A compound as a pak4 kinase inhibitor and preparation method and application thereof

Abstract

The present application provides a kind of compound as PAK4 inhibitor, with the structure shown in formula I or its tautomer, meso, racemate, enantiomer, diastereoisomer or its mixture form, pharmaceutically acceptable hydrate, solvate or salt.The test results show that the compound prepared by the present application has high inhibitory activity and selectivity for PAK4 kinase, and its liver microsomal stability and rat PK have also been improved to a certain extent.

Description

[0001] This application claims priority to Chinese Patent Application No. 202010819448.1, filed on August 14, 2020, entitled "A compound as a PAK4 kinase inhibitor and its preparation method and application", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of drug synthesis technology, and in particular to a compound as a PAK4 kinase inhibitor, its preparation method, and its application. Background Technology

[0003] P21-activated protein kinases (PAKs), a class of conserved serine / threonine protein kinases, are effector proteins of the small GTPases CDC42 and Rac1 in the Rho family, mediating the transduction of their downstream signaling pathways. Based on their sequence homology and activation modes, they can be divided into two main classes: class I PAKs (PAK1, 2, 3) and class II PAKs (PAK4, 5, 6). As important downstream molecules of the Pho family GTPases Rac and Cdc42, PAKs play crucial roles in cell proliferation, cytoskeleton remodeling, and cell motility. Studies have shown that PAK members, especially their representative members PAK1 and PAK4, exhibit gene amplification, gene mutation, upregulated expression levels, and activity in various tumor cells and tissues, which are closely related to tumorigenesis and development. Inhibiting the abnormal activity of PAKs within tumor cells holds promise for suppressing excessive tumor cell proliferation, invasion, metastasis, and angiogenesis, and promoting tumor cell apoptosis. In light of this, research on PAK inhibitors has received widespread attention from medicinal chemists over the past decade. Studies by Wang C et al. have shown that PAK4 expression levels in lung cancer, colon cancer, prostate cancer, pancreatic cancer, and breast cancer cells are significantly higher than in normal cells, exerting a crucial influence on tumor occurrence, development, invasion, and migration. Therefore, the development of PAK4 inhibitors is one of the effective strategies for treating various cancers.

[0004] Recent studies have revealed a potential correlation between inhibition of class I PAKs and safety risks such as acute cardiotoxicity and Herg's syndrome, suggesting that the development of PAK inhibitors should avoid inhibition of class I PAKs, especially PAK1. Therefore, the discovery of highly selective class II PAK inhibitors will become the mainstream of future research.

[0005] PAK4 is a promising drug development target, and the development of its inhibitors offers new avenues for treating related cancers. Currently, the number of PAK4 inhibitors is limited, and most exhibit unsatisfactory activity. Small molecule inhibitors already in clinical trials include KPT-9274, jointly developed by Antengene and Karyopharm Therapeutics, and PF-3758309 developed by Pfizer. PF-3758309, a PAKs inhibitor with a pyrrolopyrazole structure reported by Pfizer in 2009, was the first PAKs inhibitor to enter clinical trials. Its PAK4 IC50 is 19 nm, but this compound exhibits stronger inhibitory activity against PAK1, reaching 14 nm, posing significant safety risks. Due to its poor oral bioavailability (approximately 1%) and severe gastrointestinal adverse reactions, its Phase I clinical trial was terminated. ATG-019 (KPT-9274) is a first-in-class oral dual-target inhibitor of p21-activated kinase 4 (PAK4) and nicotinic acid transphosphoribosylase (NAMPT), and is currently undergoing multiple clinical trials in areas including non-Hodgkin's lymphoma, colorectal cancer, lung cancer, and melanoma. Furthermore, preclinical studies have shown that ATG-019 in combination with an anti-PD-1 antibody can effectively improve anti-tumor efficacy and is effective in patients resistant to PD-1 antibodies; related clinical trials are underway.

[0006] Based on the structure of the drugs, Hao C et al. designed and synthesized a series of aminoquinazoline PAK4 inhibitors, obtaining a highly active and selective PAK4 inhibitor (CZh-226). It has a Ki value of 9 nM for PAK4 and exhibits excellent selectivity for multiple kinases, with a Ki value of 3112 nM for PAK1, representing a 346-fold difference in selectivity. However, this compound has poor drug-likeness and extremely low bioavailability (1.92%), requiring further optimization; simultaneously, there is room for further improvement in its PAK4 inhibitory activity. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a compound as a PAK4 kinase inhibitor, a method for its preparation, and its application. The prepared compound exhibits high inhibitory activity and selectivity for PAK4 kinase, especially PAK4 / 1 selectivity, and good bioavailability.

[0008] To achieve the above objectives, the present invention provides a compound as a PAK4 inhibitor having the structure shown in Formula I or a tautomer thereof, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, solvate, or salt thereof.

[0009]

[0010] Among them, B1, B2, B3, B4, B5, and B6 are each independently selected from C-R3 or N.

[0011] Ring A is selected from substituted or unsubstituted C5-C9 aryl or heteroaryl groups.

[0012] More preferably, ring A is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl groups, and even more preferably from substituted or unsubstituted phenyl, pyrimidinyl, pyrroleyl, furanyl, thiopheneyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl or pyridinyl groups.

[0013] The substituted groups are independently selected from aryl or heteroaryl groups substituted by any group, substituted or unsubstituted alkyl or heteroalkyl groups, substituted or unsubstituted cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted alkoxy groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mercapto groups, substituted or unsubstituted amide groups, sulfonyl groups, phosphoryl groups, alkyloxyphosphoryl groups, alkyl sulfone groups, and alkyl sulfoxide groups.

[0014] More preferably, the substituted groups are independently selected from five- or six-membered aryl or heteroaryl groups substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl groups, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted alkoxy groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mercapto groups, substituted or unsubstituted amide groups, sulfonyl groups, phosphoryl groups, alkyloxyphosphoryl groups, alkyl sulfone groups, and alkyl sulfoxide groups.

[0015] Q is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkenyl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkyl sulfone, alkyl sulfoxide, borate ester, borate.

[0016] More preferably, Q is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkyl sulfone, alkyl sulfoxide, borate ester, and borate.

[0017] The substituted groups are independently selected from aryl or heteroaryl groups substituted by any group, substituted or unsubstituted alkyl or heteroalkyl groups, substituted or unsubstituted cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, hydroxyl groups, halogen groups, cyano groups, amino groups, ester groups, nitro groups, mercapto groups, substituted or unsubstituted amide groups, sulfonyl groups, phosphoryl groups, alkyloxyphosphoryl groups, alkyl sulfone groups, alkyl sulfoxide groups, borate ester groups, and borate groups.

[0018] Preferably, the substituted groups are selected independently from five- or six-membered aryl or heteroaryl groups substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl groups, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted C1-C10 alkoxy groups, substituted or unsubstituted C6-C12 aryloxy groups, hydroxyl groups, halogen groups, cyano groups, amino groups, ester groups, nitro groups, mercapto groups, substituted or unsubstituted amide groups, sulfonyl groups, phosphoryl groups, alkyloxyphosphoryl groups, alkyl sulfone groups, alkyl sulfoxide groups, borate ester groups, and borate groups.

[0019] L is selected from single bonds, O, S, NH, or alkylene groups.

[0020] Preferably, the alkylene group is a C1 to C10 alkylene group.

[0021] More preferably, the alkyl group is methylene or ethylene.

[0022] In this invention, when L is a single bond, it means that V is directly connected to the mother ring.

[0023] V is selected from substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl.

[0024] More preferably, V is selected from substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl.

[0025] The substituted groups are independently selected from aryl or heteroaryl groups substituted by any group, substituted or unsubstituted alkyl or heteroalkyl groups, substituted or unsubstituted cycloalkyl or heterocycloalkyl groups, alkoxy groups, halogen groups, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mercapto groups, substituted or unsubstituted amide groups, sulfonyl groups, phosphoryl groups, alkyloxyphosphoryl groups, alkyl sulfone groups, alkyl sulfoxide groups, borate ester groups, and borate groups.

[0026] Preferably, the substituted groups are selected independently from five- or six-membered aryl or heteroaryl groups substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl groups, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted C1-C10 alkoxy groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mercapto groups, substituted or unsubstituted amide groups, sulfonyl groups, phosphoryl groups, alkyloxyphosphoryl groups, alkyl sulfone groups, alkyl sulfoxide groups, borate ester groups, and borate groups.

[0027] R1 can be a carbonyl group, a thiocarbonyl group, a methylene group, or a single bond.

[0028] In this invention, R1 is a single bond, meaning that R2 is directly connected to the mother ring.

[0029] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide, borate ester, and borate.

[0030] More preferably, R2 and R3 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted five- or six-membered aryl or heteroaryl, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide, borate ester, or borate.

[0031] The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, amide, sulfonyl, and phosphoryl.

[0032] Preferably, the substituted groups are selected independently from halogens, hydroxyl groups, cyano groups, amino groups, mercapto groups, nitro groups, carboxyl groups, hydroxyamino groups, C1-C10 alkyl groups, C3-C10 cycloalkyl groups, C1-C10 heteroalkyl groups, C2-C10 heterocycloalkyl groups, six-membered aryl groups, five-membered or six-membered heteroaryl groups, ester groups, acyl groups, amide groups, sulfonyl groups, and phosphoryl groups.

[0033] In this invention, the aforementioned bicyclic or tricyclic compounds include, but are not limited to, spirocyclic, bridged, and fused-ring compounds.

[0034] In this invention, the aforementioned cycloalkyl or heterocycloalkyl includes, but is not limited to, monocyclic, spirocyclic, bridged, fused cycloalkyl or heterocycloalkyl.

[0035] Preferably, the compound of the present invention has the structure shown in Formula II or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts:

[0036]

[0037] A1 is selected from C-R6 or N.

[0038] R6 is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

[0039] Preferably, in this invention, R6 is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C3 heteroalkyl containing at least one N or O atom, or substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one N or O atom.

[0040] More preferably, R6 is selected from hydrogen, halogen, amino, methyl, ethyl, methoxy, cyano, trifluoromethyl, isopropyl or cyclopropyl.

[0041] R4 is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, and substituted or unsubstituted C5-C10 aryl or heteroaryl.

[0042] Preferably, in this invention, R4 is selected from substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl.

[0043] More preferably, R4 is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl groups, or substituted or unsubstituted C4-C6 heterocyclic alkyl groups containing at least one N or O atom.

[0044] The substituted groups are independently selected from halogens, cyano groups, amino groups, hydroxyl groups, substituted or unsubstituted amide groups, substituted or unsubstituted C1-C6 alkyl or heteroalkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups.

[0045] Preferably, the substituted groups are selected independently from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, and C3-C6 cycloalkyl.

[0046] In some specific embodiments of the present invention, the substituents are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxyethyl, or cyclopropyl.

[0047] X is selected from single-bonded, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, or alkenyl groups.

[0048] Preferably, in this invention, X is selected from single bonds, substituted or unsubstituted phenyl, pyridyl, alkynyl or alkenyl groups.

[0049] In this invention, X is selected from single-key symbols that are directly connected to the mother ring.

[0050] E is selected from single bonds, ester groups, amide groups, ether groups, carbonyl groups, sulfone groups, sulfoxide groups, thioamide groups, urea groups, thiourea groups, substituted or unsubstituted C1-C3 alkyl or heteroalkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups.

[0051] Preferably, in this invention, E is selected from single bonds, ester groups, amide groups, ether groups, carbonyl groups, substituted or unsubstituted C1-C3 alkyl or heteroalkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups.

[0052] In some specific embodiments of the present invention, E is selected from single bonds, ester groups, amide groups, ether groups, carbonyl groups, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and tri- to six-membered heterocyclic alkyl groups containing at least one N or O atom.

[0053] The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocyclic alkyl.

[0054] Preferably, the substituents are selected independently from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and tri- to six-membered heterocyclic alkyl groups containing at least one N or O atom.

[0055] In this invention, E is selected from a single key that directly connects R5 to X.

[0056] When both E and X are single bonds, it means that R5 is directly connected to the mother ring.

[0057] R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide, borate ester, and borate.

[0058] The alkoxy group mentioned above is preferably a substituted or unsubstituted C1 to C10 alkoxy group.

[0059] The aryloxy group mentioned above is preferably a substituted or unsubstituted C5 to C10 aryloxy group.

[0060] Preferably, in this invention, R5 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, borate ester, and borate.

[0061] More preferably, R5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, borate ester, and borate.

[0062] The substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C3-C6 heterocyclic alkyl.

[0063] Preferably, the substituted groups are selected independently from fluorine, chlorine, bromine, hydroxyl, cyano, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl, and tetrahydropyrrolyl.

[0064] W is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, hydroxyl, cyano, substituted or unsubstituted amino, ester, nitro, mercapto, amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide, borate ester, and borate group.

[0065] Preferably, W is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted five- or six-membered aryl or heteroaryl.

[0066] More preferably, W is selected from any one or more five- or six-membered heterocyclic alkyl groups containing N, O, and S.

[0067] In this invention, the heterocyclic alkyl group includes, but is not limited to, monocyclic, spirocyclic, bridged, and fused-ring heterocyclic alkyl groups.

[0068] The substituted groups are each independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl, aryl, or heteroaryl.

[0069] Preferably, the aryl or heteroaryl group is a substituted or unsubstituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl group.

[0070] Preferably, the substituted groups are selected independently from halogens, hydroxyl groups, cyano groups, amino groups, mercapto groups, nitro groups, carboxyl groups, hydroxyamino groups, C1-C3 alkyl groups, C3-C6 cycloalkyl groups, C1-C3 heteroalkyl groups, C3-C6 heterocycloalkyl groups, five- or six-membered aryl groups, five- or six-membered heteroaryl groups, ester groups, acyl groups, carbonyl groups, amide groups, sulfonyl groups, phosphoryl groups, aryl groups, or heteroaryl groups.

[0071] Preferably, the aryl or heteroaryl group is a substituted or unsubstituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl group.

[0072] In some specific embodiments of the present invention, the substituted group is selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0073] n can be either 0 or 1.

[0074] In this invention, when n is selected from 0, W is directly connected to the heteroaromatic ring containing Al atoms.

[0075] Preferably, the compound of the present invention has the structure shown in Formula III, or in the form of its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, pharmaceutically acceptable hydrate, solvate, or salt:

[0076]

[0077] R7 is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl groups, or substituted or unsubstituted C3-C10 heterocyclic alkyl groups containing at least one N or O atom.

[0078] Preferably, in this invention, R7 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, thiophene, pyrroleyl, and five- or six-membered heterocyclic alkyl containing at least one N and / or O atom.

[0079] In some specific embodiments of the present invention, R7 has any of the following structures:

[0080]

[0081] The curved line indicates the location of the connection.

[0082] Any one or more C atoms in the above structure may be optionally replaced by one or more substituents.

[0083] Preferably, the substituted groups are selected independently from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, and C3-C6 cycloalkyl.

[0084] More preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide groups, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and hydroxyethyl.

[0085] J is selected from single bonds, amides, carbonyl groups, substituted or unsubstituted C1-C3 alkyl or heteroalkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups.

[0086] Preferably, in this invention, J is selected from single bonds, amides, carbonyl groups, methylene groups, and methylene groups.

[0087] The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocyclic alkyl.

[0088] More preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrole, tetrahydrofuranyl, and hexahydropyridyl.

[0089] In this invention, when J is a single bond, it means that R8 is directly connected to the alkynyl group.

[0090] R8 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide, borate ester, and borate.

[0091] Preferably, R8 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyloxyphosphoryl, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 alkylsulfoxide, borate ester, and borate group.

[0092] More preferably, R8 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C6 alkyloxyphosphoryl, substituted or unsubstituted C1-C6 alkylsulfonyl, substituted or unsubstituted C1-C6 alkylsulfoxide, borate ester, borate.

[0093] More preferably, R8 is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, phenoxy, five- to seven-membered heterocyclic alkyl containing at least one N and / or O, five- or six-membered unsaturated cycloalkyl, pyridyl, amide, cyano, hydroxyl, halogen, amino, ester, nitro, mercapto, sulfonyl, phosphoryl, substituted or unsubstituted C1-C3 alkyloxyphosphoryl, substituted or unsubstituted C1-C3 alkylsulfonyl, substituted or unsubstituted C1-C3 alkylsulfoxide, borate ester, borate.

[0094] Preferably, the five- or six-membered unsaturated cycloalkyl group is cyclopentenyl or cyclohexenyl.

[0095] In this invention, the cycloalkyl or heterocycloalkyl groups mentioned above include, but are not limited to, monocyclic, spirocyclic, bridged, fused-ring cycloalkyl or heterocycloalkyl groups.

[0096] Preferably, the substituted groups are selected independently from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C3-C6 heterocycloalkyl.

[0097] More preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and five- or six-membered heterocyclic alkyl groups containing at least one N and / or O.

[0098] In some specific embodiments of the present invention, the five- or seven-membered heterocyclic alkyl group containing at least one N and / or O has any of the following structures:

[0099]

[0100] The curved line indicates the connection point.

[0101] Any one or more C atoms or N atoms in the above structure may be arbitrarily replaced by one or more of the above substituents.

[0102] Y is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl groups, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl groups, and substituted or unsubstituted five- or six-membered aryl or heteroaryl groups.

[0103] Preferably, Y is selected from substituted or unsubstituted five- or six-membered heterocyclic alkyl, phenyl, or pyridyl groups containing at least one N and / or O.

[0104] More preferably, Y is selected from substituted or unsubstituted five- or six-membered heterocyclic alkyl groups containing at least one N atom, and the N atom is connected to an adjacent carbonyl group to form an amide group.

[0105] In this invention, the heterocyclic alkyl group includes, but is not limited to, monocyclic, bridged, spirocyclic, and fused-ring heterocyclic alkyl groups.

[0106] The substituted groups are independently selected from halogens, hydroxyl groups, cyano groups, amino groups, mercapto groups, nitro groups, carboxyl groups, hydroxyamino groups, C1-C3 alkyl groups, C3-C6 cycloalkyl groups, C1-C3 heteroalkyl groups, C3-C6 heterocycloalkyl groups, five- or six-membered aryl groups, five- or six-membered heteroaryl groups, ester groups, acyl groups, carbonyl groups, amide groups, sulfonyl groups, phosphoryl groups, aryl groups, or heteroaryl groups.

[0107] Preferably, the aryl or heteroaryl group is a substituted or unsubstituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl group.

[0108] Preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocyclic alkyl groups containing at least one N and / or O, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl groups.

[0109] In some specific embodiments of the present invention, Y is selected from any of the following structures:

[0110]

[0111] The curved line indicates the connection point.

[0112] Any one or more C atoms or N atoms in the above structure can be arbitrarily replaced by one or more of the above substituents.

[0113] n is chosen from 0 or 1. Furthermore, n is chosen from 0.

[0114] When n is 0, Y is directly connected to the pyrimidine ring.

[0115] Preferably, the compound of the present invention has the structure shown in Formula IV, or in the form of its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, as well as a pharmaceutically acceptable hydrate, solvate, or salt.

[0116]

[0117] Where m is 0, 1, 2, 3 or 4.

[0118] In this invention, when m is not 0, the substituents on the benzene ring can be the same or different.

[0119] R9 is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl groups, or substituted or unsubstituted C3-C10 heterocyclic alkyl groups containing at least one N or O atom.

[0120] More preferably, R9 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, thiophene, pyrroleyl, and five- or six-membered heterocyclic alkyl containing at least one N and / or O.

[0121] In some specific embodiments of the present invention, R9 has any of the following structures:

[0122]

[0123] The curved line indicates the location of the connection.

[0124] Any one or more C atoms in the above structure may be optionally replaced by one or more substituents.

[0125] Preferably, the substituted groups are selected independently from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, and C3-C6 cycloalkyl.

[0126] More preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide groups, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and hydroxyethyl.

[0127] G is selected from single bonds, amides, ethers, carbonyls, substituted or unsubstituted C1-C3 alkyl or heteroalkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups.

[0128] Preferably, G is selected from single bonds, amides, ethers, carbonyls, methylenes, and difluoromethylenes.

[0129] The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocyclic alkyl.

[0130] More preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrole, tetrahydrofuranyl, and hexahydropyridyl.

[0131] In this invention, when G is selected from a single bond, it represents R. 10 It is directly connected to the benzene ring.

[0132] R 10 Selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide, borate ester, borate.

[0133] Preferably, in this invention, R 10Selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyloxyphosphoryl, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 alkylsulfoxide, borate ester, borate group.

[0134] More preferably, R 10 Selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C6 alkyloxyphosphoryl, substituted or unsubstituted C1-C6 alkylsulfonyl, substituted or unsubstituted C1-C6 alkylsulfoxide, borate ester, borate group.

[0135] Further preferred, R 10 Selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, five- to seven-membered heterocyclic alkyl containing at least one N and / or O, five- or six-membered unsaturated cycloalkyl, pyridyl, amide, cyano, hydroxyl, halogen, amino, ester, nitro, mercapto, sulfonyl, phosphoryl, substituted or unsubstituted C1-C3 alkyloxyphosphoryl, substituted or unsubstituted C1-C3 alkylsulfonyl, substituted or unsubstituted C1-C3 alkylsulfoxide, borate ester, borate group.

[0136] Preferably, the five- or six-membered unsaturated cycloalkyl group is cyclopentenyl or cyclohexenyl.

[0137] In this invention, the cycloalkyl or heterocycloalkyl groups mentioned above include, but are not limited to, monocyclic, spirocyclic, bridged, fused-ring cycloalkyl or heterocycloalkyl groups.

[0138] Preferably, the substituted groups are selected independently from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C3-C6 heterocyclic alkyl.

[0139] More preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and five- or six-membered heterocyclic alkyl groups containing at least one N and / or O.

[0140] In some specific embodiments of the present invention, the five- or seven-membered heterocyclic alkyl group containing at least one N and / or O has any of the following structures:

[0141]

[0142] The curved line indicates the location of the connection.

[0143] Any one or more C atoms or N atoms in the above structure may be arbitrarily replaced by one or more of the above substituents.

[0144] Z is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl groups, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl groups, substituted or unsubstituted five- or six-membered aryl or heteroaryl groups.

[0145] Preferably, Z is selected from substituted or unsubstituted five- or six-membered heterocyclic alkyl, phenyl, or pyridyl groups containing at least one N and / or O.

[0146] More preferably, Z is selected from substituted or unsubstituted five- or six-membered heterocyclic alkyl groups containing at least one N atom, and the N atom is connected to an adjacent carbonyl group to form an amide group.

[0147] In this invention, the heterocyclic alkyl group includes, but is not limited to, monocyclic, bridged, spirocyclic, and fused-ring heterocyclic alkyl groups.

[0148] The substituted groups are independently selected from halogens, hydroxyl groups, cyano groups, amino groups, mercapto groups, nitro groups, carboxyl groups, hydroxyamino groups, C1-C3 alkyl groups, C3-C6 cycloalkyl groups, C1-C3 heteroalkyl groups, C3-C6 heterocycloalkyl groups, five- or six-membered aryl groups, five- or six-membered heteroaryl groups, ester groups, acyl groups, carbonyl groups, amide groups, sulfonyl groups, phosphoryl groups, and substituted or unsubstituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl groups.

[0149] Preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocyclic alkyl groups containing at least one N and / or O, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl groups.

[0150] In some specific embodiments of the present invention, Z is selected from any of the following structures:

[0151]

[0152] The curved line indicates the connection point.

[0153] Any one or more C atoms or N atoms in the above structure can be arbitrarily replaced by one or more of the above substituents.

[0154] R 11 It is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.

[0155] Preferably, in this invention, R 11 It is independently selected from fluorine, chlorine, bromine, cyano, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C3-C6 heterocyclic alkyl.

[0156] n is chosen from 0 or 1. Furthermore, n is chosen from 0.

[0157] When n is 0, Z is directly connected to the pyrimidine ring.

[0158] In this invention, the cycloalkyl group includes saturated or unsaturated cycloalkyl groups.

[0159] The heterocyclic alkyl group includes saturated or unsaturated heterocyclic alkyl groups.

[0160] In this invention, the cycloalkyl group includes monocyclic, bridged, spirocyclic, and fused cycloalkyl groups.

[0161] The heterocyclic alkyl group includes monocyclic, bridged, spirocyclic, and fused-ring heterocyclic alkyl groups.

[0162] Preferably, the compound of the present invention has the structure shown in Formula V or its tautomers, meso compounds, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts:

[0163]

[0164] Wherein, X is selected from single-bonded, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl;

[0165] Preferably, in this invention, X is selected from single bonds, substituted or unsubstituted phenyl, pyridyl, ynyl or alkenyl groups.

[0166] In this invention, X is selected from single-key symbols that are directly connected to the mother ring.

[0167] E is selected from single bonds, ester groups, amide groups, ether groups, carbonyl groups, sulfone groups, sulfoxide groups, thioamide groups, urea groups, thiourea groups, substituted or unsubstituted C1-C3 alkyl or heteroalkyl groups, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.

[0168] Preferably, in this invention, E is selected from single bonds, ester groups, amide groups, ether groups, carbonyl groups, substituted or unsubstituted C1-C3 alkyl or heteroalkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups.

[0169] In some specific embodiments of the present invention, E is selected from single bonds, ester groups, amide groups, ether groups, carbonyl groups, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and tri- to six-membered heterocyclic alkyl groups containing at least one N or O atom.

[0170] Preferably, the substituents are selected independently from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and tri- to six-membered heterocyclic alkyl groups containing at least one N or O atom.

[0171] In this invention, E is selected from a single key indicating that R5 is directly connected to X;

[0172] When both E and X are single bonds, it means that R5 is directly connected to the mother ring.

[0173] R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkylsulfonyl, alkyl sulfoxide, borate ester, borate; wherein the substituted groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl;

[0174] The alkoxy group mentioned above is preferably a substituted or unsubstituted C1 to C10 alkoxy group.

[0175] The aryloxy group mentioned above is preferably a substituted or unsubstituted C5 to C10 aryloxy group.

[0176] More preferably, R5 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, borate ester, and borate.

[0177] More preferably, R5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, borate ester, and borate.

[0178] The substituted groups are independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl, tetrahydropyrrolyl, piperazine, N-methylpiperazine, tetrahydropyridyl, and morpholino.

[0179] K is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, hydroxyl, cyano, substituted or unsubstituted amino, ester, nitro, mercapto, amide, sulfonyl, phosphoryl, alkyloxyphospho, alkylsulfonyl, alkyl sulfoxide, borate ester, and borate group; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, ester, acyl, and carbonyl. Amide, sulfonyl, phosphoryl, with one or more substituents substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl groups; wherein the substituents of the monocyclic, bicyclic or tricyclic aryl or heteroaryl groups are deuterium, fluorine, chlorine, bromine, cyano, amino, hydroxyl, nitro, mercapto, sulfone, sulfoxide, borate ester, borate, alkyloxyphosphoryl, ester, amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclic alkyl;

[0180] More preferably, K is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups containing at least one N, O, or S, substituted or unsubstituted C3-C10 cycloalkyl groups, substituted or unsubstituted C3-C10 heterocycloalkyl groups containing at least one N, O, or S, and substituted or unsubstituted five- or six-membered aryl or heteroaryl groups; wherein the substituted groups are each independently selected from amino, halogen, hydroxyl, cyano, mercapto, nitro, carboxyl, amide, ester, carbonyl, sulfonyl, phosphoryl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C6 cycloalkyl, C3 ... 3. Heteroalkyl, C3-C6 heterocyclic alkyl, aryl or heteroaryl with multiple substituents, whether monocyclic, bicyclic or tricyclic; wherein the substituents of the monocyclic, bicyclic or tricyclic aryl or heteroaryl are deuterium, fluorine, chlorine, bromine, cyano, amino, hydroxyl, nitro, mercapto, sulfone, sulfoxide, borate ester, borate, alkyloxyphosphoryl, ester, amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclic alkyl;

[0181] More preferably, K is an N-containing heterocyclic group of C3 to C10, an N-containing spirocyclic group of C6 to C12, or an N-containing fused ring group of C6 to C12.

[0182] Preferably, the N atom is directly connected to the parent ring.

[0183] In some specific embodiments of the present invention, K has the following groups:

[0184]

[0185] Preferably, in this invention, any one or more carbon atoms or nitrogen atoms of the above-mentioned groups may be connected to one or more substituents;

[0186] The substituents are preferably amino, halogen, amide, sulfonyl, sulfonic acid, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amino, C6-C12 aryl, or C5-C12 heteroaryl; the aforementioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amino, C6-C12 aryl, or C5-C12 heteroaryl groups may optionally be substituted by one or more halogens, hydroxyl groups, nitro groups, cyano groups, mercapto groups, sulfonic acid groups, or amino groups.

[0187] In some specific embodiments of the present invention, the substituents are selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, amide, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and naphthyl.

[0188] Preferably, the above-mentioned substituents can be further replaced by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, or sulfonic acid groups, or any one or more carbon atoms can be oxidized or thiolated.

[0189] n is selected from 0 or 1; furthermore, n is selected from 0.

[0190] When n is 0, K is directly connected to the pyrimidine ring.

[0191] Preferably, the compound of the present invention has the structure shown in Formula VI or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts:

[0192]

[0193] Wherein, X is selected from single-bonded, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl.

[0194] E is selected from single bonds, ester groups, amide groups, ether groups, carbonyl groups, sulfone groups, sulfoxide groups, thioamide groups, urea groups, thiourea groups, substituted or unsubstituted C1-C3 alkyl or heteroalkyl groups, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl groups; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.

[0195] R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphoryl, alkyl sulfone, alkyl sulfoxide, borate ester, borate; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl.

[0196] P is selected from NR 13 CR 14 R 15 ;

[0197] R 12 R 13 R 14 R 15Independently selected from hydrogen, amino, halogen, amide, sulfonyl, sulfonic acid, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amino, C6-C12 aryl, C5-C12 heteroaryl; the above C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amino, C6-C12 aryl, C5-C12 heteroaryl may optionally be substituted by one or more halogens, hydroxyl, nitro, cyano, mercapto, sulfonic acid, amino, C1-C6 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl;

[0198] R 13 R 14 R 15 The group is preferably an amino group, halogen, amide group, sulfonyl group, sulfonic acid group, hydroxyl group, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amino group, C6-C12 aryl, or C5-C12 heteroaryl group; the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amino group, C6-C12 aryl, or C5-C12 heteroaryl group may optionally be substituted by one or more halogens, hydroxyl groups, nitro groups, cyano groups, mercapto groups, sulfonic acid groups, or amino groups.

[0199] In some specific embodiments of the present invention, the substituents are selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, amide, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and naphthyl.

[0200] Preferably, the above-mentioned substituents can be further replaced by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, or sulfonic acid groups, or any one or more carbon atoms can be oxidized or thiolated.

[0201] The R 12 A amino group is even more preferred.

[0202] Or R 12 It forms a spiroring structure with P atoms;

[0203] Or R 12 The P atom and the carbon atoms adjacent to the P atom form a fused ring structure;

[0204] n is selected from 0 or 1; furthermore, n is selected from 0.

[0205] When n is 0, the N atom in the N-containing heterocycle is directly attached to the pyrimidine ring.

[0206] n1 is selected from 0 to 5; specifically, it can be selected from 0, 1, 2, 3, 4 or 5.

[0207] Preferably, the compound of the present invention has the structure shown in Formula VII or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, pharmaceutically acceptable hydrates, solvates, or salts.

[0208]

[0209] in,

[0210] R 16 Selected from hydrogen, fluorine, chlorine, bromine, iodine, alkynyl, C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl or heterocycloalkyl; further R 16 Selected from fluorine, chlorine, bromine, and alkynyl groups;

[0211] R 17 Selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, ester, nitro, amide, mercapto, sulfonyl, alkyloxyphospho, alkylsulfonyl, alkyl sulfoxide, borate ester, borate, substituted or unsubstituted heteroalkyl groups containing at least one N, O, or S atom at C1-C6, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C1-C6 substituted amino groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted C3-C6 heterocycloalkyl groups containing at least one N, O, or S atom, substituted or unsubstituted aryl or heteroaryl groups, substituted or unsubstituted alkynyl or alkenyl groups, or two identical or different R groups. 17 Together with the attached phenyl group, they form a five- to twelve-membered cyclic structure group containing at least one of C, N, O, or S atoms, whether substituted or unsubstituted, wherein the substituted groups are independently selected from deuterium, halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, or phosphoryl.

[0212] Preferably, the five- to twelve-membered cyclic structure group of the present invention can be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. This cyclic structure, together with the attached phenyl group, constitutes the following groups, but is not limited to: substituted or unsubstituted piperonyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzopyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted benzocrown etheryl, substituted or unsubstituted anthraquinyl, substituted or unsubstituted benzomorpholinyl, substituted or unsubstituted tetrahydroquinoxaline, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzodihydrofuran, substituted or unsubstituted benzoisoxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzimidazole, and substituted or unsubstituted benzopyrazole.

[0213] Further R 17 The group is selected from methoxy, trifluoromethoxy, difluoromethoxy, methoxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethoxy, fluorine, chlorine, bromine, cyano, hydroxyl, methyl sulfone, methyl sulfoxide, dimethyl oxyphospho, or two identical or different R17 groups and the attached phenyl group, which together form a five- or six-membered cyclic structure containing at least one substituted or unsubstituted C, N, O, or S atom, wherein the substituted group is independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, mercapto, nitro, C1-C3 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl, five- or six-membered aryl or heteroaryl;

[0214] Preferably, the five- to six-membered cyclic structure group of the present invention can be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. This cyclic structure, together with the attached phenyl group, constitutes the following groups, but not limited to: substituted or unsubstituted piperonyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzopyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted benzomorpholinyl, substituted or unsubstituted benzotetrahydroquinoxaline, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzodihydrofuran, substituted or unsubstituted benzoisoxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzimidazole, and substituted or unsubstituted benzopyrazole.

[0215] n2 is selected from 0, 1, 2, 3, 4, and 5.

[0216] In this invention, the amino group or substituted amino group refers to a group formed by replacing one or two hydrogen atoms of an amino group with a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C3-C6 cycloalkyl group.

[0217] More preferably, the amino group or substituted amino group is selected from methylamino, ethylamino, propylamino, isopropylamino, or butylamino.

[0218] In some specific embodiments of the present invention, the compound has any of the following structures:

[0219]

[0220]

[0221]

[0222]

[0223]

[0224] Specifically, the present invention provides a PAK4 inhibitor comprising the above-mentioned compound and a pharmaceutically acceptable adjuvant.

[0225] The present invention does not specifically limit the type of excipients, which can be excipients well known to those skilled in the art.

[0226] In this invention, the compound can be used alone or in combination with other drugs.

[0227] This invention provides the use of the above-mentioned compound or the above-mentioned PAK4 inhibitor in the preparation of PAK4 inhibitors.

[0228] Preferably, the PAK4 inhibitor is suitable for cancers, neurodegenerative diseases, or immune system diseases related to the expression or activity of PAK4 kinase.

[0229] Preferably, the cancers mentioned in this invention include breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, biliary tract cancer, pancreatic cancer, lymphoma, pilocytic carcinoma, nasopharyngeal carcinoma, pharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancers, cervical cancer, prostate cancer, and testicular cancer. Urogenital tract cancer, lung cancer, non-small cell lung cancer, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, Hodgkin's leukemia, bronchial cancer, thyroid cancer, endometrial cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, myeloid leukemia, non-Hodgkin's lymphoma, primary macroglobulinemia.

[0230] Compared with existing technologies, this invention provides a compound as a PAK4 inhibitor, having the structure shown in Formula I or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, pharmaceutically acceptable hydrates, solvates, or salts. Experimental results show that the compound prepared by this invention exhibits high inhibitory activity and selectivity against PAK4 kinase, while also showing improved liver microsomal stability and rat pharmacokinase activity. Detailed Implementation

[0231] To further illustrate the present invention, the following detailed description, in conjunction with embodiments, describes the compounds provided by the present invention as PAK4 kinase inhibitors, their preparation methods, and applications.

[0232] The abbreviations appearing in the following examples have the following meanings:

[0233] Et3N: Triethylamine;

[0234] EA: Ethyl acetate;

[0235] THF: Tetrahydrofuran;

[0236] EtOH: Ethanol;

[0237] MeOH: Methanol;

[0238] SOCl2: thionyl chloride;

[0239] DIEA: N,N-Diisopropylethylamine;

[0240] LDA: Lithium diisopropylaminodimethylamine;

[0241] n-BuLi: n-Butyllithium;

[0242] DAST: Diethylaminosulfur trifluoride;

[0243] DME: Ethylene glycol dimethyl ether;

[0244] M: Molar concentration unit mol / L, for example 1M means 1 mol / L;

[0245] N: Equivalent concentration, for example, 1N HCl refers to hydrochloric acid with a concentration of 1 mol / L;

[0246] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate;

[0247] DMF: N,N-dimethylformamide;

[0248] TLC: Thin-layer chromatography;

[0249] PE: Petroleum ether (boiling point 60-90℃);

[0250] DCM: Dichloromethane;

[0251] H2O: Distilled water;

[0252] DMSO: Dimethyl sulfoxide;

[0253] Pd2(dba)3: 3,3,6,6-Tetramethyl-9-(1,2,3,4-tetrahydroxybutyl)-4,5,7,9-tetrahydro-2H-xanthracene-1,8-dione);

[0254] Xphos: 2-Dicyclohexylphosphine-2,4,6-triisopropylbiphenyl;

[0255] DPPF: 1,1'-bis(diphenylphosphine)ferrocene;

[0256] Pd(PPh3)2Cl2: Palladium dichloride of bis(triphenylphosphine);

[0257] Pd(dppf)Cl2.DCM:[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex;

[0258] HCl / 1,4-dioxane: hydrochloric acid / 1,4-dioxane solution;

[0259] DCC: Dicyclohexylcarbodiimide;

[0260] TBAF: Tetrabutylammonium fluoride;

[0261] 1,4-dioxane: 1,4-dioxane;

[0262] KI: Potassium iodide;

[0263] LiHMDS: Lithium hexamethyldisilamide;

[0264] Preparation of intermediates

[0265] Preparation of intermediate: (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

[0266]

[0267] Step 1: Preparation of 2-amino-5-iodobenzamide

[0268] 2-Aminobenzamide (10.00 g, 73.48 mmol) was dissolved in 250 mL of H₂O. Sodium bicarbonate (6.17 g, 73.48 mmol) and iodine powder (20.51 g, 80.83 mmol) were added sequentially, and the mixture was stirred at room temperature for 24 hours. TLC analysis confirmed the reaction was complete. The pH of the reaction solution was adjusted to approximately 7 using sodium bisulfite. The solid was filtered, washed with water, dispersed in ethanol, and heated to reflux until dissolved. After cooling, the mixture was filtered to obtain the target compound (14.20 g, yield 73.8%) as a pale purple solid.

[0269] EM (calculated value): 262.0; MS (ESI) m / z (M+H) + : 263.0

[0270] Step 2: Preparation of ethyl 2-((2-carbamoyl-4-iodophenyl)amino)-2-oxoacetate

[0271] 2-Amino-5-iodobenzamide (14.00 g, 53.44 mmol) was dissolved in THF (250 mL), and Et3N (10.80 g, 106.88 mmol) was added. The mixture was stirred at 0 °C. Oxaloyl chloride monoethyl ester (8.02 g, 58.78 mmol) was slowly added dropwise to the reaction system, and the mixture was stirred at the same temperature for 2 hours. TLC analysis showed that the reaction was complete. After most of the THF in the reaction solution was concentrated, the remainder was added to water (1 L) with stirring, resulting in the precipitation of a large amount of solid. The solid was filtered and dried to obtain the target compound (16.5 g, yield 85.3%) as a pale purple solid.

[0272] EM (calculated value): 362.0; MS (ESI) m / z (M+H) + 363.0

[0273] Step 3: Preparation of ethyl 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate

[0274] 16.00 g (44.20 mmol) of ethyl 2-((2-carbamoyl-4-iodophenyl)amino)-2-oxoethyl acetate was dissolved in 300 mL of EtOH. Sodium ethoxide (3.61 g, 53.04 mmol) was added under ice-water bath conditions, and stirring was continued for 3 hours. TLC analysis confirmed the reaction was complete. The pH of the reaction solution was adjusted to 3–4 with concentrated hydrochloric acid. The reaction solution was then added to water with stirring, resulting in the precipitation of a large amount of solid. The solid was filtered and dried to obtain the target compound (12.5 g, yield 82.3%) as a white solid.

[0275] EM (calculated value): 344.0; MS (ESI) m / z (M+H)+ 345.0

[0276] Step 4: Preparation of 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid

[0277] Ethyl 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid (12.00 g, 34.88 mmol) was dissolved in EtOH / H₂O (200 mL, 1 / 1), and sodium hydroxide (5.58 g, 139.52 mmol) was added. The mixture was stirred at room temperature for 2 hours. TLC analysis confirmed the reaction was complete. The pH of the reaction solution was adjusted to 5–6 with 2N hydrochloric acid in an ice-water bath. The solid was filtered and dried to obtain the target compound (10.28 g, yield 93.3%) as a white solid.

[0278] EM (calculated value): 315.9; MS (ESI) m / z (MH) - 315.0

[0279] Step 5: Preparation of 4-chloro-6-iodoquinazoline-2-acetyl chloride

[0280] 10.00 g (31.66 mmol) of compound 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid was dissolved in 150 mL of chloroform. DMF (1 mL) and SOCl2 (37.68 g (316.6 mmol) were then added sequentially. The mixture was heated to 80 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness to obtain the target compound (crude product), which was a brown oily liquid.

[0281] Step 6: Preparation of (R)-4-(4-chloro-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

[0282] The crude compound 4-chloro-6-iodoquinazolin-2-acetyl chloride was dissolved in DCM (200 mL), and Et3N (9.59 g, 94.98 mmol) was added. The reaction temperature was cooled to approximately -65 °C. (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (6.34 g, 31.66 mmol) was dissolved in DCM (20 mL), and this solution was slowly added dropwise to the reaction system. The mixture was stirred at this temperature for 30 minutes. TLC analysis confirmed the reaction was complete. The reaction solution was concentrated, and the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrates were combined and washed twice with H2O. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness to give the target compound (13.41 g, two-step yield 74.4%) as a brown solid.

[0283] EM (calculated value): 516.0; MS (ESI) m / z (M+H)+ 517.0

[0284] Step 7: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

[0285] Compound (R)-4-(4-chloro-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl (13.00 g, 25.19 mmol) was dissolved in DMF (150 mL), and DIEA (6.50 g, 50.38 mmol), potassium iodide (8.36 g, 50.38 mmol), and 5-cyclopropyl-1H-pyrazole-3-amine (3.10 g, 25.19 mmol) were added sequentially. The mixture was heated to 65 °C and stirred for 4 hours. TLC analysis showed that the reaction proceeded completely. The reaction solution was added to water and extracted three times with EA. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give the target compound (10.8 g, yield 71.3%) as a pale yellow solid.

[0286] EM (calculated value): 603.1; MS (ESI) m / z (M+H) + : 604.1

[0287] Product proton NMR data:

[0288] 1 H NMR(400MHz,DMSO-d6)δ0.59-0.72(2H,m),0.91-094(2H,m),1.01(1.5H,d,J=6.8Hz),1.1 7(1.5H,d,J=6.4Hz),1.39-1.40(9H,m),1.86-1.94(1H,m),2.97-3.06(2H,m),3.26-3.27 (1H,m),3.34-3.39(1H,m),3.58-3.84(1H,m),4.01-4.36(2H,m),6.48(1H,s),7.51-7.55 (1H,m),8.10-8.13(1H,m),9.15-9.17(1H,m),10.67-10.77(1H,m),12.27-12.38(1H,m).

[0289] Example Compounds

[0290] Example 1: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0291]

[0292] Step 1: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

[0293] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl (200 mg, 0.33 mmol) and 1-ethynylcyclohexanol (82 mg, 0.66 mmol) were added to DMF (5 mL), followed by Et3N (67 mg, 0.66 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol). The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with anhydrous sodium sulfate, the solution was concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain the target compound (70 mg, yield 35.4%) as a white solid.

[0294] EM (calculated value): 599.3; MS (ESI) m / z (M+H) + 600.3

[0295] Step 2: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0296] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl (70 mg, 0.12 mmol) was dissolved in DCM (5 mL), and 4N HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred in an ice-water bath for 2 hours. After the reaction was complete, the supernatant was discarded, and the remaining solid was washed twice with diethyl ether to obtain the target compound (23 mg, yield 38.4%) as a yellow solid.

[0297] EM (calculated value): 499.3; MS (ESI) m / z (M+H) + 500.3

[0298] 1H NMR(400MHz, DMSO-d6)δ0.65-0.72(2H,m),0.84-0.89(2H,m),0.95(1.5H,d,J=8.4Hz),1.09(1.5H, d,J=8.0Hz),1.21-1.28(2H,m),1.45-1.58(5H,m),1.68-1.71(2H,m),1.87-1.98(2H,m),2.62-2.67 (2H,m),2.71-2.78(2H,m),2.82-2.90(1H,m),2.99-3.09(1H,m),4.22-4.37(1H,m),6.45(1H,d,J=1 0.8Hz),7.71(1H,d,J=7.6Hz),7.79(1H,d,J=8.0Hz),8.81(1H,s),10.72(2H,brs),11.20(1H,brs).

[0299] The compounds shown in Table 1 below were synthesized according to the method described in Example 1:

[0300] Table 1

[0301]

[0302]

[0303]

[0304]

[0305]

[0306] Example 12 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazin-1-carbonyl)quinazolin-6-yl)boronic acid hydrochloride

[0307]

[0308] Step 1: Preparation of (R)-(2-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-6-yl)boronic acid

[0309] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazin-1-carboxylic acid tert-butyl (100 mg, 0.17 mmol), pinacol diboronate (86 mg, 0.34 mmol), cesium fluoride (52 mg, 0.34 mmol), and pyridine (40 mg, 0.51 mmol) were added to DMSO (4 mL) and stirred at 110 °C for 3 hours under nitrogen protection. After the reaction was complete, water (40 mL) was added to the reaction solution, and the mixture was extracted five times with DCM / MeOH (5 / 1). The organic phases were combined, dried over Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH = 5 / 1) to give the target compound (30 mg, yield 33.8%) as a yellow solid.

[0310] EM (calculated value): 521.3; MS (ESI) m / z (M+H) + 522.3

[0311] Step 2: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazin-1-carbonyl)quinazolin-6-yl)boronic acid hydrochloride

[0312] Compound (R)-(2-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-carbonyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-6-yl)boronic acid (30 mg, 0.06 mmol) was dissolved in 4N HCl / 1,4-dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with a small amount of methanol, and dried to obtain the target compound (14 mg, yield 57.8%) as a yellow solid.

[0313] EM (calculated value): 421.2; MS (ESI) m / z (M+H) + : 422.0

[0314] 1H NMR(400MHz, DMSO-d6)δ0.74-0.80(2H,m),0.95-1.01(2H,m),1.15(1.5H,d,J=5.6Hz),1.36( 1.5H,d,J=6.4Hz),1.98-2.04(1H,m),3.01-3.15(1H,m),3.19-3.28(1H,m),3.33-3.45(2H,m) ,3.60-3.66(1H,m),4.13-4.20(1H,m),4.42-4.48(1H,m),6.37(1H,d,J=3.2Hz),7.93(1H,dd ,J=8.4Hz,2.4Hz),8.37(1H,d,J=8.4Hz),9.29(1H,d,J=5.6Hz),9.94(2H,s),11.91(1H,brs).

[0315] Example 13 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0316] Step 1: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0317] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl (100 mg, 0.17 mmol), dimethylphosphine oxide (66 mg, 0.85 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), xphos (19 mg, 0.04 mmol), and Et3N (52 mg, 0.51 mmol) were added to 1,4-dioxane (4 mL), and the mixture was stirred at 110 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH = 50 / 1) to obtain the target compound (53 mg, yield 56.4%) as a yellow solid.

[0318] EM (calculated value): 553.3; MS (ESI) m / z (M+H) + 554.3

[0319] Step 2: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0320] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (53 mg, 0.10 mmol) was dissolved in 4N HCl / 1,4-dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with a small amount of methanol, and dried to give the target compound (27 mg, yield 59.6%) as a yellow solid.

[0321] EM (calculated value): 453.2; MS (ESI) m / z (M+H) + : 454.0

[0322] 1 H NMR (400MHz, DMSO-d6) δ0.75-0.78(2H,m),0.97-1.01(2H,m),1.13(1.5H,d,J=6.0Hz),1.36(1.5H,d,J=6.4Hz ),1.79(3H,s),1.82(3H,s),1.97-2.04(1H,m),2.94-3.05(1H,m),3.18-3.24(1H,m),3.28-3.31(1H,m),3.36- 3.42(1H,m),3.50-3.56(1H,m),3.92-4.00(1H,m),4.43-4.46(1H,m),6.47(1H,d,J=6.4Hz),8.00(1H,d,J=8.4 Hz),8.28-8.32(1H,m),9.21(1H,dd,J=12.8Hz,3.2Hz),9.63-9.68(1H,m),9.73-9.78(1H,m),11.79(1H,brs).

[0323] Example 14 Preparation of (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-yl)(4,7-diazaspiro[2.5]octane-7-yl) methyl ketone hydrochloride

[0324]

[0325] Step 1: Preparation of tert-butyl 7-(4-chloro-6-iodoquinazolin-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid

[0326] 4-Chloro-6-iodoquinazolin-2-acetyl chloride (300 mg, 0.85 mmol) was dissolved in DCM (200 mL), and Et3N (172 mg, 1.70 mmol) was added. The reaction temperature was cooled to approximately -65 °C. 4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (180 mg, 0.85 mmol) was dissolved in DCM (4 mL), and this solution was slowly added dropwise to the reaction system. The mixture was stirred at this temperature for 30 minutes. TLC detection showed that the reaction was complete. The reaction solution was concentrated, and the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrates were combined and washed twice with H2O. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by column chromatography (PE / EA = 3 / 1) to obtain the target compound (326 mg, yield 72.6%) as a brown solid.

[0327] EM (calculated value): 528.0; MS (ESI) m / z (M+H) + 529.0

[0328] Step 2: Preparation of tert-butyl 7-(4-(((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid

[0329] 320 mg (0.61 mmol) of 7-(4-chloro-6-iodoquinazolin-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester was dissolved in DMF (10 mL). DIEA (157 mg, 1.22 mmol), potassium iodide (203 mg, 1.22 mmol), and 5-cyclopropyl-1H-pyrazole-3-amine (75 mg, 0.61 mmol) were added sequentially, and the mixture was heated to 65 °C and stirred for 2 hours. TLC analysis confirmed the reaction was complete. The reaction solution was added to water and extracted three times with EA. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to obtain the target compound (195 mg, yield 52.1%) as a yellow solid.

[0330] EM (calculated value): 615.1; MS (ESI) m / z (M+H) + : 616.1

[0331] Step 3: Preparation of tert-butyl 7-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid

[0332] Compound 7-(4-(((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (190 mg, 0.31 mmol) and 1-ethynylcyclohexanol (77 mg, 0.62 mmol) were added to DMF (10 mL), followed by Et3N (63 mg, 0.62 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with Na2SO4, the solution was concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH = 25 / 1) to obtain the target compound (61 mg, yield 32.4%) as a white solid.

[0333] EM (calculated value): 611.3; MS (ESI) m / z (M+H) + 612.3

[0334] Step 4: Preparation of (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-yl)(4,7-diazaspiro[2.5]octane-7-yl)methyl ketone hydrochloride.

[0335] Compound 7-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) was dissolved in DCM (5 mL), and 4N HCl / 1,4-dioxane (3 mL) was added. The mixture was stirred in an ice-water bath for 2 hours. After the reaction was complete, the solid was filtered and washed with a small amount of methanol to give the target compound (16 mg, yield 30.9%) as a yellow solid.

[0336] EM (calculated value): 511.3; MS (ESI) m / z (M+H) + 512.3

[0337] 1H NMR(400MHz,DMSO-d6)δ0.34-0.37(2H,m),0.51-0.58(2H,m),0.66-0.71(2H,m),0.93-0.99(2H,m),1.2 5-1.31(1H,m),1.49-1.61(5H,m),1.61-1.71(2H,m),1.85-1.95(3H,m),2.67-2.73(1H,m),2.78-2.83(1 H,m),3.02-3.06(1H,m),3.15-3.20(1H,m),3.44-3.47(1H,m),3.57-3.61(1H,m),5.53(1H,d,J=5.2Hz), 6.53(1H,d,J=18.8Hz),7.69-7.77(2H,m),8.81-8.85(1H,m),10.66-10.76(1H,m),12.27-12.33(1H,m).

[0338] The compounds shown in Table 2 below were synthesized according to the method described in Example 14:

[0339] Table 2

[0340]

[0341]

[0342]

[0343] Example 18. Preparation of (R)-4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6-carboxynitrile hydrochloride.

[0344]

[0345] Step 1: Preparation of (R)-4-(6-cyano-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0346] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazin-1-carboxylic acid tert-butyl (100 mg, 0.17 mmol), zinc cyanide (59 mg, 0.51 mmol), DPPF (17 mg, 0.03 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and zinc powder (2 mg, 0.03 mmol) were added to DMF (6 mL) and stirred for 3 hours in an oil bath preheated to 120 °C under nitrogen protection. After the reaction was complete, water (60 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with Na2SO4, the product was concentrated to dryness. The crude product was then purified by column chromatography (DCM / MeOH = 40 / 1) to obtain the target compound (45 mg, yield 52.4%) as a yellow solid.

[0347] EM (calculated value): 502.2; MS (ESI) m / z (M+H) + 503.2

[0348] Step 2: Preparation of (R)-4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6-carboxynitrile hydrochloride.

[0349] Compound (R)-4-(6-cyano-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester (43 mg, 0.09 mmol) was dispersed in DCM (5 mL), and 4N HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred in an ice-water bath for 2 hours. After the reaction was complete, the solid was filtered and washed with a small amount of THF to obtain the target compound (18 mg, yield 50.9%) as a pale yellow solid.

[0350] EM (calculated value): 402.2; MS (ESI) m / z (M+H) + : 403.2

[0351] 1H NMR(400MHz, DMSO-d6)δ0.72-0.75(2H,m),0.94-0.99(2H,m),1.12(1.5H,d,J=5.2Hz),1.34( 1.5H,d,J=6.4Hz),1.93-2.00(1H,m),2.89-2.98(1H,m),3.08-3.24(2H,m),3.33-3.48(2H,m) ,3.73-3.83(1H,m),4.42(1H,d,J=12.8Hz),6.47(1H,d,J=10.4Hz),7.90(1H,dd,J=8.8Hz,4. 0Hz),8.20(1H,d,J=8.4Hz),9.32(1H,s),9.42-9.45(1H,m),9.54-9.57(1H,m),11.10(1H,s).

[0352] Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-yl)(3-methylpiperazin-1-yl) methyl ketone (Example 19) and (R)-(6-(5-(cyclohex-1-en-1-yl)thiophen-2-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(3-methylpiperazin-1-yl) methyl ketone (Example 20)

[0353]

[0354] Step 1: Preparation of 1-(5-bromothiophen-2-yl)cyclohexyl-1-ol

[0355] 2-Bromothiophene (1.0 g, 6.18 mmol) was dissolved in anhydrous THF (10 mL) and cooled to -70 °C under nitrogen protection. LDA (6.8 mmol, 2 M in THF, 3.2 mL) was slowly added dropwise to the reaction system, and stirring was continued at this temperature for 1 hour. Cyclohexanone (668 mg, 6.80 mmol) was dissolved in anhydrous THF (3 mL) and added dropwise to the reaction system, and stirring was continued for 30 minutes. The reaction solution was quenched with saturated ammonium chloride aqueous solution, water was added, and the mixture was extracted twice with EA. The organic phases were combined, dried over Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography (PE / EA = 10 / 1) to give the target compound (1.39 g, yield 86.3%) as a yellow oil.

[0356] EM (calculated value): 260.0; MS (ESI) m / z (M+H) + : 261.0

[0357] Step 2: Preparation of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene-2-yl)cyclohexyl-1-ol

[0358] Compound 1-(5-bromothiophene-2-yl)cyclohexyl-1-ol (1.35 g, 5.19 mmol), pinacol diboronate (2.64 g, 10.38 mmol), Pd(dppf)Cl2.DCM (375 mg, 0.52 mmol), and potassium acetate (1.02 g, 10.38 mmol) were added to 1,4-dioxane (20 mL). The mixture was stirred for 2.5 hours in an oil bath preheated to 90 °C under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness. The crude product was purified by column chromatography (PE / EA = 8 / 1) to obtain the target compound (500 mg, yield 31.3%) as a pale yellow solid.

[0359] EM (calculated value): 308.2; MS (ESI) m / z (M+H) + 309.2

[0360] Step 3: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0361] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazin-1-carboxylic acid tert-butyl (100 mg, 0.17 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene-2-yl)cyclohexyl-1-ol (105 mg, 0.34 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added to 1,4-dioxane / H2O (10 mL) and stirred for 2 hours in an oil bath preheated to 70 °C under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to obtain the target compound (70 mg, yield 31.3%), which was an off-white solid.

[0362] EM (calculated value): 657.3; MS (ESI) m / z (M+H) + : 658.3

[0363] Step 4: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-yl)(3-methylpiperazin-1-yl) methyl ketone (Example 19) and (R)-(6-(5-(cyclohex-1-en-1-yl)thiophen-2-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(3-methylpiperazin-1-yl) methyl ketone (Example 20)

[0364] The compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.11 mmol) was dispersed in DCM (5 mL), and 4N HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred in an ice-water bath for 1 hour. After the reaction was complete, the pH was adjusted to about 7 with sodium carbonate aqueous solution, and the mixture was concentrated to dryness. The residue was purified by prep-HPLC to obtain the target compound (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-yl)(3-methylpiperazin-1-yl) methyl ketone (10 mg, yield 16.3%) and (R)-(6-(5-(cyclohex-1-en-1-yl)thiophen-2-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(3-methylpiperazin-1-yl) methyl ketone (6 mg, yield 10.1%), both of which were off-white solids.

[0365] (Example 19) EM (calculated value): 557.3; MS (ESI) m / z (M+H) + 558.3;

[0366] (Example 19) 1H NMR(400MHz,DMSO-d6)δ0.67-0.70(2H,m),0.81-0.83(2H,m),0.97-0.99(1.5H,m),1.11-1.07(1.5H,m),1.56- 1.60(2H,m),1.69-1.75(2H,m),1.95-1.98(2H,m),2.22-2.24(2H,m),2.39-2.42(2H,m),2.60-2.81(4H,m),2.9 4-3.02(1H,m),3.30-3.33(1H,m),3.44-3.50(1H,m),6.30(1H,s),6.51-6.54(1H,m),7.15(1H,d,J=3.6Hz),7.6 8(1H,d,J=3.2Hz),7.77(1H,d,J=8.4Hz),8.05(1H,d,J=8.4Hz),8.19(1H,s),8.85(1H,s),10.81-10.86(1H,m).

[0367] (Example 20) EM (calculated value): 539.2; MS (ESI) m / z (M+H) + 540.2;

[0368] (Example 20) 1 H NMR(400MHz,DMSO-d6)δ0.69-0.71(2H,m),0.83-0.86(2H,m),0.95-0.97(1.5H,m),1.07-1.08(1.5H,m),1.58 -1.63(2H,m),1.71-1.74(2H,m),1.94-1.95(1H,m),2.20-2.22(2H,m),2.40-2.43(2H,m),2.61-2.83(4H,m),2 .97-3.05(1H,m),3.36-3.37(1H,m),4.30-4.32(1H,m),6.25(1H,s),6.49-6.52(1H,m),7.12(1H,d,J=3.6Hz), 7.67(1H,d,J=3.2Hz),7.75(1H,d,J=8.4Hz),8.00(1H,d,J=8.4Hz),8.22(1H,s),8.91(1H,s),10.83(1H,brs).

[0369] The compounds shown in Table 3 below were synthesized according to the method described in Example 19:

[0370] Table 3

[0371]

[0372]

[0373] Example 22 Preparation of (6-((5-chloro-2-hydroxyadamantane-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)((R)-3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0374]

[0375] Step 1: Preparation of 5-chloro-2-((trimethylsilyl)ethynyl)adamantane-2-ol

[0376] The compound trimethylsilylacetylene (500 mg, 5.10 mmol) was dissolved in anhydrous THF (10 mL) and cooled to -70 °C under nitrogen protection. n-BuLi (6.12 mmol, 2.5 M in n-hexane, 2.4 mL) was slowly added dropwise to the reaction system, and stirring continued at this temperature for 1 hour. The compound 5-chloroadamantane-2-one (1.41 g, 7.65 mmol) was dissolved in anhydrous THF (10 mL) and added dropwise to the reaction system, and stirring continued for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated NH4Cl aqueous solution, water was added, and the mixture was extracted twice with EA. The organic phases were combined, dried over Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography (PE / EA = 5 / 1) to obtain the target compound (590 mg, yield 41.0%) as a white solid.

[0377] EM (calculated value): 282.1; MS (ESI) m / z (M+H) + 283.1

[0378] Step 2: Preparation of 5-chloro-2-acetylene-2-ol

[0379] 5-Chloro-2-((trimethylsilyl)ethynyl)adamantane-2-ol (550 mg, 1.95 mmol) was dissolved in MeOH (15 mL), and potassium carbonate (323 mg, 2.34 mmol) was added with stirring. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give the target compound (374 mg, yield 91.2%) as a white solid.

[0380] EM (calculated value): 210.1; MS (ESI) m / z (M+H) + :211.1

[0381] Step 3: Preparation of (2R)-4-(6-((5-chloro-2-hydroxyadamantane-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0382] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester (150 mg, 0.25 mmol) and 5-chloro-2-ethynyl phosphono-2-ol (105 mg, 0.50 mmol) were added to DMF (6 mL), followed by the addition of Et3N (76 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol). The mixture was stirred overnight at 40 °C under nitrogen protection. After the reaction was complete, water (600 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with Na2SO4, the product was concentrated to dryness. The crude product was then purified by column chromatography (DCM / MeOH = 35 / 1) to obtain the target compound (77 mg, yield 45.1%), which was an off-white solid.

[0383] EM (calculated value): 685.3; MS (ESI) m / z (M+H) + 686.3

[0384] Step 4: Preparation of (6-((5-chloro-2-hydroxyadamantane-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)((R)-3-methylpiperazin-1-yl)methyl ketone hydrochloride.

[0385] The compound (2R)-4-(6-((5-chloro-2-hydroxyadamantane-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (75 mg, 0.11 mmol) was dissolved in DCM (10 mL), and 4N HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred in an ice-water bath for 2 hours. After the reaction was complete, the solid was filtered and washed with a small amount of acetonitrile to give the target compound (25 mg, yield 36.9%) as a pale yellow solid.

[0386] EM (calculated value): 585.3; MS (ESI) m / z (M+H) + 586.3

[0387] 1H NMR (400MHz, DMSO-d6) δ0.72-0.73(2H,m),0.93-0.95(2H,m),1.14(1.5H,d,J=2.8Hz),1.20(1H,d,J=7.2Hz) ,1.35(1.5H,d,J=5.6Hz),1.48-1.51(2H,m),1.93-2.01(2H,m),2.11-2.14(7H,m),2.92-2.94(1H,m),3.03-3 .06(2H,m),3.18-3.26(1H,m),3.48-3.50(1H,m),3.69-3.78(1H,m),4.40-4.43(1H,m),5.84(1H,s),6.42(1H ,d,J=7.2Hz),7.74-7.77(1H,m),7.83(1H,d,J=7.6Hz),8.85(1H,s),9.69-9.79(2H,m),10.75-10.79(1H,m).

[0388] The compounds shown in Table 4 below were synthesized according to the method described in Example 22:

[0389] Table 4

[0390]

[0391]

[0392]

[0393] Example 27 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0394]

[0395] Step 1: Preparation of 1-ethynyl-1-fluorocyclohexane

[0396] 1-Ethynylcyclohexanol (1.00 g, 8.06 mmol) was dissolved in DCM (10 mL) and cooled to -20 °C under nitrogen protection. DAST (1.56 g, 9.67 mmol) was slowly added dropwise to the reaction system, and stirring was continued at this temperature for 1 hour. TLC analysis confirmed the reaction was complete. The reaction solution was concentrated to dryness. The residue was purified by column chromatography (PE / EA = 50 / 1) to give the target compound (333 mg, yield 32.6%) as a colorless liquid.

[0397] Step 2: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0398] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.25 mmol) and 1-ethynyl-1-fluorocyclohexane (63 mg, 0.50 mmol) were added to DMF (6 mL), followed by the addition of Et3N (76 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, water (600 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with Na2SO4, the product was concentrated to dryness. The crude product was then purified by column chromatography (DCM / MeOH = 50 / 1) to obtain the target compound (79 mg, yield 52.6%), which was an off-white solid.

[0399] EM (calculated value): 601.3; MS (ESI) m / z (M+H) + 602.3

[0400] Step 3: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0401] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (77 mg, 0.13 mmol) was dissolved in DCM (10 mL), and 4N HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred in an ice-water bath for 2 hours. After the reaction was complete, the solid was filtered and washed with a small amount of acetonitrile to give the target compound (19 mg, yield 27.1%) as a yellow solid.

[0402] EM (calculated value): 501.3; MS (ESI) m / z (M+H) + 502.3

[0403] 1H NMR(400MHz, DMSO-d6)δ0.73-0.74(2H,m),0.95-0.98(2H,m),1.13(1.5H,d,J=6.0Hz),1.34(1 .5H,d,J=6.4Hz),1.39-1.44(1H,m),1.52-1.65(3H,m),1.70-1.75(2H,m),1.90-2.10(5H,m),3 .12-3.49(5H,m),3.77-3.86(1H,m),4.42-4.45(1H,m),6.45(1H,d,J=10.8Hz),7.79(1H,dd,J =8.8Hz,3.2Hz),7.91(1H,d,J=8.8Hz),8.95(1H,s),9.30(1H,s),9.47(1H,s),10.93(1H,brs).

[0404] Example 28 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0405]

[0406] Step 1: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0407] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.33 mmol) and trimethylsilylacetylene (129 mg, 1.32 mmol) were added to THF (6 mL), followed by the addition of Et3N (100 mg, 0.99 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH = 50 / 1) to obtain the target compound (83 mg, yield 43.9%) as a white solid.

[0408] EM (calculated value): 573.3; MS (ESI) m / z (M+H) + 574.3

[0409] Step 2: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0410] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) was dissolved in methanol (10 mL), and potassium carbonate (39 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give the target compound (63 mg, yield 89.3%) as a white solid.

[0411] EM (calculated value): 501.2; MS (ESI) m / z (M+H) + 502.2

[0412] Step 3: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0413] Compound (R)-4-(4-(((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.12 mmol) was dissolved in DCM (10 mL), and 4N HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred in an ice-water bath for 2 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was washed with tert-methyl ether / PE (1 / 1) to give the target compound (31 mg, yield 59.4%) as a yellow solid.

[0414] EM (calculated value): 401.2; MS (ESI) m / z (M+H) + 402.2

[0415] 1H NMR(400MHz,DMSO-d6)δ0.75-0.76(2H,m),0.97-0.99(2H,m),1.14(1.5H,d,J=5.2Hz),1 .35(1.5H,d,J=6.4Hz),1.96-2.03(1H,m),2.99-3.10(1H,m),3.17-3.23(1H,m),3.28-3. 56(3H,m),3.90-4.00(1H,m),4.42-4.45(1H,m),4.50(1H,s),6.42(1H,d,J=6.8Hz),7.87 (1H,d,J=8.4Hz),7.99(1H,d,J=8.4Hz),9.01(1H,s),9.68-9.76(2H,m),11.48(1H,brs).

[0416] Example 29 Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide

[0417]

[0418] Step 1: Preparation of ethyl 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-carboxylic acid

[0419] Ethyl 6-bromo-1H-indole-2-carboxylic acid (500 mg, 1.87 mmol) and 2,4-dichloropyrimidine (277 mg, 1.87 mmol) were added to DMA (10 mL), followed by potassium carbonate (310 mg, 2.24 mmol). The mixture was heated to 120 °C and stirred for 2 hours. TLC analysis showed that the starting material had completely reacted. Water (100 mL) was added to the reaction mixture, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with a small amount of EA, and dried to obtain the target compound (450 mg, yield 63.5%) as a brown solid.

[0420] EM (calculated value): 379.0; MS (ESI) m / z (M+H) + 380.0

[0421] Step 2: Preparation of 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-2-carboxylic acid ammonium

[0422] Ethyl 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-carboxylic acid (450 mg, 1.19 mmol) was added to NH3·H2O (20 mL), and the mixture was heated to 130 °C and stirred for 1 hour. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature, and a large amount of solid precipitated. After filtration and drying, the target compound (360 mg, yield 86.9%) was obtained as a yellow solid.

[0423] EM (calculated value): 331.0; MS (ESI) m / z (MH) - 330.0

[0424] Step 3: Preparation of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-indole-2-carboxamide

[0425] Compound 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-2-carboxylic acid ammonium (360 mg, 1.03 mmol) and 2-methoxyethane-1-amine (93 mg, 1.24 mmol) were added to THF (15 mL), followed by HATU (471 mg, 1.24 mmol) and DIEA (266 mg, 2.06 mmol). The mixture was stirred overnight at room temperature. TLC analysis showed that the starting material had completely reacted. Water (100 mL) was added to the reaction mixture, and the solution was extracted three times with DCM. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying in Na2SO4, the solution was concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain the target compound (100 mg, yield 25.0%) as a yellow solid.

[0426] EM (calculated value): 389.0; MS (ESI) m / z (M+H) + 390.0

[0427] Step 4: Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide

[0428] Compounds 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-indole-2-carboxamide (100 mg, 0.26 mmol) and 1-ethynylcyclohexanol (66 mg, 0.52 mmol) were added to 10 mL of DMSO. Et3N (79 mg, 0.78 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were then added. The mixture was heated to 70 °C and stirred for 1 hour under nitrogen protection. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with Na2SO4, the solution was concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain the target compound (19 mg, yield 16.8%) as a white solid.

[0429] EM (calculated value): 433.2; MS (ESI) m / z (M+H) + : 434.2

[0430] 1 H NMR(400MHz,DMSO-d6)δ1.48-1.63(8H,m),1.83-1.86(2H,m),3.28(3H,s),3.36-3.39(2H,m),3.44-3.47(2H,m),5.41(1H,s),6.46(1H,d ,J=5.2Hz),6.94(2H,s),7.14(1H,s),7.22(1H,d,J=8.0Hz),7.69(1H,d,J=8.4Hz),7.75(1H,s),8.32(1H,d,J=4.2Hz),8.75-8.78(1H,m).

[0431] Example 30 Preparation of 1-((1-(2-aminopyrimidin-4-yl)-2-((3-methoxypropyl)amino)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol

[0432]

[0433] Step 1: Preparation of tert-butyl (6-bromo-1H-indole-2-yl)carbamate

[0434] Compound 6-bromo-1H-indole-2-carboxylic acid (2.5 g, 10.46 mmol), triethylamine (1.3 g, 12.55 mmol), and diphenyl azidophosphate (3.5 g, 12.55 mmol) were added to THF (100 mL) and stirred overnight at room temperature. TLC analysis showed the reactants had reacted completely. The reaction mixture was concentrated to dryness, and tert-butanol (20 mL) was added. The mixture was stirred overnight at 80 °C. TLC analysis showed the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted three times with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with Na2SO4, the crude product was purified by column chromatography (PE / EA = 20 / 1) to obtain the target compound (1.4 g, yield 43.2%) as a yellow solid.

[0435] EM (calculated value): 310.0; MS (ESI) m / z (M+H) + 311.1

[0436] Step 2: Preparation of tert-butyl (6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-yl)carbamate

[0437] 1.3 g (4.19 mmol) of tert-butyl(6-bromo-1H-indol-2-yl)carbamate and 2,4-dichloropyrimidine (0.93 g (6.29 mmol)) were added to DMF (30 mL), followed by potassium carbonate (1.2 g (8.38 mmol). The mixture was stirred overnight at room temperature, and TLC analysis confirmed the reaction was complete. 100 mL of water was added to the reaction mixture, and the solution was extracted four times with EA. The organic phases were combined and washed twice with saturated LiCl aqueous solution. After drying with Na₂SO₄, the crude product was purified by column chromatography (PE / EA = 5 / 1) to obtain the target compound (680 mg, yield 38.4%) as a yellow solid.

[0438] EM (calculated value): 422.0; MS (ESI) m / z (M+H) + : 423.0

[0439] Step 3: Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-amine trifluoroacetate

[0440] 680 mg (1.61 mmol) of tert-butyl (6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-yl)carbamate was added to 20 mL of DCM, followed by slow addition of 4 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 hours, and TLC analysis showed that the starting material had completely reacted. The reaction mixture was evaporated to dryness to obtain a brown solid (1.1 g). The crude product was used directly in the next reaction step.

[0441] EM (calculated value): 322.0; MS (ESI) m / z (M+H) + 323.1

[0442] Step 4: Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indole-2-amine

[0443] Compound 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-amine trifluoroacetate (1.1 g, crude) and 1-bromo-3-methoxypropane (0.52 g, 3.42 mmol) were added to DCM (30 mL), followed by DIEA (2.2 g, 17.10 mmol). The mixture was stirred overnight at room temperature, and TLC analysis confirmed the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted five times with DCM. The organic phases were combined and washed twice with saturated NaCl aqueous solution. After drying with Na2SO4, the crude product was purified by column chromatography (PE / EA = 3 / 1) to obtain the target compound (530 mg, two-step yield 83.5%) as a yellow solid.

[0444] EM (calculated value): 394.0; MS (ESI) m / z (M+H) + 395.1

[0445] Step 5: Preparation of 6-bromo-1-(2-aminopyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indole-2-amine

[0446] 250 mg (0.63 mmol) of compound 6-bromo-1-(2-chloropyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indole-2-amine was added to isopropanol (10 mL), followed by 2 mL of ammonia. The mixture was stirred overnight at 100 °C, and TLC analysis confirmed the reaction was complete. Water (200 mL) was added to the reaction mixture, and the solution was extracted five times with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with Na₂SO₄, the crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain the target compound (140 mg, yield 58.8%) as a yellow solid.

[0447] EM (calculated value): 375.1; MS (ESI) m / z (M+H) + 376.1

[0448] Step 6: Preparation of 1-((1-(2-aminopyrimidin-4-yl)-2-((3-methoxypropyl)amino)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol

[0449] Compounds 6-bromo-1-(2-aminopyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indole-2-amine (100 mg, 0.27 mmol) and 1-ethynylcyclohexanol (67 mg, 0.54 mmol) were added to 10 mL of DMSO. Et3N (82 mg, 0.81 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were then added. The mixture was heated to 80 °C and stirred for 2 hours under nitrogen protection. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted four times with DCM. The organic phases were combined and washed twice with saturated NaCl aqueous solution. After drying with Na2SO4, the solution was concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain the target compound (11 mg, yield 9.8%) as a white solid.

[0450] EM (calculated value): 419.2; MS (ESI) m / z (M+H) + : 420.2

[0451] 1 H NMR(400MHz,DMSO-d6)δ1.22-1.43(4H,m),1.51-1.77(4H,m),1.81-1.88 (4H,m),3.33(3H,s),3.38-3.41(2H,m),3.52-3.56(2H,m),4.95(1H,s),6 .53(1H,d,J=8.8Hz),7.01(2H,s),7.18(1H,s),7.35(1H,d,J=8.0Hz),7.7 7(1H,d,J=7.8Hz),7.85(1H,s),8.44(1H,d,J=3.6Hz),8.66-8.75(1H,m).

[0452] Example 31. Preparation of (R)-3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazin-1-carbonyl)quinazolin-6-yl)-1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one hydrochloride.

[0453]

[0454] Step 1: Preparation of 1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one

[0455] Compound 4-(trifluoromethyl)piperidine (400 mg, 2.62 mmol) and propargyl acid (238 mg, 3.41 mmol) were added to DCM (10 mL), followed by DCC (703 mg, 3.41 mmol). The mixture was stirred at room temperature for 2 hours. TLC analysis showed that the reactants had reacted completely. DCM (20 mL) was added to the reaction mixture, and the mixture was washed successively with 2N hydrochloric acid and sodium bicarbonate aqueous solution. The organic phase was collected, dried over anhydrous Na₂SO₄, and concentrated to dryness. The crude product was purified by column chromatography (PE / EA = 10 / 1) to obtain the target compound (520 mg, yield 96.8%) as a white solid.

[0456] EM (calculated value): 205.1; MS (ESI) m / z (M+H) + 206.1

[0457] Step 2: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(3-oxo-3-(4-(trifluoromethyl)piperidin-1-one)prop-1-yn-1-yl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0458] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol) and 1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one (70 mg, 0.34 mmol) were added to THF (10 mL), followed by Et3N (52 mg, 0.51 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol). The mixture was stirred at room temperature for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH = 50 / 1) to obtain the target compound (52 mg, yield 44.8%) as a white solid.

[0459] EM (calculated value): 680.3; MS (ESI) m / z (M+H) + 681.3

[0460] Step 3: Preparation of (R)-3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazin-1-carbonyl)quinazolin-6-yl)-1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one hydrochloride.

[0461] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(3-oxo-3-(4-(trifluoromethyl)piperidin-1-one)prop-1-yn-1-yl)quinazolin-2-carbonyl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester (50 mg, 0.07 mmol) was dissolved in DCM (6 mL), and 4N HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred in an ice-water bath for 2 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was washed with tert-methyl ether / PE (1 / 1) to give the target compound (21 mg, yield 48.8%) as a yellow solid.

[0462] EM (calculated value): 580.3; MS (ESI) m / z (M+H) + 581.3

[0463] 1 H NMR(400MHz,DMSO-d6)δ0.73-0.75(2H,m),0.97-0.99(2H,m),1.14(1.5H,d,J=5.0Hz) ,1.24-1.54(3.5H,m),1.91-2.02(3H,m),2.68-2.85(2H,m),2.95-3.39(7H,m),3.94-4 .03(1H,m),4.42-4.53(2H,m),4.42-4.45(1H,m),6.45(1H,d,J=6.8Hz),7.89(1H,d,J= 8.4Hz),8.07(1H,d,J=8.4Hz),9.15(1H,s),9.50(1H,s),9.82(1H,s),11.12(1H,brs).

[0464] The compounds shown in Table 5 below were synthesized according to the method described in Example 31:

[0465] Table 5

[0466]

[0467]

[0468] Example 33. Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride.

[0469]

[0470] Step 1: Preparation of ((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)trimethylsilane

[0471] Trimethylsilylacetylene (3.0 g, 30.58 mmol) was dissolved in anhydrous THF (20 mL), and the reaction mixture was cooled to -70 °C under nitrogen protection. n-BuLi (13.5 mL, 33.64 mmol, 2.5 M in THF) was slowly added, and the mixture was stirred for 40 minutes while maintaining this temperature. 4,4-Dimethylcyclohexane-1-one (3.9 g, 30.58 mmol) was dissolved in anhydrous THF (10 mL) and slowly added to the reaction mixture. After the addition was complete, the reaction temperature was raised to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was then cooled back to 0 °C, and dimethyl sulfate (3.9 g, 30.58 mmol) was added. The mixture was allowed to return to room temperature, and the mixture was stirred overnight. TLC analysis showed that the starting material had reacted completely. Water was added to quench the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product was purified by column chromatography (PE / EA = 10 / 1) to obtain the target compound (2.1 g, yield 28.8%) as a white solid.

[0472] EM (calculated value): 238.2; MS (ESI) m / z (M+H) + : 239.2

[0473] Step 2: Preparation of 1-ethynyl-1-methoxy-4,4-dimethylcyclohexane

[0474] The compound ((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)trimethylsilane (2.0 g, 8.40 mmol) was dissolved in anhydrous THF (10 mL), and TBAF (16.8 mL, 16.80 mmol, 1.0 M in THF) was added. The mixture was stirred for 2 hours. TLC analysis showed that the starting material had reacted completely. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated to dryness. The crude product was purified by column chromatography (PE / EA = 8 / 1) to give the target compound (1.3 g, yield 92.9%) as a colorless oil.

[0475] EM (calculated value): 166.1; MS (ESI) m / z (M+H) + 167.1

[0476] Step 3: Preparation of (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0477] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.20 mmol) and 1-ethynyl-1-methoxy-4,4-dimethylcyclohexane (66 mg, 0.40 mmol) were added to DMF (6 mL), followed by Et3N (61 mg, 0.60 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol). The mixture was stirred at 40 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was added to water (100 mL) and extracted three times with DCM. The organic phases were combined and washed with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH = 50 / 1) and TLC (DCM / MeOH = 25 / 1) to obtain the target compound (20 mg, yield 15.6%) as a yellow solid.

[0478] EM (calculated value): 641.4; MS (ESI) m / z (M+H) + : 642.4

[0479] Step 4: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methyl ketone hydrochloride

[0480] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in HCl / EtOAc (10 mL) under an ice-water bath and stirred for 4 hours. After the reaction was complete, the supernatant was discarded, and the remaining solid was washed with tert-methyl ether / PE (1 / 1) to give the target compound (15 mg, yield 86.7%) as a yellow solid.

[0481] EM (calculated value): 541.3; MS (ESI) m / z (M+H) + 542.3

[0482] 1H NMR(400MHz, DMSO-d6)δ0.72-0.74(2H,m),0.93-0.97(8H,m),1.14(1.5H,d,J=5.0Hz),1.33( 1.5H,d,J=6.4Hz),1.42-1.44(4H,m),1.57-1.60(2H,m),1.85-1.95(3H,m),2.48(3H,s),3.1 0-3.23(5H,m),3.75-3.80(1H,m),4.42-4.45(1H,m),6.45(1H,d,J=11.2Hz),7.76(1H,dd,J= 8.0Hz,3.6Hz),7.88(1H,d,J=8.8Hz),8.87(1H,s),9.14(1H,s),9.34(1H,s),10.84(1H,brs).

[0483] Example 35: Preparation of (4-aminopiperidin-1-yl)(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl) methyl ketone hydrochloride.

[0484]

[0485] Step 1: Preparation of 5-cyclopropyl-4-fluoro-1H-pyrazole-3-amine

[0486] The compound 5-cyclopropyl-1H-pyrazole-3-amine (6.0 g, 48.74 mmol) was dissolved in acetonitrile (100 mL), and Selectfluor (17.3 g, 48.74 mmol) was added in portions at room temperature, with stirring continued for 2 hours. TLC analysis showed that the starting material had reacted completely, and the reaction solution was concentrated directly to dryness. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain the target compound (1.7 g, yield 24.7%) as a red solid.

[0487] EM (calculated value): 141.1; MS (ESI) m / z (M+H) + 142.1

[0488] Step 2: Preparation of 4,6-dichloroquinazoline-2-carbonyl chloride

[0489] The compound 6-chloro-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid (200 mg, 0.89 mmol) was dissolved in chloroform (10 mL), and DMF (0.2 mL) and SOCl2 (318 mg, 2.67 mmol) were added sequentially. The mixture was heated to 80 °C and stirred for 3 hours under nitrogen protection. After the reactants had reacted completely, the reaction solution was concentrated to dryness to obtain the target compound (crude product), which was a brown oily liquid and was used directly in the next reaction step.

[0490] Step 3: Preparation of tert-butyl (1-(4,6-dichloroquinazoline-2-carbonyl)piperidin-4-yl)carbamate

[0491] Compound 4,6-dichloroquinazoline-2-carbonyl chloride (crude) was dissolved in DCM (10 mL), and Et3N (360 mg, 3.56 mmol) was added. The reaction temperature was cooled to approximately -65 °C. Tert-butylpiperidin-4-ylcarbamate (178 mg, 0.89 mmol) was dissolved in DCM (2 mL), and this solution was slowly added dropwise to the reaction system. The mixture was stirred at this temperature for 30 minutes. TLC detection showed that the starting material had reacted completely. The reaction solution was concentrated, and the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrates were combined and washed twice with H2O. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the target compound (crude), which was a brown solid.

[0492] EM (calculated value): 424.1; MS (ESI) m / z (M+H) + 425.1

[0493] Step 4: Preparation of tert-butyl(1-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)piperidin-4-yl)carbamate

[0494] The crude tert-butyl (1-(4,6-dichloroquinazoline-2-carbonyl)piperidin-4-yl)carbamate was dissolved in DMF (10 mL). DIEA (230 mg, 1.78 mmol), KI (295 mg, 1.78 mmol), and 5-cyclopropyl-4-fluoro-1H-pyrazole-3-amine (126 mg, 0.89 mmol) were added sequentially, and the mixture was heated to 65 °C and stirred for 4 hours. TLC analysis confirmed the reaction was complete. The reaction solution was added to water and extracted three times with EA. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to obtain the target compound (183 mg, overall yield of the three steps was 38.9%) as a pale yellow solid.

[0495] EM (calculated value): 529.2; MS (ESI) m / z (M+H) + 530.2

[0496] Step 5: Preparation of (4-aminopiperidin-1-yl)(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methyl ketone hydrochloride

[0497] 50 mg (0.09 mmol) of tert-butyl(1-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)piperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 10 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (38 mg, yield 90.7%) as a yellow solid.

[0498] EM (calculated value): 429.1; MS (ESI) m / z (M+H) + 430.1

[0499] 1H NMR(400MHz,DMSO-d6)δ0.81-0.83(2H,m),0.92-0.94(2H,m),1.21-1.26(2H,m),1.65-1.69(1H,m),1.85-1.88(2H,m),2.93-2.98(3 H,m),3.41-3.45(1H,m),4.27-4.30(1H,m),7.69(1H,d,J=7.2Hz),7.81(1H,d,J=7.6Hz),8.27(3H,s),8.54(1H,s),12.42(1H,brs).

[0500] The compounds shown in Table 6 below were synthesized according to the method described in Example 35:

[0501] Table 6

[0502]

[0503]

[0504]

[0505] Example 40. Preparation of (R)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-2-(3-methylpiperazin-1-yl)quinazolin-4-amine hydrochloride.

[0506]

[0507] Step 1: Preparation of 2,6-dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazoline-4-amine

[0508] Compound 2,4,6-trichloroquinazoline (3.0 g, 12.94 mmol) was dissolved in DMF (20 mL). 5-Cyclopropyl-4-fluoro-1H-pyrazole-3-amine (1.8 g, 12.94 mmol), KI (4.3 g, 25.88 mmol), and DIEA (6.8 g, 51.76 mmol) were added sequentially at room temperature. The mixture was heated to 65 °C and stirred for 2 hours. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature. The reaction solution was slowly added to water (200 mL), and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness, and the residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give the target compound (3.9 g, yield 89.4%) as a yellow solid.

[0509] EM (calculated value): 337.0; MS (ESI) m / z (M+H) + 338.0

[0510] Step 2: Preparation of (R)-4-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl

[0511] Compound 2,6-dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine (30 mg, 0.09 mmol) was dissolved in DMA (1 mL). At room temperature, (R)-2-methylpiperazine-1-carboxylic acid tert-butyl (18 mg, 0.09 mmol), KI (30 mg, 0.18 mmol), and DIEA (46 mg, 0.36 mmol) were added sequentially. The mixture was heated to 125 °C and stirred for 3 hours. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature. The reaction solution was slowly added to water (10 mL), and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness, and the residue was purified by TLC (DCM / MeOH = 25 / 1) to give the target compound (28 mg, yield 62.1%) as a yellow solid.

[0512] EM (calculated value): 501.2; MS (ESI) m / z (M+H) + 502.2

[0513] Step 3: Preparation of (R)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-2-(3-methylpiperazin-1-yl)quinazolin-4-amine hydrochloride.

[0514] Compound (R)-4-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2-methylpiperazin-1-carboxylic acid tert-butyl (28 mg, 0.06 mmol) was added to a single-necked flask, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (5 mL) was added. The mixture was stirred at this temperature for 1 hour. TLC analysis showed that the starting material had reacted completely. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (24 mg, yield 91.3%) as a white solid.

[0515] EM (calculated value): 401.2; MS (ESI) m / z (M+H) + 402.2

[0516] 1H NMR(400MHz, DMSO-d6)δ0.82-0.83(2H,m),0.98-1.00(2H,m),1.28(3H,d,J=2.4Hz),1.92-1.95(1H,m),3.12-3.13(1H,m),3.7 6-3.79(5H,m),4.65-4.67(1H,m),7.88-7.90(2H,m),8.64(1H,s),9.42(1H,s),9.53(1H,s),11.12(1H,brs),12.63(1H,brs).

[0517] The compounds shown in Table 7 below were synthesized according to the method described in Example 40:

[0518] Table 7

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528] Example 56 Preparation of 2-(4-amino-4-propylpiperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazoline-4-amine

[0529]

[0530] Step 1: Preparation of tert-butyl 4-cyano-4-propylpiperidine-1-carboxylate

[0531] 1.0 g (4.76 mmol) of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester was dissolved in anhydrous THF (10 mL), and the mixture was cooled to approximately -65 °C using an ethanol dry ice bath under nitrogen protection. LiHMDS (1.3 M in THF, 5.5 mL, 7.14 mmol) was slowly added dropwise to the reaction system, and the mixture was stirred at this temperature for 3 hours after the addition was complete. Iodopropane (1.2 g, 7.14 mmol) was dissolved in THF (2 mL) and added to the reaction system. After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight. TLC analysis confirmed the reaction was complete. Water (20 mL) was added to quench the reaction, and the mixture was concentrated to remove most of the organic solvent. The residue was extracted twice using EA. The organic phases were combined and washed once with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. The residue was concentrated to dryness and purified by column chromatography (PE / EA = 9 / 1) to obtain the target compound (700 mg, yield 58.3%) as a yellow oil.

[0532] EM (calculated value): 252.2; MS (ESI) m / z (M+H) + : 253.2

[0533] Step 2: Preparation of tert-butyl 4-carbamoyl-4-propylpiperidine-1-carboxylate

[0534] 700 mg (2.78 mmol) of 4-cyano-4-propylpiperidine-1-carboxylic acid tert-butyl ester was dissolved in DMSO (5 mL), and K₂CO₃ (767 mg (5.56 mmol)) was added. The mixture was heated to 60 °C, and H₂O₂ (30%, 2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 3 hours. TLC analysis confirmed the reaction was complete. After cooling, water (50 mL) was added, and the mixture was extracted twice using EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness to give the target compound (730 mg, yield 97.2%) as a white solid.

[0535] EM (calculated value): 270.2; MS (ESI) m / z (M+H) + : 271.2

[0536] Step 3: Preparation of tert-butyl 4-amino-4-propylpiperidine-1-carboxylic acid

[0537] 100 mg (0.37 mmol) of tert-butyl 4-carbamoyl-4-propylpiperidine-1-carboxylate was dissolved in acetonitrile / H₂O (6 mL, 2 / 1). Then, 53 mg (0.19 mmol) of 1,3-dibromo-5,5-dimethylimidazoline-2,4-dione and 112 mg (2.0 mmol) of KOH were added. The mixture was stirred at room temperature for 3 hours after the addition was complete. TLC analysis confirmed the reaction was complete. The reaction solution was adjusted to pH 4–5 with concentrated hydrochloric acid, and 2 mL of H₂O was added. The mixture was extracted twice with EA. The aqueous phase was retained and adjusted to pH ~10 with sodium bicarbonate. The mixture was extracted three times with EA. The organic phases were combined and dried over anhydrous sodium sulfate. The solution was concentrated to dryness to give the target compound (48 mg, yield 53.3%) as a colorless oil.

[0538] EM (calculated value): 242.2; MS (ESI) m / z (M+H) + : 243.2

[0539] Step 4: Preparation of 4-propylpiperidine-4-amine dihydrochloride

[0540] 4-Amino-4-propylpiperidine-1-carboxylic acid tert-butyl ester (48 mg, 0.20 mmol) was dissolved in 4M HCl / 1,4-dioxane (2 mL) and stirred in an ice-water bath for 1 hour. TLC analysis showed that the starting material had reacted completely. The reaction solution was concentrated to dryness at low temperature to obtain the target compound (43 mg, 100% yield) as a white solid.

[0541] EM (calculated value): 142.2; MS (ESI) m / z (M+H) + : 143.2

[0542] Step 5: Preparation of 2-(4-amino-4-propylpiperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazoline-4-amine

[0543] 2,6-Dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine (50 mg, 0.15 mmol) was dissolved in DMA (2 mL). 4-propylpiperidin-4-amine dihydrochloride (43 mg, 0.20 mmol), KI (50 mg, 0.30 mmol), and DIEA (77 mg, 0.60 mmol) were added sequentially at room temperature. The mixture was heated to 125 °C and stirred for 2 hours. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature. The reaction solution was slowly added to water (20 mL), and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness, and the residue was purified by TLC (DCM / MeOH = 20 / 1) to give the target compound (20 mg, yield 30.0%) as a yellow solid.

[0544] EM (calculated value): 443.2; MS (ESI) m / z (M+H) + : 444.2

[0545] 1H NMR(400MHz, DMSO-d6)δ0.77-0.80(2H,m),0.87(3H,t,J=6.4Hz),0.94-0.98(2H,m),1.24-1.44(8H,m),1.85-1.92(1H,m),3.40-3.42(2 H,m),4.07-4.09(2H,m),7.31(1H,d,J=8.8Hz),7.54(1H,dd,J1=9.2Hz,J2=2.0Hz),8.33(1H,d,J=2.0Hz),9.80(1H,brs),12.33(1H,s).

[0546] The compounds shown in Table 8 below were synthesized according to the method described in Example 56:

[0547] Table 8

[0548]

[0549]

[0550]

[0551] Example 60 Preparation of 2-(4-amino-4-(4-fluorophenyl)piperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine

[0552]

[0553] Step 1: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidine-4-onitrile

[0554] NaH (60% concentration dispersed in mineral oil, 237 mg, 5.92 mmol) was added to the reaction flask, and the mixture was cooled in an ice-water bath under nitrogen protection. 2-(4-fluorophenyl)acetonitrile (200 mg, 1.48 mmol) was dissolved in anhydrous DMF (5 mL) and slowly added dropwise to the reaction flask. The mixture was stirred in an ice-water bath for 1 hour. N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine hydrochloride (395 mg, 1.48 mmol) was dissolved in DMF (3 mL) and added to the reaction system. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. TLC analysis confirmed the reaction was complete. The reaction solution was quenched by adding dropwise to water (100 mL) and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness to obtain the target compound (crude product), which was a yellow oil.

[0555] EM (calculated value): 294.2; MS (ESI) m / z (M+H) + 295.2

[0556] Step 2: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidine-4-carboxamide

[0557] The crude compound 1-benzyl-4-(4-fluorophenyl)piperidin-4-onitrile was dissolved in DMSO (5 mL), and NaOH (178 mg, 4.44 mmol) was added. The mixture was heated to 60 °C, and H₂O₂ (30%, 2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 3 hours. TLC analysis confirmed the reaction was complete. After cooling, water (50 mL) was added, and the mixture was extracted twice using EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness to obtain the target compound (crude product), which was a pale yellow oil.

[0558] EM (calculated value): 312.2; MS (ESI) m / z (M+H) + 313.2

[0559] Step 3: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidine-4-amine

[0560] The crude compound 1-benzyl-4-(4-fluorophenyl)piperidine-4-carboxamide was dissolved in acetonitrile / H₂O (10 mL, 2 / 1). 1,3-Dibromo-5,5-dimethylimidazoline-2,4-dione (210 mg, 0.74 mmol) and KOH (166 mg, 2.96 mmol) were added. After addition, the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the reaction was complete. The reaction solution was adjusted to pH 4–5 with concentrated hydrochloric acid, and H₂O (2 mL) was added. The mixture was extracted twice with EA. The aqueous phase was retained and adjusted to pH ~10 with sodium bicarbonate. The mixture was extracted three times with EA. The organic phases were combined and dried over anhydrous sodium sulfate. The solution was concentrated to dryness to give the target compound (137 mg, overall yield of the three steps: 32.5%) as a colorless oil.

[0561] EM (calculated value): 284.2; MS (ESI) m / z (M+H) + 285.2

[0562] Step 4: Preparation of 4-(4-fluorophenyl)piperidine-4-amine

[0563] 1-Benzyl-4-(4-fluorophenyl)piperidin-4-amine (137 mg, 0.48 mmol) was dissolved in methanol (10 mL), Pd / C (30 mg, 10% w / w) was added, and the mixture was stirred for 5 hours after hydrogen purging. TLC analysis showed that the reaction proceeds were complete. The reaction solution was filtered, and the filter cake was repeatedly washed with methanol. The filtrate was concentrated to dryness to give the target compound (80 mg, yield 85.9%) as a yellow oil.

[0564] EM (calculated value): 194.1; MS (ESI) m / z (M+H) + 195.1

[0565] Step 5: Preparation of 2-(4-amino-4-(4-fluorophenyl)piperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine

[0566] 2,6-Dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine (30 mg, 0.09 mmol) was dissolved in DMA (1 mL). 4-(4-fluorophenyl)piperidin-4-amine (17 mg, 0.09 mmol), KI (30 mg, 0.18 mmol), and DIEA (46 mg, 0.36 mmol) were added sequentially at room temperature. The mixture was heated to 125 °C and stirred for 2 hours. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature. The reaction solution was slowly added to water (10 mL), and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness, and the residue was purified by TLC (DCM / MeOH = 20 / 1) to give the target compound (16 mg, yield 35.9%) as a yellow solid.

[0567] EM (calculated value): 495.2; MS (ESI) m / z (M+H) + : 496.2

[0568] 1H NMR(400MHz,DMSO-d6)δ0.76-0.80(2H,m),0.92-0.99(2H,m),1.55-1.61(2H,m),1.84-1.91(3H,m),3.41-3.52(2H,m), 4.20-4.42(2H,m),7.09-7.13(2H,m),7.34(1H,d,J=8.0Hz),7.54-7.57(3H,m),8.35(1H,s),9.84(1H,s),12.33(1H,s).

[0569] The compounds shown in Table 9 below were synthesized according to the method described in Example 60:

[0570] Table 9

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577] Example 72 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine dihydrochloride

[0578]

[0579] Step 1: Preparation of 2-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine

[0580] Compound 2,4-dichloro-6-iodoquinazoline (5.0 g, 15.44 mmol) was dissolved in DMF (30 mL). 5-Cyclopropyl-4-fluoro-1H-pyrazole-3-amine (2.2 g, 15.44 mmol), KI (5.1 g, 30.88 mmol), and DIEA (8.0 g, 61.76 mmol) were added sequentially at room temperature. The mixture was heated to 65 °C and stirred for 2 hours. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature. The reaction solution was slowly added to water (300 mL), and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness, and the residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give the target compound (6.0 g, yield 90.3%) as a yellow solid.

[0581] EM (calculated value): 429.0; MS (ESI) m / z (M+H) + : 430.0

[0582] Step 2: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0583] 2-Chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine (6.0 g, 14.0 mmol) was dissolved in DMA (100 mL). Tert-butyl(4-methylpiperidin-4-yl)carbamate (3.0 g, 14.0 mmol), KI (4.6 g, 28.0 mmol), and DIEA (7.2 g, 56.0 mmol) were added sequentially at room temperature. The mixture was heated to 125 °C and stirred for 3 hours. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature. The reaction solution was slowly added to water (1000 mL), and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness, and the residue was purified by column chromatography (DCM / MeOH = 30 / 1) to give the target compound (7.3 g, yield 85.3%) as a yellow solid.

[0584] EM (calculated value): 607.2; MS (ESI) m / z (M+H) + : 608.2

[0585] Step 3: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine dihydrochloride

[0586] 30 mg (0.05 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 4 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (16 mg, yield 55.2%) as a pale yellow solid.

[0587] EM (calculated value): 507.1; MS (ESI) m / z (M+H) + 508.1

[0588] 1H NMR(400MHz,DMSO-d6)δ0.80-0.84(2H,m),0.97-1.02(2H,m),1.39(3H,s),1.81-1.96(5H,m),3.65-3.88(2H,m),4.04-4.48(2 H,m),7.89-7.97(1H,m),8.16(1H,d,J=8.0Hz),8.29(3H,brs),8.94(1H,s),11.34(1H,brs),12.75(1H,brs),13.14(1H,brs).

[0589] Example 73 Preparation of 1-((2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)ethynyl)-4,4-dimethylcyclohexane-1-ol dihydrochloride

[0590]

[0591] Step 1: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((1-hydroxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0592] tert-butyl(1-(4-(((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol) and 1-ethynyl-4,4-dimethylcyclohexane-1-ol (37 mg, 0.24 mmol) were added to DMF (2 mL), followed by Et3N (24 mg, 0.24 mmol) and Pd(PPh3)2Cl2 (15 mg, 0.02 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted three times with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying anhydrous sodium sulfate, the product was concentrated to dryness. The crude product was then purified by TLC (DCM / MeOH = 30 / 1) to obtain the target compound (22 mg, yield 43.6%), which was an off-white solid.

[0593] EM (calculated value): 631.4; MS (ESI) m / z (M+H) + : 632.4

[0594] Step 2: Preparation of 1-((2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)ethynyl)-4,4-dimethylcyclohexane-1-ol dihydrochloride)

[0595] 22 mg (0.03 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((1-hydroxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 3 mL of 4M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (13 mg, yield 71.8%) as a white solid.

[0596] EM (calculated value): 531.3; MS (ESI) m / z (M+H) + 532.3

[0597] 1H NMR(400MHz, DMSO-d6)δ0.78-0.83(2H,m),0.92(6H,d,J=5.6Hz),0.96-1.00(2H,m),1.38-1.43(7H,m),1.67-1.95(9H,m),3.60 -3.75(2H,m),4.18-4.32(2H,m),7.84(1H,s),8.05(1H,s),8.31(3H,s),8.60(1H,s),11.35(1H,s),12.73(1H,s),13.01(1H,s).

[0598] The compounds shown in Table 10 below were synthesized according to the method described in Example 73:

[0599] Table 10

[0600]

[0601]

[0602]

[0603] Example 77 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-onitrile hydrochloride.

[0604]

[0605] Step 1: Preparation of tert-butyl(1-(6-cyano-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0606] tert-butyl(1-(4-(((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol), Zn(CN)2 (28 mg, 0.24 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), DPPF (5 mg, 0.01 mmol), and Zn powder (2 mg, 0.02 mmol) were added to DMF (3 mL), and the mixture was heated to 120 °C and stirred for 6 hours under nitrogen protection. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying anhydrous sodium sulfate, the product was concentrated to dryness. The crude product was then purified by TLC (DCM / MeOH = 30 / 1) to obtain the target compound (28 mg, yield 69.1%), which was an off-white solid.

[0607] EM (calculated value): 506.3; MS (ESI) m / z (M+H) + 507.3

[0608] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-onitrile hydrochloride.

[0609] 28 mg (0.06 mmol) of tert-butyl(1-(6-cyano-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 5 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (22 mg, yield 83.0%) as a white solid.

[0610] EM (calculated value): 406.2; MS (ESI) m / z (M+H) + : 407.2

[0611] 1H NMR(400MHz,DMSO-d6)δ0.81-0.86(2H,m),0.98-1.00(2H,m),1.29(3H,s),1.69-1.98(5H,m),4.10-4 .50(4H,m),8.07-8.16(2H,m),8.29(3H,brs),8.98(1H,s),11.03-11.38(1H,m),12.55-12.86(1H,m).

[0612] Example 78 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazoline-4-amine dihydrochloride

[0613]

[0614] Step 1: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0615] 50 mg (0.08 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate and 31 mg (0.32 mmol) of trimethylsilylacetylene were added to THF (4 mL), followed by Et3N (24 mg, 0.24 mmol) and Pd(PPh3)2Cl2 (7 mg, 0.01 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by TLC (DCM / MeOH = 50 / 1) to obtain the target compound (29 mg, yield 63.8%) as a white solid.

[0616] EM (calculated value): 577.3; MS (ESI) m / z (M+H) + 578.3

[0617] Step 2: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-yl)-4-methylpiperidin-4-yl)carbamate

[0618] The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (29 mg, 0.05 mmol) was dissolved in methanol (5 mL), and potassium carbonate (14 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give the target compound (23 mg, yield 91.6%) as a white solid.

[0619] EM (calculated value): 505.3; MS (ESI) m / z (M+H) + 506.3

[0620] Step 3: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazoline-4-amine dihydrochloride

[0621] 23 mg (0.04 mmol) of tert-butyl(1-(4-(((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-yl)-4-methylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 4 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (17 mg, yield 80.9%) as a white solid.

[0622] EM (calculated value): 405.2; MS (ESI) m / z (M+H) + 406.2

[0623] 1H NMR(400MHz,DMSO-d6)δ0.80-0.84(2H,m),0.97-1.02(2H,m),1.39(3H,s),1.80-1.86(4H,m),1.90-1.97(1H,m),3.83-3.89(2H,m),4.14-4 .20(1H,m),4.36-4.46(2H,m),7.94(1H,d,J=8.4Hz),8.15(1H,s),8.43(3H,s),8.73(1H,s),11.36(1H,s),12.79(1H,brs),13.20(1H,brs).

[0624] Example 79 Preparation of 2-(4-amino-4-phenylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazoline-4-amine dihydrochloride

[0625]

[0626] Step 1: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate

[0627] 2-Chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine (295 mg, 0.69 mmol) was dissolved in DMA (10 mL). Tert-butyl(4-phenylpiperidin-4-yl)carbamate (190 mg, 0.69 mmol), KI (229 mg, 1.38 mmol), and DIEA (267 mg, 2.07 mmol) were added sequentially at room temperature. The mixture was heated to 125 °C and stirred for 3 hours. TLC analysis showed that the starting material had reacted completely. The reaction solution was cooled to room temperature. The reaction solution was slowly added to water (100 mL), and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness, and the residue was purified by column chromatography (DCM / MeOH = 40 / 1) to give the target compound (285 mg, yield 61.7%) as a yellow solid.

[0628] EM (calculated value): 669.2; MS (ESI) m / z (M+H) + : 670.2

[0629] Step 2: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate

[0630] 130 mg (0.19 mmol) of tert-butyl-(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate and 75 mg (0.76 mmol) of trimethylsilylacetylene were added to DMF (4 mL), followed by Et3N (77 mg, 0.76 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol). The mixture was heated to 50 °C and stirred for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was slowly added to water (40 mL) and extracted twice with EA. The organic phases were combined and washed once with saturated NaCl aqueous solution. After drying with anhydrous sodium sulfate, the solution was concentrated to dryness to obtain a brown oily substance, which was used directly in the next reaction.

[0631] EM (calculated value): 639.3; MS (ESI) m / z (M+H) + 640.3

[0632] Step 3: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-yl)-4-phenylpiperidin-4-yl)carbamate

[0633] The crude tert-butyl-(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate was dissolved in methanol (10 mL), and potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography (DCM / MeOH = 40 / 1) to give the target compound (60 mg, overall yield of the two-step reaction was 55.7%) as a yellow solid.

[0634] EM (calculated value): 567.3; MS (ESI) m / z (M+H) + 568.3

[0635] Step 4: Preparation of 2-(4-amino-4-phenylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazoline-4-amine dihydrochloride

[0636] 60 mg (0.11 mmol) of tert-butyl(1-(4-(((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-yl)-4-phenylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 6 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (51 mg, yield 85.9%) as a pale yellow solid.

[0637] EM (calculated value): 467.2; MS (ESI) m / z (M+H) + : 468.2

[0638] 1H NMR(400MHz,DMSO-d6)δ0.83-0.85(2H,m),0.99-1.01(2H,m),1.91-1.98(1H,m),2. 13-2.24(2H,m),2.39-2.47(1H,m),2.55-2.61(1H,m),3.64-3.80(2H,m),4.08-4.4 5(3H,m),7.43(1H,d,J=8.0Hz),7.45-7.52(2H,m),7.70(2H,d,J=8.0Hz),7.85-8.1 4(2H,m),8.68-8.93(4H,m),11.18-11.48(1H,m),12.74(1H,brs),13.03(1H,brs).

[0639] Example 80 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4-amine trihydrochloride

[0640]

[0641] Step 1: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0642] The compounds tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)piperazine (48 mg, 0.16 mmol), Pd(dppf)Cl2.DCM (8 mg, 0.01 mmol), and sodium carbonate (25 mg, 0.24 mmol) were added to 1,4-dioxane / H2O (3 mL, 5 / 1), heated to 80 °C and stirred for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by TLC (DCM / MeOH / NH3 in MeOH=10 / 1 / 0.2) to obtain the target compound (25 mg, yield 47.7%) as a white solid.

[0643] EM (calculated value): 655.4; MS (ESI) m / z (M+H) + : 656.4

[0644] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4-amine trihydrochloride

[0645] 25 mg (0.04 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 5 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (22 mg, yield 83.0%) as a white solid.

[0646] EM (calculated value): 555.3; MS (ESI) m / z (M+H) + 556.3

[0647] 1H NMR(400MHz,DMSO-d6)δ0.81-0.85(2H,m),0.98-1.03(2H,m),1.40(3H,s),1.82-1.86(4H,m),1.92- 1.96(1H,m),2.84(3H,d,J=4.4Hz),3.11-3.18(4H,m),3.47-3.53(2H,m),3.65-3.73(2H,m),3.96-3. 98(2H,m),4.25-4.29(2H,m),7.17(2H,d,J=8.8Hz),7.82(2H,d,J=8.8Hz),8.11(1H,s),8.26(1H,d, J=8.4Hz),8.33(3H,s),8.85(1H,s),10.74(1H,s),11.49(1H,brs),12.78(1H,brs),12.88(1H,brs).

[0648] The compounds shown in Table 11 below were synthesized according to the method described in Example 80:

[0649] Table 11

[0650]

[0651]

[0652]

[0653]

[0654]

[0655] Example 91 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N,N-dimethylquinazoline-6-carboxamide dihydrochloride

[0656]

[0657] Step 1: Preparation of methyl 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-carboxylic acid

[0658] 120 mg (0.20 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate, 16 mg (0.02 mmol) of Pd(dppf)Cl2·DCM, and 196 mg (0.60 mmol) of cesium carbonate were added to 10 mL of MeOH. After purging with carbon monoxide, the mixture was heated to 70 °C and stirred overnight. After the reaction was complete, the reaction solution was concentrated to dryness. The crude product was purified by TLC (DCM / MeOH = 40 / 1) to obtain the target compound (100 mg, yield 92.6%) as a brown solid.

[0659] EM (calculated value): 539.3; MS (ESI) m / z (M+H) + 540.3

[0660] Step 2: Preparation of 2-(4-((tert-Butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-carboxylic acid

[0661] 100 mg (0.19 mmol) of methyl 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxylic acid was dissolved in MeOH / H₂O (10 mL, 5 / 1). LiOH (23 mg, 0.95 mmol) was added, and the mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated, and water was added to the residue. The mixture was extracted twice with EA. The pH of the aqueous phase was adjusted to ~4 with concentrated hydrochloric acid, precipitating a solid. The solid was filtered and dried to obtain the target compound (83 mg, yield 83.2%) as a yellow solid.

[0662] EM (calculated value): 525.2; MS (ESI) m / z (M+H) + 526.2

[0663] Step 3: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(dimethylcarbamoyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0664] Compound 2-(4-((tert-Butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxylic acid (40 mg, 0.08 mmol) was dissolved in THF (6 mL). Dimethylamine hydrochloride (13 mg, 0.16 mmol), HATU (46 mg, 0.12 mmol), and DIEA (41 mg, 0.32 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, EA was dissolved, and the solution was washed twice with water. The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by TLC (DCM / MeOH = 20 / 1) to give the target compound (25 mg, yield 56.8%) as a white solid.

[0665] EM (calculated value): 552.3; MS (ESI) m / z (M+H) + 553.3

[0666] Step 4: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N,N-dimethylquinazoline-6-carboxamide dihydrochloride

[0667] 25 mg (0.05 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(dimethylcarbamoyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 5 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (14 mg, yield 53.2%) as a white solid.

[0668] EM (calculated value): 452.2; MS (ESI) m / z (M+H) + : 453.2

[0669] 1H NMR(400MHz,DMSO-d6)δ0.79-0.85(2H,m),0.96-1.05(2H,m),1.39(3H,s),1.75-1.98(5H,m),3.00(3H,s),3.03(3H,s),3.74-3.87(2H,m ),4.22-4.43(2H,m),7.90-7.93(1H,m),8.10-8.20(1H,m),8.43(3H,brs),8.64(1H,s),11.39(1H,brs),12.77(1H,brs),13.17(1H,brs).

[0670] Example 92 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(methanesulfonyl)quinazolin-4-amine hydrochloride.

[0671]

[0672] Step 1: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0673] 30 mg (0.05 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate, 20 mg (0.20 mmol) of sodium methanesulfonate, and 17 mg (0.10 mmol) of CuI were added to DMSO (2 mL) and heated to 120 °C with stirring overnight. After the reaction was complete, the reaction solution was added to water (20 mL) and extracted twice with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by TLC (DCM / MeOH = 20 / 1) to give the target compound (12 mg, yield 42.9%) as a white solid.

[0674] EM (calculated value): 559.2; MS (ESI) m / z (M+H) + 560.2

[0675] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(methylsulfonyl)quinazolin-4-amine hydrochloride.

[0676] 12 mg (0.02 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(methanesulfonyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate was added to a single-necked flask and cooled in an ice-water bath. Then, 3 mL of 4 M HCl / 1,4-dioxane was added, and the mixture was stirred at this temperature for 1 hour. TLC analysis showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (8 mg, yield 80.8%) as a yellow solid.

[0677] EM (calculated value): 459.2; MS (ESI) m / z (M+H) + 460.2

[0678] 1H NMR(400MHz,DMSO-d6)δ0.78-0.82(2H,m),0.95-0.99(2H,m),1.37(3H,s),1.66-1.70(4H,m),1.87-1.93(1H,m),3.25(3H, s),3.38-3.42(2H,m),4.19-4.34(2H,m),7.49(1H,s),8.00(1H,s),8.16(3H,s),8.94(1H,s),10.36(1H,s),12.44(1H,s).

[0679] Example 93 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazoline-4-amine trihydrochloride

[0680]

[0681] Step 1: Preparation of 4-(2-(4-((tert-butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl

[0682] The compounds tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (80 mg, 0.13 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxapentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (80 mg, 0.26 mmol), Pd(dppf)Cl2.DCM (8 mg, 0.01 mmol), and sodium carbonate (41 mg, 0.39 mmol) were added to 1,4-dioxane / H2O (6 mL, 5 / 1), heated to 80 °C and stirred for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by TLC (DCM / MeOH = 20 / 1) to obtain the target compound (65 mg, yield 75.6%) as a white solid.

[0683] EM (calculated value): 662.4; MS (ESI) m / z (M+H) + : 663.4

[0684] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazoline-4-amine trihydrochloride

[0685] Compound 4-(2-(4-((tert-Butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazole-3-yl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl (20 mg, 0.03 mmol) was added to a single-necked flask, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (3 mL) was added. The mixture was stirred at this temperature for 1 hour. TLC analysis showed that the starting material had reacted completely. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (11 mg, yield 64.0%) as a yellow solid.

[0686] EM (calculated value): 462.3; MS (ESI) m / z (M+H) + 463.3

[0687] 1H NMR(400MHz,DMSO-d6)δ0.80-0.84(2H,m),0.98-1.02(2H,m),1.40(3H,s),1.80-1 .84(4H,m),1.90-1.97(1H,m),2.80-2.83(2H,m),3.35-3.38(2H,m),3.79-3.82(3 H,m),4.25-4.30(3H,m),6.45(1H,s),8.10(1H,d,J=8.8Hz),8.18(1H,d,J=8.8Hz) ,8.43(3H,m),8.63(1H,s),9.47(2H,s),11.53(1H,s),12.80(1H,s),13.17(1H,s).

[0688] Example 94 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(piperidin-4-yl)quinazoline-4-amine trihydrochloride

[0689]

[0690] Step 1: Preparation of tert-butyl 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)piperidin-1-carboxylic acid

[0691] Compound 4-(2-(4-((tert-butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl (45 mg, 0.07 mmol) was added to MeOH (10 mL), followed by the addition of Pd(OH)₂ / C (10 mg). After hydrogen purging, the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solid was filtered, the filter cake was washed with a small amount of methanol, and the filtrate was concentrated to dryness. The crude product was purified by TLC (DCM / MeOH = 10 / 1) to obtain the target compound (22 mg, yield 47.3%) as a white solid.

[0692] EM (calculated value): 664.4; MS (ESI) m / z (M+H) + : 665.4

[0693] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(piperidin-4-yl)quinazoline-4-amine trihydrochloride

[0694] Compound 4-(2-(4-((tert-Butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)piperidin-1-carboxylic acid tert-butyl ester (22 mg, 0.03 mmol) was added to a single-necked flask, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (3 mL) was added. The mixture was stirred for 1 hour while maintaining the temperature. TLC analysis showed that the starting material had reacted completely. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (9 mg, yield 52.3%) as a yellow solid.

[0695] EM (calculated value): 464.3; MS (ESI) m / z (M+H) + 465.3

[0696] 1H NMR(400MHz,DMSO-d6)δ0.79-0.83(2H,m),0.97-1.02(2H,m),1.38(3H,s),1.78-1.8 2(4H,m),1.90-1.94(1H,m),2.05-2.08(2H,m),2.95-3.06(3H,m),3.37-3.39(2H,m), 3.63-3.69(3H,m),4.20-4.25(3H,m),7.81(1H,d,J=5.6Hz),8.04(1H,d,J=5.2Hz),8. 32-8.38(4H,m),8.94(1H,s),8.99(1H,s),11.46(1H,s),12.75(1H,s),12.83(1H,s).

[0697] Example 95 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(trifluoromethyl)quinazoline-4-amine hydrochloride.

[0698]

[0699] Step 1: Preparation of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(trifluoromethyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0700] 100 mg (0.16 mmol) of tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (61 mg (0.32 mmol)) and CuI (53 mg (0.32 mmol) were added to DMF (5 mL), and the mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was added to water (20 mL) and extracted twice with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by TLC (DCM / MeOH = 20 / 1) to give the target compound (8 mg, yield 9.1%) as a white solid.

[0701] EM (calculated value): 549.2; MS (ESI) m / z (M+H) + 550.2

[0702] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(trifluoromethyl)quinazoline-4-amine hydrochloride.

[0703] The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(trifluoromethyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (8 mg, 0.01 mmol) was added to a single-necked flask, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (2 mL) was added. The mixture was stirred for 1 hour while maintaining the temperature. TLC analysis showed that the starting material had reacted completely. The reaction solution was concentrated to dryness at low temperature. The crude product was washed successively with ethyl acetate and petroleum ether, and dried to obtain the target compound (5 mg, yield 76.9%) as a white solid.

[0704] EM (calculated value): 449.2; MS (ESI) m / z (M+H) + : 450.2

[0705] 1H NMR(400MHz,DMSO-d6)δ0.78-0.81(2H,m),0.94-0.98(2H,m),1.37(3H,s),1.64-1.68(4H,m),1.87-1.93(1H,m),3.36-3.38( 2H,m),4.21-4.24(2H,m),7.46(1H,d,J=8.8Hz),7.80(1H,d,J=8.8Hz),8.19(3H,s),8.75(1H,s),10.23(1H,s),12.43(1H,s).

[0706] Inhibitory effect of compound in Experiment Example 1 on kinase activity

[0707] 1. Experimental materials:

[0708] PAK4 (Carna, No. 13CBS-0885G), Kinase substrate31 (GL, No. P200227-CL1358781), DMSO (Sigma, No. SHBG3288V), 384-well plate (Corning, No. 12619003), PF-3758309 (selleckchem, No. S709403)

[0709] 2: Experimental Methods:

[0710] 2.1 Compound Preparation

[0711] The compound was received by the administrator, who dissolved the powder in 100% DMSO to prepare a 10mM storage solution, which was then stored in a nitrogen cabinet away from light.

[0712] 2.2 Kinase Response Process

[0713] (1) Prepare 1×Kinase buffer.

[0714] (2) Preparation of compound concentration gradients: The test compound was prepared at a concentration of 1000 nM and diluted 100 times to a final concentration of 100% DMSO in a 384 source plate. The compound was then diluted 3 times with Precision to obtain 10 concentrations. 250 nL of the 100-fold final concentration of the compound was transferred to the target 384-well plate using an Echo 550 dispenser.

[0715] (3) Prepare a kinase solution with a final concentration of 2.5 times using 1×Kinase buffer.

[0716] (4) Add 10 μL of kinase solution at 2.5 times the final concentration to the compound wells and the positive control wells respectively; add 10 μL of 1×Kinase buffer to the negative control wells.

[0717] (5) Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.

[0718] (6) Prepare a mixed solution of ATP and Kinase substrate 22 at a final concentration of 5 / 3 times using 1×Kinase buffer.

[0719] (7) Add 15 μL of a mixture of ATP and substrate at 5 / 3 times the final concentration to initiate the reaction.

[0720] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 60 min.

[0721] (9) Add 30 μL of the stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix.

[0722] (10) Read the conversion rate using Caliper EZ Reader.

[0723] 2.3 Data Analysis

[0724] Calculation formula

[0725] Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the mean value of the negative control wells, representing the conversion rate reading of wells without enzyme activity; Conversion%_max: the mean value of the positive control wells, representing the conversion rate reading of wells without compound inhibition.

[0726] Fitted dose-response curve:

[0727] Plotting the concentration logarithmic value on the X-axis and the percentage inhibition rate on the Y-axis, dose-response curves were fitted using the log(inhibitor) vs. response–variable slope function of GraphPad Prism 5 to derive the IC50 values ​​of each compound on enzyme activity. The calculation formula is:

[0728] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0729] The test results are shown in Table 12:

[0730] Table 12 Inhibitory activities of compounds against PAK4 and PAK1 kinases (IC50) 50 )

[0731]

[0732]

[0733] ND: Indicates unmeasured;

[0734] Experimental Example 2: Stability Test of Compound in Liver Microsomes

[0735] 1: Materials and Methods

[0736] Buffer solution:

[0737] (1) 100mM potassium phosphate buffer, pH 7.4; (2) 10mM MgCl2.

[0738] Preparation of compound solutions:

[0739] (1) Preparation of 100 μM working solution: Take 5 μL of the stock solution (10 mM) of the test group or control group and dilute it with 495 μL of methanol to obtain a compound concentration of 100 μM (99% MeOH).

[0740] (2) Preparation of 10 μM working solution: Take 50 μL of 100 μM working solution and dilute it with 450 μL of 100 mM potassium phosphate buffer to obtain a compound concentration of 10 μM (9.9% MeOH).

[0741] Components of the NADPH (prototype coenzyme II) regeneration system (final concentration of isocitrate dehydrogenase in culture medium is 1.0 unit / mL):

[0742] β-Nicotinamide adenine dinucleotide phosphate, Supplier: Chem-impex International, Product No.: N00616

[0743] Preparation of liver microsomal solution (final concentration 0.5 mg protein / mL), types of liver microsomes are shown in Table 13:

[0744] Table 13

[0745]

[0746] Termination solution:

[0747] An ice-cold acetonitrile solution containing 100 ng / mL tolbutamide and 100 ng / mL labetalol as internal standards.

[0748] Operating steps:

[0749] (1) Except for the blank matrix plate wells, 10 μL of working solution of the test or control drug was added to each of the other wells (T0, T5, T10, T20, T30, T60 and NCF60).

[0750] (2) Dispense 80 μL / well microparticle solution onto each plate with Apricot and incubate the mixture of microparticle solution and compound at 37°C for about 10 minutes.

[0751] (3) Add 10 μL of 100 mM potassium phosphate buffer to NCF60 / well, incubate at 37°C, and start timer 1. The time is shown in Table 14.

[0752] Table 14

[0753]

[0754] (4) After preheating, use Apricot to dispense 10 μL / well of NADPH regeneration system onto each plate to start the reaction.

[0755] Table 15 Final concentrations of each component in the incubation medium

[0756]

[0757] (5) Incubate at 37℃, start timer 2, and the data are shown in Table 16.

[0758] Table 16

[0759]

[0760] (6) Add pre-cooled stop solution (containing 100 ng / mL of internal standard tolbutamide and 100 ng / mL of sulfadiazine) to each well to terminate the reaction.

[0761] (7) Then the sample plate is shaken on the trigger for about 10 minutes.

[0762] (8) Centrifuge the sample at 4000 rpm for 20 min at 4℃.

[0763] (9) Take another 96-well plate, add 300 μL of HPLC-grade water to each well, add 100 μL of the supernatant obtained by centrifugation to the corresponding well, mix the two and use them for LC / MS / MS detection.

[0764] Data Analysis:

[0765] t1 / 2 and Clint(mic) values ​​were calculated based on first-order elimination kinetics.

[0766] The first-order elimination kinetic equation is:

[0767]

[0768]

[0769]

[0770]

[0771]

[0772] The results of liver microsomal stability tests for some compounds are shown in Table 17:

[0773] Table 17

[0774]

[0775]

[0776] Experiment 3: Detection of Compounds in Rats (PK Test)

[0777] Male SD rats (purchased from Chengdu Dashuo Experimental Animal Co., Ltd.) were used. Pharmacokinetic studies were conducted on SD rats by single oral administration (10 mg / kg, 3 rats per group) of each test compound. The test compounds were prepared on the day of administration using 5% DMSO + 10% solubilizer + 85% saline, followed by vortexing for 2 min and sonication for 5 min to prepare the drug solution. Animals were fasted for 10-14 hours before oral administration and resumed feeding 4 hours after administration. Pharmacokinetic samples were collected via the jugular vein after oral and intravenous administration to SD rats at the following time points: before administration, and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Three whole blood samples (approximately 0.2 mL) were collected at each time point and anticoagulated with heparin sodium. Blood samples were immediately placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6800 rpm, 6 minutes, 2-8℃). The collected plasma was stored in a -80°C freezer before analysis.

[0778] The pharmacokinetic test results of some compounds of this invention are shown in Table 18 below:

[0779] Table 18 Pharmacokinetic Test Results of Some Compounds of the Invention

[0780]

[0781]

[0782] *: Rats with CZh-226 pharmacokinetics data are from literature reports;

[0783] The drug-likeness studies above show that some compounds of this invention exhibit superior PAK4 protein kinase inhibitor activity compared to previously reported compounds CZh-226 and PF-3758309, while maintaining high PAK1 / PAK4 selectivity. Furthermore, and more importantly, rat pharmacokinetic tests of some compounds demonstrate significant advantages in pharmacokinetic aspects compared to compound CZh-226. In conclusion, these compounds, as PAK4 protein kinase inhibitors, show broad application prospects in the treatment of malignant tumors, neurodegenerative diseases, and immune system disorders.

[0784] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A compound as a PAK4 inhibitor, characterized in that, It has any of the following structures: 、 、 、 、 、 、 、 、 。 2. A PAK4 inhibitor comprising the compound of claim 1 and a pharmaceutically acceptable adjuvant.

3. The use of the compound of claim 1 or the PAK4 inhibitor of claim 2 in the preparation of PAK4 inhibitors.

4. The application according to claim 3, characterized in that, The PAK4 inhibitors are indicated for cancers, neurodegenerative diseases, or immune system disorders that are associated with the expression or activity of PAK4 kinase.

5. The application according to claim 4, characterized in that, The cancers mentioned include breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, hepatocellular carcinoma, gastric cancer, glioma, endometrial cancer, kidney cancer, melanoma, bladder cancer, biliary tract cancer, lymphoma, pilonidal carcinoma, pharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancers, cervical cancer, prostate cancer, testicular cancer, urogenital tract cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, bone cancer, colon cancer, pancreatic cancer, follicular carcinoma, Hodgkin's leukemia, bronchial cancer, thyroid cancer, endometrial cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and primary macroglobulinemia.

6. The application according to claim 5, characterized in that, The pharyngeal cancer mentioned is nasopharyngeal carcinoma.

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