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WO2022033420A1 - Composé utilisé en tant qu'inhibiteur de kinase pak4, son procédé de préparation et son application - Google Patents

Composé utilisé en tant qu'inhibiteur de kinase pak4, son procédé de préparation et son application Download PDF

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Publication number
WO2022033420A1
WO2022033420A1 PCT/CN2021/111472 CN2021111472W WO2022033420A1 WO 2022033420 A1 WO2022033420 A1 WO 2022033420A1 CN 2021111472 W CN2021111472 W CN 2021111472W WO 2022033420 A1 WO2022033420 A1 WO 2022033420A1
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substituted
unsubstituted
group
alkyl
amino
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Chinese (zh)
Inventor
杨茂
刘冠锋
李红波
刘龙飞
原晨光
李英富
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Chengdu Hyperway Pharmaceuticals Co Ltd
Shenzhen Hyperway Pharmaceuticals Co Ltd
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Chengdu Hyperway Pharmaceuticals Co Ltd
Shenzhen Hyperway Pharmaceuticals Co Ltd
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Priority claimed from CN202011631465.9A external-priority patent/CN114075175A/zh
Application filed by Chengdu Hyperway Pharmaceuticals Co Ltd, Shenzhen Hyperway Pharmaceuticals Co Ltd filed Critical Chengdu Hyperway Pharmaceuticals Co Ltd
Priority to CN202180036486.2A priority Critical patent/CN115943144B/zh
Priority to TW110148517A priority patent/TWI896831B/zh
Publication of WO2022033420A1 publication Critical patent/WO2022033420A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the invention relates to the technical field of drug synthesis, in particular to a compound as a PAK4 kinase inhibitor and a preparation method and application thereof.
  • P21-activated protein kinase (PAK), as a class of conserved serine/threonine protein kinases, is the effector protein of the small GTPase CDC42 and Rac1 in the Rho family, mediating the transduction of its downstream signaling pathways . According to their sequence homology and activation mode, they can be divided into two categories: class I PAKs (PAK1, 2, 3) and class II PAKs (PAK4, 5, 6). As important downstream counterparts of Pho family GTPases Rac and Cdc42, PAKs play important roles in cell proliferation, cytoskeleton reorganization, and cell motility.
  • PAKs especially its representative members PAK1 and PAK4
  • PAK1 and PAK4 have the phenomenon of gene amplification, gene mutation, expression level and activity up-regulation in various tumor cells and tissues, which is closely related to the occurrence and development of tumors.
  • PAKs inhibitors has received extensive attention from medicinal chemists in the past decade. Wang C et al.
  • PAK4 inhibitors is one of the effective strategies for the treatment of various tumors.
  • PAK4 inhibitors As a potential drug development target, the development of PAK4 inhibitors provides new ideas for the treatment of related cancers. Up to now, the number of PAK4 inhibitors is very small, and the activity of most inhibitors is not ideal.
  • the small molecule inhibitors that have entered the clinical stage include KPT-9274 jointly developed by Antengene and Karyopharm Therapeutics and PF-3758309 developed by Pfizer.
  • PF-3758309 is a PAKs inhibitor with a pyrrolopyrazole structure reported by Pfizer in 2009. It is the first PAKs inhibitor to enter clinical research. Its PAK4 IC50 is 19nm, but this compound has stronger inhibitory ability to PAK1 , up to 14nm, with serious security risks.
  • ATG-019(KPT-9274) is a world-first oral dual-target inhibitor of p21-activated kinase 4 (PAK4) and nicotinic phosphoribosyltransferase (NAMPT).
  • PAK4 p21-activated kinase 4
  • NAMPT nicotinic phosphoribosyltransferase
  • Hao C et al. designed and synthesized a series of aminoquinazoline PAK4 inhibitors, and obtained a highly active and highly selective PAK4 inhibitor (CZh-226). It has a Ki value of 9 nM for PAK4, and exhibits excellent selectivity against a variety of kinases, among which the Ki value for PAK1 is 3112 nM, a 346-fold difference in selectivity.
  • the compound has poor drugability and extremely low bioavailability (1.92%), which needs to be further optimized; at the same time, its PAK4 inhibitory activity also has room for further improvement.
  • the technical problem to be solved by the present invention is to provide a compound as a PAK4 kinase inhibitor and its preparation method and application.
  • the prepared compound has higher inhibitory activity and selectivity for PAK4 kinase, especially PAK4/1 selectivity, and better bioavailability.
  • the present invention provides a compound as a PAK4 inhibitor, having the structure shown in formula I or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts:
  • B 1 , B 2 , B 3 , B 4 , B 5 , and B 6 are independently selected from CR 3 or N, respectively.
  • Ring A is selected from substituted or unsubstituted C5-C9 aryl or heteroaryl.
  • ring A is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, further preferably substituted or unsubstituted phenyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, pyrazine group, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl or pyridyl.
  • the substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or Unsubstituted alkoxy, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkylphosphorus, alkylsulfone, alkylidene sulfone group.
  • the substituted groups are independently selected from five- or six-membered aryl or heteroaryl substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or Unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphorus Acyl group, alkyl oxyphosphorus group, alkyl sulfone group, alkyl sulfoxide group.
  • Q is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkenyl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, halogen, hydroxy, Cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronic ester, boronic acid .
  • Q is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted monocyclic, bicyclic or Tricyclic aryl or heteroaryl, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyloxyphosphorus, alkylsulfone, Alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • the substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or Unsubstituted alkoxy, substituted or unsubstituted aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl , alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • the substituted groups are independently selected from five- or six-membered aryl or heteroaryl substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or Unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C6-C12 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro group, mercapto group, substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, alkyl sulfonyl group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • L is selected from single bond, O, S, NH or alkylene.
  • the alkylene group is a C1-C10 alkylene group.
  • the alkyl group is methylene or ethylene.
  • L when L is a single bond, it means that V is directly connected to the parent ring.
  • V is selected from substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl or heteroalkyl, Substituted or unsubstituted cycloalkyl or heterocycloalkyl.
  • V is selected from substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkenyl Unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl.
  • the substituted groups are independently selected from aryl or heteroaryl substituted by any group, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, alkoxy group, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boron Acid group, boronic acid group.
  • the substituted groups are independently selected from five- or six-membered aryl or heteroaryl substituted by any group, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or Unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C1-C10 alkoxy, halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonic Acyl group, phosphoryl group, alkyl phosphoryl group, alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • R 1 is carbonyl, thiocarbonyl, methylene or a single bond.
  • R 1 is a single bond, which means that R 2 is directly connected to the parent ring.
  • R 2 and R 3 are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroalkyl Aryl, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronic acid Ester group, boronic acid group.
  • R 2 and R 3 are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl , substituted or unsubstituted five- or six-membered aryl or heteroaryl, hydroxyl, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphorous group, alkyl sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, hetero Aryl, ester, acyl, amido, sulfonyl, phosphoryl.
  • the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C10 alkyl, C3-C10 cycloalkyl, C1- C10 heteroalkyl, C2-C10 heterocycloalkyl, six-membered aryl, five- or six-membered heteroaryl, ester group, acyl group, amide group, sulfonyl group, phosphoryl group.
  • the above-mentioned bicyclic or tricyclic compounds include, but are not limited to, spirocyclic, bridged, and fused ring compounds.
  • the above-mentioned cycloalkyl or heterocycloalkyl includes, but is not limited to, monocyclic, spirocyclic, bridged, fused cycloalkyl or heterocycloalkyl.
  • the compound has the structure shown in formula II or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof.
  • a 1 is selected from CR 6 or N.
  • R 6 is selected from hydrogen, halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.
  • R 6 is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted containing at least C1-C3 heteroalkyl with one N or O atom, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one N or O atom.
  • R 6 is selected from hydrogen, halogen, amino, methyl, ethyl, methoxy, cyano, trifluoromethyl, isopropyl or cyclopropyl.
  • R 4 is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl base.
  • R 4 is selected from substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C6 aryl or heteroaryl.
  • R 4 is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C4-C6 heterocycloalkyl containing at least one N or O atom.
  • the substituted groups are independently selected from halogen, cyano, amino, hydroxyl, substituted or unsubstituted amide, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3- C6 cycloalkyl or heterocycloalkyl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkane Oxygen, C3-C6 cycloalkyl.
  • the substituent groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxyethyl or Cyclopropyl.
  • X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl.
  • X is selected from a single bond, a substituted or unsubstituted phenyl group, a pyridyl group, an alkynyl group or an alkenyl group.
  • X is selected from a single bond and means that E is directly connected to the parent ring.
  • E is selected from single bond, ester group, amido group, ether group, carbonyl group, sulfone group, sulfoxide group, thioamide group, urea group, thiourea group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl group , substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.
  • E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.
  • E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethyl Oxy, propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom .
  • the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkane base.
  • the substituents are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom.
  • E selected from a single bond means that R 5 is directly connected to X.
  • R 5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or Heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • the above-mentioned alkoxy group is preferably a substituted or unsubstituted C1-C10 alkoxy group.
  • the above-mentioned aryloxy group is preferably a substituted or unsubstituted C5-C10 aryloxy group.
  • the R 5 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C1-C10 cycloalkyl or heterocycloalkyl C5-C6 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, Nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl phosphoryl, boronic ester, boronic acid.
  • the R 5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5 -C6 aryl or heteroaryl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro group, mercapto group, substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, boronic acid ester group, boronic acid group.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3 ⁇ C6cycloalkyl, substituted or unsubstituted C3-C6heterocycloalkyl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, Methyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl, tetrahydropyrrolyl.
  • W is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, Hydroxyl, cyano, substituted or unsubstituted amino, ester, nitro, mercapto, amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronate , boronic acid group.
  • W is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted five-membered or six-membered aryl or heteroaryl.
  • W is selected from five-membered or six-membered heterocycloalkyl groups containing any one or more of N, O, and S.
  • the heterocycloalkyl group includes, but is not limited to, monocyclic, spirocyclic, bridged, and fused ring heterocycloalkyl.
  • the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, hetero Aryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or heteroaryl.
  • the aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.
  • the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1- C3 heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or hetero Aryl.
  • the aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.
  • the substituted group is selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, methyl, ethyl, propyl, isopropyl, cyclopropyl.
  • n is selected from 0 or 1.
  • W is directly connected to the heteroaromatic ring containing A 1 atom.
  • the compound has the structure shown in formula III, or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Pharmaceutically acceptable hydrates, solvates or salts:
  • R 7 is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O atom.
  • the R 7 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine radical, furyl, thienyl, pyrrolyl, five- or six-membered heterocycloalkyl containing at least one N and/or O atom.
  • R 7 has any of the following structures:
  • the curved line indicates the location of the connection.
  • Any one or more C atoms in the above structures may be optionally substituted with one or more substituents.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkane oxy, C3-C6 cycloalkyl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amido, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl.
  • J is selected from single bond, amido, carbonyl, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.
  • J is selected from a single bond, an amido group, a carbonyl group, a methylene group, and a methyleneoxy group.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkane base.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl Oxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridyl.
  • J when J is a single bond, it means that R 8 is directly connected to an alkynyl group.
  • R 8 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or Heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • R 8 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5 -C10 aryl or heteroaryl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto , substituted or unsubstituted amido, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyl oxyphosphorus, substituted or unsubstituted C1-C10 alkyl sulfone, substituted or unsubstituted C1- C10 alkyl sulfoxide group, boronic acid ester group, bor
  • R 8 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5- C10 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, Substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, substituted or unsubstituted C1-C6 alkyl oxyphosphoryl group, substituted or unsubstituted C1-C6 alkyl sulfonyl group, substituted or unsubstituted C1-C6 group
  • R 8 is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, phenoxy, five- to seven-membered heterocycloalkyl containing at least one N and/or O, five- or six-membered unsaturated cycloalkyl , pyridyl, amido, cyano, hydroxyl, halogen, amino, ester, nitro, mercapto, sulfonyl, phosphoryl, substituted or unsubstituted C1-C3 alkyl oxyphosphorus, substituted or unsubstituted C1-C3 alkyl sulfone group, substituted or unsubstituted C1-C3
  • the five-membered or six-membered unsaturated cycloalkyl group is a cyclopentenyl group or a cyclohexenyl group.
  • the above-mentioned cycloalkyl or heterocycloalkyl includes, but is not limited to, monocyclic, spirocyclic, bridged, fused-ring cycloalkyl or heterocycloalkyl.
  • 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.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkanes containing at least one N and/or O base.
  • the five-membered-seven-membered heterocycloalkyl containing at least one N and/or O has any of the following structures:
  • Curved lines indicate connection locations.
  • Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the above substituents.
  • Y is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted five- or six-membered aryl or hetero Aryl.
  • Y is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl containing at least one N and/or O, phenyl, and pyridyl.
  • Y is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl groups containing at least one N atom, and the N atom is connected to the adjacent carbonyl group to form an amide group.
  • the heterocycloalkyl group includes but is not limited to monocyclic, bridged ring, spirocyclic and fused ring heterocycloalkyl.
  • the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, aryl or heteroaryl.
  • the aryl or heteroaryl is preferably a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, Methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkyl containing at least one N and/or O , substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.
  • Y is selected from any of the following structures:
  • Curved lines indicate connection locations.
  • Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the aforementioned substituents.
  • n is selected from 0 or 1. Further, n is selected from zero.
  • the compound has the structure shown in formula IV, or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , a pharmaceutically acceptable hydrate, solvate or salt:
  • n 0, 1, 2, 3 or 4.
  • each substituent on the benzene ring may be the same or different.
  • R 9 is selected from substituted or unsubstituted five- or six-membered aryl or heteroaryl, substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O atom.
  • R 9 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furan group, thienyl, pyrrolyl, five- or six-membered heterocycloalkyl containing at least one N and/or O.
  • R 9 has any of the following structures:
  • the curved line indicates the location of the connection.
  • Any one or more C atoms in the above structures may be optionally substituted with one or more substituents.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amide, substituted or unsubstituted C1-C3 alkyl or alkane Oxygen, C3-C6 cycloalkyl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted amido, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl.
  • G is selected from single bond, amido group, ether group, carbonyl group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.
  • G is selected from a single bond, an amido group, an ether group, a carbonyl group, a methylene group, and a difluoromethylene group.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkane base.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl Oxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridyl.
  • G when G is selected from a single bond, it means that R 10 is directly connected to the benzene ring.
  • R 10 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or Heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group.
  • R 10 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5 -C10 aryl or heteroaryl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto , substituted or unsubstituted amido, sulfonyl, phosphoryl, substituted or unsubstituted C1-C10 alkyl oxyphosphorus, substituted or unsubstituted C1-C10 alkyl sulfone, substituted or unsubstituted C1- C10 alkyl sulfoxide group, boronic acid ester group, bor
  • R 10 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5- C10 aryl or heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C10 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, Substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, substituted or unsubstituted C1-C6 alkyl oxyphosphoryl group, substituted or unsubstituted C1-C6 alkyl sulfonyl group, substituted or unsubstituted C1-C6 group
  • R 10 is selected from hydrogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, five- to seven-membered heterocycloalkyl containing at least one N and/or O, five- or six-membered unsaturated cycloalkyl, pyridyl, Amido, cyano, hydroxyl, halogen, amino, ester, nitro, mercapto, sulfonyl, phosphoryl, substituted or unsubstituted C1-C3 alkyl oxyphosphorus, substituted or unsubstituted C1-C3 Alkyl sulfone group, substituted or unsubstituted C1-C3 alkyl
  • the five-membered or six-membered unsaturated cycloalkyl group is a cyclopentenyl group or a cyclohexenyl group.
  • the above-mentioned cycloalkyl or heterocycloalkyl includes, but is not limited to, monocyclic, spirocyclic, bridged, fused-ring cycloalkyl or heterocycloalkyl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkanes containing at least one N and/or O base.
  • the five-membered-seven-membered heterocycloalkyl containing at least one N and/or O has any of the following structures:
  • the curved line indicates the location of the connection.
  • Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the above substituents.
  • Z is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted five- or six-membered aryl or heteroaryl.
  • Z is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl containing at least one N and/or O, phenyl, and pyridyl.
  • Z is selected from substituted or unsubstituted five- or six-membered heterocycloalkyl groups containing at least one N atom, and the N atom is connected to the adjacent carbonyl group to form an amide group.
  • the heterocycloalkyl group includes but is not limited to monocyclic, bridged ring, spirocyclic and fused ring heterocycloalkyl.
  • the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, five- or six-membered aryl, five- or six-membered heteroaryl, ester, acyl, carbonyl, amido, sulfonyl, phosphoryl, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.
  • the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, Methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, five- or six-membered heterocycloalkyl containing at least one N and/or O , substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl.
  • Z is selected from any of the following structures:
  • Curved lines indicate connection locations.
  • Any one or more C atoms or N atoms in the above structures may be optionally substituted with one or more of the aforementioned substituents.
  • R 11 is independently selected from hydrogen, halogen, hydroxy, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Unsubstituted heterocycloalkyl.
  • R 11 is independently selected from fluorine, chlorine, bromine, cyano, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 Cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl.
  • n is selected from 0 or 1. Further, n is selected from zero.
  • the cycloalkyl group includes saturated or unsaturated cycloalkyl groups.
  • the heterocycloalkyl group includes saturated or unsaturated heterocycloalkyl groups.
  • the cycloalkyl group includes monocyclic ring, bridged ring, spirocyclic ring and fused ring cycloalkyl group.
  • the heterocycloalkyl groups include monocyclic, bridged, spiro and fused ring heterocycloalkyl groups.
  • the compound has the structure represented by formula V or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Pharmaceutically acceptable hydrates, solvates or salts:
  • X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl;
  • X is selected from a single bond, a substituted or unsubstituted phenyl group, a pyridyl group, an alkynyl group or an alkenyl group.
  • X is selected from a single bond and means that E is directly connected to the parent ring.
  • E is selected from single bond, ester group, amido group, ether group, carbonyl group, sulfone group, sulfoxide group, thioamide group, urea group, thiourea group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl group , substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1 -C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl.
  • E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl.
  • E is selected from single bond, ester group, amido group, ether group, carbonyl group, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethyl Oxy, propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom .
  • the substituents are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, three- to six-membered heterocycloalkyl groups containing at least one N or O atom.
  • E selected from single bond means that R is directly connected with X;
  • R 5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or Heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 Alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted
  • the above-mentioned alkoxy group is preferably a substituted or unsubstituted C1-C10 alkoxy group.
  • the above-mentioned aryloxy group is preferably a substituted or unsubstituted C5-C10 aryloxy group.
  • R 5 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5- C6 aryl or heteroaryl, hydroxyl, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amide, sulfonyl, phosphoryl, alkyl oxyphosphorus, boronate, boronic acid base.
  • the R 5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl or heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5 -C6 aryl or heteroaryl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C5-C6 aryloxy, hydroxyl, halogen, cyano, amino, ester, nitro group, mercapto group, substituted or unsubstituted amide group, sulfonyl group, phosphoryl group, alkyl phosphoryl group, boronic acid ester group, boronic acid group.
  • substituted groups are independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methyl , deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl, tetrahydropyrrolyl, piperazinyl, N-methyl Piperazinyl, tetrahydropyridyl, morpholinyl.
  • K is selected from substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or heteroaryl, Hydroxyl, cyano, substituted or unsubstituted amino, ester, nitro, mercapto, amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide, boronate , boronic acid group; wherein the substituted groups are independently selected from halogen, hydroxyl, cyano, amino, mercapto, nitro, carboxyl, hydroxylamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl , ester group, acyl group, carbonyl group, amide group, sulfonyl group, phospho
  • K is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl containing at least one N or O or S, substituted or unsubstituted C3-C10 cycloalkyl, Substituted or unsubstituted C3-C10 heterocycloalkyl containing at least one N or O or S, substituted or unsubstituted five- or six-membered aryl or heteroaryl; wherein the substituted groups are independently selected from Amino, halogen, hydroxyl, cyano, mercapto, nitro, carboxyl, amido, ester, carbonyl, sulfonyl, phosphoryl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 heteroalkyl, C3-C6 heterocycloalkyl, substituted or unsubstituted monocyclic, bicyclic or
  • 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.
  • the N atom is directly connected to the parent ring.
  • the K has the following groups:
  • any one or more carbon atoms or nitrogen atoms of the above-mentioned groups can be connected to one or more substituents;
  • the substituents are preferably amino, halogen, amido, sulfonyl, sulfonic acid, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 Heterocycloalkyl, amino, C6-C12 aryl, C5-C12 heteroaryl; the above-mentioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, Amine group, C6-C12 aryl group, C5-C12 heteroaryl group can be optionally substituted by one or more halogen, hydroxyl, nitro, cyano, mercapto, sulfonic acid, amino.
  • the substituent is selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, Isopropoxy, amido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl.
  • the above substituents can be further substituted by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, sulfonic acid groups, or any one or more carbon atoms can be substituted by oxo , Thio.
  • n is selected from 0 or 1; further, n is selected from 0.
  • the compound has the structure shown in formula VI or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , a pharmaceutically acceptable hydrate, solvate or salt:
  • X is selected from single bond, substituted or unsubstituted C5-C6 aryl or heteroaryl, alkynyl, alkenyl.
  • E is selected from single bond, ester group, amido group, ether group, carbonyl group, sulfone group, sulfoxide group, thioamide group, urea group, thiourea group, substituted or unsubstituted C1-C3 alkyl or heteroalkyl group , substituted or unsubstituted C3-C6 cycloalkyl or heterocycloalkyl; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, cyano, amino, hydroxyl, C1-C3 alkyl, C1 -C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl.
  • R 5 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl or heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-C10 aryl or Heteroaryl, alkoxy, aryloxy, hydroxy, halogen, cyano, amino, ester, nitro, mercapto, substituted or unsubstituted amido, sulfonyl, phosphoryl, alkyl phosphoryl, alkane sulfone group, alkyl sulfoxide group, boronic acid ester group, boronic acid group; wherein the substituted groups are independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino, substituted or unsubstituted C1-C5 Alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted
  • P is selected from NR 13 , CR 14 R 15 ;
  • R 12 , R 13 , R 14 , R 15 are independently selected from hydrogen, amino, halogen, amido, sulfonyl, sulfonic acid, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl , C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl; the above-mentioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 ring Alkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl can be optionally replaced by one or more halogen, hydroxyl, nitro, cyano, mercapto, sulfonic acid , amino, C1-C6 alkyl or heteroalkyl, C3-C6 cycloalky
  • R 13 , R 14 and R 15 are independently preferably amino, halogen, amide, sulfonyl, sulfonic acid, hydroxy, substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 ring Alkyl, C3-C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl; the above-mentioned C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3- C6 heterocycloalkyl, amine, C6-C12 aryl, C5-C12 heteroaryl can be optionally substituted by one or more halogen, hydroxyl, nitro, cyano, mercapto, sulfonic acid, amino.
  • the substituent is selected from amino, methylamino, pyridyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, Isopropoxy, amido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl.
  • the above substituents can be further substituted by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, sulfonic acid groups, or any one or more carbon atoms can be substituted by oxo , Thio.
  • Said R 12 is further preferably an amino group.
  • R 12 and P atom form a spiro ring structure
  • R 12 forms a condensed ring structure with the P atom and the carbon atom adjacent to the P atom;
  • n is selected from 0 or 1; further, n is selected from 0.
  • the N atom of the N-containing heterocycle is directly attached to the pyrimidine ring.
  • n1 is selected from 0 to 5; specifically, it can be selected from 0, 1, 2, 3, 4 or 5.
  • the compound has the structure shown in formula VII or the form of tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Pharmaceutically acceptable hydrates, solvates or salts:
  • R 16 is selected from hydrogen, fluorine, chlorine, bromine, iodine, alkynyl, C1-C3 alkyl or alkoxy, C3-C6 cycloalkyl or heterocycloalkyl; further R 16 is selected from fluorine, chlorine , bromine, alkynyl;
  • R 17 is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, ester, nitro, amide, mercapto, sulfonyl, alkylphosphorus, alkylsulfone, alkylsulfoxide, boronic acid Ester group, boronic acid group, substituted or unsubstituted heteroalkyl group containing at least one of N, O, S atoms C1-C6, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group , substituted or unsubstituted C1-C6 substituted amino, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl containing at least one N, O, S atom, substituted Or unsubstituted aryl or heteroaryl, substituted or unsubstituted alky
  • the five-membered to twelve-membered ring structure group can be a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and the ring structure and the connected phenyl group together form the following group but not limited to the following groups: substituted or unsubstituted piperonyl, substituted or unsubstituted quinolyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzene furanyl, substituted or unsubstituted benzopyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted benzocrownyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted benzene morpholinyl, substituted or unsubstituted
  • R 17 is selected from methoxy, trifluoromethoxy, difluoromethoxy, methoxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethoxy, fluorine, chlorine, Bromine, cyano, hydroxyl, methyl sulfone, methyl sulfoxide, dimethyl oxophosphine, or two identical or different R17 and the connected phenyl group contain at least one of C, N, O, S atom substituted or unsubstituted five- to six-membered cyclic structural group, wherein the substituted groups are independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, mercapto, nitro, C1 -C3 alkyl or heteroalkyl, C3-C6 cycloalkyl or heterocycloalkyl, five- or six-membered aryl or heteroaryl;
  • the above five-membered to six-membered cyclic structural group may be a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group.
  • This ring structure and the attached phenyl group together form the following groups but are not limited to the following groups: substituted or unsubstituted piperonyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted quinoxalinyl, Substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzopyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted benzomorpholinyl, substituted or unsubstituted benzotetra Hydroquinoxaline, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzodihydrofuran, substituted or
  • n2 is selected from 0, 1, 2, 3, 4, 5.
  • the amine group or substituted amine group in the present invention refers to a group formed by replacing one or two hydrogen atoms of an amino group with a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C3-C6 cycloalkyl group.
  • the amine group or substituted amine group is selected from methylamine, ethylamine, propylamine, isopropylamine or butylamine.
  • the compound has any of the following structures:
  • the present invention provides a PAK4 inhibitor, comprising the above compound and a pharmaceutically acceptable adjuvant.
  • the present invention does not specifically limit the type of the adjuvant, and it can be an adjuvant well known to those skilled in the art.
  • the compound in the present invention, can be administered alone or in combination with other drugs.
  • the present invention provides the use of the above compounds or the above PAK4 inhibitors in the preparation of PAK4 inhibitors.
  • the PAK4 inhibitor is suitable for cancer, neurodegenerative disease or immune system disease related to the expression or activity of PAK4 kinase.
  • the cancer includes breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, gastric cancer, glioma, uterus Endometrial cancer, melanoma, kidney cancer, bladder cancer, melanoma, bladder cancer, biliary tract cancer, kidney cancer, pancreatic cancer, lymphoma, hair cell cancer, nasopharyngeal cancer, pharyngeal cancer, colorectal cancer, rectal cancer, brain and Central nervous system cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lung cancer, non-small cell lung cancer, small cell cancer, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid carcinoma, follicular carcinoma, Hodgkin's leuk
  • the present invention provides a compound as a PAK4 inhibitor, having the structure shown in formula I or its tautomer, meso, racemate, enantiomer, Diastereomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts.
  • the test results show that the compounds prepared by the present invention have high inhibitory activity and selectivity for PAK4 kinase, and meanwhile, the stability of liver microsomes and rat PK are also improved to a certain extent.
  • PAK4 kinase inhibitors the compounds provided by the present invention as PAK4 kinase inhibitors and their preparation methods and applications are described in detail below with reference to the examples.
  • DIEA N,N-diisopropylethylamine
  • LDA lithium diisopropylamide
  • n-BuLi n-butyl lithium
  • DME ethylene glycol dimethyl ether
  • M molar concentration unit mol/L, for example 1M refers to 1mol/L;
  • N equivalent concentration, for example, 1N HCl refers to hydrochloric acid with a concentration of 1mol/L;
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • PE petroleum ether (boiling point 60 ⁇ 90°C);
  • DMSO dimethyl sulfoxide
  • Pd 2 (dba) 3 3,3,6,6-tetramethyl-9-(1,2,3,4-tetrahydroxybutyl)-4,5,7,9-tetrahydro-2H-hetero anthracene-1,8-dione);
  • DPPF 1,1'-bis(diphenylphosphino)ferrocene
  • Pd(PPh 3 ) 2 Cl 2 bistriphenylphosphonium palladium dichloride
  • DCC dicyclohexylcarbodiimide
  • TBAF tetrabutylammonium fluoride
  • 1,4-dioxane 1,4-dioxane
  • LiHMDS lithium hexamethyldisilazide
  • the compound 2-aminobenzamide (10.00 g, 73.48 mmol) was dissolved in H 2 O (250 mL), and sodium bicarbonate (6.17 g, 73.48 mmol) and iodine powder (20.51 g, 80.83 mmol) were sequentially added thereto, Stir at room temperature for 24 hours. TLC spot plate detection, the raw material reaction is completed. The pH of the reaction solution was adjusted to about 7 with sodium bisulfite. After the solid was suction filtered and washed with water, it was dispersed in ethanol and heated to reflux to dissolve. After cooling, it was filtered to obtain the target compound (14.20 g, yield 73.8%) as a lavender solid.
  • Step 2 Preparation of ethyl 2-((2-carbamoyl-4-iodophenyl)amino)-2-oxoacetate
  • Step 3 Preparation of ethyl 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate
  • Step 6 Preparation of (R)-4-(4-chloro-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl
  • Step 7 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-2-methylpiperazine Preparation of -1-Carboxylic acid tert-butyl
  • reaction solution was added to water, extracted three times with EA, the organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated to dryness.
  • Step 1 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazoline-2 Preparation of -carbonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl
  • Step 2 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxychlorohexyl)ethynyl)quinazolin-2-yl ) (3-methylpiperazin-1-yl) ketone.
  • Step 1 (R)-(2-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-4-((5-cyclopropyl-1H-pyrazole Preparation of -3-yl)amino)quinazolin-6-yl)boronic acid
  • Step 2 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline-6- base) boric acid.
  • Step 1 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazoline-2-carbonyl)- Preparation of 2-methylpiperazine-1-carboxylate tert-butyl ester
  • Step 2 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(dimethylphosphoryl)quinazolin-2-yl)(3- Methylpiperazin-1-yl)methanone.
  • Step 1 Preparation of tert-butyl 7-(4-chloro-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate
  • the reaction solution was concentrated, the residue was dispersed with EA, filtered, and the filter cake was washed with EA.
  • the filtrates were combined and washed twice with H 2 O, the organic phase was collected, dried over anhydrous sodium sulfate and concentrated to dryness.
  • Step 2 7-(4-(((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-iodoquinazoline-2-carbonyl)-4,7-diazaspiro[ 2.5] Preparation of tert-butyl octane-4-carboxylate
  • reaction solution was added to water, extracted three times with EA, the organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated to dryness.
  • Step 3 7-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazoline-2-carbonyl)- Preparation of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate
  • Step 4 (4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-hydroxycyclohexyl)ethynyl)quinazolin-2-yl)(4, 7-Diazaspiro[2.5]octan-7-yl)methanone.
  • Step 2 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)thiophen-2-yl)cyclohexan-1-ol preparation
  • Step 3 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl) Preparation of quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester
  • Step 4 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(5-(1-hydroxycyclohexyl)thiophen-2-yl)quinazole Lin-2-yl)(3-methylpiperazin-1-yl)methanone (Example 19) and (R)-(6-(5-(cyclohex-1-en-1-yl)thiophene- 2-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone (implementation Example 20) Preparation
  • reaction solution was quenched with saturated aqueous NH 4 Cl solution, water was added thereto and extracted twice with EA, the organic phases were combined and dried over Na 2 SO 4 and concentrated to dryness.
  • Step 3 (2R)-4-(6-((5-Chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl ) Preparation of amino)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester
  • Step 4 (6-((5-Chloro-2-hydroxyadamantan-2-yl)ethynyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazoline -2-yl)((R)-3-methylpiperazin-1-yl)methanone.
  • Step 2 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazoline-2 Preparation of -carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester
  • Step 3 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-fluorocyclohexyl)ethynyl)quinazolin-2-yl ) (3-methylpiperazin-1-yl) ketone.
  • Step 1 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinazoline-2 Preparation of -carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester
  • Step 1 Preparation of ethyl 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole-2-carboxylate
  • Step 4 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-methyl Preparation of amides
  • Step 1 Preparation of tert-butyl(6-bromo-1H-indol-2-yl)carbamate
  • Step 2 Preparation of tert-butyl (6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indol-2-yl)carbamate
  • Step 4 Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine
  • Step 5 Preparation of 6-bromo-1-(2-aminopyrimidin-4-yl)-N-(3-methoxypropyl)-1H-indol-2-amine
  • Step 6 1-((1-(2-Aminopyrimidin-4-yl)-2-((3-methoxypropyl)amino)-1H-indol-6-yl)ethynyl)cyclohex- Preparation of 1-alcohols
  • Step 1 Preparation of 1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one
  • Step 2 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-(3-oxo-3-(4-(trifluoromethyl) ) piperidin-1-one)prop-1-yn-1-yl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester preparation
  • Step 3 (R)-3-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-methylpiperazine-1-carbonyl)quinazoline- 6-yl)-1-(4-(trifluoromethyl)piperidin-1-yl)prop-2-yn-1-one.
  • Step 1 Preparation of ((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)trimethylsilane
  • the compound ((1-methoxy-4,4-dimethylcyclohexyl)ethynyl)trimethylsilane (2.0 g, 8.40 mmol) was dissolved in dry THF (10 mL), to which was added TBAF (16.8 mL, 16.80 mmol, 1.0 M in THF) and stirred for 2 hours.
  • TLC spot plate detection the reaction of the raw materials has been completed, water was added to the reaction system, and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous Na 2 SO 4 and concentrated to dryness.
  • Step 3 (R)-4-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcycle Preparation of hexyl)ethynyl)quinazoline-2-carbonyl)-2-methylpiperazine-1-carboxylate tert-butyl ester
  • Step 4 (R)-(4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-((1-methoxy-4,4-dimethylcyclohexyl) Ethynyl)quinazolin-2-yl)(3-methylpiperazin-1-yl)methanone.
  • Step 3 Preparation of tert-butyl (1-(4,6-dichloroquinazoline-2-carbonyl)piperidin-4-yl)carbamate
  • Step 4 tert-Butyl(1-(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2-carbonyl)piperidine- Preparation of 4-yl)carbamate
  • reaction solution was added to water, extracted three times with EA, the organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated to dryness.
  • Step 5 (4-Aminopiperidin-1-yl)(6-chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-2- base) ketone.
  • Step 1 Preparation of 2,6-dichloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine
  • Step 2 (R)-4-(6-Chloro-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2- Preparation of tert-butyl methylpiperazine-1-carboxylate
  • reaction solution was slowly added to water (10 mL) and extracted twice with EA.
  • Step 1 Preparation of tert-butyl 4-cyano-4-propylpiperidine-1-carboxylate
  • the compound 4-cyanopiperidine-1-carboxylate tert-butyl ester (1.0 g, 4.76 mmol) was dissolved in anhydrous THF (10 mL), and cooled to an inner temperature of about -65°C using an ethanol dry ice bath under nitrogen protection.
  • LiHMDS (1.3M in THF, 5.5 mL, 7.14 mmol) was slowly added dropwise to the reaction system, and the temperature was maintained for 3 hours after the addition was complete.
  • Iodopropane (1.2 g, 7.14 mmol) was dissolved in THF (2 mL) and added to the reaction system. After the addition was completed, the temperature was slowly raised to room temperature and stirred overnight.
  • Step 2 Preparation of tert-butyl 4-carbamoyl-4-propylpiperidine-1-carboxylate
  • Step 3 Preparation of tert-butyl 4-amino-4-propylpiperidine-1-carboxylate
  • Step 5 2-(4-Amino-4-(4-fluorophenyl)piperidin-1-yl)-6-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazole-3 -Preparation of quinazolin-4-amine
  • Step 1 Preparation of 2-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine
  • Step 2 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4- Preparation of methylpiperidin-4-yl)carbamate
  • reaction solution was slowly added to water (1000 mL) and extracted twice with EA.
  • Step 3 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazole Lin-4-amine.
  • Step 1 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((1-hydroxy-4,4-dimethyl Preparation of cyclohexyl)ethynyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate
  • Step 2 1-((2-(4-Amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino ) quinazolin-6-yl)ethynyl)-4,4-dimethylcyclohexane-1-ol.
  • Step 1 tert-Butyl(1-(6-cyano-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-4 - Preparation of methylpiperidin-4-yl)carbamate
  • Step 2 2-(4-Amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline -6-Nitrile.
  • Step 1 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinoline Preparation of oxazolin-2-yl)-4-methylpiperidin-4-yl)carbamate
  • Step 2 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4 - Preparation of methylpiperidin-4-yl)carbamate
  • Step 3 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinoline
  • Step 1 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-iodoquinazolin-2-yl)-4- Preparation of phenylpiperidin-4-yl)carbamate
  • reaction solution was slowly added to water (100 mL) and extracted with EA twice.
  • Step 2 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-((trimethylsilyl)ethynyl)quinoline Preparation of oxazolin-2-yl)-4-phenylpiperidin-4-yl)carbamate
  • reaction solution was slowly added to water (40 mL), and EA was extracted twice.
  • the organic phases were combined and washed once with saturated aqueous NaCl. After drying over anhydrous sodium sulfate, it was concentrated to dryness to obtain a brown oil, which was directly used in the next reaction.
  • Step 3 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-ethynylquinazolin-2-yl)-4 - Preparation of phenylpiperidin-4-yl)carbamate
  • Step 4 2-(4-Amino-4-phenylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinoline
  • Step 1 tert-Butyl(1-(4-((5-Cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(4-(4-methylpiperazine-1 -yl)phenyl)quinazolin-2-yl)-4-methylpiperidin-4-yl)carbamate preparation
  • Step 2 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(4- (4-Methylpiperazin-1-yl)phenyl)quinazolin-4-amine.
  • Step 1 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazole-3 - Preparation of methyl)amino)quinazoline-6-carboxylate
  • Step 2 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazole-3 Preparation of -yl)amino)quinazoline-6-carboxylic acid
  • Step 3 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(dimethylcarbamoyl)quinazoline- Preparation of 2-yl)-4-methylpiperidin-4-yl)carbamate
  • Step 4 2-(4-Amino-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N, N-Dimethylquinazoline-6-carboxamide.
  • Step 1 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)quinazoline-2- yl)-4-methylpiperidin-4-yl)carbamate preparation
  • Step 2 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(methyl Sulfonyl)quinazolin-4-amine.
  • Step 1 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyridine Preparation of oxazol-3-yl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl
  • Step 2 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(1, 2,3,6-Tetrahydropyridin-4-yl)quinazolin-4-amine.
  • Step 1 4-(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyridine Preparation of oxazol-3-yl)amino)quinazolin-6-yl)piperidine-1-carboxylate tert-butyl ester
  • Step 1 tert-Butyl(1-(4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-6-(trifluoromethyl)quinazoline-2- yl)-4-methylpiperidin-4-yl)carbamate preparation
  • Step 2 2-(4-Amino-4-methylpiperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(trifluoro Methyl)quinazolin-4-amine.
  • Test Example 1 Inhibitory effect of compound on kinase activity
  • 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)
  • test compound concentration gradient the test compound concentration was 1000nM, diluted into 100-fold final concentration 100% DMSO solution in 384source plate, and the compound was diluted 3-fold with Precision, 10 concentrations.
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min the mean value of the negative control wells, representing the conversion rate readings of the wells without enzymatic activity
  • Conversion%_max the mean ratio of the positive control wells, representing the conversion rate readings of the wells without compound inhibition .
  • ND means not tested
  • Test Example 2 Test compound liver microsome stability test
  • composition of the NADPH (prototype coenzyme II) regeneration system (the final concentration of isocitrate dehydrogenase in the culture medium is 1.0 unit/mL):
  • Beta-Nicotinamide Adenine Dinucleotide Phosphate Supplier: Chem-impex International Cat. No.: N00616
  • liver microsome solution final concentration is 0.5 mg protein/mL
  • types of liver microsomes are shown in Table 13:
  • test or control drug working solutions were added to other plate wells (T0, T5, T10, T20, T30, T60 and NCF60).
  • the first-order elimination kinetic equation is:
  • liver microsome stability test results of some compounds are shown in Table 17:
  • SD rats Male (purchased from Chengdu Dashuo Laboratory Animal Co., Ltd.). Each test compound was administered orally (10 mg/kg, 3 per group) to SD rats for pharmacokinetic study.
  • the test compound was prepared on the day of administration, and the test compound was dissolved with 5% DMSO+10% solutol+85% saline, vortexed for 2 minutes, and then sonicated for 5 minutes to prepare a dosing solution. Animals were fasted for 10-14 hours prior to oral dosing and resumed feeding 4 hours after dosing. After oral administration and intravenous administration of SD rats, pharmacokinetic samples were collected through the jugular vein.
  • the collection time points were: before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h after And 24h, 3 whole blood samples were collected at each time point, the collection volume was about 0.2mL, and anticoagulated with heparin sodium.
  • the blood samples were placed on ice immediately after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800 rpm, 6 minutes, 2-8°C). The collected plasma was stored in a –80°C freezer until analysis.
  • the rat PK data of CZh-226 are from head-to-head measurement data

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Abstract

La présente invention concerne un composé utilisé en tant qu'inhibiteur de PAK4 ayant une structure représentée par la formule I, ou un tautomère, un mésomère, un racémate, un énantiomère, un diastéréoisomère ou un mélange de ceux-ci, ou un hydrate, un solvate ou un sel pharmaceutiquement acceptable dudit composé. Les résultats expérimentaux montrent que le composé préparé dans la présente invention présente une activité inhibitrice élevée et une sélectivité vis-à-vis de la kinase PAK4, et en outre, la stabilité des microsomes du foie et de la PK du rat est également augmentée.
PCT/CN2021/111472 2020-08-14 2021-08-09 Composé utilisé en tant qu'inhibiteur de kinase pak4, son procédé de préparation et son application Ceased WO2022033420A1 (fr)

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NL2037622B1 (en) * 2024-05-03 2025-11-19 Univ Leiden Chemical probes

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