WO2022042666A1 - Selective rock2 kinase inhibitor - Google Patents

Abstract

Provided are a ROCK2 kinase inhibitor as represented by general formula (I) and the use thereof in the preparation of a drug for preventing and/or treating ROCK2-related disorders. The compound is a highly efficient selective ROCK2 kinase inhibitor and can be used for treating and/or preventing diseases such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, cardiac fibrosis or non-alcoholic steatohepatitis.

Description

Selective ROCK2 kinase inhibitor

This application claims the priority of the prior applications submitted to the State Intellectual Property Office of China on 2020.08.28, 2020.12.02, and 2021.01.20 with application numbers of 202010891846.4, 202011392113.2, and 202110079361.X.

technical field

The invention belongs to the field of medicinal chemistry, in particular to a selective ROCK2 kinase inhibitor, its pharmaceutical composition, a preparation method and its use in preparing a medicine for preventing and/or treating indications related to ROCK2 signaling pathway.

Background technique

Rho-related protein kinase (ROCK) is a serine/threonine protein kinase, and it is currently the most detailed Rho downstream target effector molecule. ROCK includes two isoforms, ROCK1 and ROCK2. The amino acid sequence identity of these two isoforms is 65%, and the kinase domain has a high similarity of 92%. Among them, ROCK1 is highly expressed in the lung, liver, spleen, kidney and testis. , ROCK2 levels are higher in the brain and heart. The body mainly activates the ROCK1/2 signaling pathway through the combination of Rho and GTP, phosphorylates the downstream substrates of ROCK1/2 (such as MLC, GFAP, LIMK, etc.), remodels the cytoskeleton, induces actin filament stabilization and actin-myosus The protein contracts, combines actin reticulum and myosin fibers, and modulates microtubule dynamics. Studies have shown that ROCK1/2 signaling is closely related to diabetic nephropathy, eye disease, tumor, fibrosis, nerve damage and other diseases, and has important development value.

Currently listed drugs are ROCK1/2 inhibitors, mainly for the treatment of ocular diseases, for improving and preventing cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemia symptoms, glaucoma, ocular hypertension, etc. . At present, there is no selective ROCK2 inhibitor on the market. Studies have shown that inhibiting ROCK2 can reduce the phosphorylation of STAT3 and enhance the phosphorylation of STAT5, thereby downregulating the overactivated Th17 and upregulating the function of Treg cells. Potential for autoimmune disease. Therefore, the development of selective ROCK2 inhibitors may provide new treatment options for autoimmune and fibrotic diseases.

Existing ROCK2 inhibitors have low activity, low inhibition rate and low selectivity for ROCK2. For example, compound 82 (drug research and development code KD-025) disclosed in patent CN101208094 has an IC50 of 105nM for ROCK2. Patent WO2012040499 discloses compound 201, and records that its inhibition rate of ROCK2 at 500 nM is 0.67. And the toxic side effects are greater. Therefore, ROCK2 inhibitors with high activity, high inhibition rate, high selectivity and low toxicity and side effects are required.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a new ROCK2 inhibitor, which has excellent inhibitory activity and good selectivity to ROCK2, and also has excellent properties such as excellent pharmacokinetic properties and high safety, which is ideal selective ROCK2 inhibitor.

For realizing the purpose of the present invention, the present invention adopts the following technical solutions:

The present invention first provides a compound having the structure shown in general formula (I):

Ring A is a five- or six-membered heterocyclic ring, the heterocyclic ring contains 1-3 heteroatoms selected from N, O, S, and the C atom in the heterocyclic ring is optionally substituted by 0 to 3 C=O;

Ring B is absent or a five- to six-membered unsaturated ring containing 0 to 3 N atoms;

L ₁ is selected from -O(CR ^a R ^b ) _n , C _1-6 alkylene or C _1-6 alkenylene;

R ¹ is selected from any substituted amide group or sulfonamide group, and S=O in the sulfonamide group can be substituted by S=NR ^c ; preferably, R ¹ is selected from

L ₂ is selected from C _1-6 alkylene or -NR ^d ;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;

R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; In the absence of B, ^R is attached to ring A;

R ^a , R ^b , R ^c , R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl ;

The alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R ⁴ ;

R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

m and n are each independently selected from an integer of 0-3.

具有如下结构：

In a preferred embodiment,

Has the following structure:

In a preferred embodiment, L ₁ is selected from -O(CR ^a R ^b ) _n or C _1-6 alkenylene, preferably -O-, -CH ₂ -, -CH ₂ CH ₂ -, -CH=CH -; more preferably -O-, _-CH2- or -CH=CH-;

其中的R ^a、R ^b优选H、-Me、-Et、- ⁱPr、- ^tBu、-CH＝CH-、环丙基或环己基； R ¹ is selected from

Among them, R ^a and R ^b are preferably H, -Me, -Et, ^-i Pr, ^-t Bu, -CH=CH-, cyclopropyl or cyclohexyl;

L ₂ is selected from C _1-6 alkylene or -NH-, preferably -CH ₂ -, -CH ₂ CH ₂ - or -NH-;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, 1H-pyrazole or cyclohexylpyridine, preferably indazole or phenyl-1H-pyrazole;

^R is selected from H, halogen, hydroxy, cyano, methyl, hydroxymethyl, trifluoromethyl, ethyl, isopropyl, methoxy, isopropoxy, cyclopropyl, cyclopentyl, cyclopropyl Hexyl or C _3-8 heterocycloalkyl, preferably H, fluorine, chlorine, methyl, trifluoromethyl, ethyl, isopropyl, methoxy, isopropoxy or cyclopropyl, when ring B is not When present, ^R is attached to ring A;

m, n are each independently selected from an integer of 0 to 3.

The present invention also provides a compound having the structure represented by the general formula (I'):

wherein Ring B does not exist or is a five- to six-membered unsaturated ring containing 0 to 3 N atoms;

L ₁ is selected from -O(CR ^a R ^b ) _n , C _1-6 alkylene or C _1-6 alkenylene;

R ¹ is selected from any substituted amide group or sulfonamide group, and S=O in the sulfonamide group can be substituted by S=NR ^c ; preferably, R ¹ is selected from

L ₂ is selected from C _1-6 alkylene or -NR ^d ;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;

R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; In the absence of B, ^R is attached to ring A;

R ^a , R ^b , R ^c , R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl ;

The alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R ⁴ ;

R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

m and n are each independently selected from an integer of 0-3.

Preferably, wherein:

Ring B is absent or a five- to six-membered unsaturated ring containing 0 to 3 N atoms;

L ₁ is selected from C _1-6 alkylene or C _1-6 alkenylene;

R ¹ is selected from

L ₂ is selected from C _1-6 alkylene or -NR ^d ;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;

R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, when ring In the absence of B, ^R is attached to ring A;

R ^a , R ^b , R ^c , R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl ;

The alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R ⁴ ;

R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

m and n are each independently selected from an integer of 0-3.

The present invention also provides a compound having the structure represented by the general formula (I-1):

Wherein, L ₁ is selected from -O(CR ^a R ^b ) _n , C _1-6 alkylene or C _1-6 alkenylene;

R ¹ is selected from any substituted amide group or sulfonamide group, and S=O in the sulfonamide group can be substituted by S=NR ^c ; preferably, R ¹ is selected from

L ₂ is selected from C _1-6 alkylene or -NR ^d ;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;

R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; In the absence of B, ^R is attached to ring A;

R ^a , R ^b , R ^c , R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl ;

The alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R ⁴ ;

R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

m and n are each independently selected from an integer of 0-3.

The present invention also provides a compound having the structure represented by the general formula (I-2):

in,

R ¹ is selected from any substituted amide group or sulfonamide group, and S=O in the sulfonamide group can be substituted by S=NR ^c ; preferably, R ¹ is selected from

L ₂ is selected from C _1-6 alkylene or -NR ^d ;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;

R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the Alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted with 0-3 R4, when ring B is absent, ^R3 is attached to ring ^A ;

R ^a , R ^b , R ^c , R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl ;

The alkyl, alkylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R4 ^;

R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

m is selected from an integer of 0-3.

The present invention also provides compounds with the structures represented by the general formulas (I-3) and (I-3'):

in,

L ₁ is selected from -O(CR ^a R ^b ) _n , C _1-6 alkylene or C _1-6 alkenylene;

L ₂ is selected from C _1-6 alkylene or -NR ^d ;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;

R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; In the absence of B, ^R is attached to ring A;

R ^a , R ^b , R ^c , R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl ;

The alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R ⁴ ;

R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

m and n are each independently selected from an integer of 0-3.

In some more specific embodiments, the compound has the structure represented by the general formula (I-4),

Ring B does not exist or is a parallel five- to six-membered aromatic ring containing 0 to 3 N atoms;

wherein R ^a and R ^b are independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;

R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, when ring In the absence of B, ^R is linked to a pyrimidine;

The alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R4 ^;

R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl;

m is selected from an integer of 0-3.

In certain more specific embodiments, the compounds also have the following characteristics:

Ring B does not exist or is a benzene ring;

wherein R ^a and R ^b are independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy radical, cyclopropoxy, cyclobutoxy, and optionally substituted with 0-2 F atoms;

R ² is selected from indazole, phenyl-1H-pyrazole;

R ³ is selected from H, halogen, hydroxyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, and when ring B is absent, R ³ is linked to a pyrimidine;

m is selected from an integer of 0-3.

In some specific embodiments, the compound has the structure represented by the general formula (I-5):

in:

R ^a is selected from H, R ^b is selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutyl oxy, and optionally substituted with 0-2 F atoms;

R ² is selected from indazole, phenyl-1H-pyrazole; preferably indazole.

In some specific embodiments, the compound has the structure represented by the general formula (I-6):

in:

R ^a is selected from H, R ^b is selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutyl oxy, and optionally substituted with 0-2 F atoms;

R ² is selected from indazole, phenyl-1H-pyrazole;

^R3 is selected from H, halogen, methyl, ethyl, trifluoromethyl; preferably H, halogen, methyl, ethyl.

As preferably, the new compounds provided by the present invention include but are not limited to the following compounds:

The above-mentioned compounds can be prepared by the following methods.

First, compound (I-41) is reacted with R ² NH ₂ to obtain compound (I-42), wherein X can be halogen; ring B is present or absent, and R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, when ring B is absent, R ³ is attached to ring A. R2 may be selected from indazole, phenyl ^- 1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine.

When R ² is a phenyl-1H-pyrazole group, in order to avoid the active hydrogen on the pyrazole to participate in the subsequent reaction, the (trimethylsilyl)ethoxymethyl group is usually modified on the phenyl-1H-pyrazole (SEM) as a protecting group, which can be further removed in the subsequent reaction process.

Compound (I-42) is further reacted with the shown E)-(3-(3- ^Re -3-oxoprop-1-en-1-yl)phenyl)boronic acid compound to obtain compound (I-43) . where R ^e is a branched simple alkyl group, which can be methyl, ethyl, isopropyl and the like.

Compound (I-43) is reacted with an acid or a base to remove the group ^Re to obtain compound (I-44). This step reaction can be operated together with the previous step reaction, or the group ^Re can be removed at the same time as the previous step reaction.

Compound (I-44) is further reacted with R ^a R ^b NH to obtain compound (I-4).

Most of the above compounds contain amino groups, in order to reduce the active hydrogen on the amino group to participate in side reactions, the amino group can be protected, such as tert-butoxycarbonyl and the like.

The compound (I-4) obtained in the above steps is in the form of a crude product, which is usually further purified by preparative column chromatography, wherein the eluent environment used in preparative column chromatography will vary depending on the compound. Differences such as formic acid, trifluoroacetic acid or other common acids.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable excipient and/or diluent thereof.

Another aspect of the present invention provides the use of the compounds and pharmaceutical compositions of the present invention in the manufacture of a medicament for the treatment and/or prevention of ROCK2-related disorders.

Preferably, the ROCK2-related disorder is selected from pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis or nonalcoholic steatohepatitis.

The compound provided by the invention has novel structure, strong activity, good selectivity, excellent pharmacokinetic properties, high safety and other excellent properties. Most of the compounds provided in this application have less toxic and side effects, and have better inhibitory effects on inflammatory factors, and are ideal selective ROCK2 kinase inhibitors.

detailed description

The present invention will be described in further detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

The raw materials or reagents used in the present invention can be prepared by conventional methods or commercially available.

Example 1: (E)-3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-isopropylacrylamide (21 )

Step 1: 2-Chloro-N-(1H-indazol-5-yl)quinazolin-4-amine (1a)

2,4-Dichloroquinazoline (440 mg, 2.21 mmol), 1H-indazol-5-amine (324 mg, 2.43 mmol) and triethylamine (0.9 mL, 6.63 mmol) were dissolved in N,N-dimethyl In formamide (5 mL), the reaction was stirred at 0°C for 2 hours. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL×2), the organic phase was washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated into layers Column purification (ethyl acetate/petroleum ether (v/v)=1:1) gave 2-chloro-N-(1H-indazol-5-yl)quinazolin-4-amine 1a (540 mg, yield : 83%, yellow solid). MS(ESI) m/z: 296 [M+H] ⁺ .

Step 2: (E) Ethyl 3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)acrylate (1b)

2-Chloro-N-(1H-indazol-5-yl)quinazolin-4-amine 1a (100 mg, 0.34 mmol), (E)-(3-(3-ethoxy-3-oxo) Prop-1-en-1-yl)phenyl)boronic acid (90 mg, 0.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.04 mmol) Potassium carbonate (94 mg, 0.68 mmol) was added to a solution of dioxane/water (10 mL/5 mL). The reaction was carried out overnight at 100°C under nitrogen protection. The reaction system was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase column to give (E) 3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl ) ethyl acrylate 1b (60 mg, yield: 43%, yellow solid). MS (ESI) m/z: 436.4 [M+H] ⁺ .

The third step: (E)-3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)acrylic acid (1c)

(E)-ethyl 3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)acrylate 1b (60 mg, 0.15 mmol) and hydroxide Lithium (14 mg, 0.59 mmol) was dissolved in a mixed solution of tetrahydrofuran/water (10 mL/5 mL) and reacted at room temperature for 3 hours. The reaction solution was directly purified by reverse phase column to obtain (E)-3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)acrylic acid 1c (33 mg, Yield: 59%, yellow solid). MS (ESI) m/z: 408.3 [M+H] ⁺ .

The fourth step: (E)-3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-isopropylacrylamide (21 )

(E)-3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)acrylic acid 1c (35 mg, 0.086 mmol), triethylamine ( 17mg, 0.17mmol) and isopropylamine (5mg, 0.13mmol) were dissolved in N,N-dimethylformamide (1mL), to the reaction solution was added 2-(7-azabenzotriazole)-N , N,N',N'-tetramethylurea hexafluorophosphate (65 mg, 0.17 mmol), the mixture was stirred and reacted at room temperature for 1 hour. The reaction system was dispersed in water (10 mL), extracted with ethyl acetate (10 mL×2), the organic phase was washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. ((E)-3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-isopropylpropene was obtained by prep-HPLC Amide 21 (7.3 mg, yellow solid). ¹ H NMR (400 MHz, DMSO-d ₆ ) 13.11 (s, 1H), 10.00 (s, 1H), 8.63-859 (m, 2H), 8.37-8.33 (m, 2H), 8.14(s, 1H), 8.02(d, J=8.0Hz, 1H), 7.89-7.88(m, 2H), 7.84-7.81(m, 1H), 7.65-7.61(m, 3H), 7.59 -7.46(m, 2H), 6.73(d, J=16.0Hz, 1H), 4.01-3.95(m, 1H), 1.15(d, J=6.8Hz, 6H). MS(ESI) m/z: 449.2 [M+H] ⁺ .

Example 2: 2-(3-(1-((1H-Indazol-5-yl)methyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl )phenoxy)-N-isopropylacetamide (7)

The first step: methyl 2-isocyanatobenzoate (2a)

Methyl 2-aminobenzoate (1.51 g, 10 mmol) was dissolved in tetrahydrofuran (25 mL), and triethylamine (4.2 mL, 30 mmol) was added followed by triphosgene (1.2 g, 4 mmol). The reaction solution was stirred at 60°C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 2-isocyanatobenzoate 2a (2 g crude product, yield: 100%, yellow oil).

Step 2: 3-(3-(Benzyloxy)phenyl)quinazoline-2,4(1H,3H)-dione (2b)

Methyl 2-isocyanatobenzoate 2a (1.65 g, 9.3 mmol) was dissolved in tetrahydrofuran (35 mL), 3-benzyloxyaniline (1.85 g, 9.3 mmol) and 4-dimethylaminopyridine ( 4.5 g, 37.2 mmol). The reaction solution was stirred at room temperature overnight. 1,8-Diazabicycloundec-7-ene (2 g, 13.1 mmol) was added and heated to 80°C and stirred for 1 hour. The reaction solution was concentrated, the residue was purified by column chromatography (dichloromethane/methanol (v/v)=50:1), and slurried with 30 mL of methanol to obtain 3-(3-(benzyloxy)phenyl)quinazoline- 2,4(1H,3H)-dione 2b (1.5 g, yield: 47%, white solid). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 11.58 (brs, 1H), 7.97 (dd, J=10.4 Hz, 1.6 Hz, 1H), 7.76-7.71 (m, 1H), 7.52-7.37 (m, 6H), 7.28-7.24 (m, 2H), 7.13-7.07 (m, 2H), 6.95-6.93 (m, 2H), 5.13 (s, 2H). MS (ESI) m/z: 345.2 [M+H] ⁺ .

The third step: methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-carboxylate (2c)

Methyl 1H-indazole-5-carboxylate (3.0 mg, 17.0 mmol) was dissolved in N,N-dimethylformamide (30 mL), NaH (1.3 g, 20.5 mmol) was added at 0 °C, and the reaction solution was The reaction was stirred at 0°C for 15 minutes. Then add 2-(trimethylsilyl)ethoxymethyl chloride (3.42g, 20.5mmol), warm to room temperature and react for 3 hours, LCMS shows that the reaction is complete, add water (30mL) to quench, and extract with ethyl acetate (25mL×2) , spin-dried through silica gel column (ethyl acetate/petroleum ether (v/v)=10:1) to obtain 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -5-Carboxylic acid methyl ester 2c (2.7 g, yield: 51.9%, colorless oil). MS (ESI) m/z: 307.1 [M+H] ⁺ .

Step 4: 5-(Chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2d)

1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazole-5-carboxylate methyl ester 2c (2.6 g, 8.5 mmol) was dissolved in tetrahydrofuran (25 mL), Lithium borohydride (224 mg, 10.2 mmol) was added at 0°C and the reaction system was raised to 60°C and stirred for 3 hours. TLC showed that the reaction was completed, water (25 mL) was added to the reaction system, extracted with ethyl acetate (25 mL × 2), spin-dried and purified by reverse-phase column (acetonitrile/water) to obtain (1-((2-(trimethyl) Silyl)ethoxy)methyl)-1H-indazol-5-yl)methanol (2.2 g, yield: 93.2%, colorless liquid). (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)methanol (2.2 g, 7.9 mmol) was dissolved in tetrahydrofuran and added to the reaction system Triethylamine (1.82 g, 23.7 mmol) was added, and methanesulfonyl chloride (1.82 g, 9.48 mmol) was added at 0°C. The reaction system was reacted at room temperature for 4 hours. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (25 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was reversed Column purification gave 5-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 2d (800 mg, yield: 34.2%, colorless oil) ). MS (ESI) m/z: 297.1 [M+H] ⁺ .

The fifth step: 3-(3-(benzyloxy)phenyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5 -yl)methyl)quinazoline-2,4(1H,3H)-dione (2e)

Potassium carbonate (739 mg, 5.4 mmol) was added to 5-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 2d (800 mg, 2.7 mmol) and 3-(3-(benzyloxy)phenyl)quinazoline-2,4(1H,3H)-dione 2b (1.2 g, 2.97 mmol) in dimethylformamide (10 mL) , heated to 50 °C under nitrogen and stirred overnight. The reaction system was purified by reverse-phase column (acetonitrile/water (v/v)=1:2), and the target product 3-(3-(benzyloxy)phenyl)-1-(((1) was obtained after the target component was spin-dried. -((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)methyl)quinazoline-2,4(1H,3H)-dione 2e( 320 mg, yield: 19.6%, white solid). MS(ESI) m/z: 605.2 [M+H] ⁺ .

The sixth step: 2-(3-(2,4-dioxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5- (yl)methyl)-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide (2f)

Palladium-carbon catalyst (20 mg) was added to 3-(3-(benzyloxy)phenyl)-1-((1-((2-(trimethylsilyl)ethoxy)methane under nitrogen) yl)-1H-indazol-5-yl)methyl)quinazoline-2,4(1H,3H)-dione 2e (320 mg, 0.53 mmol) in methanol (8 mL), the reaction system was heated to 50 The mixture was stirred at °C for 3 hours, filtered, and concentrated under reduced pressure to obtain the crude product. Potassium carbonate (25 mg, 0.178 mmol) was added to a solution of the above crude (46 mg, 0.089 mmol) and 2-bromo-N-isopropylacetamide (15 mg, 0.107 mmol) in dimethylformamide (4 mL) at The tube was heated to 100°C and stirred overnight. The liquid quality monitored the formation of the target product. The reaction system was purified by reverse-phase column (acetonitrile/water (v/v)=3:10), and the target component was spin-dried to obtain the target product 2. -(3-(2,4-Dioxy-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)methyl) -1,2-Dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide 2f (26 mg, yield: 48%, yellow oil). MS(ESI) m/z: 614.3 [M+H] ⁺ .

Step 7: 2-(3-(1-((1H-indazol-5-yl)methyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl )phenoxy)-N-isopropylacetamide (7)

Add 2-(3-(2,4-dioxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5 to the reaction flask in turn -yl)methyl)-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide 2f (26 mg, 0.042 mmol) and trifluoroacetic acid (2 mL) , and stirred overnight at room temperature. Adjusted to pH=7 with saturated sodium bicarbonate solution, spin-dried and purified by Prep-HPLC to obtain the target product 2-(3-(1-((1H-indazol-5-yl)methyl)-2, 4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide 7 (6.5 mg, yield: 32.5%, white solid). ¹ H NMR (400MHz, DMSO-d ₆ ) 13.54(s,1H), 8.09-8.07(m,1H), 8.01(s,1H), 7.93-7.91(m,1H), 7.77(s,1H), 7.70-7.66(m,1H), 7.54-7.52(m,1H), 7.45-7.39(m,2H), 7.29-7.28(m,1H), 7.10(s,1H), 7.09-7.03(m,2H) ), 5.47(s, 2H), 4.46(s, 2H), 3.96-3.90(m, 1H), 1.10-1.08(d, J=8Hz, 6H). MS (ESI) m/z: 484.2 [M+H] ⁺ .

Example 3: 2-(3-(1-(4-(1H-pyrazol-4-yl)benzyl)-2,4-dioxo-1,2-dihydroquinazoline-3(4H) -yl)phenoxy)-N-isopropylacetamide (8)

The first step: (4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)methanol (3a)

(4-(hydroxymethyl)phenyl)boronic acid (608 mg, 4.0 mmol), 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole (1.42 g, 4.4 mmol), dioxane (8 mL), water (2 mL) and potassium carbonate (1.10 g, 8.0 mmol) were heated to 85 °C under nitrogen and stirred overnight. The reaction system was purified by silica gel column (petroleum ether/ethyl acetate (v/v)=6:1) to obtain the target product (4-(1-((2-(trimethylsilyl)ethoxy)methyl) )-1H-pyrazol-4-yl)phenyl)methanol 3a (522 mg, yield: 43%, yellow solid). MS (ESI) m/z: 305.5 [M+H] ⁺ .

Step 2: 4-(4-(Bromomethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (3b)

Triphenylphosphorus (516 mg, 1.97 mmol) was added to (4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl ) methanol 3a (500 mg, 1.64 mmol) in dichloromethane (8 mL) was stirred under nitrogen for 1 hour. Carbon tetrabromide (986 mg, 1.97 mmol) was added to the system, followed by stirring at room temperature overnight. The reaction system was purified by silica gel column (petroleum ether/ethyl acetate (v/v)=6:1 to obtain the target product 4-(4-(bromomethyl)phenyl)-1-((2-(trimethyl) Silyl)ethoxy)methyl)-1H-pyrazole 3b (200 mg, yield: 33%, white solid). MS (ESI) m/z: 369.3 [M+H] ⁺ .

The third step: 3-(3-(benzyloxy)phenyl)-1-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)benzyl)quinazoline-2,4(1H,3H)-dione (3c)

Using 3b as raw material, referring to the fifth step of Example 2, the target product 3-(3-(benzyloxy)phenyl)-1-(4-(1-((2-(trimethylsilane) was obtained yl)ethoxy)methyl)-1H-pyrazol-4-yl)benzyl)quinazoline-2,4(1H,3H)-dione 3c (200 mg, yield: 58%, yellow solid) . MS (ESI) m/z: 631.5 [M+H] ⁺ .

Fourth step: 2-(3-(2,4-dioxo-1-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)benzyl)-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide (3d)

Using 3c as a raw material, with reference to the sixth step of Example 2, the target product 2-(3-(2,4-dioxo-1-(4-(1-((2-(trimethylsilyl) )ethoxy)methyl)-1H-pyrazol-4-yl)benzyl)-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylethyl Amide 3d (100 mg, 52% yield, yellow solid). MS(ESI) m/z: 640.6 [M+H] ⁺ .

Step 5: 2-(3-(1-(4-(1H-pyrazol-4-yl)benzyl)-2,4-dioxo-1,2-dihydroquinazoline-3(4H) -yl)phenoxy)-N-isopropylacetamide (8)

Using 3d as raw material, referring to the seventh step of Example 2, the target product 2-(3-(1-(4-(1H-pyrazol-4-yl)benzyl)-2 was obtained after preparation and purification by Prep-HPLC ,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide 8 (41.8 mg, yield: 55%, white solid). ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.91 (s, 1H), 8.16-8.05 (m, 2H), 7.93-7.86 (m, 2H), 7.75-7.68 (m, 1H), 7.59-7.54 (m) , 2H), 7.45-7.25(m, 5H), 7.10-7.00(m, 3H), 5.37(s, 2H), 4.46(s, 2H), 3.98(m, 1H), 1.08(d, J=6.4 Hz, 6H). MS (ESI) m/z: 510.2 [M+H] ⁺ .

Example 4: (E)-3-(3-(4-((4-(1 Hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)-nitrogen- Isopropylacrylamide (22)

The first step: 2-chloro-nitrogen-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1hydro-pyrazol-4-yl)phenyl)quinoline oxazolin-4-amine

2,4-Dichloroquinazoline (500 mg, 2.53 mmol), 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1hydro-pyrazol-4-yl ) aniline (731 mg, 2.53 mmol) and potassium acetate (743 mg, 7.59 mmol) were dissolved in tetrahydrofuran/water (10/5 mL), and the reaction system was stirred at 50° C. for 2 hours. Water (10 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The product was purified by column chromatography (ethyl acetate:petroleum ether=10:1) to give 2-chloro-nitrogen-(4-(1-((2-(trimethylsilyl)ethoxy)methyl) -1 Hydro-pyrazol-4-yl)phenyl)quinazolin-4-amine (610 mg, white solid), yield: 55%. MS (ESI) m/z: 452.1 [M+H] ⁺ .

The second step: (E)-ethyl 3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1hydro-pyrazole -4-yl)phenyl)amino)quinazolin-2-yl)phenylacrylate

2-Chloro-nitrogen-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1hydro-pyrazol-4-yl)phenyl)quinazoline- 4-amine (200 mg, 0.44 mmol), (E)-(3-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)boronic acid (97 mg, 0.44 mmol), [ To a solution of 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.022 mmol) and dioxane/water (6 mL/3 mL) was added potassium carbonate (183 mg, 1.33 mmol). Under nitrogen protection, the temperature was raised to 100°C and the reaction was stirred overnight, and the reaction system was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase column to give (E)-ethyl 3-(3-(4-((4-(1-((2-(trimethylsilyl)ethyl) Oxy)methyl)-1hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl acrylate (80 mg, white solid), yield: 31%. MS (ESI) m/z: 592.3[M+H] ⁺ .

The third step: (E) 3-(3-(3-(4-((4-(1hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylic acid ethyl ester

E)-ethyl 3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1hydro-pyrazol-4-yl )phenyl)amino)quinazolin-2-yl)phenyl acrylate (70 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 2 hours. The liquid is directly dried under reduced pressure to obtain (E) 3-(3-(3-(4-((4-(1hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)benzene base) ethyl acrylate (91 mg crude, white solid). MS (ESI) m/z: 462.1 [M+H] ⁺ .

The fourth step: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylic acid

Ethyl ((E) 3-(3-(3-(4-((4-(1hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylate (91mg, 0.12mmol) and lithium hydroxide (10mg, 0.36mmol) were dissolved in a mixed solution of methanol/water (5mL/2mL), and the reaction was stirred at 50 ° C for 2 hours. The reaction solution was directly purified using a reversed-phase column to obtain ( E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylic acid (32 mg, white solid), two Step yield: 54%. MS (ESI) m/z: 434.1 [M+H] ⁺ .

Step 5: (E)-3-(3-(4-((4-(1 Hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)-nitrogen- Isopropylacrylamide (22)

(E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylic acid (32 mg, 0.074 mmol) , isopropylamine (17mg, 0.30mmol) was dissolved in N,N-dimethylformamide (5mL), 2-(7-azabenzotriazole)-N,N,N' was added to the reaction solution , N'-tetramethylurea hexafluorophosphate (42 mg, 0.11 mmol), the mixture was stirred and reacted at room temperature for 1 hour. The reaction system was dispersed in water (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phase was washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was subjected to prep-HPLC to give (E)-3-(3-(4-((4-(1hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl) - Nitro-isopropylacrylamide 22 (14.1 mg, yellow solid), yield: 40%. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=12.88(s,1H), 9.92(s,1H), 8.68(s,1H), 8.61(d, J=8.4Hz,1H), 8.43(d ,J=7.6Hz,1H),8.13-8.08(m,3H),8.00(d,J=8.8Hz,2H),7.90(d,J=4.0Hz,2H),7.75-7.72(m,2H) , 8.67-7.49 (m, 4H), 6.75 (d, J=15.6Hz, 1H), 4.01-3.95 (m, 1H), 1.14 (d, J=6.4Hz, 6H). MS (ESI) m/z: 475.3 [M+H] ⁺ .

Example 5: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl)-N-isopropyl Acrylamide(23)

The first step: N-(2-chloro-5-methylpyrimidin-4-yl)-1H-indazol-5-amine

2,4-Dichloro-5-methylpyrimidine (500mg, 3mmol), 1H-indazol-5-amine (408mg, 3mmol) and sodium carbonate (1.3g, 12mmol) were dissolved in ethanol (10mL), the reaction was The system was stirred at 80°C overnight. The reaction solution was spin-dried, water (20 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated brine (20 mL) in turn, dried over anhydrous sodium sulfate, filtered, and then reduced Concentrated under pressure, purified by reverse phase column to obtain N-(2-chloro-5-methylpyrimidin-4-yl)-1H-indazol-5-amine (180 mg, yellow solid), yield: 23%. MS (ESI) m/z: 260.2 [M+H] ⁺ .

The second step: 5-((tert-butoxycarbonyl)(2-chloro-5-methylpyrimidin-4-yl)amino)-1H-indazole-1-carboxylic acid tert-butyl ester

N-(2-Chloro-5-methylpyrimidin-4-yl)-1H-indazol-5-amine (1 g, 3.8 mmol), di-tert-butyl dicarbonate (3.3 g, 18.4 mmol) and triethyl The amine (1.5 g, 15.4 mmol) was dissolved in dichloromethane (10 mL), 4-dimethylaminopyridine was added, and the reaction system was stirred at room temperature overnight. The reaction solution was directly rotated to dryness, and purified by silica gel column (ethyl acetate:petroleum ether=5:1) to obtain 5-((tert-butoxycarbonyl)(2-chloro-5-methylpyrimidin-4-yl)amino)- 1H-Indazole-1-carboxylic acid tert-butyl ester (1.68 g, white solid), yield: 95%. MS(ESI) m/z: 460.2 [M+H] ⁺ .

The third step: (E) tert-butyl 5-((tert-butoxycarbonyl)(2-(3-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)- 5-Methylpyrimidin-4-yl)amino)-1H-indazole-1-carboxylate

Referring to the method of the second step of Example 4, use 5-((tert-butoxycarbonyl)(2-chloro-5-methylpyrimidin-4-yl)amino)-1H-indazole-1-carboxylic acid tert-butyl ester ( 300 mg, 0.65 mmol) as starting material to obtain (E) tert-butyl 5-((tert-butoxycarbonyl)(2-(3-(3-ethoxy-3-oxoprop-1-en-1-yl) )phenyl)-5-methylpyrimidin-4-yl)amino)-1H-indazole-1-carboxylate (190 mg, yellow oil), yield: 49%. MS(ESI) m/z: 600.3 [M+H] ⁺ .

The fourth step: (E) 3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl) ethyl acrylate

(E) tert-butyl 5-((tert-butoxycarbonyl)(2-(3-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)-5-methyl pyrimidin-4-yl)amino)-1H-indazole-1-carboxylate (110 mg, 0.22 mmol) was dissolved in formic acid (5 mL), and the reaction system was stirred at room temperature overnight. The reaction solution was directly spin-dried and cast into the next step to obtain (E) ethyl 3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid Ester (88 mg, yellow oil). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=13.03 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.30-8.25 (m, 3H), 8.11(s, 1H), 7.81-7.50(m, 5H), 6.62(d, J=16.0Hz, 1H), 4.25-4.20(m, 2H), 2.27(s, 3H), 1.31(t , J=7.2 Hz, 3H). MS (ESI) m/z: 400.2 [M+H] ⁺ .

The fifth step: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid

Referring to the method of the fourth step of Example 4, with (E) 3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl) Ethyl acrylate (88 mg, 0.22 mmol) was used as raw material, and tetrahydrofuran/water (5 mL/1 mL) was used as a mixed solution to obtain (E)-3-(3-(4-(((1hydro-indazol-5-yl) )amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid (30 mg, white solid), yield: 36%. MS (ESI) m/z: 372.1 [M+H] ⁺ .

The sixth step: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl)-N-isopropyl Acrylamide

Referring to the method of the fifth step of Example 4, with (E)-3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl ) acrylic acid (30 mg, 0.08 mmol) as starting material to give (E)-3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)benzene yl)-N-isopropylacrylamide 23 (5.0 mg, white solid), yield: 15%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=13.03 (s, 1H), 8.65 (s, 1H), 8.50(s, 1H), 8.25-7.99(m, 5H), 7.70-7.41(m, 5H), 6.69(d, J＝15.6Hz, 1H), 3.99-3.94(m, 1H), 2.27 (s, 3H), 1.13 (d, J=6.8 Hz, 6H). MS (ESI) m/z: 413.2 [M+H] ⁺ .

Example 6: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl)-N-isopropyl Acrylamide(25)

The first step: nitrogen-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1hydro-indazol-5-amine

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.31 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-hydro-indone was added at minus 40°C Azol-5-amine (308 mg, 2.31 mmol) and triethylamine (0.9 mL, 6.93 mmol), the reaction system was stirred at minus 40° C. for 2 hours. Water (20 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (20 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The product was purified by reverse phase column to obtain nitrogen-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1hydro-indazol-5-amine (310 mg, white solid), yield: 43% . MS (ESI) m/z: 314.0 [M+H] ⁺ .

Step 2: (E) Ethyl 3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)phenyl)acrylate ester

Referring to the second step of Example 4, using nitrogen-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1hydro-indazol-5-amine 3 (200mg, 0.64mmol) as raw material, Obtained (E) ethyl 3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)phenyl)acrylate (32 mg , white solid), yield: 11%. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=13.12(s, 1H), 9.26(s, 1H), 8.75(s, 1H), 8.42(s, 1H), 8.20(d, J＝8.0Hz, 1H), 8.12(s, 1H), 7.94(d, J＝1.2Hz, 1H), 7.87(d, J＝8.0Hz, 1H), 7.65-7.48( m, 4H), 6.56 (d, J=16.0Hz, 1H), 4.24 (q, J=6.8Hz, 2H), 1.31 (t, J=6.8Hz, 3H). MS (ESI) m/z: 454.2 [M+H] ⁺ .

The third step: (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)phenyl)acrylic acid

Referring to the fourth step of Example 4, with (E) 3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Phenyl) ethyl acrylate as raw material to obtain (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidine-2- (17 mg, white solid), yield: 71%.

Fourth step: (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)phenyl)- Nitrogen-isopropylacrylamide

Referring to the fifth step of Example 4, use (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )phenyl)acrylic acid (17 mg, 0.040 mmol) as starting material to give (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl) )pyrimidin-2-yl)phenyl)-nitrogen-isopropylacrylamide (4.9 mg, white solid), yield: 30%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=13.18 (brs, 1H), 9.26(s, 1H), 8.74(s, 1H), 8.42(s, 1H), 8.12(s, 1H), 8.07(d, J=7.6Hz, 1H), 7.93(d, J=7.6 Hz,1H),7.88(d,J=1.6Hz,1H),7.68-7.37(m,5H),6.61(d,J=15.2Hz,1H),3.92(overlap,1H),1.33(d,J = 6.4 Hz, 6H). MS (ESI) m/z: 467.2 [M+H] ⁺ .

Example 7: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-cyclobutylacrylamide ( 27)

With reference to the method for Example 1, the isopropylamine in the 4th step is changed to cyclobutylamine to obtain (E)-3-(3-(4-(((1H-indazol-5-yl)amino)quinazole Lino-2-yl)phenyl)-N-cyclobutylacrylamide (13.1 mg, yellow solid), yield: 40%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=13.10 (brs, 1H ),10.00(s,1H),8.64-8.57(m,2H),8.43-8.30(m,3H),8.14(s,1H),7.92-7.80(m,3H),7.68-7.60(m,3H ),7.58-7.42(m,2H),6.67(d,J＝1.6Hz,1H),4.38-4.30(m,1H),2.28-2.20(m,2H),2.00-1.90(m,2H), 1.75-1.65 (m, 2H). MS (ESI) m/z: 461.3 [M+H] ⁺ .

Example 8: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-cyclopropylacrylamide ( 33)

With reference to the method for embodiment 1, isopropylamine in the 4th step is changed to cyclopropylamine, obtains ((E)-3-(3-(4-(((1 hydrogen-indazol-5-yl)amino)quinoline oxazolin-2-yl)phenyl)-nitro-cyclopropylacrylamide (6.7 mg, yellow solid), yield: 18%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=13.11 (s, 1H), 10.00(s, 1H), 8.63-859(m, 2H), 8.38-8.32(m, 2H), 8.22-8.21(m, 1H), 8.13(s, 1H), 7.89-7.82(m, 3H), 7.65-7.61(m, 3H), 7.53-7.46(m, 2H), 6.73(d, J=15.6Hz, 1H), 2.81-2.78(m, 1H), 0.72-0.68(m, 2H, 0.52-0.48 (m, 2H). MS (ESI) m/z: 447.2 [M+H] ⁺ .

Example 9: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-cyclopropylacrylamide ( 37)

The first step: N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine

1H-indazol-5-amine (50mg, 0.38mmol) and 2,4-dichloropyrimidine (65mg, 0.41mmol) and triethylamine (76mg, 0.75mmol) were added to ethanol (4mL), heated for 80 Stir at °C for 16 hours. The reaction was completed, concentrated and spin-dried to obtain the crude product N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (80 mg, purple solid), yield: 86.9%. MS(ESI) m/z: 246.2 [M+H] ⁺ .

Step 2: (E)-3-(3-(4-(((1H-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)acrylic acid

N-(2-Chloropyrimidin-4-yl)-1hydro-indazol-5-amine (80 mg, 0.33 mmol), E)-(3-(3-methoxy-3-oxoprop-1 -en-1-yl)phenyl)boronic acid (74 mg, 0.36 mmol) and potassium carbonate (180 mg, 0.94 mmol) were added to dioxane/H ₂ O (6 mL, 5:2), and Pd(dppf) was added under nitrogen Cl ₂ (12 mg, 0.02 mmol), the reaction system was stirred at 100° C. for 16 hours, added with water (6 mL), extracted with ethyl acetate (6 mL×2), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain crude Product, crude product was passed through silica gel column PE: EA=10:1 to 1:1 to give (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)pyrimidine-2- (30 mg, colorless oil), yield: 25.8%. MS (ESI) m/z: 358.1 [M+H] ⁺ .

The third step: (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)-N-isopropylacrylamide

(E)-3-(3-(4-(((1H-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)acrylic acid (80 mg, 0.22 mmol) was added to DMF (3 mL) , then added isopropylamine (13 mg, 0.26 mmol) and HATU (101 mg, 0.26 mol), stirred at room temperature for 30 minutes, LCMS showed that the reaction was complete, added water (6 mL), extracted with ethyl acetate (6 mL x 2), washed with saturated brine, no Dry over sodium sulfate, concentrated and spin-dried to obtain crude product, which was purified by prep-HPLC to obtain (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)pyrimidine-2 -yl)phenyl)-nitro-isopropylacrylamide (6 mg, white solid), yield: 6.7%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=13.02 (brs, 1H), 9.65 ( s,1H),8.58(s,1H),8.37-8.31(m,2H),8.22(s,1H),8.07-8.02(m,2H),7.66-7.46(m,5H),6.76-6.70( m, 2H), 4.00-3.95 (m, 1H), 1.14 (d, J=6.4Hz, 6H). MS (ESI) m/z: 399.2 [M+H] ⁺ .

Example 10: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Phenyl)-N-isopropylacrylamide (26)

The first step: 2-chloro-5-(trifluoromethyl)-N-(4-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)phenyl)pyrimidin-4-amine

2-Chloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.30 mmol), 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)aniline (666 mg, 2.30 mmol) and triethylamine (699 mg, 6.91 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction system was stirred at -40°C for 2 hours. Water (10 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The compound was purified by column chromatography (EA:PE=5:1) to give 2-chloro-5-(trifluoromethyl)-N-(4-(1-(((2-(trimethylsilyl) Ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-amine (490 mg, yellow liquid), yield: 38%. MS (ESI) m/z: 470.0 [M+ H] ⁺ .

Step 2: (E)-Ethyl 3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)) Methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylate

To 2-chloro-5-(trifluoromethyl)-N-(4-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- (E)-(3-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)boronic acid ( 280mg, 1.27mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (78mg, 0.11mmol) in dioxane/water (8mL/4mL) was added Potassium carbonate (293.8 mg, 2.12 mmol). Under nitrogen protection, the temperature was raised to 100 °C and the reaction was stirred overnight, and the reaction system was filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by chromatography (EA:PE=5:1) gives (E)-ethyl 3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl) -1H-Pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylate (360 mg, white solid), yield: 48.7%. MS (ESI) m/z: 610.1 [M +H] ⁺ .

The third step: (E)-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl) )-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid

(E)-ethyl 3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl) -1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylate (360 mg, 0.59 mmol) and lithium hydroxide (247.86 mg, 5.90 mmol) were dissolved in methanol/water (5 mL) /2mL), the reaction was stirred at room temperature overnight. The reaction solution was directly purified by reverse phase column to obtain (E)-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethyl) Oxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid (280 mg, white solid), 81% yield over two steps. MS(ESI) m/z: 582.0 [M+H] ⁺ .

The fourth step: (E)-N-isopropyl-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)) Ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylamide

(E)-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H - Pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid (90 mg, 0.16 mmol), isopropylamine (26.5 mg, 0.47 mmol) in N,N-dimethylformamide (5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (88.3mg, 0.23mmol) was added to the reaction solution, The mixture was stirred at room temperature overnight. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (EA:PE=2:1) to give (E)-N-isopropyl-3-(3-(5-(trifluoromethyl)-) 4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)benzene yl) acrylamide (75.2 mg, white solid), yield: 78%. MS(ESI) m/z: 623.1 [M+H] ⁺ .

The fifth step: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Phenyl)-N-isopropylacrylamide

(E)-N-isopropyl-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylamide (75.2 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction system was The reaction was stirred at room temperature overnight. The reaction solution was directly rotated to dryness, and the residue was purified by prep-HPLC to obtain (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(tris Fluoromethyl)pyrimidin-2-yl)phenyl)-N-isopropylacrylamide (2.6 mg, white solid), yield: 5.3%. MS (ESI) m/z: 493.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ=9.16(s,1H), 8.77(s,1H), 8.50(s,1H), 8.19(d, J=7.6,1H), 8.11(s, 2H), 8.10(d, J＝8.0, 1H), 7.73(t, J＝8.0Hz, 3H), 7.62(d, J＝8.4Hz, 2H), 7.53(t, J＝7.6Hz, 1H), 7.47 (d, J=16.0 Hz, 1H), 6.71 (d, J=16.0 Hz, 1H), 3.99-3.94 (m, 1H), 1.13 (d, J=8.4 Hz, 6H).

Example 11: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)-N-ring Propyl acrylamide (34)

The first step: (E)-N-cyclopropyl-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylamide

(E)-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylic acid (100 mg, 0.18 mmol), cyclopropylamine (30 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) , 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (82mg, 0.22mmol) was added to the reaction solution, and the mixture was at room temperature The reaction was stirred for 1 hour. The reaction system was dispersed in water (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phase was washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase column to give (E)-3-(3-(4-((4-(1hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl )-nitro-isopropylacrylamide 2 (78 mg, yellow solid), yield: 72%. MS (ESI) m/z: 603.1 [M+H] ⁺ .

Step 2: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)-N-ring Propyl acrylamide

(E)-3-(3-(4-((4-(1 Hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)-nitrogen-isopropyl Acrylamide (40 mg, 0.066 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was directly spin-dried under reduced pressure to obtain the crude product, which was purified by Prep-HPLC to obtain the target product (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinoline oxazolin-2-yl)phenyl)-N-cyclopropylacrylamide (17.4 mg, white solid). Yield: 56%. MS (ESI) m/z: 473.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ=8.69-8.67(m,1H), 8.56(s,1H), 8.36-8.26(m,2H), 8.10(s,2H), 8.03-7.90( m, 4H), 7.76(d, J＝8.4Hz, 4H), 7.66-7.62(m, 1H), 7.53(d, J＝15.6Hz, 1H), 6.66(d, J＝16.0Hz, 1H), 2.85-2.76 (m, 1H), 0.76-0.66 (m, 2H), 0.53-0.45 (m, 2H).

Example 12: (E)-3-(3-(4-(((1H-Indazol-5-yl)amino)pyrimidin-2-yl)phenyl)-N-cyclopropylacrylamide (38)

((E)-3-(3-(4-(((1H-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)acrylic acid (46 mg, 0.08 mmol) obtained in Example 9, Cyclopropylamine (11mg, 0.19mmol) was dissolved in N,N-dimethylformamide (4mL), 2-(7-azabenzotriazole)-N,N,N' was added to the reaction solution, N'-tetramethylurea hexafluorophosphate (58 mg, 0.15 mmol), the mixture was stirred at room temperature for 1 hour. The reaction system was dispersed in water (10 mL), and extracted with ethyl acetate (10 mL×2). The organic phase was washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was subjected to prep-HPLC to obtain (E)-3-(3-(4-((((1H) -Indazol-5-yl)amino)pyrimidin-2-yl)phenyl)-N-cyclopropylacrylamide (10 mg, white solid), yield: 20%. MS (ESI) m/z: 397.3 [ M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.39 (brs, 1H), 8.46 (s, 1H), 8.38 (d, J=6.8 Hz, 1H), 8.29-8.10 ( m, 4H), 7.76(d, J=7.2Hz, 1H), 7.64-7.48(m, 4H), 6.81(d, J=6.8Hz, 1H), 6.66(d, J=15.6Hz, 1H), 2.80-2.77 (m, 1H), 0.72-0.46 (m, 4H).

Example 13: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)-N-cyclopropyl Acrylamide(39)

The first step: 2-chloro-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidine

2,4-Dichloropyrimidine (200 mg, 1.01 mmol) was dissolved in ethanol (8 mL) and 4-(1-((2-(trimethylsilyl)ethoxy)methyl was added at 25°C )-1H-pyrazol-4-yl)aniline (322 mg, 1.16 mmol) and triethylamine (205 mg, 2.03 mmol), the reaction system was stirred at 80° C. for 16 hours. Spin dry to obtain crude product N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (240 mg, purple solid), yield: 58.9%. MS (ESI) m/z: 402.1 [M+H] ⁺ .

The second step: (E)-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid

2-Chloro-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidine (180 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.041 mmol) and (E)-(3-(3-ethoxy-3-oxo) To a solution of prop-1-en-1-yl)phenyl)boronic acid (118 mg, 0.54 mmol) in dioxane/water (4 mL/1 mL) was added potassium carbonate (129 mg, 0.90 mmol). Under nitrogen protection, the temperature was raised to 100°C and the reaction was stirred overnight, and the reaction system was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase to give (E)-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)) Methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid (120 mg, white solid), yield: 52.3%. MS (ESI) m/z: 514.0 [M+H] ⁺ .

The third step: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid

(E)-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)benzene yl)amino)pyrimidin-2-yl)phenyl)acrylic acid (120 mg, 0.233 mmol) was dissolved in dichloromethane (4 mL), formic acid (4 mL) was added at 25 °C, and the reaction system was stirred at 25 °C for 2 hours . Spin dry to obtain crude product (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid (130mg, yellow oil), yield: 134%. MS (ESI) m/z: 384.0 [M+H] ⁺ .

The fourth step: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)-N-cyclopropyl Acrylamide

(E)-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)benzene yl)amino)pyrimidin-2-yl)phenyl)acrylic acid (65mg, 0.17mmol), cyclopropylamine (12mg, 0.20mmol) was dissolved in N,N-dimethylformamide (4mL), added to the reaction solution 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (77 mg, 0.20 mmol), the mixture was stirred and reacted at room temperature for 1 hour. The reaction system was dispersed in water (10 mL), and extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. (E)-3-(3-(4-(((1H-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)-N-cyclopropylacrylamide ( 4 mg, white solid), yield: 5.6%. MS (ESI) m/z: 423.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.41 (brs, 1H), 8.50 -8.27(m, 4H), 8.10(s, 2H), 7.81-7.52(m, 8H), 6.88(d, J=8.4Hz, 1H), 6.73-6.67(m, 1H), 2.88-2.80(m , 1H), 0.76-0.70 (m, 2H), 0.53-0.50 (s, 2H).

Example 14: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)- N-Cyclopropylacrylamide (40)

The first step: 2-chloro-5-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl) phenyl)pyrimidin-4-amine

2,4-Dichloro-5-methylpyrimidine (300 mg, 1.8 mmol), 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)aniline (532 mg, 1.8 mmol) and sodium carbonate (780 mg, 7.4 mmol) were dissolved in DMF (10 mL), and the reaction system was stirred at 80 °C overnight. Direct filtration and purification by reverse phase column gave 2-chloro-5-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)phenyl)pyrimidin-4-amine 3 (130 mg, colorless oil), yield: 17%. MS (ESI) m/z: 416.1 [M+H] ⁺ .

The second step: tert-butyl(2-chloro-5-methylpyrimidin-4-yl)(4-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H -Pyrazol-4-yl)phenyl)carbamate

2-Chloro-5-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl) Pyrimidine-4-amine (90 mg, 0.2 mmol), di-tert-butyl dicarbonate (94 mg, 0.4 mmol) and triethylamine (44 mg, 0.4 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol) were dissolved in di- In methyl chloride (10 mL), the reaction system was stirred at room temperature overnight. The reaction solution was directly rotated to dryness, and purified by silica gel column (EA:PE=5:1) to obtain tert-butyl(2-chloro-5-methylpyrimidin-4-yl)(4-(1-((((2- (Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)carbamate 5 (100 mg, colorless oil), yield: 91%. MS (ESI )m/z: 516.0[M+H] ⁺ .

The third step: (E)-ethyl 3-(3-(4-((tert-butoxycarbonyl)(4-(1-((2-(trimethylsilyl)ethoxy)methyl) )-1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylate

tert-Butyl(2-chloro-5-methylpyrimidin-4-yl)(4-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)phenyl)carbamate (100 mg, 0.2 mmol), (E)-(3-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl) Boronic acid (43 mg, 0.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (15 mg, 0.02 mmol) in dioxane/water (5 mL/1 mL) Potassium carbonate (52 mg, 0.4 mmol) was added in the middle. Under nitrogen protection, be warming up to 90 ° C and stirring the reaction overnight. The reaction solution was filtered and spin-dried, water (20 mL) was added to the reaction system, and the mixed solution was separated using ethyl acetate (20 mL×2). Extraction, the organic phase was washed with saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column (EA:PE=5:1) to obtain (E)-ethyl 3-( 3-(4-((tert-butoxycarbonyl)(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl )amino)-5-methylpyrimidin-2-yl)phenyl)acrylate (110 mg, colorless oil), yield: 86%. MS (ESI) m/z: 656.1 [M+H] ⁺ .

The fourth step: (E) 3-(3-(4-(((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid ethyl ester

(E)-ethyl 3-(3-(4-((tert-butoxycarbonyl)(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylate (50 mg, 0.07 mmol) in trifluoroacetic acid (5 mL) in dichloromethane (5 mL) ), the reaction system was stirred at room temperature overnight. The reaction solution is directly spin-dried and cast into the next step to obtain (E) 3-(3-(4-(((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl ) phenyl) ethyl acrylate (32 mg, crude, yellow oil). MS (ESI) m/z: 426.0 [M+H] ⁺ .

The fifth step: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid

(E) Ethyl 3-(3-(4-(((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylate ( 32mg, 0.07mmol) and Lithium Hydroxide (16mg, 0.37mmol) are dissolved in the mixed solution of tetrahydrofuran/water (5mL/1mL), room temperature stirring reaction 3 hours.Reaction solution is adjusted to PH=6 with dilute hydrochloric acid, directly uses reaction Phase column purification to obtain (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid (25 mg, white solid), yield: 83%.

Step 6: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)- N-Cyclopropylacrylamide

(E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid (30 mg, 0.07mmol), isopropylamine (9mg, 0.15mmol) was dissolved in N,N-dimethylformamide (5mL), 2-(7-azabenzotriazole)-N,N was added to the reaction solution , N', N'-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol), the mixture was stirred at room temperature to react overnight. The reaction system was dispersed in water (10 mL), and extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl was obtained by prep-HPLC )-N-cyclopropylacrylamide (10.0 mg, yellow solid), yield: 30%. MS (ESI) m/z: 437.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ=9.37(s,1H), 8.41(s,1H), 8.35(s,1H), 8.30(d, J=4.4Hz,1H), 8.16(d , J＝7.6Hz, 1H), 8.08(s, 2H), 7.77-7.70(m, 5H), 7.59(t, J＝7.6Hz, 1H), 7.48(d, J＝16.0Hz, 1H), 6.64 (d, J=16.0 Hz, 1H), 2.81-2.77 (m, 1H), 2.31 (s, 3H), 0.72-0.68 (m, 2H), 0.50-0.46 (m, 2H).

Example 15: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Phenyl)-N-cyclopropylacrylamide (41)

The first step: (E)-N-cyclopropyl-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)) Ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylamide

(E)-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy) obtained in Example 10) Methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid (90 mg, 0.16 mmol), cyclopropylamine (26.5 mg, 0.47 mmol) in N,N- In dimethylformamide (5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (88.3 mg) was added to the reaction solution. , 0.23 mmol), and the mixture was stirred overnight at room temperature. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate:petroleum ether=2:1) to obtain (E)-N-cyclopropyl-3-(3-(5-(trifluoromethyl) yl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidine-2- yl)phenyl)acrylamide (65 mg, white solid), yield: 67%. MS(ESI) m/z: 621.0 [M+H] ⁺ .

Step 2: (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Phenyl)-N-cyclopropylacrylamide

(E)-N-isopropyl-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylamide (65 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (5 mL), the reaction system was at room temperature The reaction was stirred overnight under conditions. The reaction solution was directly rotated to dryness, and the residue was purified by prep-HPLC to obtain (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(tris Fluoromethyl)pyrimidin-2-yl)phenyl)-N-cyclopropylacrylamide (2.7 mg, white solid), yield: 5.3%. MS (ESI) m/z: 491.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ=9.15(s,1H), 8.77(s,1H), 8.49(s,1H), 8.28(d, J=4.4,1H), 8.18(d, J=12.0, 1H), 8.09(s, 2H), 7.69(t, J=8.4Hz, 3H), 7.68(d, J=8.8Hz, 2H), 7.52(t, J=8.0Hz, 1H), 7.49(d,J＝16.0Hz,1H),6.63(d,J＝15.6Hz,1H),2.80-2.75(m,1H),0.71-0.67(m,2H),0.49-0.45(m,2H) .

Example 16: (E)-3-(3-(4-((1H-Indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-(2-fluorocyclopropyl ) acrylamide (42)

HATU (38 mg, 0.10 mmol) was added to (E)-3-(3-(4-(((1H-indazol-5-yl)amino)quinazolin-2-yl)benzene obtained in Example 1 base) acrylic acid (30 mg, 0.07 mmol), 2-fluorocyclopropanamine (10 mg, 0.14 mmol) and DIEA (14 mg, 0.14 mmol) in a mixed DMF solution (1 mL), the reaction system was stirred at room temperature for 1 hour, The formation of the target product was monitored by LC and purified by prep-HPLC to obtain the target product (E)-3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl )-N-(2-fluorocyclopropyl)acrylamide (13.1 mg, yellow solid), yield: 40%. MS (ESI) m/z: 465.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.87(brs, 1H), 8.71(d, J=8.0, 1H), 8.47(s, 1H), 8.31-8.18(m, 4H), 8.04-7.97(m, 2H) ,7.81-7.78(m,3H),7.71-7.69(m,1H),7.63(t,J=7.6,1H),7.52(d,J=15.6,1H),6.61(d,J=15.6,1H) ), 4.83-4.66 (m, 1H), 3.25-3.02 (m, 1H), 1.49-1.31 (m, 1H), 1.03-0.89 (m, 1H).

Example 17: (E)-3-(3-(4-((1H-Indazol-5-yl)amino)quinazolin-2-yl)phenyl)-N-(2-fluorocyclopropyl ) acrylamide (44)

(E)-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid (65 mg, 0.17 mmol), isopropylamine (12 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (4 mL), 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (77mg, 0.20mmol) was added to the reaction solution, and the mixture was stirred at room temperature React for 1 hour. The reaction system was dispersed in water (10 mL), and extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. (E)-3-(3-(4-(((1H-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)-N-cyclopropylacrylamide ( 5.3 mg, white solid), yield: 7.5%. MS (ESI) m/z: 425.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.45 (brs, 1H), 8.49-8.43(m, 2H), 8.27(d, J=10.0Hz, 1H), 8.15(d, J=10.0Hz, 1H), 8.10(s, 2H), 7.81-7.64(m, 7H), 7.52( d,J＝20.8Hz,1H),6.88(d,J＝8.8Hz,1H),6.76(d,J＝21.2Hz,1H),4.03-3.96(m,1H),1.25-1.14(d,J =7.6Hz, 6H).

Experimental Example 1: Detection of ROCK1/2 Kinase Activity

Kinase activity was detected by Mobility shift assay with KD-025 as positive control. The ROCK1 kinase used was purchased from Carna, the ROCK2 kinase was purchased from signalchem, and the substrate LIMKtide was purchased from GL.

The 10 mM test compound prepared with DMSO was diluted to a concentration of 10 μM, followed by 3-fold gradient dilution to obtain a total of 10 test compound solutions of different concentrations, which were tested in duplicate. Positive and negative control wells were added with 250 nL DMSO. Use 1× Kinase buffer to prepare 2.5 times the final concentration of kinase solution. Add 10 μL of 2.5 times final concentration of kinase solution to compound wells and positive control wells respectively, and add 10 μL of 1×Kinase buffer to negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 10 minutes. The reaction was initiated by adding 15 μL of a mixed solution of ATP and LIMKtide at 5/3 times the final concentration. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, incubate at room temperature for a corresponding time after shaking and mixing, add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake and mix. Conversion rates were read with the Caliper EZ Reader II.

Inhibition % = (positive control conversion read-sample conversion read)/(positive control conversion read-negative control conversion read) x 100%. Taking the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, use the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism5 to fit the dose-response curve to obtain the _IC50 value of the test substance on the enzyme activity .

The _IC50 values of each compound are shown in Table 1 below. A means <50nM; B means 50-250nM; C means >250nM; + means the inhibition rate is greater than 80%; - means the inhibition rate is less than 80%.

Table 1. ROCK1/2 Kinase _IC50 Values

Patent CN101208094 discloses the compound KD-025, and records that its IC50 for ROCK2 is 105nM. In addition, this application also tested the ROCK2 inhibitory activity of CN101208094 compound 80 and CN105101996 compound 164 head-to-head. The IC50s of ROCK2 and ROCK1 of CN101208094 compound 80 were both >250 nM. CN105101996 Compound 164 has ROCK2 IC50>250nM and ROCK1 IC50 of 50-250nM. Most of the compounds in this application have better IC50 for ROCK2 than compound KD-025 and the above-mentioned patented compounds, and the IC50 of compounds 21, 23, 27, 33, 37, 38, and 42 have obvious advantages.

Patent WO2012040499 discloses compound 201, and records that its inhibition rate of ROCK2 at 500 nM is 0.67. When the compounds of the present application have the same inhibition rate to the ROCK2 target, the required concentration is much less than 500 nM, especially compounds 21, 23, 27, 33, 37, 38, 39, 42, and 44 have obvious advantages.

Experimental Example 2: Mouse Toxicity Test

experimental method:

The CD-1 mice were administered continuously for 14 days, and each compound was set up in 3 dose groups (100mpk, 300mpk, 600mpk), and the death and toxicity of the mice were observed after daily administration for 14 days. In each dose group, there were 2 male and 2 CD-1 mice, and the mice were all 6-8 weeks old and weighing 18-22 grams.

Toxicity observation indicators mainly include: vital signs, breathing, nutritional status, mental status, behavioral activities, muscles, reflexes, eye, nose, oral cavity, gastrointestinal tract reactions, abdominal status, urine, coat, skin and mucous membranes, perineal status, etc. .

Experimental data:

Observation results of positive reference substance KD-025: 100mpk mice showed no abnormal reaction; 300mpk mice observed erection in 1 mouse, other mice had no abnormality; 600mpk mice had 1 death, and the rest of the mice observed lack of energy , arched back, bristles.

Observation results of compound 21: all mice at 100mpk and 300mpk showed no abnormal reaction; some mice at 600mpk had piloerection, and other mice had no abnormality.

Observation results of compound 23: 100mpk and 300mpk mice showed no abnormal reaction; 600mpk mice showed lack of energy and skin discoloration.

Observation results of compound 27: 100mpk mice showed no abnormal reaction; 300mpk mice appeared piloerection, and 600mpk mice showed no abnormality.

Observation results of compound 33: 100mpk, 300mpk, 600mpk all mice showed no abnormal reaction.

Test Conclusions:

The toxicity of compounds 21, 23, 27, and 33 was significantly less than that of the positive control KD-025.

Experimental Example 3: Cytokine Experiment

experimental method:

1) The leukocyte layer containing PBMC (human peripheral blood mononuclear cells) was collected, washed with DPBS (phosphate buffered saline), and centrifuged.

2) Discard the supernatant, resuspend the cells with buffer, and adjust the concentration to 5×10 ⁷ /mL.

CD4+T细胞，并调整浓度为2×10 ⁶/mL。 3) further isolated from PBMC to obtain

CD4+ T cells were adjusted to a concentration of 2×10 ⁶ /mL.

CD4+T细胞(50μL/well)和anti-human CD3/CD28 beads细胞(50μL/well)加入到96孔微孔板中。 4) will

CD4+ T cells (50 μL/well) and anti-human CD3/CD28 beads cells (50 μL/well) were added to a 96-well microplate.

5) Prepare 4*cytokines cocktail with complete culture medium, add the prepared cytokines cocktail, compound and positive control to the corresponding wells respectively, with a total volume of 200 μL.

6) Incubate for 5-6 days in a 37°C, 5% _CO2 incubator.

7) Cells were stimulated with 100 ng/ml PMA and 1 μg/ml Ionomycin for 4 hours. 8) After centrifugation, the supernatant was collected to detect the secretion of IL-17.

The experimental data is shown in Table 2:

Table 2

compound twenty one twenty three 27 KD-025 10uM inhibition rate % 100 99 100 53

Test Conclusions:

The inhibitory activity of compounds 21, 23 and 27 on IL-17 was significantly higher than that of KD-025 in a dose-dependent manner.

Claims (10)

A compound having the structure shown in general formula (I):

in, Ring A is a five- or six-membered heterocyclic ring, the heterocyclic ring contains 1-3 heteroatoms selected from N, O, and S, and the C atom in the heterocyclic ring is optionally substituted by 0 to 3 C=O; Ring B is absent or a five- to six-membered unsaturated ring containing 0 to 3 N atoms; L ₁ is selected from -O(CR ^a R ^b ) _n , C _1-6 alkylene or C _1-6 alkenylene; R ¹ is selected from any substituted amide group or sulfonamide group, and S=O in the sulfonamide group can be substituted by S=NR ^c ; preferably, R ¹ is selected from

L ₂ is selected from C _1-6 alkylene or -NR ^d ; R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine; R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, when ring In the absence of B, ^R is attached to ring A; R ^a , R ^b , R ^c , R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl ; The alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by 0-3 R ⁴ ; R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; m and n are each independently selected from an integer of 0-3. The compound of claim 1, wherein:

Has the following structure:

The compound according to claim 2, characterized in that it has the structure represented by the general formula (I-4),

Ring B does not exist or is a parallel five- to six-membered aromatic ring containing 0 to 3 N atoms; wherein R ^a and R ^b are independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; R ² is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine; R ³ is selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, when ring In the absence of B, ^R is linked to a pyrimidine; The alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R4 ^; R ⁴ is selected from H, halogen, cyano, hydroxyl, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; m is selected from an integer of 0-3. The compound of claim 3, wherein: Ring B does not exist or is a benzene ring; wherein R ^a and R ^b are independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy radical, cyclopropoxy, cyclobutoxy, and optionally substituted with 0-2 F atoms; R ² is selected from indazole, phenyl-1H-pyrazole; R ³ is selected from H, halogen, hydroxyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, and when ring B is absent, R ³ is linked to pyrimidine; m is selected from an integer of 0-3. The compound according to claim 4, is characterized in that, has the structure shown in general formula (I-5):

in: R ^a is selected from H, R ^b is selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutyl oxy, and optionally substituted with 0-2 F atoms; R ² is selected from indazole, phenyl-1H-pyrazole; preferably indazole. The compound according to claim 4, is characterized in that, has the structure shown in general formula (I-6):

in: R ^a is selected from H, R ^b is selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutyl oxy, and optionally substituted with 0-2 F atoms; R ² is selected from indazole, phenyl-1H-pyrazole; ^R3 is selected from H, halogen, methyl, ethyl, trifluoromethyl; preferably H, halogen, methyl, ethyl. The compound of claim 1, wherein the compound is selected from the group consisting of:

A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for the treatment and/or prevention of ROCK2-related disorders. The use according to claim 9, wherein the ROCK2-related disorder is selected from the group consisting of pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis or nonalcoholic steatohepatitis.