A compound as a PAK4 kinase inhibitor and its preparation method and application

Abstract

The present invention provides a compound as a PAK4 inhibitor, having a structure as shown in Formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt. The test results show that the compound prepared by the present invention has high inhibitory activity and selectivity for PAK4 kinase, and its liver microsome stability and rat PK are also improved to a certain extent.

Description

[0001] This application claims priority to the Chinese patent application filed with the Chinese Patent Office on August 14, 2020, with application number 202010819448.1, and invention name “A compound as a PAK4 kinase inhibitor, and its preparation method and use”, and the Chinese patent application filed with the Chinese Patent Office on December 31, 2020, with application number 202011631465.9, and invention name “A compound as a PAK4 kinase inhibitor, and its preparation method and use”, the entire contents of which are incorporated into this application by reference. Technical Field

[0002] The present invention relates to the technical field of drug synthesis, and in particular to a compound used as a PAK4 kinase inhibitor, and a preparation method and application thereof. Background Art

[0003] As a conservative serine / threonine protein kinase, p21-activated protein kinase (PAK) is an effector protein of the small GTPases CDC42 and Rac1 in the Rho family, mediating the transduction of their 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 corresponding molecules of Pho family GTPases Rac and Cdc42, PAKs play an important role in cell proliferation, cytoskeleton reorganization, and cell movement. Studies have shown that each member of PAKs, especially its representative members PAK1 and PAK4, has gene amplification, gene mutation, expression level and activity upregulation in a variety of 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 on PAKs inhibitors has received extensive attention from medicinal chemists in the past decade. Wang C et al.'s research 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.

[0004] 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 inhibition of class I PAKs, especially PAK1. Therefore, the discovery of highly selective class II PAKs inhibitors will become the mainstream of future research.

[0005] As a potential target for drug development, the development of PAK4 inhibitors provides new ideas for the treatment of related cancers. So far, there are very few PAK4 inhibitors, 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 Pharmaceuticals 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 earliest PAKs inhibitor to enter clinical research. Its PAK4 IC50 is 19nm, but the compound has a stronger inhibitory ability against PAK1, reaching 14nm, and has serious safety 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). It is currently conducting multiple clinical studies in the fields of non-Hodgkin's lymphoma, colorectal cancer, lung cancer, melanoma, etc. In addition, preclinical studies have shown that ATG-019 combined with anti-PD-1 antibodies can effectively improve the anti-tumor efficacy and is effective for patients resistant to anti-PD-1 antibodies. Related clinical studies are underway.

[0006] 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 selective PAK4 inhibitor (CZh-226). Its Ki value for PAK4 is 9nM, and it shows excellent selectivity for multiple kinases, among which the Ki value for PAK1 is 3112nM, and the selectivity difference reaches 346 times. However, the drugability of this compound is poor and its bioavailability is extremely low (1.92%), which needs to be further optimized; at the same time, its inhibitory activity against PAK4 also has room for further improvement. Summary of the invention

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

[0008] To achieve the above object, the present invention provides a compound as a PAK4 inhibitor having a structure as shown in Formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt:

[0009]

[0010]

[0011] Among them, B1, B2, B3, B4, B5, and B6 are independently selected from C-R3 or N.

[0012] Ring A is selected from substituted or unsubstituted C5-C9 aryl or heteroaryl.

[0013] More preferably, ring A is selected from substituted or unsubstituted five-membered or six-membered aryl or heteroaryl, further preferably substituted or unsubstituted phenyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl or pyridyl.

[0014] 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, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide.

[0015] More preferably, the substituted groups are independently selected from a five-membered or six-membered aromatic or heteroaromatic group substituted by any group, a substituted or unsubstituted C1-C10 alkyl or heteroalkyl group, a substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted alkoxy group, a halogen, a hydroxyl group, a cyano group, an amino group, an ester group, a nitro group, a thiol group, a substituted or unsubstituted amide group, a sulfonyl group, a phosphoryl group, an alkyloxyphosphine group, an alkylsulfone group, and an alkylsulfoxide group.

[0016] Q is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkenyl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aromatic or heteroaromatic groups, halogen, hydroxyl, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkylphosphino, alkylsulfone, alkylsulfoxide, borate, and boronic acid.

[0017] 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 aromatic or heteroaromatic groups, halogen, hydroxyl, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkylphosphinoyl, alkylsulfone, alkylsulfoxide, borate, and boric acid.

[0018] 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, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate ester, and boric acid.

[0019] Preferably, the substituted groups are independently selected from a five-membered or six-membered aromatic or heteroaromatic group substituted by any group, a substituted or unsubstituted C1-C10 alkyl or heteroalkyl group, a substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl group, a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C6-C12 aryloxy group, a hydroxyl group, a halogen group, a cyano group, an amino group, an ester group, a nitro group, a thiol group, a substituted or unsubstituted amide group, a sulfonyl group, a phosphoryl group, an alkyloxyphosphino group, an alkylsulfone group, an alkylsulfoxide group, a borate ester group, and a boric acid group.

[0020] L is selected from a single bond, O, S, NH or an alkylene group.

[0021] Preferably in the present invention, the alkylene group is a C1-C10 alkylene group.

[0022] More preferably, the alkyl group is a methylene group or an ethylene group.

[0023] In the present invention, when L is a single bond, it means that V is directly connected to the parent ring.

[0024] 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.

[0025] More preferably, V is selected from substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl.

[0026] 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, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate, and boric acid.

[0027] Preferably, the substituted groups are independently selected from a five-membered or six-membered aromatic or heteroaromatic group substituted by any group, a substituted or unsubstituted C1-C10 alkyl group or heteroalkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group or heterocycloalkyl group, a substituted or unsubstituted C1-C10 alkoxy group, a halogen, a hydroxyl group, a cyano group, an amino group, an ester group, a nitro group, a thiol group, a substituted or unsubstituted amide group, a sulfonyl group, a phosphoryl group, an alkyloxyphosphine group, an alkylsulfone group, an alkylsulfoxide group, a borate group, and a boric acid group.

[0028] R1 is a carbonyl group, a thiocarbonyl group, a methylene group or a single bond.

[0029] In the present invention, R1 is a single bond, which means that R2 is directly connected to the parent ring.

[0030] R2 and R3 are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxyl, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate, and boric acid.

[0031] More preferably, R2 and R3 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-membered or six-membered aryl or heteroaryl, hydroxyl, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate, and boric acid.

[0032] The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, amide, sulfonyl, and phosphoryl.

[0033] Preferably, the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 heteroalkyl, C2-C10 heterocycloalkyl, six-membered aromatic, five-membered or six-membered heteroaromatic, ester, acyl, amide, sulfonyl and phosphoryl.

[0034] In the present invention, the above-mentioned bicyclic or tricyclic rings include but are not limited to spirocyclic, bridged and condensed ring compounds.

[0035] In the present invention, the above-mentioned cycloalkyl or heterocycloalkyl includes but is not limited to a monocyclic, spirocyclic, bridged, condensed cycloalkyl or heterocycloalkyl.

[0036] Preferably, the compound has a structure shown in Formula II or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt:

[0037]

[0038] Wherein, A1 is selected from C-R6 or N.

[0039] R6 is selected from hydrogen, halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.

[0040] Preferably, R6 is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C3 heteroalkyl containing at least one N or O atom, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one N or O atom.

[0041] Further preferably, R6 is selected from hydrogen, halogen, amino, methyl, ethyl, methoxy, cyano, trifluoromethyl, isopropyl or cyclopropyl.

[0042] R4 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.

[0043] In the present invention, preferably, R4 is selected from substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl.

[0044] Further preferably, R4 is selected from a substituted or unsubstituted five-membered or six-membered aryl or heteroaryl group, or a substituted or unsubstituted C4-C6 heterocycloalkyl group containing at least one N or O atom.

[0045] 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.

[0046] Preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl.

[0047] 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.

[0048] X is selected from a single bond, a substituted or unsubstituted C5-C6 aryl or heteroaryl, an alkynyl, or an alkenyl.

[0049] In the present invention, X is preferably selected from a single bond, a substituted or unsubstituted phenyl, a pyridyl, an alkynyl or an alkenyl.

[0050] In the present invention, X is selected from a single bond, which means that E is directly connected to the parent ring.

[0051] E is selected from a single bond, an ester group, an acylamino group, an ether group, a carbonyl group, a sulfone group, a sulfoxide group, a thioamide group, a urea group, a thiourea group, a substituted or unsubstituted C1-C3 alkyl group or heteroalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group or heterocycloalkyl group.

[0052] In the present invention, preferably, E is selected from a single bond, an ester group, an acylamino group, an ether group, a carbonyl group, a substituted or unsubstituted C1-C3 alkyl group or heteroalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group or heterocycloalkyl group.

[0053] In some specific embodiments of the present invention, E is selected from a single bond, an ester group, an acylamino group, an ether group, a carbonyl group, a substituted or unsubstituted methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a substituted or unsubstituted cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a three-membered to six-membered heterocycloalkyl group containing at least one N atom or an O atom.

[0054] The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.

[0055] Preferably, the substituents are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a three-membered to six-membered heterocycloalkyl group containing at least one N atom or O atom.

[0056] In the present invention, E is selected from a single bond, which means that R5 is directly connected to X.

[0057] When E and X are both single bonds, it means that R5 is directly connected to the parent ring.

[0058] R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate, and boronic acid.

[0059] The alkoxy group is preferably a substituted or unsubstituted C1-C10 alkoxy group.

[0060] The aryloxy group is preferably a substituted or unsubstituted C5-C10 aryloxy group.

[0061] Preferably, in the present invention, R5 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, substituted or unsubstituted C1~C6 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, borate ester, and boric acid.

[0062] Further preferably, R5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, substituted or unsubstituted C1~C3 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, borate, and boric acid.

[0063] 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.

[0064] Preferably, 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, and tetrahydropyrrolyl.

[0065] 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, sulfhydryl, amide, sulfonyl, phosphoryl, alkylphosphino, alkylsulfone, alkylsulfoxide, borate, and boronic acid.

[0066] In the present invention, W is preferably 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.

[0067] More preferably, W is selected from a five-membered or six-membered heterocycloalkyl group containing any one or more of N, O, and S.

[0068] In the present invention, the heterocycloalkyl group includes but is not limited to monocyclic, spirocyclic, bridged, and condensed-ring heterocycloalkyl groups.

[0069] The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl, aryl or heteroaryl.

[0070] In the present invention, the aryl or heteroaryl group is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl group.

[0071] Preferably, the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, five-membered or six-membered aromatic group, five-membered or six-membered heteroaromatic group, ester group, acyl group, carbonyl group, amide group, sulfonyl group, phosphoryl group, aromatic group or heteroaromatic group.

[0072] In the present invention, the aryl or heteroaryl group is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl group.

[0073] In some specific embodiments of the present invention, the substituted group is selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0074] n is selected from 0 or 1.

[0075] In the present invention, when n is selected from 0, W is directly connected to the heteroaromatic ring containing the A1 atom.

[0076] Preferably, the compound has a structure shown in Formula III, or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, a pharmaceutically acceptable hydrate, solvate or salt thereof:

[0077]

[0078] Wherein, R7 is selected from a substituted or unsubstituted five-membered or six-membered aryl or heteroaryl group, a substituted or unsubstituted C3-C10 heterocycloalkyl group containing at least one N or O atom.

[0079] Preferably, R7 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, or a five-membered or six-membered heterocycloalkyl group containing at least one N and / or O atom.

[0080] In some specific embodiments of the present invention, R7 has any of the following structures:

[0081]

[0082] The curved lines indicate where the connections are.

[0083] Any one or more C atoms in the above structures may be optionally substituted with one or more substituents.

[0084] Preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl.

[0085] Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and hydroxyethyl.

[0086] J is selected from a single bond, an acylamino group, a carbonyl group, a substituted or unsubstituted C1-C3 alkyl group or heteroalkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group or heterocycloalkyl group.

[0087] In the present invention, preferably, J is selected from a single bond, an acylamino group, a carbonyl group, a methylene group, and a methyleneoxy group.

[0088] The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.

[0089] Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, and hexahydropyridinyl.

[0090] In the present invention, when J is a single bond, it means that R8 is directly connected to the alkynyl group.

[0091] R8 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate, and boronic acid.

[0092] Preferably, R8 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyloxyphosphinyl, substituted or unsubstituted C1-C10 alkylsulfone, substituted or unsubstituted C1-C10 alkylsulfoxide, borate, boric acid.

[0093] More preferably, R8 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C6 alkyloxyphosphino, substituted or unsubstituted C1-C6 alkylsulfone, substituted or unsubstituted C1-C6 alkylsulfoxide, borate, and boric acid.

[0094] Further preferably, R8 is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, phenoxy, a five-membered to seven-membered heterocycloalkyl group containing at least one N and / or O, a five-membered or six-membered unsaturated cycloalkyl group, a pyridyl group, an amide group, a cyano group, a hydroxyl group, a halogen group, an amino group, an ester group, a nitro group, a thiol group, a sulfonyl group, a phosphoryl group, a substituted or unsubstituted C1-C3 alkyloxyphosphinyl group, a substituted or unsubstituted C1-C3 alkylsulfone group, a substituted or unsubstituted C1-C3 alkylsulfoxide group, a borate group, and a boric acid group.

[0095] In the present invention, the five-membered or six-membered unsaturated cycloalkyl group is a cyclopentenyl group or a cyclohexenyl group.

[0096] In the present invention, the above-mentioned cycloalkyl or heterocycloalkyl includes but is not limited to monocyclic, spirocyclic, bridged, condensed-ring cycloalkyl or heterocycloalkyl.

[0097] Preferably, 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.

[0098] 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, and a five-membered or six-membered heterocycloalkyl group containing at least one N and / or O.

[0099] In some specific embodiments of the present invention, the five-membered to seven-membered heterocycloalkyl group containing at least one N and / or O has any of the following structures:

[0100]

[0101] Curved lines indicate connection locations.

[0102] Any one or more C atoms or N atoms in the above structure may be arbitrarily substituted by one or more of the above substituents.

[0103] Y 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.

[0104] Preferably, Y is selected from substituted or unsubstituted five-membered or six-membered heterocycloalkyl containing at least one N and / or O, phenyl, pyridyl.

[0105] Further preferably, Y is selected from a substituted or unsubstituted five-membered or six-membered heterocycloalkyl group containing at least one N atom, and the N atom is connected to the adjacent carbonyl group to form an amide group.

[0106] In the present invention, the heterocycloalkyl group includes but is not limited to monocyclic, bridged, spirocyclic, and condensed-ring heterocycloalkyl groups.

[0107] The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, five-membered or six-membered aryl, five-membered or six-membered heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl, aryl or heteroaryl.

[0108] In the present invention, the aryl or heteroaryl group is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl group.

[0109] 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, a five-membered or six-membered heterocycloalkyl containing at least one N and / or O, a substituted or unsubstituted monocyclic, bicyclic or tricyclic aromatic or heteroaromatic group.

[0110] In some specific embodiments of the present invention, Y is selected from any of the following structures:

[0111]

[0112] Curved lines indicate connection locations.

[0113] Any one or more C atoms or N atoms in the above structures may be arbitrarily substituted by one or more of the above substituents.

[0114] n is selected from 0 or 1. Further, n is selected from 0.

[0115] When n is 0, Y is directly linked to the pyrimidine ring.

[0116] Preferably, the compound of the present invention has a structure shown in Formula IV, or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt:

[0117]

[0118] Wherein, m is 0, 1, 2, 3 or 4.

[0119] In the present invention, when m is not 0, the substituents on the benzene ring may be the same or different.

[0120] R9 is selected from a substituted or unsubstituted five-membered or six-membered aryl or heteroaryl group, or a substituted or unsubstituted C3-C10 heterocycloalkyl group containing at least one N or O atom.

[0121] More preferably, R9 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, a five-membered or six-membered heterocycloalkyl group containing at least one N and / or O.

[0122] In some specific embodiments of the present invention, R9 has any of the following structures:

[0123]

[0124] The curved lines indicate where the connections are.

[0125] Any one or more C atoms in the above structures may be optionally substituted with one or more substituents.

[0126] Preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl.

[0127] Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and hydroxyethyl.

[0128] G is selected from a single bond, an acylamino group, an ether group, a carbonyl group, a substituted or unsubstituted C1-C3 alkyl group or heteroalkyl group, and a substituted or unsubstituted C3-C6 cycloalkyl group or heterocycloalkyl group.

[0129] Preferably, G is selected from a single bond, an acylamino group, an ether group, a carbonyl group, a methylene group, and a difluoromethylene group.

[0130] The substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.

[0131] Further preferably, the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, and hexahydropyridinyl.

[0132] In the present invention, when G is selected from a single bond, it means R 10 Directly connected to the benzene ring.

[0133] R 10 Selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate, and boronic acid.

[0134] The present invention preferably has R 10Selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyloxyphosphino, substituted or unsubstituted C1-C10 alkylsulfone, substituted or unsubstituted C1-C10 alkylsulfoxide, borate, boric acid.

[0135] More preferably, R 10 Selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, substituted or unsubstituted C1-C6 alkyloxyphosphino, substituted or unsubstituted C1-C6 alkylsulfone, substituted or unsubstituted C1-C6 alkylsulfoxide, borate, boric acid.

[0136] More preferably, R 10 Selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, a five-membered to seven-membered heterocycloalkyl group containing at least one N and / or O, a five-membered or six-membered unsaturated cycloalkyl group, a pyridyl group, an amide group, a cyano group, a hydroxyl group, a halogen group, an amino group, an ester group, a nitro group, a mercapto group, a sulfonyl group, a phosphoryl group, a substituted or unsubstituted C1-C3 alkyloxyphosphino group, a substituted or unsubstituted C1-C3 alkylsulfone group, a substituted or unsubstituted C1-C3 alkylsulfoxide group, a borate group, and a boronic acid group.

[0137] In the present invention, the five-membered or six-membered unsaturated cycloalkyl group is a cyclopentenyl group or a cyclohexenyl group.

[0138] In the present invention, the above-mentioned cycloalkyl or heterocycloalkyl includes but is not limited to monocyclic, spirocyclic, bridged, condensed-ring cycloalkyl or heterocycloalkyl.

[0139] Preferably, 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.

[0140] 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, and a five-membered or six-membered heterocycloalkyl group containing at least one N and / or O.

[0141] In some specific embodiments of the present invention, the five-membered to seven-membered heterocycloalkyl group containing at least one N and / or O has any of the following structures:

[0142]

[0143] The curved lines indicate where the connections are.

[0144] Any one or more C atoms or N atoms in the above structure may be arbitrarily substituted by one or more substituents mentioned above.

[0145] Z 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.

[0146] Preferably, Z is selected from substituted or unsubstituted five-membered or six-membered heterocycloalkyl containing at least one N and / or O, phenyl, and pyridyl.

[0147] Further preferably, Z is selected from a substituted or unsubstituted five-membered or six-membered heterocycloalkyl group containing at least one N atom, and the N atom is connected to the adjacent carbonyl group to form an amide group.

[0148] In the present invention, the heterocycloalkyl group includes but is not limited to monocyclic, bridged, spirocyclic, and condensed-ring heterocycloalkyl groups.

[0149] The substituted groups are independently selected from halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, five-membered or six-membered aromatic group, five-membered or six-membered heteroaromatic group, ester group, acyl group, carbonyl group, amide group, sulfonyl group, phosphoryl group, substituted or unsubstituted monocyclic, bicyclic or tricyclic aromatic group or heteroaromatic group.

[0150] 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, a five-membered or six-membered heterocycloalkyl containing at least one N and / or O, a substituted or unsubstituted monocyclic, bicyclic or tricyclic aromatic or heteroaromatic group.

[0151] In some specific embodiments of the present invention, Z is selected from any of the following structures:

[0152]

[0153] Curved lines indicate connection locations.

[0154] Any one or more C atoms or N atoms in the above structures may be arbitrarily substituted by one or more of the above substituents.

[0155] R 11 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 heterocycloalkyl.

[0156] The present invention preferably has R 11 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.

[0157] n is selected from 0 or 1. Further, n is selected from 0.

[0158] When n is 0, Z is directly attached to the pyrimidine ring.

[0159] In the present invention, the cycloalkyl group includes a saturated or unsaturated cycloalkyl group.

[0160] The heterocycloalkyl group includes a saturated or unsaturated heterocycloalkyl group.

[0161] In the present invention, the cycloalkyl group includes monocyclic, bridged, spirocyclic and condensed ring cycloalkyl groups.

[0162] The heterocycloalkyl group includes monocyclic, bridged, spirocyclic and condensed heterocycloalkyl groups.

[0163] Preferably, the compound of the present invention has a structure shown in Formula V or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt:

[0164]

[0165] Wherein, X is selected from a single bond, a substituted or unsubstituted C5-C6 aryl or heteroaryl, an alkynyl, an alkenyl;

[0166] In the present invention, X is preferably selected from a single bond, a substituted or unsubstituted phenyl, a pyridyl, an alkynyl or an alkenyl.

[0167] In the present invention, X is selected from a single bond, which means that E is directly connected to the parent ring.

[0168] E is selected from a single bond, an ester group, an acylamino group, an ether group, a carbonyl group, a sulfone group, a sulfoxide group, a thioamide group, a urea group, a thiourea group, a substituted or unsubstituted C1-C3 alkyl group or heteroalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group or heterocycloalkyl group; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl group, C1-C3 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 heterocycloalkyl group.

[0169] In the present invention, preferably, E is selected from a single bond, an ester group, an acylamino group, an ether group, a carbonyl group, a substituted or unsubstituted C1-C3 alkyl group or heteroalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group or heterocycloalkyl group.

[0170] In some specific embodiments of the present invention, E is selected from a single bond, an ester group, an acylamino group, an ether group, a carbonyl group, a substituted or unsubstituted methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a substituted or unsubstituted cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a three-membered to six-membered heterocycloalkyl group containing at least one N atom or an O atom.

[0171] Preferably, the substituents are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a three-membered to six-membered heterocycloalkyl group containing at least one N atom or O atom.

[0172] In the present invention, E is selected from a single bond means that R5 is directly connected to X;

[0173] When E and X are both single bonds, it means that R5 is directly connected to the parent ring.

[0174] R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, sulfhydryl, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphine, alkyl sulfone, alkyl sulfoxide, borate, boric acid; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxy, 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;

[0175] The alkoxy group is preferably a substituted or unsubstituted C1-C10 alkoxy group.

[0176] The aryloxy group is preferably a substituted or unsubstituted C5-C10 aryloxy group.

[0177] More preferably, R5 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, borate, and boric acid.

[0178] Further preferably, R5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl, substituted or unsubstituted C1~C3 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, borate, and boric acid.

[0179] 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-methylpiperazinyl, tetrahydropyridinyl, and morpholinyl.

[0180] 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, sulfhydryl, amide, sulfonyl, phosphoryl, alkyl phosphoyl, alkyl sulfone, alkyl sulfoxide, borate, boric acid; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, sulfhydryl, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, ester, acyl, carbonyl , amide, sulfonyl, phosphoryl, a single or multiple substituents substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl; wherein the substituent of the monocyclic, bicyclic or tricyclic aryl or heteroaryl is deuterium, fluorine, chlorine, bromine, cyano, amino, hydroxyl, nitro, sulfhydryl, sulfone, sulfoxide, borate, boric acid, alkylphosphine, 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;

[0181] More preferably, K is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl containing at least one N, O or S, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N, O or S, substituted or unsubstituted five-membered or six-membered aryl or heteroaryl; wherein the substituted groups are independently selected from amino, halogen, hydroxyl, cyano, thiol, nitro, carboxyl, amido, ester, carbonyl, sulfonyl, phosphoryl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C 3 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, sulfhydryl, sulfone, sulfoxide, borate, boric acid, alkylphospho, 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;

[0182] 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.

[0183] And preferably, the N atom is directly connected to the parent ring.

[0184] In some specific embodiments of the present invention, the K has the following groups:

[0185]

[0186] Preferably, any one or more carbon atoms or nitrogen atoms of the above groups may be connected to one or more substituents;

[0187] The substituent is preferably an amino group, a halogen, an amide group, a sulfonyl group, a sulfonic acid group, a hydroxyl group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 heterocycloalkyl group, an amine group, a C6-C12 aryl group, a C5-C12 heteroaryl group; the above-mentioned C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, C3-C6 heterocycloalkyl group, an amine group, a C6-C12 aryl group, a C5-C12 heteroaryl group may be optionally substituted by one or more halogen, hydroxyl group, nitro group, cyano group, thiol group, sulfonic acid group, and amino group.

[0188] In some specific embodiments of the present invention, the substituent is selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, amide, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and naphthyl.

[0189] Preferably, the above substituents may be further substituted by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, or sulfonic acid groups, or any one or more carbon atoms may be oxo or thio.

[0190] n is selected from 0 or 1; further, n is selected from 0.

[0191] When n is 0, K is directly attached to the pyrimidine ring.

[0192] Preferably, the compound of the present invention has the structure shown in Formula VI or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt:

[0193]

[0194] Wherein, X is selected from a single bond, a substituted or unsubstituted C5-C6 aryl or heteroaryl, an alkynyl, or an alkenyl.

[0195] E is selected from a single bond, an ester group, an acylamino group, an ether group, a carbonyl group, a sulfone group, a sulfoxide group, a thioamide group, a urea group, a thiourea group, a substituted or unsubstituted C1-C3 alkyl group or heteroalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group or heterocycloalkyl group; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl group, C1-C3 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 heterocycloalkyl group.

[0196] R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphino, alkylsulfone, alkylsulfoxide, borate, and boric acid; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxy, cyano, amino, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C3-C6 heterocycloalkyl.

[0197] P is selected from NR 13 , CR 14 R 15 ;

[0198] R 12 , R 13 , R 14 , R 15independently selected from hydrogen, amino, halogen, amide, sulfonyl, sulfonic acid, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl; the above C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl may be optionally substituted by one or more halogen, hydroxyl, nitro, cyano, thiol, sulfonic acid, amino, C1-C6 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl;

[0199] R 13 , R 14 , R 15 Independently preferred are amino, halogen, amide, 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 C1~C6 alkyl, C1~C6 heteroalkyl, C3~C6 cycloalkyl, C3~C6 heterocycloalkyl, amine, C6~C12 aryl, C5~C12 heteroaryl may be optionally substituted by one or more halogen, hydroxyl, nitro, cyano, thiol, sulfonic acid, amino.

[0200] In some specific embodiments of the present invention, the substituent is selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, amide, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and naphthyl.

[0201] Preferably, the above substituents may be further substituted by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, or sulfonic acid groups, or any one or more carbon atoms may be oxo or thio.

[0202] The R 12 An amino group is more preferred.

[0203] or R 12 It forms a spiro ring structure with the P atom;

[0204] or R 12 It forms a condensed ring structure with the P atom and the carbon atoms adjacent to the P atom;

[0205] n is selected from 0 or 1; further, n is selected from 0.

[0206] When n is 0, the N atom of the N-containing heterocyclic ring is directly connected to the pyrimidine ring.

[0207] n1 is selected from 0 to 5; specifically, it can be selected from 0, 1, 2, 3, 4 or 5.

[0208] Preferably, the compound of the present invention has the structure shown in Formula VII or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt:

[0209]

[0210] in,

[0211] 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;

[0212] R 17 R is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, ester, nitro, amide, mercapto, sulfonyl, alkylphosphine, alkylsulfone, alkylsulfoxide, borate, boric acid, substituted or unsubstituted C1-C6 heteroalkyl containing at least one atom of N, O, and S, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 substituted amino, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one atom of N, O, and S, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted alkynyl or alkenyl, or two identical or different R 17 Together with the connected phenyl group, it forms a substituted or unsubstituted five- to twelve-membered cyclic structure group containing at least one atom of C, N, O, or S, wherein the substituted groups are independently selected from deuterium, halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, and phosphoryl;

[0213] Preferably, the five-membered to twelve-membered cyclic structure group may be a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and the cyclic structure and the connected phenyl group together constitute the following groups but are 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 benzofuranyl, substituted or unsubstituted benzopyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted benzocrown ether, substituted or unsubstituted anthracenyl, substituted or unsubstituted benzomorpholinyl, substituted or unsubstituted tetrahydroquinoxaline, 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.

[0214] Further R 17 Selected from methoxy, trifluoromethoxy, difluoromethoxy, methoxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethoxy, fluorine, chlorine, bromine, cyano, hydroxyl, methylsulfone, methylsulfoxide, dimethylphosphine, or two identical or different R17 and the connected phenyl group form a five-membered to six-membered cyclic structure group containing at least one C, N, O, S atom substituted or unsubstituted, wherein the substituted groups are independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, thiol, nitro, C1-C3 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl, five-membered or six-membered aryl or heteroaryl;

[0215] Preferably, the five-membered to six-membered cyclic structure group can be a cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl. The cyclic structure and the connected phenyl group together form the following groups but are not limited to the following groups: substituted or unsubstituted piperonyl, substituted or unsubstituted quinolyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzopyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted benzomorpholinyl, substituted or unsubstituted benzotetrahydroquinoxaline, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzodihydrofuran, substituted or unsubstituted benzisoxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzopyrazole.

[0216] n2 is selected from 0, 1, 2, 3, 4, 5.

[0217] The amino group or substituted amino group in the present invention refers to a group in which one or two hydrogen atoms of the amino group are substituted by a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C3-C6 cycloalkyl group.

[0218] More preferably, the amino group or substituted amino group is selected from methylamino, ethylamino, propylamino, isopropylamino or butylamino.

[0219] In some specific embodiments of the present invention, the compound has any of the following structures:

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] Specifically, the present invention provides a PAK4 inhibitor, comprising the above compound and a pharmaceutically acceptable adjuvant.

[0227] The present invention has no particular limitation on the type of the adjuvant, and the adjuvant may be any adjuvant well known to those skilled in the art.

[0228] In the present invention, the compound can be used alone or in combination with other drugs.

[0229] The present invention provides use of the above compound or the above PAK4 inhibitor in preparing a PAK4 inhibitor.

[0230] Preferably, the PAK4 inhibitor of the present invention is suitable for cancers, neurodegenerative diseases or immune system diseases related to the expression or activity of PAK4 kinase.

[0231] Preferably, the cancer includes breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, gastric cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, melanoma, bladder cancer, bile duct cancer, kidney cancer, pancreatic cancer, lymphoma, hairy 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 carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, Hodgkin's leukemia, bronchial cancer, thyroid cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, primary macroglobulinemia.

[0232] Compared with the prior art, the present invention provides a compound as a PAK4 inhibitor, having a structure as shown in Formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt. The test results show that the compound prepared by the present invention has high inhibitory activity and selectivity for PAK4 kinase, and its liver microsome stability and rat PK are also improved to a certain extent. DETAILED DESCRIPTION

[0233] To further illustrate the present invention, the compounds used as PAK4 kinase inhibitors provided by the present invention, as well as the preparation method and application thereof are described in detail below in conjunction with the examples.

[0234] The abbreviations in the following examples have the following meanings:

[0235] Et3N: triethylamine;

[0236] EA: ethyl acetate;

[0237] THF: tetrahydrofuran;

[0238] EtOH: ethanol;

[0239] MeOH: methanol;

[0240] SOCl2: thionyl chloride;

[0241] DIEA: N,N-diisopropylethylamine;

[0242] LDA: lithium diisopropylamide;

[0243] n-BuLi: n-butyllithium;

[0244] DAST: diethylaminosulfur trifluoride;

[0245] DME: ethylene glycol dimethyl ether;

[0246] M: molar concentration unit mol / L, for example 1M means 1 mol / L;

[0247] N: Normal concentration, for example, 1N HCl means hydrochloric acid with a concentration of 1 mol / L;

[0248] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;

[0249] DMF: N,N-dimethylformamide;

[0250] TLC: thin layer chromatography;

[0251] PE: petroleum ether (boiling point 60-90°C);

[0252] DCM: dichloromethane;

[0253] H2O: distilled water;

[0254] DMSO: dimethyl sulfoxide;

[0255] Pd2(dba)3: 3,3,6,6-tetramethyl-9-(1,2,3,4-tetrahydroxybutyl)-4,5,7,9-tetrahydro-2H-anthracene-1,8-dione);

[0256] Xphos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl;

[0257] DPPF: 1,1′-bis(diphenylphosphino)ferrocene;

[0258] Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium dichloride;

[0259] Pd(dppf)Cl2.DCM: [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex;

[0260] HCl / 1,4-dioxane: hydrochloric acid / 1,4-dioxane solution;

[0261] DCC: dicyclohexylcarbodiimide;

[0262] TBAF: tetrabutylammonium fluoride;

[0263] 1,4-dioxane: 1,4-dioxane;

[0264] KI: potassium iodide;

[0265] LiHMDS: lithium hexamethyldisilazide;

[0266] Preparation of intermediates

[0267] Intermediate: Preparation of tert-butyl (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0268]

[0269] Step 1: Preparation of 2-amino-5-iodobenzamide

[0270] The compound 2-aminobenzamide (10.00 g, 73.48 mmol) was dissolved in H2O (250 mL), and sodium bicarbonate (6.17 g, 73.48 mmol) and iodine powder (20.51 g, 80.83 mmol) were added thereto in sequence, and stirred at room temperature for 24 hours. TLC spot plate detection showed that the raw material reaction was complete. The reaction solution was adjusted to pH 7 with sodium bisulfite. The solid was filtered and washed with water, then dispersed in ethanol and heated to reflux to dissolve. After cooling, the target compound (14.20 g, yield 73.8%) was obtained by filtration as a light purple solid.

[0271] EM (calculated): 262.0; MS (ESI) m / z (M+H) + :263.0

[0272] Step 2: Preparation of ethyl 2-((2-carbamoyl-4-iodophenyl)amino)-2-oxoacetate

[0273] The compound 2-amino-5-iodobenzamide (14.00 g, 53.44 mmol) was dissolved in THF (250 mL), Et3N (10.80 g, 106.88 mmol) was added thereto, and stirred at 0°C. Ethyl oxalyl chloride (8.02 g, 58.78 mmol) was slowly added dropwise to the reaction system, and the temperature was maintained and stirred for 2 hours. TLC spot plate detection showed that the raw material reaction was complete. After most of the THF in the reaction solution was concentrated, the residue was added to water (1 L) under stirring, and a large amount of solid was precipitated. The solid was filtered and dried to obtain the target compound (16.5 g, yield was 85.3%), which was a light purple solid.

[0274] EM (calculated): 362.0; MS (ESI) m / z (M+H) + :363.0

[0275] Step 3: Preparation of ethyl 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate

[0276] The compound 2-((2-carbamoyl-4-iodophenyl)amino)-2-oxoacetic acid ethyl ester (16.00 g, 44.20 mmol) was dissolved in EtOH (300 mL), and sodium ethoxide (3.61 g, 53.04 mmol) was added thereto under an ice-water bath, and stirring was continued for 3 hours. TLC spot plate detection showed that the reaction of the raw materials was complete. The reaction solution was adjusted to pH 3-4 with concentrated hydrochloric acid. The reaction solution was added to water under stirring, and a large amount of solid precipitated. The solid was filtered and dried to obtain the target compound (12.5 g, yield was 82.3%) as an off-white solid.

[0277] EM (calculated): 344.0; MS (ESI) m / z (M+H)+ :345.0

[0278] Step 4: Preparation of 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid

[0279] The compound 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid ethyl ester (12.00 g, 34.88 mmol) was dissolved in EtOH / H2O (200 mL, 1 / 1), sodium hydroxide (5.58 g, 139.52 mmol) was added thereto, and stirred at room temperature for 2 hours. TLC spot plate detection showed that the raw material reaction was complete. Under an ice-water bath, the reaction solution was adjusted to pH 5-6 with 2N hydrochloric acid. The solid was filtered and dried to obtain the target compound (10.28 g, yield 93.3%) as an off-white solid.

[0280] EM (calculated): 315.9; MS (ESI) m / z (MH) - :315.0

[0281] Step 5: Preparation of 4-chloro-6-iodoquinazoline-2-acetyl chloride

[0282] The compound 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid (10.00 g, 31.66 mmol) was dissolved in chloroform (150 mL), and DMF (1 mL) and SOCl2 (37.68 g, 316.6 mmol) were added thereto in sequence, and the mixture was heated to 80° C. and stirred for 3 hours under nitrogen protection. After the reaction of the raw materials was completed, the reaction solution was concentrated to dryness to obtain the target compound (crude product) as a brown oily liquid.

[0283] Step 6: Preparation of (R)-tert-butyl 4-(4-chloro-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0284] The compound 4-chloro-6-iodoquinazoline-2-acetyl chloride (crude product) was dissolved in DCM (200 mL), Et3N (9.59 g, 94.98 mmol) was added thereto, and the reaction temperature was cooled to about -65 ° C. (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (6.34 g, 31.66 mmol) was dissolved in DCM (20 mL), and the solution was slowly added dropwise to the reaction system and stirred at this temperature for 30 minutes. TLC spot plate detection showed that the raw material reaction was complete. The reaction solution was concentrated, the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrate was combined and washed twice with H2O, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the target compound (13.41 g, two-step yield was 74.4%) as a brown solid.

[0285] EM (calculated): 516.0; MS (ESI) m / z (M+H)+ :517.0

[0286] Step 7: Preparation of (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0287] 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-pyrazole-3-amine (3.10 g, 25.19 mmol) were added thereto in sequence, and the mixture was heated to 65° C. and stirred for 4 hours. TLC spot plate detection showed that the raw material reaction was complete. The reaction solution was added to water, extracted with EA 3 times, the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH=50 / 1) to obtain the target compound (10.8 g, yield was 71.3%) as a light yellow solid.

[0288] EM (calculated): 603.1; MS (ESI) m / z (M+H) + :604.1

[0289] Product H NMR data:

[0290] 1 H NMR (400MHz, DMSO-d6) δ0.59-0.72 (2H, m), 0.91-094 (2H, m), 1.01 (1.5H, d, J=6.8Hz), 1.1 7 (1.5H, d, J=6.4Hz), 1.39-1.40 (9H, m), 1.86-1.94 (1H, m), 2.97-3.06 (2H, m), 3.26-3.27 (1H, m), 3.34-3.39 (1H, m), 3.58-3.84 (1H, m), 4.01-4.36 (2H, m), 6.48 (1H, s), 7.51-7.55 (1H, m), 8.10-8.13 (1H, m), 9.15-9.17 (1H, m), 10.67-10.77 (1H, m), 12.27-12.38 (1H, m).

[0291] Example compounds

[0292] Example 1 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0293]

[0294] Step 1: Preparation of tert-butyl (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0295] 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), Et3N (67 mg, 0.66 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were added thereto, and the mixture 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, and the mixture was extracted 3 times with EA. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying over anhydrous sodium sulfate, the mixture was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH=30 / 1) to obtain the target compound (70 mg, yield was 35.4%) as an off-white solid.

[0296] EM (calculated): 599.3; MS (ESI) m / z (M+H) + :600.3

[0297] Step 2: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0298] 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 thereto, and stirred in an ice-water bath for 2 hours. After the reaction was completed, the supernatant was poured off, and the remaining solid was washed twice with ether to obtain the target compound (23 mg, yield 38.4%) as a yellow solid.

[0299] EM (calculated): 499.3; MS (ESI) m / z (M+H) + :500.3

[0300] 1H NMR (400MHz, DMSO-d6) δ0.65-0.72 (2H, m), 0.84-0.89 (2H, m), 0.95 (1.5H, d, J=8.4Hz), 1.09 (1.5H, d, J=8.0Hz), 1.21-1.28 (2H, m), 1.45-1.58 (5H, m), 1.68-1.71 (2H, m), 1.87-1.98 (2H, m), 2.62-2.67 (2H, m), 2.71-2.78 (2H, m), 2.82-2.90 (1H, m), 2.99-3.09 (1H, m), 4.22-4.37 (1H, m), 6.45 (1H, d, J = 1 0.8Hz), 7.71 (1H, d, J = 7.6Hz), 7.79 (1H, d, J = 8.0Hz), 8.81 (1H, s), 10.72 (2H, brs), 11.20 (1H, brs).

[0301] The following example compounds shown in Table 1 were synthesized according to the method described in Example 1:

[0302] Table 1

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314] Example 12 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazolin-6-yl)boric acid hydrochloride

[0315]

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

[0317] 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), biboronic acid pinacol ester (86 mg, 0.34 mmol), cesium fluoride (52 mg, 0.34 mmol) and pyridine (40 mg, 0.51 mmol) were added to DMSO (4 mL) and stirred at 110° C. for 3 hours under nitrogen protection. After the reaction was completed, water (40 mL) was added to the reaction solution, and extracted with DCM / MeOH (5 / 1) 5 times. The organic phases were combined, dried over Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH=5 / 1) to obtain the target compound (30 mg, yield 33.8%) as a yellow solid.

[0318] EM (calculated): 521.3; MS (ESI) m / z (M+H) + :522.3

[0319] Step 2: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazolin-6-yl)boronic acid hydrochloride

[0320] The compound (R)-(2-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-6-yl)boric acid (30 mg, 0.06 mmol) was dissolved in 4N HCl / 1,4-dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with a small amount of methanol, and dried to obtain the target compound (14 mg, yield 57.8%) as a yellow solid.

[0321] EM (calculated): 421.2; MS (ESI) m / z (M+H) + :422.0

[0322] 1H NMR (400MHz, DMSO-d6) δ0.74-0.80 (2H, m), 0.95-1.01 (2H, m), 1.15 (1.5H, d, J=5.6Hz), 1.36 ( 1.5H, d, J=6.4Hz), 1.98-2.04 (1H, m), 3.01-3.15 (1H, m), 3.19-3.28 (1H, m), 3.33-3.45 (2H, m) , 3.60-3.66 (1H, m), 4.13-4.20 (1H, m), 4.42-4.48 (1H, m), 6.37 (1H, d, J = 3.2Hz), 7.93 (1H, dd , J=8.4Hz, 2.4Hz), 8.37 (1H, d, J=8.4Hz), 9.29 (1H, d, J=5.6Hz), 9.94 (2H, s), 11.91 (1H, brs).

[0323] Example 13 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0324]

[0325] Step 1: Preparation of (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0326] 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), Pd2(dba)3 (18 mg, 0.02 mmol), xphos (19 mg, 0.04 mmol) and Et3N (52 mg, 0.51 mmol) were added to 1,4-dioxane (4 mL) and 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 was 56.4%) as a yellow solid.

[0327] EM (calculated): 553.3; MS (ESI) m / z (M+H) + :554.3

[0328] Step 2: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0329] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (53 mg, 0.10 mmol) was dissolved in 4N HCl / 1,4-dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and 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.

[0330] EM (calculated): 453.2; MS (ESI) m / z (M+H) + :454.0

[0331] 1 H NMR (400MHz, DMSO-d6) δ0.75-0.78 (2H, m), 0.97-1.01 (2H, m), 1.13 (1.5H, d, J = 6.0Hz), 1.36 (1.5H, d, J = 6.4Hz ), 1.79 (3H, s), 1.82 (3H, s), 1.97-2.04 (1H, m), 2.94-3.05 (1H, m), 3.18-3.24 (1H, m), 3.28-3.31 (1H, m), 3.36- 3.42 (1H, m), 3.50-3.56 (1H, m), 3.92-4.00 (1H, m), 4.43-4.46 (1H, m), 6.47 (1H, d, J = 6.4Hz), 8.00 (1H, d, J = 8.4 Hz), 8.28-8.32 (1H, m), 9.21 (1H, dd, J = 12.8Hz, 3.2Hz), 9.63-9.68 (1H, m), 9.73-9.78 (1H, m), 11.79 (1H, brs).

[0332] Example 14 Preparation of (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-yl)(4,7-diazaspiro[2.5]octan-7-yl)methanone hydrochloride

[0333]

[0334] Step 1: Preparation of tert-butyl 7-(4-chloro-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0335] The compound 4-chloro-6-iodoquinazoline-2-acetyl chloride (300 mg, 0.85 mmol) was dissolved in DCM (200 mL), Et3N (172 mg, 1.70 mmol) was added thereto, and the reaction temperature was cooled to -65 ° C. 4,7-diazaspiro [2.5] octane-4-carboxylic acid tert-butyl ester (180 mg, 0.85 mmol) was dissolved in DCM (4 mL), the solution was slowly added dropwise to the reaction system, and stirred at this temperature for 30 minutes. TLC spot plate detection showed that the raw material reaction was complete. The reaction solution was concentrated, the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrate was combined and washed twice with H2O, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness, and the crude product was purified by column chromatography (PE / EA=3 / 1) to obtain the target compound (326 mg, yield was 72.6%) as a brown solid.

[0336] EM (calculated): 528.0; MS (ESI) m / z (M+H) + :529.0

[0337] Step 2: Preparation of tert-butyl 7-(4-(((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0338] The compound 7-(4-chloro-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (320 mg, 0.61 mmol) was dissolved in DMF (10 mL), DIEA (157 mg, 1.22 mmol), potassium iodide (203 mg, 1.22 mmol) and 5-cyclopropyl-1H-pyrazole-3-amine (75 mg, 0.61 mmol) were added thereto in sequence, and the mixture was heated to 65 ° C and stirred for 2 hours. TLC spot plate detection showed that the raw material reaction was complete. The reaction solution was added to water, extracted 3 times with EA, the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH=50 / 1) to obtain the target compound (195 mg, yield was 52.1%) as a yellow solid.

[0339] EM (calculated): 615.1; MS (ESI) m / z (M+H) + :616.1

[0340] Step 3: Preparation of tert-butyl 7-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0341] Compound 7-(4-(((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (190 mg, 0.31 mmol) and 1-ethynylcyclohexanol (77 mg, 0.62 mmol) were added to DMF (10 mL), to which Et3N (63 mg, 0.62 mmol) and Pd(PPh3)2 were added. Cl2 (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 three times. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying over Na2SO4, the mixture was concentrated to dryness and the crude product was purified by column chromatography (DCM / MeOH=25 / 1) to obtain the target compound (61 mg, yield 32.4%) as a white solid.

[0342] EM (calculated): 611.3; MS (ESI) m / z (M+H) + :612.3

[0343] Step 4: Preparation of (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-yl)(4,7-diazaspiro[2.5]octan-7-yl)methanone hydrochloride

[0344] Compound 7-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) was dissolved in DCM (5 mL), 4N HCl / 1,4-dioxane (3 mL) was added thereto, 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 methanol to obtain the target compound (16 mg, yield 30.9%) as a yellow solid.

[0345] EM (calculated): 511.3; MS (ESI) m / z (M+H) + :512.3

[0346] 1H NMR (400MHz, DMSO-d6) δ0.34-0.37 (2H, m), 0.51-0.58 (2H, m), 0.66-0.71 (2H, m), 0.93-0.99 (2H, m), 1.2 5-1.31(1H,m), 1.49-1.61(5H,m), 1.61-1.71(2H,m), 1.85-1.95(3H,m), 2.67-2.73(1H,m), 2.78-2.83(1 H, m), 3.02-3.06 (1H, m), 3.15-3.20 (1H, m), 3.44-3.47 (1H, m), 3.57-3.61 (1H, m), 5.53 (1H, d, J = 5.2Hz), 6.53 (1H, d, J = 18.8Hz), 7.69-7.77 (2H, m), 8.81-8.85 (1H, m), 10.66-10.76 (1H, m), 12.27-12.33 (1H, m).

[0347] The example compounds shown in Table 2 below were synthesized by referring to the method described in Example 14:

[0348] Table 2

[0349]

[0350]

[0351]

[0352]

[0353] Example 18 Preparation of (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6-carbonitrile hydrochloride

[0354]

[0355] Step 1: Preparation of (R)-tert-butyl 4-(6-cyano-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0356] 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), Pd2(dba)3 (27 mg, 0.03 mmol) and zinc powder (2 mg, 0.03 mmol) were added to DMF (6 mL), and the mixture was placed in an oil bath preheated to 120° C. and stirred for 3 hours under nitrogen protection. After the reaction was completed, water (60 mL) was added to the reaction solution, and the mixture was extracted 3 times with DCM. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying over Na2SO4, the residue was concentrated to dryness and the crude product was purified by column chromatography (DCM / MeOH=40 / 1) to give the target compound (45 mg, yield: 52.4%) as a yellow solid.

[0357] EM (calculated): 502.2; MS (ESI) m / z (M+H) + :503.2

[0358] Step 2: Preparation of (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6-carbonitrile hydrochloride

[0359] Compound (R)-tert-butyl 4-(6-cyano-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate (43 mg, 0.09 mmol) was dispersed in DCM (5 mL), 4N HCl / 1,4-dioxane (2 mL) was added thereto, 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 THF to obtain the target compound (18 mg, yield 50.9%) as a light yellow solid.

[0360] EM (calculated): 402.2; MS (ESI) m / z (M+H) + :403.2

[0361] 1H NMR (400MHz, DMSO-d6) δ0.72-0.75 (2H, m), 0.94-0.99 (2H, m), 1.12 (1.5H, d, J = 5.2Hz), 1.34 ( 1.5H, d, J=6.4Hz), 1.93-2.00 (1H, m), 2.89-2.98 (1H, m), 3.08-3.24 (2H, m), 3.33-3.48 (2H, m) , 3.73-3.83 (1H, m), 4.42 (1H, d, J = 12.8Hz), 6.47 (1H, d, J = 10.4Hz), 7.90 (1H, dd, J = 8.8Hz, 4. 0Hz), 8.20 (1H, d, J = 8.4Hz), 9.32 (1H, s), 9.42-9.45 (1H, m), 9.54-9.57 (1H, m), 11.10 (1H, s).

[0362] Examples 19 and 20 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-yl)(3-methylpiperazin-1-yl)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)

[0363]

[0364] Step 1: Preparation of 1-(5-bromothiophen-2-yl)cyclohexan-1-ol

[0365] The 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 continued to stir 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 continued to stir for 30 minutes. The reaction solution was quenched with saturated aqueous ammonium chloride solution, water was added thereto and extracted twice with EA, the organic phases were combined and dried with Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography (PE / EA=10 / 1) to obtain the target compound (1.39 g, yield was 86.3%) as a yellow oil.

[0366] EM (calculated): 260.0; MS (ESI) m / z (M+H) + :261.0

[0367] Step 2: Preparation of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)cyclohexan-1-ol

[0368] Compound 1-(5-bromothiophen-2-yl)cyclohexan-1-ol (1.35 g, 5.19 mmol), bipyraclostrobin (2.64 g, 10.38 mmol), Pd(dpp()Cl2.DCM (375 mg, 0.52 mmol) and potassium acetate (1.02 g, 10.38 mmol) were added to 1,4-dioxane (20 mL), and placed in an oil bath preheated to 90° C. under nitrogen protection and stirred for 2.5 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (PE / EA=8 / 1) to obtain the target compound (500 mg, yield 31.3%) as a light yellow solid.

[0369] EM (calculated): 308.2; MS (ESI) m / z (M+H) + :309.2

[0370] Step 3: Preparation of (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0371] Compound (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate (100 mg, 0.17 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)thiophene-2-yl)cyclohexan-1-ol (105 mg, 0.34 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added to 1,4-dioxane / H2O (10 mL), and the mixture was placed in an oil bath preheated to 70°C and stirred 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=20 / 1) to obtain the target compound (70 mg, yield: 31.3%) as an off-white solid.

[0372] EM (calculated): 657.3; MS (ESI) m / z (M+H) + :658.3

[0373] Step 4: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-yl)(3-methylpiperazin-1-yl)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)

[0374] Compound (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate (70 mg, 0.11 mmol) was dispersed in DCM (5 mL), 4N HCl / 1,4-dioxane (2 mL) was added thereto, and the mixture was stirred in an ice-water bath for 1 hour. After the reaction was completed, the pH was adjusted to about 7 with aqueous sodium carbonate solution, and the mixture was concentrated to dryness. The residue was purified by prep-HPLC to obtain the target compounds (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone (10 mg, yield was 16.3%) and (R)-(6-(5-(cyclohex-1-en-1-yl)thiophen-2-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone (6 mg, yield was 10.1%), both as off-white solids.

[0375] (Example 19) EM (calculated value): 557.3; MS (ESI) m / z (M+H) + :558.3;

[0376] (Example 19) 1H NMR (400MHz, DMSO-d6) δ0.67-0.70 (2H, m), 0.81-0.83 (2H, m), 0.97-0.99 (1.5H, m), 1.11-1.07 (1.5H, m), 1.56- 1.60(2H,m), 1.69-1.75(2H,m), 1.95-1.98(2H,m), 2.22-2.24(2H,m), 2.39-2.42(2H,m), 2.60-2.81(4H,m), 2.9 4-3.02 (1H, m), 3.30-3.33 (1H, m), 3.44-3.50 (1H, m), 6.30 (1H, s), 6.51-6.54 (1H, m), 7.15 (1H, d, J = 3.6Hz), 7.6 8(1H,d,J=3.2Hz), 7.77(1H,d,J=8.4Hz), 8.05(1H,d,J=8.4Hz), 8.19(1H,s), 8.85(1H,s), 10.81-10.86(1H,m).

[0377] (Example 20) EM (calculated value): 539.2; MS (ESI) m / z (M+H) + :540.2;

[0378] (Example 20) 1 H NMR (400MHz, DMSO-d6) δ0.69-0.71 (2H, m), 0.83-0.86 (2H, m), 0.95-0.97 (1.5H, m), 1.07-1.08 (1.5H, m), 1.58 -1.63(2H,m),1.71-1.74(2H,m),1.94-1.95(1H,m),2.20-2.22(2H,m),2.40-2.43(2H,m),2.61-2.83(4H,m),2 .97-3.05(1H,m), 3.36-3.37(1H,m), 4.30-4.32(1H,m), 6.25(1H,s), 6.49-6.52(1H,m), 7.12(1H,d,J=3.6Hz), 7.67 (1H, d, J = 3.2Hz), 7.75 (1H, d, J = 8.4Hz), 8.00 (1H, d, J = 8.4Hz), 8.22 (1H, s), 8.91 (1H, s), 10.83 (1H, brs).

[0379] The example compounds shown in Table 3 below were synthesized by referring to the method described in Example 19:

[0380] Table 3

[0381]

[0382]

[0383]

[0384] Example 22 Preparation of (6-((5-chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)((R)-3-methylpiperazin-1-yl)methanone hydrochloride

[0385]

[0386] Step 1: Preparation of 5-chloro-2-((trimethylsilyl)ethynyl)adamantan-2-ol

[0387] The compound trimethylsilyl acetylene (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 continued to stir at this temperature for 1 hour. The compound 5-chloroadamantane-2-one (1.41 g, 7.65 mmol) was dissolved in anhydrous THF (10 mL), added dropwise to the reaction system and continued to stir for 1 hour. After the reaction was completed, the reaction solution was quenched with a saturated NH4Cl aqueous solution, water was added thereto and extracted twice with EA, the organic phases were combined and dried with Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography (PE / EA=5 / 1) to obtain the target compound (590 mg, yield was 41.0%) as a white solid.

[0388] EM (calculated): 282.1; MS (ESI) m / z (M+H) + :283.1

[0389] Step 2: Preparation of 5-chloro-2-ethynyl adamantane-2-ol

[0390] The compound 5-chloro-2-((trimethylsilyl)ethynyl)adamantan-2-ol (550 mg, 1.95 mmol) was dissolved in MeOH (15 mL), and potassium carbonate (323 mg, 2.34 mmol) was added thereto under stirring, and stirred at room temperature for 1 hour. After the reaction was completed, 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.

[0391] EM (calculated): 210.1; MS (ESI) m / z (M+H) + :211.1

[0392] Step 3: Preparation of tert-butyl (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

[0393] 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 5-chloro-2-ethynyl adamantane-2-ol (105 mg, 0.50 mmol) were added to DMF (6 mL), Et3N (76 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were added thereto, and stirred overnight at 40°C under nitrogen protection. After the reaction was completed, water (600 mL) was added to the reaction solution, and extracted 3 times with DCM. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying over Na2SO4, the residue was concentrated to dryness and the crude product was purified by column chromatography (DCM / MeOH=35 / 1) to give the target compound (77 mg, yield: 45.1%) as an off-white solid.

[0394] EM (calculated): 685.3; MS (ESI) m / z (M+H) + :686.3

[0395] Step 4: Preparation of (6-((5-chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)((R)-3-methylpiperazin-1-yl)methanone hydrochloride

[0396] 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-carboxylic acid tert-butyl ester (75 mg, 0.11 mmol) was dissolved in DCM (10 mL), 4N HCl / 1,4-dioxane (2 mL) was added thereto, 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 target compound (25 mg, yield 36.9%) as a light yellow solid.

[0397] EM (calculated): 585.3; MS (ESI) m / z (M+H) + :586.3

[0398] 1H NMR (400MHz, DMSO-d6) δ0.72-0.73 (2H, m), 0.93-0.95 (2H, m), 1.14 (1.5H, d, J = 2.8Hz), 1.20 (1H, d, J = 7.2Hz) , 1.35 (1.5H, d, J = 5.6Hz), 1.48-1.51 (2H, m), 1.93-2.01 (2H, m), 2.11-2.14 (7H, m), 2.92-2.94 (1H, m), 3.03-3 .06(2H,m),3.18-3.26(1H,m),3.48-3.50(1H,m),3.69-3.78(1H,m),4.40-4.43(1H,m),5.84(1H,s),6.42(1H , d, J=7.2Hz), 7.74-7.77 (1H, m), 7.83 (1H, d, J=7.6Hz), 8.85 (1H, s), 9.69-9.79 (2H, m), 10.75-10.79 (1H, m).

[0399] The example compounds shown in Table 4 below were synthesized by referring to the method described in Example 22:

[0400] Table 4

[0401]

[0402]

[0403]

[0404]

[0405]

[0406] Example 27 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0407]

[0408] Step 1: Preparation of 1-ethynyl-1-fluorocyclohexane

[0409] Dissolve the compound 1-ethynylcyclohexanol (1.00 g, 8.06 mmol) in DCM (10 mL) and cool to -20 ° C under nitrogen protection. Slowly add DAST (1.56 g, 9.67 mmol) to the reaction system and continue stirring at this temperature for 1 hour. TLC spot plate detection shows that the raw material reaction is complete. Concentrate the reaction solution to dryness. The residue is purified by column chromatography (PE / EA=50 / 1) to obtain the target compound (333 mg, yield 32.6%) as a colorless liquid.

[0410] Step 2: Preparation of (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0411] 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), Et3N (76 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were added thereto, and stirred overnight at room temperature under nitrogen protection. After the reaction was completed, water (600 mL) was added to the reaction solution, and extracted 3 times with DCM. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying over Na2SO4, the residue was concentrated to dryness and the crude product was purified by column chromatography (DCM / MeOH=50 / 1) to give the target compound (79 mg, yield: 52.6%) as an off-white solid.

[0412] EM (calculated): 601.3; MS (ESI) m / z (M+H) + :602.3

[0413] Step 3: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0414] Compound (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate (77 mg, 0.13 mmol) was dissolved in DCM (10 mL), 4N HCl / 1,4-dioxane (2 mL) was added thereto, 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 target compound (19 mg, yield 27.1%) as a yellow solid.

[0415] EM (calculated): 501.3; MS (ESI) m / z (M+H) + :502.3

[0416] 1H NMR (400MHz, DMSO-d6) δ0.73-0.74 (2H, m), 0.95-0.98 (2H, m), 1.13 (1.5H, d, J = 6.0Hz), 1.34 (1 .5H, d, J=6.4Hz), 1.39-1.44 (1H, m), 1.52-1.65 (3H, m), 1.70-1.75 (2H, m), 1.90-2.10 (5H, m), 3 .12-3.49(5H,m), 3.77-3.86(1H,m), 4.42-4.45(1H,m), 6.45(1H,d,J=10.8Hz), 7.79(1H,dd,J =8.8Hz, 3.2Hz), 7.91 (1H, d, J = 8.8Hz), 8.95 (1H, s), 9.30 (1H, s), 9.47 (1H, s), 10.93 (1H, brs).

[0417] Example 28 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0418]

[0419] Step 1: Preparation of (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0420] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.33 mmol) and trimethylsilyl acetylene (129 mg, 1.32 mmol) were added to THF (6 mL), Et3N (100 mg, 0.99 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were added thereto, and the mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH=50 / 1) to obtain the target compound (83 mg, yield was 43.9%) as a white solid.

[0421] EM (calculated): 573.3; MS (ESI) m / z (M+H) + :574.3

[0422] Step 2: Preparation of (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0423] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) was dissolved in methanol (10 mL), potassium carbonate (39 mg, 0.28 mmol) was added thereto, and stirred at room temperature for 2 hours. After the reaction was completed, 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.

[0424] EM (calculated): 501.2; MS (ESI) m / z (M+H) + :502.2

[0425] Step 3: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0426] 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 stirred in 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 tert-methyl ether / PE (1 / 1) to obtain the target compound (31 mg, yield 59.4%) as a yellow solid.

[0427] EM (calculated): 401.2; MS (ESI) m / z (M+H) + :402.2

[0428] 1 H NMR (400MHz, DMSO-d6) δ0.75-0.76 (2H, m), 0.97-0.99 (2H, m), 1.14 (1.5H, d, J=5.2Hz), 1 .35 (1.5H, d, J=6.4Hz), 1.96-2.03 (1H, m), 2.99-3.10 (1H, m), 3.17-3.23 (1H, m), 3.28-3. 56 (3H, m), 3.90-4.00 (1H, m), 4.42-4.45 (1H, m), 4.50 (1H, s), 6.42 (1H, d, J = 6.8Hz), 7.87 (1H, d, J = 8.4Hz), 7.99 (1H, d, J = 8.4Hz), 9.01 (1H, s), 9.68-9.76 (2H, m), 11.48 (1H, brs).

[0429] Example 29 Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide

[0430]

[0431] Step 1: Preparation of ethyl 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-carboxylate

[0432] 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), potassium carbonate (310 mg, 2.24 mmol) was added thereto, and the temperature was raised to 120 ° C and stirred for 2 hours. TLC spot plate detection showed that the raw materials had reacted completely. Water (100 mL) was added to the reaction solution to precipitate a large amount of solid. Filter, wash with a small amount of EA, and dry to obtain the target compound (450 mg, yield 63.5%) as a brown solid.

[0433] EM (calculated): 379.0; MS (ESI) m / z (M+H) + :380.0

[0434] Step 2: Preparation of 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-2-carboxylic acid ammonium

[0435] The compound 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester (450 mg, 1.19 mmol) was added to NH3.H2O (20 mL), and the temperature was raised to 130°C and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely. The reaction solution was cooled to room temperature and a large amount of solid precipitated. After filtration and drying, the target compound (360 mg, yield 86.9%) was obtained as a yellow solid.

[0436] EM (calculated): 331.0; MS (ESI) m / z (MH)-: 330.0

[0437] Step 3: Preparation of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-indole-2-carboxamide

[0438] Compound 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-2-carboxylic acid ammonium (360 mg, 1.03 mmol) and 2-methoxyethane-1-amine (93 mg, 1.24 mmol) were added to THF (15 mL), 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 showed that the raw material had reacted completely. Water (100 mL) was added to the reaction solution, and extracted with DCM 3 times. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying with Na2SO4, the mixture was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH=30 / 1) to obtain the target compound (100 mg, yield was 25.0%) as a yellow solid.

[0439] EM (calculated): 389.0; MS (ESI) m / z (M+H) + :390.0

[0440] Step 4: Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide

[0441] Compound 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-indole-2-carboxamide (100 mg, 0.26 mmol) and 1-ethynylcyclohexanol (66 mg, 0.52 mmol) were added to DMSO (10 mL), Et3N (79 mg, 0.78 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were added thereto, and the mixture was heated to 70°C and stirred for 1 hour under nitrogen protection. After the reaction was completed, water (100 mL) was added to the reaction solution, and the mixture was extracted 3 times with DCM. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying over Na2SO4, the mixture was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH=40 / 1) to obtain the target compound (19 mg, yield was 16.8%) as an off-white solid.

[0442] EM (calculated): 433.2; MS (ESI) m / z (M+H) + :434.2

[0443] 1 H NMR (400MHz, DMSO-d6) δ1.48-1.63 (8H, m), 1.83-1.86 (2H, m), 3.28 (3H, s), 3.36-3.39 (2H, m), 3.44-3.47 (2H, m), 5.41 (1H, s), 6.46 (1H, d) , J=5.2Hz), 6.94 (2H, s), 7.14 (1H, s), 7.22 (1H, d, J=8.0Hz), 7.69 (1H, d, J=8.4Hz), 7.75 (1H, s), 8.32 (1H, d, J=4.2Hz), 8.75-8.78 (1H, m).

[0444] Example 30 Preparation of 1-((1-(2-aminopyrimidin-4-yl)-2-((3-methoxypropyl)amino)-1H-indol-6-yl)ethynyl)cyclohexan-1-ol

[0445]

[0446] Step 1: Preparation of tert-butyl (6-bromo-1H-indol-2-yl) carbamate

[0447] Compound 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, TLC plate detection showed that the raw material had reacted completely, the reaction system was concentrated to dryness, tert-butyl alcohol (20 mL) was added thereto, stirred at 80°C overnight, TLC plate detection showed that the reaction was complete, water (100 mL) was added to the reaction solution, and extracted with EA 3 times. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying with Na2SO4, 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.

[0448] EM (calculated): 310.0; MS (ESI) m / z (M+H) + :311.1

[0449] Step 2: Preparation of tert-butyl (6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-yl)carbamate

[0450] 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 thereto, and stirred overnight at room temperature. TLC spot plate detection showed that the raw materials had reacted completely. Water (100 mL) was added to the reaction solution, and EA was extracted 4 times. The organic phases were combined and washed twice with saturated LiCl aqueous solution. After drying with Na2SO4, the obtained crude product was purified by column chromatography (PE / EA=5 / 1) to obtain the target compound (680 mg, yield was 38.4%) as a yellow solid.

[0451] EM (calculated): 422.0; MS (ESI) m / z (M+H) + :423.0

[0452] Step 3: Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-amine trifluoroacetate

[0453] 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 thereto, and stirred at room temperature for 3 hours. TLC spot plate detection showed that the raw material had reacted completely. The reaction system was spin-dried to obtain a brown solid (1.1 g), and the crude product was directly used in the next step reaction.

[0454] EM (calculated): 322.0; MS (ESI) m / z (M+H) + :323.1

[0455] Step 4: Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine

[0456] Compound 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-amine trifluoroacetate (1.1 g, crude product) and 1-bromo-3-methoxypropane (0.52 g, 3.42 mmol) were added to DCM (30 mL), DIEA (2.2 g, 17.10 mmol) was added thereto, and the mixture was stirred overnight at room temperature. TLC spot plate detection showed that the raw material had reacted completely. Water (100 mL) was added to the reaction solution, and it was extracted with DCM 5 times. The organic phases were combined and washed twice with saturated aqueous NaCl solution. After drying with Na2SO4, the crude product was purified by column chromatography (PE / EA=3 / 1) to obtain the target compound (530 mg, two-step yield was 83.5%) as a yellow solid.

[0457] EM (calculated): 394.0; MS (ESI) m / z (M+H) + :395.1

[0458] Step 5: Preparation of 6-bromo-1-(2-aminopyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine

[0459] 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), and ammonia water (2 mL) was added thereto. The mixture was stirred overnight at 100°C. TLC plate detection showed that the raw material had reacted completely. Water (200 mL) was added to the reaction solution, and it was extracted with EA 5 times. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying with Na2SO4, the crude product was purified by column chromatography (DCM / MeOH=40 / 1) to obtain the target compound (140 mg, yield 58.8%) as a yellow solid.

[0460] EM (calculated): 375.1; MS (ESI) m / z (M+H) + :376.1

[0461] Step 6: Preparation of 1-((1-(2-aminopyrimidin-4-yl)-2-((3-methoxypropyl)amino)-1H-indol-6-yl)ethynyl)cyclohexan-1-ol

[0462] Compound 6-bromo-1-(2-aminopyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine (100 mg, 0.27 mmol) and 1-ethynylcyclohexanol (67 mg, 0.54 mmol) were added to DMSO (10 mL), Et3N (82 mg, 0.81 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were added thereto, and the mixture was heated to 80°C and stirred for 2 hours under nitrogen protection. After the reaction was completed, water (100 mL) was added to the reaction solution, and the mixture was extracted 4 times with DCM. The organic phases were combined and washed twice with a saturated aqueous NaCl solution. After drying over Na2SO4, the mixture was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH=30 / 1) to obtain the target compound (11 mg, yield was 9.8%) as an off-white solid.

[0463] EM (calculated): 419.2; MS (ESI) m / z (M+H) + :420.2

[0464] 1 H NMR (400MHz, DMSO-d6) δ1.22-1.43 (4H, m), 1.51-1.77 (4H, m), 1.81-1.88 (4H, m), 3.33 (3H, s), 3.38-3.41 (2H, m), 3.52-3.56 (2H, m), 4.95 (1H, s), 6 .53 (1H, d, J = 8.8Hz), 7.01 (2H, s), 7.18 (1H, s), 7.35 (1H, d, J = 8.0Hz), 7.7 7(1H,d,J=7.8Hz), 7.85(1H,s), 8.44(1H,d,J=3.6Hz), 8.66-8.75(1H,m).

[0465] Example 31 Preparation of (R)-3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazolin-6-yl)-1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one hydrochloride

[0466]

[0467] Step 1: Preparation of 1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one

[0468] Compound 4-(trifluoromethyl)piperidine (400 mg, 2.62 mmol) and propiolic acid (238 mg, 3.41 mmol) were added to DCM (10 mL), and DCC (703 mg, 3.41 mmol) was added thereto, and stirred at room temperature for 2 hours. TLC spot plate detection showed that the raw materials had reacted completely, and DCM (20 mL) was added to the reaction system, and washed with 2N hydrochloric acid and sodium bicarbonate aqueous solution in sequence. The organic phase was collected and dried with anhydrous Na2SO4, and then concentrated to dryness. The crude product was purified by column chromatography (PE / EA=10 / 1) to obtain the target compound (520 mg, yield was 96.8%) as an off-white solid.

[0469] EM (calculated): 205.1; MS (ESI) m / z (M+H) + :206.1

[0470] Step 2: Preparation of (R)-tert-butyl 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

[0471] 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), Et3N (52 mg, 0.51 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) were added thereto, and the mixture was stirred at room temperature for 5 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (DCM / MeOH=50 / 1) to obtain the target compound (52 mg, yield was 44.8%) as a white solid.

[0472] EM (calculated): 680.3; MS (ESI) m / z (M+H) + :681.3

[0473] Step 3: Preparation of (R)-3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazolin-6-yl)-1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one hydrochloride

[0474] 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-carboxylic acid 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 stirred in 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 tert-methyl ether / PE (1 / 1) to obtain the target compound (21 mg, yield 48.8%) as a yellow solid.

[0475] EM (calculated): 580.3; MS (ESI) m / z (M+H) + :581.3

[0476] 1 H NMR (400MHz, DMSO-d6) δ0.73-0.75 (2H, m), 0.97-0.99 (2H, m), 1.14 (1.5H, d, J=5.0Hz) ,1.24-1.54(3.5H,m),1.91-2.02(3H,m),2.68-2.85(2H,m),2.95-3.39(7H,m),3.94-4 .03 (1H, m), 4.42-4.53 (2H, m), 4.42-4.45 (1H, m), 6.45 (1H, d, J = 6.8Hz), 7.89 (1H, d, J = 8.4Hz), 8.07 (1H, d, J=8.4Hz), 9.15 (1H, s), 9.50 (1H, s), 9.82 (1H, s), 11.12 (1H, brs).

[0477] The following example compounds shown in Table 5 were synthesized by referring to the method described in Example 31:

[0478] Table 5

[0479]

[0480]

[0481] Example 33 Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0482]

[0483] Step 1: Preparation of ((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)trimethylsilane

[0484] The compound trimethylsilyl acetylene (3.0g, 30.58mmol) was dissolved in anhydrous THF (20mL), and the reaction was cooled to -70°C under nitrogen protection. n-BuLi (13.5mL, 33.64mmol, 2.5M in THF) was slowly added thereto, and the temperature was maintained and stirred for 40 minutes. 4,4-dimethylcyclohexane-1-one (3.9g, 30.58mmol) was dissolved in anhydrous THF (10mL) and slowly added to the reaction system. After the addition, the reaction temperature was raised to room temperature and continued to stir for 1 hour. The reaction was cooled to 0°C again, dimethyl sulfate (3.9g, 30.58mmol) was added thereto, returned to room temperature, and stirred overnight. TLC spot plate detection showed that the raw material had reacted completely, water was added to the reaction system for quenching, and extracted twice with ethyl acetate. The organic phases were combined and dried with anhydrous Na2SO4, and then concentrated to dryness. The crude product was purified by column chromatography (PE / EA=10 / 1) to obtain the target compound (2.1 g, yield: 28.8%) as a white solid.

[0485] EM (calculated): 238.2; MS (ESI) m / z (M+H) + :239.2

[0486] Step 2: Preparation of 1-ethynyl-1-methoxy-4,4-dimethylcyclohexane

[0487] The compound ((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)trimethylsilane (2.0 g, 8.40 mmol) was dissolved in anhydrous THF (10 mL), TBAF (16.8 mL, 16.80 mmol, 1.0 M in THF) was added thereto, and stirred for 2 hours. TLC spot plate detection showed that the raw material had reacted completely, water was added to the reaction system, and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous Na2SO4, and then concentrated to dryness. The crude product was purified by column chromatography (PE / EA=8 / 1) to obtain the target compound (1.3 g, yield was 92.9%) as a colorless oil.

[0488] EM (calculated): 166.1; MS (ESI) m / z (M+H) + :167.1

[0489] Step 3: Preparation of (R)-tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate

[0490] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.20 mmol) and 1-ethynyl-1-methoxy-4,4-dimethylcyclohexane (66 mg, 0.40 mmol) were added to DMF (6 mL), Et3N (61 mg, 0.60 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) were added thereto, and stirred at 40°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to water (100 mL) and extracted 3 times with DCM. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography (DCM / MeOH=50 / 1) and TLC (DCM / MeOH=25 / 1) to give the target compound (20 mg, yield: 15.6%) as a yellow solid.

[0491] EM (calculated): 641.4; MS (ESI) m / z (M+H) + :642.4

[0492] Step 4: Preparation of (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride

[0493] Compound (R)-4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in HCl / EtOAc (10 mL) under ice-water bath and stirred for 4 hours. After the reaction was completed, the supernatant was poured off and the remaining solid was washed with tert-methyl ether / PE (1 / 1) to obtain the target compound (15 mg, yield 86.7%) as a yellow solid.

[0494] EM (calculated): 541.3; MS (ESI) m / z (M+H) + :542.3

[0495] 1H NMR (400MHz, DMSO-d6) δ0.72-0.74 (2H, m), 0.93-0.97 (8H, m), 1.14 (1.5H, d, J=5.0Hz), 1.33 ( 1.5H, d, J=6.4Hz), 1.42-1.44 (4H, m), 1.57-1.60 (2H, m), 1.85-1.95 (3H, m), 2.48 (3H, s), 3.1 0-3.23 (5H, m), 3.75-3.80 (1H, m), 4.42-4.45 (1H, m), 6.45 (1H, d, J = 11.2Hz), 7.76 (1H, dd, J = 8.0Hz, 3.6Hz), 7.88 (1H, d, J=8.8Hz), 8.87 (1H, s), 9.14 (1H, s), 9.34 (1H, s), 10.84 (1H, brs).

[0496] Example 35 Preparation of (4-aminopiperidin-1-yl)(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanone hydrochloride

[0497]

[0498] Step 1: Preparation of 5-cyclopropyl-4-fluoro-1H-pyrazol-3-amine

[0499] The compound 5-cyclopropyl-1H-pyrazole-3-amine (6.0 g, 48.74 mmol) was dissolved in acetonitrile (100 mL), and selectfluor (17.3 g, 48.74 mmol) was added in batches at room temperature, and stirring was continued for 2 hours. TLC spot plate detection showed that the raw material had reacted completely, and the reaction solution was directly concentrated to dryness. The obtained crude product was purified by column chromatography (DCM / MeOH=40 / 1) to obtain the target compound (1.7 g, yield was 24.7%) as a red solid.

[0500] EM (calculated): 141.1; MS (ESI) m / z (M+H) + :142.1

[0501] Step 2: Preparation of 4,6-dichloroquinazoline-2-carbonyl chloride

[0502] The compound 6-chloro-4-oxo-3,4-dihydroquinazoline-2-carboxylic acid (200 mg, 0.89 mmol) was dissolved in chloroform (10 mL), and DMF (0.2 mL) and SOCl2 (318 mg, 2.67 mmol) were added thereto in sequence, and the mixture was heated to 80° C. and stirred for 3 hours under nitrogen protection. After the reaction of the raw materials was completed, the reaction solution was concentrated to dryness to obtain the target compound (crude product) as a brown oily liquid, which was directly used in the next reaction.

[0503] Step 3: Preparation of tert-butyl (1-(4,6-dichloroquinazoline-2-carbonyl)piperidin-4-yl)carbamate

[0504] The compound 4,6-dichloroquinazoline-2-carbonyl chloride (crude product) 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), and the solution was slowly added dropwise to the reaction system and stirred at this temperature for 30 minutes. TLC spot plate detection showed that the raw material reaction was complete. The reaction solution was concentrated, the residue was dispersed with EA, filtered, and the filter cake was washed with EA. The filtrate was combined and washed twice with H2O, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the target compound (crude product) as a brown solid.

[0505] EM (calculated): 424.1; MS (ESI) m / z (M+H) + :425.1

[0506] Step 4: Preparation of tert-butyl (1-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)piperidin-4-yl)carbamate

[0507] The compound tert-butyl (1-(4,6-dichloroquinazoline-2-carbonyl) piperidin-4-yl) carbamate (crude product) was dissolved in DMF (10 mL), DIEA (230 mg, 1.78 mmol), KI (295 mg, 1.78 mmol) and 5-cyclopropyl-4-fluoro-1H-pyrazole-3-amine (126 mg, 0.89 mmol) were added thereto in sequence, and the mixture was heated to 65° C. and stirred for 4 hours. The reaction of the raw materials was completed by TLC spot plate detection. The reaction solution was added to water, extracted with EA 3 times, the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH=50 / 1) to obtain the target compound (183 mg, total yield of three-step reaction was 38.9%) as a light yellow solid.

[0508] EM (calculated): 529.2; MS (ESI) m / z (M+H) + :530.2

[0509] Step 5: Preparation of (4-aminopiperidin-1-yl)(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanone hydrochloride

[0510] The compound tert-butyl (1-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)piperidin-4-yl)carbamate (50 mg, 0.09 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (10 mL) was added thereto, and stirred at this temperature for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (38 mg, yield was 90.7%) was obtained after drying as a yellow solid.

[0511] EM (calculated): 429.1; MS (ESI) m / z (M+H) + :430.1

[0512] 1H NMR (400MHz, DMSO-d6) δ0.81-0.83(2H,m), 0.92-0.94(2H,m), 1.21-1.26(2H,m), 1.65-1.69(1H,m), 1.85-1.88(2H,m), 2.93-2.98(3 H, m), 3.41-3.45 (1H, m), 4.27-4.30 (1H, m), 7.69 (1H, d, J = 7.2Hz), 7.81 (1H, d, J = 7.6Hz), 8.27 (3H, s), 8.54 (1H, s), 12.42 (1H, brs).

[0513] The example compounds shown in Table 6 below were synthesized by referring to the method described in Example 35:

[0514] Table 6

[0515]

[0516]

[0517]

[0518]

[0519]

[0520] Example 40 Preparation of (R)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-2-(3-methylpiperazin-1-yl)quinazolin-4-amine hydrochloride

[0521]

[0522] Step 1: Preparation of 2,6-dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine

[0523] 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) were added thereto in sequence at room temperature. The mixture was heated to 65 ° C and stirred for 2 hours. TLC spot plate detection showed that the raw materials had reacted completely, and 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 a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM / MeOH=50 / 1) to obtain the target compound (3.9 g, yield was 89.4%) as a yellow solid.

[0524] EM (calculated): 337.0; MS (ESI) m / z (M+H) + :338.0

[0525] Step 2: Preparation of (R)-tert-butyl 4-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2-methylpiperazine-1-carboxylate

[0526] Compound 2,6-dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazoline-4-amine (30 mg, 0.09 mmol) was dissolved in DMA (1 mL), and (R)-2-methylpiperazine-1-carboxylic acid tert-butyl (18 mg, 0.09 mmol), KI (30 mg, 0.18 mmol) and DIEA (46 mg, 0.36 mmol) were added thereto in sequence at room temperature. The mixture was heated to 125 ° C and stirred for 3 hours. The reaction mixture was cooled to room temperature after TLC plate detection, indicating that the raw material had reacted completely. The reaction mixture was slowly added to water (10 mL) and extracted with EA twice. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by TLC (DCM / MeOH=25 / 1) to obtain the target compound (28 mg, yield was 62.1%) as a yellow solid.

[0527] EM (calculated): 501.2; MS (ESI) m / z (M+H) + :502.2

[0528] Step 3: Preparation of (R)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-2-(3-methylpiperazin-1-yl)quinazolin-4-amine hydrochloride

[0529] Compound (R)-4-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl (28 mg, 0.06 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (5 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw materials had reacted completely, and 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 the target compound (24 mg, yield was 91.3%) was obtained after drying as a white solid.

[0530] EM (calculated): 401.2; MS (ESI) m / z (M+H) + :402.2

[0531] 1H NMR (400MHz, DMSO-d6) δ0.82-0.83 (2H, m), 0.98-1.00 (2H, m), 1.28 (3H, d, J = 2.4Hz), 1.92-1.95 (1H, m), 3.12-3.13 (1H, m), 3.7 6-3.79 (5H, m), 4.65-4.67 (1H, m), 7.88-7.90 (2H, m), 8.64 (1H, s), 9.42 (1H, s), 9.53 (1H, s), 11.12 (1H, brs), 12.63 (1H, brs).

[0532] The example compounds shown in Table 7 below were synthesized by referring to the method described in Example 40:

[0533] Table 7

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546] Example 56 Preparation of 2-(4-amino-4-propylpiperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine

[0547]

[0548] Step 1: Preparation of tert-butyl 4-cyano-4-propylpiperidine-1-carboxylate

[0549] The compound 4-cyanopiperidin-1-carboxylic acid tert-butyl ester (1.0g, 4.76mmol) was dissolved in anhydrous THF (10mL), and cooled to an internal temperature of about -65°C using an ethanol dry ice bath after nitrogen protection. LiHMDS (1.3M inTHF, 5.5mL, 7.14mmol) was slowly added dropwise to the reaction system, and the temperature was maintained and stirred for 3 hours after the addition. Iodopropane (1.2g, 7.14mmol) was dissolved in THF (2mL) and added to the reaction system, and the temperature was slowly raised to room temperature after the addition, and stirred overnight. TLC spot plate detection, the raw material reaction was complete, water (20mL) was added for quenching, and after concentrating to remove most of the organic solvent, the residue was extracted twice with EA. The organic phases were combined and washed once with a saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. The residue was concentrated to dryness and purified by column chromatography (PE / EA=9 / 1) to give the target compound (700 mg, yield 58.3%) as a yellow oil.

[0550] EM (calculated): 252.2; MS (ESI) m / z (M+H) + :253.2

[0551] Step 2: Preparation of tert-butyl 4-carbamoyl-4-propylpiperidine-1-carboxylate

[0552] The compound 4-cyano-4-propylpiperidine-1-carboxylic acid tert-butyl ester (700 mg, 2.78 mmol) was dissolved in DMSO (5 mL), and K2CO3 (767 mg, 5.56 mmol) was added. After heating to 60°C, H2O2 (30%, 2 mL) was slowly added dropwise to the reaction, and stirring was continued for 3 hours after the addition. TLC spot plate detection showed that the raw material reaction was complete. After cooling, water (50 mL) was added and extracted twice with EA. The organic phases were combined and washed once with a saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. Concentrated to dryness, the target compound (730 mg, yield was 97.2%) was obtained as a white solid.

[0553] EM (calculated): 270.2; MS (ESI) m / z (M+H) + :271.2

[0554] Step 3: Preparation of tert-butyl 4-amino-4-propylpiperidine-1-carboxylate

[0555] The compound 4-carbamoyl-4-propylpiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.37 mmol) was dissolved in acetonitrile / H2O (6 mL, 2 / 1), and 1,3-dibromo-5,5-dimethylimidazoline-2,4-dione (53 mg, 0.19 mmol) and KOH (112 mg, 2.0 mmol) were added. After the addition, the mixture was stirred at room temperature for 3 hours. The reaction of the raw materials was completed by TLC spot plate detection. The reaction solution was adjusted to pH 4-5 with concentrated hydrochloric acid, H2O (2 mL) was added, and EA was extracted twice. The aqueous phase was retained and the pH was adjusted to ~10 with sodium bicarbonate, and EA was extracted 3 times. The organic phases were combined and dried over anhydrous sodium sulfate. Concentrated to dryness to obtain the target compound (48 mg, yield 53.3%) as a colorless oil.

[0556] EM (calculated): 242.2; MS (ESI) m / z (M+H) + :243.2

[0557] Step 4: Preparation of 4-propylpiperidin-4-amine dihydrochloride

[0558] The compound 4-amino-4-propylpiperidine-1-carboxylic acid tert-butyl ester (48 mg, 0.20 mmol) was dissolved in 4M HCl / 1,4-dioxane (2 mL) and stirred for 1 hour in an ice-water bath. TLC spot plate detection showed that the raw material had reacted completely, and the reaction solution was concentrated to dryness at low temperature to obtain the target compound (43 mg, yield 100%) as a white solid.

[0559] EM (calculated): 142.2; MS (ESI) m / z (M+H) + :143.2

[0560] Step 5: Preparation of 2-(4-amino-4-propylpiperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine

[0561] Compound 2,6-dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazoline-4-amine (50 mg, 0.15 mmol) was dissolved in DMA (2 mL), and 4-propylpiperidin-4-amine dihydrochloride (43 mg, 0.20 mmol), KI (50 mg, 0.30 mmol) and DIEA (77 mg, 0.60 mmol) were added thereto in sequence at room temperature. The mixture was heated to 125 °C and stirred for 2 hours. The reaction mixture was completely reacted by TLC plate detection, and the reaction mixture was cooled to room temperature. The reaction mixture was slowly added to water (20 mL) and extracted with EA twice. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. The mixture was concentrated to dryness, and the residue was purified by TLC (DCM / MeOH=20 / 1) to obtain the target compound (20 mg, yield 30.0%) as a yellow solid.

[0562] EM (calculated): 443.2; MS (ESI) m / z (M+H) + :444.2

[0563] 1H NMR (400MHz, DMSO-d6) δ0.77-0.80 (2H, m), 0.87 (3H, t, J = 6.4Hz), 0.94-0.98 (2H, m), 1.24-1.44 (8H, m), 1.85-1.92 (1H, m), 3.40-3.42 (2 H, m), 4.07-4.09 (2H, m), 7.31 (1H, d, J = 8.8Hz), 7.54 (1H, dd, J1 = 9.2Hz, J2 = 2.0Hz), 8.33 (1H, d, J = 2.0Hz), 9.80 (1H, brs), 12.33 (1H, s).

[0564] The following example compounds shown in Table 8 were synthesized by referring to the method described in Example 56:

[0565] Table 8

[0566]

[0567]

[0568]

[0569] Example 60 Preparation of 2-(4-amino-4-(4-fluorophenyl)piperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine

[0570]

[0571] Step 1: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidine-4-carbonitrile

[0572] NaH (60% content dispersed in mineral oil, 237mg, 5.92mmol) was added to the reaction bottle, and an ice-water bath was used to cool after nitrogen protection. The compound 2-(4-fluorophenyl)acetonitrile (200mg, 1.48mmol) was dissolved in anhydrous DMF (5mL) and slowly added dropwise to the reaction bottle. Stirring in an ice-water bath for 1 hour. The compound N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine.hydrochloride (395mg, 1.48mmol) was dissolved in DMF (3mL) and added to the reaction system. After the addition, the temperature was slowly raised to room temperature and stirred for 2 hours. TLC spot plate detection showed that the raw material reaction was complete. The reaction solution was added dropwise to water (100mL) for quenching and extracted twice with EA. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. Concentrated to dryness to obtain the target compound (crude product) as a yellow oil.

[0573] EM (calculated): 294.2; MS (ESI) m / z (M+H) + :295.2

[0574] Step 2: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidine-4-carboxamide

[0575] The compound 1-benzyl-4-(4-fluorophenyl)piperidine-4-carbonitrile (crude product) was dissolved in DMSO (5 mL) and NaOH (178 mg, 4.44 mmol) was added. After heating to 60°C, H2O2 (30%, 2 mL) was slowly added dropwise to the reaction and continued to stir for 3 hours after the addition. The reaction of the raw material was completed by TLC spot plate detection. After cooling, water (50 mL) was added and extracted twice with EA. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. Concentrated to dryness to obtain the target compound (crude product) as a light yellow oil.

[0576] EM (calculated): 312.2; MS (ESI) m / z (M+H) + :313.2

[0577] Step 3: Preparation of 1-benzyl-4-(4-fluorophenyl)piperidin-4-amine

[0578] The compound 1-benzyl-4-(4-fluorophenyl)piperidine-4-carboxamide (crude product) was dissolved in acetonitrile / H2O (10mL, 2 / 1), and 1,3-dibromo-5,5-dimethylimidazoline-2,4-dione (210mg, 0.74mmol) and KOH (166mg, 2.96mmol) were added. After the addition, the mixture was stirred at room temperature for 3 hours. The reaction of the raw materials was completed by TLC spot plate detection. The reaction solution was adjusted to pH 4-5 with concentrated hydrochloric acid, H2O (2mL) was added, and EA was extracted twice. The aqueous phase was retained and the pH was adjusted to ~10 with sodium bicarbonate, and EA was extracted 3 times. The organic phases were combined and dried over anhydrous sodium sulfate. Concentrated to dryness, the target compound (137mg, total yield of three-step reaction was 32.5%) was obtained as a colorless oil.

[0579] EM (calculated): 284.2; MS (ESI) m / z (M+H) + :285.2

[0580] Step 4: Preparation of 4-(4-fluorophenyl)piperidin-4-amine

[0581] The 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, and the mixture was stirred for 5 hours after hydrogen replacement. TLC spot plate detection showed that the raw material had reacted completely, the reaction solution was filtered, and the filter cake was repeatedly washed with methanol. The filtrate was concentrated to dryness to obtain the target compound (80 mg, yield 85.9%) as a yellow oil.

[0582] EM (calculated): 194.1; MS (ESI) m / z (M+H) + :195.1

[0583] Step 5: Preparation of 2-(4-amino-4-(4-fluorophenyl)piperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine

[0584] Compound 2,6-dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazoline-4-amine (30 mg, 0.09 mmol) was dissolved in DMA (1 mL), and 4-(4-fluorophenyl)piperidin-4-amine (17 mg, 0.09 mmol), KI (30 mg, 0.18 mmol) and DIEA (46 mg, 0.36 mmol) were added thereto in sequence at room temperature. The mixture was heated to 125°C and stirred for 2 hours. The reaction mixture was completely reacted by TLC plate detection, and the reaction mixture was cooled to room temperature. The reaction mixture was slowly added to water (10 mL) and extracted with EA twice. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. The mixture was concentrated to dryness, and the residue was purified by TLC (DCM / MeOH=20 / 1) to obtain the target compound (16 mg, yield 35.9%) as a yellow solid.

[0585] EM (calculated): 495.2; MS (ESI) m / z (M+H) + :496.2

[0586] 1H NMR (400MHz, DMSO-d6) δ0.76-0.80 (2H, m), 0.92-0.99 (2H, m), 1.55-1.61 (2H, m), 1.84-1.91 (3H, m), 3.41-3.52 (2H, m), 4.20-4.42(2H,m), 7.09-7.13(2H,m), 7.34(1H,d,J=8.0Hz), 7.54-7.57(3H,m), 8.35(1H,s), 9.84(1H,s), 12.33(1H,s).

[0587] The following example compounds shown in Table 9 were synthesized by referring to the method described in Example 60:

[0588] Table 9

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602] Example 72 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine dihydrochloride

[0603]

[0604] Step 1: Preparation of 2-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine

[0605] 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-3-amine (2.2 g, 15.44 mmol), KI (5.1 g, 30.88 mmol) and DIEA (8.0 g, 61.76 mmol) were added thereto in sequence at room temperature. The mixture was heated to 65 ° C and stirred for 2 hours. The reaction mixture was detected by TLC spot plate, and the raw materials had reacted completely, and the reaction mixture was cooled to room temperature. The reaction mixture was slowly added to water (300 mL) and extracted with EA twice. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM / MeOH=50 / 1) to obtain the target compound (6.0 g, yield was 90.3%) as a yellow solid.

[0606] EM (calculated): 429.0; MS (ESI) m / z (M+H) + :430.0

[0607] Step 2: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0608] The compound 2-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazoline-4-amine (6.0 g, 14.0 mmol) was dissolved in DMA (100 mL), and tert-butyl (4-methylpiperidin-4-yl) carbamate (3.0 g, 14.0 mmol), KI (4.6 g, 28.0 mmol) and DIEA (7.2 g, 56.0 mmol) were added thereto in sequence at room temperature. The temperature was raised to 125 ° C and stirred for 3 hours. TLC spot plate detection showed that the raw materials had reacted completely, and the reaction solution was cooled to room temperature. The reaction solution was slowly added to water (1000 mL) and extracted with EA twice. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM / MeOH=30 / 1) to obtain the target compound (7.3 g, yield was 85.3%) as a yellow solid.

[0609] EM (calculated): 607.2; MS (ESI) m / z (M+H) + :608.2

[0610] Step 3: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine dihydrochloride

[0611] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (30 mg, 0.05 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (4 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw materials had reacted completely, and 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 the target compound (16 mg, yield was 55.2%) was obtained after drying as a light yellow solid.

[0612] EM (calculated): 507.1; MS (ESI) m / z (M+H) + :508.1

[0613] 1H NMR (400MHz, DMSO-d6) δ0.80-0.84 (2H, m), 0.97-1.02 (2H, m), 1.39 (3H, s), 1.81-1.96 (5H, m), 3.65-3.88 (2H, m), 4.04-4.48 (2 H, m), 7.89-7.97 (1H, m), 8.16 (1H, d, J = 8.0Hz), 8.29 (3H, brs), 8.94 (1H, s), 11.34 (1H, brs), 12.75 (1H, brs), 13.14 (1H, brs).

[0614] Example 73 Preparation of 1-((2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)ethynyl)-4,4-dimethylcyclohexane-1-ol dihydrochloride

[0615]

[0616] Step 1: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((1-hydroxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0617] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol) and 1-ethynyl-4,4-dimethylcyclohexane-1-ol (37 mg, 0.24 mmol) were added to DMF (2 mL), Et3N (24 mg, 0.24 mmol) and Pd(PPh3)2Cl2 (15 mg, 0.02 mmol) were added thereto, and stirred at room temperature overnight under nitrogen protection. After the reaction was completed, water (20 mL) was added to the reaction solution, and extracted with EA three times. The organic phases were combined and washed once with a saturated NaCl aqueous solution. After drying over anhydrous sodium sulfate and concentrating to dryness, the 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.

[0618] EM (calculated): 631.4; MS (ESI) m / z (M+H) + :632.4

[0619] Step 2: Preparation of 1-((2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)ethynyl)-4,4-dimethylcyclohexane-1-ol, dihydrochloride

[0620] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((1-hydroxy-4,4-dimethylcyclohexyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (22 mg, 0.03 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (3 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (13 mg, yield was 71.8%) was obtained after drying as an off-white solid.

[0621] EM (calculated): 531.3; MS (ESI) m / z (M+H) + :532.3

[0622] 1H NMR (400MHz, DMSO-d6) δ0.78-0.83 (2H, m), 0.92 (6H, d, J = 5.6Hz), 0.96-1.00 (2H, m), 1.38-1.43 (7H, m), 1.67-1.95 (9H, m), 3.60 -3.75(2H,m), 4.18-4.32(2H,m), 7.84(1H,s), 8.05(1H,s), 8.31(3H,s), 8.60(1H,s), 11.35(1H,s), 12.73(1H,s), 13.01(1H,s).

[0623] The following example compounds shown in Table 10 were synthesized by referring to the method described in Example 73:

[0624] Table 10

[0625]

[0626]

[0627]

[0628]

[0629] Example 77 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carbonitrile hydrochloride

[0630]

[0631] Step 1: Preparation of tert-butyl (1-(6-cyano-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0632] Compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol), Zn(CN)2 (28 mg, 0.24 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), DPPF (5 mg, 0.01 mmol) and Zn powder (2 mg, 0.02 mmol) were added to DMF (3 mL), 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, and extracted twice with EA. The organic phases were combined and washed once with a saturated NaCl aqueous solution. After drying over anhydrous sodium sulfate and concentrating to dryness, the 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.

[0633] EM (calculated): 506.3; MS (ESI) m / z (M+H) + :507.3

[0634] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carbonitrile hydrochloride

[0635] 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 (28 mg, 0.06 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (5 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (22 mg, yield was 83.0%) was obtained after drying as a white solid.

[0636] EM (calculated): 406.2; MS (ESI) m / z (M+H) + :407.2

[0637] 1H NMR (400MHz, DMSO-d6) δ0.81-0.86 (2H, m), 0.98-1.00 (2H, m), 1.29 (3H, s), 1.69-1.98 (5H, m), 4.10-4 .50 (4H, m), 8.07-8.16 (2H, m), 8.29 (3H, brs), 8.98 (1H, s), 11.03-11.38 (1H, m), 12.55-12.86 (1H, m).

[0638] Example 78 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazolin-4-amine dihydrochloride

[0639]

[0640] Step 1: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0641] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol) and trimethylsilylacetylene (31 mg, 0.32 mmol) were added to THF (4 mL), Et3N (24 mg, 0.24 mmol) and Pd(PPh3)2Cl2 (7 mg, 0.01 mmol) were added thereto, and the mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by TLC (DCM / MeOH=50 / 1) to obtain the target compound (29 mg, yield was 63.8%) as an off-white solid.

[0642] EM (calculated): 577.3; MS (ESI) m / z (M+H) + :578.3

[0643] Step 2: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0644] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (29 mg, 0.05 mmol) was dissolved in methanol (5 mL), potassium carbonate (14 mg, 0.10 mmol) was added thereto, and stirred at room temperature for 2 hours. After the reaction was completed, 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.

[0645] EM (calculated): 505.3; MS (ESI) m / z (M+H) + :506.3

[0646] Step 3: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazolin-4-amine dihydrochloride

[0647] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (23 mg, 0.04 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (4 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (17 mg, yield was 80.9%) was obtained after drying as a white solid.

[0648] EM (calculated): 405.2; MS (ESI) m / z (M+H) + :406.2

[0649] 1H NMR (400MHz, DMSO-d6) δ0.80-0.84 (2H, m), 0.97-1.02 (2H, m), 1.39 (3H, s), 1.80-1.86 (4H, m), 1.90-1.97 (1H, m), 3.83-3.89 (2H, m), 4.14-4 .20 (1H, m), 4.36-4.46 (2H, m), 7.94 (1H, d, J = 8.4Hz), 8.15 (1H, s), 8.43 (3H, s), 8.73 (1H, s), 11.36 (1H, s), 12.79 (1H, brs), 13.20 (1H, brs).

[0650] Example 79 Preparation of 2-(4-amino-4-phenylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazolin-4-amine dihydrochloride

[0651]

[0652] Step 1: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate

[0653] The compound 2-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazoline-4-amine (295 mg, 0.69 mmol) was dissolved in DMA (10 mL), and tert-butyl (4-phenylpiperidin-4-yl) carbamate (190 mg, 0.69 mmol), KI (229 mg, 1.38 mmol) and DIEA (267 mg, 2.07 mmol) were added thereto in sequence at room temperature. The mixture was heated to 125 ° C and stirred for 3 hours. The reaction mixture was detected by TLC spot plate, and the raw materials had reacted completely, and the reaction mixture was cooled to room temperature. The reaction mixture was slowly added to water (100 mL) and extracted with EA twice. The organic phases were combined and washed once with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by column chromatography (DCM / MeOH=40 / 1) to obtain the target compound (285 mg, yield was 61.7%) as a yellow solid.

[0654] EM (calculated): 669.2; MS (ESI) m / z (M+H) + :670.2

[0655] Step 2: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate

[0656] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-yl)-4-phenylpiperidin-4-yl)carbamate (130 mg, 0.19 mmol) and trimethylsilyl acetylene (75 mg, 0.76 mmol) were added to DMF (4 mL), Et3N (77 mg, 0.76 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) were added thereto, and the mixture was heated to 50°C and stirred for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was slowly added to water (40 mL) and extracted twice with EA. The organic phases were combined and washed once with a saturated aqueous NaCl solution. After drying over anhydrous sodium sulfate, the mixture was concentrated to dryness to obtain a brown oil, which was directly used in the next reaction.

[0657] EM (calculated): 639.3; MS (ESI) m / z (M+H) + :640.3

[0658] Step 3: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate

[0659] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazolin-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 hours. 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, total yield of two-step reaction was 55.7%) as a yellow solid.

[0660] EM (calculated): 567.3; MS (ESI) m / z (M+H) + :568.3

[0661] Step 4: Preparation of 2-(4-amino-4-phenylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazolin-4-amine dihydrochloride

[0662] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate (60 mg, 0.11 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (6 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (51 mg, yield was 85.9%) was obtained after drying as a light yellow solid.

[0663] EM (calculated): 467.2; MS (ESI) m / z (M+H) + :468.2

[0664] 1H NMR (400MHz, DMSO-d6) δ0.83-0.85 (2H, m), 0.99-1.01 (2H, m), 1.91-1.98 (1H, m), 2. 13-2.24(2H,m), 2.39-2.47(1H,m), 2.55-2.61(1H,m), 3.64-3.80(2H,m), 4.08-4.4 5 (3H, m), 7.43 (1H, d, J = 8.0Hz), 7.45-7.52 (2H, m), 7.70 (2H, d, J = 8.0Hz), 7.85-8.1 4(2H, m), 8.68-8.93(4H, m), 11.18-11.48(1H, m), 12.74(1H, brs), 13.03(1H, brs).

[0665] Example 80 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4-amine trihydrochloride

[0666]

[0667] Step 1: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0668] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (50 mg, 0.08 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)phenyl)piperazine (48 mg, 0.16 mmol), Pd(dppf)Cl2.DCM (8 mg, 0.01 mmol), and sodium carbonate (25 mg, 0.24 mmol) were added to 1,4-dioxane / H2O (3 mL, 5 / 1), and heated to 80°C with stirring 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 TLC (DCM / MeOH / NH3in MeOH=10 / 1 / 0.2) to obtain the target compound (25 mg, yield: 47.7%) as a white solid.

[0669] EM (calculated): 655.4; MS (ESI) m / z (M+H) + :656.4

[0670] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4-amine trihydrochloride

[0671] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (25 mg, 0.04 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (5 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (22 mg, yield was 83.0%) was obtained after drying as a white solid.

[0672] EM (calculated): 555.3; MS (ESI) m / z (M+H) + :556.3

[0673] 1H NMR (400MHz, DMSO-d6) δ0.81-0.85 (2H, m), 0.98-1.03 (2H, m), 1.40 (3H, s), 1.82-1.86 (4H, m), 1.92- 1.96 (1H, m), 2.84 (3H, d, J = 4.4Hz), 3.11-3.18 (4H, m), 3.47-3.53 (2H, m), 3.65-3.73 (2H, m), 3.96-3. 98 (2H, m), 4.25-4.29 (2H, m), 7.17 (2H, d, J = 8.8Hz), 7.82 (2H, d, J = 8.8Hz), 8.11 (1H, s), 8.26 (1H, d, J=8.4Hz), 8.33 (3H, s), 8.85 (1H, s), 10.74 (1H, s), 11.49 (1H, brs), 12.78 (1H, brs), 12.88 (1H, brs).

[0674] The following example compounds shown in Table 11 were synthesized by referring to the method described in Example 80:

[0675] Table 11

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685] Example 91 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N,N-dimethylquinazoline-6-carboxamide dihydrochloride

[0686]

[0687] Step 1: Preparation of methyl 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxylate

[0688] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-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), and 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.

[0689] EM (calculated): 539.3; MS (ESI) m / z (M+H) + :540.3

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

[0691] Compound 2-(4-((tert-butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxylic acid methyl ester (100 mg, 0.19 mmol) was dissolved in MeOH / H2O (10 mL, 5 / 1), LiOH (23 mg, 0.95 mmol) was added thereto, and the mixture was heated to 50°C and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated, water was added to the residue, and extracted twice with EA. The aqueous phase was adjusted to pH ~4 with concentrated hydrochloric acid to precipitate a solid. After filtering and drying the solid, the target compound (83 mg, yield 83.2%) was obtained as a yellow solid.

[0692] EM (calculated): 525.2; MS (ESI) m / z (M+H) + :526.2

[0693] Step 3: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(dimethylcarbamoyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0694] The compound 2-(4-((tert-butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxylic acid (40 mg, 0.08 mmol) was dissolved in THF (6 mL), and dimethylamine hydrochloride (13 mg, 0.16 mmol), HATU (46 mg, 0.12 mmol) and DIEA (41 mg, 0.32 mmol) were added thereto, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, EA was dissolved, and then washed with water twice, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by TLC (DCM / MeOH=20 / 1) to obtain the target compound (25 mg, yield was 56.8%) as a white solid.

[0695] EM (calculated): 552.3; MS (ESI) m / z (M+H) + :553.3

[0696] Step 4: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N,N-dimethylquinazoline-6-carboxamide dihydrochloride

[0697] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(dimethylcarbamoyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (25 mg, 0.05 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (5 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (14 mg, yield was 53.2%) was obtained after drying as an off-white solid.

[0698] EM (calculated): 452.2; MS (ESI) m / z (M+H) + :453.2

[0699] 1H NMR (400MHz, DMSO-d6) δ0.79-0.85 (2H, m), 0.96-1.05 (2H, m), 1.39 (3H, s), 1.75-1.98 (5H, m), 3.00 (3H, s), 3.03 (3H, s), 3.74-3.87 (2H, m) ), 4.22-4.43(2H, m), 7.90-7.93(1H, m), 8.10-8.20(1H, m), 8.43(3H, brs), 8.64(1H, s), 11.39(1H, brs), 12.77(1H, brs), 13.17(1H, brs).

[0700] Example 92 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(methylsulfonyl)quinazolin-4-amine hydrochloride

[0701]

[0702] Step 1: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0703] Compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (30 mg, 0.05 mmol), sodium methanesulfinate (20 mg, 0.20 mmol) and CuI (17 mg, 0.10 mmol) were added to DMSO (2 mL), heated to 120 ° C and stirred overnight. 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 obtain the target compound (12 mg, yield 42.9%) as a white solid.

[0704] EM (calculated): 559.2; MS (ESI) m / z (M+H) + :560.2

[0705] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(methylsulfonyl)quinazolin-4-amine hydrochloride

[0706] 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 (12 mg, 0.02 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (3 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (8 mg, yield was 80.8%) was obtained after drying as a yellow solid.

[0707] EM (calculated): 459.2; MS (ESI) m / z (M+H) + :460.2

[0708] 1H NMR (400MHz, DMSO-d6) δ0.78-0.82 (2H, m), 0.95-0.99 (2H, m), 1.37 (3H, s), 1.66-1.70 (4H, m), 1.87-1.93 (1H, m), 3.25 (3H, s), 3.38-3.42 (2H, m), 4.19-4.34 (2H, m), 7.49 (1H, s), 8.00 (1H, s), 8.16 (3H, s), 8.94 (1H, s), 10.36 (1H, s), 12.44 (1H, s).

[0709] Example 93 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine trihydrochloride

[0710]

[0711] Step 1: Preparation of tert-butyl 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0712] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (80 mg, 0.13 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.26 mmol), Pd(dppf)Cl2.DCM (8 mg, 0.01 mmol), and sodium carbonate (41 mg, 0.39 mmol) were added to 1,4-dioxane / H2O (6 mL, 5 / 1), heated to 80°C 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.

[0713] EM (calculated): 662.4; MS (ESI) m / z (M+H) + :663.4

[0714] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine trihydrochloride

[0715] The compound 4-(2-(4-((tert-butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl (20 mg, 0.03 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (3 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (11 mg, yield was 64.0%) was obtained after drying as a yellow solid.

[0716] EM (calculated): 462.3; MS (ESI) m / z (M+H) + :463.3

[0717] 1H NMR (400MHz, DMSO-d6) δ0.80-0.84 (2H, m), 0.98-1.02 (2H, m), 1.40 (3H, s), 1.80-1 .84(4H,m), 1.90-1.97(1H,m), 2.80-2.83(2H,m), 3.35-3.38(2H,m), 3.79-3.82(3 H, m), 4.25-4.30 (3H, m), 6.45 (1H, s), 8.10 (1H, d, J = 8.8Hz), 8.18 (1H, d, J = 8.8Hz) , 8.43 (3H, m), 8.63 (1H, s), 9.47 (2H, s), 11.53 (1H, s), 12.80 (1H, s), 13.17 (1H, s).

[0718] Example 94 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(piperidin-4-yl)quinazolin-4-amine trihydrochloride

[0719]

[0720] Step 1: Preparation of tert-butyl 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)piperidine-1-carboxylate

[0721] Compound 4-(2-(4-((tert-butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl (45 mg, 0.07 mmol) was added to MeOH (10 mL), Pd(OH)2 / C (10 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours after hydrogen replacement. 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 crude product was purified by TLC (DCM / MeOH=10 / 1) to obtain the target compound (22 mg, yield 47.3%) as a white solid.

[0722] EM (calculated): 664.4; MS (ESI) m / z (M+H) + :665.4

[0723] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(piperidin-4-yl)quinazolin-4-amine trihydrochloride

[0724] The compound 4-(2-(4-((tert-butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-yl)piperidine-1-carboxylic acid tert-butyl ester (22 mg, 0.03 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (3 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (9 mg, yield was 52.3%) was obtained after drying as a yellow solid.

[0725] EM (calculated): 464.3; MS (ESI) m / z (M+H) + :465.3

[0726] 1H NMR (400MHz, DMSO-d6) δ0.79-0.83 (2H, m), 0.97-1.02 (2H, m), 1.38 (3H, s), 1.78-1.8 2(4H,m), 1.90-1.94(1H,m), 2.05-2.08(2H,m), 2.95-3.06(3H,m), 3.37-3.39(2H,m), 3.63-3.69 (3H, m), 4.20-4.25 (3H, m), 7.81 (1H, d, J = 5.6Hz), 8.04 (1H, d, J = 5.2Hz), 8. 32-8.38 (4H, m), 8.94 (1H, s), 8.99 (1H, s), 11.46 (1H, s), 12.75 (1H, s), 12.83 (1H, s).

[0727] Example 95 Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(trifluoromethyl)quinazolin-4-amine hydrochloride

[0728]

[0729] Step 1: Preparation of tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(trifluoromethyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0730] Compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4-methylpiperidin-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) were added to DMF (5 mL), and heated to 100° C. and stirred for 3 hours under nitrogen protection. 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 obtain the target compound (8 mg, yield was 9.1%) as a white solid.

[0731] EM (calculated): 549.2; MS (ESI) m / z (M+H) + :550.2

[0732] Step 2: Preparation of 2-(4-amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(trifluoromethyl)quinazolin-4-amine hydrochloride

[0733] The compound tert-butyl (1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(trifluoromethyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate (8 mg, 0.01 mmol) was added to a single-mouth bottle, cooled in an ice-water bath, and then 4M HCl / 1,4-dioxane (2 mL) was added thereto, and the temperature was maintained and stirred for 1 hour. TLC spot plate detection showed that the raw material had reacted completely, and 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 the target compound (5 mg, yield was 76.9%) was obtained after drying as a white solid.

[0734] EM (calculated): 449.2; MS (ESI) m / z (M+H) + :450.2

[0735] 1H NMR (400MHz, DMSO-d6) δ0.78-0.81 (2H, m), 0.94-0.98 (2H, m), 1.37 (3H, s), 1.64-1.68 (4H, m), 1.87-1.93 (1H, m), 3.36-3.38 ( 2H, m), 4.21-4.24 (2H, m), 7.46 (1H, d, J = 8.8Hz), 7.80 (1H, d, J = 8.8Hz), 8.19 (3H, s), 8.75 (1H, s), 10.23 (1H, s), 12.43 (1H, s).

[0736] Experimental Example 1 Inhibitory effect of compounds on kinase activity

[0737] 1: Test materials:

[0738] 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)

[0739] 2: Experimental methods:

[0740] 2.1 Compound preparation

[0741] The compound was received by the administrator, and the powder was dissolved in 100% DMSO to prepare a 10 mM stock solution and stored in a nitrogen cabinet away from light.

[0742] 2.2 Kinase reaction process

[0743] (1) Prepare 1× Kinase buffer.

[0744] (2) Preparation of compound concentration gradient: The test compound was tested at a concentration of 1000 nM. It was diluted to a 100% DMSO solution with a 100-fold final concentration in the 384 source plate. The compound was diluted 3-fold with Precision, with 10 concentrations. 250 nL of the compound with a 100-fold final concentration was transferred to the destination 384-well plate using a dispenser Echo 550.

[0745] (3) Use 1× Kinase buffer to prepare a kinase solution with a final concentration of 2.5 times.

[0746] (4) Add 10 μL of kinase solution at 2.5 times the final concentration to the compound wells and positive control wells respectively; add 10 μL of 1× Kinase buffer to the negative control wells.

[0747] (5) Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.

[0748] (6) Use 1× Kinase buffer to prepare a mixed solution of ATP and Kinase substrate 22 at 5 / 3 times the final concentration.

[0749] (7) Add 15 μL of a mixed solution of ATP and substrate at 5 / 3 times the final concentration to start the reaction.

[0750] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 60 minutes.

[0751] (9) Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix.

[0752] (10) Read the conversion rate using Caliper EZ Reader.

[0753] 2.3 Data Analysis

[0754] Calculation formula

[0755] Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the mean of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; Conversion%_max: the mean of the positive control well ratio, representing the conversion rate reading of the wells without compound inhibition.

[0756] Fitting dose-effect curve:

[0757] The log value of the concentration was used as the X-axis, and the percentage inhibition rate was used as the Y-axis. The log (inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC50 value of each compound on the enzyme activity. The calculation formula is:

[0758] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0759] The test results are shown in Table 12:

[0760] Table 12 Inhibitory activity of compounds against PAK4 and PAK1 kinases (IC 50 )

[0761]

[0762]

[0763]

[0764] ND: means not tested;

[0765] Test Example 2: Stability test of liver microsomes of test compounds

[0766] 1: Materials and methods

[0767] Buffer:

[0768] (1) 100 mM potassium phosphate buffer, pH 7.4; (2) 10 mM MgCl2.

[0769] Preparation of compound solution:

[0770] (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 it with 495 μL of methanol to obtain a compound concentration of 100 μM (99% MeOH).

[0771] (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).

[0772] Components of the NADPH (prototype coenzyme II) regeneration system (the final concentration of isocitrate dehydrogenase in the culture medium is 1.0 unit / mL):

[0773] β-Nicotinamide adenine dinucleotide phosphate, Supplier: Chem-impex international, Catalog Number: N00616

[0774] Preparation of liver microsome solution (final concentration is 0.5 mg protein / mL), liver microsome types are shown in Table 13:

[0775] Table 13

[0776]

[0777] Stop Solution:

[0778] An ice-cold solution in acetonitrile containing 100 ng / mL tolbutamide and 100 ng / mL labetalol as internal standards.

[0779] Steps:

[0780] (1) Except for the blank matrix well, 10 μL of the working solution of the test or control drug was added to each well (T0, T5, T10, T20, T30, T60 and NCF60).

[0781] (2) 80 μL / well of the microsome solution was dispensed onto each plate using Apricot, and the mixture of the microsome solution and the compound was incubated at 37°C for about 10 minutes.

[0782] (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.

[0783] Table 14

[0784]

[0785] (4) After preheating, 10 μL / well of NADPH regeneration system was dispensed onto each plate using Apricot to start the reaction.

[0786] Table 15 Final concentration of each component in the incubation medium

[0787]

[0788] (5) Incubate at 37°C and start timer 2. The data are shown in Table 16.

[0789] Table 16

[0790]

[0791] (6) Add 4°C precooled stop solution (containing internal standards 100 ng / mL tolbutamide and 100 ng / mL isothiocyanate) to each well to terminate the reaction.

[0792] (7) The sample plate is then shaken on a shaker for about 10 minutes.

[0793] (8) Centrifuge the sample at 4000 rpm for 20 min at 4°C.

[0794] (9) Take another 96-well plate and add 300 μL of HPLC-grade water to each well. Take 100 μL of the supernatant obtained by centrifugation and add it to the corresponding well. Mix the two wells and use them for LC / MS / MS detection.

[0795] Data Analysis:

[0796] Calculation of t 1 / 2 and Clint(mic) values ​​based on first-order elimination kinetics

[0797] The first-order elimination kinetic equation is:

[0798]

[0799] when

[0800]

[0801]

[0802]

[0803] The results of liver microsome stability test of some compounds are shown in Table 17:

[0804] Table 17

[0805]

[0806]

[0807] Experimental Example 3: PK test of the test compound in rats

[0808] SD rats, male (purchased from Chengdu Dashuo Experimental 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, and the administration solution was prepared after vortexing for 2 minutes and ultrasonication for 5 minutes. The animals were fasted for 10-14 hours before oral administration, and the feeding was resumed 4 hours after administration. After oral gavage 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 and 24h after administration. Three whole blood samples were collected at each time point, with a collection volume of about 0.2mL, and anticoagulated with sodium heparin. After blood samples were collected, they were immediately placed on ice 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 refrigerator before analysis.

[0809] The pharmacokinetic test results of some compounds of the present invention are shown in Table 18 below:

[0810] Table 18 Pharmacokinetic test results of some compounds of the present invention

[0811]

[0812]

[0813] *: The rat PK data of CZh-226 are from literature reports;

[0814] #: The rat PK data of CZh-226 were derived from head-to-head assay data;

[0815] From the above drugability research data, it can be seen that some compounds of the present invention have better activity as PAK4 protein kinase inhibitors than the reported CZh-226 and PF-3758309, and the compounds still maintain a high selectivity for PAK1 / PAK4; more importantly, according to the rat PK pharmacokinetic test results of some compounds, compared with compounds CZh-226 and PF-3758309, their pharmacokinetic aspects have very obvious advantages. In summary, these compounds are used as PAK4 protein kinase inhibitors and have broad application prospects in the fight against malignant tumors, neurodegenerative diseases or immune system diseases.

[0816] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound as a PAK4 inhibitor, characterized in that It has the structure shown in Formula VI or its salt: wherein X is selected from a single bond, a C2-C10 alkynyl group; E is selected from a single bond, acylamino, carbonyl, sulfone, sulfoxide, substituted or unsubstituted C1-C3 alkyl or heteroalkyl; 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; R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, C1-C5 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; P is selected from NR 13 , CR 14 R 15 ; R 12 , R 13 , R 14 , R 15 independently selected from hydrogen, amino, halogen, amide, sulfonyl, sulfonic acid, hydroxyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C12 aryl, C5-C12 heteroaryl; the above C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C12 aryl, C5-C12 heteroaryl may be optionally substituted with one or more halogen, hydroxyl, nitro, cyano, thiol, sulfonic acid, amino, C1-C6 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl; n is 0; n1 is selected from 0 to 5.

2. A compound as a PAK4 inhibitor, characterized in that It has the structure shown in Formula VII or its salt: in, R 16 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C2-C10 alkynyl, C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl or heterocycloalkyl; R 17 R is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, ester, nitro, amide, mercapto, sulfonyl, C2-C6 alkylphosphino, C2-C6 alkylsulfone, C2-C6 alkylsulfoxide, borate, boric acid, substituted or unsubstituted C1-C6 heteroalkyl containing at least one atom of N, O, and S, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 substituted amino, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one atom of N, O, and S, substituted or unsubstituted C5-C10 aryl or heteroaryl, substituted or unsubstituted C2-C10 alkynyl or alkenyl, or two identical or different R 17 Together with the connected phenyl group, it forms a substituted or unsubstituted five- to twelve-membered cyclic structure group containing at least one atom of C, N, O, or S, wherein the substituted groups are independently selected from deuterium, halogen, hydroxyl, cyano, amino, thiol, nitro, carboxyl, hydroxyamino, C1-C3 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl, five- or six-membered aryl or heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, and phosphoryl; n2 is selected from 0, 1, 2, 3, 4, 5.

3. The compound according to claim 2, characterized in that The R 16 is selected from fluorine, chlorine, bromine, C2-C10 alkynyl; The R 17 Selected from methoxy, trifluoromethoxy, difluoromethoxy, methoxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethoxy, fluorine, chlorine, bromine, cyano, hydroxyl, methylsulfone, methylsulfoxide, dimethylphosphine, or two identical or different R17 and the connected phenyl group form a five-membered to six-membered cyclic structure group containing at least one C, N, O, S atom substituted or unsubstituted, wherein the substituted groups are independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, thiol, nitro, C1-C3 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl, five-membered or six-membered aryl or heteroaryl.

4. A compound as a PAK4 inhibitor, characterized in that Having the structure shown in formula V or its salt: wherein X is selected from a single bond, a C2-C10 alkynyl group; E is selected from a single bond, acylamino, carbonyl, sulfone, sulfoxide, substituted or unsubstituted C1-C3 alkyl or heteroalkyl; 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; R5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, hydroxyl, halogen, cyano, amino, ester, nitro, thiol, substituted or unsubstituted amide; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, C1-C5 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; The K is a C6-C12 N-containing spirocyclic group or a C6-C12 N-containing fused ring group; n is 0.

5. The compound according to claim 4, characterized in that The K has the following groups:

6. A compound as a PAK4 inhibitor, characterized in that Has any of the following structures:

7. A PAK4 inhibitor, comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant.

8. Use of the compound according to any one of claims 1 to 6 or the PAK4 inhibitor according to claim 7 in the preparation of a PAK4 inhibitor.

9. The use according to claim 8, characterized in that: The PAK4 inhibitor is suitable for cancer, neurodegenerative disease or immune system disease related to the expression or activity of PAK4 kinase.

10. The use according to claim 9, characterized in that: The cancers are mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, hepatocellular carcinoma, gastric cancer, glioma, endometrial cancer, melanoma, bladder cancer, biliary tract cancer, kidney cancer, lymphoma, hairy cell cancer, nasopharyngeal cancer, pharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, testicular cancer, genitourinary tract cancer, lung cancer, small cell cancer, bone cancer, colon cancer, adenocarcinoma, follicular carcinoma, Hodgkin's leukemia, bronchial cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and primary macroglobulinemia.

11. The use according to claim 10, characterized in that: The lung cancer is non-small cell lung cancer.

12. The use according to claim 10, characterized in that: The adenocarcinoma is breast cancer, prostate cancer, lung adenocarcinoma, pancreatic cancer, and thyroid cancer.

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