CN113801108B - 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 PDFInfo
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- CN113801108B CN113801108B CN202010547369.XA CN202010547369A CN113801108B CN 113801108 B CN113801108 B CN 113801108B CN 202010547369 A CN202010547369 A CN 202010547369A CN 113801108 B CN113801108 B CN 113801108B
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- amino
- pyrimidin
- acetyl
- benzopyran
- methyl
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
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- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000026447 protein localization Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000003607 serino group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07D471/04—Ortho-condensed systems
-
- 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 compound of the protein kinase inhibitor is shown as a formula (I), and the protein kinase inhibitor derivative relates to an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of the solvate, a pharmaceutically acceptable salt or a mixture of the isomers, the diastereoisomer, the enantiomer, the tautomer, the solvate and the pharmaceutically acceptable salt of the protein kinase inhibitor. The protein kinase inhibitor and the derivative 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 medicinal effects on molecular level and cellular level, and have wide application, and the compound has simple synthesis method and easy operation.
Description
Technical Field
The invention relates to a protein kinase inhibitor and a derivative thereof, a preparation method, a pharmaceutical composition and application thereof, in particular to a protein kinase inhibitor and a derivative thereof which can be prepared into medicines for treating and/or preventing hyperproliferative diseases such as cancers, virus-induced infectious diseases and/or cardiovascular diseases, a preparation method, a pharmaceutical composition and application thereof.
Background
Protein kinases are key mediators of cellular function, and by adding phosphatase groups to substrate proteins, can direct a variety of protein activities, localization and overall function, and are involved in orchestrating and activating all cellular activities. Protein kinase is widely existed in human body and plays an important physiological function, and when abnormal regulation or mutation occurs in protein kinase, hyperproliferative diseases, cardiovascular and cerebrovascular diseases, diabetes, inflammation and immune system diseases are often caused.
Cyclin-dependent kinases (CDKs) are an important class of serine/threonine protein kinases, totaling 21 members. Studies have shown that dysregulation of CDK activity has become an important hallmark of cancer. CDKs form complexes with cell cycle (Cyclin) proteins, phosphorylating downstream associated signaling pathway proteins, affecting cell cycle progression. The CDKs can be classified into periodic CDKs and transcriptional CDKs according to the function of the CDKs/Cyclin complex. Of these, CDK9 plays an important role in transcription of intracellular genetic information as a transcriptional CDK. The complex formed by CDK9 and cyclin T1, T2a, T2b or K is positive transcription elongation factor (P-TEFb); when negative transcription elongation factors such as NELF and DSIF participate in negative regulation of cell transcription, transcription is inhibited in an initial complex stage, and P-TEFb is recruited to a system of NELF and DSIF for inhibiting transcription elongation, and acts on a C-terminal domain Ser-2 of a large subunit II (RNA polymerase II) of phosphorylating RNA polymerase to release the negative transcription elongation factors from the transcription complex, thereby promoting continuous transcription. In many malignant cells, cell cycle regulation and transcription abnormalities result from the high activation of CDK protein kinases.
Aberrant activation of CDK9 activity in P-TEFb heterodimers is primarily associated with hyperproliferative diseases (e.g., cancer), virus-induced infectious diseases, or cardiovascular diseases. Biopsy results isolated from chronic lymphocytic leukemia or multiple myeloma patients revealed that overactive CDK9 pathway could increase the expression of anti-apoptotic proteins such as Mcl-1, thereby inhibiting normal apoptosis of cells. In addition, in other malignancies such as lymphomas, neuroblastomas, primary neuroectodermal tumors, rhabdomyosarcomas, and prostate cancers, there are CDK 9-mediated abnormalities in the expression of related pathway genes or protein levels, and these abnormalities are all associated with CDK9 being involved in the expression of anti-apoptotic factors and in the proliferation process of tumor cells.
Disclosure of Invention
The invention aims to: the first object of the invention is to provide a protein kinase inhibitor and a derivative thereof, the second object is to provide a preparation method of the protein kinase inhibitor and the derivative thereof, the third object is to provide a pharmaceutical composition containing the protein kinase inhibitor and/or the derivative thereof, and the fourth object is to provide the 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 shown in the formula (I), wherein the derivative is an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of the solvate, a pharmaceutically acceptable salt or a mixture of the isomers and the diastereoisomer, the enantiomer, the tautomer, the solvate and the salt of the solvate of the compound:
wherein:
bicyclic AB is
V is N or CH;
R 1 or R is 2 Is hydrogen atom, halogen, nitro, amino, hydroxy, carboxyl and C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or C 3 -C 6 Cycloalkyl group, wherein C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or C 3 -C 6 Cycloalkyl groups also contain one or more halogens, hydroxy, amino, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkylamino or C 1 -C 6 An alkoxy substituent;
R 3 is hydrogen atom, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or Het 1 Substituents, wherein C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or Het 1 The substituents also containing one or more halogen, hydroxy, amino, hetero atoms, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or Het 1 A substituent; het 1 Substituents are morpholinyl, morpholinylalkyl, morpholinylalkoxy, morpholinylalkylamino, piperazinyl, piperazinylalkyl, piperazinylalkoxy, piperazinylalkylamino, homopiperazinyl, homopiperazinylalkyl, homopiperazinylalkoxy, homopiperazinylalkylamino, piperidinyl, piperidinylalkyl, piperidinylalkoxy, piperidinylalkylamino, tetrahydropyrrolyl, tetrahydropyrrolylalkyl, tetrahydropyrrolylalkoxy, tetrahydropyrrolylalkylamino, tetrahydrofuranyl, tetrahydrofuranalkyl, tetrahydrofuranalkoxy, tetrahydrofuranalkylamino, tetrahydropyridineA pyranyl, tetrahydropyranyl oxy or tetrahydropyranyl amino group;
R 4 is hydrogen atom, halogen, C 1 -C 6 Alkyl or-C (O) R 7 Wherein R is 7 Is a hydrogen atom or C 1 -C 6 An alkyl group;
R 5 or R is 6 Is hydrogen atom, halogen, C 1 -C 6 Alkyl, cyano or C 1 -C 6 An alkoxy group.
Preferably, the protein kinase inhibitor and its derivative structure are as follows:
bicyclic AB and R 1 、R 2 、R 6 The substituents being co-formed
R 1 Or R is 2 Is hydrogen atom, halogen, nitro, amino, hydroxy, carboxyl and C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or C 3 -C 6 Cycloalkyl group, wherein C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or C 3 -C 6 Cycloalkyl groups also contain one or more halogens, hydroxy, amino, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkylamino or C 1 -C 6 An alkoxy substituent;
R 3 is hydrogen atom, C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or Het 1 Substituents, wherein C 1 -C 6 Alkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or Het 1 The substituents also containing one or more fluorine atoms, hetero atoms, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxy or Het 1 A substituent; het 1 Substituents are morpholinyl, morpholinylalkyl, morpholinylalkoxy, morpholinylalkylamino, piperazinyl, piperazinylalkyl, piperazinylalkoxy, piperazinylalkylamino, homopiperazinyl, homopiperazinylalkyl, homopiperazinylalkoxy, homopiperazinylalkylamino, piperidinyl, piperidinylalkyl, piperidinylalkoxy, piperidinylalkylamino, tetrahydropyrrolyl, tetrahydropyrrolylalkyl, tetrahydropyrrolylalkoxy, tetrahydropyrrolylalkylamino, tetrahydrofuranyl, tetrahydrofuranalkyl, tetrahydrofuranalkoxy, tetrahydrofuranylamino, tetrahydropyranyl, tetrahydropyranoxy or tetrahydropyran alkylamino;
R 4 is hydrogen atom, halogen, C 1 -C 6 Alkyl or-C (O) R 7 Wherein R is 7 Is a hydrogen atom or C 1 -C 6 An alkyl group;
R 5 or R is 6 Is hydrogen atom, fluorine atom, chlorine atom, C 1 -C 3 Alkyl, cyano or C 1 -C 3 An alkoxy group.
Preferably, the protein kinase inhibitor and its derivative structure are as follows:
R 3 is 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-dimethylpiperazinyl, (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, 2-methoxyethylamino, 3-methoxypropylamino, 2, 5-diazabicyclo [2.2.1]Heptyl-2-yl, 4-methylpiperazin-3-one, (S) -3-methylpiperazin, (R) -3-methylpiperazin, (8-azabicyclo [ 3.2.1)]Octane-3-yl) amino, (R) -2-methylpiperazinyl, (S) -2-methylpiperazinyl, pyrrolidinyl, (2-methylOxyethyl) amino, (3-methoxypropyl) amino, (tetrahydropyran-4-yl) amino, (tetrahydrofuran-3-yl) amino, N-dimethylamino or 4, 4-difluoropiperidinyl;
R 4 is a hydrogen atom, halogen, acetyl, propionyl, methyl or ethyl;
R 5 or R is 6 Is hydrogen atom, fluorine atom, chlorine atom, cyano group, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
Preferably, the protein kinase inhibitor and its derivative structure are as follows:
R 4 is a hydrogen atom, halogen, acetyl, propionyl or methyl;
R 5 or R is 6 Is hydrogen atom, fluorine atom, chlorine atom, cyano group, C 1 -C 3 Alkyl 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-morpholino-2H-benzopyran-2-one (I-1),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-2),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholino-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-morpholino-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-morpholino-2H-benzopyran-2-one (I-8),
3-acetyl-7- ((4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-9),
3-acetyl-7- ((4- (benzo [ d ] oxazol-5-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-10),
3-acetyl-7- ((4- (benzo [ d ] thiazol-5-yl) pyrimidin-2-yl) amino) -4-morpholino-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-morpholino-2H-benzopyran-2-one (I-14),
3-acetyl-7- ((4- (2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholino-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-morpholino-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-benzopyran-2-one (I-19),
3-acetyl-7- ((4- (isoquinolin-7-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-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-morpholin-2H-benzopyran-2-one (I-25),
3-acetyl-7- ((4- (indol-1-yl) -pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-26),
3-acetyl-7- ((4- (2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-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-morpholin-2H-benzopyran-2-one (I-28),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholino-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-morpholino-2H-benzopyran-2-one (I-31),
3-acetyl-7- ((4- (2-methyl-3-propyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-32),
3-acetyl-7- ((4- (3-butyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholino-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-benzopyran-2-one (I-38),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- (4-methyl homopiperazinyl) -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-benzopyran-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] hept-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] hept-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-benzopyran-2-one (I-50),
3-acetyl-7- ((4- (1-isopropyl-1H-benzo [ d ] imidazol-6-yl ] pyrimidin-2-yl) amino) -4-morpholino-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-morpholino-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 being 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, the base being an inorganic base containing a basic metal cation, alkaline earth metal cation or ammonium cation salt.
The preparation method of the protein kinase inhibitor and the derivative thereof comprises the following steps:
the primary amine compound 1,3 or 4 is respectively subjected to alkylation reaction with a compound 2 with a trifluoromethanesulfonic acid ester group or halogen to obtain a compound (I);
wherein, the dicyclic AB, V, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 X is a trifluoromethanesulfonate group or a halogen, as defined above;
adding the corresponding acid or alkali solution into the solution of the compound (I) prepared by the method, and removing the solvent under reduced pressure after complete salification to obtain the pharmaceutically acceptable salt of the protein kinase inhibitor.
The pharmaceutical composition of the 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 injection, and the preparations can be added with common medicinal auxiliary materials such as perfume, sweetener, liquid/solid filler, diluent and the like.
The application of the protein kinase inhibitor and the derivatives thereof in preparing medicines for treating and/or preventing hyperproliferative 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 myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, burkitt's 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.
The beneficial effects are 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 CDK9 kinase activity, and CDK9 kinase inhibits IC 50 The optimal value is less than 0.1 mu M, and the nanomolar concentration level is reached; can also inhibit proliferation of MV4-11 tumor cells, and inhibit proliferation of MV4-11 tumor cells 50 The optimal value is less than 0.1 mu M, and the nanomolar concentration level is reached; and has inhibiting effect on various tumor cells, and various tumor cells inhibit IC 50 Values are all less than 0.1. Mu.M, reaching nanomolar concentration levels, optimally less than 10nM;
(2) The protein kinase inhibitor and the derivative and the pharmaceutical composition thereof have wide application and can be prepared into medicaments for treating and/or preventing hyperproliferative diseases, virus-induced infectious diseases and/or cardiovascular diseases; the medicine can exert drug effect at molecular level and cell level, and has more excellent therapeutic effect, and IC 50 The value is optimal and 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 diagram of Compound I-29 1 H-NMR spectrum;
FIG. 2 is a mass spectrum of Compound I-29.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Reagent and material:
the chemical reagent used for preparing the compound is from Shanghai Pi De medical science and technology Co., shanghai Haohong biological medicine science and technology Co., ltd;
CDK9/Cyclin T1 was derived from the American Reaction Biology Corp (Malvern PA) company and MV4-11 tumor cell line was derived from Nanjing An Nakang Biotech Co.
Instrument:
1 H-NMR was measured using a BRUKER AVANCE-300 nuclear magnetic resonance apparatus (Brucker, switzerland) with TMS as the internal standard and displacement value (δ) in ppm; low resolution mass spectrometry was 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-morpholino-2H-benzopyran-2-one (compound I-1)
(1) Synthesis of benzofuran-7-boronic acid pinacol ester (Compound 1 a)
In a 25mL double-necked flask was charged 7-bromobenzofuran (390 mg,2 mmol), pinacol biborate (762 mg,3 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (146 mg,0.2 mmol), sodium carbonate (424 mg,4 mmol), 2mL of water and 12mL of 1, 4-dioxane were reacted at 100℃under nitrogen protection for 12 hours, after the reaction was completed, 50mL of water and 100mL of ethyl acetate were added, the organic layer was collected, and after concentration, 346mg of purified colorless oil was analyzed by column chromatography, 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 double-necked flask was charged compound 1a (293 mg,1.20 mmol), 2-amino-4-chloropyrimidine (130 mg,1.00 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (73 mg,0.1 mmol), sodium carbonate (212 mg,2.00 mmol), 1, 4-dioxane 12mL and purified water 2mL were degassed with nitrogen, the reaction was heated at 100℃for 6h under nitrogen protection, the reaction solution was extracted with ethyl acetate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether=1:1), and recrystallized and purified to give 150mg of pale yellow powder in 71% yield. ESI-MS m/z 212[ M+H ]] + 。
(3) Synthesis of 4-hydroxy-7-methoxy-2H-benzopyran-2-one (Compound 2 a)
2-hydroxy-4-methoxy group was added to a 500mL eggplant-shaped bottleAcetophenone (10.0 g,60.20 mmol) and diethyl carbonate (10.7 g,90.30 mmol), anhydrous toluene (100 mL) were dissolved, sodium hydride (12.0 g,300.90 mmol) was dissolved in 50mL of anhydrous toluene, dropwise added to the reaction solution with a constant pressure dropping funnel under ice bath conditions, stirred under ice bath for 30min after the completion of the dropwise addition, then heated at 100 ℃ for reaction for 4h, the reaction solution was cooled to room temperature, quenched with ice water dropwise in ice bath conditions to quench excess sodium hydride, extracted with diethyl ether (100 mL. Times.3), the aqueous phase was collected, the pH was adjusted to 2 to 3 with 2N HCl, a large amount of white precipitate was precipitated, filtered with suction and dried to obtain a white solid (10.67 g) in 92% yield. ESI-MS m/z 215[ M+Na ]] + 。 1 H-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,OCH 3 )。
(4) Synthesis of 3-acetyl-4-hydroxy-7-methoxy-2H-benzopyran-2-one (Compound 2 b)
Compound 2a (3.00 g,15.61 mmol), glacial acetic acid 16mL and phosphorus oxychloride 5.6mL are added into a 100mL eggplant-shaped bottle, the reaction is heated for 30min at 105 ℃, the reaction solution is cooled to room temperature, the solid is separated out after standing, the solid precipitate is filtered to obtain a crude product, and then absolute ethyl alcohol is used for recrystallization and purification to obtain white solid 132.65g, and the yield is 72%. ESI-MS m/z 257[ M+Na ]] + 。 1 H-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,OCH 3 ),2.64(s,3H,COCH 3 )。
(5) Synthesis of 3-acetyl-7-methoxy-4-morpholinyl-2H-benzopyran-2-one (Compound 2 c)
In a 100mL eggplant-shaped bottle, compound 2b (1.00 g,4.27 mmol) and morpholine (3.72 mL,42.70 mmol) were added, the temperature was raised to 160℃for 2h, and TLC detected the disappearance of the starting material. The reaction solution was cooled to room temperature, 50mL of water was added, extraction (50 ml×3) was performed with dichloromethane, the organic layers were combined, washed (25 ml×3) with saturated sodium chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off 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 in a yield of 52%. ESI-MS m/z 326[ M+Na ]] + 。 1 H-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,OCH 3 ),3.24–3.72(m,8H,2×NCH 2 CH 2 O),2.34(s,3H,COCH 3 )。
(6) Synthesis of 3-acetyl-7-hydroxy-4-morpholinyl-2H-benzopyran-2-one (Compound 2 d)
Compound 2c (1.00 g,3.30 mmol) and aluminum trichloride (1.45 g,10.90 mmol) were added to a 100mL eggplant-shaped bottle, 30mL of anhydrous toluene was dissolved, reflux was performed at 100 ℃ for 4h, the disappearance of the starting material point was detected by tlc, the reaction solution was cooled to room temperature, the excess solvent was removed under reduced pressure, and column chromatography purification (petroleum ether: ethyl acetate=1:2) was performed to obtain 653mg of white solid with a yield of 68%. ESI-MS m/z 312[ M+Na ]] + 。
(7) Synthesis of 3-acetyl-4-morpholino-2-oxo-2H-benzopyran-7-yl-trifluoromethanesulfonate (Compound 2-1)
In a 25mL eggplant-shaped bottle, compound 2d (289 mg,1.00 mmol) and triethylamine (156. Mu.L, 1.20 mmol) were added, 10mL of anhydrous dichloromethane was dissolved, stirred under ice-salt bath for 15min, and trifluoromethanesulfonic anhydride (201. Mu.L, 1.20 mmol) was added dropwise, stirred at room temperature for 1h, and TLC detected the disappearance of the starting material. Pouring the reaction solution into saturated NaHCO 3 50mL of the solution was extracted with dichloromethane (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 ]] + 。 1 H-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×NCH 2 CH 2 O),2.39(s,3H,COCH 3 )。
(8) Synthesis of 3-acetyl-7- ((4- (benzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (compound I-1)
In a 25mL double-necked flask under nitrogen protection, compound 1-1 (127 mg,0.60 mmol), compound 2-1 (274 mg,0.66 mmol), palladium acetate (14 mg,0.06 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (36 mg,0.06 mmol) and cesium carbonate (399mg, 1.20 mmol) were added, 10mL of anhydrous toluene was added, and the reaction mixture was heated at 100℃for 2 to 6 hours, filtered and concentrated, and the residue was purified with SiColumn chromatography separation and purification (dichloromethane: methanol=60:1) gave 83mg of solid after recrystallization and purification in 29% yield. ESI-MS m/z 483[ M+H ]] + 。 1 H 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,COCH 3 )。
By operating in a similar manner to example 1, the following compounds were prepared:
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example 2: synthesis of 7- ((4- (1H-indol-1-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-21)
(1) Synthesis of 4- ((1H-indol-1-yl) pyrimidin-2-amine (compound 3-1)
In a 50mL single necked flask, indole (702 mg,6 mmol), 2-amino-4-chloropyrimidine (650 mg,5 mmol), cesium carbonate (3.26 g,10 mmol) and 15mL DMF were added, and after completion of the reaction, 100mL of water was added, 3X 50mL of ethyl acetate was used for extraction, and the organic layer was collected, concentrated and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give 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)
Using Compound 3-1 (126 mg,0.6 mmol) and Compound 2-1 (218 mg,0.66 mmol) as raw materials, referring to the preparation method of Compound I-1, compound I-21 was obtained as a yellow solid 173mg in 60% yield. ESI-MS m/z 483[ M+H ]] + 。 1 H-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×NCH 2 CH 2 O),2.35(s,3H,COCH 3 )。
By operating in a similar manner to example 2, the following compounds were prepared:
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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)
(1) Synthesis of 5-bromo-2-methyl-2H-indazole (Compound 4 a)
In a 250mL single-necked flask, 5-bromoindazole (9.95 g,50 mmol) was added, 150mL DMF was added for dissolution, sodium hydride (1.44 g,60 mmol) was slowly added under ice bath, methyl iodide (8.52 g,60 mmol) was added after stirring for 30min, after reaction at room temperature for 5h, the reaction was quenched with saturated solution of sodium thiosulfate, extracted with ethyl acetate and concentrated, and the residue was chromatographed on silica gel columnAnalytical purification (petroleum ether: ethyl acetate=5:1) afforded 4.1g of a pale yellow solid in 32.4% yield. 1 H-NMR(300MHz,DMSO-d 6 )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 4 b)
Under the protection of nitrogen, compound 4a (2.1 g,10 mmol) was added into a 50mL double-necked flask, 10mL of anhydrous tetrahydrofuran was added for dissolution, LDA (15 mmol) was slowly added at-78 ℃, the temperature was raised to 0 ℃ for reaction for 10min, acetone (1.1 mL,15 mmol) was added at-78 ℃ for reaction, the reaction solution was slowly warmed to room temperature for reaction for 12h, the reaction solution was filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to obtain yellow solid 1.0g with a yield of 37%. 1 H-NMR(300MHz,CDCl 3 )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,NCH 3 ),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 4 c)
In a 50mL single-necked flask, compound 4b (538 mg,2 mmol), triethylsilane (3.20 mL,20 mmol) was added, and the mixture was dissolved in 20mL of methylene chloride, trifluoroacetic acid (1.50 mL,20 mmol) was slowly added, and reacted at room temperature for 24 hours, and saturated sodium bicarbonate solution, methylene chloride extraction, drying over anhydrous sodium sulfate, and silica gel column chromatography separation and purification (petroleum ether: ethyl acetate=6:1) were added to give 260mg of yellow oil in a yield of 51%. 1 H NMR(300MHz,CDCl 3 )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,NCH 3 ),3.27-3.36(m,1H,CH(CH 3 ) 2 ),1.42(d,J＝7.1Hz,6H,CH 3 2 (CH)).
(4) Synthesis of 3-isopropyl-2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-indazole (Compound 4 d)
Using compound 4c (255 mg,1 mmol) as a starting material, with reference to the method for synthesizing compound 1a, compound 4d as a white solid 245mg was obtained in 82% yield.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)
Using compound 4d (200 mg,0.67 mmol) as a raw material, referring to the synthetic method of compound 1-1, compound 4-1 was obtained as 165mg of white solid with a yield of 92%. ESI-MS m/z 268[ M+H ]] + 。 1 H-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,NCH 3 ),3.54-3.63(m,1H,CH(CH 3 ) 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 (160 mg,0.6 mmol) and compound 2-1 (218 mg,0.66 mmol) as raw materials, compound I-29 as a white solid was obtained in 115mg, yield 36% by referring to the synthetic method of compound I-1. ESI-MS m/z 539[ M+H ]] + 。 1 H-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,NCH 3 ),3.42-3.81(m,8H,2×NCH 2 CH 2 O),3.19-3.30(m,1H,CH(CH 3 ) 2 ),2.36(s,3H,COCH 3 ),1.55(d,J＝7.0Hz,6H,CH 3 2 (CH))。
By operating in a similar manner to example 3, the following compounds were prepared:
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example 4: inhibition of CDK9 kinase activity by Compounds
The synthesized compounds were tested for their inhibitory activity on CDK9 by HotSpotSM kinase method/Fluorescence Resonance Energy Transfer (FRET) method by the American Reaction Biology Corp. (Malvern PA), for example CDK9/Cyclin T1.
The specific operation method comprises the following steps: CDK9/Cyclin T1 was diluted to the appropriate concentration with kinase diluent for use. The kinase reaction mixture contains CDK9/Cyclin T1, peptide substrate, HEPES (pH 7.5), BRIJ-35, and MgCl 2 And EDTA. CDK9phospho-peptide substrate was used as a 100% phosphorylation control, and no ATP was added as a 0% phosphorylation control. After 1h of reaction at room temperature, development Reagent A was added to the reaction system in moderate dilution. The reaction was continued at room temperature for 1 hour, and Stop Reagent was added to Stop the reaction. The excitation light wavelength was 400nm, and fluorescence intensities at 445nm (coumarin) and 520nm (fluorescein) were detected. Test compound inhibition (n=2) was calculated as per the formula, IC 50 The results of the analysis are shown in Table 1, which are obtained by plotting the percent inhibition and the logarithmic concentration values.
Inhibition of CDK9 kinase Activity by Compounds of Table 1
| Cpd. | IC 50 (μM) | Cpd. | IC 50 (μM) | Cpd. | IC 50 (μM) | Cpd. | IC 50 (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 that: "A" represents IC 50 The value is less than 0.1. Mu.M, and "B" represents IC 50 The value is between 0.1. Mu.M and 1. Mu.M, and "C" represents IC 50 The value is greater than 1. Mu.M.
As shown in Table 1, all test compounds inhibited CDK9 kinase activity and wherein compounds I-2-I-4, I-6-I-7, I-9, I-13, I-15, I-21-I-22, I-29-I-31, I-34-I-38, I-40-I-50, and I-53-I-54 inhibited CDK9 kinase IC 50 Values are all less than 0.1 μm, allowing nanomolar concentration levels to be achieved; IC for inhibiting CDK9 kinase by other compounds 50 Values are in the micromolar range.
Example 5: antiproliferative effect of compounds on tumor cells
Experimental principle: the MTT method for measuring the inhibition of leukemia cell line MV4-11 tumor cell line by MTT method and in vitro test of anti-tumor proliferation activity is a method for detecting survival and growth of cells, wherein the detection principle is that NADP related dehydrogenase (succinate dehydrogenase) in mitochondria of living cells can reduce exogenous MTT into insoluble blue purple crystalline Formazan (Formazan) and deposit in cells, and dead cells have no function. Purple crystal formazan in cells is dissolved by using dimethyl sulfoxide (DMSO) or triple solution (10% SDS-5% isobutanol-0.01 mol/L HCl), and the light absorption value (OD value) at 570nm wavelength is detected by an ELISA detector, so that the living cell quantity can be indirectly reflected.
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 after suspending cell plate), and culturing at 37deg.C with 5% CO 2 After culturing for 48h or 72h, adding MTT, culturing for 4h, dissolving in DMSO, crystallizing, measuring OD value at 570nm wavelength by ELISA, and calculating inhibition rate and IC of the compound 50 Values, analytical results are shown in Table 2.
Antiproliferative effect of compounds of Table 2 on MV4-11 tumor cells
| Cpd. | IC 50 (μM) | Cpd. | IC 50 (μM) | Cpd. | IC 50 (μM) | Cpd. | IC 50 (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 that: "A" represents IC 50 The value is less than 0.1. Mu.M, and "B" represents IC 50 The value is between 0.1. Mu.M and 1. Mu.M, and "C" represents IC 50 Values greater than 1 μm, n.d. represent untested.
As shown in Table 2, all of the test compounds inhibited MV4-11 tumor cells, wherein compounds I-13, I-29, I-35-I-38 and I-40-I-50 inhibited the IC of MV4-11 tumor cells 50 Values are all less than 0.1 μm, allowing nanomolar concentration levels to be achieved; IC of compounds I-2-I-3, I-6, I-8-I-12, I-14-I-20, I-25, I-30, I-31, I-34 and I-53-I-54 inhibiting MV4-11 tumor cells 50 Values are in the micromolar range.
Example 6: antitumor cell profiling of compounds
Experimental materials: the materials used in the experiments were all from the national cancer center.
The experimental 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 a plate density of 5,000 to 40,000 cells/well at a concentration of 100 μl, depending on the doubling time of the individual cell lines. After cell inoculation, the microtiter plates were incubated at 37℃with 5% CO prior to the addition of the test drugs 2 Incubate for 24h with 95% air and 100% relative humidity. After the drug was added, the plate was cooled to 37℃with 5% CO 2 Incubate for another 48h with 95% air and 100% relative humidity. After staining, unbound dye was removed by washing 5 times with 1% acetic acid and the plate was air dried. The bound stains were then dissolved with 10mM tri zma base and absorbance was read on an automatic microplate reader at a wavelength of 515nm to calculate compound GI 50 Values.
Screening anti-tumor cell spectrum for partial tumor cell strain in NCI-60 cell library for compound I-29, and testing the obtained GI 50 The values are shown in Table 3.
TABLE 3 NCI-60 cell Spectrum of Compound I-29
As shown in Table 3, the compound I-29 has an inhibitory effect on various solid organ cancers, and the inhibitory concentration reaches the nanomolar concentration level; including but not limited to various hematological malignancies such as acute myelogenous leukemia, chronic myelogenous 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 (9)
1. A protein kinase inhibitor and derivatives thereof, wherein the protein kinase inhibitor and derivatives thereof have the structure of formula (I), and wherein the derivatives are pharmaceutically acceptable salts of the compounds:
wherein:
bicyclic AB and R 1 、R 2 、R 6 The substituents being co-formed
V is N;
R 1 or R is 2 Is hydrogen atom, C 1 -C 6 Alkyl, wherein C 1 -C 6 The alkyl groups also containing one or more C' s 1 -C 6 An alkyl substituent;
R 3 is morpholin-4-yl, piperazinyl, piperidinyl, 4-methylpiperazineAmino, homopiperazinyl, N-methyl homopiperazinyl, (2-methoxyethyl) amino, (3-methoxypropyl) amino, (N-methylpiperidin-4-yl) amino, 2, 5-diazabicyclo [2.2.1]Heptyl-2-yl, (8-azabicyclo [ 3.2.1)]Octan-3-yl) amino;
R 4 is hydrogen atom, halogen, C 1 -C 6 Alkyl or-C (O) R 7 Wherein R is 7 Is a hydrogen atom or C 1 -C 6 An alkyl group;
R 5 or R is 6 Is hydrogen atom, halogen, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group.
2. The protein kinase inhibitor and derivatives thereof according to claim 1, wherein the protein kinase inhibitor and derivatives thereof are of the structure:
R 4 is hydrogen atom, halogen, C 1 -C 6 Alkyl or-C (O) R 7 Wherein R is 7 Is a hydrogen atom or C 1 -C 6 An alkyl group;
R 5 or R is 6 Is hydrogen atom, fluorine atom, chlorine atom, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
3. The protein kinase inhibitor and derivatives thereof according to claim 1, wherein the protein kinase inhibitor and derivatives thereof are of the structure:
R 4 is a hydrogen atom, halogen, acetyl, propionyl, methyl or ethyl;
R 5 or R is 6 Is hydrogen atom, fluorine atom, chlorine atom, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
4. The protein kinase inhibitor and derivatives thereof according to claim 1, wherein the protein kinase inhibitor and derivatives thereof are of the structure:
R 4 is a hydrogen atom, halogen, acetyl or methyl;
R 5 or R is 6 Is hydrogen atom, fluorine atom, chlorine atom, C 1 -C 3 Alkyl or methoxy.
5. A protein kinase inhibitor and derivatives thereof, wherein the protein kinase inhibitor is any one of the following compounds:
3-acetyl-7- ((4- (benzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-1),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-2),
3-acetyl-7- ((4- (4-fluorobenzofuran-7-yl) pyrimidin-2-yl) amino) -4-morpholino-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-morpholino-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-morpholino-2H-benzopyran-2-one (I-8),
3-acetyl-7- ((4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-morpholino-2H-benzopyran-2-one (I-9),
3-acetyl-7- ((4- (imidazo [1,2-a ] pyridin-6-yl) pyrimidin-2-yl) amino) -4-morpholinyl-2H-benzopyran-2-one (I-13),
7- ((4- (1H-indol-5-yl) pyrimidin-2-yl) amino) -3-acetyl-4-morpholinyl-2H-benzopyran-2-one (I-16),
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),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4-morpholino-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-morpholino-2H-benzopyran-2-one (I-31),
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-benzopyran-2-one (I-38),
3-acetyl-7- ((4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-yl) amino) -4- ((1-methylpiperidin-4-yl) amino) -2H-benzopyran-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] hept-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] hept-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-benzopyran-2-one (I-50),
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).
6. The protein kinase inhibitor and its derivatives 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 being 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 being an inorganic base containing a basic metal cation.
7. A process for the preparation of a protein kinase inhibitor and derivatives thereof as claimed in any one of claims 1 to 6, wherein the process comprises:
the primary amine compound 1,3 or 4 is respectively subjected to alkylation reaction with a compound 2 with a trifluoromethanesulfonic acid ester group or halogen to obtain a compound (I);
wherein, the dicyclic AB, V, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 The definition of (c) is as defined in any one of claims 1 to 4, X is a trifluoromethanesulfonate group or halogen;
adding the corresponding acid or alkali solution into the solution of the compound (I) prepared by the method, and removing the solvent under reduced pressure after complete salification to obtain the pharmaceutically acceptable salt of the protein kinase inhibitor.
8. A pharmaceutical composition comprising a protein kinase inhibitor or a derivative thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
9. Use of a protein kinase inhibitor and derivatives thereof according to any one of claims 1 to 6 for the preparation of a medicament for the treatment and/or prophylaxis of lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer, breast cancer, renal cancer, nervous system tumors, lymphomas or leukemias.
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| CN101374818A (en) * | 2006-01-26 | 2009-02-25 | 阿斯利康(瑞典)有限公司 | Pyrimidine derivatives |
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