A ripk1 kinase target inhibitor and preparation method and application thereof

Abstract

The application discloses a RIPK1 kinase target inhibitor and a preparation method and application thereof, and relates to the technical field of biological medicines.The quinazoline amide derivative (fragment A) and different benzopentaheterocyclic-2-amide derivatives (fragments B, C, D and E) are respectively obtained through chemical synthesis, and the two are coupled to obtain the target product of formula (I) or formula (II). The coupling product is a derivative of the skeleton, has good RIPK1 inhibiting effect, has good effects of resisting programmed necrosis, resisting acute ischemic stroke and resisting acute colitis, and is expected to have good application prospects in the fields of neurodegenerative diseases, inflammation and autoimmune diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, and particularly relates to a RIPK1 kinase target inhibitor and a preparation method and application thereof. BACKGROUND

[0002] Programmed necrosis is a highly regulated process involving various signaling pathways, and its core proteins include receptor-interacting serine / threonine-protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like pseudokinase (MLKL), and caspase-8. Programmed necrosis mediates immune responses by activating RIPK1, RIPK3, and MLKL. RIPK1 helps produce cytokines and DAMPs mediated by Nuclear factor-kappa B (NF-kappa B) kinase subunit alpha (IKK-alpha) or TBK1 (TANK-binding kinase 1). MLKL maximally releases the above factors by forming a plasma membrane pore. This process will eventually lead to morphological changes in cells, cell swelling, plasma membrane rupture, and content outflow. RIPK1 is widely involved in regulating cell death and survival signaling pathways, and plays an important role in inflammation and immune regulation.

[0003] During the onset of acute ischemic stroke (AIS), the cerebral blood flow in the infarct area is significantly reduced, and the supply of sugar and oxygen and energy depletion can induce a variety of signal cascades, causing nearby neurons to undergo programmed necrosis, which is an important pathway of cell death, and its morphological characteristics are cell swelling, plasma membrane rupture, and eventually release of cell contents, which is an important pathological feature of AIS. Degterev et al. first reported the involvement of programmed necrosis in cerebral ischemia, abnormal expression of phosphorylated RIPK1, promotion of inflammation development, and aggravation of brain injury, and when RIPK1 was inhibited, the degree of brain injury could be significantly reduced. The first selective programmed necrosis inhibitor Necrostatin-1 (Nec-1) was found. In addition, intracerebroventricular administration of Nec-1 can significantly reduce the infarct volume, indicating that Nec-1 has therapeutic potential for AIS. More and more studies have shown that the development of a highly active and highly selective inhibitor targeting RIPK1 can be a very important therapeutic target for the treatment of acute ischemic stroke, and provide a new way for the treatment of the disease.

[0004] Studies have shown that RIPK1 is related to a variety of nervous system diseases, systemic inflammatory diseases, tumors, sepsis, etc., and phosphorylated RIPK1 is also abnormally expressed, and the application of RIPK1 inhibitors is expected to provide a new way for the treatment of nervous system diseases, systemic inflammatory diseases, tumors, sepsis, etc. SUMMARY

[0005] Based on this, the purpose of the present application is to overcome the shortcomings of the prior art and provide a RIPK1 kinase target inhibitor and a preparation method and application thereof.

[0006] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows: a RIPK1 kinase target inhibitor, the structural general formula of the RIPK1 kinase target inhibitor is as shown in formula (I) or formula (II):

[0007]

[0008] Among them, X, Y, Z are nitrogen atoms at the same time; or, Z is a carbon atom, X, Y are one of nitrogen atom, sulfur atom, the atom selection of X, Y is different; or, Z is a carbon atom, X, Y are nitrogen atoms; or, Y, Z are carbon atoms, X is oxygen, nitrogen or sulfur atom;

[0009] Among them, R 1 is selected from one of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, substituted phenyl; R 2 and R 3 are each independently selected from alkyl of 6 carbons or halogen substitution thereof, cycloalkyl of 6 carbons or halogen substitution thereof, phenyl or halogen substitution thereof, benzyl, substituted benzyl, aryl heterocycle substituted methylene or halogen substitution thereof;

[0010] Among them, G in formula (II) is one of CH2, NH, O.

[0011] Preferably, X, Y, Z are nitrogen atoms at the same time to form a triazole ring, or Z is a carbon atom, X, Y are one of nitrogen atom, sulfur atom, the atom selection of X, Y is different to form a thiazole ring; or, Z is a carbon atom, X, Y are nitrogen atoms to form an imidazole ring; or, Y, Z are carbon atoms, X is oxygen, nitrogen or sulfur atom to form a furan ring, a pyrrole ring or a thiophene ring.

[0012] Preferably, in formula (I) or formula (II), X, Y, Z are nitrogen atoms at the same time to form a triazole ring; or Z is a carbon atom, X, Y are one of nitrogen atom, sulfur atom, the atom selection of X, Y is different to form a thiazole ring.

[0013] Preferably, the structural formula of the RIPK1 kinase target inhibitor is selected from at least one of the following:

[0014]

[0015]

[0016]

[0017] Preferably, the RIPK1 kinase target inhibitor is selected from at least one of the following: (R)-6-(2-isobutyramamido-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazoline-4-carboxamide, (R)-6-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazoline- 4-Carboxamide, (S)-6-(2-isobutamido-[1,2,4]triazolyl[1,5-a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazoline-4-carboxamide, (S)-2-methyl-N-(1-phenylethyl)-6-(2-neoamido-[1,2,4]triazolo[1,5-a]pyridin-7-yl)quinazoline-4-carboxamide, (S)-2-methyl-6-(2-pentamido-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropylcarboxamide)-[1,2,4]triazolyl ... (S)-6-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-(pyridin-2-yl)ethyl)quinazolin-4-carboxamide, (S)-6-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-(pyridin-3-yl)ethyl)quinazolin-4-carboxamide, (S)-6-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-(pyridin-4-yl)ethyl)quinazolin-4-carboxamide, (S)-6-(2-(cyclopropylformamide)-[1,2,4]triazolo[ (1,5-a)pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-6-(2-(cyclopentylcarboxamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropylcarboxamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-fluorophenyl)ethyl)-2-methyl ...

[0018] (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-2-methyl-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclohexanecarboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-(l-(S)-N-(1-(4-fluorophenyl)ethyl)-2-methyl-6-(2-(3-methylbutanamido)benzo[d]thiazol-6- yl)quinazoline-4-carboxamide, (S)-N-(1-(4-fluorophenyl)ethyl)-2-methyl-6-(2-neopentanamido- benzo[d]thiazol-6-yl)quinazoline-4-carboxamide, (S)-6-(2-(Cyclobutanecarboxamido)benzo[d]thiazol- 6-yl)-N-(1-(4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-6-(2-(Cyclopentanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)-2- methylquinazoline-4-carboxamide, (S)-6-(2-(Cyclohexanecarboxamido)benzo[d]thiazol-6-yl)-N-(1- (4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-6-(2-Benzylaminobenzo[d]thiazol-6-yl)- N-(1-(4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-6-(2-Butyramidobenzo[d]thiazol- 6-yl)-N-(1-(4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-N-(1-(4-Fluorophenyl)ethyl)- 2-methyl-6-(2-propanamidobenzo[d]thiazol-6-yl)quinazoline-4-carboxamide, (S)-6-(2-Acetylamino- benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, N-Benzyl-6-(2- (cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methylquinazoline-4-carboxamide, (S)-6-(2- (Cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1-phenylpropyl)quinazoline-4-carboxamide, 6-(2-(Cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-phenylquinazoline-4- carboxamide, 6-(2-(Cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-phenethylquinazoline-4- carboxamide, 6-(2-(Cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(tetrahydro-2H-pyran-4- yl)quinazoline-4-carboxamide, (S)-N-(1-Cyclohexylethyl)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol- 6-yl)-2-methylquinazoline-4-carboxamide, (S)-6-(2-(Cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-(1-(p-tolyl)ethyl)quinazoline-4-carboxamide, (S)-6-(2-(Cyclopropanecarboxamido)benzo[d]thiazol- 6-yl)-2-methyl-N-(1-(pyridin-4-yl)ethyl)quinazoline-4-carboxamide,(S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4- methoxyphenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-6-(2- (cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(2-methyl-1- phenylpropyl)quinazoline-4-carboxamide, (R)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1-(4- nitrophenyl)ethyl)quinazoline-4-carboxamide, (S)-6-((2- (cyclopropanecarboxamido)benzo[d]thiazol-6-yl)methyl)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide, (S)-6-((2- (cyclopropanecarboxamido)benzo[d]thiazol-6-yl)amino)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide, (S)-6-((2- (cyclopropanecarboxamido)benzo[d]thiazol-6-yl)oxy)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide.

[0019] Preferably, the RIPK1 kinase target inhibitor is selected from at least one of (S)-6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4- fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-N-(1-(4- fluorophenyl)ethyl)-2-methyl-6-(2-propionamidobenzo[d]thiazol-6-yl)quinazoline-4- carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1- phenylpropyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1-(p- tolyl)ethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4- methoxyphenyl)ethyl)-2-methylquinazoline-4-carboxamide.

[0020] Preferably, the RIPK1 kinase target inhibitor is selected from at least one of (S)-6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1- phenylethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4- fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide, (S)-N-(1-(4- fluorophenyl)ethyl)-2-methyl-6-(2-propionamidobenzo[d]thiazol-6-yl)quinazoline-4- carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1- phenylpropyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methyl-N-(1-(p- tolyl)ethyl)quinazoline-4-carboxamide, (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4- methoxyphenyl)ethyl)-2-methylquinazoline-4-carboxamide.

[0021] The inventors found in actual experiments that the above-mentioned RIPK1 kinase target inhibitors have better comprehensive effects, and the optimal compounds are from the comprehensive results of enzymatic and cellular experiments.

[0022] Further, the present application provides a preparation method of the RIPK1 kinase target inhibitor, comprising the following steps:

[0023] (1) Synthesis of 6-bromo quinazoline amide derivative: taking 5-bromo indigo as raw material, after alkaline hydrolysis, adjusting pH to neutral with dilute hydrochloric acid to obtain indigo hydrolysis product sodium salt; the indigo hydrolysis product sodium salt and acetaldehyde, ammonium acetate are subjected to three-component reaction to close ring to obtain quinazoline carboxylic acid sodium salt; in the presence of condensing agent, the quinazoline carboxylic acid sodium salt is condensed with amine compound to generate 6-bromo quinazoline amide derivative, which is segment A;

[0024] (2) is at least one of the following (2a)-(2d):

[0025] (2a) Preparation of segment B: taking 7 or 6-bromo 2-amino-benzoheterocyclic compound as raw material, adding acyl chloride or carboxylic acid, in the presence of acid binding agent or condensing agent, preparing 7 or 6-bromo benzoheterocyclic-2-amino acylated derivative, which is segment B;

[0026] (2b) Preparation of segment C: taking 6-bromo 2-amino-benzoheterocyclic compound as raw material, adding carboxylic acid, in the presence of condensing agent, preparing 6-bromomethyl substituted benzoheterocyclic-2-amino acylated derivative, which is segment C;

[0027] (2c) Preparation of segment D, taking 6-nitro substituted 2-amino-benzoheterocyclic compound as raw material, adding carboxylic acid, in the presence of condensing agent, preparing 6-nitro substituted benzoheterocyclic-2-amino acylated derivative, adding nitro reduction reagent, preparing the corresponding 6-amino substituted benzoheterocyclic-2-amino acylated derivative, which is segment D;

[0028] (2d) Preparation of segment E, taking 6-hydroxy substituted 2-amino-benzoheterocyclic compound as raw material, adding phenolic hydroxyl protection reagent to protect the hydroxyl group, adding carboxylic acid, in the presence of condensing agent, preparing 6-silylether protected benzoheterocyclic-2-amino acylated derivative, adding deprotection reagent, preparing the corresponding 6-phenolic hydroxyl substituted benzoheterocyclic-2-amino acylated derivative, which is segment E;

[0029] (3) is at least one of the following (3a)-(3c):

[0030] (3a) the fragment B prepared in step (2) is reacted with pinacol diboronic acid ester in the presence of an organic base A and a palladium catalyst to prepare an aryl boronic acid ester of the fragment B, and then reacted with the fragment A prepared in step (1) in the presence of an organic base B, a palladium catalyst and a phosphine ligand to obtain the RIPK1 kinase target inhibitor represented by formula (I); the organic base A is potassium acetate, and the organic base B is at least one of Cs2CO3 and K3PO4;

[0031] (3b) the fragment A prepared in step (1) is reacted with pinacol diboronic acid ester in the presence of an organic base A and a palladium catalyst to prepare a corresponding aryl boronic acid ester, and then reacted with the fragment C prepared in step (2) in the presence of an organic base B, a palladium catalyst and a phosphine ligand to obtain the RIPK1 kinase target inhibitor represented by formula (II);

[0032] (3c) the fragment D or the fragment E prepared in step (2) is reacted with the fragment A prepared in step (1) in the presence of an organic base B, a palladium catalyst and a phosphine ligand to obtain the RIPK1 kinase target inhibitor represented by formula (II).

[0033] Preferably, in the step (2), the synthesis route of the fragment A is as follows formula (i):

[0034]

[0035] Preferably, in the step (2), the synthesis route of the fragment B is as follows formula (ii):

[0036]

[0037] or,

[0038] Preferably, in the step (2), the synthesis route of the fragment C is as follows formula (iv):

[0039]

[0040] Preferably, in the step (2), the synthesis route of the fragment D is as follows formula (v):

[0041]

[0042] Preferably, in the step (2), the synthesis route of the fragment E is as follows formula (vi):

[0043]

[0044] Preferably, in the step (1), the base is at least one of sodium hydroxide and potassium hydroxide;

[0045] and / or, the condensing agent is one of mixture A, mixture B, the mixture A is a mixture of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole, and the molar ratio of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole is 1:2-3; the mixture B is a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, and the molar ratio of them is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride:1-hydroxybenzotriazole:triethylamine = 1:1:1;

[0046] and / or, the amine compound is at least one of (R)-1-phenylethylamine, (S)-1-phenylethylamine, (S)-1-phenylpropylamine, (S)-2-methyl-1-phenylpropylamine, (S)-1-cyclohexylethylamine, (S)-1-(4-methylphenyl)ethylamine, (S)-1-(4-methoxyphenyl)ethylamine, (S)-1-(4-nitrophenyl)ethylamine, (S)-1-(pyridin-2-yl)ethylamine, (S)-1-(pyridin-3-yl)ethylamine, (S)-1-(pyridin-4-yl)ethylamine, (S)-1-(2-fluorophenyl)ethylamine, (S)-1-(3-fluorophenyl)ethylamine, (S)-1-(4-fluorophenyl)ethylamine, aniline, benzylamine, phenethylamine, tetrahydro-2H-pyran-4-amine, 4-trifluoromethylbenzylamine, 3-trifluoromethylbenzylamine, 4-trifluoromethoxybenzylamine, 3-trifluoromethoxybenzylamine;

[0047] and / or, the molar ratio of the 5-bromoindirubin, the base is 5-bromoindirubin:base = 1:1-3;

[0048] and / or, the molar ratio of the indigo hydrate sodium salt, acetaldehyde, ammonium acetate is indigo hydrate sodium salt:acetaldehyde:ammonium acetate = 1:1-3:2-5;

[0049] and / or, the molar ratio of the quinazoline carboxylic acid sodium salt, the amine compound, the condensing agent is 1:1:2-3.

[0050] Preferably, in the steps (2a)-(2d):

[0051] the acyl chloride is at least one of n-butyryl chloride, isobutyryl chloride, n-valeryl chloride, pivaloyl chloride, cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, cyclopentylcarbonyl chloride, cyclohexylcarbonyl chloride, 3-oxocyclobutylcarbonyl chloride;

[0052] and / or, the carboxylic acid is at least one of acetic acid, propionic acid, n-butyric acid, isobutyric acid, n-valeric acid, isovaleric acid, pivalic acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic acid, benzoic acid;

[0053] and / or, the acid-binding agent is at least one of triethylamine, N,N-diisopropylethylamine;

[0054] and / or, the condensing agent is one of mixture A, mixture B, the mixture A is a mixture of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole, and the molar ratio of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole is 1:2-3; the mixture B is a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, and the molar ratio of them is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride:1-hydroxybenzotriazole:triethylamine = 1:1:1;

[0055] and / or, the nitro-reducing agent is stannous chloride;

[0056] and / or, the phenolic hydroxyl-protecting agent is a mixture of tert-butyldimethylsilyl chloride and imidazole, and the molar ratio of tert-butyldimethylsilyl chloride, imidazole is 1:1-2;

[0057] and / or, the deprotecting agent is tetrabutylammonium fluoride.

[0058] Preferably, in the step (2a), the molar ratio of the 2-amino-benzoheterocyclic ring compound, the acyl chloride, the acid-binding agent is 2-amino-benzoheterocyclic ring compound:acyl chloride:acid-binding agent = 1:1-2:1-3;

[0059] and / or, in the steps (2a), (2b), (2c), (2d), the molar ratio of the 2-amino-benzoheterocyclic ring compound, the carboxylic acid, the condensing agent is 2-amino-benzoheterocyclic ring compound:carboxylic acid:condensing agent = 1:1:1.1-1.5;

[0060] and / or, in the step (2c), the molar ratio of the 6-nitro-substituted benzoheterocyclic ring-2-amino acylated derivative, the nitro-reducing agent is 6-nitro-substituted benzoheterocyclic ring-2-amino acylated derivative:nitro-reducing agent = 1:3-6;

[0061] and / or, in the step (2d), the molar ratio of the 6-hydroxyl-substituted 2-amino-benzoheterocyclic ring, the phenolic hydroxyl-protecting agent is 1:1-3;

[0062] and / or, in the step (2d), the molar ratio of the 6-silylether-protected benzoheterocyclic ring-2-amino acylated derivative, the deprotecting agent is 6-silylether-protected benzoheterocyclic ring-2-amino acylated derivative:deprotecting agent = 1:2-5.

[0063] In the steps (3a), (3b), (3c), the palladium catalyst is at least one of Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, and the phosphine ligand is PCy3;

[0064] In the step (3a), the molar ratio of the fragment B, the bis(pinacolato)diboron, the palladium catalyst, and the organic base A prepared from the step (2) is fragment B: bis(pinacolato)diboron: palladium catalyst: organic base A = 1:2-3:0.01-0.3:2-5;

[0065] In the step (3a), the molar ratio of the aryl borate of the fragment B, the fragment A, the palladium catalyst, the phosphine ligand, and the organic base B is aryl borate of the fragment B: fragment A: palladium catalyst: phosphine ligand: organic base B = 1:1:0.01-0.2:0.01-0.2:2-5;

[0066] In the step (3b), the molar ratio of the fragment A, the bis(pinacolato)diboron, the palladium catalyst, and the organic base A prepared from the step (1) is fragment A: bis(pinacolato)diboron: palladium catalyst: organic base A = 1:2-3:0.01-0.3:2-5;

[0067] In the step (3b), the molar ratio of the aryl borate of the fragment A, the fragment C, the palladium catalyst, the phosphine ligand, and the organic base B is aryl borate of the fragment A: fragment C: palladium catalyst: phosphine ligand: organic base B = 1:1:0.01-0.2:0.01-0.2:2-5;

[0068] In the step (3c), the molar ratio of the fragment A prepared from the step (1), the fragment D or the fragment E prepared from the step (2), the palladium catalyst, the phosphine ligand, and the organic base B is fragment A: fragment D / fragment E: palladium catalyst: phosphine ligand: organic base B = 1:1:0.01-0.2:0.01-0.2:2-5.

[0069] In the step (3), the fragment B prepared from the step (2) is reacted with the bis(pinacolato)diboron in the presence of the organic base A and the palladium catalyst to prepare the aryl borate of the fragment B, and then the aryl borate of the fragment B is reacted with the fragment A prepared from the step (1) in the presence of the organic base B, the palladium catalyst, and the phosphine ligand to obtain the RIPK1 kinase target inhibitor shown in the formula (I), and specifically, the synthesis route is as follows formula (vii), formula (viii);

[0070]

[0071] Preferably, the fragment A prepared in step (1) is coupled with the fragments C, D and E prepared in step (2) to obtain the RIPK1 kinase target inhibitor of formula (II), and the synthesis route is as follows formula (ix) :

[0072]

[0073] The present application provides a pharmaceutical composition, wherein the pharmaceutical composition contains the RIPK1 kinase target inhibitor.

[0074] Preferably, the pharmaceutical composition is prepared into any one of injection, solid oral preparation and sustained-release preparation.

[0075] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0076] The present application also provides the use of the RIPK1 kinase target inhibitor or the pharmaceutical composition in the preparation of a medicament for treating neurodegenerative diseases, inflammation, autoimmune diseases and sepsis.

[0077] Preferably, the inflammation medicament comprises an anti-acute colitis medicament.

[0078] The present application provides a medicament containing the RIPK1 kinase target inhibitor or the pharmaceutical composition.

[0079] Compared with the prior art, the present application has the following beneficial effects: the present application obtains quinazoline amide derivatives (fragment A) and different benzopentacyclic ring-2-amide derivatives (fragments B, C, D and E) by chemical synthesis, and then couples them to obtain the target product of formula (I) or formula (II). These conjugates are derivatives of the backbone and have good RIPK1 inhibitory effect, good anti-programmed necrosis effect, anti-acute ischemic stroke effect and anti-acute colitis effect, and are expected to have good application prospect in the field of neurodegenerative diseases, inflammation and autoimmune diseases. BRIEF DESCRIPTION OF DRAWINGS

[0080] Figure 1 Figure 1 is a graph showing the effect of compound 1-23 on the viability of HT-29 cells, note: compared with the blank group, *p<0.05, **p<0.01, ***p<0.001, data is represented as Mean±SEM;

[0081] Figure 2 Figure 2 is a graph showing the protective effect of compound 2 on TSZ-induced programmed necrosis of HT-29, U937, L929 and HT-22 (A-D) cells; note: data is represented as Mean±SEM.

[0082] Figure 3 Figure 2 is a graph showing the dose-dependent protection of compound 2 against programmed necrosis of HT-29 (A), U937 (B), L929 (C), HT-22 (D) cells induced by TSZ; Note: *p<0.05, **p<0.01, ***p<0.001, data expressed as Mean ± SEM;

[0083] Figure 4 Figure 3 is a microscope graph showing the protection of compound 2 against programmed necrosis of four kinds of cells;

[0084] Figure 5 Figure 4 is a fluorescence staining graph showing the protection of compound 2 against programmed necrosis of L929 cells;

[0085] Figure 6 Figure 5 is a fluorescence staining graph showing the protection of compound 2 against programmed necrosis of HT-29 cells;

[0086] Figure 7 Figure 6 is a graph showing the Zea Longa (A) and MNSS (B) scores of compound 2 in the rat MCAO model; Note: *p<0.05, **p<0.01, ***p<0.001 compared with the model group; n=9-12, data expressed as Mean ± SEM;

[0087] Figure 8 Figure 7 is a graph showing the TTC staining (A) and the percentage of cerebral infarction volume of each group of animals (B); Note: **p<0.01, ***p<0.001 compared with the model group; n=9-12, data expressed as Mean ± SEM;

[0088] Figure 9 Figure 8 is a graph showing the changes in serum SOD, MDA, TNF-α and IL-1β contents after 24 h of reperfusion of the rat MCAO;

[0089] Figure 10 Figure 9 is a graph showing the oral and intravenous pharmacokinetic-time curves of compound 2;

[0090] Figure 11 Figure 10 is a graph showing the pharmacokinetic-time curves of compound 2; 1 H NMR spectrum. DETAILED DESCRIPTION

[0091] For better illustrating the purpose, technical scheme and advantages of the present application, the present application will be further described below in conjunction with the drawings and specific examples. The purpose is to understand the content of the present application in detail, rather than to limit the present application. All other examples obtained by the ordinary skilled in the art without making creative efforts fall within the protection scope of the present application. The experimental reagents and instruments designed in the implementation and comparative examples of the present application are all common reagents and instruments unless specifically stated, and can be obtained from commercial channels. In the implementation and comparative examples, the experimental methods used are all conventional methods unless specifically stated; and the raw materials used in parallel experiments are the same batch of raw materials unless specifically stated, and all the raw materials used in the present application are commercially available, and can be purchased from any one of Aldrich, Macron Fine Chemicals or Avocado.

[0092] The preparation methods of 51 kinds of RIPK1 kinase target inhibitors are shown in Examples 1-51, and the structural formulas of the 51 kinds of RIPK1 kinase target inhibitors are shown in Formula 1-Formula 51. The following examples are only a part of the examples of the present application, and should not be used to limit the protection scope of the present application. The target products can also be prepared by using other conditions in the preparation method of the pyridine amide compounds described in the foregoing of the present application, but due to the limitation of the space, they will not be listed one by one.

[0093]

[0094]

[0095]

[0096] Example 1: Synthesis of (R)-6-(2-isobutyramidyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazoline-4-carboxamide

[0097] (1) Synthesis of 6-bromo-2-methylquinazoline-4-carboxylate sodium:

[0098] Put 5-bromo isatin (45.2 g, 200 mmol) into a beaker to stir the suspension with 2000 mL of water, then add NaOH (8.8 g, 220 mmol), stir for 3 h to obtain the sodium salt of isatin hydrolysis product, slowly drop 2N HCl solution to adjust pH = 7. Spin dry the aqueous solution, dry in vacuum to obtain 52.0 g of 2-(2-amino-5-bromophenyl)-2-oxoacetic acid sodium, yield: 97%.

[0099] Into a 1000 mL round bottom flask, was placed 6-bromo-2-methylquinazoline-4- carboxylate sodium salt (51.9 g, 195 mmol), ammonium acetate (30.1 g, 390 mmol), ethanol (500 mL), acetaldehyde-tetrahydrofuran solution (9.0 g, 205 mmol), and the reaction mixture was heated to 90 °C under a balloon protection. After 24 h, the reaction mixture was concentrated to half of the volume, and the resulting mixture was allowed to stand at -18 °C for 1 h. The precipitate was collected by filtration, and the filter cake was washed with ethanol and ethyl acetate, and dried to give 6-bromo-2-methylquinazoline-4-carboxylate sodium salt (22.7 g, 40% yield) as a brown powder. 1 HNMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.98 (dd, J = 8.9, 2.3 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 2.69 (s, 3H).

[0100] (2) Synthesis of (R)-6-bromo-2-methyl-N-(l-phenylethyl)quinazoline-4- carboxamide:

[0101] Into a 100 mL round bottom flask, was placed 6-bromo-2-methylquinazoline-4- carboxylate sodium salt (578 mg, 2.0 mmol), small molecule aryl amine (2.2 mmol), dichloromethane (20 mL), and N-methylimidazole (411 mg, 5.0 mmol), and the reaction mixture was mixed well. N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (729.5 mg, 2.6 mmol) was added slowly under an ice water bath. After the addition was completed, the ice water bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for another 2 h. The reaction was monitored by TLC, and the reaction was completed. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated. The residue was purified by column chromatography to give (R)-6-bromo-2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide (56% yield) as an off-white powder. 1 H NMR (400 MHz, Chloroform-d) δ 9.73 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H), 7.94 (dd, J = 9.0, 2.2 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.46 - 7.43 (m, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.35 - 7.26 (m, 1H), 5.33 (p, J = 7.1 Hz, 1H), 2.89 (s, 3H), 1.68 (d, J = 6.9 Hz, 3H).

[0102] (3) Synthesis of N-(7-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)isobutyramide:

[0103] N-(7-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)isobutyramide (707.8 mg, 2.50 mmol), bis(pinacolato)diboron (952.3 mg, 3.75 mmol), KOAc (736.1 mg, 7.50 mmol) were taken in a 100 mL completely dried round bottom flask, Pd(dppf)Cl2(91.5 mg, 0.13 mmol) and anhydrous dioxane (30 mL) were added successively; the flask and the spherical condenser were flushed with argon gas using a three-way valve and a balloon. The reaction was carried out at 90 °C for 12 h. After completion of the reaction, TLC monitoring, silica gel was added and the solvent was evaporated. Column chromatography was carried out directly to obtain N-(7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- [l,2,4]triazolo[l,5-a]pyridin-2-yl)isobutyramide as a light brown powder in 68% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.29 (dd, J = 7.1, 2.1 Hz, 1H), 2.52 (s, 1H), 1.10 (d, J = 6.8 Hz, 6H).

[0104] (4) Synthesis of N-(7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- [l,2,4]triazolo[l,5-a]pyridin-2-yl)isobutyramide:

[0105] N-(7-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)isobutyramide (707.8 mg, 2.50 mmol), bis(pinacolato)diboron (952.3 mg, 3.75 mmol), KOAc (736.1 mg, 7.50 mmol) were taken in a 100 mL completely dried round bottom flask, Pd(dppf)Cl2(91.5 mg, 0.13 mmol) and anhydrous dioxane (30 mL) were added successively; the flask and the spherical condenser were flushed with argon gas using a three-way valve and a balloon. The reaction was carried out at 90 °C for 12 h. After completion of the reaction, TLC monitoring, silica gel was added and the solvent was evaporated. Column chromatography was carried out directly to obtain N-(7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- [l,2,4]triazolo[l,5-a]pyridin-2-yl)isobutyramide as a light brown powder in 68% yield.

[0106] (5) (R)-6-(2-isobutyrylamido-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-2-methyl-N-(l- phenylethyl)quinazoline

[0107] Synthesis of 4-carboxamide:

[0108] (R)-6-bromo-2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide (370.3 mg, 1.0 mmol), N-(7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl)isobutyramide (330.2 mg, 1.0 mmol), Pd(dppf)Cl2CH2Cl2(81.7 mg, 0.1 mmol), PCy3(14.0 mg, 0.05 mmol), Cs2CO3(814.6 mg, 2.50 mmol) and anhydrous dioxane (30 mL) were added into a 100 mL round bottom flask successively, which was purged with argon gas by a three-way valve and a balloon. After the flask and the balloon were purged with argon gas, the reaction was refluxed at 110 °C for 3 h. After the reaction was monitored by TLC, the solution was directly concentrated in the original flask and purified by column chromatography to give (R)-6-(2-isobutyramido-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide.

[0109] The product prepared in this example was a light yellow powder, and its structural formula was shown as Formula 1 above.

[0110] Yield: 75%, melting point: >220 °C, purity: 97.9%.

[0111] Test method: The yield was calculated by weighing the mass of the target compound after purification in ChemDraw software. The melting point of the target compound was tested in triplicate on a full-automatic melting point instrument (OptiMelt MPA100, Stanford Research Systems, USA). The purity of the target compound was tested using UPLC. The chromatographic conditions: the compound purity was determined in an ultra-high performance liquid chromatograph equipped with an Agilent C8 column (2.1 mm x 50 mm, 1.8 μm), using a diode array (DAD) detector. The chromatographic conditions were as follows: initial MeOH / H2O = 70 / 30, gradient elution, MeOH ratio gradually increased to 100% within 10 min; the water phase contained 10 mM NH4OAc, and the pH was adjusted to 9 with ammonia; the flow rate was 1.0 mL / min; the retention time was 25 min; the chromatographic temperature was set to 30 °C; and the sample injection amount was 10 μL each time.

[0112] The subsequent test methods were the same, and were not described here.

[0113] 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.47 (d, J = 8.2 Hz, 1H), 8.96 (d, J = 7.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.50 (dd, J = 8.9, 2.2 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.39 (dt, J = 7.1, 5.1 Hz, 3H), 7.30 (t, J = 7.3 Hz, 1H), 5.30 (p, J = 7.1 Hz, 1H), 2.87 - 2.49 (m, 4H), 1.56 (d, J = 7.0 Hz, 3H), 1.13 (d, J = 6.8 Hz, 6H). HRMS (m / z): calculated for C 28 H 28 O2N7[M+H] + 494.22990, found 494.23013.

[0114] Example 2: Synthesis of (S)-6-(2-(cyclopropylcarboxamide)-[1,2,4]triazolo[1,5- a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazoline-4-carboxamide

[0115] The starting material is cyclopropylcarboxylic acid chloride, (S)-1-phenylethylamine, and the rest of the steps (1)-(5) are the same as (1)-(5) of Example 1.

[0116] The product prepared in this example is a white powder, and the structural formula is shown as Formula 2 above.

[0117] Physical and spectral data: yield: 87%, melting point: >278°C, purity: 96.9%. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 7.0 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.49 (dd, J = 8.9, 2.2 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 8.01 (s, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.45 - 7.34 (m, 3H), 7.30 (t, J = 7.3 Hz, 1H), 5.31 (p, J = 7.2 Hz, 1H), 2.87 (s, 3H), 2.10 (s, 1H), 1.56 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 5.4 Hz, 4H). HRMS (m / z): calculated for C28 H 26 O2N7[M+H] + 492.21425, found 492.21448.

[0118] Taking compound 2 prepared in this embodiment as an example, for 1 The H NMR spectrum is explained.

[0119] Compound 2 1 H spectrum Figure 11 As shown, the d-peak integrals at δ = 11.12 and 8.95 in the low-field region are each 1, corresponding to the two protons on the amide bond at the triazolidine pyridylation and quinazoline amide, respectively; the interval δ = 9.46-7.28 corresponds to 11 protons in the aromatic region; the p-peak integral at δ = 5.31 is 1, corresponding to the proton on the chiral carbon; the s-peak integral at δ = 2.87 is 3, corresponding to the methyl group at position 2 of the quinazoline ring; the s-peak integral at δ = 2.10 is 1, corresponding to the proton at the acyl ortho position of the cyclopropyl group; the d-peak integral at δ = 1.56 is 3, corresponding to the methyl group at the α-position of the chiral carbon; and the d-peak integral at δ = 0.85 is 4, corresponding to the two methylene groups on the cyclopropyl group.

[0120] Example 3: Synthesis of (R)-6-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methyl-N-(1-phenylethyl)quinazolin-4-carboxamide

[0121] The raw materials are cyclopropylformyl chloride and (R)-1-phenylethylamine, reacted in equimolar amounts, and the remaining steps (1)-(5) are the same as (1)-(5) in Example 1.

[0122] The product obtained in this embodiment is a white powder with the structural formula shown in Formula 3 above.

[0123] Physicochemical and spectroscopic data: Yield: 85%, Melting point: >275℃, Purity: 97.6%. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 7.1 Hz, 1H), 8.71 (s, 1H), 8.49 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 8.01 (s, 1H), 7.50 (d, J = 7.5 Hz, 2H), 7.45 - 7.35 (m, 3H), 7.30 (t, J = 7.3 Hz, 1H), 5.30 (p, J = 7.2 Hz, 1H), 2.87 (s, 3H), 2.10 (s, 1H), 1.56 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.2 Hz, 4H). HRMS (m / z): calcd for C 28 H 26 O2N7[M+H] + 492.21425, found 492.21433.

[0124] Example 4: Synthesis of (S)-6-(2-isobutyramidino-[l,2,4]triazolyl[l,5-a]pyridin-7-yl)-2- methyl-N-(l-phenylethyl)quinazoline-4-carboxamide

[0125] The starting material was isobutyryl chloride, (S)-l-phenylethylamine, and the reaction was carried out in equimolar amounts, and the remaining steps (1) - (5) were the same as (1) - (5) of Example 1.

[0126] The product prepared in this example was a white powder, and the structural formula is shown in Formula 4 above.

[0127] Physical and spectral data: white powder, yield: 78%, melting point: 241.3 - 242.6 °C, purity: 97.2%. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 7.1 Hz, 1H), 8.71 (s, 1H), 8.49 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 8.01 (s, 1H), 7.50 (d, J = 7.5 Hz, 2H), 7.45 - 7.35 (m, 3H), 7.30 (t, J = 7.3 Hz, 1H), 5.30 (p, J = 7.2 Hz, 1H), 2.87 (s, 3H), 2.10 (s, 1H), 1.56 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.2 Hz, 4H). HRMS (m / z): calcd for C 28 H 28O2N7[M+H] + 494.22990, found 494.23006.

[0128] Example 5: Synthesis of (S)-2-methyl-N-(l-phenylethyl)-6-(2-pivalamido- [l,2,4]triazolo[l,5-a]pyridin-7-yl)quinazoline-4-carboxamide

[0129] The starting material is pivaloyl chloride, (S)-l-phenylethylamine, and the reaction is carried out in equimolar amounts. The remaining steps (1)-(5) are the same as (1)-(5) in Example 1.

[0130] The product of this example is a white powder and has the structural formula shown above as Formula 5.

[0131] Physical and spectral data: Yield: 85%, Melting point: 251.1-251.9 °C, Purity: 99.5%. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.44 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 7.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.48 (dd, J = 8.9, 2.1 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 8.00 (s, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.44 - 7.35 (m, 3H), 7.30 (t, J = 7.3 Hz, 1H), 5.31 (p, J = 7.2 Hz, 1H), 2.87 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.27 (s, 9H). HRMS (m / z): calcd for C 29 H 30 O2N7[M+H] + 508.24555, found 508.24574.

[0132] Example 6: Synthesis of (S)-2-methyl-6-(2-pentanamido-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-N-(l-phenylethyl)quinazoline-4-carboxamide

[0133] The starting material is pivaloyl chloride, (S)-l-phenylethylamine, and the reaction is carried out in equimolar amounts. The remaining steps (1)-(5) are the same as (1)-(5) in Example 1.

[0134] The product of this example is a white powder and has the structural formula shown above as Formula 6.

[0135] Physical and spectral data: Yield: 64%, Melting point: >250 °C, Purity: 98.6%.1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 7.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.48 (dd, J = 8.9, 2.1 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.51 (d, J = 7.4 Hz, 2H), 7.45 - 7.34 (m, 3H), 7.30 (t, J = 7.3 Hz, 1H), 5.31 (p, J = 7.2 Hz, 1H), 2.87 (s, 3H), 2.48 (s, 2H), 1.66 - 1.53 (m, 5H), 1.35 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). HRMS (m / z): calcd for C 29 H 30 O2N7[M+H] + 508.24555, found 508.24562.

[0136] Example 7: Synthesis of (S)-6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(l-(pyridin-2-yl)ethyl)quinazoline-4-carboxamide

[0137] The starting material is cyclopropylcarboxylic acid chloride, (S)-l-(2-pyridinyl)ethylamine, and the rest of the steps (1)-(5) are the same as (1)-(5) of Example 1.

[0138] The product prepared in this example is a white powder, and its structural formula is shown as Formula 7 above.

[0139] Physical and spectral data: yield: 51%, melting point: >262°C, purity: 97.4%. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.51 (d, J = 7.7 Hz, 1H), 9.09 - 8.92 (m, 2H), 8.60 (d, J = 4.9 Hz, 1H), 8.51 (d, J = 8.7 Hz, 1H), 8.17 - 8.02 (m, 2H), 7.84 (t, J = 7.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.39 - 7.27 (m, 1H), 5.33 (p, J = 7.1 Hz, 1H), 2.88 (s, 3H), 2.10 (s, 1H), 1.57 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 5.6 Hz, 4H). HRMS (m / z): calcd for C 27 H 25 O2N8[M+H] + 493.20950, found 493.20966.

[0140] Example 8: Synthesis of (S)-6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(l-(pyridin-3-yl)ethyl)quinazoline-4-carboxamide

[0141] The starting material is cyclopropylcarboxylic acid chloride, (S)-l-(3- pyridinyl)ethylamine, and the rest of the steps (1)-(5) are the same as (1)-(5) of Example 1.

[0142] The product prepared in this example is a white powder, and the structural formula is shown as Formula 8 above.

[0143] Physical and spectral data: yield: 48%, melting point: >272°C, purity: 98.1%. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.51 (d, J = 7.7 Hz, 1H), 9.09 - 8.92 (m, 2H), 8.60 (d, J = 4.9 Hz, 1H), 8.51 (d, J = 8.7 Hz, 1H), 8.17 - 8.02 (m, 2H), 7.84 (t, J = 7.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.39 - 7.27 (m, 1H), 5.33 (p, J = 7.1 Hz, 1H), 2.88 (s, 3H), 2.10 (s, 1H), 1.57 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 5.6 Hz, 4H). HRMS (m / z): calcd for C 27 H 25O2N8[M+H] + 493.20950, found 493.20965.

[0144] Example 9: Synthesis of (S)-6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(l-(pyridin-4-yl)ethyl)quinazoline-4-carboxamide

[0145] The starting material was cyclopropylcarboxylic acid chloride, (S)-l-(4- pyridyl)ethylamine, and the reaction was carried out in equimolar amounts, and the remaining steps (1)-(5) were the same as (1)-(5) in Example 1.

[0146] The product prepared in this example was a white powder, and the structural formula is shown in Formula 9 above.

[0147] Physical and spectral data: yield: 53%, melting point: >249°C, purity: 99.3%. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.58 (d, J = 7.8 Hz, 1H), 8.95 (d, J = 7.1 Hz, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 6.0 Hz, 2H), 8.51 (dd, J = 9.0, 2.1 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.05 (s, 1H), 7.49 (d, J = 6.1 Hz, 2H), 7.43 (dd, J = 7.1, 2.0 Hz, 1H), 5.29 (p, J = 7.2 Hz, 1H), 2.89 (s, 3H), 2.09 (s, 1H), 1.57 (d, J = 7.1 Hz, 3H), 0.85 (d, J = 6.1 Hz, 4H). HRMS (m / z): calcd for C 27 H 25 O2N8[M+H] + 493.20950, found 493.20964.

[0148] Example 10: Synthesis of (S)-6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-N-(l-(3-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0149] The starting material was cyclopropylcarboxylic acid chloride, (S)-l-(3- fluorophenyl)ethylamine, and the reaction was carried out in equimolar amounts, and the remaining steps (1)-(5) were the same as (1)-(5) in Example 1.

[0150] The product prepared in this example was a light yellow powder, and the structural formula is shown in Formula 10 above.

[0151] Physical and spectral data: Yield: 68%, Melting point: >266°C, Purity: 97.2%. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.50 (d, J = 8.2 Hz, 1H), 8.92 (d, J = 7.1 Hz, 1H), 8.74 (s, 1H), 8.47 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.50 - 7.30 (m, 4H), 7.13 (t, J = 8.5 Hz, 1H), 5.33 (p, J = 7.2 Hz, 1H), 2.88 (s, 3H), 2.10 (s, 1H), 1.57 (d, J = 7.1 Hz, 3H), 0.87 (d, J = 4.3 Hz, 4H). HRMS (m / z): calcd for C 28 H 25 O2N7F[M+H] + 510.20483, found 510.20498.

[0152] Example 11: Synthesis of (S)-6-(2-(cyclopentylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide

[0153] The starting material is cyclopentylcarboxylic acid chloride, (S)-l-phenylethylamine, and the rest of the steps (1)-(5) are the same as (1)-(5) in Example 1.

[0154] The product prepared in this example is a white powder, and its structural formula is shown as Formula 11 above.

[0155] Physical and spectral data: White powder, yield: 50%, melting point: >271°C, purity: 98.9%. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.93 (d, J = 7.1 Hz, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.45 (dd, J = 8.9, 2.2 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.37 - 7.26 (m, 2H), 5.32 (p, J = 7.2 Hz, 1H), 3.03 (s, 1H), 2.86 (s, 3H), 1.97 - 1.84 (m, 2H), 1.81 - 1.53 (m, 9H). HRMS (m / z): calculated for C 30 H 30 O2N7[M+H] + 520.24555, found 520.24572.

[0156] Example 12: Synthesis of (S)-6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-N-(l-(2-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0157] The starting material is cyclopropylcarboxamide chloride, (S)-l-(2- fluorophenyl)ethylamine, and the rest of the steps (1)-(5) are the same as (1)-(5) of Example 1.

[0158] The product prepared in this example is a light yellow powder, and its structural formula is shown as Formula 12 above.

[0159] Physical and spectral data: light yellow powder, yield: 56%, melting point: >272°C, purity: 92.7%. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.53 (d, J = 7.9 Hz, 1H), 8.97 (d, J = 7.0 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.51 (dd, J = 8.9, 2.2 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 8.06 - 8.00 (m, 1H), 7.64 - 7.53 (m, 1H), 7.44 - 7.33 (m, 2H), 7.29 - 7.19 (m, 2H), 5.53 (p, J = 7.2 Hz, 1H), 2.88 (s, 3H), 2.09 (s, 1H), 1.56 (d, J = 7.1 Hz, 3H), 0.86 (d, J = 5.8 Hz, 4H). HRMS (m / z): calculated for C 28 H 25 O2N7F[M+H] + 510.20483, found 510.20496.

[0160] Example 13: Synthesis of (S)-6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-N-(l-(4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0161] The starting material was cyclopropylcarbonyl chloride, (S)-l-(4-fluorophenyl)ethylamine, and the reaction was carried out in equimolar amount. The remaining steps (1) - (5) were the same as (1) - (5) in Example 1.

[0162] The product prepared in this example was a light yellow powder, and its structural formula is shown in Formula 13 above.

[0163] Physical and spectral data: yield: 58%, melting point: >267°C, purity: 98.8%. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.53 (d, J = 7.9 Hz, 1H), 8.97 (d, J = 7.0 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.51 (dd, J = 8.9, 2.2 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 8.06 - 8.00 (m, 1H), 7.64 - 7.53 (m, 1H), 7.44 - 7.33 (m, 2H), 7.29 - 7.19 (m, 2H), 5.53 (p, J = 7.2 Hz, 1H), 2.88 (s, 3H), 2.09 (s, 1H), 1.56 (d, J = 7.1 Hz, 3H), 0.86 (d, J = 5.8 Hz, 4H). HRMS (m / z): calculated for C 28 H 25O2N7[M+H] + 510.20483, found 510.20499.

[0164] Example 14: Synthesis of N-benzyl-6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methylquinazoline-4-carboxamide

[0165] The starting material is cyclopropylcarboxamide chloride, benzylamine, and the reaction is carried out in equimolar amounts, and the remaining steps (1)-(5) are the same as (1)-(5) in Example 1.

[0166] The product prepared in this example is a white powder, and the structural formula is shown as Formula 14 above.

[0167] Physical and spectral data: yield: 43%, melting point: >295°C, purity: 90.6%. 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.65 (t, J = 6.2 Hz, 1H), 9.07 (d, J = 2.1 Hz, 1H), 8.96 (d, J = 7.1 Hz, 1H), 8.51 (dd, J = 8.9, 2.2 Hz, 1H), 8.18 - 8.03 (m, 2H), 7.49 - 7.42 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 2.87 (s, 3H), 2.09 (s, 1H), 0.85 (d, J = 6.2 Hz, 4H). HRMS (m / z): calcd for C 27 H 24 O2N7[M+H] + 478.19860, found 478.19875.

[0168] Example 15: Synthesis of 6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-2- methyl-N-(4-(trifluoromethyl)benzyl)quinazoline-4-carboxamide

[0169] The starting material is cyclopropylcarboxamide chloride, 4-trifluoromethylbenzylamine, and the reaction is carried out in equimolar amounts, and the remaining steps (1)-(5) are the same as (1)-(5) in Example 1.

[0170] The product prepared in this example is a white powder, and the structural formula is shown as Formula 15 above.

[0171] Physical and spectral data: yield: 47%, melting point: >314°C, purity: 93.0%. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.78 (s, 1H), 9.19 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.53 (d, J = 8.9 Hz, 1H), 8.21 - 8.00 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.3 Hz, 1H), 4.70 (d, J = 6.4 Hz, 2H), 2.89 (s, 3H), 2.09 (s, 1H), 0.85 (d, J = 6.3 Hz, 4H). HRMS (m / z): calculated for C 28 H 23 O2N7F3[M+H] + 546.18598, found 546.18617.

[0172] Example 16: Synthesis of (S)-6-(2-(cyclohexylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide

[0173] The starting material was cyclohexylcarboxylic acid chloride, (S)-l- phenylethylamine, and the rest of the steps (1)-(5) were the same as (1)-(5) of Example 1.

[0174] The product prepared in this example was a white powder, and the structural formula is shown in Formula 16 above.

[0175] Physical and spectral data: yield: 58%, melting point: 278.2-278.8°C, purity: 97.0%. 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.78 (s, 1H), 9.19 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.53 (d, J = 8.9 Hz, 1H), 8.21 - 8.00 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.3 Hz, 1H), 4.70 (d, J = 6.4 Hz, 2H), 2.89 (s, 3H), 2.09 (s, 1H), 0.85 (d, J = 6.3 Hz, 4H). HRMS (m / z): calculated for C31 H 32 O2N7[M+H] + 534.26120, found 534.26132.

[0176] Example 17: Synthesis of (S)-6-(2-butylamino-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-2- methyl-N-(l-phenylethyl)quinazoline-4-carboxamide

[0177] The starting material is n-butyryl chloride, (S)-l-phenylethylamine, and the reaction is carried out in equimolar amounts, and the remaining steps (1)-(5) are the same as (1)-(5) in Example 1.

[0178] The product prepared in this example is a white powder, and the structural formula is shown as Formula 17 above.

[0179] Physical and spectral data: yield: 52%, melting point: > 259°C, purity: 98.8%. 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 7.1 Hz, 1H), 8.71 (s, 1H), 8.48 (d, J = 9.0 Hz, 1H), 8.19 - 7.91 (m, 2H), 7.60 - 7.25 (m, 6H), 5.50 - 5.14 (m, 1H), 2.86 (s, 3H), 2.46 (s, 2H), 1.76 - 1.49 (m, 5H), 0.94 (t, J = 7.3 Hz, 3H). HRMS (m / z): calcd for C 28 H 28 O2N7[M+H] + 494.22990, found 494.22997.

[0180] Example 18: Synthesis of 6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-2- methyl-N-(4-(trifluoromethoxy)benzyl)quinazoline-4-carboxamide

[0181] The starting material is cyclopropylcarboxamide, 4-trifluoromethoxybenzylamine, and the reaction is carried out in equimolar amounts, and the remaining steps (1)-(5) are the same as (1)-(5) in Example 1.

[0182] The product prepared in this example is a white powder, and the structural formula is shown as Formula 18 above.

[0183] Physical and spectral data: yield: 45%, melting point: > 305°C, purity: 95.9%. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.70 (d, J = 7.6 Hz, 1H), 9.18 (s, 1H), 8.96 (s, 1H), 8.52 (s, 1H), 8.11 (s, 2H), 7.60 - 7.46 (m, 3H), 7.37 (s, 2H), 4.63 (s, 2H), 2.88 (s, 3H), 2.09 (s, 1H), 0.85 (s, 4H). HRMS (m / z): calcd for C 28 H 23 O3N7F3[M+H] + 562.18090, found 562.18108.

[0184] Example 19: Synthesis of (S)-6-(2-(cyclobutanecarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide

[0185] The starting material was cyclobutanecarbonyl chloride, (S)-l-phenylethylamine, and the reaction was carried out in equimolar amounts, and the remaining steps (1) - (5) were the same as (1) - (5) of Example 1.

[0186] The product prepared in this example was a white powder, and the structural formula is shown in Formula 19 above.

[0187] Physical and spectral data: yield: 51%, melting point: 257.2 - 257.9 °C, purity: 98.8%. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.46 (d, J = 8.1 Hz, 1H), 9.07 - 8.90 (m, 1H), 8.71 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.20 - 7.96 (m, 2H), 7.61 - 7.25 (m, 6H), 5.31 (s, 1H), 3.47 (s, 1H), 2.87 (s, 3H), 2.31 - 2.09 (m, 4H), 2.02 - 1.89 (m, 1H), 1.89 - 1.76 (m, 1H), 1.68 - 1.45 (m, 3H). HRMS (m / z): calcd for C 29 H 28 O2N7[M+H] + 506.22990, found 506.23007.

[0188] Example 20: Synthesis of 6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(3-(trifluoromethyl)benzyl)quinazoline-4-carboxamide

[0189] The starting material was cyclopropylcarboxamide chloride, 3- trifluoromethylbenzylamine, and the reaction was carried out in equimolar amounts, and the remaining steps (1)-(5) were the same as (1)-(5) of Example 1.

[0190] The product prepared in this example was a white powder, and the structural formula is shown above as Formula 20.

[0191] Physical and spectral data: yield: 46%, melting point: >299°C, purity: 94.0%. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.75 (s, 1H), 9.11 (s, 1H), 8.96 (d, J = 7.1 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.20-8.00 (m, 2H), 7.82-7.72 (m, 2H), 7.71-7.57 (m, 2H), 7.47 (d, J = 7.2 Hz, 1H), 4.70 (d, J = 6.2 Hz, 2H), 2.88 (s, 3H), 2.09 (s, 1H), 0.85 (d, J = 6.0 Hz, 4H). HRMS (m / z): calcd for C 28 H 23 O2N7F3[M+H] + 546.18598, found 546.18608.

[0192] Example 21: Synthesis of 6-(2-(cyclopropylcarboxamide)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-methyl-N-(3-(trifluoromethoxy)benzyl)quinazoline-4-carboxamide

[0193] The starting material was cyclopropylcarboxamide chloride, 3- trifluoromethoxybenzylamine, and the reaction was carried out in equimolar amounts, and the remaining steps (1)-(5) were the same as (1)-(5) of Example 1.

[0194] The product prepared in this example was a white powder, and the structural formula is shown above as Formula 21.

[0195] Physical and spectral data: yield: 47%, melting point: >289°C, purity: 96.0%. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.72 (s, 1H), 9.21 - 8.87 (m, 2H), 8.52 (s, 1H), 8.24 - 7.97 (m, 2H), 7.57 - 7.34 (m, 4H), 7.28 (s, 1H), 4.65 (s, 2H), 2.87 (s, 3H), 2.07 (s, 1H), 0.85 (s, 4H). HRMS (m / z): calcd for C 28 H 23 O3N7F3[M+H] + 562.18090, found 562.18096.

[0196] Example 22: Synthesis of (S)-2-methyl-6-(2-(3-oxocyclobutane-1-carboxamido)- [1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-phenylethyl)quinazoline-4-carboxamide

[0197] The starting material was 3-oxocyclobutylcarbonyl chloride, (S)-1- phenylethylamine, and the reaction was carried out in equimolar amount. The remaining steps (1)-(5) were the same as (1)-(5) in Example 1.

[0198] The product prepared in this example was a light yellow powder, and its structural formula is shown as Formula 22 above.

[0199] Physical and spectral data: yield: 54%, melting point: >210 °C. 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.46 (d, J = 8.3 Hz, 1H), 8.97 (t, J = 6.5 Hz, 1H), 8.72 (s, 1H), 8.49 (d, J = 9.0 Hz, 1H), 8.06 (m, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.39 (d, J = 7.2 Hz, 3H), 7.30 (t, J = 7.0 Hz, 1H), 5.30 (q, J = 7.2 Hz, 1H), 3.57 (s, 1H), 3.13 - 3.02 (m, 2H), 2.87 (s, 3H), 2.44 - 2.21 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H). HRMS (m / z): calcd for C 29 H 24 O3N7[M-H] - 518.19461, found518.19502.

[0200] Example 23: Synthesis of (S)-N-(l-(4-fluorophenyl)ethyl)-2-methyl-6-(2-(3- oxocyclobutane-l-carboxamido)-[l,2,4]triazolo[l,5-a]pyridin-7-yl)quinazoline-4- carboxamide

[0201] The starting material was 3-oxocyclobutylcarbonyl chloride, (S)-l-(4- fluorophenyl)ethylamine, and the reaction was carried out in equimolar amounts. The remaining steps (1)-(5) were the same as (1)-(5) in Example 1.

[0202] The product prepared in this example was a light yellow powder, and the structural formula is shown as Formula 23 above.

[0203] Physical and spectral data: yield: 56%, melting point: >257 °C. 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.46 (d, J = 8.2 Hz, 1H), 8.96 (t, J = 6.5 Hz, 1H), 8.79 (s, 1H), 8.50 (d, J = 10.3 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 6.5 Hz, 1H), 7.54 (dd, J = 8.4, 5.6 Hz, 2H), 7.41 (td, J = 7.3, 2.0 Hz, 1H), 7.21 (t, J = 8.8 Hz, 2H), 5.31 (p, J = 7.2 Hz, 1H), 3.57 (s, 1H), 3.33 (s, 1H), 3.08 (m, 2H), 2.87 (s, 3H), 2.33 (m, 2H), 1.56 (d, J = 7.0 Hz, 3H). HRMS (m / z): calcd for C 29 H 23 O3N7F [M-H] - 536.18519, found 536.18557.

[0204] Example 24: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)- 2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide

[0205] The starting material was cyclopropanecarboxylic acid, 2-amino-6-bromobenzothiazole, (S)-l-phenylethylamine, and the reaction was carried out in equimolar amounts. The remaining steps (1)-(5) were the same as (1)-(5) in Example 1. Among them, step (3) was modified as follows:

[0206] (3) Synthesis of N-(6-bromobenzo[d]thiazol-2-yl)cyclopropanecarboxamide:

[0207] Into a 100 mL round bottom flask, 2-amino-6-bromobenzothiazole (2.29 g, 10.0 mmol), small molecule carboxylic acid (11.0 mmol), dichloromethane (50 mL) and N-methylimidazole (2.05 g, 25.0 mmol) were added sequentially, mixed well, N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (3.65 g, 13 mmol) was added slowly under ice water bath, after the drop was completed, the ice bath was removed, and the temperature was raised to room temperature, and reacted for another 2 h. The reaction was stopped after TLC monitoring. The reaction liquid was extracted with ethyl acetate, the organic layer was dried and rotary evaporated, and purified by column chromatography to obtain compound N-(6-bromobenzo[d]thiazol-2-yl)cyclopropanecarboxamide, light pink powder, yield: 85%.

[0208] The product prepared in this example was a white powder, and the structural formula was shown as formula 24.

[0209] Physical and spectral data: yield: 76%. 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.44 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.39 (dd, J = 8.9, 2.1 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.4, 1.9 Hz, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 5.30 (p, J = 7.2 Hz, 1H), 2.85 (s, 3H), 2.04 (p, J = 6.3 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H), 0.99 (d, J = 5.3 Hz, 4H).

[0210] Example 25: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0211] The starting material was cyclopropane carboxylic acid, (S)-1-(4-fluorophenyl) ethylamine, and the reaction was carried out in equimolar amount, and the remaining steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) in Example 1, and step (3) was the same as modified (3) in Example 24.

[0212] The product prepared in this example was a white powder, and the structural formula was shown as formula 25.

[0213] Physical and spectral data: yield: 75%. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.44 (s, 1H), 8.57 (s, 1H), 8.36 (d, J = 18.3 Hz, 2H), 8.06 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.59 - 7.42 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 5.46 - 5.07 (m, 1H), 2.85 (s, 3H), 2.02 (s, 1H), 1.54 (s, 3H), 0.96 (d, J = 19.2 Hz, 4H).

[0214] Example 26: Synthesis of (S)-N-(l-(4-fluorophenyl)ethyl)-6-(2-isobutyramidobenzo[d]thiazol-6-yl)-2-methylquinazoline-4-carboxamide

[0215] The starting material is isobutyric acid, (S)-l-(4-fluorophenyl)ethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0216] The product prepared in this example is a light yellow powder, and the structural formula is shown as formula 26 above.

[0217] Physical and spectral data: yield: 80%. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.44 (s, 1H), 8.57 (s, 1H), 8.36 (d, J = 18.3 Hz, 2H), 8.06 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.59 - 7.42 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 5.46 - 5.07 (m, 1H), 2.85 (s, 3H), 2.02 (s, 1H), 1.54 (s, 3H), 0.96 (d, J = 19.2 Hz, 4H).

[0218] Example 27: Synthesis of (S)-N-(l-(4-fluorophenyl)ethyl)-2-methyl-6-(2-pentanamidobenzo[d]thiazol-6-yl)quinazoline-4-carboxamide

[0219] The starting material was isovaleric acid, (S)-1-(4-fluorophenyl)ethylamine, equimolar amounts were used, the remaining steps (1), (2), (4), (5) were identical to (1), (2), (4), (5) of Example 1, step (3) was identical to modified (3) of Example 24.

[0220] The product of this example was obtained as a white powder and had the structural formula shown above as Formula 27.

[0221] Physical and spectral data: Yield: 67%. 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.46 - 8.31 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.9 Hz, 1H), 7.60 - 7.48 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 5.31 (p, J = 7.2 Hz, 1H), 2.86 (s, 3H), 2.56 - 2.52 (m, 2H), 1.63 (p, J = 7.5 Hz, 2H), 1.54 (d, J = 7.0 Hz, 3H), 1.35 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0222] Example 28: Synthesis of (S)-N-(1-(4-fluorophenyl)ethyl)-2-methyl-6-(2-(3- methylbutanamido)benzo[d]thiazol-6-yl)quinazoline-4-carboxamide

[0223] The starting material was isovaleric acid, (S)-1-(4-fluorophenyl)ethylamine, equimolar amounts were used, the remaining steps (1), (2), (4), (5) were identical to (1), (2), (4), (5) of Example 1, step (3) was identical to modified (3) of Example 24.

[0224] The product of this example was obtained as a yellow powder and had the structural formula shown above as Formula 28.

[0225] Physical and spectral data: Yield: 74%. 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 8.8, 2.1 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.27 - 7.16 (m, 2H), 5.30 (p, J = 7.2 Hz, 1H), 2.86 (s, 3H), 2.41 (d, J = 7.2 Hz, 2H), 2.14 (dp, J = 13.5, 6.7 Hz, 1H), 1.54 (d, J = 7.1 Hz, 3H), 0.96 (d, J = 6.7 Hz, 6H).

[0226] Example 29: Synthesis of (S)-N-(l-(4-fluorophenyl)ethyl)-2-methyl-6-(2- neopentylamido benz[d]thiazol-6-yl)quinazoline-4-carboxamide

[0227] The starting material was neopentanoic acid, (S)-l-(4-fluorophenyl)ethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) of Example 1, step (3) was the same as modified (3) of Example 24.

[0228] The product prepared in this example was a yellow powder, and the structural formula is shown as Formula 29 above.

[0229] Physical and spectral data: yield: 78%. 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 8.8, 2.1 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.27 - 7.16 (m, 2H), 5.30 (p, J = 7.2 Hz, 1H), 2.86 (s, 3H), 2.41 (d, J = 7.2 Hz, 2H), 2.14 (dp, J = 13.5, 6.7 Hz, 1H), 1.54 (d, J = 7.1 Hz, 3H), 0.96 (d, J = 6.7 Hz, 6H).

[0230] Example 30: Synthesis of (S)-6-(2-(cyclobutanecarboxamido)benzo[d]thiazol-6-yl)-N-(l-(4- fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0231] The starting material is cyclobutane carboxylic acid, (S)-1-(4-fluorophenyl)ethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0232] The product of this example is a white powder, and the structural formula is shown as Formula 30 above.

[0233] Physical and spectral data: yield: 75%. 1 H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.48 - 8.25 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.9 Hz, 1H), 7.62 - 7.45 (m, 2H), 7.33 - 7.10 (m, 2H), 5.31 (p, J = 7.2 Hz, 1H), 3.44 (p, J = 8.3 Hz, 1H), 2.86 (s, 3H), 2.38 - 2.14 (m, 4H), 2.07 - 1.80 (m, 2H), 1.55 (d, J = 7.0 Hz, 3H).

[0234] Example 31: Synthesis of (S)-6-(2-(cyclopentanecarboxamido)benzo[d]thiazol-6-yl)-N-(l-(4- fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0235] The starting material is cyclopentane carboxylic acid, (S)-1-(4-fluorophenyl)ethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0236] The product of this example is a yellow powder, and the structural formula is shown as Formula 31 above.

[0237] Physical and spectral data: yield: 66%. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.46 (d, J = 8.2 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.48 - 8.28 (m, 2H), 8.07 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.5, 1.9 Hz, 1H), 7.63 - 7.44 (m, 2H), 7.21 (dd, J = 10.1, 7.7 Hz, 2H), 5.30 (p, J = 7.2 Hz, 1H), 3.01 (p, J = 7.9 Hz, 1H), 2.86 (s, 3H), 2.00 - 1.88 (m, 2H), 1.83 - 1.51 (m, 9H).

[0238] Example 32: Synthesis of (S)-6-(2-(cyclohexanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0239] The starting material is cyclohexanecarboxylic acid, (S)-1-(4-fluorophenyl)ethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0240] The product prepared in this example is a yellow powder, and the structural formula is shown as Formula 32 above.

[0241] Physical and spectral data: yield: 81%. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.46 (d, J = 8.2 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.48 - 8.28 (m, 2H), 8.07 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.5, 1.9 Hz, 1H), 7.63 - 7.44 (m, 2H), 7.21 (dd, J = 10.1, 7.7 Hz, 2H), 5.30 (p, J = 7.2 Hz, 1H), 3.01 (p, J = 7.9 Hz, 1H), 2.86 (s, 3H), 2.00 - 1.88 (m, 2H), 1.83 - 1.51 (m, 9H).

[0242] Example 33: Synthesis of (S)-6-(2-benzylaminobenzo[d]thiazol-6-yl)-N-(1-(4- fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0243] The starting material was benzoic acid, (S)-1-(4-fluorophenyl)ethylamine, equimolar amounts were reacted, the remaining steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) of Example 1, and step (3) was the same as modified (3) of Example 24.

[0244] The product of this example was prepared as a yellow powder, and the structural formula is shown above as Formula 33.

[0245] Physical and spectral data: Yield: 70%. 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 9.46 (d, J = 8.2 Hz, 1H), 8.60 (s, 1H), 8.39 (d, J = 7.8 Hz, 2H), 8.17 (d, J = 7.6 Hz, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.64 - 7.51 (m, 4H), 7.22 (t, J = 8.7 Hz, 2H), 5.32 (p, J = 7.2 Hz, 1H), 2.86 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H).

[0246] Example 34: Synthesis of (S)-6-(2-butyrylaminobenzo[d]thiazol-6-yl)-N-(1-(4- fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0247] The starting material was n-butyric acid, (S)-1-(4-fluorophenyl)ethylamine, equimolar amounts were reacted, the remaining steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) of Example 1, and step (3) was the same as modified (3) of Example 24.

[0248] The product of this example was prepared as a white powder, and the structural formula is shown above as Formula 34.

[0249] Physical and spectral data: Yield: 66%. 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.45 (d, J = 8.1 Hz, 1H), 8.58 (s, 1H), 8.44-8.31 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.9 Hz, 1H), 7.54 (dd, J = 8.4, 5.5 Hz, 2H), 7.20 (t, J = 8.8 Hz, 2H), 5.31 (p, J = 7.2 Hz, 1H), 2.86 (s, 3H), 2.53-2.51 (m, 2H), 1.67 (h, J = 7.4 Hz, 2H), 1.54 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0250] Example 35: Synthesis of (S)-N-(l-(4-fluorophenyl)ethyl)-2-methyl-6-(2- propionamidobenzo[d]thiazol-6-yl)quinazoline-4-carboxamide

[0251] The starting material was n-propionic acid, (S)-l-(4-fluorophenyl)ethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) of Example 1, step (3) was the same as modified (3) of Example 24.

[0252] The product prepared in this example was a white powder, and the structural formula is shown as Formula 35 above.

[0253] Physical and spectral data: yield: 66%. 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.45 (d, J = 8.1 Hz, 1H), 8.58 (s, 1H), 8.44-8.31 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.9 Hz, 1H), 7.54 (dd, J = 8.4, 5.5 Hz, 2H), 7.20 (t, J = 8.8 Hz, 2H), 5.31 (p, J = 7.2 Hz, 1H), 2.86 (s, 3H), 2.53-2.51 (m, 2H), 1.67 (h, J = 7.4 Hz, 2H), 1.54 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0254] Example 36: Synthesis of (S)-6-(2-acetamidobenzo[d]thiazol-6-yl)-N-(l-(4- fluorophenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0255] Starting material was acetic acid, (S)-1 -(4-fluorophenyl) ethylamine, equimolar amounts were reacted, the remaining steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) of Example 1, step (3) was the same as modified (3) of Example 24.

[0256] The product of this example was prepared as a white powder and had the structural formula shown above as Formula 36.

[0257] Physical and spectral data: Yield: 69%. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.46 - 8.30 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4, 1.9 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.20 (t, J = 8.8 Hz, 2H), 5.31 (p, J = 7.3 Hz, 1H), 2.86 (s, 3H), 2.24 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H).

[0258] Example 37: Synthesis of N-benzyl-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methylquinazoline-4-carboxamide

[0259] Starting material was cyclopropanecarboxylic acid, benzylamine, equimolar amounts were reacted, the remaining steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) of Example 1, step (3) was the same as modified (3) of Example 24.

[0260] The product of this example was prepared as a white powder and had the structural formula shown above as Formula 37.

[0261] Physical and spectral data: Yield: 62%. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.60 (t, J = 6.3 Hz, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.45 - 8.31 (m, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.5, 1.9 Hz, 1H), 7.45 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 2.85 (s, 3H), 2.04 (p, J = 6.2 Hz, 1H), 0.99 (d, J = 6.1 Hz, 4H).

[0262] Example 38: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-(l-phenylpropyl)quinazoline-4-carboxamide

[0263] The starting material is cyclopropanecarboxylic acid, (S)-l-phenylpropylamine, and the reaction is carried out in equimolar amounts. The remaining steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, and step (3) is the same as modified (3) of Example 24.

[0264] The product prepared in this example is a white powder, and the structural formula is shown as Formula 38 above.

[0265] Physical and spectral data: yield: 71%. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.40 (d, J = 8.5 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 8.8, 2.1 Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.9 Hz, 1H), 7.48 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 5.05 (q, J = 7.9 Hz, 1H), 2.85 (s, 3H), 2.04 (p, J = 6.2 Hz, 1H), 1.88 (ddp, J = 20.7, 13.7, 7.1 Hz, 2H), 1.05 - 0.91 (m, 7H).

[0266] Example 39: Synthesis of 6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-phenylquinazoline-4-carboxamide

[0267] The starting material is cyclopropanecarboxylic acid, aniline, equimolar reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0268] The product prepared in this example is a yellow powder, and its structural formula is shown as formula 39 above.

[0269] Physical and spectral data: yield: 76%. 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.93 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.48 - 8.37 (m, 2H), 8.10 (d, J = 8.9 Hz, 1H), 7.93 - 7.82 (m, 4H), 7.43 (dd, J = 8.5, 7.4 Hz, 2H), 7.25 - 7.16 (m, 1H), 2.91 (s, 3H), 2.03 (ddd, J = 9.8, 8.0, 5.7 Hz, 1H), 1.05 - 0.93 (m, 4H).

[0270] Example 40: Synthesis of 6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-phenethylquinazoline-4-carboxamide

[0271] The starting material is cyclopropanecarboxylic acid, aniline, equimolar reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0272] The product prepared in this example is a yellow powder, and its structural formula is shown as formula 40 above.

[0273] Physical and spectral data: yield: 65%. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.45 - 8.28 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 8.4, 1.9 Hz, 1H), 7.34 - 7.24 (m, 4H), 7.19 - 7.11 (m, 1H), 3.65 (q, J = 6.6 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 2.84 (s, 3H), 2.05 (p, J = 6.2 Hz, 1H), 1.14 - 0.90 (m, 4H).

[0274] Example 41 : Synthesis of 6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-carboxamide

[0275] The starting material is cyclopropanecarboxylic acid, 4-aminotetrahydropyran, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0276] The product of this example is a light yellow powder, and the structural formula is shown as Formula 41 above.

[0277] Physical and spectral data: yield: 78%. 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.98 (d, J = 8.0 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.40 (dt, J = 5.5, 2.9 Hz, 2H), 8.07 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.82 (dd, J = 8.5, 1.9 Hz, 1H), 4.16 (ddp, J = 11.5, 8.3, 4.2 Hz, 1H), 3.98 - 3.86 (m, 2H), 3.44 (td, J = 11.7, 2.1 Hz, 2H), 2.85 (s, 3H), 2.10 - 1.99 (m, 1H), 1.87 (dt, J = 12.8, 2.7 Hz, 2H), 1.66 (qd, J = 11.9, 4.4 Hz, 2H), 1.09 - 0.89 (m, 4H).

[0278] Example 42: Synthesis of (S)-N-(1-cyclohexylethyl)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2-methylquinazoline-4-carboxamide

[0279] The starting material is cyclopropanecarboxylic acid, (S)-1-cyclohexylethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0280] The product of this example is a yellow powder, and the structural formula is shown as Formula 42 above.

[0281] Physical and spectral data: yield: 79%. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.82-8.66 (m, 2H), 8.45-8.34 (m, 2H), 8.06 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 8.4, 1.9 Hz, 1H), 3.99 (dt, J = 8.7, 6.8 Hz, 1H), 2.84 (s, 3H), 2.09-1.99 (m, 1H), 1.90-1.68 (m, 4H), 1.66-1.42 (m, 2H), 1.27-1.03 (m, 8H), 1.02-0.96 (m, 4H).

[0282] Example 43: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-(l-(p-tolyl)ethyl)quinazoline-4-carboxamide

[0283] The starting material was cyclopropanecarboxylic acid, (S)-l-(4-methylphenyl)ethylamine, and the reaction was carried out in equimolar amounts. The remaining steps (1), (2), (4), (5) were the same as (1), (2), (4), (5) of Example 1, and step (3) was the same as modified (3) of Example 24.

[0284] The product prepared in this example was a yellow powder, and the structural formula is shown above as Formula 43.

[0285] Physical and spectral data: yield: 62%. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.38 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.39 (dd, J = 8.9, 2.1 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.5, 1.9 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.18 (d, J = 7.8 Hz, 2H), 5.26 (p, J = 7.2 Hz, 1H), 2.85 (s, 3H), 2.29 (s, 3H), 2.10 - 1.98 (m, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.07 - 0.92 (m, 4H).

[0286] Example 44: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-(l-(pyridin-4-yl)ethyl)quinazoline-4-carboxamide

[0287] The starting material is cyclopropanecarboxylic acid, (S)-1-(4- methoxyphenyl)ethylamine, equimolar amounts are reacted, the remaining steps (1), (2), (4), (5) are identical to (1), (2), (4), (5) of Example 1, step (3) is identical to modified (3) of Example 24.

[0288] The product of this preparation is a yellow powder, the structural formula of which is shown above as Formula 44.

[0289] Physical and spectral data: Yield: 75%. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.57 (d, J = 7.9 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.60 - 8.55 (m, 2H), 8.41 (dd, J = 8.9, 2.1 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 - 7.45 (m, 2H), 5.28 (p, J = 7.1 Hz, 1H), 2.88 (s, 3H), 2.04 (p, J = 6.4 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H), 1.13 - 0.88 (m, 4H).

[0290] Example 45: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-methoxyphenyl)ethyl)-2-methylquinazoline-4-carboxamide

[0291] The starting material is cyclopropanecarboxylic acid, (S)-1-(4- methoxyphenyl)ethylamine, equimolar amounts are reacted, the remaining steps (1), (2), (4), (5) are identical to (1), (2), (4), (5) of Example 1, step (3) is identical to modified (3) of Example 24.

[0292] The product of this preparation is a yellow powder, the structural formula of which is shown above as Formula 45.

[0293] Physical and spectral data: Yield: 79%. 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.35 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.43 - 8.28 (m, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 1.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 5.26 (p, J = 7.2 Hz, 1H), 3.74 (s, 3H), 2.84 (s, 3H), 2.04 (p, J = 6.3 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H), 1.07 - 0.94 (m, 4H).

[0294] Example 46: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-2- methyl-N-(2-methyl-l-phenylpropyl)quinazoline-4-carboxamide

[0295] The starting material is cyclopropanecarboxylic acid, (S)-2-methyl-l-phenylpropan-l- amine, and the reaction is carried out in equimolar amounts. The remaining steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, and step (3) is the same as modified (3) of Example 24.

[0296] The product of this example is prepared as a yellow powder and has the structural formula shown above as Formula 46.

[0297] Physical and spectral data: Yield: 71%. 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.35 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.43 - 8.28 (m, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 1.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 5.26 (p, J = 7.2 Hz, 1H), 3.74 (s, 3H), 2.84 (s, 3H), 2.04 (p, J = 6.3 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H), 1.07 - 0.94 (m, 4H).

[0298] Example 47: Synthesis of (R)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6- yl)-2-methyl-N-(l-phenylethyl)quinazoline-4-carboxamide

[0299] The starting material is cyclopropanecarboxylic acid, (R)-l-phenylethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0300] The product of this example is a white powder, and the structural formula is shown as Formula 47 above.

[0301] Physical and spectral data: yield: 63%. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.45 (d, J = 8.2 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 8.9, 2.1 Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.5, 1.9 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.39 (dd, J = 8.4, 6.8 Hz, 2H), 7.33 - 7.27 (m, 1H), 5.29 (p, J = 7.2 Hz, 1H), 2.85 (s, 3H), 2.04 (dt, J = 12.5, 6.2 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H), 1.04 - 0.95 (m, 4H).

[0302] Example 48: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6- yl)-2-methyl-N-(l-(4-nitrophenyl)ethyl)quinazoline-4-carboxamide

[0303] The starting material is cyclopropanecarboxylic acid, (S)-l-(4-nitrophenyl)ethylamine, equimolar amount of reaction, the rest of the steps (1), (2), (4), (5) are the same as (1), (2), (4), (5) of Example 1, step (3) is the same as modified (3) of Example 24.

[0304] The product of this example is a yellow powder, and the structural formula is shown as Formula 48 above.

[0305] Physical and spectral data: yield: 74%. 1H NMR (400MHz, DMSO-d6) δ12.74(s,1H),9.64(d,J=7.8Hz,1H),8.61(d,J=2.1Hz,1H),8. 40(dd,J=8.9,2.1Hz,1H),8.37(d,J=1.9Hz,1H),8.29-8.23(m,2H),8.08(d,J=8.8Hz, 1H),7.82(d,J=8.5Hz,1H),7.80-7.74(m,2H),7.69(dd,J=8.4,1.9Hz,1H),5.40(p,J= 7.1Hz,1H),2.88(s,3H),2.15-1.97(m,1H),1.58(d,J=7.0Hz,3H),1.02-0.94(m,4H).

[0306] Example 49: Synthesis of (S)-6-((2-(cyclopropanecarbamoyl)benzo[d]thiazolyl-6-yl)methyl)-2-methyl-N-(1-phenylethyl)quinazolin-4-carboxamide

[0307] The raw materials are cyclopropionic acid, 6-(bromomethyl)benzo[d]thiazole-2-amine, and (S)-1-phenylethylamine, reacted in equimolar amounts. The remaining steps (1), (2), and (4) are the same as (1), (2), and (5) of Example 1, and step (3) is the same as the modified (3) of Example 24.

[0308] The structural formula obtained in this embodiment is shown in Formula 49 above.

[0309] Example 50: Synthesis of (S)-6-((2-(cyclopropanecarbamoyl)benzo[d]thiazolyl-6-yl)amino)-2-methyl-N-(1-phenylethyl)quinazolin-4-carboxamide

[0310] The raw materials are cyclopropionic acid, 6-nitrobenzo[d]thiazol-2-amine, and (S)-1-phenylethylamine, reacted in equimolar amounts. The remaining steps (1), (2), and (5) are the same as (1), (2), and (5) of Example 1, and step (3) is the same as the modified (3) of Example 24. Step (4) is modified as follows:

[0311] (4) Synthesis of N-(6-aminobenzo[d]thiazolyl)cyclopropaneformamide:

[0312] N-(6-nitrobenzo[d]thiazol-2-yl)cyclopropaneformamide and stannous chloride were refluxed in a methanol / chloroform mixture or reacted overnight at room temperature. After the reaction was complete as monitored by TLC, part of the solvent was evaporated, the pH was adjusted to alkaline, the product was extracted with dichloromethane, the organic layer was dried, and evaporated to dryness to obtain the compound N-(6-aminobenzo[d]thiazol-2-yl)cyclopropaneformamide, which can be used directly in the next reaction without further purification.

[0313] The structural formula obtained in this embodiment is shown in Formula 50 above.

[0314] Example 51: Synthesis of (S)-6-((2-(cyclopropanecarbamoyl)benzo[d]thiazolyl-6-yl)oxy)-2-methyl-N-(1-phenylethyl)quinazolin-4-carboxamide

[0315] The raw materials are cyclopropionic acid, 6-hydroxybenzo[d]thiazole-2-amine, and (S)-1-phenylethylamine, reacted in equimolar amounts. The remaining steps (1), (2), and (4) are the same as (1), (2), and (5) of Example 1, and step (3) is the same as the modified (3) of Example 24. Specifically, the condensation reaction in step (3) requires the hydroxyl groups to be protected with tert-butyldimethylchlorosilane before the reaction, and the protecting group to be removed with tetrabutylammonium fluoride after condensation. The modification is as follows:

[0316] Protection of the hydroxyl group in 2-aminobenzo[d]thiazole-6-phenol:

[0317] 2-Aminobenzo[d]thiazol-6-phenol, tert-butyldimethylchlorosilane, and imidazole were stirred overnight in N,N-dimethylformamide. After the reaction was completed by TLC monitoring, the product with the protective agent was extracted with ethyl acetate. The organic layer was dried and evaporated to dryness to obtain the hydroxyl-protected compound 6-((tert-butyldimethylsilyl)oxy)benzo[d]thiazol-2-amino.

[0318] Remove hydroxyl protecting group:

[0319] N-(6-((tert-butyldimethylsilyl)oxy)benzo[d]thiazo-2-yl)cyclopropaneformamide was added to a tetrabutylammonium fluoride solution in tetrahydrofuran and stirred overnight at room temperature. After the reaction was completed by TLC monitoring, the tetrahydrofuran was evaporated to dryness, and the deprotected hydroxyl product was extracted with dichloromethane. The organic layer was dried and evaporated to dryness to obtain the deprotected compound N-(6-hydroxybenzo[d]thiazo-2-yl)cyclopropaneformamide.

[0320] The structural formula obtained in this embodiment is shown in Formula 51 above.

[0321] Example 52: Inhibitory effect of compounds 1-23 on RIPK1

[0322] The inhibitory effects of compounds 1-23 on RIPK1 and RIPK3 were determined using the ADP-Glo ​​Kinase Assay Kit, and their selectivity indices were calculated. GSK2982772 was selected as the positive control for RIPK1, and GSK-872 was selected as the positive control for RIPK3. Based on this, the inhibitory ability of compounds 1-23 on RIPK1 was tested, and the measured IC50 values ​​were analyzed. 50 Compounds with values ​​less than 200 nM were further examined for their inhibitory ability on RIPK3, and the selectivity index (SI) was calculated.

[0323] Following the instructions of the ADP-Glo ​​Kinase Assay Kit (catalog number: #V9102), read the fluorescence intensity and calculate the inhibition rate. Record the fluorescence intensity of the compound well as Lum. compound The fluorescence intensity of the control well is recorded as Lum. vehicle The fluorescence intensity of the blank control well is recorded as Lum. blank The inhibition rate is calculated using the following formula:

[0324] Inhibition rate = (Lum) vehicle -Lum compound ) / (Lum vehicle -Lum blank )×100%.

[0325] The structural formulas of compounds 1-23 are shown in formula (III), and the results are shown in Table 1.

[0326]

[0327] Nonlinear regression fitting was performed based on the scatter plots of GraphPad Prizm, and IC was calculated. 50 value.

[0328] The results showed that, as shown in Table 1, ① the positive control and the reported IC in the literature were: 50 The values ​​are close, indicating successful modeling and reliable experimental results; ② The IC50 values ​​of compounds 2, 7, 9, 11, 12, and 14 for RIPK1 50 Value less than 200 nM (IC) 50 =122.4~188.2nM). Further experimental results showed that the above 6 compounds did not have an inhibitory effect on RIPK3 at the maximum test concentration of 10μM, and the calculated SI values ​​were all greater than 50. Among them, the SI values ​​of compounds 2 and 15 were close to or greater than 80, which proved that compounds 1 and 15 had good selective inhibitory effects on RIPK1.

[0329] Example 53: Inhibitory effect of compound 24-48 on RIPK1

[0330] The inhibitory effects of the compounds on RIPK1 and RIPK3 were determined using the ADP-Glo ​​Kinase Assay Kit, and their selectivity indices were calculated. The implementation scheme was the same as in Example 52. The ADP-Glo ​​Kinase Assay Kit (catalog number: #V9102) was used.

[0331] The structural formulas of compounds 24-48 are shown in formula (IV), and the results are shown in Table 2.

[0332]

[0333] The results showed that, as shown in Table 2, ① the positive control and the reported IC in the literature were: 50 The values ​​are close, indicating successful modeling and reliable experimental results; ② Compounds 24, 25, 27, 28, 30, 31, 32, 33, 34, 35, 36, 38, 43, 45, 48 have IC50 values ​​for RIPK1. 50 The values ​​were relatively small. Further experimental results showed that compounds 25, 27, 28, 30, 31, 32, 33, 34, 35, 36, 38, 43, and 45 all had SI values ​​greater than 75 for RIPK3, proving that these compounds all had good selective inhibitory effects on RIPK1.

[0334] Example 54: Protective effect of compound 1-23 on HT-29 cells

[0335] (1) Cell Culture

[0336] The HT-29 cells used in the experiment were cultured in RPMI 1640 medium containing 10% FBS; the HT-22 cells were cultured in DMEM high-glucose medium containing 10% FBS and grown at 37°C in a 5% CO2 environment. All cells were in the logarithmic growth phase.

[0337] (2) Establishment of a programmed cell necrosis model using the TSZ method

[0338] HT-29 cells were digested with trypsin, centrifuged, and counted before being packaged at 1×10⁻⁶ cells per cell. 4 Cells were evenly seeded at a density of 10 cells / well in a 96-well plate. After complete cell adhesion, the culture medium was replaced, and TSZ modeling reagent was added to achieve the following concentrations in each well: 10 ng / mL TNF-α, 500 nM Smac-mimetic BV6, and 20 μM Z-VAD(OMe)-FMK, with 100 μL of culture medium per well. After 24 hours, CCK-8 assay reagent was added, and the cells were incubated in an incubator for 2-3 hours before measuring the OD value.

[0339] (3) CCK-8 cytotoxicity detection

[0340] The cell plating procedure is described in step (2); pre-prepared culture medium containing different concentrations of the compound to be tested is added to the wells, and after culturing for 24 hours, the cell viability is determined by the CCK-8 assay.

[0341] (4) CCK-8 assay for cell viability and calculation of EC 50 value

[0342] Cell plating was performed as described in step (2). Pre-prepared culture media containing different concentrations of the target compound were added to the wells, and TSZ was added after a 30-minute pre-incubation. Cell viability was determined using the CCK-8 assay after 24 hours. Nonlinear regression was performed based on the GraphPadPrizm scatter plots, and EC50 was calculated. 50 value.

[0343] The research results are shown in Table 1. Figures 1-4 As shown, compounds 2, 10, 12, 13, 15, and 23 performed well, with their EC values... 50 The values ​​ranged from 66 to 103 nM. Compounds 6-10, 14, 15, and 19 all exhibited toxicity to the normal growth of HT-29 cells. Compound 2 showed better protective activity and lower cytotoxicity.

[0344] Example 55: Protective effect of compound 23-48 on HT-29 cells

[0345] The implementation scheme is the same as in Example 24. HT-22 cells were used to induce a programmed necrosis model using the TSZ method, and CCK-8 cytotoxicity and cell viability were tested; the toxicity of compound 23-48 and its protective effect on HT-29 cells were evaluated.

[0346] The results showed that, as shown in Table 2, the EC values ​​of compounds 24, 25, 35, 38, 42, 43, 44, 46, and 48 were... 50 Values ​​less than 35 nM have a good protective effect on HT-29 cells.

[0347] Example 56: Protective effect of compound 2 on HT-22, HT-29, L929 and U937 cells

[0348] Logarithmically growing HT-22, HT-29, L929, and U937 cells were seeded in 24-well plates and incubated overnight at 37°C with 5% CO2. After pre-incubation with compound 2 for 30 minutes, HT-22, HT-29, and U937 cells were treated with TSZ for 6 hours; L929 cells were treated with TZ for 4 hours. Cell morphology was observed and photographed under a microscope.

[0349] Research results are as follows Figures 2-4As shown, compound 2 affects EC2 cells of HT-22, HT-29, L929, and U937. 50 The concentrations were 38.45±2.96 nM, 71.61±3.32 nM, 24.84±4.14 nM, and 152.9±34.56 nM, respectively. Among these, the concentrations in L929 cells were found in EC50... 50 =24.84±4.14 nM, EC50 of HT-22 cells 50 =38.45±2.96 nM; Compound 2 effectively restored cell viability in TSZ-induced programmed necrosis models in different cell lines.

[0350] Example 57: Fluorescent staining experiment to protect cells with compound 2

[0351] HT-29 or L929 cells were digested with trypsin, centrifuged, and counted before being seeded at a specific density in 24-well plates. After cell adhesion and growth, the drug-treated groups were treated with fresh medium at concentrations of 1, 10, and 100 nM of the compound, while the control and model groups were treated with an equal volume of RPMI 1640 complete medium containing 10% FBS. After pre-incubation for 30 min, except for the control group, the drug-treated and model groups were treated with TSZ for a certain period of time. The medium was then aspirated, and the cells were washed with PBS, followed by the addition of Hoechst 33342 and PI dyes, respectively. The cells were then incubated at 37°C in the dark for 30 min. After incubation, the cells were washed again with PBS, and fresh blank medium was added. The staining of Hoechst 33342 and PI within the cells was observed and photographed under a fluorescence microscope.

[0352] The research results indicate that: Figure 5 , Figure 6 As shown, compared with the control group, the blue fluorescence of the TSZ-induced model group was enhanced. However, the blue fluorescence decreased among the different dosage groups after drug administration, but the difference was not significant. This is because the increased membrane permeability after programmed necrosis of cells leads to more Hoechst 33342 dye entering the cell nucleus and staining DNA. The red fluorescence of PI staining was more obvious in the TSZ group compared with the control group, and the red fluorescence of L929 cells almost disappeared after drug administration; the red fluorescence of HT-29 cells also decreased in a dose-dependent manner after drug administration. These findings demonstrate that compound 2 can exert a protective effect by preventing cells from programmed necrosis.

[0353] Example 58: Protective effect of compound 2 on MCAO rats

[0354] 1. Experimental Methods:

[0355] Approximately 72 male SD rats were randomly divided into 6 groups according to body weight: A. sham-operated group, B. model control group, C. low-dose compound 2 group (0.5 mg / kg), D. medium-dose compound 2 group (1.5 mg / kg), E. high-dose compound 2 group (4.5 mg / kg), and F. positive control group. Each group consisted of 12 rats. Each group received an intravenous injection of compound 2 0.5 h before model establishment, followed by a second injection after reperfusion, for a total of two injections. Except for the control group, all other groups underwent MCAO model establishment. Neurological assessments were performed 24 h later. After assessment, blood samples were collected to measure the levels of SOD, MDA, IL-1β, and TNF-α. Brain sections were collected for TTC staining to observe cerebral ischemia and infarction.

[0356] 2. Research Results:

[0357] ①Zea Longa Neurological Score: Neurological scores were assessed in animals 24 hours post-surgery using the 4-point Zea Longa scoring system. Results showed that, compared to the model control group, neurological scores in all drug-treated groups tended to decrease, with significant reductions observed in the high-dose test sample group and the positive control group (p < 0.05 or p < 0.01). (See Table 3). Figure 7 .

[0358] ②mNSS neurological score: Neurological scores were assessed in animals 24 hours post-surgery using the 18-point mNSS scoring system. Results showed that, compared to the model control group, the neurological scores of all treatment groups were significantly lower (p < 0.05 or p < 0.001), as shown in Table 3. Figure 7 .

[0359] ③ Percentage of cerebral infarction volume: Compared with the model control group, the percentage of cerebral infarction volume in all drug-treated groups showed a decreasing trend, with significant reductions in the medium and high dose groups (p < 0.01 or p < 0.001), as shown in Table 4. Figure 8 .

[0360] ④ Serum antioxidant index results: Compared with the model control group, the serum SOD content of animals in all treatment groups showed an increasing trend, with a significant increase in the positive control group (p < 0.05); compared with the model control group, the serum MDA content of animals in all treatment groups showed a decreasing trend, with significant decreases in the medium- and high-dose groups of the test samples and the positive control group (p < 0.05 or p < 0.01); compared with the model control group, the serum TNF-α and IL-1β content of animals in all treatment groups showed a decreasing trend, with significant decreases in the medium- and high-dose groups of the test samples and the positive control group (p < 0.05 or p < 0.01), see Table 5. Figure 9 .

[0361] Under the conditions of this experiment, the compound has an obvious improvement effect on acute cerebral ischemia-reperfusion injury in rats, can significantly reduce the neurological behavioral score of cerebral ischemia injury, and reduce the cerebral infarction volume. Its mechanism of action may be related to its antioxidant and anti-inflammatory effects.

[0362] Example 59: Acute Toxicity of Compound 2

[0363] SPF-grade male Kunming mice weighing 18 - 22 g were purchased from the Experimental Animal Center of the School of Pharmacy, Sun Yat-sen University. The experimental animal certificate number is: 44008500033846, and the experimental animal use license number is: SYXK(Guangdong)2021 - 0029.

[0364] The maximum dissolved concentration of the liquid medicine was prepared to be 2 mg / ml, and it was intraperitoneally injected into mice at a large dose of 0.4 mL / 10 g. High, medium, and low doses were set down with a coefficient of 0.7, which were 160, 112, and 78.4 mg / kg respectively.

[0365] Sixteen mice were randomly divided into 4 groups according to their mass, with 4 mice in each group. The groups were the high-dose group of Compound 2 (160 mg / kg), the medium-dose group of Compound 2 (112 mg / kg), the low-dose group of Compound 2 (78.4 mg / kg), and the solvent control group. Intraperitoneal injection was administered (twice in total, with an interval of 1 h). After administration, the behavior of the animals was immediately observed for abnormalities, lasting for 12 hours, and then continuously observed for 7 days. The general status and body weight of the mice were recorded.

[0366] The research results showed that: as shown in Table 6, compared with the solvent control group, the animals in the high- and medium-dose groups of Compound 2 (160, 112 mg / kg) had a slight tendency to decrease in body weight within 7 days after administration, but there was no statistical difference. Compound 2 showed no obvious abnormalities in other general status of each group of animals such as diet, appearance, behavior, secretions, excretions, etc.

[0367] Under the conditions of this experiment, when Compound 2 was intraperitoneally injected within the dose range of the maximum concentration and a large dose of 160 mg / kg, no obvious acute toxicity was observed in Kunming mice. Only a tendency of body weight reduction was seen, and no obvious changes in the status and no toxic phenomena such as death were observed. It was inferred that the LD of its intraperitoneal injection 50 The dose is above 160 mg / kg. It can be concluded that.

[0368] Example 60: Pharmacokinetic Experiment of Compound 2

[0369] SPF-grade SD male rats weighing 180 - 200 g were purchased from the Experimental Animal Center of the School of Pharmacy, Sun Yat-sen University. The experimental animal certificate number is: No.44007200122654; the experimental animal use license number is: SYXK(Guangdong)2016 - 0029.

[0370] Rats were randomly divided into two groups of six each: an intravenous injection group (0.5 mg / kg) and an oral administration group (20 mg / kg). Rats were fasted for 15 hours before the experiment, and withheld from water for 2 hours and 4 hours after administration. In the oral administration group, approximately 0.5 mL of blood was collected from the orbital venous plexus before administration and at 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, and anticoagulated with EDTA. In the intravenous administration group, approximately 0.5 mL of blood was collected from the orbital venous plexus before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, and anticoagulated with EDTA. All blood samples were stored at 4℃. Plasma was collected after centrifugation at 4000 rpm for 10 min at 4℃ and stored at -80℃. The concentration of compound 2 in the plasma samples was determined by LC / MS, and pharmacokinetic parameters were calculated using PKSolver 2.0.

[0371] The formula for calculating absolute oral bioavailability is as follows:

[0372] F(%) = AUC 0-inf口服 *D 静注 / AUC 0-inf静注 *D 口服

[0373] AUC is the area under the curve during drug administration, and D is the administered dose.

[0374] The research results indicate that: Figure 10 As shown in Table 7, compound 2 reached a peak plasma concentration of 30.53 ng / mL 2 hours after oral administration, with a half-life of 8.03 h and an area under the drug-time curve of 307.90 ng / mL*h. After intravenous injection of compound 2, the peak plasma concentration was 462.57 ng / mL, the area under the drug-time curve was 2065.12 ng / mL*h, and the half-life decreased to 6.39 h compared to the oral administration route. The calculated absolute oral bioavailability F = 14.90%.

[0375] Example 61: Brain-targeting effect experiment of compound 2

[0376] Six SPF-grade male Kunming mice weighing 22-26g were purchased from the Experimental Animal Center of the School of Pharmaceutical Sciences, Sun Yat-sen University.

[0377] Compound 2 was administered intravenously (2 mg / kg). Patients were fasting for 15 hours prior to the experiment, and abstaining from water for 2 hours and 4 hours after administration. Blood samples (approximately 0.5 mL) and the whole brain were collected at 0.5 h and 2 h after administration. Serum was anticoagulated with EDTA; the whole brain was stored at -80°C. The concentration of compound 2 in plasma samples was determined using LC / MS, and the brain / blood distribution ratio was calculated.

[0378] The results are shown in Table 8. At the two time points of 0.5h and 2h, the brain / blood ratio of compound 2 was 0.45 and 0.48, respectively, indicating that compound 2 can be rapidly and evenly distributed in plasma and brain tissue within 0.5h after intravenous administration. This shows that compound 2 has a fast distribution speed in vivo and has the ability to cross the blood-brain barrier.

[0379] Example 62: In vitro pharmacokinetic studies of compounds 25, 35, 38, 43, 45

[0380] [Intermediate solution]: Intermediate solution in which the sample is diluted with methanol; [Stop solution]: Internal standard + methanol;

[0381] [Liver Microparticle Working Solution]: Liver microparticle stock solution + phosphate buffer (ice bath environment);

[0382] [Incubation system]: Methanol + water + phosphate buffer (ice bath environment);

[0383] [Incubation working solution]: Add [intermediate solution] to [incubation system] and mix well (ice bath environment);

[0384] For the 0-minute reaction tube: directly add [incubation working solution] + [liver microparticle working solution]; incubate the remaining [incubation working solution] at 37°C for 5 minutes, then take the [incubation working solution] and [liver microparticle working solution] and mix them immediately. Maintain incubation at 37°C. At 5, 15, 30, and 60 minutes, take the tubes out and add the stop solution (4 tubes at each time point). Vortex mix to quickly stop the reaction. After stopping the reaction, keep the sample on ice until detection. After centrifugation at 10,000 rpm, take the supernatant and detect it using a triple quadrupole ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS / MS). Calculate the half-life based on the results.

[0385] The results are shown in Table 2. The half-life of fluorine-substituted compounds was significantly prolonged, indicating that different side chain substitutions have a significant impact on the metabolism of compounds.

[0386] Example 63: Experiment on the anti-acute colitis effect of compound 24

[0387] (1) Methods: Ninety C57BL / 6J mice were randomly divided into nine groups of 10 mice each, based on their body weight. These groups were: A. Blank control group, B. Model control group, C. Low-dose (5 mg / kg) compound 24 group, D. Medium-dose (10 mg / kg) compound 24 group, E. High-dose (20 mg / kg) compound 24 group, and F. Positive control group (sulfasalazine colonic-coated capsules, SASP, 200 mg / kg). After the quarantine period, except for the blank control group, all other groups were given 3.5% DSS, and the mice were allowed free access to the water for 7 days to induce an acute ulcerative colitis model. The blank and model control groups were given the solvent (2% Tween 80) by gavage. Each drug administration group was given the corresponding low, medium, and high concentrations of the drug solution by gavage daily. At the same time, the positive control group was given SASP by gavage daily until the end of the experiment. The mice's activity signs, weight changes, stool consistency, and bleeding were recorded daily. Seven days later, after the mice were completely anesthetized, 1 mL of blood was collected from the eye sockets of the mice, and then the mice were euthanized due to cervical dislocation. Samples were collected for relevant index testing and observation.

[0388] (2) Data analysis: Experimental data were statistically processed using GraphPad Prism 9.2 biostatistics software: Quantitative data were expressed as Mean±SD and analyzed using ANOVA combined with Dunnett's multiple comparison method; Categorical data were analyzed using Kruskal-Wallis rank-sum test combined with Dunnett's multiple comparison method; P<0.05 was considered statistically significant for intergroup comparisons.

[0389] (3) Research results:

[0390] ① As shown in Table 9, compared with the blank control group, mice in the model control, all drug-treated and positive control groups showed rectal bleeding starting from day 2 of modeling. As the number of days of modeling increased, the severity of rectal bleeding gradually worsened (P<0.05), indicating that the model was successfully established. Compared with the model control group, on day 5 of modeling, the severity of rectal bleeding in all drug-treated groups and the positive control group showed a decreasing trend, but no significant difference was observed (P>0.05). On day 6 of modeling, the severity of rectal bleeding in all drug-treated groups and the positive control group showed a decreasing trend, with the high-dose compound 24 group and the positive drug control group showing significantly lower scores (P<0.05). On day 7 of modeling, the severity of rectal bleeding in all drug-treated groups and the positive control group showed a decreasing trend, with the positive drug control group showing a significantly lower score (P<0.05).

[0391] ② Effect on Disease Activity Index (DAI) score: As shown in Table 10, compared with the blank control group, starting from day 3 of modeling, mice in the model control, all drug-treated, and positive control groups showed decreased stool consistency and bloody stool. As the number of days of modeling increased, the DAI score gradually worsened (P<0.05), indicating successful model preparation. Compared with the model control group, on days 4 and 5 of modeling, the DAI scores of all drug-treated groups and the positive control group showed a decreasing trend, but no significant difference was observed (P>0.05). On day 6 of modeling, the DAI scores of all drug-treated groups and the positive control group showed a decreasing trend, with the high-dose compound 24 group and the positive drug control group showing significantly lower DAI scores (P<0.05). On day 7 of modeling, the DAI scores of all drug-treated groups and the positive control group showed a decreasing trend, with the high-dose compound 24 group and the positive drug control group showing significantly lower DAI scores (P<0.05).

[0392] ③ Effects on spleen weight and colon length: As shown in Table 11, compared with the blank control group, the spleen weight and spleen coefficient of the model control group were significantly increased (P<0.05), and the colon length was significantly shortened (P<0.05), indicating that the model was successfully established. Compared with the model control group, the spleen weight and spleen coefficient of each drug-treated group and the positive control group showed a decreasing trend, but no significant difference was observed (P>0.05). Compared with the model control group, the colon length of each drug-treated group and the positive control group showed an increasing trend, with the positive drug control group showing a significant increase (P<0.05).

[0393] Under the conditions of this experiment, compound 24 showed a certain ameliorative effect on DSS-induced acute ulcerative colitis in mice.

[0394] Tables 1-11 are shown below during the testing process of this invention.

[0395] Table 1. Evaluation of the bioactivity of compounds 1-23

[0396]

[0397]

[0398] Note: Selectivity Index=RIPK3 IC 50 / RIPK1 IC 50 .

[0399] Table 2. Bioactivity evaluation of compounds 24-48

[0400]

[0401]

[0402]

[0403] Note: R 1 For methyl groups, Selectivity Index = RIPK3 IC 50 / RIPK1 IC 50 .

[0404] Table 3 Neurological function scores of animals in each group

[0405] Group Number of animals (N) Longa score MNSS score Sham group 12 0.00±0.00 0.00±0.00 Model control group 11 1.73±0.79 7.45±3.39 2 low-dose group 10 1.30±0.95 5.20±2.74* 2 middle-dose group 11 1.27±0.47 5.09±1.87* 2 high-dose group 11 1.00±0.00** 3.82±0.40*** Positive control group 9 1.00±0.00* 3.78±0.97***

[0406] Note: Compared with the model group, *p<0.05, **p<0.01, ***p<0.001; n=9-12, data are expressed as Mean±SEM.

[0407] Table 4 Percentage of cerebral infarction volume in each group of animals

[0408] Group Number of animals (N) Percentage of cerebral infarction volume (%) Sham group 12 0.00±0.00 Model control group 11 24.38±5.16 2 low-dose group 10 20.60±6.15 2 middle-dose group 11 18.32±4.07** 2 high-dose group 11 16.51±2.66*** Positive control group 9 19.65±4.03

[0409] Note: Compared with the model group, **p<0.01, ***p<0.001; n=9-12, data are expressed as Mean±SEM.

[0410] Table 5 Serum SOD, MDA, TNF-α and IL-1β levels in rats 24 h after MCAO reperfusion.

[0411]

[0412]

[0413] Note: Compared with the model group, **p<0.01, ***p<0.001, ****p<0.0001; n=9-12, data are expressed as Mean±SEM.

[0414] Table 6 Effects on body weight of Kunming mice over 7 days

[0415] Group Body weight before administration (g) 1 day after administration (g) 3 days after administration (g) 5 days after administration (g) 7 days after administration (g) 2 high-dose group 26.70±2.40 25.65±2.58 27.05±2.18 27.33±2.07 28.58±2.06 2 middle-dose group 26.85±1.14 27.10±0.57 27.25±1.70 27.35±1.38 28.10±1.53 2 low-dose group 26.73±0.78 26.50±1.46 28.28±1.28 28.45±1.00 29.20±1.30 2 vehicle control group 26.30±0.57 27.85±1.33 28.55±0.99 28.70±1.00 29.35±1.22

[0416] Note: n=4, The data are represented as Mean±SEM.

[0417] Table 7. Pharmacokinetic parameters of compound 2 after oral and intravenous administration.

[0418]

[0419] Table 8. Brain / blood distribution ratio of compound 2

[0420]

[0421] Note: ***The concentration is abnormal and differs significantly from the data in the same group; therefore, this group of data is not accepted.

[0422] Table 9. Effects on the degree of rectal bleeding in mice (n=10, )

[0423]

[0424]

[0425] Note: Compared with the blank control group #: P<0.05, compared with the model control group*: P<0.05.

[0426] Table 10 Effects on DAI in mice (n=10, )

[0427]

[0428] Note: Compared with the blank control group #: P<0.05, compared with the model control group*: P<0.05.

[0429] Table 11 Effects of spleen coefficient and colon length in mice (n=10, )

[0430]

[0431] Note: Compared with the blank control group #: P<0.05, compared with the model control group*: P<0.05.

[0432] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A RIPK1 kinase target inhibitor, characterized in that, The general structural formula of the RIPK1 kinase target inhibitor is shown in formula (I): In this case, X, Y, and Z are all nitrogen atoms; or, Z is a carbon atom, and X and Y are either nitrogen atoms or sulfur atoms, with different choices of atoms for X and Y. R 1 Selected from methyl; R 2 and R 3 Each is independently selected from one of the following: alkyl groups with 6 or fewer carbon atoms or their halogenated derivatives, cycloalkyl groups with 6 or fewer carbon atoms or their halogenated derivatives, phenyl groups or their halogenated derivatives, and benzyl groups.

2. A RIPK1 kinase target inhibitor, characterized in that, The structural formula of the RIPK1 kinase target inhibitor is selected from at least one of the following:

3. A method for preparing a RIPK1 kinase target inhibitor as described in any one of claims 1-2, characterized in that, Includes the following steps: (1) Synthesis of 6-bromoquinazonamide derivative: Using 5-bromoindigo as raw material, after alkaline hydrolysis, the pH was adjusted to neutral by adding dilute hydrochloric acid to obtain sodium salt of indigo hydrolysis product; the sodium salt of indigo hydrolysis product was cyclized by a three-component reaction with acetaldehyde and ammonium acetate to obtain sodium quinazonoline carboxylate; in the presence of a condensing agent, the sodium quinazonoline carboxylate was condensed with an amine compound to generate 6-bromoquinazonamide derivative, which is fragment A; (2) Preparation of fragment B: Using 7- or 6-brominated 2-amino-benzo5-membered heterocyclic compounds as raw materials, add acyl chloride or carboxylic acid, and prepare 7- or 6-brominated benzo5-membered heterocyclic-2-aminoacylated derivatives in the presence of an acid-binding agent or condensing agent, which are fragment B; (3) The fragment B obtained in step (2) is reacted with pinacol diboronic acid ester in the presence of organic base A and palladium catalyst to prepare arylboronic acid ester of fragment B. Then, the fragment A obtained in step (1) is reacted with organic base B, palladium catalyst and phosphine ligand to obtain the RIPK1 kinase target inhibitor shown in formula (I). The organic base A is potassium acetate and the organic base B is at least one of Cs2CO3 and K3PO4.

4. The method for preparing the RIPK1 kinase target inhibitor as described in claim 3, characterized in that, In step (1): The alkali is at least one of sodium hydroxide and potassium hydroxide; And / or, the condensing agent is one of mixture A and mixture B, wherein mixture A is a mixture of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole, and the molar ratio of the mixture of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole is 1:2-3; and mixture B is a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, and triethylamine, and their molar ratio is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 1-hydroxybenzotriazole: triethylamine = 1:1:1; And / or, the amine compounds are (R)-1-phenylethylamine, (S)-1-phenylethylamine, (S)-1-phenylpropylamine, (S)-2-methyl-1-phenylpropylamine, (S)-1-cyclohexylethylamine, (S)-1-(4-methylphenyl)ethylamine, (S)-1-(4-methoxyphenyl)ethylamine, (S)-1-(4-nitrophenyl)ethylamine, (S)-1-(pyridin-2-yl)ethylamine, (S)- At least one of 1-(pyridin-3-yl)ethylamine, (S)-1-(pyridin-4-yl)ethylamine, (S)-1-(2-fluorophenyl)ethylamine, (S)-1-(3-fluorophenyl)ethylamine, (S)-1-(4-fluorophenyl)ethylamine, aniline, benzylamine, phenethylamine, tetrahydro-2H-pyran-4-amine, 4-trifluoromethylbenzylamine, 3-trifluoromethylbenzylamine, 4-trifluoromethoxybenzylamine, and 3-trifluoromethoxybenzylamine; And / or, the molar ratio of 5-bromoindigo to base is 5-bromoindigo:base = 1:1-3; And / or, the molar ratio of the sodium salt of indigo hydrolysis product, acetaldehyde, and ammonium acetate is sodium salt of indigo hydrolysis product: acetaldehyde: ammonium acetate = 1:1-3:2-5; And / or, the molar ratio of the sodium quinazoline carboxylate, the amine compound, and the condensing agent is 1:1:2-3.

5. The method for preparing the RIPK1 kinase target inhibitor as described in claim 3, characterized in that, In step (2): The acyl chloride is at least one selected from n-butyryl chloride, isobutyryl chloride, n-valeryl chloride, neovaleryl chloride, cyclopropylformyl chloride, cyclobutylformyl chloride, cyclopentylformyl chloride, cyclohexylformyl chloride, and 3-oxocyclobutylformyl chloride; And / or, the carboxylic acid is at least one selected from acetic acid, propionic acid, n-butyric acid, isobutyric acid, n-valeric acid, isovaleric acid, neovaleric acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, and benzoic acid; And / or, the acid-binding agent is at least one of triethylamine and N,N-diisopropylethylamine; And / or, the condensing agent is one of mixture A and mixture B, wherein mixture A is a mixture of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole, and the molar ratio of the mixture of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole is 1:2-3; and mixture B is a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine, and their molar ratio is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 1-hydroxybenzotriazole: triethylamine = 1:1:

1.

6. The method for preparing the RIPK1 kinase target inhibitor as described in claim 3, characterized in that, In step (2), the molar ratio of 2-amino-benzo5-membered heterocyclic compound, acyl chloride, and acid-binding agent is 2-amino-benzo5-membered heterocyclic compound: acyl chloride: acid-binding agent = 1:1-2:1-3; And / or, in step (2), the molar ratio of the 2-amino-benzo5-membered heterocyclic compound, carboxylic acid, and condensing agent is 2-amino-benzo5-membered heterocyclic compound: carboxylic acid: condensing agent = 1:1:1.1-1.

5.

7. The method for preparing the RIPK1 kinase target inhibitor as described in claim 3, characterized in that, In step (3), the palladium catalyst is at least one of Pd(dppf)Cl2 and Pd(dppf)Cl2·CH2Cl2, and the phosphine ligand is PCy3; And / or, in step (3), the molar ratio of fragment B, pinacol diboronate, palladium catalyst, and organic base A prepared in step (2) is fragment B: pinacol diboronate: palladium catalyst: organic base A = 1:2-3:0.01-0.3:2-5; And / or, in step (3), the molar ratio of arylborate of fragment B, fragment A, palladium catalyst, phosphine ligand, and organic base B is arylborate of fragment B: fragment A: palladium catalyst: phosphine ligand: organic base B = 1:1:0.01-0.2:0.01-0.2:2-5.

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains an inhibitor of the RIPK1 kinase target as described in any one of claims 1-2.

9. A drug, characterized in that, The drug contains an RIPK1 kinase target inhibitor as described in any one of claims 1-2 or a pharmaceutical composition as described in claim 8.

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