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Protein kinase inhibitor and derivatives thereof, preparation method, pharmaceutical composition and application

A technology of protein kinase inhibitors and derivatives, which is applied in the field of protein kinase inhibitors and derivatives, can solve the problems of cell cycle regulation and transcription abnormality, and achieve the effects of simple preparation method, excellent therapeutic effect and easy operation

Pending Publication Date: 2021-12-17
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In many malignant tumor cells, due to hyperactivation of CDK protein kinases, cell cycle regulation and transcriptional abnormalities

Method used

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  • Protein kinase inhibitor and derivatives thereof, preparation method, pharmaceutical composition and application
  • Protein kinase inhibitor and derivatives thereof, preparation method, pharmaceutical composition and application
  • Protein kinase inhibitor and derivatives thereof, preparation method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: 3-acetyl-7-((4-(benzofuran-7-yl)pyrimidin-2-yl)amino)-4-morpholinyl-2H-benzopyran-2-one ( Synthesis of compound I-1)

[0109]

[0110] (1) Synthesis of benzofuran-7-boronic acid pinacol ester (compound 1a)

[0111]Add 7-bromobenzofuran (394mg, 2mmol), pinacol diborate (762mg, 3mmol), [1,1'-bis(diphenylphosphino)ferrocene] to a 25mL two-necked flask Palladium chloride (146mg, 0.2mmol), sodium carbonate (424mg, 4mmol), 2mL of water and 12mL of 1,4-dioxane, under nitrogen protection, react at 100°C for 12h, after the reaction, add 50mL of water and 100 mL of ethyl acetate, the organic layer was collected, concentrated and purified by column chromatography to obtain 346 mg of a colorless oil, with a yield of 71%. ESI-MS m / z:245[M+H] + .

[0112] (2) Synthesis of 4-(benzofuran-7-yl)pyrimidin-2-amine (compound 1-1)

[0113] Add compound 1a (293mg, 1.20mmol), 2-amino-4-chloropyrimidine (130mg, 1.00mmol), [1,1'-bis(diphenylphosphino)ferrocene] di Palladium c...

Embodiment 2

[0131] Example 2: 7-((4-(1H-indol-1-yl)pyrimidin-2-yl)amino)-3-acetyl-4-morpholinyl-2H-benzopyran-2-one Synthesis of (I-21)

[0132]

[0133] (1) Synthesis of 4-((1H-indol-1-yl)pyrimidin-2-amine (compound 3-1)

[0134] In a 50mL single-necked bottle, add indole (702mg, 6mmol), 2-amino-4-chloropyrimidine (650mg, 5mmol), cesium carbonate (3.26g, 10mmol) and 15mL DMF, react overnight at 100°C, After the reaction, add 100mL of water, extract with 3×50mL of ethyl acetate, collect the organic layer, concentrate and separate and purify by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain 370mg of white solid, yield 35% . ESI-MS m / z:211[M+H] + .

[0135] (2) 7-((4-(1H-indol-1-yl)pyrimidin-2-yl)amino)-3-acetyl-4-morpholinyl-2H-benzopyran-2-one ( Compound I-21) Synthesis

[0136] Using compound 3-1 (126 mg, 0.6 mmol) and compound 2-1 (278 mg, 0.66 mmol) as raw materials, referring to the preparation method of compound I-1, 173 mg of compound I-21 was obtained ...

Embodiment 3

[0140] Example 3: 3-acetyl-7-((4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino)-4-morpholinyl Synthesis of -2H-benzopyran-2-one (I-29)

[0141]

[0142] (1) Synthesis of 5-bromo-2-methyl-2H-indazole (compound 4a)

[0143] Add 5-bromoindazole (9.95g, 50mmol) into a 250mL single-necked flask, add 150mL DMF to dissolve, slowly add sodium hydride (1.44g, 60mmol) under ice-cooling, add iodomethane (8.52g, 60mmol) after stirring for 30min , after reacting at room temperature for 5 h, the reaction was quenched by adding 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 obtain light yellow Solid 4.1g, yield 32.4%. 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).

[0144] (2) Synthesis of 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (compound 4b)

...

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Abstract

The invention discloses a protein kinase inhibitor and derivatives thereof, a preparation method, a pharmaceutical composition and application. The compound structure of the protein kinase inhibitor is as shown in formula (I). The protein kinase inhibitor derivatives relate to an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of the solvate, a pharmaceutically acceptable salt or a mixture thereof of the protein kinase inhibitor. The protein kinase inhibitor and the derivatives thereof have an efficient inhibition effect on protein kinase and can be used for preparing drugs for treating and / or preventing hyperproliferative diseases, virus-induced infectious diseases and / or cardiovascular diseases, and the prepared drugs can exert drug effects at the molecular level and the cellular level, and are wide in application. The synthesis method of the compound is simple and easy to operate.

Description

technical field [0001] The present invention relates to a protein kinase inhibitor and its derivatives, preparation method, pharmaceutical composition and application, especially to a protein kinase inhibitor that can be prepared for treating and / or preventing hyperproliferative diseases such as cancer, virus-induced infectious diseases and / or A protein kinase inhibitor and a derivative thereof for cardiovascular disease drugs, a preparation method, a pharmaceutical composition and applications. Background technique [0002] Protein kinases are key regulators of cell function. By adding phosphatase groups to substrate proteins, they can guide the activity, location and overall function of various proteins, and participate in the orchestration and activation of all cellular activities. Protein kinases exist widely in the human body and play important physiological functions. When protein kinases are abnormally regulated or mutated, it is easy to cause hyperproliferative disea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D471/04C07D413/14C07D417/14C07D487/08A61P31/12A61P9/00A61P35/00A61P35/02A61K31/5377A61K31/506A61K31/551
CPCC07D405/14C07D471/04C07D413/14C07D417/14C07D487/08A61P31/12A61P9/00A61P35/00A61P35/02
Inventor 陆涛陈亚东黄健航董瑞楠王信人李红玫唐伟方
Owner CHINA PHARM UNIV
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