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Benzimidazole compound kinase inhibitor and preparation method and application thereof

A compound, a technology of a general formula compound, applied in the field of drug development, can solve problems such as good therapeutic effect

Active Publication Date: 2021-01-15
JIANGSU HANSOH PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some compounds including Eli Lilly's Abemaciclib (LY2835219) are in clinical research, and all of them have shown good therapeutic effects

Method used

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  • Benzimidazole compound kinase inhibitor and preparation method and application thereof
  • Benzimidazole compound kinase inhibitor and preparation method and application thereof
  • Benzimidazole compound kinase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] 1,4-diazoheptan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole- Preparation of 6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

[0149]

[0150] Step 1: Preparation of tert-butyl 4-(6-chloro-2-methylnicotinyl)-1,4-diazoheptane-1-carboxylate

[0151]

[0152] 6-Chloro-2-methylnicotine acid (0.7g, 4.1mmol), tert-butyl 1,4-diazoheptane-1-carboxylate (1.0g, 4.9mmol), TEA (1.2g ,12.2mmol) dissolved in CH 2 Cl 2 (15 mL), HATU (1.87 g, 4.9 mmol) was added, and the reaction was stirred at room temperature for two hours. CH 2 Cl 2 (30mL) diluted with NaHCO 3 Solution (30mL), washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated and column chromatography [eluent: CH 2 Cl 2 ~CH 2 Cl 2 / MeOH (10:1)] to get the product tert-butyl 4-(6-chloro-2-methylnicotyryl)-1,4-diazoheptane-1-carboxylate (1.4g, yield 96%).

[0153] MS m / z(ESI):354.1[M+H] + .

[0154] The second step: the preparation of 5-fluor...

Embodiment 2

[0169] 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino) Preparation of -2-methylpyridin-3-yl)-4-(methylamino)piperidin-2-one

[0170]

[0171] The first step: preparation of (1-(6-chloro-2-methylpyridin-3-yl)-2-oxopiperidin-4-yl)carbamate tert-butyl ester

[0172]

[0173] 3-Bromo-6-chloro-2-methylpyridine (200mg, 0.969mmol), (2-oxopiperidin-4-yl) tert-butyl carbamate (249mg, 1.162mmol), Pd 2 (dba) 3 (89mg, 0.0972mmol), Xantphos (112mg, 0.194mmol), cesium carbonate (947mg, 2.907mmol) were stirred overnight in dioxane (10mL) at 100°C under nitrogen protection, cooled, concentrated and obtained by column chromatography ( 31mg, yield 9.4%).

[0174] MS m / z(ESI):340.1,342.1[M+H] + .

[0175] The second step: (1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 Preparation of -yl)amino)-2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl)carbamate tert-butyl ester

[0176]

[0177] 5-fluoro...

Embodiment 3

[0189] (4-(cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d] Preparation of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

[0190]

[0191] Step 1: Preparation of 1-(6-chloro-2-methylnicotinoyl)piperidin-4-one

[0192]

[0193] Add 6-chloro-2-methylnicotinic acid (1.0g, 5.8mmol), piperidin-4-one (866mg, 8.7mmol), HATU (2.2g, 17.5mmol), DIEA (2mL) into dichloromethane in sequence (50mL). The reaction was stirred at room temperature for 4 hours, and LCMS showed that the reaction was complete. The reaction solution was separated by adding dichloromethane (50mL) and water (50mL), and the organic phase was washed with saturated sodium bicarbonate (3×20 mL). Dry over sodium sulfate, filter and concentrate. The remaining crude product was purified by flash silica gel column (CH 2 Cl 2 :MeOH=20:1) to obtain the product 1-(6-chloro-2-methylnicotinoyl)piperidin-4-one (1.2g, 81%).

[0194] The second step: the prep...

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Abstract

The invention provides a benzimidazole compound kinase inhibitor and a preparation method and application thereof. Specifically, the invention provides a compound as shown in a general formula (I), apreparation method thereof and a pharmaceutical composition containing the compound, and application of the compound as a benzimidazole compound kinase inhibitor in the preparation of drugs for preventing and / or treating cancers or tumor-related diseases, especially bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital tract cancer, testis cancer, gastrointestinal stromal tumor or prostate tumor.

Description

[0001] This application is a divisional application of the Chinese patent application with the application number 201780050147.3, the application date is September 6, 2017, and the invention title is "Benzimidazole Compound Kinase Inhibitor and Its Preparation Method and Application". technical field [0002] The invention belongs to the field of drug development, and in particular relates to a benzimidazole compound kinase inhibitor and a preparation method and application thereof. Background technique [0003] Cyclin-dependent kinase (CDK) is a class of serine (Ser) / threonine (Thr) kinases. This family contains 13 members, which are divided into A-L for cyclin. Different CDKs and cyclins form CDK-cyclin complexes, through CDK kinase activity, catalyze the phosphorylation of different substrates, initiate DNA synthesis, and realize the advancement and transformation of different phases of the cell cycle; regulate gene transcription, participate in Cell growth, proliferation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00
CPCC07D401/14A61P35/00A61P35/04A61K31/517
Inventor 刘世强周远峰吴雪松包如迪
Owner JIANGSU HANSOH PHARMA CO LTD
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