CN113801108A - Protein kinase inhibitor and derivative thereof, preparation method, pharmaceutical composition and application - Google Patents

Protein kinase inhibitor and derivative thereof, preparation method, pharmaceutical composition and application Download PDF

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CN113801108A
CN113801108A CN202010547369.XA CN202010547369A CN113801108A CN 113801108 A CN113801108 A CN 113801108A CN 202010547369 A CN202010547369 A CN 202010547369A CN 113801108 A CN113801108 A CN 113801108A
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amino
pyrimidin
acetyl
benzopyran
morpholinyl
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CN113801108B (en
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陆涛
陈亚东
黄健航
董瑞楠
王信人
李红玫
唐伟方
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China Pharmaceutical University
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China Pharmaceutical University
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • 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
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    • C—CHEMISTRY; METALLURGY
    • 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

Abstract

The invention discloses a protein kinase inhibitor and derivatives thereof, a preparation method, a pharmaceutical composition and application. The structure of the protein kinase inhibitor compound is shown in formula (I), and the protein kinase inhibitor derivative relates to isomers, diastereoisomers, enantiomers, tautomers, solvates, solvate salts, pharmaceutically acceptable salts or mixtures thereof of the protein kinase inhibitor. The protein kinase inhibitor and the derivatives thereof have high-efficiency inhibition effect on protein kinase, can be used for preparing medicaments for treating and/or preventing hyperproliferative diseases, virus-induced infectious diseases and/or cardiovascular diseases, can exert the drug effect on the molecular level and the cell level, have wide application, and have simple and convenient synthesis method and easy operation.
Figure DDA0002541206030000011

Description

Protein kinase inhibitor and derivative thereof, preparation method, pharmaceutical composition and application
Technical Field
The invention relates to a protein kinase inhibitor and a derivative thereof, a preparation method, a pharmaceutical composition and application, in particular to a protein kinase inhibitor which can be prepared into a medicament for treating and/or preventing hyperproliferative diseases such as cancers, virus-induced infectious diseases and/or cardiovascular diseases, a derivative thereof, a preparation method, a pharmaceutical composition and application.
Background
Protein kinase is a key regulator of cell function, and can guide the activity, location and overall function of various proteins by adding phosphatase group to substrate protein, and participate in the arrangement and activation of all cell activities. Protein kinases exist widely in human bodies and play important physiological functions, and when abnormal regulation or mutation occurs in the protein kinases, hyperproliferative diseases, cardiovascular and cerebrovascular diseases, diabetes, inflammation, immune system diseases and the like are often caused.
Cyclin-dependent kinases (CDKs) are an important class of serine/threonine protein kinases, with a total of 21 members. Studies have shown that deregulation of CDK activity has become an important marker of cancer. CDKs complex with cell cycle (Cyclin) proteins, phosphorylate downstream related signaling pathway proteins, and influence cell cycle progression. CDKs can be classified into periodic CDKs and transcriptional CDKs according to their function in the CDKs/Cyclin complex. Among them, CDK9 plays an important role in transcription of intracellular genetic information as a transcription CDK. The complex formed by CDK9 and the binding of its cyclins T1, T2a, T2b or K is a positive transcription elongation factor (P-TEFb); when negative transcription elongation factors such as NELF and DSIF are involved in negative regulation of cell transcription, transcription is inhibited in the initial complex stage, P-TEFb is recruited into a system for inhibiting transcription elongation by NELF and DSIF, and acts on the C-terminal domain Ser-2 of the large subunit of phosphorylated RNA polymerase II (RNA polymerase II) to separate the negative transcription elongation factors from the transcription complex, thereby promoting the continuous transcription. In many malignant cells, abnormal cell cycle regulation and transcription result from high activation of CDK protein kinases.
Abnormal activation of CDK9 activity in P-TEFb heterodimers is primarily associated with hyperproliferative diseases (e.g., cancer), virus-induced infectious diseases, or cardiovascular diseases. As a result of examination of living cells isolated from patients with chronic lymphocytic leukemia or multiple myeloma, the over-activated CDK9 pathway can increase the expression of anti-apoptotic proteins such as Mcl-1, thereby inhibiting normal apoptosis of cells. In addition, CDK 9-mediated abnormalities of the relevant pathway genes or abnormally elevated protein level expression are present in other malignancies such as lymphomas, neuroblastoma, primary neuroectodermal tumors, rhabdomyosarcoma and prostate cancer, and these abnormalities are associated with the excessive involvement of CDK9 in the expression of anti-apoptotic factors and the proliferation of tumor cells.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a protein kinase inhibitor and a derivative thereof, a preparation method of the protein kinase inhibitor and the derivative thereof, a third purpose of a pharmaceutical composition containing the protein kinase inhibitor and/or the derivative thereof, and a fourth purpose of application of the protein kinase inhibitor and the derivative thereof in preparing medicines for treating and/or preventing hyperproliferative diseases, virus-induced infectious diseases and/or cardiovascular diseases.
The technical scheme is as follows: the protein kinase inhibitor and the derivative thereof have the structure of formula (I), and the derivative is an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of a solvate, a pharmaceutically acceptable salt or a mixture of the isomer, the diastereoisomer, the enantiomer, the tautomer, the solvate, the salt of the solvate and the pharmaceutically acceptable salt of the compound:
Figure BDA0002541206010000021
wherein:
bicyclic ring AB is
Figure BDA0002541206010000022
Figure BDA0002541206010000023
V is N or CH;
R1or R2Is hydrogen atom, halogen, nitro, amino, hydroxyl, carboxyl, C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6Cycloalkyl radicals, in which C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6The cycloalkyl group further comprises one or more of halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino or C1-C6An alkoxy substituent;
R3is hydrogen atom, hydroxyl, C1-C6Alkyl radical、C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group wherein C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1The substituent also comprises one or more halogens, hydroxyl, amino, hetero atoms and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group; het1The substituent is morpholinyl, morpholinylalkyl, morpholinylalkoxy, morpholinylalkylamino, piperazinyl, piperazinylalkyl, piperazinylalkoxy, piperazinylalkylamino, homopiperazinylalkyl, homopiperazinylalkoxy, homopiperazinylalkylamino, piperidinyl, piperidinylalkyl, piperidinylalkoxy, piperidinylalkylamino, tetrahydropyrrolyl, tetrahydropyrrolylalkyl, tetrahydropyrrolylalkoxy, tetrahydropyrrolylalkylamino, tetrahydrofuranyl alkoxy, tetrahydrofuranyl, tetrahydropyranyl alkoxy, or tetrahydropyranyl alkylamino;
R4is hydrogen atom, halogen, C1-C6Alkyl or-C (O) R7Wherein R is7Is a hydrogen atom or C1-C6An alkyl group;
R5or R6Is hydrogen atom, halogen, C1-C6Alkyl, cyano or C1-C6An alkoxy group.
Preferably, the protein kinase inhibitor and the derivative thereof have the following structure:
bicyclic AB and R1、R2、R6Substituents which together form
Figure BDA0002541206010000031
Figure BDA0002541206010000032
R1Or R2Is hydrogen atom, halogen, nitroAmino, hydroxy, carboxyl, C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6Cycloalkyl radicals, in which C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6The cycloalkyl group further comprises one or more of halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino or C1-C6An alkoxy substituent;
R3is a hydrogen atom, C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group wherein C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1The substituents further comprising one or more fluorine atoms, hetero atoms, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group; het1The substituent is morpholinyl, morpholinylalkyl, morpholinylalkoxy, morpholinylalkylamino, piperazinyl, piperazinylalkyl, piperazinylalkoxy, piperazinylalkylamino, homopiperazinylalkyl, homopiperazinylalkoxy, homopiperazinylalkylamino, piperidinyl, piperidinylalkyl, piperidinylalkoxy, piperidinylalkylamino, tetrahydropyrrolyl, tetrahydropyrrolylalkyl, tetrahydropyrrolylalkoxy, tetrahydropyrrolylalkylamino, tetrahydrofuranyl alkoxy, tetrahydrofuranyl, tetrahydropyranyl alkoxy, or tetrahydropyranyl alkylamino;
R4is hydrogen atom, halogen, C1-C6Alkyl or-C (O) R7Wherein R is7Is a hydrogen atom or C1-C6An alkyl group;
R5or R6Is hydrogen atom, fluorine atom, chlorine atom, C1-C3Alkyl, cyano or C1-C3An alkoxy group.
Preferably, the protein kinase inhibitor and the derivative thereof have the following structure:
R3is a hydrogen atom, a methyl group, a morpholin-4-yl group, a piperazinyl group, a 4-methylpiperazinyl group, a 4-ethylpiperazinyl group, a 4- (2-methoxyethyl) piperazinyl group, a homopiperazinyl group, an N-methylpiperazinyl group, a thiomorpholin-4-yl group, a piperidinyl group, a 4- (N, N-dimethyl) aminopiperidinyl group, an (N-methylpiperazin-4-yl) piperidinyl group, a 3-methylaminopyrrolidinyl group, a (morpholin-4-yl) methyl group, a (piperazin-1-yl) methyl group, a (4-methylpiperazin-1-yl) methyl group, a (N-methylpiperazin-1-yl) methyl group, a (tetrahydropyran-4-yl) amino group, a (tetrahydrofuran-3-yl) amino group, a, (N-methylpiperidin-4-yl) amino, 2- (dimethylamino) ethylamino, 2-methoxyethylamino, 3-methoxypropylamino, 2, 5-diazabicyclo [2.2.1]Heptyl-2-yl, 4-methylpiperazin-3-onyl, (S) -3-methylpiperazinyl, (R) -3-methylpiperazinyl, (8-azabicyclo [ 3.2.1)]Octane-3-yl) amino, (R) -2-methylpiperazinyl, (S) -2-methylpiperazinyl, pyrrolidinyl, (2-methoxyethyl) amino, (3-methoxypropyl) amino, (tetrahydropyran-4-yl) amino, (tetrahydrofuran-3-yl) amino, N-dimethylamino, or 4, 4-difluoropiperidinyl;
R4is hydrogen, halogen, acetyl, propionyl, methyl or ethyl;
R5or R6Is hydrogen atom, fluorine atom, chlorine atom, cyano group, C1-C3Alkyl or C1-C3An alkoxy group.
Preferably, the protein kinase inhibitor and the derivative thereof have the following structure:
R4is hydrogen, halogen, acetyl, propionyl or methyl;
R5or R6Is hydrogen atom, fluorine atom, chlorine atom, cyano group, C1-C3Alkyl or methoxy.
Preferably, the protein kinase inhibitor is any one of the following compounds:
3-acetyl-7- ((4- (benzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-1),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-2),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-3),
7- ((4- (1H-indol-7-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-4),
3-acetyl-7- ((4- (1-methyl-1H-indol-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-5),
3-acetyl-7- ((4- (imidazo [1,2-a ] pyridin-3-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-6),
7- ((4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-7),
3-acetyl-7- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-8),
3-acetyl-7- ((4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-9),
3-acetyl-7- ((4- (benzo [ d ] oxazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-10),
3-acetyl-7- ((4- (benzo [ d ] thiazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-11),
3-acetyl-7- ((4- (benzo [ d ] [1,3] dioxol-4-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-12),
3-acetyl-7- ((4- (imidazo [1,2-a ] pyridin-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-13),
3-acetyl-7- ((4- (1-methyl-1H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-14),
3-acetyl-7- ((4- (2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-15),
7- ((4- (1H-indol-5-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-16),
3-acetyl-7- ((4- (1-isopropyl-1H-indol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-17),
7- ((4- (1H-benzo [ d ] imidazol-5-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-18),
3-acetyl-4-morpholinyl-7- ((4- (quinolin-7-yl) pyrimidin-2-yl) amino) -2H-chromen-2-one (I-19),
3-acetyl-7- ((4- (isoquinolin-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-chromen-2-one (I-20),
7- ((4- (1H-indol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-21),
7- ((4- (1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-22),
7- ((4- (1H-pyrrolo [2,3-b ] pyridin-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-23),
7- ((4- (1H-indazol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-24),
3-acetyl-7- ((4- (5-methoxy-1H-indol-1-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-25),
3-acetyl-7- ((4- (indol-1-yl) -pyrimidin-2-yl) amino) -4-morpholinyl-2H-chromen-2-one (I-26),
3-acetyl-7- ((4- (2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridinyl-1-yl ] pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2 one (I-27),
3-acetyl-7- ((4- (3, 4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-28),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-29),
3-acetyl-7- ((4- (2, 3-dimethyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-30),
3-acetyl-7- ((4- (3-ethyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-31),
3-acetyl-7- ((4- (2-methyl-3-propyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-32),
3-acetyl-7- ((4- (3-butyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-33),
3-acetyl-7- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-34),
3-acetyl-7- ((5-chloro-4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-35),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-piperazinyl-2H-benzopyran-2-one (I-36),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (4-methylpiperazin-1-yl) -2H-benzopyran-2-one (I-37),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-homopiperazinyl-2H-chromen-2-one (I-38),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (4-methylpiperazino) -2H-benzopyran-2-one (I-39),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- ((1-methylpiperidin-4-yl) amino) -2H-chromen-2-one (I-40),
4- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-41),
4- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) -3-fluoro-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-42),
3-acetyl-4- (2, 5-diazabicyclo [2.2.1] heptyl-2-yl) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-43),
4- (2, 5-diazabicyclo [2.2.1] heptyl-2-yl) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -3-methyl-2H-benzopyran-2-one (I-44),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) -2H-benzopyran-2-one (I-45),
4- ((1R,5S) -8-azabicyclo [3.2.1] oct-3-ylamino) -3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-46),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (((1R, 5S) -8-methyl 8-azabicyclo [3.2.1] oct-3-yl) amino) -2H-benzopyran-2-one (I-47),
3-acetyl-4- ((2- (dimethylamino) ethyl) amino) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-pyran-2-one (I-48),
3-acetyl-7- (((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- ((3-methoxypropyl) amino) -2H-pyran-2-one (I-49),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- ((2-methoxyethyl) amino) -2H-chromen-2-one (I-50),
3-acetyl-7- ((4- (1-isopropyl-1H-benzo [ d ] imidazol-6-yl ] pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-51),
3-acetyl-7- ((4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-52),
3-acetyl-7- ((4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-53),
3-acetyl-7- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-54),
3-acetyl-7- ((4- (1-methyl-1H-benzo [ d ] [1,2,3] triazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-55),
3-acetyl-7- ((4- (1-isopropyl-1H-benzo [ d ] [1,2,3] triazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-56),
3-acetyl-7- ((4- (1-isopropyl-1H-benzo [ d ] [1,2,3] triazol-6-yl ] pyridin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-57).
Preferably, the pharmaceutically acceptable salt is a salt of the protein kinase inhibitor with an acid or a base, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid, and the base is an inorganic base containing a basic metal cation, an alkaline earth metal cation or an ammonium cation salt.
The preparation method of the protein kinase inhibitor and the derivative thereof comprises the following steps:
carrying out alkylation reaction on primary amine compounds 1,3 or 4 and a compound 2 with trifluoromethanesulfonate or halogen respectively to obtain a compound (I);
Figure BDA0002541206010000081
wherein, bicyclic AB, V, R1、R2、R3、R4、R5、R6As defined above, X is triflate or halogen;
and (3) adding a corresponding acid or alkali solution into the solution of the compound (I) prepared by the method, and removing the solvent under reduced pressure after salt formation is completed to obtain the pharmaceutically acceptable salt of the protein kinase inhibitor.
The pharmaceutical composition of the present invention comprises the protein kinase inhibitor and/or a derivative thereof and a pharmaceutically acceptable carrier.
The protein kinase inhibitor and the derivatives thereof can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, syrup, suspending agents or injections, and the preparations can be added with common medicinal auxiliary materials such as spices, sweeteners, liquid/solid fillers, diluents and the like.
The invention relates to the application of protein kinase inhibitor and the derivative thereof in preparing the medicine for treating and/or preventing hyperproliferation diseases, virus-induced infectious diseases and/or cardiovascular diseases; the hyperproliferative disease is lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer, breast cancer, renal cancer, nervous system tumor, lymphoma or leukemia.
The protein kinase inhibitor and the derivative thereof can be prepared into medicines for treating and/or preventing acute myelocytic leukemia, chronic myelocytic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, follicular lymphoma, breast cancer, non-small cell lung cancer, melanoma, renal cancer, ovarian cancer, prostate cancer, colon cancer or central nervous system tumor.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages:
(1) the protein kinase inhibitor, the derivative and the pharmaceutical composition thereof can effectively inhibit the activity of CDK9 kinase, and CDK9 kinase inhibition IC50The optimal value is less than 0.1 mu M, and the nanomolar concentration level is reached; can also inhibit MV4-11 tumor cell proliferation, and MV4-11 tumor cell proliferation inhibition IC50The optimal value is less than 0.1 mu M, and the nanomolar concentration level is reached; and has inhibitory effect on multiple tumor cells, and multiple tumor cells inhibit IC50The values are all less than 0.1 mu M, reach nanomolar concentration level, and are optimally less than 10 nM;
(2) the protein kinase inhibitor, the derivative thereof and the pharmaceutical composition thereof have wide application and can be prepared into medicines for treating and/or preventing hyperproliferative diseases, virus-induced infectious diseases and/or cardiovascular diseasesAn agent; the drug can exert drug effect at both molecular level and cellular level, and has excellent therapeutic effect, IC50The optimal value can reach the nanomolar concentration level;
(3) the preparation method of the compound is simple and convenient and is easy to operate.
Drawings
FIG. 1 is a drawing of compound I-291H-NMR spectrum;
FIG. 2 is a mass spectrum of compound I-29.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Reagents and materials:
the chemical reagents used for preparing the compounds are from Shanghai Bide medicine science and technology Limited, Shanghai Haohnhong biological medicine science and technology Limited and Saen chemical technology Limited;
CDK9/Cyclin T1 was obtained from Reaction Biology Corp (Malvern PA) of America, and MV4-11 tumor cell line was obtained from Angon bioscience, Inc. of Nanjing.
The instrument comprises the following steps:
1H-NMR was measured using a BRUKER AVANCE-300 nuclear magnetic resonance apparatus (Brucker, Switzerland) using TMS as an internal standard and the displacement value (. delta.) in ppm; the low resolution mass spectra were determined using an expression compact fourier transform mass spectrometer.
Example 1: synthesis of 3-acetyl-7- ((4- (benzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (Compound I-1)
Figure BDA0002541206010000101
(1) Synthesis of benzofuran-7-boronic acid pinacol ester (Compound 1a)
In a 25mL two-necked flask was added 7-bromobenzofuran (394mg, 2mmol), pinacol ester diboron (762mg, 3mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (146mg, 0.2mmol), sodium carbonate (424mg, 4mmol), 2mL of water and 12mL of 1, 4-dioxane, nitrogenThe reaction was carried out at 100 ℃ for 12 hours under the protection of gas, after completion of the reaction, 50mL of water and 100mL of ethyl acetate were added, and the organic layer was collected, concentrated, and purified by column chromatography to obtain 346mg of a colorless oily substance with a yield of 71%. ESI-MS M/z 245[ M + H ]]+。
(2) Synthesis of 4- (benzofuran-7-yl) pyrimidin-2-amine (Compound 1-1)
In a 25mL two-necked flask, compound 1a (293mg, 1.20mmol), 2-amino-4-chloropyrimidine (130mg, 1.00mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (73mg, 0.1mmol), sodium carbonate (212mg, 2.00mmol), 1, 4-dioxane 12mL and purified water 2mL, degassed with nitrogen, heated at 100 ℃ for reaction for 6h under the protection of nitrogen, the reaction solution is extracted with ethyl acetate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether ═ 1: 1), and then recrystallized and purified to obtain light yellow powder 150mg, with the yield of 71%. ESI-MS M/z 212[ M + H ]]+。
(3) Synthesis of 4-hydroxy-7-methoxy-2H-benzopyran-2-one (Compound 2a)
Adding 2-hydroxy-4-methoxyacetophenone (10.0g, 60.20mmol) and diethyl carbonate (10.7g, 90.30mmol) into a 500mL eggplant-shaped bottle, dissolving in 100mL anhydrous toluene, dissolving sodium hydride (12.0g, 300.90mmol) in 50mL anhydrous toluene, dropwise adding the mixture into the reaction solution by using a constant-pressure dropping funnel under the ice bath condition, stirring for 30min under the ice bath after dropwise adding, heating at 100 ℃ for reaction for 4h, cooling the reaction solution to room temperature, dropwise adding ice water into the reaction solution under the ice bath condition to quench excessive sodium hydride, extracting with diethyl ether (100mL multiplied by 3), collecting an aqueous phase, adjusting the pH to 2-3 by using 2N HCl, precipitating a large amount of white precipitate, and drying to obtain 10.67g of a white solid with the yield of 92%. ESI-MS M/z 215[ M + Na ]]+。1H-NMR(300MHz,DMSO-d6)δ12.36(s,1H,ArOH),7.72(d,J＝8.5Hz,1H,ArH),6.95(dd,J＝8.5,2.4Hz,1H,ArH),6.91(d,J＝2.4Hz,1H,ArH),5.45(s,1H,ArH),3.85(s,3H,OCH3)。
(4) Synthesis of 3-acetyl-4-hydroxy-7-methoxy-2H-benzopyran-2-one (Compound 2b)
Adding compound 2a (3.00g, 15.61mmol), glacial acetic acid 16mL and phosphorus oxychloride 5.6mL into a 100mL eggplant-shaped bottle, heating at 105 deg.C for reaction for 30min, and mixingAnd cooling the reaction liquid to room temperature, standing to separate out a solid, filtering the solid precipitate to obtain a crude product, and recrystallizing and purifying by using absolute ethyl alcohol to obtain 132.65g of a white solid with the yield of 72%. ESI-MS M/z 257[ M + Na ]]+。1H-NMR(300MHz,DMSO-d6)δ17.98(s,1H,ArOH),7.93(d,J＝9.5Hz,1H,ArH),6.99-7.04(m,2H,ArH),3.91(s,3H,OCH3),2.64(s,3H,COCH3)。
(5) Synthesis of 3-acetyl-7-methoxy-4-morpholinyl-2H-benzopyran-2-one (Compound 2c)
Compound 2b (1.00g, 4.27mmol) and morpholine (3.72mL, 42.70mmol) were added to a 100mL eggplant-shaped bottle, the temperature was raised to 160 ℃ and the reaction was carried out for 2h, and the starting material spot was lost by TLC. The reaction mixture was cooled to room temperature, 50mL of water was added, dichloromethane extraction (50mL × 3) was performed, the organic layers were combined, washed with saturated sodium chloride (25mL × 3), dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1: 1) to give 677mg of a white solid, yield 52%. ESI-MS M/z 326[ M + Na ]]+。1H-NMR(300MHz,DMSO-d6)δ7.92(d,J＝8.8Hz,1H,ArH),7.16(d,J＝2.4Hz,1H,ArH),7.07(dd,J＝8.8,2.4Hz,1H,ArH),3.90(s,3H,OCH3),3.24–3.72(m,8H,2×NCH2CH2O),2.34(s,3H,COCH3)。
(6) Synthesis of 3-acetyl-7-hydroxy-4-morpholinyl-2H-benzopyran-2-one (Compound 2d)
Compound 2c (1.00g, 3.30mmol) and aluminum trichloride (1.45g, 10.90mmol) were added to a 100mL eggplant-shaped bottle, and dissolved in 30mL of anhydrous toluene, and the mixture was refluxed at 100 ℃ for 4 hours, and the starting material was detected by TLC and disappeared, and the reaction mixture was cooled to room temperature, and the excess solvent was removed under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate: 1: 2) to obtain 653mg of a white solid with a yield of 68%. ESI-MS M/z 312[ M + Na ]]+。
(7) Synthesis of 3-acetyl-4-morpholinyl-2-oxo-2H-benzopyran-7-yl-trifluoromethanesulfonate (Compound 2-1)
In a 25mL eggplant-shaped bottle, compound 2d (289mg, 1.00mmol) and triethylamine (156. mu.L, 1.20mmol) were added, 10mL of anhydrous dichloromethane was dissolved, the mixture was stirred for 15min in an ice salt bath, trifluoromethanesulfonic anhydride (201. mu.L, 1.20mmol) was added dropwise, and the mixture was stirredStirring for 1h, and detecting by TLC that the raw material point disappears. The reaction solution was poured into saturated NaHCO350mL of the solution was extracted with methylene chloride (25 mL. times.3), the organic layers were combined, washed with saturated sodium chloride (25 mL. times.3), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 353mg of a white solid in 84% yield. ESI-MS M/z 444[ M + Na ]]+。1H-NMR(300MHz,DMSO-d6)δ8.20(d,J＝8.9Hz,1H,ArH),8.06(d,J＝2.4Hz,1H,ArH),7.63(dd,J＝8.8,2.4Hz,1H,ArH),3.26-3.80(m,8H,2×NCH2CH2O),2.39(s,3H,COCH3)。
(8) Synthesis of 3-acetyl-7- ((4- (benzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (Compound I-1)
Under nitrogen protection, compound 1-1(127mg, 0.60mmol), compound 2-1(278mg, 0.66mmol), palladium acetate (14mg, 0.06mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (36mg, 0.06mmol) and cesium carbonate (391mg, 1.20mmol) were added to a 25mL two-necked flask, 10mL of anhydrous toluene was added, the reaction was heated at 100 ℃ for 2 to 6 hours, the reaction solution was filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 60: 1), and after purification by recrystallization, 83mg of a solid was obtained, with a yield of 29%. ESI-MS M/z 483[ M + H ]]+。1H NMR(300MHz,DMSO)δ10.54(s,1H,ArNH),8.76(s,1H,ArH),8.35(s,1H,ArH),7.96(s,1H,ArH),7.86(s,3H,ArH),7.73(s,1H,ArH),7.53(s,2H,ArH),7.38(s,1H,ArH),3.19-3.67(m,8H),2.40(s,3H,COCH3)。
In a similar procedure to example 1, the following compound was prepared:
Figure BDA0002541206010000121
Figure BDA0002541206010000131
Figure BDA0002541206010000141
Figure BDA0002541206010000151
example 2: synthesis of 7- ((4- (1H-indol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-21)
Figure BDA0002541206010000152
(1) Synthesis of 4- ((1H-indol-1-yl) pyrimidin-2-amine (compound 3-1)
Indole (702mg, 6mmol), 2-amino-4-chloropyrimidine (650mg, 5mmol), cesium carbonate (3.26g, 10mmol) and 15mL of DMF were added to a 50mL single-necked flask, and reacted at 100 ℃ overnight, after completion of the reaction, 100mL of water was added, and 3 × 50mL of ethyl acetate was extracted, and the organic layer was collected, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate ═ 3: 1) to obtain 370mg of a white solid in a yield of 35%. ESI-MS M/z 211[ M + H ]]+。
(2) Synthesis of 7- ((4- (1H-indol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (Compound I-21)
By using compound 3-1(126mg, 0.6mmol) and compound 2-1(278mg, 0.66mmol) as starting materials in accordance with the method for producing compound I-1, 173mg of compound I-21 was obtained as a yellow solid with a yield of 60%. ESI-MS M/z 483[ M + H ]]+。1H-NMR(300MHz,DMSO)δ10.43(s,1H,ArNH),8.87(d,J＝8.3Hz,1H,ArH),8.65(d,J＝5.8Hz,1H,ArH),8.45(d,J＝1.8Hz,1H,ArH),8.19(d,J＝3.7Hz,1H,ArH),7.96(d,J＝8.8Hz,1H,ArH),7.70(dd,J＝13.7,4.8Hz,2H,ArH),7.42(d,J＝5.9Hz,1H,ArH),7.34-7.38(m,1H,ArH),7.25-7.30(m,1H,ArH),6.88(d,J＝3.6Hz,1H,ArH),3.22-3.77(m,8H,2×NCH2CH2O),2.35(s,3H,COCH3)。
In a similar procedure to example 2, the following compound was prepared:
Figure BDA0002541206010000161
Figure BDA0002541206010000171
example 3: synthesis of 3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-29)
Figure BDA0002541206010000172
(1) Synthesis of 5-bromo-2-methyl-2H-indazole (Compound 4a)
In a 250mL single neck flask was added 5-bromoindazole (9.95g, 50mmol), dissolved in 150mL DMF, slowly added sodium hydride (1.44g, 60mmol) under ice bath, stirred for 30min, added iodomethane (8.52g, 60mmol), reacted at room temperature for 5h, quenched by addition of a saturated solution of sodium thiosulfate, extracted with ethyl acetate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to give 4.1g of a pale yellow solid in 32.4% yield.1H-NMR(300MHz,DMSO-d6)δ8.34(s,1H),7.92-7.98(m,1H),7.57(dd,J＝9.1,0.8Hz,1H),7.30(dd,J＝9.1,1.9Hz,1H),4.17(s,3H)。
(2) Synthesis of 2- (5-bromo-2-methyl-2H-indazol-3-yl) propan-2-ol (Compound 4b)
Under the protection of nitrogen, compound 4a (2.1g, 10mmol) is added into a 50mL double-neck flask, 10mL of anhydrous tetrahydrofuran is added for dissolution, LDA (15mmol) is slowly added at-78 ℃, the temperature is increased to 0 ℃ for reaction for 10min, acetone (1.1mL, 15mmol) is added after the temperature is reduced to-78 ℃, the temperature is slowly increased to room temperature for reaction for 12h, the reaction solution is filtered and concentrated, and the residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5: 1) to obtain 1.0g of yellow solid with the yield of 37%.1H-NMR(300MHz,CDCl3)δ7.75(d,J＝1.3Hz,1H,ArH),7.28(d,J＝9.1Hz,1H,ArH),7.20-7.11(m,1H,ArH),4.17(s,3H,NCH3),3.30-2.75(m,1H,COH),1.72(s,6H,C 3 2(CH))。
(3) Synthesis of 5-bromo-3-isopropyl-2-methyl-2H-indazole (Compound 4c)
In a 50mL single-neck flask, compound 4b (538mg, 2mmol), triethylsilane (3.20mL, 20mmol) were added, and dissolved in 20mL of dichloromethane, trifluoroacetic acid (1.50mL, 20mmol) was slowly added, and the mixture was reacted at room temperature for 24 hours, followed by addition of a saturated sodium bicarbonate solution, extraction with dichloromethane, drying over anhydrous sodium sulfate, and separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6: 1) to obtain 260mg of a yellow oil with a yield of 51%.1H NMR(300MHz,CDCl3)δ7.84(d,J＝1.3Hz,1H,ArH),7.47(d,J＝9.0Hz,1H,ArH),7.26(dd,J＝9.1,1.8Hz,1H,ArH),4.06(s,3H,NCH3),3.27-3.36(m,1H,CH(CH3)2),1.42(d,J＝7.1Hz,6H,CH 3 2(CH)).
(4) Synthesis of 3-isopropyl-2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-indazole (Compound 4d)
Using compound 4c (253mg, 1mmol) as a starting material, compound 4d was obtained as a white solid (245 mg, yield 82%) according to the method for synthesizing compound 1 a. ESI-MS M/z 301[ M + H ]]+。
(5) Synthesis of 4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-amine (compound 4-1)
With the compound 4d (200mg, 0.67mmol) as a starting material, 165mg of a compound 4-1 white solid was obtained with a yield of 92% with reference to the synthesis method of the compound 1-1. ESI-MS M/z 268[ M + H ]]+。1H-NMR(300MHz,DMSO)δ8.50-8.61(m,1H,ArH),8.27(d,J＝5.2Hz,1H,ArH),7.92(dd,J＝9.1,1.3Hz,1H,ArH),7.52-7.66(m,1H,ArH),7.20(d,J＝5.3Hz,1H,ArH),6.69-6.54(m,2H,ArH),4.12(s,3H,NCH3),3.54-3.63(m,1H,CH(CH3)2),1.50(d,J＝7.0Hz,6H,CH 3 2(CH))。
(6) Synthesis of 3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (Compound I-29)
Using compound 4-1(160mg, 0.6mmol) and compound 2-1(278mg, 0.66mmol) as starting materials, 115mg of compound I-29 as a white solid was obtained in a yield of 36, in accordance with the synthesis method of compound I-1％。ESI-MS m/z:539[M+H]+。1H-NMR(300MHz,DMSO)δ10.39(s,1H,ArNH),8.77(s,1H,ArH),8.65(d,J＝5.3Hz,1H,ArH),8.41(d,J＝1.8Hz,1H,ArH),8.01(dd,J＝9.2,1.4Hz,1H,ArH),7.94(d,J＝8.8Hz,1H,ArH),7.78(dd,J＝8.9,1.9Hz,1H,ArH),7.62-7.71(m,2H,ArH),4.15(s,3H,NCH3),3.42-3.81(m,8H,2×NCH2CH2O),3.19-3.30(m,1H,CH(CH3)2),2.36(s,3H,COCH3),1.55(d,J＝7.0Hz,6H,CH 3 2(CH))。
In a similar procedure to example 3, the following compound was prepared:
Figure BDA0002541206010000191
Figure BDA0002541206010000201
Figure BDA0002541206010000211
Figure BDA0002541206010000221
Figure BDA0002541206010000231
example 4: inhibition of CDK9 kinase activity by compounds
The synthesized compounds were tested for CDK9 inhibitory activity by the hotspot kinase method/Fluorescence Resonance Energy Transfer (FRET) method, exemplified by CDK9/Cyclin T1, by Reaction Biology Corp.
The specific operation method comprises the following steps: CDK9/Cyclin T1 was diluted to appropriate concentration with kinase diluent for use. The kinase reaction mixture contained CDK9/Cyclin T1, Peptide substrate, HEPES (pH7.5)、BRIJ-35、MgCl2And EDTA. CDK9phospho-peptide substrate was used as a 100% phosphorylation control and ATP was not added as a 0% phosphorylation control. After 1h at room temperature, Development Reagent A was added to the reaction system at moderate dilution. The reaction was continued at room temperature for 1h and stopped by the addition of Stop Reagent. The excitation wavelength was set at 400nm, while the fluorescence intensities at 445nm (coumarin) and 520nm (fluorescein) were detected. The inhibition rate (n-2), IC, of the test compound was calculated according to the formula50The percent inhibition and logarithmic concentration values were plotted and the results are shown in Table 1.
Inhibition of CDK9 kinase activity by the compounds of Table 1
Cpd. IC50(μM) Cpd. IC50(μM) Cpd. IC50(μM) Cpd. IC50(μM)
I-1 B I-12 B I-25 B I-42 A
I-2 A I-13 A I-29 A I-43 A
I-3 A I-14 B I-30 A I-44 A
I-4 A I-15 A I-31 A I-45 A
I-5 B I-16 B I-34 A I-46 A
I-6 A I-17 C I-35 A I-47 A
I-7 A I-18 C I-36 A I-48 A
I-8 B I-19 C I-37 A I-49 A
I-9 A I-20 C I-38 A I-50 A
I-10 B I-21 A I-40 A I-53 A
I-11 B I-22 A I-41 A I-54 A
Note: "A" represents IC50The value is less than 0.1. mu.M, "B" represents IC50The value is between 0.1. mu.M and 1. mu.M, "C" represents IC50The value is greater than 1. mu.M.
As shown in Table 1, all of the compounds tested had inhibitory effects on CDK9 kinase activity, with compounds I-2 through I-4, I-6 through I-7, I-9, I-13, I-15, I-21 through I-22, I-29 through I-31, I-34 through I-38, I-40 through I-50, and I-53 through I-54 inhibiting the IC of CDK9 kinase50The values are all less than 0.1 mu M and can reach nanomolar concentration level; IC of the remaining Compounds for inhibiting CDK9 kinase50Values are in the micromolar range.
Example 5: antiproliferative effect of compounds on tumor cells
The experimental principle is as follows: MTT method was used to determine the inhibitory effect on leukemia cell line MV4-11 tumor cell line, and MTT method for in vitro testing of anti-tumor proliferation activity is a method for detecting cell survival and growth, which is based on the principle that NADP-related dehydrogenase (succinate dehydrogenase) in mitochondria of living cells can reduce exogenous MTT into insoluble blue-violet crystalline Formazan (Formazan) and deposit it in cells, while dead cells do not have this function. Purple crystal formazan in cells was dissolved in dimethyl sulfoxide (DMSO) or a triple solution (10% SDS-5% isobutanol-0.01 mol/L HCl), and the light absorption (OD value) at a wavelength of 570nm was detected by an enzyme-linked immunosorbent assay, which indirectly reflected the amount of living cells.
The specific operation method comprises the following steps: inoculating tumor cells in logarithmic growth phase into 96-well culture plate according to certain cell amount, culturing for 24 hr, adding test compound (directly adding after suspending cells are connected with plate), culturing at 37 deg.C with 5% CO2Continuously culturing for 48h or 72h under the condition, adding MTT, continuously culturing for 4h, dissolving with DMSO for crystallization, measuring OD value at 570nm wavelength with enzyme linked immunosorbent assay detector, and calculating the inhibition rate and IC of the compound50The values and analytical results are shown in Table 2.
TABLE 2 antiproliferative effect of Compounds on MV4-11 tumor cells
Cpd. IC50(μM) Cpd. IC50(μM) Cpd. IC50(μM) Cpd. IC50(μM)
I-1 n.d. I-12 C I-25 C I-42 A
I-2 B I-13 A I-29 A I-43 A
I-3 B I-14 C I-30 B I-44 A
I-4 n.d. I-15 C I-31 B I-45 A
I-5 n.d. I-16 B I-34 B I-46 A
I-6 B I-17 C I-35 A I-47 A
I-7 n.d. I-18 C I-36 A I-48 A
I-8 B I-19 B I-37 A I-49 A
I-9 B I-20 B I-38 A I-50 A
I-10 C I-21 n.d. I-40 A I-53 B
I-11 C I-22 n.d. I-41 A I-54 B
Note: "A" represents IC50The value is less than 0.1. mu.M, "B" represents IC50The value is between 0.1. mu.M and 1. mu.M, "C" represents IC50Values greater than 1 μ M, n.d. represent not tested.
As shown in Table 2, all the tested compounds showed inhibitory effects on MV4-11 tumor cells, wherein compounds I-13, I-29, I-35 to I-38 and I-40 to I-50 inhibited the IC of MV4-11 tumor cells50The values are all less than 0.1 mu M and can reach nanomolar concentration level; compounds I-2 to I-3, I-6, I-8 to I-12, I-14 to I-20, I-25, I-30, I-31, I-34 and I-53 to I-54 inhibit the IC of MV4-11 tumor cells50Values are in the micromolar range.
Example 6: anti-tumor cell profiling detection of compounds
Experimental materials: the materials used in the experiments were all from the national cancer center of the united states.
Experiment ofThe method comprises the following steps: tumor cell lines were grown in RPMI 1640 medium containing 5% fetal bovine serum and 2mM L-glutamine. Cells were seeded into 96-well microtiter plates at plate densities of 5,000 to 40,000 cells/well at a concentration of 100 μ L, depending on the doubling time of the individual cell line. After cell inoculation, the microtiter plates were placed at 37 ℃ in 5% CO prior to addition of experimental drug2Incubate for 24h at 95% air and 100% relative humidity. After addition of the drug, plates were incubated at 37 ℃ with 5% CO2Further incubation for 48h at 95% air and 100% relative humidity. After dyeing, unbound dye was removed by washing 5 times with 1% acetic acid and the plates were air dried. The bound stain was then dissolved in 10mM trizma base and the absorbance read at 515nm on an automatic microplate reader and the compound GI calculated50The value is obtained.
Further testing of Compound I-29 against a portion of tumor cell lines in the NCI-60 cell Bank, screening for anti-tumor cell profiles, and testing the resulting GI50The values are shown in Table 3.
TABLE 3 NCI-60 cell Profile of Compound I-29
Figure BDA0002541206010000261
As shown in Table 3, the compound I-29 has inhibitory effect on various parenchymal organ cancers, and the inhibitory concentration reaches nanomolar concentration level; these include, but are not limited to, various hematological malignancies, such as acute myelocytic leukemia, chronic myelocytic leukemia, lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, follicular lymphoma, and solid tumors such as breast cancer, non-small cell lung cancer, melanoma, renal cancer, ovarian cancer, prostate cancer, colon cancer, and central nervous system tumors.

Claims (10)

1. A protein kinase inhibitor and derivatives thereof, characterized in that the protein kinase inhibitor and derivatives thereof have the structure of formula (I) and the derivatives are isomers, diastereomers, enantiomers, tautomers, solvates, salts of solvates, pharmaceutically acceptable salts, or mixtures thereof of the compound:
Figure FDA0002541204000000011
wherein:
bicyclic ring AB is
Figure FDA0002541204000000012
Figure FDA0002541204000000013
V is N or CH;
R1or R2Is hydrogen atom, halogen, nitro, amino, hydroxyl, carboxyl, C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6Cycloalkyl radicals, in which C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6The cycloalkyl group further comprises one or more of halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino or C1-C6An alkoxy substituent;
R3is hydrogen atom, hydroxyl, C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group wherein C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1The substituent also comprises one or more halogens, hydroxyl, amino, hetero atoms and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group; het1The substituent is morpholinyl or morpholinylMorpholinylalkyl, morpholinylalkoxy, morpholinylalkylamino, piperazinyl, piperazinylalkyl, piperazinyl alkoxy, piperazinyl alkylamino, homopiperazinyl, homopiperazinylalkyl, homopiperazinyl alkoxy, homopiperazinylalkylamino, piperidinyl, piperidinylalkyl, piperidinylalkoxy, piperidinylalkylamino, tetrahydropyrrolyl, tetrahydropyrrolylalkyl, tetrahydropyrrolylalkoxy, tetrahydropyrrolylalkylamino, tetrahydrofuranyl alkoxy, tetrahydrofuranyl, tetrahydropyranyl alkoxy, or tetrahydropyranyl alkylamino;
R4is hydrogen atom, halogen, C1-C6Alkyl or-C (O) R7Wherein R is7Is a hydrogen atom or C1-C6An alkyl group;
R5or R6Is hydrogen atom, halogen, C1-C6Alkyl, cyano or C1-C6An alkoxy group.
2. The protein kinase inhibitor and the derivative thereof according to claim 1, wherein the structure of the protein kinase inhibitor and the derivative thereof is as follows:
bicyclic AB and R1、R2、R6Substituents which together form
Figure FDA0002541204000000021
Figure FDA0002541204000000022
R1Or R2Is hydrogen atom, halogen, nitro, amino, hydroxyl, carboxyl, C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6Cycloalkyl radicals, in which C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or C3-C6The cycloalkyl group further comprises one or more of halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino or C1-C6An alkoxy substituent;
R3is a hydrogen atom, C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group wherein C1-C6Alkyl radical, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1The substituents further comprising one or more fluorine atoms, hetero atoms, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkylamino radical, C1-C6Alkoxy or Het1A substituent group; het1The substituent is morpholinyl, morpholinylalkyl, morpholinylalkoxy, morpholinylalkylamino, piperazinyl, piperazinylalkyl, piperazinylalkoxy, piperazinylalkylamino, homopiperazinylalkyl, homopiperazinylalkoxy, homopiperazinylalkylamino, piperidinyl, piperidinylalkyl, piperidinylalkoxy, piperidinylalkylamino, tetrahydropyrrolyl, tetrahydropyrrolylalkyl, tetrahydropyrrolylalkoxy, tetrahydropyrrolylalkylamino, tetrahydrofuranyl alkoxy, tetrahydrofuranyl, tetrahydropyranyl alkoxy, or tetrahydropyranyl alkylamino;
R4is hydrogen atom, halogen, C1-C6Alkyl or-C (O) R7Wherein R is7Is a hydrogen atom or C1-C6An alkyl group;
R5or R6Is hydrogen atom, fluorine atom, chlorine atom, C1-C3Alkyl, cyano or C1-C3An alkoxy group.
3. The protein kinase inhibitor and the derivative thereof according to claim 1, wherein the structure of the protein kinase inhibitor and the derivative thereof is as follows:
R3is hydrogen atom, methyl, morpholin-4-yl, piperazinyl,4-methylpiperazinyl, 4-ethylpiperazinyl, 4- (2-methoxyethyl) piperazinyl, homopiperazinyl, N-methylpiperazinyl, thiomorpholin-4-yl, piperidinyl, 4- (N, N-dimethyl) aminopiperidinyl, (N-methylpiperazin-4-yl) piperidinyl, 3-methylaminopyrrolidinyl, (morpholin-4-yl) methyl, (piperazin-1-yl) methyl, (4-methylpiperazin-1-yl) methyl, (N-methylpiperazin-1-yl) methyl, (tetrahydropyran-4-yl) amino, (tetrahydrofuran-3-yl) amino, (N-methylpiperidin-4-yl) amino, 2- (dimethylamino) ethylamino, N-methylpiperazin-4-yl) amino, and mixtures thereof, 2-methoxyethylamino, 3-methoxypropylamino, 2, 5-diazabicyclo [2.2.1]Heptyl-2-yl, 4-methylpiperazin-3-onyl, (S) -3-methylpiperazinyl, (R) -3-methylpiperazinyl, (8-azabicyclo [ 3.2.1)]Octane-3-yl) amino, (R) -2-methylpiperazinyl, (S) -2-methylpiperazinyl, pyrrolidinyl, (2-methoxyethyl) amino, (3-methoxypropyl) amino, (tetrahydropyran-4-yl) amino, (tetrahydrofuran-3-yl) amino, N-dimethylamino, or 4, 4-difluoropiperidinyl;
R4is hydrogen, halogen, acetyl, propionyl, methyl or ethyl;
R5or R6Is hydrogen atom, fluorine atom, chlorine atom, cyano group, C1-C3Alkyl or C1-C3An alkoxy group.
4. The protein kinase inhibitor and the derivative thereof according to claim 1, wherein the structure of the protein kinase inhibitor and the derivative thereof is as follows:
R4is hydrogen, halogen, acetyl, propionyl or methyl;
R5or R6Is hydrogen atom, fluorine atom, chlorine atom, cyano group, C1-C3Alkyl or methoxy.
5. The protein kinase inhibitor and derivatives thereof according to claim 1, wherein the protein kinase inhibitor is any one of the following compounds:
3-acetyl-7- ((4- (benzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-1),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-2),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-3),
7- ((4- (1H-indol-7-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-4),
3-acetyl-7- ((4- (1-methyl-1H-indol-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-5),
3-acetyl-7- ((4- (imidazo [1,2-a ] pyridin-3-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-6),
7- ((4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-7),
3-acetyl-7- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-8),
3-acetyl-7- ((4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-9),
3-acetyl-7- ((4- (benzo [ d ] oxazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-10),
3-acetyl-7- ((4- (benzo [ d ] thiazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-11),
3-acetyl-7- ((4- (benzo [ d ] [1,3] dioxol-4-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-12),
3-acetyl-7- ((4- (imidazo [1,2-a ] pyridin-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-13),
3-acetyl-7- ((4- (1-methyl-1H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-14),
3-acetyl-7- ((4- (2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-15),
7- ((4- (1H-indol-5-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-16),
3-acetyl-7- ((4- (1-isopropyl-1H-indol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-17),
7- ((4- (1H-benzo [ d ] imidazol-5-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-18),
3-acetyl-4-morpholinyl-7- ((4- (quinolin-7-yl) pyrimidin-2-yl) amino) -2H-chromen-2-one (I-19),
3-acetyl-7- ((4- (isoquinolin-7-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-chromen-2-one (I-20),
7- ((4- (1H-indol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-21),
7- ((4- (1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-22),
7- ((4- (1H-pyrrolo [2,3-b ] pyridin-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-23),
7- ((4- (1H-indazol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-24),
3-acetyl-7- ((4- (5-methoxy-1H-indol-1-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-25),
3-acetyl-7- ((4- (indol-1-yl) -pyrimidin-2-yl) amino) -4-morpholinyl-2H-chromen-2-one (I-26),
3-acetyl-7- ((4- (2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridinyl-1-yl ] pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2 one (I-27),
3-acetyl-7- ((4- (3, 4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-28),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-29),
3-acetyl-7- ((4- (2, 3-dimethyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-30),
3-acetyl-7- ((4- (3-ethyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-31),
3-acetyl-7- ((4- (2-methyl-3-propyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-32),
3-acetyl-7- ((4- (3-butyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-33),
3-acetyl-7- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-34),
3-acetyl-7- ((5-chloro-4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-35),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-piperazinyl-2H-benzopyran-2-one (I-36),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (4-methylpiperazin-1-yl) -2H-benzopyran-2-one (I-37),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-homopiperazinyl-2H-chromen-2-one (I-38),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (4-methylpiperazino) -2H-benzopyran-2-one (I-39),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- ((1-methylpiperidin-4-yl) amino) -2H-chromen-2-one (I-40),
4- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-41),
4- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) -3-fluoro-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-42),
3-acetyl-4- (2, 5-diazabicyclo [2.2.1] heptyl-2-yl) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-43),
4- (2, 5-diazabicyclo [2.2.1] heptyl-2-yl) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -3-methyl-2H-benzopyran-2-one (I-44),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) -2H-benzopyran-2-one (I-45),
4- ((1R,5S) -8-azabicyclo [3.2.1] oct-3-ylamino) -3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-benzopyran-2-one (I-46),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (((1R, 5S) -8-methyl 8-azabicyclo [3.2.1] oct-3-yl) amino) -2H-benzopyran-2-one (I-47),
3-acetyl-4- ((2- (dimethylamino) ethyl) amino) -7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -2H-pyran-2-one (I-48),
3-acetyl-7- (((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- ((3-methoxypropyl) amino) -2H-pyran-2-one (I-49),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- ((2-methoxyethyl) amino) -2H-chromen-2-one (I-50),
3-acetyl-7- ((4- (1-isopropyl-1H-benzo [ d ] imidazol-6-yl ] pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-51),
3-acetyl-7- ((4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-52),
3-acetyl-7- ((4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-53),
3-acetyl-7- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-54),
3-acetyl-7- ((4- (1-methyl-1H-benzo [ d ] [1,2,3] triazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-55),
3-acetyl-7- ((4- (1-isopropyl-1H-benzo [ d ] [1,2,3] triazol-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-56),
3-acetyl-7- ((4- (1-isopropyl-1H-benzo [ d ] [1,2,3] triazol-6-yl ] pyridin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-57).
6. The protein kinase inhibitor and the derivative thereof according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is a salt of the protein kinase inhibitor with an acid or a base, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid, and the base is an inorganic base containing an alkali metal cation, an alkaline earth metal cation, or an ammonium cation salt.
7. A method for preparing the protein kinase inhibitor and the derivative thereof according to any one of claims 1 to 6, wherein the method comprises the following steps:
carrying out alkylation reaction on primary amine compounds 1,3 or 4 and a compound 2 with trifluoromethanesulfonate or halogen respectively to obtain a compound (I);
Figure FDA0002541204000000071
wherein, bicyclic AB, V, R1、R2、R3、R4、R5、R6X is triflate or halogen as defined in any of claims 1 to 4;
and (3) adding a corresponding acid or alkali solution into the solution of the compound (I) prepared by the method, and removing the solvent under reduced pressure after salt formation is completed to obtain the pharmaceutically acceptable salt of the protein kinase inhibitor.
8. A pharmaceutical composition comprising the protein kinase inhibitor and/or a derivative thereof according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.
9. Use of the protein kinase inhibitor and derivatives thereof according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of hyperproliferative diseases, virus-induced infectious diseases and/or cardiovascular diseases.
10. Use according to claim 9, wherein the hyperproliferative disease is lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer, breast cancer, renal cancer, nervous system tumors, lymphomas or leukemia.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5576338A (en) * 1995-02-15 1996-11-19 Merck Frosst Canada, Inc. Bis (biaryl) compounds as inhibitors of leukotriene biosynthesis
CN101374818A (en) * 2006-01-26 2009-02-25 阿斯利康(瑞典)有限公司 Pyrimidine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5576338A (en) * 1995-02-15 1996-11-19 Merck Frosst Canada, Inc. Bis (biaryl) compounds as inhibitors of leukotriene biosynthesis
CN101374818A (en) * 2006-01-26 2009-02-25 阿斯利康(瑞典)有限公司 Pyrimidine derivatives

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