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Kinase inhibitor of benzimidazole compound and its preparation method and application

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: 2020-11-03
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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  • Kinase inhibitor of benzimidazole compound and its preparation method and application
  • Kinase inhibitor of benzimidazole compound and its preparation method and application
  • Kinase inhibitor of benzimidazole compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] 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

[0148]

[0149] Step 1: Preparation of tert-butyl 4-(6-chloro-2-methylnicotinyl)-1,4-diazoheptane-1-carboxylate

[0150]

[0151] 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 chromatographed [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%).

[0152] MS m / z(ESI): 354.1[M+H] + .

[0153] The second step: the preparation of 5-fl...

Embodiment 2

[0168] 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

[0169]

[0170] The first step: preparation of (1-(6-chloro-2-methylpyridin-3-yl)-2-oxopiperidin-4-yl)carbamate tert-butyl ester

[0171]

[0172] 3-Bromo-6-chloro-2-methylpyridine (200mg, 0.969mmol), tert-butyl (2-oxopiperidin-4-yl)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, and concentrated to obtain the product by column chromatography ( 31 mg, yield 9.4%).

[0173] MS m / z (ESI): 340.1, 342.1 [M+H] + .

[0174] 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

[0175] ...

Embodiment 3

[0188] (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

[0189]

[0190] Step 1: Preparation of 1-(6-chloro-2-methylnicotinoyl)piperidin-4-one

[0191]

[0192] 6-Chloro-2-methylnicotinic acid (1.0g, 5.8mmol), piperidin-4-one (866mg, 8.7mmol), HATU (2.2g, 17.5mmol), DIEA (2mL) were sequentially added to dichloromethane (50mL). The reaction was stirred at room temperature for 4 hours, LCMS showed that the reaction was complete, the reaction solution was separated by adding dichloromethane (50mL) and water (50mL), the organic phase was washed with saturated sodium bicarbonate (3x20mL), the organic phase was separated, and washed with anhydrous 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)piperidi...

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Abstract

Provide a compound represented by general formula (I), its preparation method and pharmaceutical composition containing the compound, and its use as a benzimidazole compound kinase inhibitor in the preparation of prevention and / or treatment of cancer or tumor-related diseases, especially Bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female reproductive tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor Uses in medicine.

Description

technical field [0001] 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 [0002] 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, dormancy or apoptosis. Therefore, CDKs have important functions in the regulation of proliferation and death of all cells, including tumor cells and normal cells. Among them, the CDK4 / 6-Cyclin D complex plays an important role in the transformation of cells from G1 phase to S phase. ...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/4184A61P35/00A61P35/04
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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