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Pyrimidine or pyridopyridone compound and its preparation method and application

A kind of technology of pyridopyridone and compound, applied in the field of pharmaceutical preparation, can solve problems such as lack of selectivity

Active Publication Date: 2018-10-02
GUANGZHOU BEBETTER MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Based on this, the object of the present invention is to overcome the lack of selectivity of CDK inhibitors in the prior art, and provide a pyrimidine or pyridopyridone compound, which can selectively inhibit cell cycle-dependent kinases (Cdks) CDK4 and CDK6 can be used in the treatment of various diseases, especially malignant tumors, caused by the disorder of cell cycle control that CDK4 and CDK6 participate in

Method used

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  • Pyrimidine or pyridopyridone compound and its preparation method and application
  • Pyrimidine or pyridopyridone compound and its preparation method and application
  • Pyrimidine or pyridopyridone compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Preparation of Example 1 Compound 1 (prepared according to scheme one line)

[0150] Step 1a: Preparation of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic Acid Ethyl Ester) (compound 102): 4 -Chloro-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester (101) (30.06 g, 129 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (300 mL), then cyclopentylamine (12.3 g, mol, 1.1 eq) and triethylamine (39.6 g, 387 mmol, 3.0 eq) were gradually and slowly added to the solution, and the mixture was stirred at room temperature for 14 hours. The precipitated salt was filtered, and the solvent was removed by concentration under reduced pressure. The resulting oil was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate. The salt was filtered, and the solvent was removed by concentration under reduced pressure to obtai...

Embodiment 2

[0166] Preparation of Example 2 Compound 3 (prepared according to scheme one line)

[0167] The preparation of compound 110-3 is as in step 1i in Example 1, except that 2-benzyloctahydropyrrolyl[3,4-c]pyrrole is replaced by 2.5-bicyclo[2.2.1]heptane- 2 – tert-butyl formate, prepared to obtain tert-butyl 5-(6-aminopyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (tert-butyl5- (6-aminopyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate) (compound 110-3). Target product characterization data: LCMS(ESI):m / z 291[M+1] + .

[0168] The preparation of compound 111-3, the synthesis method is the same as 1j in Example 1, only the compound 110-1 is replaced by 110-3, and 5-(6-((6-bromo-8-cyclopentyl- 5-methyl-7-oxo-7,8-dihydropyrimidin[2,3-d]-2-pyrimidine)amine)-3-pyridine)-2,5-diazabicyclo[2.2.1] Heptane-2-carboxylic acid tert-butyl ester (tert-butyl5-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2 -yl)amino)pyridin-3-yl)-2,5-diazabicy...

Embodiment 3

[0171] Preparation of Example 3 Compound 2 (prepared according to scheme two lines)

[0172] Step 3a: Preparation of 5-iodine-2-chloro-4-cyclopentylaminopyrimidine (5-iodine-2-chloro-4-cyclopentyl-aminopyrimidine) (compound 202): 2,4-dichloro-5- Iodopyrimidine (Compound 201) (80.00 g, 0.291 mol, 1.0 eq) was dissolved in ethanol (800 ml), triethylamine (88.18 g, 0.873 mol, 3.0 eq) was added, and then the mixture was stirred under an ice bath, When the temperature dropped to 0°C-5°C, cyclopentylamine (49.50 g, 0.582 mol, 2.0 equivalents) was added dropwise, and the dropwise addition was completed in 30 minutes, and then kept stirring at about 5°C. HPLC monitoring, when the peak area ratio of 2,4-dichloro-5-iodopyrimidine is less than 1%, the reaction is terminated. The reaction solution was concentrated, diluted with ethyl acetate (300 mL), added with water (300 mL), extracted and separated. The aqueous phase was extracted with ethyl acetate (200 mL x 2). The organic phases w...

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Abstract

The invention discloses a pyrimido or pyridopyridone compound shown in the formula I and its preparation method and use and belongs to the technical field of drug preparation. The pyrimido or pyridopyridone compound can efficiently and selectively inhibit cyclin-depedent kinase (Cdks) CDK4 and CDK6 activity and prevent tumor cell division through inhibiting CDK4 / CDK6. The pyrimido or pyridopyridone compound can be used for treating various diseases caused through imbalance of cell cycle control based on CDK4 and CDK6 and is especially suitable for cancer treatment.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a pyrimidine or pyridopyridone compound and its preparation method and application. Background technique [0002] Cyclin-dependent kinase (CDK) and cyclin (cyclin) are important factors in cell cycle regulation. CDK can combine with cyclin to form a heterodimer, in which CDK is the catalytic subunit, and cyclin is the regulatory subunit, forming various cyclin-CDK complexes, phosphorylating different substrates, and promoting and regulating different phases of the cell cycle. Transformation. [0003] There are at least nine CDKs in mammals. Cell transition from G1 phase to S phase is mainly controlled by CDK kinases in G1 phase. CDK kinases that bind to cell cycle proteins in the G1 phase mainly include CDK2, CDK4 and CDK6. Cyclin D mainly binds to CDK4 and CDK6 and regulates the activity of the latter; cyclin E binds to CDK2 in the G1 / S phase, and the kinase act...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00C07D471/04A61K31/519A61K31/496A61K31/444A61K31/4545A61P35/00A61P35/04
Inventor 蔡雄钱长庚刘斌李军旗林明生卿远辉翁运幄王艳艳薛伟才游华金周石清
Owner GUANGZHOU BEBETTER MEDICINE TECH CO LTD
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