopropylcarbamate;

[0098] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopropylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate;

[0099] (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate;

[0100] (S)-N-{{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(4-methylpiperazin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl}-4-(dimethylamino)benzamide.

[0101] The salt of the compound represented by the general formula (I) is a pharmaceutically acceptable salt obtained by reacting the compound with an acid, and the corresponding acid is hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, citric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, tartaric acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.

[0102] The application of the (1H-indazol-5-yl)amino-2-pyridine derivative, the compound represented by the general formula (I) and the pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors or fibrosis diseases as a ROCK2 inhibitor.

[0103] The tumor is selected from lung cancer, breast cancer, gastric cancer, colon cancer, hepatocellular carcinoma, oral cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, neuroblastoma, osteosarcoma, fibrosarcoma; and the fibrosis is selected from pulmonary fibrosis, renal fibrosis, hepatic fibrosis, myocardial fibrosis.

[0104] Advantages of the present application

[0105] The application provides a (1H-indazol-5-yl)amino-2-pyridine derivative as a ROCK2 inhibitor, which fills the research blank; the (1H-indazol-5-yl)amino-2-pyridine derivative is novel in structure type and shows high inhibitory activity on ROCK2. In in-vitro cell experiments, the (1H-indazol-5-yl)amino-2-pyridine derivative can effectively inhibit the proliferation of MDA-MB-231 breast cancer cells and TGF-β-induced NIH-3T3 mouse embryonic fibroblasts and inhibit the migration of MDA-MB-231 cells. Meanwhile, in a bleomycin-induced C57BL / 6 mouse pulmonary fibrosis model, the (1H-indazol-5-yl)amino-2-pyridine derivative can effectively improve the inflammation degree of the lung tissue of the mouse, and has a therapeutic potential for tumor and fibrosis diseases. The application also provides a preparation method of the (1H-indazol-5-yl)amino-2-pyridine derivative, which is simple, easy to purify, and has good realizability. BRIEF DESCRIPTION OF DRAWINGS

[0106] Figure 1 Figure 4 is an anti-MDA-MB-231 cell migration experiment result of the compound 21.

[0107] Figure 2 Figure 6 is a mouse lung tissue HE staining experiment result. DETAILED DESCRIPTION

[0108] The application will be further described below in combination with specific implementation examples, but the application is not limited to these examples.

[0109] The (1H-indazol-5-yl)amino-2-pyridine derivative formed by combining an indazole fragment and introducing an amino pyridine structure as a linker is a novel ROCK2 inhibitor, and the compound is novel in structure type, has high inhibitory efficiency on ROCK2, and shows diverse biological activities in vitro and in vivo, and is expected to improve the targeted therapeutic effect on tumors and fibrosis, and is a very potential drug structure type. At present, no (1H-indazol-5-yl)amino-2-pyridine derivative has been reported as a ROCK2 inhibitor.

[0110] In the following examples, the nuclear magnetic resonance hydrogen spectrum of the compound is measured by using a Bruker ARX-400 / 600, and the mass spectrum is measured by using an Agilent 110 LC / MSD; and the reagents used are analytical pure or chemical pure.

[0111] Examples 1-12

[0112]

[0113]

[0114] Example 13

[0115]

[0116] Examples 14-41

[0117]

[0118]

[0119]

[0120] Example 42

[0121]

[0122] Example 1: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l- yl]pyridin-3-yl}-2-(pyrrolidin-l-yl)acetamide (1);

[0123] The route is shown below:

[0124]

[0125] Step Al: Synthesis of Intermediate A-I

[0126] Dissolve 5-nitroindazole (5.0 g, 61.3 mmol) in ethyl acetate (50 mL), add p-toluenesulfonic acid monohydrate (2.3 g, 12.3 mmol) and 3,4-2H-pyrane (15.5 g, 183.9 mmol), stir the reaction at room temperature for 2 h. Add water (30 mL) to the reaction, wash the organic phase with water (30 mL) twice, evaporate the organic phase to dryness, recrystallize the crude product from methanol to obtain a light yellow solid 12.5 g, yield 83.2%.

[0127] Step A2: Synthesis of Intermediate A-II

[0128] Dissolve Intermediate A-I (10.0 g, 40.5 mmol) in a mixture of methanol (50 mL) and tetrahydrofuran (50 mL), add wet palladium on carbon (1.0 g, 5%), stir the reaction at room temperature under hydrogen for 8 h. Filter the reaction, wash the filter cake with methanol (10 mL), evaporate the filtrate to dryness to obtain a light purple solid 8.1 g, yield 92.0%. Analytical data: ESI-MS [M+H] (m / z): 218.3. +

[0129] Step A3: Synthesis of Intermediate A-III

[0130] ​Dissolve 2,6-dichloro-3-nitropyridine (10.0 g, 52.09 mmol) in tetrahydrofuran (150 mL), add potassium carbonate (14.4 g, 104.18 mmol), slowly add N-Boc-piperazine (8.8 g, 47.35 mmol) at low temperature, stir the reaction at room temperature for 12 h. Filter the reaction, dry the filtrate, purify the crude product by column chromatography to obtain 13.6 g of yellow solid with a yield of 76.3%. Analytical data: ESI-MS [M+Na] + (m / z): 365.0.

[0131] Step A4: Synthesis of intermediate A-IV

[0132] Dissolve intermediate A-III (10.0 g, 29.2 mmol) in 4 M hydrochloric acid / ethyl acetate solution (80 mL), stir the reaction at room temperature for 3 h. Filter the reaction, wash the filter cake with ethyl acetate (20 mL) twice, and dry to obtain 7.1 g of light yellow solid with a yield of 78.6%. Analytical data: ESI-MS [M+H] + (m / z): 242.3.

[0133] Step A5: Synthesis of intermediate A-V

[0134] Dissolve 4-fluorobenzoyl chloride (1.0 g, 6.4 mmol) and N,N-diisopropylethylamine (1.4 g, 10.8 mmol) in dichloromethane (15 mL), add intermediate A-IV (1.5 g, 5.4 mmol) in batches at low temperature, stir the reaction at room temperature for 1 h. Stir the reaction with water (10 mL), separate the organic phase, wash the organic phase with saturated sodium bicarbonate solution (5 mL) twice, dry over anhydrous sodium sulfate, and dry to obtain 2.15 g of yellow solid with a yield of 99.1%. Analytical data: ESI-MS [M-H] - (m / z): 363.2.

[0135] Step A6: Synthesis of intermediate A-VI

[0136] Dissolve intermediate A-V (0.4 g, 1.1 mmol) and intermediate A-II (0.29 g, 1.3 mmol) in DMF (5 mL), add N,N-diisopropylethylamine (0.21 g, 1.65 mmol), stir the reaction at 80°C for 12 h. Pour the reaction into water (200 mL) and stir, precipitate a large amount of yellow solid, filter, wash the filter cake with water (5 mL), and dry, purify the crude product by column chromatography to obtain 0.6 g of yellow solid with a yield of 64.1%. Analytical data: ESI-MS [M+H] + (m / z): 568.4.

[0137] Step A7: Synthesis of intermediate A-VII

[0138] Intermediate A-VI (0.3 g, 0.55 mmol) was dissolved in methanol (5 mL), wet palladium on carbon (0.03 g, 5%) was added, and the reaction was stirred at room temperature under hydrogen for 8 h. The reaction was filtered, the filter cake was washed with methanol (3 mL), and the filtrate was evaporated to give 0.27 g of a green solid with a yield of 98%. Analytical data: ESI-MS [M+H] + (m / z): 516.4.

[0139] Step A8: Synthesis of intermediate A-VIII

[0140] Intermediate A-VII (0.3 g, 0.58 mmol) was dissolved in methanol, N,N- diisopropylethylamine (0.15 g, 0.87 mmol) was added, and chloroacetyl chloride (0.09 g, 0.87 mmol) was added dropwise at low temperature. The reaction was stirred at room temperature for 30 min. The reaction was evaporated, water (15 mL) was added, the mixture was filtered, the filter cake was washed with water (5 mL) and dried, and the crude product was purified by column chromatography to give 0.2 g of a yellowish solid with a yield of 58%. Analytical data: ESI-MS [M+H] + (m / z): 592.4.

[0141] Step A9: Synthesis of Example 1

[0142] Intermediate A-VIII (0.11 g, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL), potassium carbonate (0.06 g, 0.50 mmol) and tetrahydropyrrole (0.02 g, 0.38 mmol) were added, and the reaction was stirred at 45 °C for 2 h. The reaction was evaporated, water (5 mL) was added, and a greyish solid was filtered. The filter cake was dried, dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added dropwise, and the reaction was stirred at room temperature for 2 h. The reaction was evaporated, water (5 mL) was added, the solution was adjusted to pH 8 with saturated sodium bicarbonate solution, and dichloromethane (5 mL) was added. The organic phase was dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography to give 79 mg of a white solid with a yield of 59.0%. Analytical data: ESI-MS [M+H] + (m / z): 543.2. 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.58-7.50 (m, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.31 (t, J = 8.9 Hz, 2H), 6.54 (d, J = 8.7 Hz, 1H), 3.82 (m, 4H), 3.25 (s, 2H), 3.09 (s, 4H), 2.66 (d, J = 6.0 Hz, 4H), 1.80 (q, J = 3.2 Hz, 4H). 13 C NMR (101 MHz, DMSO) δ 168.82, 168.60, 164.27, 161.82, 151.69, 150.87, 136.37, 135.42, 133.32, 132.78, 132.74, 131.28, 130.10, 130.02, 123.63, 121.11, 117.41, 116.01, 115.80, 110.49, 107.36, 105.02, 59.89, 53.49, 49.22, 23.60.

[0143] Example 2: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l- yl]pyridin-3-yl}-2-morpholinoacetamide (2);

[0144] According to the method of step A9 in example 1, intermediate A-VIII was used as raw material, and nucleophilic substitution reaction with morpholine was carried out, and then deprotection under acidic condition to obtain example 2, with a yield of 63.2%. Analytical data: ESI-MS [M+H] + (m / z): 559.5.

[0145] Example 3: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l- yl]pyridin-3-yl}-2-(piperidin-l-yl)acetamide (3);

[0146] According to the method of step A9 in example 1, intermediate A-VIII was used as raw material, and nucleophilic substitution reaction with morpholine was carried out, and then deprotection under acidic condition to obtain example 2, with a yield of 63.2%. Analytical data: ESI-MS [M+H] + (m / z): 557.6.

[0147] Example 4: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l- yl]pyridin-3-yl}-2-(cyclopentylamino)acetamide (4);

[0148] According to the method of step A9 in example 1, intermediate A-VIII was used as raw material to react with cyclopentylamine by nucleophilic substitution, then deprotection under acidic condition to give example 4, yield 43.4%. Analytical data: ESI-MS [M+H] + (m / z): 557.5.

[0149] Example 5: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-fluorobenzoyl)piperazin-l- yl]pyridin-3-yl}-2-(4-methylpiperazin-l-yl)acetamide (5);

[0150] According to the method of step A9 in example 1, intermediate A-VIII was used as raw material to react with 4-methylpiperazine by nucleophilic substitution, then deprotection under acidic condition to give example 5, yield 55.2%. Analytical data: ESI-MS [M+H] + (m / z): 572.3. 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.20 (s, 1H), 8.84 (s, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.54 (dd, J = 8.4, 5.4 Hz, 2H), 7.44 (d, J = 2.8 Hz, 2H), 7.31 (t, J = 8.7 Hz, 2H), 6.54 (d, J = 8.7 Hz, 1H), 3.95 - 3.55 (m, 5H), 3.11 (s, 6H), 2.55 (s, 4H), 2.40 (s, 4H), 2.19 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 168.90, 168.12, 164.28, 161.83, 151.76, 150.95, 135.40, 132.78, 132.75, 131.52, 130.06, 129.98, 123.64, 121.17, 117.40, 116.05, 115.84, 110.49, 107.46, 105.01, 62.20, 55.37, 55.29, 53.44, 49.98, 46.25.

[0151] Example 6: N-{6-[(lH-indazol-5-yl)amino]-2-{4-[4-(dimethylamino)benzoyl]piperazin-l- yl}pyridin-3-yl}-2-(pyrrolidin-l-yl)acetamide (6);

[0152] The synthesis route is as follows:

[0153]

[0154] Step A9: Synthesis of intermediate A-IX

[0155] According to the method in step A4 in example 1, acylation reaction of intermediate A-IV with 4-dimethylaminobenzoyl chloride was carried out to give intermediate A-IX in 89.5% yield.

[0156] Step A10: Synthesis of intermediate A-X

[0157] According to the method in step A6 in example 1, nucleophilic substitution reaction of intermediate A-IX with intermediate A-II was carried out to give intermediate A-X in 49.6% yield. Analytical data: ESI-MS [M+H] + (m / z): 571.3.

[0158] Step A11: Synthesis of intermediate A-XI

[0159] According to the method in step A7 in example 1, reduction reaction of intermediate A-X with hydrogen and palladium on carbon was carried out to give intermediate A-XI in 82.3% yield.

[0160] Step A12: Synthesis of intermediate A-XII

[0161] According to the method in step A8 in example 1, acylation reaction of intermediate A-XI with chloroacetyl chloride was carried out to give intermediate A-XII in 74.3% yield.

[0162] Step A13: Synthesis of example 6

[0163] According to the method in step A9 in example 1, nucleophilic substitution reaction of intermediate A-XII with tetrahydropyrrole followed by deprotection under acidic condition was carried out to give example 6 in 37.5% yield. Analytical data: ESI-MS [M+H] + (m / z): 568.1. 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.11 (t, J = 1.4 Hz, 1H), 7.93 (s, 1H), 7.46 - 7.42 (m, 2H), 7.35 (s, 1H), 7.33 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 3.70 (t, J = 4.7 Hz, 4H), 3.26 (s, 2H), 3.08 (t, J = 5.0 Hz, 4H), 2.96 (s, 6H), 2.74 - 2.63 (m, 4H), 1.82 - 1.78 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 170.44, 168.56, 151.73, 150.92, 136.39, 135.45, 133.25, 131.09, 129.51, 123.63, 122.48, 121.12, 117.58, 111.54, 110.52, 107.35, 105.04, 59.88, 55.37, 54.68, 50.30, 45.86, 24.22.

[0164] Example 7: N-{6-[(lH-indazol-5-yl)amino]-2-{4-[4-(dimethylamino)benzoyl]piperazin-l- yl}pyridin-3-yl}-2-(dimethylamino)acetamide; (7);

[0165] According to the method of step A9 in example 1, using intermediate A-XII as raw material, nucleophilic substitution reaction with dimethylamine hydrochloride, and then deprotection under acidic condition to obtain example 7, yield 29.9%. Analytical data: ESI-MS [M+Na] + (m / z): 564.4. 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.33 (s, 1H), 8.84 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.44 (s, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.3 Hz, 2H), 6.54 (d, J = 8.7 Hz, 1H), 3.72 (s, 4H), 3.11 - 3.04 (m, 4H), 2.96 (s, 6H), 2.50 (s, 2H), 2.35 (s, 6H). 13C NMR (101 MHz, DMSO) δ 170.41, 168.26, 151.72, 151.00, 136.39, 135.46, 133.27, 131.09, 129.56, 123.63, 122.51, 121.11, 117.39, 111.54, 110.51, 107.34, 104.90, 65.38, 63.70, 55.37, 50.23, 46.24.

[0166] Example 8: N-{6-[(lH-indazol-5-yl)amino]-2-{4-[4-(dimethylamino)benzoyl]piperazin- 1-yl}pyridin-3-yl}-2-(cyclopropylamino)acetamide (8);

[0167] According to the method of step A9 in example 1, intermediate A-XII was used as raw material, nucleophilic substitution reaction with cyclopropylamine, and then deprotection under acidic condition to give example 8, yield 40.1%. Analytical data: ESI-MS [M+H] + (m / z): 554.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.33 (s, 1H), 8.82 (s, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 2.0 Hz, 2H), 7.37 - 7.31 (m, 2H), 6.77 - 6.70 (m, 2H), 6.53 (d, J = 8.6 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.73 - 3.68 (m, 4H), 3.08 (t, J = 4.9 Hz, 4H), 2.96 (s, 6H), 2.21 (tt, J = 6.7, 3.6 Hz, 1H), 1.99 (s, 1H), 1.18 (t, J = 7.1 Hz, 1H), 0.49 - 0.38 (m, 2H), 0.35 (dd, J = 4.6, 2.3 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 170.41, 168.26, 151.72, 151.00, 136.39, 135.46, 133.27, 131.09, 129.56, 123.63, 122.51, 121.11, 117.39, 111.54, 110.51, 107.34, 104.90, 65.38, 63.70, 55.37, 50.23, 46.24.

[0168] Example 9: N-{6-[(lH-indazol-5-yl)amino]-2-{4-[4- (dimethylamino)benzoyl]piperazin-l-yl}pyridin-3-yl}-2-[(2- hydroxyethyl)amino]acetamide (9);

[0169] According to the method of step A9 in example 1, intermediate A-XII was used as raw material, nucleophilic substitution reaction with ethanolamine, and deprotection under acidic conditions to obtain example 9, yield 23.5%. Analytical data: ESI-MS [M+H] + (m / z): 558.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.59 (s, 1H), 8.82 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.44 (s, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 8.7 Hz, 1H), 4.62 (d, J = 5.3 Hz, 1H), 3.73 (t, J = 4.7 Hz, 4H), 3.54 (q, J = 5.7, 5.2 Hz, 2H), 3.29 (s, 2H), 3.18 (s, 1H), 3.10 (t, J = 5.0 Hz, 4H), 2.96 (s, 6H), 2.69 (t, J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 170.39, 169.99, 151.71, 151.63, 151.10, 136.42, 135.51, 133.01, 131.22, 129.53, 123.64, 122.58, 121.11, 117.37, 111.54, 110.50, 107.29, 104.68, 60.96, 53.09, 52.34, 50.03, 49.07, 40.26.

[0170] Example 10: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4- methylbenzoyl)piperazin-l-yl]pyridin-3-yl}-2-[(2- hydroxyethyl)amino]acetamide (10);

[0171] The synthetic route is shown as follows:

[0172]

[0173] Step A14: synthesis of intermediate A-XIII

[0174] According to the method in Step A4 in Example 1, acylation reaction of intermediate A-IV with 4-methylbenzoyl chloride was carried out to obtain intermediate A-XIII in a yield of 92.3%.

[0175] Step A15: Synthesis of intermediate A-XIV

[0176] According to the method in Step A6 in Example 1, nucleophilic substitution reaction of intermediate A-XIII with intermediate A-II was carried out to obtain intermediate A-XIV in a yield of 41.2%.

[0177] Step A16: Synthesis of intermediate A-XV

[0178] According to the method in Step A7 in Example 1, reduction reaction of intermediate A-XIII with hydrogen and palladium carbon was carried out to obtain intermediate A-XV in a yield of 88.2%.

[0179] Step A17: Synthesis of intermediate A-XVI

[0180] According to the method in Step A8 in Example 1, acylation reaction of intermediate A-XV with chloroacetyl chloride was carried out to obtain intermediate A-XVI in a yield of 79.1%.

[0181] Step A18: Synthesis of Example 10

[0182] According to the method in Step A9 in Example 1, nucleophilic substitution reaction of intermediate A-XVI with ethanolamine was carried out, and then deprotection under acidic conditions to obtain Example 10 in a yield of 52.1%. Analytical data: ESI-MS [M+H] + (m / z): 529.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.58 (s, 1H), 8.83 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.44 (s, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 6.53 (d, J = 8.6 Hz, 1H), 4.65 (s, 1H), 3.77 (m, 5H), 3.53 (q, J = 6.5, 6.1 Hz, 2H), 3.11 (s, 4H), 2.70 (t, J = 5.6 Hz, 2H), 2.36 (s, 3H). 13C NMR (101 MHz, DMSO) δ 169.79, 169.72, 151.73, 151.20, 139.68, 136.46, 135.48, 133.53, 133.19, 131.60, 129.38, 127.56, 123.64, 121.15, 117.13, 110.53, 107.38, 104.62, 60.76, 55.36, 52.87, 52.20, 49.90, 21.38.

[0183] Example 11: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-methylbenzoyl)piperazin-l- yl]pyridin-3-yl}-2-(4-hydroxypiperidin-l-yl)acetamide (11);

[0184] Example 11 was obtained according to the procedure of Example 1, Step A9, using intermediate A-XVI as starting material, nucleophilic substitution with 4-hydroxypiperidine and deprotection under acidic conditions in 55.7% yield. Analytical data: ESI-MS [M+H] + (m / z): 569.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.28 (s, 1H), 8.84 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.49 - 7.40 (m, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.55 (d, J = 8.7 Hz, 1H), 4.68 (d, J = 4.2 Hz, 1H), 3.72 (s, 4H), 3.56 - 3.50 (m, 1H), 3.38 (q, J = 7.1 Hz, 1H), 3.09 (s, 4H), 2.79 (dt, J = 10.1, 4.3 Hz, 2H), 2.36 (s, 3H), 2.30 (t, J = 10.9 Hz, 2H), 1.79 (dq, J = 12.2, 3.8 Hz, 2H), 1.57 - 1.45 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 169.79, 168.35, 151.71, 150.87, 139.74, 136.42, 135.42, 133.44, 133.25, 131.21, 129.42, 127.53, 123.64, 121.18, 117.61, 110.48, 107.47, 105.11, 66.04, 65.37, 62.24, 51.96, 50.20, 35.03, 21.38.

[0185] Example 12: N-{6-[(lH-indazol-5-yl)amino]-2-[4-(4-methylbenzoyl)piperazin-l- yl]pyridin-3-yl}-2-[4-(2-hydroxyethyl)piperazin-l-yl]acetamide (12);

[0186] Example 12 was obtained according to the procedure of Example 1, Step A9, using intermediate A-XVI as starting material, nucleophilic substitution with N-hydroxyethylpiperazine followed by deprotection under acidic conditions in 46.5% yield. Analytical data: ESI-MS [M+H] + (m / z): 598.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.21 (s, 1H), 8.84 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.44 (d, J = 2.9 Hz, 2H), 7.36 (d, J = 7.7 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 1H), 4.43 (s, 1H), 3.70 (s, 4H), 3.52 (d, J = 6.0 Hz, 2H), 3.10 (d, J = 8.6 Hz, 4H), 2.55 (s, 8H), 2.44 (t, J = 6.1 Hz, 2H), 2.36 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 169.89, 168.09, 151.75, 150.92, 139.75, 136.46, 135.42, 133.47, 133.25, 131.36, 129.44, 127.49, 123.63, 121.17, 117.52, 110.50, 107.46, 105.05, 62.27, 60.71, 58.90, 53.72, 53.51, 50.11, 21.38.

[0187] Example 13: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-(methylsulfonamido)pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate (13);

[0188] The synthetic route is shown below:

[0189]

[0190] Step B1: Synthesis of intermediate B-I

[0191] Step B2: Synthesis of intermediate B-II 1 H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.79 (s, 1H), 4.31 (qd, J = 7.0, 3.3 Hz, 1H), 3.65 (dd, J = 10.6, 3.4 Hz, 1H), 3.45 (dd, J = 10.6, 6.3 Hz, 1H), 3.40 - 3.26 (m, 1H), 2.78 (ddd, J = 10.6, 7.8, 2.5 Hz, 1H), 2.12 - 2.02 (m, 1H), 2.01 - 1.86 (m, 2H), 1.80 - 1.63 (m, 1H).

[0192] Step B2: Synthesis of intermediate B-II

[0193] Step B2: Synthesis of intermediate B-II + (m / z): 442.0.

[0194] Step B3: Synthesis of intermediate B-III

[0195] According to the method of step A6 in example 1, intermediate B-II was used as raw material to react with intermediate A-II by nucleophilic substitution to obtain intermediate B-III, with a yield of 51.2%.

[0196] Step B4: Synthesis of intermediate B-IV

[0197] According to the method of Step A7 in Example 1, intermediate B-III was used as raw material to undergo reduction reaction under the action of hydrogen and palladium-carbon to obtain intermediate B-IV, with a yield of 73.1%.

[0198] Step B5: Synthesis of Example 13

[0199] According to the method of Step A8 in Example 1, intermediate B-IV was used as raw material to undergo acylation reaction with methanesulfonyl chloride, and then deprotection under acidic conditions to obtain Example 13, with a yield of 43.9%. Analytical data: ESI-MS [M+H] + (m / z): 565.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.26 (s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.40 (s, 2H), 7.23 (s, 3H), 6.65 (s, 2H), 6.14 (s, 1H), 4.51 (d, J = 173.8 Hz, 2H), 3.91 (s, 2H), 3.47 (s, 1H), 2.80 (s, 6H), 2.01 (s, 2H), 1.93-1.73 (m, 3H), 1.23 (s, 2H).

[0200] Example 14: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(pyrrolidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl{4-(dimethylamino)phenyl}carbamate (14);

[0201]

[0202] According to the method of Step A9 in Example 1, intermediate B-V was used as raw material to undergo nucleophilic substitution reaction with tetrahydropyrrole, and then deprotection under acidic conditions to obtain Example 14, with a yield of 39.5%. Analytical data: ESI-MS [M+H] + (m / z): 598.0. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.17 (d, J = 81.6 Hz, 2H), 8.71 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.40 (s, 2H), 7.28 - 7.22 (m, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.24 (d, J = 8.4 Hz, 1H), 4.68 - 4.23 (m, 2H), 3.91 (s, 1H), 3.65 (d, J = 8.4 Hz, 1H), 3.21 (s, 3H), 2.81 (s, 6H), 2.07 (s, OH), 1.97 (s, 1H), 1.85 (s, 2H), 1.73 (s, 4H), 1.23 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 162.78, 154.29, 153.28, 152.69, 147.21, 135.47, 130.12, 123.62, 121.06, 120.61, 113.37, 110.50, 107.10, 100.04, 57.17, 54.52, 50.48, 41.08, 29.50, 28.67, 24.55, 23.53.

[0203] Example 15: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(dimethylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate (15);

[0204] According to the method of Example 1, Step A9, using intermediate B-V as starting material, nucleophilic substitution reaction with dimethylamine hydrochloride, followed by deprotection under acidic condition, to give Example 15 in 23.4% yield. Analytical data: ESI-MS [M+H] + (m / z): 572.0. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.29 (s, 1H), 9.02 (s, 1H), 8.72 (s, 1H), 8.14 - 8.07 (m, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.24 (s, 2H), 6.69 - 6.62 (m, 2H), 6.21 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 12.2 Hz, 1H), 4.29 (dd, J = 10.2, 3.8 Hz, 1H), 3.90 (t, J = 9.2 Hz, 1H), 3.68 (dd, J = 9.8, 6.6 Hz, 1H), 3.25 (dt, J = 9.3, 6.6 Hz, 1H), 3.03 (s, 2H), 2.81 (s, 6H), 2.28 (s, 6H), 1.23 (s, 4H).

[0205] Example 16: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(4-methylpiperazin-1- yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate (16);

[0206] According to the method of Example 1, Step A9, intermediate B-V was used as the starting material to undergo nucleophilic substitution reaction with N-methylpiperazine, followed by deprotection under acidic condition to give Example 37 in 40.5% yield. Analytical data: ESI-MS [M+H] + (m / z): 627.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.29 (s, 1H), 9.12 (s, 1H), 8.76 (s, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.40 (s, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.25 (d, J = 8.3 Hz, 1H), 4.58 (t, J = 6.3 Hz, 1H), 4.28 (dd, J = 10.4, 4.1 Hz, 1H), 3.89 (t, J = 9.3 Hz, 1H), 3.74 - 3.52 (m, 2H), 3.23 - 3.07 (m, 2H), 2.81 (s, 6H), 2.50 (s, 3H), 2.38 (d, 8H), 2.11 - 1.81 (m, 4H).

[0207] Example 17: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate (17);

[0208] According to the method of step A9 in example 1, using intermediate B-V as starting material, nucleophilic substitution reaction with cyclopropylmethylamine, followed by deprotection under acidic condition to give example 17, yield 32.4%. Analytical data: ESI-MS [M+H] + (m / z): 598.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.16 (s, 1H), 9.09 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.31 (s, 1H), 7.27 (s, 2H), 7.12 (s, 2H), 6.53 (d, J = 8.3 Hz, 2H), 6.11 (d, J = 7.8 Hz, 1H), 4.48 (s, 1H), 4.18 (s, 1H), 3.77 (s, 1H), 3.59 (s, 1H), 3.19 (s, 2H), 3.12 - 2.92 (m, 2H), 2.69 (s, 6H), 1.91 (d, J = 38.9 Hz, 2H), 1.12 (s, 4H), 0.77 (s, 1H), 0.15 (d, J = 117.1 Hz, 4H).

[0209] Example 18: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-{2-[(2-hydroxyethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate (18);

[0210] According to the method of step A9 in example 1, using intermediate B-V as starting material, nucleophilic substitution reaction with ethanolamine, followed by deprotection under acidic condition to give example 42, yield 40.5%. Analytical data: ESI-MS [M+H] + (m / z): 588.2.

[0211] 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 9.43 (s, 1H), 9.33 (s, 1H), 8.78 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.39 (s, 1H), 7.26 (s, 2H), 7.11 (s, 2H), 6.65 (s, 2H), 6.21 (s, 1H), 5.32 (s, 1H), 4.87 (s, 1H), 4.63-4.59 (m, 1H), 4.32 (s, 1H), 3.87-3.83 (m, 1H), 3.70 (s, 2H), 3.54 (s, 2H), 2.80 (s, 6H), 1.98 (s, 2H), 1.85-1.81 (m, 2H), 0.87-0.82 (m, 4H).

[0212] Example 19: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-propenoylamino pyridin-2- yl}pyrrolidin-2-yl}p-tolylcarbamate (19);

[0213] The synthetic route is shown below:

[0214]

[0215] Step B6: Synthesis of intermediate B-VI

[0216] According to the method of step B2 in Example 13, intermediate B-VI was generated from p-toluic acid and intermediate B-I by Curtis rearrangement reaction in yield of 65.8%. Analytical data: ESI-MS [M+H] + (m / z): 391.9.

[0217] Step B7: Synthesis of intermediate B-VII

[0218] According to the method of step A6 in Example 1, intermediate B-VII was generated from intermediate B-VI by nucleophilic substitution reaction with intermediate A-II in yield of 41.9%. ESI-MS [M+H] + (m / z): 572.0.

[0219] Step B8: Synthesis of intermediate B-VIII

[0220] According to the method of step A7 in Example 1, intermediate B-VIII was generated from intermediate B-VII by reduction reaction under the action of hydrogen and palladium on carbon in yield of 89.4%.

[0221] Step B9: Synthesis of Example 19

[0222] According to the method of step A8 in example 1, intermediate B-IX was used as raw material, acylation reaction with acryloyl chloride, then deprotection under acidic condition to obtain example 20, yield 42.5%. Analytical data: ESI-MS [M+H]+(m / z): 598.1.

[0223] Example 20: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(4-methylpiperazin-1- yl)acetamido]pyridin-2-yl}pyrrolidin-2-yl}p-tolylcarbamate (20);

[0224]

[0225] According to the method of step A9 in example 1, intermediate B-IX was used as raw material, nucleophilic substitution reaction with 4-methylpiperazine, then deprotection under acidic condition to obtain example 20, yield 42.5%. Analytical data: ESI-MS [M+H] + (m / z): 598.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.54 (s, 1H), 9.09 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 2.9 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.28 (d, J = 8.4 Hz, 1H), 4.58 (t, J = 5.9 Hz, 1H), 4.28 (dd, J = 10.4, 4.2 Hz, 1H), 3.99 - 3.90 (m, 1H), 3.75 - 3.45 (m, 2H), 3.22 - 3.15 (m, 2H), 3.05 (s, 2H), 2.36 (s, 4H), 2.22 (s, 3H), 2.16 (s, 3H), 2.13 - 2.05 (m, 2H), 2.02 - 1.78 (m, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 169.02, 154.04, 152.47, 151.65, 137.01, 136.20, 135.56, 133.27, 131.63, 129.52, 123.63, 121.05, 118.83, 112.49, 110.39, 107.00, 101.16, 65.84, 61.87, 57.33, 55.19, 53.37, 51.18, 46.17, 28.67, 24.55, 20.79.

[0226] Example 21: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}p-tolylcarbamate (21);

[0227] According to the method of Step A9 in Example 1, using intermediate B-IX as starting material, nucleophilic substitution reaction with cyclopentylamine, followed by deprotection under acidic condition to give Example 21 in 38.2% yield. Analytical data: ESI-MS [M+H] + (m / z): 583.3. 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.55 (s, 1H), 9.22 (s, 1H), 8.71 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 2.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.25 (d, J = 8.4 Hz, 1H), 4.59 (s, 1H), 4.30 (dd, J = 10.3, 4.0 Hz, 1H), 3.91 (t, J = 9.2 Hz, 1H), 3.70 (d, J = 8.3 Hz, 1H), 3.23 (d, J = 6.3 Hz, 2H), 3.19 - 3.04 (m, 2H), 3.02 (s, 1H), 2.22 (s, 3H), 2.16 - 1.88 (m, 4H), 1.86 - 1.65 (m, 4H), 1.54 (d, J = 60.8 Hz, 4H).

[0228] Example 22: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(4-hydroxypiperidin-1-yl)acetylamino]pyridin-2- yl}pyrrolidin-2-yl}methyl p-tolylcarbamate (22);

[0229] According to the method of Step A9 in Example 1, using intermediate B-IX as starting material, nucleophilic substitution reaction with 4-hydroxypiperidine, followed by deprotection under acidic condition to give Example 22 in 41.9% yield. Analytical data: ESI-MS [M+H] + (m / z): 599.3. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.53 (s, 1H), 9.11 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.39 (s, 2H), 7.34 - 7.23 (m, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.35 - 6.18 (m, 1H), 4.60 (s, 1H), 4.29 (s, 1H), 3.80 (d, J = 92.2 Hz, 1H), 3.48 (s, 1H), 3.18 (s, 1H), 3.02 (s, 2H), 2.73 (s, 2H), 2.22 (s, 3H), 1.93 (d, J = 49.6 Hz, 4H), 1.59 (d, J = 106.2 Hz, 4H), 1.26 - 0.83 (m, 4H).

[0230] Example 23: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(4-ethylpiperazin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl-p-tolylcarbamate (23);

[0231] Example 23 was obtained according to the procedure of Example 1, Step A9, using intermediate B-IX as starting material, nucleophilic substitution with N-ethylpiperazine and deprotection under acidic conditions in 40.5% yield. Analytical data: ESI-MS [M+H] + (m / z): 612.3. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.53 (s, 1H), 9.11 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.39 (s, 2H), 7.34 - 7.23 (m, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.35 - 6.18 (m, 1H), 4.60 (s, 1H), 4.29 (s, 1H), 3.80 (d, J = 92.2 Hz, 1H), 3.48 (s, 1H), 3.18 (s, 1H), 3.02 (s, 2H), 2.73 (s, 2H), 2.22 (s, 3H), 1.93 (d, J = 49.6 Hz, 4H), 1.59 (d, J = 106.2 Hz, 4H), 1.26 - 0.83 (m, 4H). + (m / z): 612.3. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.53 (s, 1H), 9.11 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.39 (s, 2H), 7.34 - 7.23 (m, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.35 - 6.18 (m, 1H), 4.60 (s, 1H), 4.29 (s, 1H), 3.80 (d, J = 92.2 Hz, 1H), 3.48 (s, 1H), 3.18 (s, 1H), 3.02 (s, 2H), 2.73 (s, 2H), 2.22 (s, 3H), 1.93 (d, J = 49.6 Hz, 4H), 1.59 (d, J = 106.2 Hz, 4H), 1.26 - 0.83 (m, 4H).13 C NMR (151 MHz, DMSO-d6) δ 169.01, 154.03, 152.46, 151.64, 137.02, 136.25, 135.57, 133.27, 131.62, 129.51, 123.64, 121.05, 118.81, 110.39, 107.00, 101.17, 65.80, 61.90, 57.34, 53.46, 52.81, 52.05, 51.19, 28.66, 24.55, 20.79, 12.32.

[0232] Example 24: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-{2-[4-(2-hydroxyethyl)piperazin-1- yl]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}p-tolylcarbamate (24);

[0233] According to the method of Example 1, Step A9, intermediate B-IX was used as starting material, nucleophilic substitution reaction with 4-hydroxyethylpiperazine, followed by deprotection under acidic condition to give Example 50 in 40.5% yield. Analytical data: ESI-MS [M+H] + (m / z): 628.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.72-9.52 (m, 1H), 9.44 (s, 1H), 9.13 (s, 1H), 8.77 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.39 (s, 2H), 7.34-7.20 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.26 (s, 1H), 4.58 (s, 1H), 4.37-4.22 (m, 1H), 3.93 (s, 1H), 3.68 (s, 1H), 3.60 (s, 2H), 3.58 (s, 2H), 3.10 (s, 2H), 2.21 (s, 3H), 1.85 (t, J = 9 Hz, 2H), 1.65 (d, J = 42.4 Hz, 4H), 1.75 (s, 4H), 1.15 (d, 4H).

[0234] Example 25: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(pyrrolidin-1-yl)acetylamino]pyridin- 2-yl}pyrrolidin-2-yl}methyl(4-fluorophenyl)carbamate (25);

[0235] The synthetic route is shown below:

[0236]

[0237] Step B10: Synthesis of intermediate B-X

[0238] According to the method in step B2 of example 13, starting from p-fluorobenzoic acid and intermediate B-I, intermediate B-X was generated by Curtis rearrangement reaction in 62.9% yield. Analytical data: ESI-MS [M-H] - (m / z): 392.9.

[0239] Step B11: Synthesis of intermediate B-XI

[0240] According to the method in step A6 of example 1, starting from intermediate B-X, nucleophilic substitution reaction with intermediate A-II gave intermediate B-XI in 43.5% yield. Analytical data: ESI-MS [M+H] + (m / z): 575.9.

[0241] Step B12: Synthesis of intermediate B-XII

[0242] According to the method in step A7 of example 1, starting from intermediate B-XI, reduction reaction under the action of hydrogen and palladium on carbon gave intermediate B-XII in 92.4% yield.

[0243] Step B13: Synthesis of intermediate B-XIII

[0244] According to the method in step A8 of example 1, starting from intermediate B-XII, acylation reaction with chloroacetyl chloride gave intermediate B-XIII in 89.3% yield.

[0245] Step B14: Synthesis of example 25

[0246] According to the method in step A9 of example 1, starting from intermediate B-XIII, nucleophilic substitution reaction with tetrahydropyrrole followed by deprotection under acidic condition gave example 25 in 51.2% yield. Analytical data: ESI-MS [M+H] + (m / z): 573.0. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.73-9.68 (m, 1H), 9.05 (s, 1H), 8.72 (s, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 22.3 Hz, 1H), 7.46 (s, 1H), 7.44 (s, 2H), 7.39 (d, J = 1.9 Hz, 2H), 7.14-7.05 (m, 2H), 6.24 (d, J = 8.4 Hz, 1H), 4.58 (tt, J = 7.7, 4.5 Hz, 1H), 4.37-4.26 (m, 1H), 3.96 (dd, J = 10.3, 7.7 Hz, 1H), 3.65 (dt, J = 9.6, 6.3 Hz, 1H), 3.24 (dd, J = 9.6, 6.8 Hz, 1H), 3.18 (s, 2H), 2.58 (p, J = 3.8 Hz, 4H), 2.17-1.79 (m, 4H), 1.72 (td, J = 4.6, 2.1 Hz, 4H).

[0247] Example 26: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-pivalamidopyridin-2-yl}pyrrolidin-2- yl}methyl(4-fluorophenyl)carbamate (26);

[0248] Example 26 was obtained by acylation of intermediate B-XII with pivaloyl chloride according to the procedure of Example 1, Step A8, followed by deprotection under acidic conditions in 74.2% yield. Analytical data: ESI-MS [M+H] + (m / z): 546.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.73 (s, 1H), 8.69 (s, 2H), 8.14 (s, 1H), 7.91 (s, 1H), 7.45 (s, 2H), 7.40 (s, 2H), 7.11 (d, J = 8.9 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.16 (d, J = 8.3 Hz, 1H), 4.64 (s, 1H), 4.39 (d, J = 10.1 Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 9.1 Hz, 1H), 3.34 (s, 2H), 2.01 (s, 2H), 1.92-1.80 (m, 2H), 1.19 (s, 9H).

[0249] Example 27: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-[2-(4-hydroxypiperidin-l- yl)acetamido]pyridin-2-yl}pyrrolidin-2-yl}methyl(4-fluorophenyl)carbamate (27);

[0250] According to the method of Step A9 in Example 1, using intermediate B-XIII as starting material, nucleophilic substitution reaction with 4-hydroxypiperidine followed by deprotection under acidic condition afforded Example 27 in 54.7% yield. Analytical data: ESI-MS [M+H] + (m / z): 603.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.80 - 9.61 (m, 1H), 9.11 (s, 1H), 8.74 (s, 1H), 8.11 (s, 1H), 7.89 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.43 (s, 2H), 7.39 (s, 2H), 7.09 (t, J = 8.9 Hz, 2H), 6.27 (d, J = 8.4 Hz, 1H), 4.61 (d, J = 4.1 Hz, 1H), 4.58 (d, J = 9.0 Hz, 1H), 4.30 (dd, J = 10.3, 4.1 Hz, 1H), 3.95 (dd, J = 10.4, 7.7 Hz, 1H), 3.69 (dt, J = 9.7, 6.3 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.24 - 3.14 (m, 1H), 3.02 (s, 2H), 2.32 - 2.02 (m, 4H), 1.99 - 1.76 (m, 4H), 1.60 (d, J = 96.4 Hz, 4H).

[0251] Example 28: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methyl(4-fluorophenyl)carbamate (28);

[0252] According to the method of Step A9 in Example 1, using intermediate B-XIII as starting material, nucleophilic substitution reaction with cyclopropylmethylamine followed by deprotection under acidic condition afforded Example 28 in 49.6% yield. Analytical data: ESI-MS [M+H] + (m / z): 573.7. 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.59 (s, 1H), 9.10 (s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.32 (d, 3H), 7.28 (s, 2H), 6.97 (s, 2H), 6.22 - 6.03 (m, 1H), 4.49 (s, 2H), 3.81 (s, 1H), 3.58 (s, 1H), 3.21 (s, 2H), 3.09 (s, 2H), 1.96 (d, 2H), 1.85 (s, 2H), 1.73 (s, 2H), 1.46 - 1.30 (d, 1H), 0.29 - 0.10 (s, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 170.52, 157.31, 156.48, 154.12, 152.74, 152.25, 137.52, 135.90, 135.56, 133.18, 130.12, 123.61, 121.06, 120.46, 115.76, 115.61, 110.97, 106.99, 100.44, 65.93, 57.15, 54.24, 52.12, 50.84, 29.48, 28.65, 11.05, 3.69.

[0253] Example 29: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(pyrrolidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylpiperidin-4-ylcarbamate (29);

[0254] The synthetic route is shown below:

[0255]

[0256] Step B15: Synthesis of intermediate B-XIV

[0257] According to the method of Step B2 in Example 13, intermediate B-XIV was generated from 1-Boc-4-piperidinecarboxylic acid and intermediate B-I by Curtis rearrangement reaction in a yield of 52.6%. Analytical data: ESI-MS [M+Na] (m / z): 506.2. + (m / z): 506.2. 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.05 (s, 1H), 8.72 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.41 (d, J = 8.2 Hz, 3H), 7.19 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 4.71 - 4.12 (m, 2H), 3.73 (t, J = 9.4 Hz, 1H), 3.62 (t, J = 6.4 Hz, 0H), 3.56 (t, 7H), 3.20 (s, 2H), 2.93 (d, J = 12.2 Hz, 2H), 2.63 - 2.58 (m, 4H), 2.11 - 2.01 (m, 1H), 1.88 (ddd, J = 52.0, 12.2, 6.1 Hz, 2H), 1.75 (t, J = 5.7 Hz, 4H), 1.67 (d, 2H).

[0258] Step B16: Synthesis of intermediate B-XV

[0259] According to the method of Step A6 in Example 1, nucleophilic substitution reaction of intermediate B-XIV with intermediate A-II was carried out to give intermediate B-XV in a yield of 49.8%. Analytical data: ESI-MS [M+H] + (m / z): 665.2.

[0260] Step B17: Synthesis of intermediate B-XVI

[0261] According to the method of Step A7 in Example 1, reduction reaction of intermediate B-XV with hydrogen and palladium on carbon was carried out to give intermediate B-XVI in a yield of 92.8%.

[0262] Step B18: Synthesis of intermediate B-XVII

[0263] According to the method of Step A8 in Example 1, acylation reaction of intermediate B-XVI with chloroacetyl chloride was carried out to give intermediate B-XVII in a yield of 85.1%. Analytical data: ESI-MS [M+Na] + (m / z): 733.4

[0264] Step B19: Synthesis of Example 29

[0265] According to the method of Step A9 in Example 1, nucleophilic substitution reaction of intermediate B-XVII with tetrahydropyrrole was carried out, followed by deprotection under acidic condition to give Example 29 in a yield of 36.7%. Analytical data: ESI-MS [M+H] + (m / z): 562.5. 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.05 (s, 1H), 8.72 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.41 (d, J = 8.2 Hz, 3H), 7.19 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 4.71 - 4.12 (m, 2H), 3.73 (t, J = 9.4 Hz, 1H), 3.62 (t, J = 6.4 Hz, 1H), 3.56 (t, 4H), 3.20 (s, 2H), 2.93 (d, J = 12.2 Hz, 2H), 2.63 - 2.58 (m, 4H), 2.11 - 2.01 (m, 1H), 1.88 (ddd, J = 52.0, 12.2, 6.1 Hz, 4H), 1.75 (t, J = 5.7 Hz, 6H), 1.67 (d, 2H).

[0266] Example 30: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-(2-thiomorpholinoacetamido)pyridin-2- yl}pyrrolidin-2-yl}methylpiperidin-4-ylcarbamate (30);

[0267] According to the method of step A9 in example 1, intermediate B-XVII was used as raw material, nucleophilic substitution reaction with thiomorpholine, and then deprotection under acidic condition to give example 61 with a yield of 45.6%. Analytical data: ESI-MS [M+H] + (m / z): 594.5.

[0268] Example 31: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(4-methylpiperidin-1-yl)acetamido]pyridin- 2-yl}pyrrolidin-2-yl}methylpiperidin-4-ylcarbamate (31);

[0269] According to the method of step A9 in example 1, intermediate B-XVII was used as raw material, nucleophilic substitution reaction with 4-methylpiperidine, and then deprotection under acidic condition to give example 31 with a yield of 40.2%. Analytical data: ESI-MS [M+H] + (m / z): 590.5.

[0270] Example 32: (S)-1-{2-{{6-[(1H-indazol-5-yl)amino]-2-{2-[(piperidin-4-ylcarbamoyl)oxy]methyl}pyrrolidin- 1-yl}pyridin-3-yl}amino-2-oxoethyl}piperidine-4-carboxylate (32);

[0271] According to the method of Step A9 in Example 1, using intermediate B-XVII as starting material, nucleophilic substitution reaction with methyl 4-piperidinecarboxylate was carried out, followed by deprotection under acidic condition to give Example 32 in 37.4% yield. Analytical data: ESI-MS [M+H] + (m / z): 634.7.

[0272] Example 33: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-[2-(pyrrolidin-l- yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl isopropylcarbamate (33);

[0273] The synthetic route is shown below:

[0274]

[0275] Step B20: Synthesis of intermediate B-XVIII

[0276] According to the method of Step B2 in Example 13, using isobutyric acid and intermediate B-I as starting material, Curtis rearrangement reaction was carried out to give intermediate B-XVIII in 63.7% yield. Analytical data: 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.57 (d, J = 35.4 Hz, 1H), 4.27 (dd, J = 11.0, 5.3 Hz, 1H), 4.04 (dd, J = 11.1, 3.5 Hz, 1H), 3.61 - 3.48 (m, 1H), 3.38 - 3.33 (m, 1H), 2.75 (ddd, J = 10.4, 7.4, 2.7 Hz, 1H), 2.08 (t, J = 7.7 Hz, 1H), 1.98 (ddp, J = 9.9, 6.6, 2.8 Hz, 1H), 1.93 - 1.80 (m, 1H), 1.74 (dtt, J = 11.4, 9.5, 7.2 Hz, 1H), 1.03 (dd, J = 6.6, 3.1 Hz, 6H).

[0277] Step B21: Synthesis of intermediate B-XX

[0278] According to the method of Step A6 in Example 1, using intermediate B-XVIII as starting material, nucleophilic substitution reaction with intermediate A-II was carried out to give intermediate B-XX in 55.4% yield. Analytical data: ESI-MS [M+H] + (m / z): 524.2.

[0279] Step B22: Synthesis of intermediate B-XXI

[0280] According to the method in Step A7 in Example 1, intermediate B-XIX was used as a raw material to undergo a reduction reaction under the action of hydrogen and palladium-carbon to obtain intermediate B-XX, with a yield of 93.4%.

[0281] Step B23: synthesis of intermediate B-XXI

[0282] According to the method in Step A8 in Example 1, intermediate B-XX was used as a raw material to undergo an acylation reaction with chloroacetyl chloride to obtain intermediate B-XXI, with a yield of 88.1%.

[0283] Step B24: synthesis of Example 68

[0284] According to the method in Step A9 in Example 1, intermediate B-XXI was used as a raw material to undergo a nucleophilic substitution reaction with tetrahydropyrrole and then deprotection under acidic conditions to obtain Example 33, with a yield of 49.1%. Analytical data: ESI-MS [M+H] + (m / z): 521.8. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.40 (t, J = 4.6 Hz, 3H), 7.06 (d, J = 7.8 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 4.51 (dt, J = 8.4, 4.5 Hz, 1H), 4.20 (dd, J = 10.4, 4.1 Hz, 1H), 3.72 (t, J = 9.3 Hz, 1H), 3.63 (dt, J = 12.5, 6.4 Hz, 1H), 3.54 (p, J = 6.7 Hz, 1H), 3.24 (d, J = 6.6 Hz, 1H), 3.18 (s, 2H), 2.68 - 2.55 (m, 4H), 2.06 - 1.79 (m, 4H), 1.74 (d, J = 6.5 Hz, 4H), 1.04 (d, J = 6.5 Hz, 6H). 13 C NMR (101 MHz, DMSO) δ 169.81, 155.86, 152.73, 152.27, 137.60, 135.61, 133.42, 123.66, 120.93, 111.18, 110.37, 106.83, 100.45, 65.43, 59.46, 57.35, 54.44, 50.65, 42.74, 28.66, 24.48, 24.02.

[0285] Example 34: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-[2- (cyclopropylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl isopropylcarbamate (34);

[0286] According to the procedure of Example 1, Step A9, intermediate B-XIII was used as starting material, nucleophilic substitution with cyclopropylamine followed by deprotection under acidic conditions gave Example 34 in 41.2% yield. Analytical data: ESI-MS [M+H] + (m / z): 507.8. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.43 - 7.31 (m, 3H), 7.07 (d, J = 7.8 Hz, 1H), 6.20 (d, J = 8.3 Hz, 1H), 4.52 (s, 1H), 4.21 (dd, J = 10.6, 3.9 Hz, 1H), 3.74 - 3.61 (m, 2H), 3.55 (dq, J = 13.8, 6.9 Hz, 1H), 3.38 (q, J = 7.0 Hz, 1H), 3.29 (s, 2H), 3.19 (dt, J = 9.5, 6.4 Hz, 1H), 2.18 (tt, J = 6.7, 3.6 Hz, 1H), 1.29 (d, J = 47.1 Hz, 4H), 1.04 (d, J = 6.6 Hz, 6H), 0.39 (m, J = 6.3, 3.0 Hz, 2H), 0.30 (m, J = 3.8 Hz, 2H).

[0287] Example 35: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-[2- (cyclopentylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl isopropylcarbamate (35);

[0288] According to the procedure of Example 1, Step A9, intermediate B-XIII was used as starting material, nucleophilic substitution with cyclopropylamine followed by deprotection under acidic conditions gave Example 34 in 41.2% yield. Analytical data: ESI-MS [M+H] + (m / z): 535.8. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.20 (s, 1H), 8.71 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 4.2 Hz, 2H), 7.06 (d, J = 7.9 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 4.52 (s, 1H), 4.20 (dd, J = 10.3, 4.0 Hz, 1H), 3.75 - 3.63 (m, 2H), 3.54 (dt, J = 13.6, 6.8 Hz, 1H), 3.22 (d, J = 5.2 Hz, 2H), 3.15 (dt, J = 13.1, 4.8 Hz, 1H), 3.04 (p, J = 6.0 Hz, 1H), 1.98 (dtd, J = 34.2, 11.4, 9.4, 5.0 Hz, 2H), 1.80 (td, J = 12.1, 10.3, 6.2 Hz, 2H), 1.76 - 1.61 (m, 4H), 1.48 (tq, J = 10.4, 6.0 Hz, 2H), 1.35 (dq, J = 11.6, 6.0 Hz, 2H), 1.23 (s, 1H), 1.04 (d, J = 6.6 Hz, 6H).

[0289] Example 36: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-[2-(pyrrolidin-l- yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylcyclopropylcarbamate (36);

[0290] The synthetic route is shown below:

[0291]

[0292] Step B25: Synthesis of intermediate B-XIV

[0293] Intermediate B-XIV was prepared according to the procedure of Example 13, Step B2, using cyclopropylcarboxylic acid and intermediate B-I as starting materials, in a Curtis rearrangement reaction to give intermediate B-XIV in 66.2% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.54 (s, 1H), 4.32-4.27 (t, 1H), 4.04 (d, J = 10.6 Hz, 1H), 3.34 (s, 1H), 2.74 (ddd, J = 10.3, 7.4, 2.5 Hz, 1H), 2.42 (tq, J = 7.0, 3.6 Hz, 1H), 2.08 (s, 1H), 2.01-1.95 (m, 1H), 1.85 (s, 1H), 1.82-1.66 (m, 1H), 0.54 (dqd, J = 8.2, 4.9, 2.0 Hz, 2H), 0.40-0.34 (m, 2H).

[0294] Step B26: Synthesis of intermediate B-XXIII

[0295] According to the method of Step A6 in Example 1, intermediate B-XXIII was obtained by nucleophilic substitution reaction of intermediate B-XXII with intermediate A-II, in a yield of 48.9%. Analytical data: ESI-MS [M+Na] + (m / z): 544.2.

[0296] Step B27: Synthesis of intermediate B-XXIV

[0297] According to the method of Step A7 in Example 1, intermediate B-XXIV was obtained by reduction reaction of intermediate B-XXIII with hydrogen and palladium on carbon, in a yield of 91.8%.

[0298] Step B28: Synthesis of intermediate B-XXV

[0299] According to the method of Step A8 in Example 1, intermediate B-XXV was obtained by acylation reaction of intermediate B-XXIV with chloroacetyl chloride, in a yield of 89.4%.

[0300] Step B29: Synthesis of Example 36

[0301] According to the method of Step A9 in Example 1, Example 36 was obtained by nucleophilic substitution reaction of intermediate B-XXV with tetrahydropyrrole, followed by deprotection under acidic condition, in a yield of 50.3%. Analytical data: ESI-MS [M+H] + (m / z): 519.5. 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.39 (d, J = 3.9 Hz, 3H), 7.37 (s, 1H), 6.22 (d, J = 8.4 Hz, 1H), 4.50 (s, 1H), 4.20 (d, J = 11.5 Hz, 1H), 3.74 (t, J = 9.3 Hz, 1H), 3.63 (dt, J = 9.5, 6.4 Hz, 1H), 3.24 (d, J = 6.5 Hz, 1H), 3.21 (s, 2H), 2.63 - 2.59 (m, 4H), 2.41 (tq, J = 7.0, 3.5 Hz, 1H), 2.09 - 1.88 (m, 2H), 1.85 - 1.77 (m, 2H), 1.77 - 1.68 (m, 4H), 0.56 - 0.46 (m, 2H), 0.43 - 0.32 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 169.76, 157.33, 152.74, 152.27, 137.67, 136.22, 135.61, 133.37, 123.65, 120.94, 110.36, 106.81, 100.43, 65.54, 59.44, 57.30, 54.45, 50.64, 28.64, 24.51, 24.00, 23.38, 6.38, 6.19.

[0302] Example 37: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2- (cyclopropylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl cyclopropylcarbamate (37);

[0303] Example 37 was obtained according to the procedure of Example 1, Step A9, using intermediate B-XXV as starting material, nucleophilic substitution with cyclopropylamine and deprotection under acidic conditions in 54.1% yield. Analytical data: ESI-MS [M+H] + (m / z): 505.5. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.04 (s, 1H), 8.71 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.38 (d, J = 3.7 Hz, 3H), 7.34 (d, J = 11.8 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 4.51 (s, 1H), 4.22 (d, J = 10.2 Hz, 1H), 3.72 (s, 1H), 3.64 (d, J = 11.5 Hz, 1H), 3.29 (s, 2H), 3.22 - 2.81 (m, 2H), 2.42 (tq, J = 7.0, 3.6 Hz, 1H), 2.17 (tt, J = 6.8, 3.6 Hz, 1H), 2.08 - 1.90 (m, 2H), 1.80 (dd, J = 12.8, 6.4 Hz, 2H), 0.56 - 0.46 (m, 2H), 0.45 - 0.39 (m, 2H), 0.36 (dd, J = 5.6, 3.0 Hz, 2H), 0.30 (q, J = 3.3 Hz, 2H).

[0304] Example 38: (S)-{l-{6-[(lH-indazol-5-yl)amino]-3-[2-(pyrrolidin-l- yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate (38);

[0305] The synthetic route is shown below:

[0306]

[0307] Step B30: Synthesis of intermediate B-XXVI

[0308] Intermediate B-XXVI was prepared according to the procedure of Example 13, Step B2, using cyclohexanecarboxylic acid and intermediate B-I as starting materials, in a Curtis rearrangement reaction to give intermediate B-XXVI in 63.5% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.52 (s, 1H), 4.27 (dd, J = 11.0, 5.3 Hz, 1H), 4.04 (dd, J = 11.1, 3.4 Hz, 1H), 3.35 (dd, J = 9.9, 6.5 Hz, 1H), 3.18 (s, 1H), 2.75 (ddd, J = 10.6, 7.5, 2.7 Hz, 1H), 2.15 - 1.93 (m, 2H), 1.93 - 1.75 (m, 1H), 1.74 - 1.60 (m, 5H), 1.20 - 1.01 (m, 5H).

[0309] Step B31 : Synthesis of intermediate B-XXVII

[0310] According to the method of step A6 in example 1, nucleophilic substitution reaction of intermediate B-XXVI with intermediate A-II was carried out to give intermediate B-XXVII in a yield of 50.7%. Analytical data: ESI-MS [M+H] + (m / z): 564.3.

[0311] Step B32: Synthesis of intermediate B-XXVIII

[0312] According to the method of step A7 in example 1, reduction reaction of intermediate B-XXVII with hydrogen and palladium on carbon was carried out to give intermediate B-XXVIII in a yield of 88.6%.

[0313] Step B33: Synthesis of intermediate B-XXIX

[0314] According to the method of step A8 in example 1, acylation reaction of intermediate B-XXVIII with chloroacetyl chloride was carried out to give intermediate B-XXIX in a yield of 90.1%.

[0315] Step B34: Synthesis of example 38

[0316] According to the method of step A9 in example 1, nucleophilic substitution reaction of intermediate B-XXIX with tetrahydropyrrole followed by deprotection under acidic condition was carried out to give example 38 in a yield of 47.0%. Analytical data: ESI-MS [M+H] + (m / z): 561.6. 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.04 (s, 1H), 8.71 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.41-7.37 (m, 3H), 7.09 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 8.5 Hz, 1H), 4.51 (s, 1H), 4.20 (dd, J = 10.1, 3.8 Hz, 1H), 3.71 (t, J = 9.3 Hz, 1H), 3.66-3.55 (m, 1H), 3.26-3.20 (m, 2H), 3.20 (s, 2H), 2.59 (d, J = 6.4 Hz, 4H), 2.04-1.91 (m, 2H), 1.81 (dd, J = 12.7, 6.4 Hz, 2H), 1.74 (d, J = 5.3 Hz, 4H), 1.58 (d, J = 51.8 Hz, 4H), 1.23 (s, 2H), 1.18-1.05 (m, 4H).

[0317] Example 39: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-(2-morpholinoacetylamino)pyridin- 2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate (39);

[0318] According to the method of step A9 in example 1, starting from intermediate B-XXIX, nucleophilic substitution reaction with morpholine followed by deprotection under acidic condition gave example 39 in 45.2% yield. Analytical data: ESI-MS [M+H] + (m / z): 577.7.

[0319] Example 40: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-[2-(cyclopropylamino)acetylamino]pyridin- 2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate (40);

[0320] According to the method of step A9 in example 1, starting from intermediate B-XXIX, nucleophilic substitution reaction with cyclopropylamine followed by deprotection under acidic condition gave example 40 in 44.1% yield. Analytical data: ESI-MS [M+H] + (m / z): 547.6. 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.04 (s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.36 (dd, J = 17.9, 6.6 Hz, 3H), 7.10 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 4.55 - 4.50 (m, 1H), 4.22 (dd, J = 10.3, 3.9 Hz, 1H), 3.72 (d, J = 9.6 Hz, 1H), 3.65 (dt, J = 13.0, 6.7 Hz, 1H), 3.29 (s, 1H), 3.22 - 3.18 (m, 2H), 2.18 (dq, J = 6.7, 3.4 Hz, 1H), 2.06 - 1.90 (m, 2H), 1.76 (d, J = 15.3 Hz, 4H), 1.59 (dd, J = 51.0, 11.7 Hz, 4H), 1.22 (d, J = 10.6 Hz, 2H), 1.17 - 1.02 (m, 4H), 0.34 (dp, J = 36.0, 4.0, 3.4 Hz, 4H). 13C NMR (101 MHz, DMSO) δ 171.40, 155.90, 152.81, 152.45, 138.00, 135.61, 133.47, 123.67, 120.92, 110.70, 110.36, 106.84, 100.25, 65.45, 57.26, 55.38, 52.75, 50.56, 49.97, 33.18, 33.06, 30.86, 28.72, 25.64, 25.17, 24.47, 6.65, 6.55.

[0321] Example 41: (S)-{1-{6-[(1H-indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate (41);

[0322] Example 41 was obtained according to the procedure of Example 1, Step A9, using intermediate B-XXIX as the starting material, nucleophilic substitution with cyclopropylmethylamine, and deprotection under acidic conditions in 39.8% yield. Analytical data: ESI-MS [M+H] + (m / z): 561.6. 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 9.03 (s, 1H), 8.58 (s, 1H), 8.00 (t, J = 1.3 Hz, 1H), 7.78 (s, 1H), 7.32 - 7.21 (m, 3H), 6.96 (d, J = 8.1 Hz, 1H), 6.09 (d, J = 8.3 Hz, 1H), 4.40 (s, 1H), 4.09 (dd, J = 10.2, 3.9 Hz, 1H), 3.63 - 3.50 (m, 1H), 3.17 (s, 1H), 3.13 (d, J = 2.5 Hz, 1H), 3.10 - 3.00 (m, 2H), 2.34 - 2.22 (m, 2H), 1.86 (ddt, J = 27.1, 15.5, 8.2 Hz, 2H), 1.71 - 1.56 (m, 4H), 1.54 - 1.30 (m, 4H), 1.09 (d, J = 6.9 Hz, 1H), 1.06 - 0.94 (m, 4H), 0.85 - 0.68 (m, 2H), 0.34 - 0.20 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 171.10, 155.88, 152.64, 152.21, 137.41, 135.61 (2C), 133.45, 123.68, 120.89, 111.04, 110.37, 106.78, 100.40, 65.49, 57.29, 54.53 (2C), 52.62, 50.76, 49.96, 33.18, 33.05, 28.78, 25.64 (2C), 25.17 (2C), 24.52, 11.48 (3C), 3.70 (4C), 3.64 (4C).

[0323] Example 42: (S)-N-{{l-{6-[(lH-indazol-5-yl)amino]-3-[2-(4-methylpiperazin-l- yl)acetamido]pyridin-2-yl}pyrrolidin-2-yl}methyl}-4-(dimethylamino)benzamide (42);

[0324] The synthetic route is shown below:

[0325]

[0326] Step C1 : Synthesis of intermediate C-I

[0327] B-1 (3.0 g, 11.67 mmol) was dissolved in THF (30 mL), triphenylphosphine (3.67 g, 14.00 mmol) and phthalimide (2.06 g, 14.00 mmol) were added, diethyl azodicarboxylate (2.44 g, 14.00 mmol) was added dropwise at low temperature, after dropping, the reaction was stirred at room temperature for 24 h. The reaction solution was evaporated to dryness, and the crude product was purified by column chromatography to obtain 3.2 g of a light yellow solid, with a yield of 71%.

[0328] Step C2: Synthesis of intermediate C-II

[0329] C-I (3.0 g, 7.77 mmol) was dissolved in ethanol (30 mL), hydrazine hydrate (3 mL) was added, and the reaction was refluxed for 2 h. The reaction solution was evaporated to dryness, and the crude product was slurried with dichloromethane (15 mL). After filtration, the product was dried to obtain 1.2 g of a yellow solid, with a yield of 60.3%.

[0330] Step C3: Synthesis of intermediate C-III

[0331] According to the method of step A5 in Example 1, intermediate C-II was used as a raw material to undergo acylation reaction with 4-dimethylaminobenzoyl chloride to obtain intermediate C-III, with a yield of 87.2%.

[0332] Step C4: Synthesis of intermediate C-IV

[0333] According to the method in step A6 of example 1, intermediate C-III was used as raw material to react with intermediate A-II by nucleophilic substitution to obtain intermediate C-IV, with a yield of 44.2%.

[0334] Step C5: synthesis of intermediate C-V

[0335] According to the method in step A6 of example 1, intermediate C-IV was used as raw material to react with intermediate A-II by nucleophilic substitution to obtain intermediate C-V, with a yield of 44.2%.

[0336] Step C6: synthesis of intermediate C-VI

[0337] According to the method in step A7 of example 1, intermediate C-V was used as raw material to react with hydrogen and palladium carbon by reduction to obtain intermediate C-VI, with a yield of 84.6%.

[0338] Step C7: synthesis of intermediate C-VII

[0339] According to the method in step A8 of example 1, intermediate C-VI was used as raw material to react with chloroacetyl chloride by acylation to obtain intermediate C-VII, with a yield of 88.1%.

[0340] Step C8: synthesis of example 42

[0341] According to the method in step A9 of example 1, intermediate C-VII was used as raw material to react with N-methylpiperazine by nucleophilic substitution, and then deprotection under acidic conditions to obtain example 80, with a yield of 51.4%. Analysis data: ESI-MS [M+H] + (m / z): 611.3.

[0342] Example 43: anti-tumor and anti-fibrosis activity experiments on the compounds prepared in the above examples

[0343] I. ROCK2 inhibition activity in vitro

[0344] Promega The kinase assay kit was used to test the inhibition of ROCK2 by the compounds obtained above. The compound to be tested was configured into a 10 mM stock solution with DMSO, and gradient dilution was performed with a reaction buffer (50 mM HEPES (pH 7.5), 10 mM magnesium chloride hexahydrate, 100 mM sodium orthovanadate, 0.01% CHAPS and 0.1% bovine serum albumin) to obtain compound solutions of different concentrations. In a white flat-bottom 96-well plate, 20 μL of ROCK2 enzyme solution (1 nM), 10 μL of compound solution, 10 μL of reaction substrate (20 μM RSK2 peptide KKRNRTLTK) and 10 μL of ATP solution (10 μM) were sequentially added to each well, and incubated at room temperature for 3 h. The reaction was terminated by adding 50 μL of reaction detection solution in the kit to each well, and the chemiluminescence signal was detected using a Tecan multifunctional enzyme marker. All dose settings were triplicated, and non-linear fitting was performed using GraphPad Prism 8 to calculate the IC 50 values.

[0345] The results of the inhibition of ROCK2 activity by the compounds disclosed in the present application are shown in Table 1, in which “A” represents an IC 50 value < 50 nM; “B” represents 50 nM < IC 50 value < 100 nM; “C” represents 100 nM < IC 50 value < 1 μM; “D” represents 1 μM < IC 50 value < 10 μM.

[0346] Table 1: Results of the inhibition of ROCK2 activity by the compounds

[0347] Examples ROCK2 IC 50 ]]> Examples ROCK2 IC 50 ]]> Examples ROCK2 IC 50 ]]> 1 A 16 A 31 C 2 B 17 B 32 C 3 B 18 A 33 A 4 A 19 B 34 A 5 A 20 A 35 A 6 A 21 A 36 A 7 B 22 A 37 B 8 A 23 A 38 A 9 A 24 A 39 B 10 B 25 B 40 A 11 A 26 A 41 A 12 A 27 A 42 A 13 A 28 A Belumosudil 0.153 μΜ 14 A 29 B 15 B 30 A

[0348] As can be seen from the above, the compounds obtained in the present application have high overall inhibition of ROCK2 activity, with IC50 values mostly below 100 nM, which is better than Belumosudil.

[0349] II. Anti-tumor and fibrosis cell proliferation activity in vitro

[0350] Anti-human breast cancer cell line MDA-MB-231 and TGF-β-induced mouse embryonic fibroblast NIH / 3T3 proliferation experiments were performed on some of the compounds in the present application.

[0351] The cells were cultured in a 37°C incubator containing 5% CO2, and the medium was replaced every 2-3 days. When the cells grew to 80%-90% density, they were trypsinized and centrifuged to collect the cells. The collected cells were resuspended and diluted to 2×10 4The cell suspension was inoculated into a 96-well cell culture plate at a density of 100 μL / well, and incubated overnight. The medium was replaced with the test compound or solvent (DMSO) at each concentration gradient, and incubated in an incubator for 48 hours. After the treatment, the medium in the plate was discarded, washed twice with PBS, 100 μL of CCK-8 working solution was added to each well, and incubated at 37°C for 1.5 hours in the dark. The OD value of each well was detected on an enzyme-labeled instrument 450 nm The CC 50 value of each compound was analyzed and calculated.

[0352] The anti-proliferation activity of some compounds in the present application on MDA-MB-231 cells and TGF-β-NIH / 3T3 cells is shown in Table 2, where "A" represents a CC 50 value < 1 μM; "B" represents 1 μM < CC 50 value < 10 μM; and "C" represents 10 μM < CC 50 value < 100 μM.

[0353] Table 2 Anti-proliferation activity of some compounds on MDA-MB-231 cells and TGF-β-NIH / 3T3 cells

[0354]

[0355] As can be seen from the above, some compounds obtained in the present application have anti-proliferation effects on MDA-MB-231 cells and TGF-β-induced NIH / 3T3 cells, wherein the anti-proliferation effects of compound 21 and compound 30 on the two cell strains are the best, and the CC 50 values are both below 1 μM.

[0356] III. Anti-tumor cell migration activity in vitro

[0357] Some compounds in the present application were subjected to MDA-MB-231 cell scratch experiments.

[0358] Logarithmic growth period MDA-MB-231 cells were inoculated in a 6-well plate at a density of 250,000 cells / well / 2 mL, and cultured in an incubator for 24 hours. The medium was discarded, 200 microliters of a gun head was used to scratch each well, and 1 mL of PBS was used to wash twice to remove the scratched cells. Compound 21 and Belumosudil were respectively given in a serum-free solution of 2 mL, and the cell migration was observed by inverted microscope at 0h, 24h, and 48h. Migration rate (%) = (Area 0h -Area th ) / Area 0h × 100%, and a Control group was given 2 mL of a serum-free blank medium as a control.

[0359] Compound 21 significantly reduced the migration rate of MDA-MB-231 cells compared with the control group. At a concentration of 5 μM, the anti-migration effect of Compound 21 was superior to that of bleomycin. The above results show that Compound 21 has good anti-tumor migration effect in vitro.

[0360] IV. Anti-fibrosis activity in vivo

[0361] Some of the compounds in the present application were subjected to a bleomycin-induced C57BL / 6 mouse pulmonary fibrosis animal model experiment.

[0362] Forty 6-8 week old C57BL / 6 mice (male, body weight 20-22 g) were randomly divided into four groups, 10 mice in each group. The mice were fasted for 12 hours before modeling but were not deprived of water. All experimental mice were anesthetized by intraperitoneal injection of 0.05 mg / kg of 2% sodium pentobarbital solution, and after losing response, the limbs were vertically suspended and fixed. A tracheal instillation was performed by inserting a retention needle into the trachea of the mouse at the glottis, and each mouse was given 3 U / kg of bleomycin sulfate solution (BLM) to induce a pulmonary fibrosis model. After 7 days of modeling, different concentrations of drug solutions were given to the mice by gavage once a day. After 14 days of administration, the lung tissues of the mice were taken for HE staining to observe the alveolar wall thickness and the degree of neutrophil infiltration, and the lung tissues of healthy C57BL / 6 mice were used as a negative control. As shown in FIG. 6, the lung tissue morphology of the model group was abnormal, the alveolar wall was thickened, and there was a large amount of inflammatory cell infiltration. After Compound 21 was administered to the experimental group, the alveolar wall became thinner, and the lung tissue morphology returned to normal. When Compound 21 100 mg / kg was administered, the inflammatory cell infiltration was significantly reduced, indicating that Compound 21 improved the degree of inflammation in the lung tissue of bleomycin-induced pulmonary fibrosis mice. Figure 2 As shown in FIG. 6, the lung tissue morphology of the model group was abnormal, the alveolar wall was thickened, and there was a large amount of inflammatory cell infiltration. After Compound 21 was administered to the experimental group, the alveolar wall became thinner, and the lung tissue morphology returned to normal. When Compound 21 100 mg / kg was administered, the inflammatory cell infiltration was significantly reduced, indicating that Compound 21 improved the degree of inflammation in the lung tissue of bleomycin-induced pulmonary fibrosis mice.

Claims

1. A (1 H -indazol-5-yl)amino-2-pyridine derivative, characterized in that: Derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, In the formula: L is or ; R1 is (C1-C6) alkyl, (C1-C6) alkoxy, (C 2- C6)alkenyl, (C2-C6)alkynyl, or (CH2) p NR3R4; p is 1; R3 and R4 are the same or different, and are independently selected from hydrogen, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, and (C3-C8)cycloalkyl; or R3 and R4 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group containing at least one heteroatom, which heterocyclyl group is optionally substituted with 0-3 independent hydroxy, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, (C1-C6)alkoxy, or (C1-C6)alkoxycarbonyl; R6 is halogen, amino, hydroxy, cyano, or (C3-C6)cycloalkyl; A is or ; X is selected from , or ; R2is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, 4-6 membered heterocyclyl, phenyl, heteroaryl, , , ; R5 is halogen, hydroxy, amino, cyano, or carboxyl.

2. The (1 H - indazol-5-yl)amino-2-pyridine derivatives characterized in that, The derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, in the formula: L is or ; R1is (Ci-C6)alkyl, (C2-C6)alkenyl or (CH2) p NR3R4; In the formula: p is 1; R3 and R4 are the same or different, and are independently selected from hydrogen, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, and (C3-C8)cycloalkyl; or R3 and R4 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group containing at least one heteroatom, which heterocyclyl group is optionally substituted with 0-3 independent hydroxy, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, (C1-C6)alkoxy, or (C1-C6)alkoxycarbonyl; A is or ; X is selected from , or ; R2is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, 4-6 membered heterocyclyl, phenyl, heteroaryl, , , ; R6 is halogen, amino, hydroxy, cyano, or (C3-C6)cycloalkyl; 3. The (1 H - indazol-5-yl)amino-2-pyridine derivatives characterized in that, R5 is halogen, hydroxy, amino, cyano, or carboxyl. L is or ; R1is (Ci-C4)alkyl, (C2-C4)alkenyl or (CH2) p NR3R4; The derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, in the formula: In the formula: p is 1; A is or ; X is selected from , or ; R2is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, 5-6 membered heterocyclyl, phenyl, heteroaryl, , , ; R3 and R4 are the same or different, and are independently selected from hydrogen, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, and (C3-C8)cycloalkyl; or R3 and R4 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group containing at least one heteroatom, which heterocyclyl group is optionally substituted with 0-3 independent hydroxy, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, (C1-C6)alkoxy, or (C1-C6)alkoxycarbonyl; 4. The (1 H - indazol-5-yl)amino-2-pyridine derivatives characterized in that, R6 is halogen, amino, hydroxy, cyano, or (C3-C6)cycloalkyl; L is or ; R5 is halogen, hydroxy, amino, cyano, or carboxyl. The derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, in the formula: In the formula: p is 1; R3 and R4 are the same or different, and are independently selected from hydrogen, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, and (C3-C8)cycloalkyl; or R3 and R4 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group containing at least one heteroatom, which heterocyclyl group is optionally substituted with 0-3 independent hydroxy, (C1-C6)alkyl unsubstituted or substituted with at least one R6 which is the same or different, (C1-C6)alkoxy, or (C1-C6)alkoxycarbonyl; R6 is halogen, amino, hydroxy, cyano, or (C3-C6)cycloalkyl; R5 is halogen, hydroxy, amino, cyano, or carboxyl. The derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof, in the formula: R1 is (C1-C4)alkyl, (C2-C4)alkenyl, or CH2NR3R4; R3 and R4 are the same or different, and are independently selected from hydrogen, (C1-C4)alkyl unsubstituted or substituted with at least one R6 which is the same or different, and (C3-C6)cycloalkyl; or R3 and R4 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group containing at least one heteroatom, which heterocyclyl group is optionally substituted with 0-1 independent hydroxy, (C1-C3)alkyl, (C1-C3)alkyl unsubstituted or substituted with at least one R6 which is the same or different, methoxycarbonyl; R6 is hydroxy or cyclopropyl; A is or ; X is selected from , or ; R2is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, 4-piperidinyl, , , .

5. The (1 H - indazol-5-yl)amino-2-pyridine derivatives characterized in that, The derivative is a compound shown in general formula (I) and a pharmaceutically acceptable salt thereof, wherein: L is or ; R1is methyl, tert-butyl, vinyl, , , , , , , , , , , , , or ; X is selected from , or ; A is or ; R2 is , , , , , or .

6. The (1 H - indazol-5-yl)amino-2-pyridine derivatives characterized in that, The derivative is a compound shown in general formula (I) and a pharmaceutically acceptable salt thereof, wherein: N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - { N - {6-[(1 H - 2-[4-(4-fluorobenzoyl)piperazin- 1 -yl]-6-(lH-indol-5-ylamino)pyridin-3-yl}-2- morpholinoacetamide; N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[( N - {6-[(1 H - 2-[4-(4-fluorobenzoyl)piperazin- 1 -yl]-6-(lH-indol-5-ylamino)pyridin-3-yl}-2- (cyclopentylamino)acetamide; N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6 N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6- N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[( N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6- N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - N - {6-[(1 H - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - {6-[(1 - { S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-(methylsulfonamido)pyridin-2-yl}pyrrolidin-2-yl}methyl[4- (dimethylamino)phenyl]carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(pyrrolidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl {4-(dimethylamino)phenyl}carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(dimethylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(4-methylpiperazin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-{2-[(2-hydroxyethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methyl[4-(dimethylamino)phenyl]carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-propenoylamino pyridin-2-yl}pyrrolidin-2-yl} p-tolylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(4-methylpiperazin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}p-tolylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl} p-tolylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(4-hydroxypiperidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl-p-tolylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(4-ethylpiperazin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl-p-tolylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetylamino}pyridin-2- yl}pyrrolidin-2-yl}p-tolylcarbamate;​ S )-{1-{6-[(1 H - { 1 -[3-(4-methylpiperazin- 1 -yl)propyl]- 1 H-indol-5-yl} - amino)oxy]pyrrolidin-2-yl}methyl (4- fluorophenyl)carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-neopentanoylaminopyrid-2-yl}pyrrolidin-2-yl}methyl (4- fluorophenyl)carbamate;​ ( S )-{1-{6-[(1 H -indazol-5-yl)amino]-3-[2-(4-hydroxypiperidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl (4-fluorophenyl)carbamate; S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetylamino}pyridin-2-yl}pyrrolidin-2-yl}methyl(4-fluorophenyl)carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(pyrrolidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylpiperidin-4-ylcarbamate;​ S )-{1-{6-[(1 H - 3-(2-thioxomorpholinoacetylamino)pyrid-2-yl}pyrrolidin-2-yl}methylpiperidin-4- ylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(4-methylpiperidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylpiperidin-4-ylcarbamate;​ S - 1-{2-{{6-[(1 H - methyl {2-oxo-3-[2-(2-oxoethyl)piperidin-1-yl]pyridin-4-yl}carbonyl)piperidin-4-yl}carbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(pyrrolidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl isopropylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(cyclopropylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl isopropylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(cyclopentylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl isopropylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(pyrrolidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylcyclopropylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(cyclopropylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl cyclopropylcarbamate;​ S )-{1-{6-[(1 H - 3-[2-(pyrrolidin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-(2-morpholinoacetylamino)pyridin-2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-[2-(cyclopropylamino)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methylcyclohexylcarbamate;​ S )-{1-{6-[(1 H - indazol-5-yl)amino]-3-{2-[(cyclopropylmethyl)amino]acetylamino}pyridin-2- yl}pyrrolidin-2-yl)methylcyclohexylcarbamate;​ S )-{1-{6-[(1 N -{{1-{6-[(1 H -Indazol-5-ylamino]-3-[2-(4-methylpiperazin-1-yl)acetylamino]pyridin-2-yl}pyrrolidin-2-yl}methyl}-4-(dimethylamino)benzamide.​ 7. The (1 H - indazol-5-yl)amino-2-pyridine derivatives characterized in that: The pharmaceutically acceptable salt of the compound shown in general formula (I) is obtained by reacting the compound with an acid, and the corresponding acid is hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, citric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, tartaric acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.

8. A method according to claim 1 (1 H -indazol-5-yl)amino-2-pyridine derivatives, characterized in that: The compound shown in general formula (I) and the pharmaceutically acceptable salt thereof are used for preparing a medicament for treating a tumor or a fibrosis disease.

9. A compound of claim 1 wherein R is ###00009### H - the use of indazol-5-yl)amino-2-pyridine derivatives, characterized by the formula: ###00010### The compound shown in general formula (I) and the pharmaceutically acceptable salt thereof are used for preparing a ROCK2 inhibitor.

10. Use according to claim 8, characterized in that, The tumor is selected from lung cancer, breast cancer, gastric cancer, colon cancer, hepatocellular carcinoma, oral cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, neuroblastoma, osteosarcoma and fibrosarcoma; and the fibrosis is selected from pulmonary fibrosis, renal fibrosis, liver fibrosis and myocardial fibrosis.

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