WO2022033420A1 - Compound as pak4 kinase inhibitor, and preparation method therefor and application thereof - Google Patents

Abstract

The present invention provides a compound as a PAK4 inhibitor having a structure shown in formula I, or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable hydrate, solvate, or salt thereof. Experimental results show that the compound prepared in the present invention has high inhibitory activity and selectivity on PAK4 kinase, and moreover, the stability of liver microsomes and rat PK are also increased.

Description

A kind of compound as PAK4 kinase inhibitor and preparation method and application thereof

This application requires that the Chinese patent application with the application number of 202010819448.1 and the invention titled "a compound as a PAK4 kinase inhibitor and its preparation method and application" be submitted to the China Patent Office on August 14, 2020, and filed on December 2020. The priority of the Chinese patent application filed with the Chinese Patent Office on March 31, the application number is 202011631465.9, and the invention title is "a compound as a PAK4 kinase inhibitor and its preparation method and application", the entire content of which is incorporated by reference in this application middle.

technical field

The invention relates to the technical field of drug synthesis, in particular to a compound as a PAK4 kinase inhibitor and a preparation method and application thereof.

Background technique

P21-activated protein kinase (PAK), as a class of conserved serine/threonine protein kinases, is the effector protein of the small GTPase CDC42 and Rac1 in the Rho family, mediating the transduction of its downstream signaling pathways . According to their sequence homology and activation mode, they can be divided into two categories: class I PAKs (PAK1, 2, 3) and class II PAKs (PAK4, 5, 6). As important downstream counterparts of Pho family GTPases Rac and Cdc42, PAKs play important roles in cell proliferation, cytoskeleton reorganization, and cell motility. Studies have shown that each member of PAKs, especially its representative members PAK1 and PAK4, has the phenomenon of gene amplification, gene mutation, expression level and activity up-regulation in various tumor cells and tissues, which is closely related to the occurrence and development of tumors. By inhibiting the abnormal activity of PAKs in tumor cells, it is expected to inhibit the excessive proliferation, invasion and metastasis of tumor cells and angiogenesis, and promote the apoptosis of tumor cells. In view of this, the research of PAKs inhibitors has received extensive attention from medicinal chemists in the past decade. Wang C et al. showed that the expression level of PAK4 in lung cancer, colon cancer, prostate cancer, pancreatic cancer and breast cancer cells is much higher than that in normal cells, which has an important impact on the occurrence, development, invasion and migration of tumors. Therefore, the development of PAK4 inhibitors is one of the effective strategies for the treatment of various tumors.

Recent studies have found that inhibition of class I PAKs is potentially associated with safety risks such as acute cardiac toxicity and Herg side effects, suggesting that the development of PAKs inhibitors should avoid the inhibition of class I PAKs, especially PAK1. Therefore, the discovery of highly selective inhibitors of class II PAKs will become the mainstream of future research.

As a potential drug development target, the development of PAK4 inhibitors provides new ideas for the treatment of related cancers. Up to now, the number of PAK4 inhibitors is very small, and the activity of most inhibitors is not ideal. The small molecule inhibitors that have entered the clinical stage include KPT-9274 jointly developed by Antengene and Karyopharm Therapeutics and PF-3758309 developed by Pfizer. Among them, PF-3758309 is a PAKs inhibitor with a pyrrolopyrazole structure reported by Pfizer in 2009. It is the first PAKs inhibitor to enter clinical research. Its PAK4 IC50 is 19nm, but this compound has stronger inhibitory ability to PAK1 , up to 14nm, with serious security risks. Due to its poor oral bioavailability, only about 1%, and serious gastrointestinal adverse reactions and other factors, the Phase I clinical study was forced to terminate. ATG-019(KPT-9274) is a world-first oral dual-target inhibitor of p21-activated kinase 4 (PAK4) and nicotinic phosphoribosyltransferase (NAMPT). A number of clinical studies in the fields of colorectal cancer, lung cancer, melanoma, etc. In addition, preclinical studies have shown that ATG-019 combined with anti-PD-1 antibody can effectively improve the anti-tumor efficacy and is effective in patients with anti-PD-1 antibody resistance, and relevant clinical studies are being carried out.

Based on the structure of the drug, Hao C et al. designed and synthesized a series of aminoquinazoline PAK4 inhibitors, and obtained a highly active and highly selective PAK4 inhibitor (CZh-226). It has a Ki value of 9 nM for PAK4, and exhibits excellent selectivity against a variety of kinases, among which the Ki value for PAK1 is 3112 nM, a 346-fold difference in selectivity. However, the compound has poor drugability and extremely low bioavailability (1.92%), which needs to be further optimized; at the same time, its PAK4 inhibitory activity also has room for further improvement.

SUMMARY OF THE INVENTION

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

In order to achieve the above object, the present invention provides a compound as a PAK4 inhibitor, having the structure shown in formula I or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts:

Wherein, B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ are independently selected from CR ₃ or N, respectively.

Ring A is selected from substituted or unsubstituted C5-C9 aryl or heteroaryl.

More preferably, ring A is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, further preferably substituted or unsubstituted phenyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, pyrazine group, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl or pyridyl.

The substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or Unsubstituted alkoxy, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkylphosphorus, alkylsulfone, alkylidene sulfone group.

More preferably, the substituted groups are independently selected from five- or six-membered aryl or heteroaryl substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or Unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphorus Acyl group, alkyl oxyphosphorus group, alkyl sulfone group, alkyl sulfoxide group.

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, hydroxy, Cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronic ester, boronic acid .

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, alkyloxyphosphorus, alkylsulfone, Alkyl sulfoxide group, boronic acid ester group, boronic acid group.

The substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or Unsubstituted alkoxy, substituted or unsubstituted aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl , alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.

Preferably in the present invention, the substituted groups are independently selected from five- or six-membered aryl or heteroaryl substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or Unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C6-C12 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro group, mercapto group, substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, alkyl sulfonyl group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.

L is selected from single bond, O, S, NH or alkylene.

Preferably in the present invention, the alkylene group is a C1-C10 alkylene group.

Further preferably, the alkyl group is methylene or ethylene.

In the present invention, when L is a single bond, it means that V is directly connected to the parent ring.

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.

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 C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkenyl Unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl.

The substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, alkoxy group, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boron Acid group, boronic acid group.

Preferably in the present invention, the substituted groups are independently selected from five- or six-membered aryl or heteroaryl substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or Unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C1-C10 alkoxy, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonic Acyl group, phosphoryl group, alkyl phosphoryl group, alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.

R ₁ is carbonyl, thiocarbonyl, methylene or a single bond.

In the present invention, R ₁ is a single bond, which means that R ₂ is directly connected to the parent ring.

R ₂ and R ₃ are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroalkyl Aryl, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronic acid Ester group, boronic acid group.

More preferably, R ₂ and R ₃ are 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, alkyl phosphorous group, alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.

The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, hetero Aryl, ester, acyl, amido, sulfonyl, phosphoryl.

Preferably in the present invention, the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C10 alkyl, C3-C10 cycloalkyl, C1- C10 heteroalkyl, C2-C10 heterocycloalkyl, six-membered aryl, five- or six-membered heteroaryl, ester group, acyl group, amide group, sulfonyl group, phosphoryl group.

In the present invention, the above-mentioned bicyclic or tricyclic compounds include, but are not limited to, spirocyclic, bridged, and fused ring compounds.

In the present invention, the above-mentioned cycloalkyl or heterocycloalkyl includes, but is not limited to, monocyclic, spirocyclic, bridged, fused cycloalkyl or heterocycloalkyl.

Preferably in the present invention, the compound has the structure shown in formula II or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof. An acceptable hydrate, solvate or salt of:

Wherein, A ₁ is selected from CR ₆ or N.

R ₆ is selected from hydrogen, halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

Preferably in the present invention, R ₆ is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted containing at least C1-C3 heteroalkyl with one N or O atom, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one N or O atom.

Further preferably, R ₆ is selected from hydrogen, halogen, amino, methyl, ethyl, methoxy, cyano, trifluoromethyl, isopropyl or cyclopropyl.

R ₄ 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 base.

Preferably in the present invention, R ₄ is selected from substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl.

Further preferably, R ₄ is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C4-C6 heterocycloalkyl containing at least one N or O atom.

The substituted groups are independently selected from halogen, cyano, amino, hydroxyl, substituted or unsubstituted amide, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3- C6 cycloalkyl or heterocycloalkyl.

Preferably in the present invention, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkane Oxygen, C3-C6 cycloalkyl.

In some specific embodiments of the present invention, the substituent groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxyethyl or Cyclopropyl.

X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl.

Preferably in the present invention, X is selected from a single bond, a substituted or unsubstituted phenyl group, a pyridyl group, an alkynyl group or an alkenyl group.

In the present invention, X is selected from a single bond and means that E is directly connected to the parent ring.

E is selected from single bond, ester group, amido group, ether group, carbonyl group, sulfone group, sulfoxide group, thioamide group, urea group, thiourea group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl group , substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

Preferably in the present invention, E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

In some specific embodiments of the present invention, E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethyl Oxy, propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom .

The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkane base.

Preferably in the present invention, the substituents are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom.

In the present invention, E selected from a single bond means that R ₅ is directly connected to X.

When both E and X are single bonds, it means that R ₅ is directly connected to the parent ring.

R ₅ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.

The above-mentioned alkoxy group is preferably a substituted or unsubstituted C1-C10 alkoxy group.

The above-mentioned aryloxy group is preferably a substituted or unsubstituted C5-C10 aryloxy group.

Preferably in the present invention, the R ₅ is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C1-C10 cycloalkyl or heterocycloalkyl 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, alkyl phosphoryl, boronic ester, boronic acid.

Further preferably, the R ₅ 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 group, mercapto group, substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, boronic acid ester group, boronic acid group.

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 ~C6cycloalkyl, substituted or unsubstituted C3-C6heterocycloalkyl.

Preferably in the present invention, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, Methyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl, tetrahydropyrrolyl.

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, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronate , boronic acid group.

Preferably in the present invention, W is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted five-membered or six-membered aryl or heteroaryl.

Further preferably, W is selected from five-membered or six-membered heterocycloalkyl groups containing any one or more of N, O, and S.

In the present invention, the heterocycloalkyl group includes, but is not limited to, monocyclic, spirocyclic, bridged, and fused ring heterocycloalkyl.

The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, hetero Aryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or heteroaryl.

Preferably in the present invention, the aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.

Preferably in the present invention, the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1- C3 heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or hetero Aryl.

Preferably in the present invention, the aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.

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

n is selected from 0 or 1.

In the present invention, when n is selected from 0, W is directly connected to the heteroaromatic ring containing A ₁ atom.

Preferably in the present invention, the compound has the structure shown in formula III, or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Pharmaceutically acceptable hydrates, solvates or salts:

wherein, R ₇ is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O atom.

Preferably in the present invention, the R ₇ is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine radical, furyl, thienyl, pyrrolyl, five- or six-membered heterocycloalkyl containing at least one N and/or O atom.

In some specific embodiments of the present invention, R ₇ has any of the following structures:

The curved line indicates the location of the connection.

Any one or more C atoms in the above structures may be optionally substituted with one or more substituents.

Preferably in the present invention, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkane oxy, C3-C6 cycloalkyl.

Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amido, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl.

J is selected from single bond, amido, carbonyl, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

Preferably in the present invention, J is selected from a single bond, an amido group, a carbonyl group, a methylene group, and a methyleneoxy group.

The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkane base.

Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl Oxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridyl.

In the present invention, when J is a single bond, it means that R ₈ is directly connected to an alkynyl group.

R ₈ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.

Preferably in the present invention, R ₈ 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 amido, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyl oxyphosphorus, substituted or unsubstituted C1-C10 alkyl sulfone, substituted or unsubstituted C1- C10 alkyl sulfoxide group, boronic acid ester group, boronic acid group.

More preferably, R ₈ 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 group, sulfonyl group, phosphoryl group, substituted or unsubstituted C1-C6 alkyl oxyphosphoryl group, substituted or unsubstituted C1-C6 alkyl sulfonyl group, substituted or unsubstituted C1-C6 group The alkyl sulfoxide group, boronic acid ester group, boronic acid group.

Further preferably, R ₈ is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, phenoxy, five- to seven-membered heterocycloalkyl containing at least one N and/or O, five- or six-membered unsaturated cycloalkyl , pyridyl, amido, cyano, hydroxyl, halogen, amino, ester, nitro, mercapto, sulfonyl, phosphoryl, substituted or unsubstituted C1-C3 alkyl oxyphosphorus, substituted or unsubstituted C1-C3 alkyl sulfone group, substituted or unsubstituted C1-C3 alkyl sulfoxide group, boronic acid ester group, boronic acid group.

Preferably in the present invention, the five-membered or six-membered unsaturated cycloalkyl group is a cyclopentenyl group or a cyclohexenyl group.

In the present invention, the above-mentioned cycloalkyl or heterocycloalkyl includes, but is not limited to, monocyclic, spirocyclic, bridged, fused-ring cycloalkyl or heterocycloalkyl.

Preferably in the present invention, the substituted groups are independently selected 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, substituted or unsubstituted C3-C6 heterocycloalkyl.

Further 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 heterocycloalkanes containing at least one N and/or O base.

In some specific embodiments of the present invention, the five-membered-seven-membered heterocycloalkyl containing at least one N and/or O has any of the following structures:

Curved lines indicate connection locations.

Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the above substituents.

Y 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 hetero Aryl.

Preferably, Y is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl containing at least one N and/or O, phenyl, and pyridyl.

Further preferably, Y is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl groups containing at least one N atom, and the N atom is connected to the adjacent carbonyl group to form an amide group.

In the present invention, the heterocycloalkyl group includes but is not limited to monocyclic, bridged ring, spirocyclic and fused ring heterocycloalkyl.

The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or heteroaryl.

Preferably in the present invention, the aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.

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 heterocycloalkyl containing at least one N and/or O , substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.

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

Curved lines indicate connection locations.

Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the aforementioned substituents.

n is selected from 0 or 1. Further, n is selected from zero.

When n is 0, Y is directly attached to the pyrimidine ring.

Preferably in the present invention, the compound has the structure shown in formula IV, or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , a pharmaceutically acceptable hydrate, solvate or salt:

where m is 0, 1, 2, 3 or 4.

In the present invention, when m is not 0, each substituent on the benzene ring may be the same or different.

R ₉ is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O atom.

More preferably, R ₉ is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furan group, thienyl, pyrrolyl, five- or six-membered heterocycloalkyl containing at least one N and/or O.

In some specific embodiments of the present invention, R ₉ has any of the following structures:

The curved line indicates the location of the connection.

Any one or more C atoms in the above structures may be optionally substituted with one or more substituents.

Preferably in the present invention, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkane Oxygen, C3-C6 cycloalkyl.

Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amido, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl.

G is selected from single bond, amido group, ether group, carbonyl group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

Preferably, G is selected from a single bond, an amido group, an ether group, a carbonyl group, a methylene group, and a difluoromethylene group.

The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkane base.

Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl Oxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridyl.

In the present invention, when G is selected from a single bond, it means that R ₁₀ is directly connected to the benzene ring.

R ₁₀ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.

Preferably in the present invention, R ₁₀ 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 amido, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyl oxyphosphorus, substituted or unsubstituted C1-C10 alkyl sulfone, substituted or unsubstituted C1- C10 alkyl sulfoxide group, boronic acid ester group, boronic acid group.

More preferably, R ₁₀ 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 group, sulfonyl group, phosphoryl group, substituted or unsubstituted C1-C6 alkyl oxyphosphoryl group, substituted or unsubstituted C1-C6 alkyl sulfonyl group, substituted or unsubstituted C1-C6 group The alkyl sulfoxide group, boronic acid ester group, boronic acid group.

Further preferably, R ₁₀ is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, five- to seven-membered heterocycloalkyl containing at least one N and/or O, five- or six-membered unsaturated cycloalkyl, pyridyl, Amido, cyano, hydroxyl, halogen, amino, ester, nitro, mercapto, sulfonyl, phosphoryl, substituted or unsubstituted C1-C3 alkyl oxyphosphorus, substituted or unsubstituted C1-C3 Alkyl sulfone group, substituted or unsubstituted C1-C3 alkyl sulfoxide group, boronic acid ester group, boronic acid group.

Preferably in the present invention, the five-membered or six-membered unsaturated cycloalkyl group is a cyclopentenyl group or a cyclohexenyl group.

In the present invention, the above-mentioned cycloalkyl or heterocycloalkyl includes, but is not limited to, monocyclic, spirocyclic, bridged, fused-ring cycloalkyl or heterocycloalkyl.

Preferably in the present invention, 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.

Further 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 heterocycloalkanes containing at least one N and/or O base.

In some specific embodiments of the present invention, the five-membered-seven-membered heterocycloalkyl containing at least one N and/or O has any of the following structures:

The curved line indicates the location of the connection.

Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the above substituents.

Z 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.

Preferably, Z is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl containing at least one N and/or O, phenyl, and pyridyl.

Further preferably, Z is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl groups containing at least one N atom, and the N atom is connected to the adjacent carbonyl group to form an amide group.

In the present invention, the heterocycloalkyl group includes but is not limited to monocyclic, bridged ring, spirocyclic and fused ring heterocycloalkyl.

The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.

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 heterocycloalkyl containing at least one N and/or O , substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.

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

Curved lines indicate connection locations.

Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the aforementioned substituents.

R ₁₁ is independently selected from hydrogen, halogen, hydroxy, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Unsubstituted heterocycloalkyl.

Preferably in the present invention, R ₁₁ 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, substituted or unsubstituted C3-C6 heterocycloalkyl.

n is selected from 0 or 1. Further, n is selected from zero.

When n is 0, Z is directly attached to the pyrimidine ring.

In the present invention, the cycloalkyl group includes saturated or unsaturated cycloalkyl groups.

The heterocycloalkyl group includes saturated or unsaturated heterocycloalkyl groups.

In the present invention, the cycloalkyl group includes monocyclic ring, bridged ring, spirocyclic ring and fused ring cycloalkyl group.

The heterocycloalkyl groups include monocyclic, bridged, spiro and fused ring heterocycloalkyl groups.

Preferably in the present invention, the compound has the structure represented by formula V or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Pharmaceutically acceptable hydrates, solvates or salts:

Wherein, X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl;

Preferably in the present invention, X is selected from a single bond, a substituted or unsubstituted phenyl group, a pyridyl group, an alkynyl group or an alkenyl group.

In the present invention, X is selected from a single bond and means that E is directly connected to the parent ring.

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

Preferably in the present invention, E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

In some specific embodiments of the present invention, E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethyl Oxy, propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom .

Preferably in the present invention, the substituents are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom.

_In the present invention, E selected from single bond means that R is directly connected with X;

When both E and X are single bonds, it means that R ₅ is directly connected to the parent ring.

R ₅ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; 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;

The above-mentioned alkoxy group is preferably a substituted or unsubstituted C1-C10 alkoxy group.

The above-mentioned aryloxy group is preferably a substituted or unsubstituted C5-C10 aryloxy group.

More preferably, R ₅ 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, alkyl oxyphosphorus, boronate, boronic acid base.

Further preferably, the R ₅ 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 group, mercapto group, substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, boronic acid ester group, boronic acid group.

wherein 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, piperazinyl, N-methyl Piperazinyl, tetrahydropyridyl, morpholinyl.

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, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronate , boronic acid group; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl , ester group, acyl group, carbonyl group, amide group, sulfonyl group, phosphoryl group, single or multiple substituent substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; wherein monocyclic, bicyclic or tricyclic The substituents of the aryl or heteroaryl groups are deuterium, fluorine, chlorine, bromine, cyano, amino, hydroxyl, nitro, mercapto, sulfone, sulfoxide, boronate, boronate, alkyl phosphorous group, ester group, amide group, sulfonyl group, phosphoryl group, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl;

More preferably, K is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl containing at least one N or O or S, substituted or unsubstituted C3-C10 cycloalkyl, Substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O or S, substituted or unsubstituted five- or six-membered aryl or heteroaryl; wherein the substituted groups are independently selected from Amino, halogen, hydroxyl, cyano, mercapto, nitro, carboxyl, amido, ester, carbonyl, sulfonyl, phosphoryl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl with multiple substituents; wherein the substituent of the monocyclic, bicyclic or tricyclic aryl or heteroaryl is Deuterium, fluorine, chlorine, bromine, cyano, amino, hydroxyl, nitro, mercapto, sulfone, sulfoxide, boronic ester, boronic acid, alkyl phosphorous, 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 heterocycloalkyl ;

Further preferably, the K is a C3-C10 N-containing heterocyclic group, a C6-C12 N-containing spirocyclic group, or a C6-C12 N-containing fused ring group.

And preferably, the N atom is directly connected to the parent ring.

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

Preferably in the present invention, any one or more carbon atoms or nitrogen atoms of the above-mentioned groups can be connected to one or more substituents;

The substituents are preferably amino, halogen, amido, 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-mentioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, Amine group, C6-C12 aryl group, C5-C12 heteroaryl group can be optionally substituted by one or more halogen, hydroxyl, nitro, cyano, mercapto, sulfonic acid, amino.

In some specific embodiments of the present invention, the substituent is selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, Isopropoxy, amido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl.

Preferably in the present invention, the above substituents can be further substituted by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, sulfonic acid groups, or any one or more carbon atoms can be substituted by oxo , Thio.

n is selected from 0 or 1; further, n is selected from 0.

When n is 0, K is directly attached to the pyrimidine ring.

Preferably in the present invention, the compound has the structure shown in formula VI or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , a pharmaceutically acceptable hydrate, solvate or salt:

Wherein, X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl.

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

R ₅ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; 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.

P is selected from NR ₁₃ , CR ₁₄ R ₁₅ ;

R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ are independently selected from hydrogen, amino, halogen, amido, sulfonyl, sulfonic acid, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl , C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl; the above-mentioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 ring Alkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl can be optionally replaced by one or more halogen, hydroxyl, nitro, cyano, mercapto, sulfonic acid , amino, C1-C6 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl substitution;

R ₁₃ , R ₁₄ and R ₁₅ are independently preferably amino, halogen, amide, sulfonyl, sulfonic acid, hydroxy, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 ring Alkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl; the above-mentioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3- C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl can be optionally substituted by one or more halogen, hydroxyl, nitro, cyano, mercapto, sulfonic acid, amino.

In some specific embodiments of the present invention, the substituent is selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, Isopropoxy, amido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl.

Preferably in the present invention, the above substituents can be further substituted by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, sulfonic acid groups, or any one or more carbon atoms can be substituted by oxo , Thio.

Said R ₁₂ is further preferably an amino group.

Or R ₁₂ and P atom form a spiro ring structure;

Or R ₁₂ forms a condensed ring structure with the P atom and the carbon atom adjacent to the P atom;

n is selected from 0 or 1; further, n is selected from 0.

When n is 0, the N atom of the N-containing heterocycle is directly attached to the pyrimidine ring.

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

Preferably in the present invention, the compound has the structure shown in formula VII or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Pharmaceutically acceptable hydrates, solvates or salts:

in,

R ₁₆ is selected from hydrogen, fluorine, chlorine, bromine, iodine, alkynyl, C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl or heterocycloalkyl; further R ₁₆ is selected from fluorine, chlorine , bromine, alkynyl;

R ₁₇ is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, ester, nitro, amide, mercapto, sulfonyl, alkylphosphorus, alkylsulfone, alkylsulfoxide, boronic acid Ester group, boronic acid group, substituted or unsubstituted heteroalkyl group containing at least one of N, O, S atoms C1-C6, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group , substituted or unsubstituted C1-C6 substituted amino, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one N, O, S atom, substituted Or unsubstituted aryl or heteroaryl, substituted or unsubstituted alkynyl or alkenyl, or two identical or different R ₁₇ and the attached phenyl group together form a substituted or unsubstituted at least C, N, O , S a five-membered to twelve-membered ring structure group of an atom, wherein the substituted groups are independently selected from deuterium, halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino , alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl;

Preferably in the present invention, the five-membered to twelve-membered ring structure group can be a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and the ring structure and the connected phenyl group together form the following group but not limited to the following groups: substituted or unsubstituted piperonyl, substituted or unsubstituted quinolyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzene furanyl, substituted or unsubstituted benzopyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted benzocrownyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted benzene morpholinyl, substituted or unsubstituted tetrahydroquinoxaline, substituted or unsubstituted benzoxazole, substituted or unsubstituted chromodihydrofuran, substituted or unsubstituted benzisoxazole, substituted or unsubstituted Unsubstituted benzothiazoles, substituted or unsubstituted benzisothiazoles, substituted or unsubstituted benzothiazoles, substituted or unsubstituted benzimidazoles, substituted or unsubstituted benzopyrazoles.

Further R ₁₇ is selected from methoxy, trifluoromethoxy, difluoromethoxy, methoxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethoxy, fluorine, chlorine, Bromine, cyano, hydroxyl, methyl sulfone, methyl sulfoxide, dimethyl oxophosphine, or two identical or different R17 and the connected phenyl group contain at least one of C, N, O, S atom substituted or unsubstituted five- to six-membered cyclic structural group, wherein the substituted groups are 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;

Preferably in the present invention, the above five-membered to six-membered cyclic structural group may be a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group. This ring structure and the attached phenyl group together form the following groups but are not limited to the following groups: 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 benzotetra Hydroquinoxaline, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzodihydrofuran, substituted or unsubstituted benzisoxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted Benzisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzopyrazole.

n2 is selected from 0, 1, 2, 3, 4, 5.

The amine group or substituted amine group in the present invention 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.

More preferably, the amine group or substituted amine group is selected from methylamine, ethylamine, propylamine, isopropylamine or butylamine.

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

Specifically, the present invention provides a PAK4 inhibitor, comprising the above compound and a pharmaceutically acceptable adjuvant.

The present invention does not specifically limit the type of the adjuvant, and it can be an adjuvant well known to those skilled in the art.

In the present invention, the compound can be administered alone or in combination with other drugs.

The present invention provides the use of the above compounds or the above PAK4 inhibitors in the preparation of PAK4 inhibitors.

Preferably in the present invention, the PAK4 inhibitor is suitable for cancer, neurodegenerative disease or immune system disease related to the expression or activity of PAK4 kinase.

Preferably in the present invention, the cancer includes breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, gastric cancer, glioma, uterus Endometrial cancer, melanoma, kidney cancer, bladder cancer, melanoma, bladder cancer, biliary tract cancer, kidney cancer, pancreatic cancer, lymphoma, hair cell cancer, nasopharyngeal cancer, pharyngeal cancer, colorectal cancer, rectal cancer, brain and Central nervous system cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lung cancer, non-small cell lung cancer, small cell cancer, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid carcinoma, follicular carcinoma, Hodgkin's leukemia, bronchial carcinoma, thyroid carcinoma, endometrial carcinoma, cervical carcinoma, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic Lymphoid leukemia, myeloid leukemia, non-Hodgkin lymphoma, primary macroglobulinemia.

Compared with the prior art, the present invention provides a compound as a PAK4 inhibitor, having the structure shown in formula I or its tautomer, meso, racemate, enantiomer, Diastereomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts. The test results show that the compounds prepared by the present invention have high inhibitory activity and selectivity for PAK4 kinase, and meanwhile, the stability of liver microsomes and rat PK are also improved to a certain extent.

detailed description

In order to further illustrate the present invention, the compounds provided by the present invention as PAK4 kinase inhibitors and their preparation methods and applications are described in detail below with reference to the examples.

Abbreviations appearing in the following examples have the following meanings:

Et ₃ N: triethylamine;

EA: ethyl acetate;

THF: tetrahydrofuran;

EtOH: ethanol;

MeOH: methanol;

SOCl ₂ : thionyl chloride;

DIEA: N,N-diisopropylethylamine;

LDA: lithium diisopropylamide;

n-BuLi: n-butyl lithium;

DAST: diethylaminosulfur trifluoride;

DME: ethylene glycol dimethyl ether;

M: molar concentration unit mol/L, for example 1M refers to 1mol/L;

N: equivalent concentration, for example, 1N HCl refers to hydrochloric acid with a concentration of 1mol/L;

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate;

DMF: N,N-dimethylformamide;

TLC: thin layer chromatography;

PE: petroleum ether (boiling point 60～90℃);

DCM: dichloromethane;

H ₂ O: distilled water;

DMSO: dimethyl sulfoxide;

Pd ₂ (dba) ₃ : 3,3,6,6-tetramethyl-9-(1,2,3,4-tetrahydroxybutyl)-4,5,7,9-tetrahydro-2H-hetero anthracene-1,8-dione);

Xphos: 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl;

DPPF: 1,1'-bis(diphenylphosphino)ferrocene;

Pd(PPh ₃ ) ₂ Cl ₂ : bistriphenylphosphonium palladium dichloride;

Pd(dppf) _Cl2.DCM : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex;

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

DCC: dicyclohexylcarbodiimide;

TBAF: tetrabutylammonium fluoride;

1,4-dioxane: 1,4-dioxane;

KI: potassium iodide;

LiHMDS: lithium hexamethyldisilazide;

Preparation of intermediates

Intermediate: (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine Preparation of -1-Carboxylic acid tert-butyl

Step 1: Preparation of 2-amino-5-iodobenzamide

The compound 2-aminobenzamide (10.00 g, 73.48 mmol) was dissolved in H ₂ O (250 mL), and sodium bicarbonate (6.17 g, 73.48 mmol) and iodine powder (20.51 g, 80.83 mmol) were sequentially added thereto, Stir at room temperature for 24 hours. TLC spot plate detection, the raw material reaction is completed. The pH of the reaction solution was adjusted to about 7 with sodium bisulfite. After the solid was suction filtered and washed with water, it was dispersed in ethanol and heated to reflux to dissolve. After cooling, it was filtered to obtain the target compound (14.20 g, yield 73.8%) as a lavender solid.

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

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

The compound 2-amino-5-iodobenzamide (14.00 g, 53.44 mmol) was dissolved in THF (250 mL), Et ₃ N (10.80 g, 106.88 mmol) was added thereto, and the mixture was stirred at 0°C. Oxalyl chloride monoethyl ester (8.02 g, 58.78 mmol) was slowly added dropwise to the reaction system, and stirring was continued at this temperature for 2 hours. TLC spot plate detection, the raw material reaction is completed. After most of the THF in the reaction solution was concentrated, the residue was added to water (1 L) with stirring, and a large amount of solid was precipitated. The solid was suction filtered and dried to obtain the title compound (16.5 g, yield 85.3%) as a lavender solid.

EM (calcd): 362.0; MS (ESI) m/z (M+H) ⁺ : 363.0

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

Compound 2-((2-carbamoyl-4-iodophenyl)amino)-2-oxoacetate (16.00 g, 44.20 mmol) was dissolved in EtOH (300 mL), and sodium ethoxide was added thereto under ice-water bath (3.61 g, 53.04 mmol) and stirring was continued for 3 hours. TLC spot plate detection, the raw material reaction is completed. The pH of the reaction solution was adjusted to 3-4 with concentrated hydrochloric acid. With stirring, the reaction solution was added to water, and a large amount of solid was precipitated. The solid was suction filtered and dried to obtain the title compound (12.5 g, yield 82.3%) as an off-white solid.

EM (calcd): 344.0; MS (ESI) m/z (M+H) ⁺ : 345.0

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

The compound 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate ethyl ester (12.00 g, 34.88 mmol) was dissolved in EtOH/H ₂ O (200 mL, 1/1 ) and added to Sodium hydroxide (5.58 g, 139.52 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. TLC spot plate detection, the raw material reaction is completed. Under an ice-water bath, the pH of the reaction solution was adjusted to 5-6 with 2N hydrochloric acid. The solid was suction filtered and dried to obtain the target compound (10.28 g, yield 93.3%) as an off-white solid.

EM (calculated): 315.9; MS (ESI) m/z (MH) ⁻ : 315.0

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

Compound 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid (10.00 g, 31.66 mmol) was dissolved in chloroform (150 mL), to which was added DMF (1 mL) and SOCl ₂ (37.68 g, 316.6 mmol) was heated to 80° C. under nitrogen protection and stirred for 3 hours. After the completion of the reaction of the raw materials, the reaction solution was concentrated to dryness to obtain the target compound (crude product) in the form of a brown oily liquid.

Step 6: Preparation of (R)-4-(4-chloro-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

Compound 4-chloro-6-iodoquinazoline-2-acetyl chloride (crude) was dissolved in DCM (200 mL), to which was added _Et3N (9.59 g, 94.98 mmol), the reaction temperature was cooled to about -65 °C. (R)-2-Methylpiperazine-1-carboxylate tert-butyl ester (6.34 g, 31.66 mmol) was dissolved in DCM (20 mL), the solution was slowly added dropwise to the reaction system, and stirred at this temperature 30 minutes. TLC spot plate detection, the raw material reaction is completed. The reaction solution was concentrated, the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrates were combined and washed twice with H ₂ O, the organic phase was collected, dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound (13.41 g, 74.4% for two steps) as a brown solid.

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

Step 7: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine Preparation of -1-Carboxylic acid tert-butyl

Compound (R)-4-(4-chloro-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl (13.00 g, 25.19 mmol) was dissolved in DMF ( 150 mL), DIEA (6.50 g, 50.38 mmol), potassium iodide (8.36 g, 50.38 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (3.10 g, 25.19 mmol) were sequentially added thereto, and the temperature was raised to Stir at 65°C for 4 hours. TLC spot plate detection, the raw material reaction is completed. The reaction solution was added to water, extracted three times with EA, the organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (DCM/MeOH=50/1) to obtain the title compound (10.8 g, yield 71.3%) as a pale yellow solid.

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

Product hydrogen spectrum NMR data:

¹ H NMR (400MHz, DMSO-d ₆ )δ0.59-0.72(2H,m), 0.91-094(2H,m), 1.01(1.5H,d,J=6.8Hz), 1.17(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).

Example compounds

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

Step 1: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazoline-2 Preparation of -carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-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), to which was added _Et3N (67 mg, 0.66 mmol) and Pd ( PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol) was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, water (50 mL) was added to the reaction solution, followed by extraction with EA three times. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over anhydrous sodium sulfate, it was concentrated to dryness, and the obtained crude product was purified by column chromatography (DCM/MeOH=30/1) to obtain the target compound (70 mg, yield 35.4%) as an off-white solid.

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

Step 2: (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-yl ) (3-methylpiperazin-1-yl) ketone. Preparation of hydrochloride

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazoline-2- Carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl (70 mg, 0.12 mmol) was dissolved in DCM (5 mL), 4N HCl/1,4-dioxane (2 mL) was added to it, and the solution was cooled in an ice-water bath. Stir for 2 hours. After the reaction was completed, the supernatant liquid was poured off, and the remaining solid was washed twice with diethyl ether to obtain the target compound (23 mg, yield 38.4%) as a yellow solid.

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

1H NMR (400MHz, DMSO-d ₆ )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=10.8Hz),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).

The example compounds shown in Table 1 below are synthesized with reference to the method described in Example 1:

Table 1

Example 12 (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6- base) boric acid. Preparation of hydrochloride

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

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine- 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) was stirred at 110 °C for 3 hours under nitrogen protection. After the reaction was completed, water (40 mL) was added to the reaction solution, followed by extraction with DCM/MeOH (5/1) 5 times. The organic phases were combined and dried over Na ₂ SO ₄ and concentrated to dryness. The obtained crude product was purified by column chromatography (DCM/MeOH=5/1) to obtain the title compound (30 mg, 33.8% yield) as a yellow solid.

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

Step 2: (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6- base) boric acid. Preparation of hydrochloride

Compound (R)-(2-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-4-((5-cyclopropyl-1H-pyrazole- 3-yl)amino)quinazolin-6-yl)boronic acid (30mg, 0.06mmol) was dissolved in 4N HCl/1,4-dioxane (3mL), stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was Filtration, 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.

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

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 13 (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-yl)(3- Methylpiperazin-1-yl)methanone. Preparation of hydrochloride

Step 1: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazoline-2-carbonyl)- Preparation of 2-methylpiperazine-1-carboxylate tert-butyl ester

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine- 1-Carboxylic acid tert-butyl (100 mg, 0.17 mmol), dimethylphosphine oxide (66 mg, 0.85 mmol), Pd ₂ (dba) ₃ (18 mg, 0.02 mmol), xphos (19 mg, 0.04 mmol) and Et ₃ N (52 mg, 0.51 mmol) was added to 1,4-dioxane (4 mL) and stirred at 110°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness, and the obtained 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.

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

Step 2: (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-yl)(3- Methylpiperazin-1-yl)methanone. Preparation of hydrochloride

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

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

¹ H NMR (400MHz, DMSO-d ₆ )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=8.4Hz),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).

Example 14 (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-yl)(4, 7-Diazaspiro[2.5]octan-7-yl)methanone. Preparation of hydrochloride

Step 1: Preparation of tert-butyl 7-(4-chloro-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

The compound 4-chloro-6-iodoquinazoline-2-acetyl chloride (300 mg, 0.85 mmol) was dissolved in DCM (200 mL), Et ₃ N (172 mg, 1.70 mmol) was added thereto, and the reaction temperature was cooled to ~ -65°C. 4,7-Diazaspiro[2.5]octane-4-carboxylate tert-butyl ester (180 mg, 0.85 mmol) was dissolved in DCM (4 mL), the solution was slowly added dropwise to the reaction system, at this temperature Stir for 30 minutes. TLC spot plate detection, the raw material reaction is completed. The reaction solution was concentrated, the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrates were combined and washed twice with H ₂ O, the organic phase was collected, dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crude product was purified by column chromatography (PE/EA=3/1) to obtain the target compound (326 mg, yield). rate of 72.6%) as a brown solid.

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

Step 2: 7-(4-(((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[ 2.5] Preparation of tert-butyl octane-4-carboxylate

Compound 7-(4-chloro-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate tert-butyl ester (320 mg, 0.61 mmol) was dissolved in In DMF (10 mL), DIEA (157 mg, 1.22 mmol), potassium iodide (203 mg, 1.22 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (75 mg, 0.61 mmol) were sequentially added thereto, and the temperature was increased to 65 °C was stirred for 2 hours. TLC spot plate detection, the raw material reaction is completed. The reaction solution was added to water, extracted three times with EA, the organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (DCM/MeOH=50/1) to obtain the title compound (195 mg, yield 52.1%) as a yellow solid.

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

Step 3: 7-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazoline-2-carbonyl)- Preparation of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate

The compound 7-(4-(((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5 ] Octane-4-carboxylate tert-butyl ester (190 mg, 0.31 mmol) and 1-ethynylcyclohexanol (77 mg, 0.62 mmol) were added to DMF (10 mL), to which was added _Et3N (63 mg, 0.62 mmol) ) and Pd(PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol), stirred at room temperature overnight under nitrogen protection. After the reaction was completed, water (100 mL) was added to the reaction solution, and extracted with DCM for 3 times. The organic phases were combined and saturated with Washed with NaCl aqueous solution once, dried over Na2SO4 and concentrated to dryness, the obtained crude product was purified by column chromatography (DCM/MeOH=25/1) to obtain the title compound (61 mg, yield 32.4%) as a white solid.

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

Step 4: (4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-yl)(4, 7-Diazaspiro[2.5]octan-7-yl)methanone. Preparation of hydrochloride

Compound 7-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazoline-2-carbonyl)-4 , tert-butyl ,7-diazaspiro[2.5]octane-4-carboxylate (60 mg, 0.10 mmol) was dissolved in DCM (5 mL), to which was added 4N HCl/1,4-dioxane (3 mL), Stir under an ice-water bath for 2 hours. After the reaction was completed, the solid was filtered and rinsed with a small amount of methanol to obtain the title compound (16 mg, 30.9% yield) as a yellow solid.

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

¹ H NMR (400MHz, DMSO-d ₆ ) δ 0.34-0.37(2H,m), 0.51-0.58(2H,m), 0.66-0.71(2H,m), 0.93-0.99(2H,m), 1.25 -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(1H, 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).

The example compounds shown in Table 2 below were synthesized with reference to the method described in Example 14:

Table 2

Example 18 (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6-methyl Nitrile. Preparation of hydrochloride

Step 1: (R)-4-(6-cyano-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)-2-methylpiperin Preparation of tert-butyl oxazine-1-carboxylate

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

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

Step 2: (R)-4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6-methyl Nitrile. Preparation of hydrochloride

Compound (R)-4-(6-cyano-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)-2-methylpiperazine tert-Butyl-1-carboxylate (43 mg, 0.09 mmol) was dispersed in DCM (5 mL), 4N HCl/1,4-dioxane (2 mL) was added thereto, and the mixture was stirred under an ice-water bath for 2 hours. After the reaction was completed, the solid was filtered and rinsed with a small amount of THF to obtain the title compound (18 mg, 50.9% yield) as a pale yellow solid.

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

¹ H NMR (400MHz, DMSO-d ₆ )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＝8.4 Hz), 9.32(1H,s), 9.42-9.45(1H,m), 9.54-9.57(1H,m), 11.10(1H,s).

Examples 19 and 20 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl) Quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone (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)methanone (Example 20) Preparation

Step 1: Preparation of 1-(5-bromothiophen-2-yl)cyclohexan-1-ol

Compound 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, 2M in THF, 3.2 mL) was slowly added dropwise to the reaction system and stirring was continued at this temperature for 1 hour. The compound cyclohexanone (668 mg, 6.80 mmol) was dissolved in anhydrous THF (3 mL), added dropwise to the reaction system, and stirring was continued for 30 minutes. The reaction solution was quenched with saturated aqueous ammonium chloride solution, water was added and extracted twice with EA, the organic phases were combined and dried _{over Na2SO4} and concentrated to dryness. The obtained crude product was purified by column chromatography (PE/EA=10/1) to obtain the target compound (1.39 g, yield 86.3%) as a yellow oil.

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

Step 2: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)thiophen-2-yl)cyclohexan-1-ol preparation

Compound 1-(5-bromothiophen-2-yl)cyclohexan-1-ol (1.35 g, 5.19 mmol), pinacol biboronate (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), placed in an oil bath preheated to 90° C. and stirred for 2.5 hours under nitrogen protection. After completion of the reaction, the reaction solution was concentrated to dryness, and the obtained 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.

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

Step 3: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl) Preparation of quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine- 1-Carboxylic acid tert-butyl (100 mg, 0.17 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)thiophene- 2-yl)cyclohexan-1-ol (105 mg, 0.34 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added to 1,4-dioxane/H ₂ O (10 mL), placed in an oil bath preheated to 70°C under nitrogen protection, and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the obtained crude product was purified by column chromatography (DCM/MeOH=20/1) to obtain the target compound (70 mg, yield 31.3%) as an off-white solid.

EM (calcd): 657.3; MS (ESI) m/z (M+H) ⁺ : 658.3

Step 4: (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazole Lin-2-yl)(3-methylpiperazin-1-yl)methanone (Example 19) and (R)-(6-(5-(cyclohex-1-en-1-yl)thiophene- 2-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone (implementation Example 20) Preparation

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinoline oxazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (70 mg, 0.11 mmol) was dispersed in DCM (5 mL), to which was added 4N HCl/1,4-dioxane (2 mL) , and stirred in an ice-water bath for 1 hour. After the completion of the reaction, the pH was adjusted to about 7 with an aqueous sodium carbonate solution, concentrated to dryness, and the residue was purified by prep-HPLC to obtain the target compound (R)-(4-((5-cyclopropyl-1H-pyrazole-3 -yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone (10 mg, received rate was 16.3%) and (R)-(6-(5-(cyclohex-1-en-1-yl)thiophen-2-yl)-4-((5-cyclopropyl-1H-pyrazole- 3-yl)amino)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone (6 mg, 10.1% yield), all as off-white solids.

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

(Example 19) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.67-0.70(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),2.94-3.02(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),7.68(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).

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

(Example 20) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.69-0.71(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).

The example compounds shown in Table 3 below were synthesized with reference to the method described in Example 19:

table 3

Example 22 (6-((5-Chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline -2-yl)((R)-3-methylpiperazin-1-yl)methanone. Preparation of hydrochloride

Step 1: Preparation of 5-chloro-2-((trimethylsilyl)ethynyl)adamantan-2-ol

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 was continued at this temperature for 1 hour. The compound 5-chloroadamantan-2-one (1.41 g, 7.65 mmol) was dissolved in anhydrous THF (10 mL), added dropwise to the reaction system, and stirring was continued for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated aqueous NH ₄ Cl solution, water was added thereto and extracted twice with EA, the organic phases were combined and dried over Na ₂ SO ₄ and concentrated to dryness. The obtained 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.

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

Step 2: Preparation of 5-Chloro-2-ethynyladamantan-2-ol

The compound 5-chloro-2-((trimethylsilyl)ethynyl)adamantan-2-ol (550 mg, 1.95 mmol) was dissolved in MeOH (15 mL), to which potassium carbonate (323 mg, 323 mg was added with stirring, 2.34 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain the target compound (374 mg, yield 91.2%) as a white solid.

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

Step 3: (2R)-4-(6-((5-Chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl ) Preparation of amino)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine- tert-Butyl 1-carboxylate (150 mg, 0.25 mmol) and 5-chloro-2-ethynadamantan-2-ol (105 mg, 0.50 mmol) were added to DMF (6 mL), to which was added _Et3N (76 mg , 0.75 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol) were stirred at 40° C. overnight under nitrogen protection. After completion of the reaction, water (600 mL) was added to the reaction solution, followed by extraction with DCM 3 times. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over Na ₂ SO ₄ and concentrating to dryness, the obtained crude product was purified by column chromatography (DCM/MeOH=35/1) to obtain the title compound (77 mg, yield 45.1%) as an off-white solid.

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

Step 4: (6-((5-Chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline -2-yl)((R)-3-methylpiperazin-1-yl)methanone. Preparation of hydrochloride

Compound (2R)-4-(6-((5-chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl) Amino)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (75 mg, 0.11 mmol) was dissolved in DCM (10 mL) to which was added 4N HCl/1,4-dioxane (2 mL), and stirred in an ice-water bath for 2 hours. After the reaction was completed, the solid was filtered and rinsed with a small amount of acetonitrile to obtain the title compound (25 mg, 36.9% yield) as a pale yellow solid.

EM (calcd): 585.3; MS (ESI) m/z (M+H) ⁺ : 586.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.72-0.73 (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).

The example compounds shown in Table 4 below were synthesized with reference to the method described in Example 22:

Table 4

Example 27 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-yl ) (3-methylpiperazin-1-yl) ketone. Preparation of hydrochloride

Step 1: Preparation of 1-ethynyl-1-fluorocyclohexane

Compound 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 spot plate detection, the raw material reaction is completed. The reaction solution was concentrated to dryness. The residue was purified by column chromatography (PE/EA=50/1) to obtain the title compound (333 mg, yield 32.6%) as a colorless liquid.

Step 2: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazoline-2 Preparation of -carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-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), to which was added _Et3N (76 mg, 0.75 mmol) ) and Pd(PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol) and stirred at room temperature overnight under nitrogen protection. After completion of the reaction, water (600 mL) was added to the reaction solution, followed by extraction with DCM 3 times. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over Na ₂ SO ₄ and concentrating to dryness, the obtained crude product was purified by column chromatography (DCM/MeOH=50/1) to obtain the title compound (79 mg, yield 52.6%) as an off-white solid.

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

Step 3: (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-yl ) (3-methylpiperazin-1-yl) ketone. Preparation of hydrochloride

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazoline-2- Carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (77 mg, 0.13 mmol) was dissolved in DCM (10 mL), to which was added 4N HCl/1,4-dioxane (2 mL), under ice-water bath Stir for 2 hours. After the reaction was completed, the solid was filtered and rinsed with a small amount of acetonitrile to obtain the title compound (19 mg, 27.1% yield) as a yellow solid.

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

1H NMR (400MHz, DMSO-d ₆ )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).

Example 28 (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)(3-methylpiperazine- 1-yl) ketone. Preparation of hydrochloride

Step 1: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazoline-2 Preparation of -carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine- tert-Butyl 1-carboxylate (200 mg, 0.33 mmol) and trimethylsilylacetylene (129 mg, 1.32 mmol) were added to THF (6 mL), to which was added _Et3N (100 mg, 0.99 mmol) and Pd ( _PPh3 ) ₂ Cl ₂ (21 mg, 0.03 mmol) and stirred at room temperature overnight under nitrogen. After completion of the reaction, the reaction solution was concentrated to dryness, and the obtained 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.

EM (calcd): 573.3; MS (ESI) m/z (M+H) ⁺ : 574.3

Step 2: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-carbonyl)-2-methylpiperin Preparation of tert-butyl oxazine-1-carboxylate

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazoline-2- Carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (80 mg, 0.14 mmol) was dissolved in methanol (10 mL), potassium carbonate (39 mg, 0.28 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain the target compound (63 mg, yield 89.3%) as an off-white solid.

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

Step 3: (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)(3-methylpiperazine- 1-yl) ketone. Preparation of hydrochloride

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), 4N HCl/1,4-dioxane (2 mL) was added thereto, and the mixture was stirred under an ice-water bath for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was washed with methyl tertiary ether/PE (1/1) to obtain the target compound (31 mg, yield 59.4%) as a yellow solid.

EM (calcd): 401.2; MS (ESI) m/z (M+H) ⁺ : 402.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.75-0.76 (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=6.8 Hz), 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).

Example 29 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-methyl Preparation of amides

Step 1: Preparation of ethyl 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-carboxylate

The compound 6-bromo-1H-indole-2-carboxylic acid ethyl ester (500 mg, 1.87 mmol) and 2,4-dichloropyrimidine (277 mg, 1.87 mmol) were added to DMA (10 mL), to which potassium carbonate was added (310 mg, 2.24 mmol), the temperature was raised to 120°C and stirred for 2 hours. TLC spot plate detection, the raw material has been reacted. Water (100 mL) was added to the reaction solution, and a large amount of solid was precipitated. Filtration, washing with a small amount of EA, and drying gave the title compound (450 mg, 63.5% yield) as a brown solid.

EM (calcd): 379.0; MS (ESI) m/z (M+H) ⁺ : 380.0

Step 2: Preparation of ammonium 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-2-carboxylate

The compound 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester (450 mg, 1.19 mmol) was added to NH ₃ .H ₂ O (20 mL), the temperature was raised Stir to 130°C for 1 hour. TLC spot plate detection, the raw material has been reacted. The reaction solution was cooled to room temperature, and a large amount of solid was precipitated. Filtration and drying gave the title compound (360 mg, yield 86.9%) as a yellow solid.

EM (calculated): 331.0; MS (ESI) m/z (MH) ⁻ : 330.0

Step 3: Preparation of 1-(2-Aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-indole-2-carboxamide

Compound 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-2-carboxylate ammonium (360 mg, 1.03 mmol) and 2-methoxyethane-1-amine (93 mg, 1.24 mmol) was added to THF (15 mL), HATU (471 mg, 1.24 mmol) and DIEA (266 mg, 2.06 mmol) were added thereto, and the mixture was stirred at room temperature overnight. TLC spot plate detection, the raw material has been reacted. Water (100 mL) was added to the reaction solution, followed by extraction with DCM 3 times. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over Na ₂ SO ₄ and concentrating to dryness, the obtained 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.

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

Step 4: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-methyl Preparation of amides

Compound 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-indole-2-carboxamide (100 mg, 0.26 mmol) and 1-acetylene Cyclohexanol (66 mg, 0.52 mmol) was added to DMSO (10 mL), Et ₃ N (79 mg, 0.78 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol) were added thereto, and the temperature was raised under nitrogen protection. Stir to 70°C for 1 hour. After completion of the reaction, water (100 mL) was added to the reaction solution, followed by extraction with DCM 3 times. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over Na ₂ SO ₄ and concentrating to dryness, the obtained crude product was purified by column chromatography (DCM/MeOH=40/1) to obtain the title compound (19 mg, yield 16.8%) as an off-white solid.

EM (calcd): 433.2; MS (ESI) m/z (M+H) ⁺ : 434.2

¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.48-1.63(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).

Example 30 1-((1-(2-Aminopyrimidin-4-yl)-2-((3-methoxypropyl)amino)-1H-indol-6-yl)ethynyl)cyclohexyl- Preparation of 1-alcohols

Step 1: Preparation of tert-butyl(6-bromo-1H-indol-2-yl)carbamate

Compounds 6-bromo-1H-indole-2-carboxylic acid (2.5 g, 10.46 mmol), triethylamine (1.3 g, 12.55 mmol) and diphenylphosphoryl azide (3.5 g, 12.55 mmol) were added to THF (100 mL), stirred at room temperature overnight, detected by TLC spotting, the reaction of the raw materials had been completed, the reaction system was concentrated to dryness, tert-butanol (20 mL) was added to it, stirred at 80°C overnight, TLC spotting detected, After the reaction was completed, water (100 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 aqueous NaCl. After drying over Na ₂ SO ₄ , the obtained 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.

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

Step 2: Preparation of tert-butyl (6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-yl)carbamate

Compound tert-butyl(6-bromo-1H-indol-2-yl)carbamate (1.3 g, 4.19 mmol) and 2,4-dichloropyrimidine (0.93 g, 6.29 mmol) were added to DMF (30 mL) ), potassium carbonate (1.2 g, 8.38 mmol) was added to it, and the mixture was stirred at room temperature overnight. TLC spotting detected that the reaction of the raw materials had been completed. Water (100 mL) was added to the reaction solution, followed by extraction with EA 4 times. The organic phases were combined and washed twice with saturated aqueous LiCl. After drying over Na ₂ SO ₄ , the obtained 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.

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

Step 3: Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-amine trifluoroacetate

The compound tert-butyl(6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-yl)carbamate (680 mg, 1.61 mmol) was added to DCM (20 mL), Trifluoroacetic acid (4 mL) was slowly added to it, and the mixture was stirred at room temperature for 3 hours. TLC spotting detected that the reaction of the raw materials had been completed. The reaction system was spin-dried to obtain a brown solid (1.1 g), and the crude product was directly used in the next reaction.

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

Step 4: Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine

The compound 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-amine trifluoroacetate (1.1 g, crude) and 1-bromo-3-methoxypropane ( 0.52 g, 3.42 mmol) was added to DCM (30 mL), DIEA (2.2 g, 17.10 mmol) was added to it, stirred at room temperature overnight, and detected by TLC spot plate, the reaction of the raw materials had been completed. Water (100 mL) was added to the reaction solution, followed by extraction with DCM 5 times. The organic phases were combined and washed twice with saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the obtained crude product was purified by column chromatography (PE/EA=3/1) to obtain the target compound (530 mg, 83.5% in two-step yield) as a yellow solid.

EM (calcd): 394.0; MS (ESI) m/z (M+H) ⁺ : 395.1

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

Compound 6-bromo-1-(2-chloropyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine (250 mg, 0.63 mmol) was added to isopropanol (10 mL), ammonia water (2 mL) was added thereto, and the mixture was stirred at 100° C. overnight. TLC spot plate detection showed that the reaction of the raw materials had been completed. Water (200 mL) was added to the reaction solution, followed by 5 extractions with EA. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the obtained crude product was purified by column chromatography (DCM/MeOH=40/1) to obtain the title compound (140 mg, yield 58.8%) as a yellow solid.

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

Step 6: 1-((1-(2-Aminopyrimidin-4-yl)-2-((3-methoxypropyl)amino)-1H-indol-6-yl)ethynyl)cyclohex- Preparation of 1-alcohols

Compound 6-bromo-1-(2-aminopyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine (100 mg, 0.27 mmol) and 1-ethynyl Cyclohexanol (67 mg, 0.54 mmol) was added to DMSO (10 mL), Et ₃ N (82 mg, 0.81 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol) were added to it, and the temperature was raised to Stir at 80°C for 2 hours. After completion of the reaction, water (100 mL) was added to the reaction solution, followed by extraction with DCM 4 times. The organic phases were combined and washed twice with saturated aqueous NaCl. After drying over Na ₂ SO ₄ and concentrating to dryness, the obtained crude product was purified by column chromatography (DCM/MeOH=30/1) to obtain the title compound (11 mg, yield 9.8%) as an off-white solid.

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

¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.22-1.43(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),7.77(1H,d,J＝7.8Hz),7.85(1H,s),8.44(1H,d,J＝3.6Hz),8.66-8.75(1H,m).

Example 31 (R)-3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline- 6-yl)-1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one. Preparation of hydrochloride salt

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

Compound 4-(trifluoromethyl)piperidine (400 mg, 2.62 mmol), propynoic acid (238 mg, 3.41 mmol) were added to DCM (10 mL), to which was added DCC (703 mg, 3.41 mmol), at room temperature Stir for 2 hours. TLC spot plate detection showed that the reaction of the raw materials had been completed, DCM (20 mL) was added to the reaction system, and the mixture was washed with 2N hydrochloric acid and aqueous sodium bicarbonate successively. After collecting the organic phase and drying _over anhydrous _Na2SO4 , it was concentrated to dryness. The obtained crude product was purified by column chromatography (PE/EA=10/1) to obtain the target compound (520 mg, yield 96.8%) as an off-white solid.

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

Step 2: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(3-oxo-3-(4-(trifluoromethyl) ) piperidin-1-one)prop-1-yn-1-yl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester preparation

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine- 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), Et ₃ N (52 mg, 0.51 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol) were added thereto, and the mixture was stirred at room temperature for 5 hours under nitrogen protection. After completion of the reaction, the reaction solution was concentrated to dryness, and the obtained 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.

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

Step 3: (R)-3-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline- 6-yl)-1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one. Preparation of hydrochloride salt

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)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (50 mg, 0.07 mmol) was dissolved in DCM ( 6 mL), 4N HCl/1,4-dioxane (2 mL) was added thereto, and the mixture was stirred under an ice-water bath for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the residue was washed with methyl tertiary ether/PE (1/1) to obtain the target compound (21 mg, yield 48.8%) as a yellow solid.

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

¹ H NMR (400MHz, DMSO-d ₆ )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).

The example compounds shown in Table 5 below were synthesized with reference to the method described in Example 31:

table 5

Example 33 (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl) Ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone. Preparation of hydrochloride

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

The compound trimethylsilylacetylene (3.0 g, 30.58 mmol) was dissolved in anhydrous THF (20 mL), and the reaction was cooled to -70°C under nitrogen protection. To this was slowly added n-BuLi (13.5 mL, 33.64 mmol, 2.5 M in THF) and stirring was continued for 40 min maintaining this temperature. 4,4-Dimethylcyclohexane-1-one (3.9 g, 30.58 mmol) was dissolved in dry THF (10 mL) and slowly added to the reaction system. After the addition was complete, the reaction temperature was raised to room temperature and stirring was continued for 1 hour. The reaction was cooled to 0°C again, and dimethyl sulfate (3.9 g, 30.58 mmol) was added thereto, returned to room temperature, and stirred overnight. TLC spot plate detection, the raw materials have been reacted, water was added to the reaction system for quenching, and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The obtained 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.

EM (calcd): 238.2; MS (ESI) m/z (M+H) ⁺ : 239.2

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

The compound ((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)trimethylsilane (2.0 g, 8.40 mmol) was dissolved in dry THF (10 mL), to which was added TBAF (16.8 mL, 16.80 mmol, 1.0 M in THF) and stirred for 2 hours. TLC spot plate detection, the reaction of the raw materials has been completed, water was added to the reaction system, and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The obtained crude product was purified by column chromatography (PE/EA=8/1) to obtain the title compound (1.3 g, yield 92.9%) as a colorless oil.

EM (calcd): 166.1; MS (ESI) m/z (M+H) ⁺ : 167.1

Step 3: (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcycle Preparation of hexyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine- tert-Butyl 1-carboxylate (120 mg, 0.20 mmol) and 1-ethynyl-1-methoxy-4,4-dimethylcyclohexane (66 mg, 0.40 mmol) were added to DMF (6 mL) and added to Et ₃ N (61 mg, 0.60 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol) were added thereto, and the mixture was stirred at 40° C. for 3 hours under nitrogen protection. After completion of the reaction, the reaction solution was added to water (100 mL) and extracted with DCM for 3 times. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crude product was purified by column chromatography (DCM/MeOH=50/1) and TLC (DCM/MeOH=25/1), The title compound (20 mg, 15.6% yield) was obtained as a yellow solid.

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

Step 4: (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl) Ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone. Preparation of hydrochloride

Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl) )ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (20 mg, 0.03 mmol) was dissolved in HCl/EtOAc (10 mL) under ice-water bath and stirred for 4 h . After the reaction was completed, the supernatant liquid was poured off, and the remaining solid was washed with methyl tertiary ether/PE (1/1) to obtain the target compound (15 mg, yield 86.7%) as a yellow solid.

EM (calcd): 541.3; MS (ESI) m/z (M+H) ⁺ : 542.3

¹ H NMR (400MHz, DMSO-d ₆ )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), 3.10-3.23(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).

Example 35 (4-Aminopiperidin-1-yl)(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2- base) ketone. Preparation of hydrochloride

Step 1: Preparation of 5-cyclopropyl-4-fluoro-1H-pyrazol-3-amine

Compound 5-cyclopropyl-1H-pyrazol-3-amine (6.0 g, 48.74 mmol) was dissolved in acetonitrile (100 mL), and selectfluor (17.3 g, 48.74 mmol) was added to it in batches at room temperature, and stirring was continued. 2 hours. TLC spot plate detection, the raw material has been reacted, the reaction solution is directly concentrated to dryness. The obtained crude product was purified by column chromatography (DCM/MeOH=40/1) to obtain the title compound (1.7 g, yield 24.7%) as a red solid.

EM (calcd): 141.1; MS (ESI) m/z (M+H) ⁺ : 142.1

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

Compound 6-chloro-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid (200 mg, 0.89 mmol) was dissolved in chloroform (10 mL), to which was added DMF (0.2 mL) and SOCl ₂ (318 mg, 2.67 mmol) was heated to 80° C. under nitrogen and stirred for 3 hours. After the completion of the reaction of the raw materials, the reaction solution was concentrated to dryness to obtain the target compound (crude product) in the form of a brown oily liquid, which was directly used in the next reaction.

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

Compound 4,6-dichloroquinazoline-2-carbonyl chloride (crude) was dissolved in DCM (10 mL), _Et3N (360 mg, 3.56 mmol) was added thereto, and the reaction temperature was cooled to about -65°C. tert-Butylpiperidin-4-ylcarbamate (178 mg, 0.89 mmol) was dissolved in DCM (2 mL), the solution was slowly added dropwise to the reaction system, and stirred at this temperature for 30 minutes. TLC spot plate detection, the raw material reaction is completed. The reaction solution was concentrated, 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 title compound (crude) as a brown solid.

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

Step 4: tert-Butyl(1-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)piperidine- Preparation of 4-yl)carbamate

The compound tert-butyl(1-(4,6-dichloroquinazoline-2-carbonyl)piperidin-4-yl)carbamate (crude product) was dissolved in DMF (10 mL), and DIEA ( 230 mg, 1.78 mmol), KI (295 mg, 1.78 mmol) and 5-cyclopropyl-4-fluoro-1H-pyrazol-3-amine (126 mg, 0.89 mmol), warmed to 65°C and stirred for 4 hours. TLC spot plate detection, the raw material reaction is completed. The reaction solution was added to water, extracted three times with EA, the organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (DCM/MeOH=50/1) to obtain the title compound (183 mg, the total yield of the three-step reaction was 38.9%) as a pale yellow solid.

EM (calcd): 529.2; MS (ESI) m/z (M+H) ⁺ : 530.2

Step 5: (4-Aminopiperidin-1-yl)(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2- base) ketone. Preparation of hydrochloride

The compound tert-butyl(1-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)piperidine-4 -yl) carbamate (50 mg, 0.09 mmol) was added to a single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (10 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (38 mg, yield 90.7%) as a yellow solid.

EM (calcd): 429.1; MS (ESI) m/z (M+H) ⁺ : 430.1

1H NMR (400MHz, DMSO-d ₆ )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(3H,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).

The example compounds shown in Table 6 below were synthesized with reference to the method described in Example 35:

Table 6

Example 40 (R)-6-Chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-2-(3-methylpiperazin-1-yl)quinazole Lin-4-amine. Preparation of hydrochloride

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

Compound 2,4,6-trichloroquinazoline (3.0 g, 12.94 mmol) was dissolved in DMF (20 mL), and 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). The temperature was raised to 65°C and stirred for 2 hours. TLC spot plate detection, raw materials have been reacted, the reaction solution was cooled to room temperature. The reaction solution was slowly added to water (200 mL) and extracted with EA twice. The organic phases were combined and washed once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM/MeOH=50/1) to obtain the title compound (3.9 g, yield 89.4%) as a yellow solid.

EM (calcd): 337.0; MS (ESI) m/z (M+H) ⁺ : 338.0

Step 2: (R)-4-(6-Chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2- Preparation of tert-butyl methylpiperazine-1-carboxylate

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) , to which were sequentially added (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) at room temperature. The temperature was raised to 125°C and stirred for 3 hours. TLC spot plate detection, raw materials have been reacted, 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 aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by TLC (DCM/MeOH=25/1) to give the title compound (28 mg, 62.1% yield) as a yellow solid.

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

Step 3: (R)-6-Chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-2-(3-methylpiperazin-1-yl)quinazole Lin-4-amine. Preparation of hydrochloride

Compound (R)-4-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2-methyl Piperazine-1-carboxylic acid tert-butyl (28mg, 0.06mmol) was added to the single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (5mL) was added thereto, and the temperature was maintained and stirred for 1 hour . TLC spot plate detection, the raw material has been reacted, the reaction solution is concentrated to dryness at low temperature. The obtained 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.

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

1H NMR (400MHz, DMSO-d ₆ )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),3.76-3.79(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).

The example compounds shown in Table 7 below were synthesized with reference to the method described in Example 40:

Table 7

Example 56 2-(4-Amino-4-propylpiperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazole Preparation of olin-4-amines

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

The compound 4-cyanopiperidine-1-carboxylate tert-butyl ester (1.0 g, 4.76 mmol) was dissolved in anhydrous THF (10 mL), and cooled to an inner temperature of about -65°C using an ethanol dry ice bath under nitrogen protection. LiHMDS (1.3M in THF, 5.5 mL, 7.14 mmol) was slowly added dropwise to the reaction system, and the temperature was maintained 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 completed, the temperature was slowly raised to room temperature and stirred overnight. TLC spot plate detection, the reaction of the raw materials was completed, water (20 mL) was added for quenching, after concentration to remove most of the organic solvent, the residue was extracted twice with EA. The organic phases were combined and washed once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. It was concentrated to dryness, and the residue was purified by column chromatography (PE/EA=9/1) to obtain the title compound (700 mg, yield 58.3%) as a yellow oil.

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

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

Compound 4-cyano-4-propylpiperidine-1-carboxylate tert-butyl ester (700 mg, 2.78 mmol) was dissolved in DMSO ( ₅ mL) and K2CO3 ₍ 767 mg, 5.56 mmol) was added. After the temperature was raised to 60°C, H ₂ O ₂ (30%, 2 mL) was slowly added dropwise to the reaction, and stirring was continued for 3 hours after the addition. TLC spot plate detection, the reaction of the raw materials was completed, after cooling, water (50 mL) was added, and EA was used for extraction twice. The organic phases were combined and washed once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentration to dryness gave the title compound (730 mg, 97.2% yield) as a white solid.

EM (calcd): 270.2; MS (ESI) m/z (M+H) ⁺ : 271.2

Step 3: Preparation of tert-butyl 4-amino-4-propylpiperidine-1-carboxylate

Compound 4-carbamoyl-4-propylpiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.37 mmol) was dissolved in acetonitrile/H ₂ O (6 mL, 2/1), 1,3-dibromo was added -5,5-Dimethylimidazoline-2,4-dione (53 mg, 0.19 mmol) and KOH (112 mg, 2.0 mmol). After the addition was completed, it was stirred at room temperature for 3 hours. TLC spot plate detection, the reaction of the raw materials was completed, the pH of the reaction solution was adjusted to 4-5 with concentrated hydrochloric acid, H ₂ O (2 mL) was added, and EA was extracted twice. The aqueous phase was retained and pH adjusted to ~10 with sodium bicarbonate and extracted 3 times with EA. The organic phases were combined and dried over anhydrous sodium sulfate. Concentration to dryness gave the title compound (48 mg, 53.3% yield) as a colorless oil.

EM (calcd): 242.2; MS (ESI) m/z (M+H) ⁺ : 243.2

Step 4: Preparation of 4-propylpiperidin-4-amine.dihydrochloride

Compound 4-amino-4-propylpiperidine-1-carboxylate tert-butyl ester (48 mg, 0.20 mmol) was dissolved in 4M HCl/1,4-dioxane (2 mL), and stirred under ice-water bath for 1 hour. TLC spot plate detection showed that the reaction of the raw materials had been completed, and the reaction solution was concentrated to dryness at low temperature to obtain the target compound (43 mg, yield 100%) as a white solid.

EM (calcd): 142.2; MS (ESI) m/z (M+H) ⁺ : 143.2

Step 5: 2-(4-Amino-4-propylpiperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazole Preparation of olin-4-amines

Compound 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 sequentially added at room temperature. The temperature was raised to 125°C and stirred for 2 hours. TLC spot plate detection, raw materials have been reacted, 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 aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by TLC (DCM/MeOH=20/1) to give the title compound (20 mg, 30.0% yield) as a yellow solid.

EM (calcd): 443.2; MS (ESI) m/z (M+H) ⁺ : 444.2

1H NMR (400MHz, DMSO-d ₆ )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(2H,m),4.07-4.09(2H,m),7.31(1H,d,J=8.8Hz),7.54(1H,dd,J ₁ =9.2 Hz, J ₂ = 2.0 Hz), 8.33 (1H, d, J = 2.0 Hz), 9.80 (1H, brs), 12.33 (1H, s).

The example compounds shown in Table 8 below were synthesized with reference to the method described in Example 56:

Table 8

Example 60 2-(4-Amino-4-(4-fluorophenyl)piperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazole-3 -Preparation of quinazolin-4-amine

Step 1: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidine-4-carbonitrile

NaH (60% content dispersed in mineral oil, 237 mg, 5.92 mmol) was added to the reaction flask, and cooled with an ice-water bath after nitrogen protection. Compound 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 ice-water bath was maintained under stirring for 1 hour. Compound 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 completed, the temperature was slowly raised to room temperature, and the mixture was stirred for 2 hours. TLC spot plate detection, the raw material reaction is completed. The reaction was quenched by dropwise addition to water (100 mL) and extracted twice with EA. The organic phases were combined and washed once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentration to dryness gave the title compound (crude) as a yellow oil.

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

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

Compound 1-benzyl-4-(4-fluorophenyl)piperidine-4-carbonitrile (crude) was dissolved in DMSO (5 mL) and NaOH (178 mg, 4.44 mmol) was added. After the temperature was raised to 60°C, H ₂ O ₂ (30%, 2 mL) was slowly added dropwise to the reaction, and stirring was continued for 3 hours after the addition. TLC spot plate detection, the reaction of the raw materials was completed, after cooling, water (50 mL) was added, and EA was used for extraction twice. The organic phases were combined and washed once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentration to dryness gave the title compound (crude) as a pale yellow oil.

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

Step 3: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidin-4-amine

Compound 1-benzyl-4-(4-fluorophenyl)piperidine-4-carboxamide (crude) was dissolved in acetonitrile/H ₂ O (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). After the addition was completed, it was stirred at room temperature for 3 hours. TLC spot plate detection, the reaction of the raw materials was completed, the pH of the reaction solution was adjusted to 4-5 with concentrated hydrochloric acid, H ₂ O (2 mL) was added, and EA was extracted twice. The aqueous phase was retained and pH adjusted to ~10 with sodium bicarbonate and extracted 3 times with EA. The organic phases were combined and dried over anhydrous sodium sulfate. Concentration to dryness gave the title compound (137 mg, 32.5% total yield over three steps) as a colorless oil.

EM (calcd): 284.2; MS (ESI) m/z (M+H) ⁺ : 285.2

Step 4: Preparation of 4-(4-Fluorophenyl)piperidin-4-amine

Compound 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, After hydrogen replacement, it was stirred for 5 hours. TLC spot plate detection, raw materials have been reacted, the reaction solution was filtered, and the filter cake was repeatedly washed with methanol. The filtrate was concentrated to dryness to give the title compound (80 mg, 85.9% yield) as a yellow oil.

EM (calcd): 194.1; MS (ESI) m/z (M+H) ⁺ : 195.1

Step 5: 2-(4-Amino-4-(4-fluorophenyl)piperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazole-3 -Preparation of quinazolin-4-amine

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) 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 sequentially added thereto at room temperature. The temperature was raised to 125°C and stirred for 2 hours. TLC spot plate detection, raw materials have been reacted, the reaction solution was cooled to room temperature. The reaction solution was slowly added to water (10 mL) and extracted with EA twice. The organic phases were combined and washed once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by TLC (DCM/MeOH=20/1) to give the title compound (16 mg, 35.9% yield) as a yellow solid.

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

1H NMR (400MHz, DMSO-d ₆ )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).

The example compounds shown in Table 9 below were synthesized with reference to the method described in Example 60:

Table 9

Example 72 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazole Lin-4-amine. Preparation of dihydrochloride

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

The compound 2,4-dichloro-6-iodoquinazoline (5.0 g, 15.44 mmol) was dissolved in DMF (30 mL), and 5-cyclopropyl-4-fluoro-1H-pyrazole was sequentially added thereto at room temperature -3-amine (2.2 g, 15.44 mmol), KI (5.1 g, 30.88 mmol) and DIEA (8.0 g, 61.76 mmol). The temperature was raised to 65°C and stirred for 2 hours. TLC spot plate detection, raw materials have been reacted, 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 aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM/MeOH=50/1) to give the title compound (6.0 g, yield 90.3%) as a yellow solid.

EM (calcd): 429.0; MS (ESI) m/z (M+H) ⁺ : 430.0

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

Compound 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) were sequentially added at room temperature , 56.0 mmol). The temperature was raised to 125°C and stirred for 3 hours. TLC spot plate detection, raw materials have been reacted, 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 aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM/MeOH=30/1) to obtain the title compound (7.3 g, yield 85.3%) as a yellow solid.

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

Step 3: 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazole Lin-4-amine. Preparation of dihydrochloride

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl Piperidin-4-yl) carbamate (30mg, 0.05mmol) was added to the single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (4mL) was added thereto, and the temperature was kept stirring for 1 Hour. TLC spot plate detection, the raw material has been reacted, the reaction solution is concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (16 mg, yield 55.2%) as a pale yellow solid.

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

1H NMR (400MHz, DMSO-d ₆ )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(2H,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).

Example 73 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. Preparation of dihydrochloride

Step 1: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((1-hydroxy-4,4-dimethyl Preparation of cyclohexyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl ylpiperidin-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) , Et ₃ N (24 mg, 0.24 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (15 mg, 0.02 mmol) were added thereto, and the mixture was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, water (20 mL) was added to the reaction solution, followed by extraction with EA three times. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over anhydrous sodium sulfate, it was concentrated to dryness, and the obtained crude product was purified by TLC (DCM/MeOH=30/1) to obtain the target compound (22 mg, yield 43.6%) as an off-white solid.

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

Step 2: 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. Preparation of dihydrochloride

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((1-hydroxy-4,4-dimethyl Cyclohexyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (22mg, 0.03mmol) was added to a single-necked flask, cooled in an ice-water bath, and added to it 4M HCl/1,4-dioxane (3 mL) was added and stirred at this temperature for 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (13 mg, yield 71.8%) as an off-white solid.

EM (calcd): 531.3; MS (ESI) m/z (M+H) ⁺ : 532.3

1H NMR (400MHz, DMSO-d ₆ )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).

The example compounds shown in Table 10 below were synthesized with reference to the method described in Example 73:

Table 10

Example 77 2-(4-Amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline -6-Nitrile. Preparation of hydrochloride

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

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl ylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol), Zn(CN) ₂ (28 mg, 0.24 mmol), Pd ₂ (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), heated to 120° C. and stirred for 6 hours under nitrogen protection. After the reaction was completed, water (30 mL) was added to the reaction solution, followed by extraction with EA twice. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over anhydrous sodium sulfate, it was concentrated to dryness, and the obtained crude product was purified by TLC (DCM/MeOH=30/1) to obtain the target compound (28 mg, yield 69.1%) as an off-white solid.

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

Step 2: 2-(4-Amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline -6-Nitrile. Preparation of hydrochloride

The compound tert-butyl(1-(6-cyano-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-4- Methylpiperidin-4-yl)carbamate (28mg, 0.06mmol) was added to the single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (5mL) was added thereto, and the temperature was kept stirring 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (22 mg, yield 83.0%) as a white solid.

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

1H NMR (400MHz, DMSO-d ₆ )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).

Example 78 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinoline The preparation of oxazolin-4-amine. dihydrochloride

Step 1: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinoline Preparation of oxazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl ylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol) and trimethylsilylacetylene (31 mg, 0.32 mmol) were added to THF (4 mL), to which was added _Et3N (24 mg, 0.24 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (7 mg, 0.01 mmol) and stirred at room temperature overnight under nitrogen. After completion of the reaction, the reaction solution was concentrated to dryness, and the obtained crude product was purified by TLC (DCM/MeOH=50/1) to obtain the target compound (29 mg, yield 63.8%) as an off-white solid.

EM (calcd): 577.3; MS (ESI) m/z (M+H) ⁺ : 578.3

Step 2: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4 - Preparation of methylpiperidin-4-yl)carbamate

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazole Lin-2-yl)-4-methylpiperidin-4-yl)carbamate (29 mg, 0.05 mmol) was dissolved in methanol (5 mL), potassium carbonate (14 mg, 0.10 mmol) was added thereto, and the mixture was heated to room temperature. under stirring for 2 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain the target compound (23 mg, yield 91.6%) as an off-white solid.

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

Step 3: 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinoline The preparation of oxazolin-4-amine. dihydrochloride

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4- Methylpiperidin-4-yl)carbamate (23mg, 0.04mmol) was added to the single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (4mL) was added thereto, and the temperature was kept stirring 1 hour. TLC spot plate detection, the raw material has been reacted, the reaction solution is concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (17 mg, yield 80.9%) as a white solid.

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

1H NMR (400MHz, DMSO-d ₆ )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).

Example 79 2-(4-Amino-4-phenylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinoline The preparation of oxazolin-4-amine. dihydrochloride

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

Compound 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 sequentially added thereto at room temperature . The temperature was raised to 125°C and stirred for 3 hours. TLC spot plate detection, raw materials have been reacted, the reaction solution was cooled to room temperature. The reaction solution was slowly added to water (100 mL) and extracted with EA twice. The organic phases were combined and washed once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM/MeOH=40/1) to give the title compound (285 mg, yield 61.7%) as a yellow solid.

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

Step 2: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinoline Preparation of oxazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-benzene ylpiperidin-4-yl)carbamate (130 mg, 0.19 mmol) and trimethylsilylacetylene (75 mg, 0.76 mmol) were added to DMF (4 mL), to which was added _Et3N (77 mg, 0.76 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), warmed to 50° C. under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was slowly added to water (40 mL), and EA was extracted twice. The organic phases were combined and washed once with saturated aqueous NaCl. After drying over anhydrous sodium sulfate, it was concentrated to dryness to obtain a brown oil, which was directly used in the next reaction.

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

Step 3: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4 - Preparation of phenylpiperidin-4-yl)carbamate

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazole Lin-2-yl)-4-phenylpiperidin-4-yl)carbamate (crude product) was dissolved in methanol (10 mL), potassium carbonate (131 mg, 0.95 mmol) was added thereto, and stirred at room temperature for 2 Hour. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography (DCM/MeOH=40/1) to obtain the target compound (60 mg, the total yield of the two-step reaction was 55.7%), which was yellow solid.

EM (calcd): 567.3; MS (ESI) m/z (M+H) ⁺ : 568.3

Step 4: 2-(4-Amino-4-phenylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinoline The preparation of oxazolin-4-amine. dihydrochloride

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4- Phenylpiperidin-4-yl)carbamate (60mg, 0.11mmol) was added to the single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (6mL) was added thereto, and the temperature was kept stirring 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (51 mg, yield 85.9%) as a pale yellow solid.

EM (calcd): 467.2; MS (ESI) m/z (M+H) ⁺ : 468.2

1H NMR (400MHz, DMSO-d ₆ )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), 4.08-4.45(3H,m), 7.43(1H,d,J=8.0Hz), 7.45-7.52( 2H,m), 7.70(2H,d,J=8.0Hz), 7.85-8.14(2H,m), 8.68-8.93(4H,m), 11.18-11.48(1H,m), 12.74(1H,brs) ,13.03(1H,brs).

Example 80 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. Preparation of trihydrochloride

Step 1: tert-Butyl(1-(4-((5-Cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(4-(4-methylpiperazine-1 -yl)phenyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate preparation

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

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

Step 2: 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. Preparation of trihydrochloride

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(4-(4-methylpiperazine-1- Base)phenyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (25mg, 0.04mmol) was added to the single-necked flask, and after cooling in an ice-water bath, added 4M HCl/1,4-dioxane (5 mL), stirred at this temperature for 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (22 mg, yield 83.0%) as a white solid.

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

1H NMR (400MHz, DMSO-d ₆ )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).

The example compounds shown in Table 11 below were synthesized with reference to the method described in Example 80:

Table 11

Example 91 2-(4-Amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N, N-Dimethylquinazoline-6-carboxamide. Preparation of Dihydrochloride

Step 1: 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazole-3 - Preparation of methyl)amino)quinazoline-6-carboxylate

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl ylpiperidin-4-yl)carbamate (120 mg, 0.20 mmol), Pd(dppf) _Cl2.DCM (16 mg, 0.02 mmol) and cesium carbonate (196 mg, 0.60 mmol) were added to MeOH (10 mL), After carbon monoxide gas replacement, the mixture was heated to 70°C and stirred overnight. After the reaction was completed, the reaction solution was concentrated to dryness, and the obtained crude product was purified by TLC (DCM/MeOH=40/1) to obtain the target compound (100 mg, yield 92.6%) as a brown solid.

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

Step 2: 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazole-3 Preparation of -yl)amino)quinazoline-6-carboxylic acid

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

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

Step 3: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(dimethylcarbamoyl)quinazoline- Preparation of 2-yl)-4-methylpiperidin-4-yl)carbamate

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

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

Step 4: 2-(4-Amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N, N-Dimethylquinazoline-6-carboxamide. Preparation of Dihydrochloride

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(dimethylcarbamoyl)quinazoline-2 -yl)-4-methylpiperidin-4-yl)carbamate (25 mg, 0.05 mmol) was added to a single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (5 mL) was added thereto. ) and kept stirring at this temperature for 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (14 mg, yield 53.2%) as an off-white solid.

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

1H NMR (400MHz, DMSO-d ₆ )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).

Example 92 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(methyl Sulfonyl)quinazolin-4-amine. Preparation of hydrochloride

Step 1: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)quinazoline-2- yl)-4-methylpiperidin-4-yl)carbamate preparation

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl ylpiperidin-4-yl)carbamate (30 mg, 0.05 mmol), sodium methylsulfinate (20 mg, 0.20 mmol) and CuI (17 mg, 0.10 mmol) were added to DMSO (2 mL) and heated to 120 Stir overnight at °C. After the reaction was completed, the reaction solution was added to water (20 mL) and extracted with EA twice. 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 title compound (12 mg, 42.9% yield) as a white solid.

EM (calcd): 559.2; MS (ESI) m/z (M+H) ⁺ : 560.2

Step 2: 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(methyl Sulfonyl)quinazolin-4-amine. Preparation of hydrochloride

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)quinazolin-2-yl )-4-methylpiperidin-4-yl) carbamate (12mg, 0.02mmol) was added to the single-necked flask, and after cooling in an ice-water bath, 4M HCl/1,4-dioxane (3mL) was added thereto, This temperature was maintained with stirring for 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (8 mg, yield 80.8%) as a yellow solid.

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

1H NMR (400MHz, DMSO-d ₆ )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).

Example 93 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(1, 2,3,6-Tetrahydropyridin-4-yl)quinazolin-4-amine. Preparation of trihydrochloride

Step 1: 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyridine Preparation of oxazol-3-yl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl ylpiperidin-4-yl)carbamate (80 mg, 0.13 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) -3,6-Dihydropyridine-1(2H)-carboxylate tert-butyl ester (80 mg, 0.26 mmol), Pd(dppf)Cl ₂ .DCM (8 mg, 0.01 mmol), sodium carbonate (41 mg, 0.39 mmol) were added into 1,4-dioxane/H ₂ O (6 mL, 5/1), heated to 80°C under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the obtained crude product was purified by TLC (DCM/MeOH=20/1) to obtain the target compound (65 mg, yield 75.6%) as a white solid.

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

Step 2: 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(1, 2,3,6-Tetrahydropyridin-4-yl)quinazolin-4-amine. Preparation of trihydrochloride

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 and cooled in an ice-water bath After that, 4M HCl/1,4-dioxane (3 mL) was added thereto, and the temperature was maintained for 1 hour with stirring. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained crude product was washed with ethyl acetate and petroleum ether in turn, and dried to obtain the target compound (11 mg, yield 64.0%) as a yellow solid.

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

1H NMR (400MHz, DMSO-d ₆ )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(3H,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).

Example 94 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(piperidine -4-yl)quinazolin-4-amine. Preparation of trihydrochloride

Step 1: 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyridine Preparation of oxazol-3-yl)amino)quinazolin-6-yl)piperidine-1-carboxylate tert-butyl ester

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 (45 mg, 0.07 mmol) was added to MeOH (10 mL), to which Pd(OH) ₂ /C (10 mg) was added, and the mixture was replaced with hydrogen and stirred at room temperature for 4 hours. After the reaction was completed, the solid was filtered, the filter cake was rinsed with a small amount of methanol, the filtrate was concentrated to dryness, and the obtained crude product was purified by TLC (DCM/MeOH=10/1) to obtain the target compound (22 mg, yield 47.3%). ) as a white solid.

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

Step 2: 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(piperidine -4-yl)quinazolin-4-amine. Preparation of trihydrochloride

Compound 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazole -3-yl)amino)quinazolin-6-yl)piperidine-1-carboxylate tert-butyl ester (22mg, 0.03mmol) was added to a single-necked flask, and after cooling in an ice-water bath, 4M HCl/1 , 4-dioxane (3 mL) and stirred at this temperature for 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained 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.

EM (calcd): 464.3; MS (ESI) m/z (M+H) ⁺ : 465.3

1H NMR (400MHz, DMSO-d ₆ )δ0.79-0.83(2H,m), 0.97-1.02(2H,m), 1.38(3H,s), 1.78-1.82(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).

Example 95 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(trifluoro Methyl)quinazolin-4-amine. Preparation of hydrochloride

Step 1: tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(trifluoromethyl)quinazoline-2- yl)-4-methylpiperidin-4-yl)carbamate preparation

The compound tert-butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methyl ylpiperidin-4-yl)carbamate (100 mg, 0.16 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (61 mg, 0.32 mmol) and CuI (53 mg, 0.32 mmol) It was added to DMF (5 mL), heated to 100°C under nitrogen protection, and stirred for 3 hours. After the reaction was completed, the reaction solution was added to water (20 mL) and extracted with EA twice. 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 title compound (8 mg, 9.1% yield) as a white solid.

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

Step 2: 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(trifluoro Methyl)quinazolin-4-amine. Preparation of hydrochloride

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 (8mg, 0.01mmol) was added to the single-necked flask, after cooling in an ice-water bath, 4M HCl/1,4-dioxane (2mL) was added thereto, This temperature was maintained with stirring for 1 hour. TLC spot plate detection, raw materials have been reacted, the reaction solution was concentrated to dryness at low temperature. The obtained 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.

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

1H NMR (400MHz, DMSO-d ₆ )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).

Test Example 1 Inhibitory effect of compound on kinase activity

1: Test material:

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)

2: Experimental method:

2.1 Compound preparation

Compounds were received by administrators and powders were dissolved in 100% DMSO, formulated as 10 mM stock solutions, and stored in a nitrogen cabinet protected from light.

2.2 Kinase reaction process

(1) Prepare 1×Kinase buffer.

(2) Preparation of compound concentration gradient: the test compound concentration was 1000nM, diluted into 100-fold final concentration 100% DMSO solution in 384source plate, and the compound was diluted 3-fold with Precision, 10 concentrations. Use a dispenser Echo 550 to transfer 250nL of 100x final concentration of compound to the 384-well plate of interest.

(3) Prepare 2.5 times the final concentration of kinase solution with 1×Kinase buffer.

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

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

(6) Use 1×Kinase buffer to prepare a mixed solution of 5/3 times the final concentration of ATP and Kinase substrate22.

(7) Add 15 μL of a mixed solution of 5/3 times the final concentration of ATP and substrate to initiate the reaction.

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

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

(10) The conversion rate was read with Caliper EZ Reader.

2.3 Data Analysis

Calculation formula

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 readings of the wells without enzymatic activity; Conversion%_max: the mean ratio of the positive control wells, representing the conversion rate readings of the wells without compound inhibition .

Fitting a dose-response curve:

Taking the log value of the concentration as the X-axis and the percentage inhibition rate on the Y-axis, the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-response curve, so as to obtain the IC50 value of each compound on the enzyme activity . The calculation formula is:

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

The test results are shown in Table 12:

Table 12 Inhibitory activity of compounds on PAK4 and PAK1 kinases (IC ₅₀ )

ND: means not tested;

Test Example 2 Test compound liver microsome stability test

1: Materials and methods

Buffer:

(1) 100 mM potassium phosphate buffer, pH 7.4; (2) 10 mM MgCl ₂ .

Compound solution preparation:

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

(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).

The composition of the NADPH (prototype coenzyme II) regeneration system (the final concentration of isocitrate dehydrogenase in the culture medium is 1.0 unit/mL):

Beta-Nicotinamide Adenine Dinucleotide Phosphate, Supplier: Chem-impex International Cat. No.: N00616

Preparation of liver microsome solution (final concentration is 0.5 mg protein/mL), the types of liver microsomes are shown in Table 13:

Table 13

Stop solution:

An ice-cold solution of acetonitrile containing 100 ng/mL tolbutamide and 100 ng/mL labetalol as internal standard.

Steps:

(1) Except for the blank matrix plate wells, 10 μL of test or control drug working solutions were added to other plate wells (T0, T5, T10, T20, T30, T60 and NCF60).

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

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

Table 14

(4) After preheating, 10 μL/well of the NADPH regeneration system was dispensed onto each plate with Apricot to start the reaction.

Table 15 Final concentration of each component in incubation medium

(5) Incubate at 37°C, start timer 2, see Table 16 for data.

Table 16

(6) 4°C pre-cooled stop solution (containing internal standard tolbutamide 100 ng/mL and sulfabrazine 100 ng/mL) was added to each well to terminate the reaction.

(7) The sample plate is then shaken on the rocker trigger for about 10 minutes.

(8) Centrifuge the sample at 4000rpm for 20min at 4°C.

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

data analysis:

Calculate t 1/2 and Clint(mic) values from first-order elimination kinetics

The first-order elimination kinetic equation is:

when

The liver microsome stability test results of some compounds are shown in Table 17:

Table 17

Test Example 3 Detecting compound in vivo PK test in rats

SD rats, male (purchased from Chengdu Dashuo Laboratory Animal Co., Ltd.). Each test compound was administered orally (10 mg/kg, 3 per group) to SD rats for pharmacokinetic study. The test compound was prepared on the day of administration, and the test compound was dissolved with 5% DMSO+10% solutol+85% saline, vortexed for 2 minutes, and then sonicated for 5 minutes to prepare a dosing solution. Animals were fasted for 10-14 hours prior to oral dosing and resumed feeding 4 hours after dosing. After oral administration and intravenous administration of SD rats, pharmacokinetic samples were collected through the jugular vein. The collection time points were: before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h after And 24h, 3 whole blood samples were collected at each time point, the collection volume was about 0.2mL, and anticoagulated with heparin sodium. The blood samples were placed on ice immediately after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800 rpm, 6 minutes, 2-8°C). The collected plasma was stored in a –80°C freezer until analysis.

The pharmacokinetic test results of some compounds of the present invention are shown in Table 18 below:

Table 18 Pharmacokinetic test results of some compounds of the present invention

*: The rat PK data of CZh-226 are from literature reports;

#: The rat PK data of CZh-226 are from head-to-head measurement data;

It can be seen from the above druggability research data that some of the compounds of the present invention are more active against PAK4 protein kinase inhibitors than the reported CZh-226 and PF-3758309, while the compounds still maintain high PAK1/PAK4 selectivity; , and more importantly, according to the rat PK pharmacokinetic test results of some compounds, compared with the compounds CZh-226 and PF-3758309, its pharmacokinetics has a very obvious advantage. In conclusion, these compounds are used as PAK4 protein kinase inhibitors and have broad application prospects against malignant tumors, neurodegenerative diseases or immune system diseases.

The descriptions of the above embodiments are only used to help understand the method and the core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can also be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (16)

A compound as a PAK4 inhibitor, characterized in that it has the structure shown in formula I or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of mixtures, pharmaceutically acceptable hydrates, solvates or salts thereof:

wherein, B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ are independently selected from CR ₃ or N; Ring A is selected from substituted or unsubstituted C5-C9 aryl or heteroaryl; wherein the substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkane alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, halogen, hydroxy, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, alkyl sulfone group, alkyl sulfoxide group; 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, hydroxy, Cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronic ester, boronic acid wherein the substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, Substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyloxy Phosphorus group, alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; L is a single bond, O, S, NH or alkylene; 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; wherein the substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, alkoxy, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphorous group, alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; R ₁ is carbonyl, thiocarbonyl, methylene or single bond; R ₂ and R ₃ are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroalkyl Aryl, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronic acid Ester group, boronic acid group; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycle Alkyl, aryl, heteroaryl, ester, acyl, amido, sulfonyl, phosphoryl. The compound according to claim 1, characterized in that it has the structure represented by formula II or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of mixtures, pharmaceutically acceptable hydrates, solvates or salts thereof:

Wherein, A ₁ is selected from CR ₆ or N; R ₆ is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; R ₄ 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 wherein the substituted groups are independently selected from halogen, cyano, amino, hydroxyl, substituted or unsubstituted amido, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl; E is selected from single bond, ester group, amido group, ether group, carbonyl group, sulfone group, sulfoxide group, thioamide group, urea group, thiourea group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl group , substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1 -C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R ₅ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; 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; 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, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronate , boronic acid group; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl , aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl, aryl or heteroaryl; The aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; n is selected from 0 or 1. The compound according to claim 2, wherein the R ₆ is selected from hydrogen, halogen, amino, methyl, ethyl, methoxy, cyano, trifluoromethyl, isopropyl, cyclopropyl ; _The R4 is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C4-C6 heterocycloalkyl containing at least one N or O atom; wherein the substituted group The groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, and C3-C6 cycloalkyl; X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl; E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl ; R ₅ 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, alkyl phosphoryl, boronic ester, boronic acid group; The substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methyl, deuterated methyl base, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl, tetrahydropyrrolyl; 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 hetero Aryl; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 Heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or heteroaryl base; The aryl or heteroaryl group is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl group. The compound according to claim 2, characterized in that it has the structure shown in formula III, or its tautomer, meso, racemate, enantiomer, and diastereomer or in the form of mixtures, pharmaceutically acceptable hydrates, solvates or salts thereof:

wherein, R ₇ is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O atom; wherein the substituted group The groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, and C3-C6 cycloalkyl; J is selected from single bond, amido, carbonyl, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein the substituted group independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R ₈ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronate group, boronic acid group; wherein the substituted groups are independently selected 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, substituted or unsubstituted C3-C6 heterocycloalkyl; Y 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 hetero Aryl; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 Heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or heteroaryl base; The aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; n is selected from 0 or 1. The compound of claim 4, wherein said R ₇ is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidine group, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, five- or six-membered heterocycloalkyl containing at least one N and/or O; wherein the substituted groups are independently selected from Fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amido, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl; J is selected from single bond, amido, carbonyl, methylene, methyleneoxy; R ₈ is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopropyl Amyl, cyclohexyl, adamantyl, phenyl, five- to seven-membered heterocycloalkyl containing at least one N and/or O, five- or six-membered unsaturated cycloalkyl, pyridyl, amido, cyano group, hydroxyl, halogen, amino, ester group, nitro group, mercapto group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, alkyl sulfone group, alkyl sulfoxide group, boronic ester group, boronic acid group; wherein said The substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethyl oxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkyl containing at least one N and/or O; Y is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl containing at least one N and/or O, phenyl, and pyridyl; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxy, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkyl containing at least one N and/or O, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; n is selected from 0 or 1; further, n is selected from 0. The compound according to claim 2, characterized in that it has the structure shown in formula IV, or its tautomer, meso, racemate, enantiomer, and diastereomer or in the form of mixtures, pharmaceutically acceptable hydrates, solvates or salts thereof:

where m is 0, 1, 2, 3 or 4; R ₉ is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O atom; wherein the substituted groups are respectively independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amido, substituted or unsubstituted C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl; G is selected from single bond, amido, ether, carbonyl, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein the substituted The groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R ₁₀ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; 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; Z 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; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1 ~C3 heteroalkyl, C3~C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, substituted or non- Substituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; R ₁₁ is independently selected from hydrogen, halogen, hydroxy, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted unsubstituted heterocycloalkyl; n is selected from 0 or 1. The compound according to claim 6, wherein the m is 0, 1, 2, 3 or 4; R ₉ is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl , pyrrolyl, five- or six-membered heterocycloalkyl containing at least one N and/or O; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or Unsubstituted amido, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , hydroxyethyl; G is selected from single bond, amido, ether, carbonyl, methylene, difluoromethylene; R ₁₀ is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopropyl Amyl, cyclohexyl, adamantyl, phenyl, five- to seven-membered heterocycloalkyl containing at least one N and/or O, five- or six-membered unsaturated cycloalkyl, pyridyl, amido, cyano group, hydroxyl, halogen, amino, ester group, nitro group, mercapto group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, alkyl sulfone group, alkyl sulfoxide group, boronic ester group, boronic acid group; wherein said The substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethyl oxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkyl containing at least one N and/or O; Z is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl containing at least one N and/or O, phenyl, and pyridyl; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxy, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkyl containing at least one N and/or O, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; n is selected from 0 or 1; further, n is selected from 0; R ₁₁ 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, substituted or unsubstituted C3-C6 heterocycloalkyl. The compound according to claim 2, characterized in that it has the structure represented by formula V or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of mixtures, pharmaceutically acceptable hydrates, solvates or salts thereof:

Wherein, X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl; E is selected from single bond, ester group, amido group, ether group, carbonyl group, sulfone group, sulfoxide group, thioamide group, urea group, thiourea group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl group , substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1 -C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R ₅ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; 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; 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, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronate , boronic acid group; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl , ester group, acyl group, carbonyl group, amide group, sulfonyl group, phosphoryl group, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl group with single or multiple substituents; wherein monocyclic, bicyclic or tricyclic The substituents of the aryl or heteroaryl groups are deuterium, fluorine, chlorine, bromine, cyano, amino, hydroxyl, nitro, mercapto, sulfone, sulfoxide, boronate, boronate, alkyl phosphorous group, ester group, amide group, sulfonyl group, phosphoryl group, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl; n is selected from 0 or 1. The compound according to claim 8, wherein X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl; E is selected from single bond, ester group, amido group, ether group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein said The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R ₅ 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, alkyl phosphoryl, boronic ester, boronic acid group; The substituted groups are independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methyl, deuterium methyl, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl, tetrahydropyrrolyl, piperazinyl, N-methylpiperazine base, tetrahydropyridyl, morpholinyl; K is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl containing at least one N or O or S, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C6 cycloalkyl C3-C10 heterocycloalkyl, substituted or unsubstituted five- or six-membered aryl or heteroaryl containing at least one N or O or S; wherein the substituted groups are independently selected from amino, halogen, Hydroxyl, cyano, mercapto, nitro, carboxyl, amido, ester, carbonyl, sulfonyl, phosphoryl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 hetero Cycloalkyl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; wherein the substituents of the monocyclic, bicyclic or tricyclic aryl or heteroaryl are deuterium, fluorine, Chlorine, bromine, cyano, amino, hydroxyl, nitro, mercapto, sulfone, sulfoxide, boronic ester, boronic acid, alkyl phosphoryl, 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 heterocycloalkyl; n is selected from 0 or 1; further, n is selected from 0. The compound according to claim 8, characterized in that it has the structure represented by formula VI or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of mixtures, pharmaceutically acceptable hydrates, solvates or salts thereof:

Wherein, X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl; E is selected from single bond, ester group, amido group, ether group, carbonyl group, sulfone group, sulfoxide group, thioamide group, urea group, thiourea group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl group , substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1 -C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R ₅ 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, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; 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; P is selected from NR ₁₃ , CR ₁₄ R ₁₅ ; R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ are independently selected from hydrogen, amino, halogen, amido, sulfonyl, sulfonic acid, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl , C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amine group, C6-C12 aryl, C5-C12 heteroaryl; the above-mentioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 ring Alkyl, C3-C6 heterocycloalkyl, amine, C5-C12 aryl, C5-C12 heteroaryl can be optionally replaced by one or more halogen, hydroxyl, nitro, cyano, mercapto, sulfonic acid groups , amino, C1-C6 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl substitution; Or R ₁₂ and P atom form a spiro ring structure; Or R ₁₂ forms a condensed ring structure with the P atom and the carbon atom adjacent to the P atom; n is selected from 0 or 1; further, n is selected from 0; n1 is selected from 0-5. The compound according to claim 10, characterized in that it has the structure represented by formula VII or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of mixtures, pharmaceutically acceptable hydrates, solvates or salts thereof:

in, R ₁₆ is selected from hydrogen, fluorine, chlorine, bromine, iodine, alkynyl, C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl or heterocycloalkyl; further R ₁₆ is selected from fluorine, chlorine , bromine, alkynyl; R ₁₇ is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, ester, nitro, amide, mercapto, sulfonyl, alkylphosphorus, alkylsulfone, alkylsulfoxide, boronic acid Ester group, boronic acid group, substituted or unsubstituted heteroalkyl group containing at least one of N, O, S atoms C1-C6, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group , substituted or unsubstituted C1-C6 substituted amino, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one N, O, S atom, substituted Or unsubstituted aryl or heteroaryl, substituted or unsubstituted alkynyl or alkenyl, or two identical or different R ₁₇ and the attached phenyl group together form a substituted or unsubstituted at least C, N, O , S a five- to twelve-membered cyclic structural group of an atom, wherein the substituted groups are independently selected from deuterium, halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino , alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl; Further R ₁₇ is selected from methoxy, trifluoromethoxy, difluoromethoxy, methoxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethoxy, fluorine, chlorine, Bromine, cyano, hydroxyl, methyl sulfone, methyl sulfoxide, dimethyl oxophosphine, or two identical or different R17 and the connected phenyl group contain at least one of C, N, O, S atom substituted or unsubstituted five- to six-membered cyclic structural group, wherein the substituted groups are 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; n ₂ is selected from 0, 1, 2, 3, 4, 5. The compound according to claim 1, is characterized in that, has any of the following structures:

A PAK4 inhibitor, comprising the compound of any one of claims 1 to 12 and a pharmaceutically acceptable adjuvant. Use of the compound of any one of claims 1 to 12 or the PAK4 inhibitor of claim 13 in the preparation of a PAK4 inhibitor. The use according to claim 14, wherein the PAK4 inhibitor is suitable for cancer, neurodegenerative disease or immune system disease related to the expression or activity of PAK4 kinase. The use according to claim 15, wherein the cancer comprises breast cancer, mantle cell lymphoma, ovarian cancer, esophagus cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma , gastric cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, melanoma, bladder cancer, biliary tract cancer, kidney cancer, pancreatic cancer, lymphoma, hair cell cancer, nasopharyngeal cancer, pharyngeal cancer, Colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lung cancer, non-small cell lung cancer, small cell cancer, lung adenocarcinoma, bone cancer, colon cancer, adenoma , pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, Hodgkin's leukemia, bronchial cancer, thyroid cancer, endometrial cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid origin leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, non-Hodgkin lymphoma, primary macroglobulinemia.