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2,4-disubstituted pyrimidine derivatives as cdk inhibitors and their applications

A technology of pyrimidine derivatives and di-substitution, applied in 2 fields, can solve problems such as severe toxicity and side effects

Active Publication Date: 2019-04-12
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the analysis of serious toxic and side effects, it was found that some CDK inhibitor drugs lack selectivity for CDK subtypes, thus producing relatively large toxic and side effects

Method used

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  • 2,4-disubstituted pyrimidine derivatives as cdk inhibitors and their applications
  • 2,4-disubstituted pyrimidine derivatives as cdk inhibitors and their applications
  • 2,4-disubstituted pyrimidine derivatives as cdk inhibitors and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Compound (I-1) N-(5-(4-ethylpiperazine-1-methyl)-pyridin-2-yl)-5-fluoro-4-(1-isopropyl-1H-indole- 5-yl)pyrimidin-2-amine

[0059] Step 1: 5-bromoindole (1.0g, 5.1mmol), 2-bromopropane (0.94g, 7.65mmol), potassium hydroxide (0.43g, 7.65mmol) were added to N,N-dimethylformamide (DMF , 10mL), N 2 Under protection, react at 70°C for 10h. Add H to the reaction solution 2 O (50mL) / ethyl acetate (50mL) was stirred and extracted, the organic layer was dried, filtered, concentrated and passed through a silica gel column (eluent ethyl acetate / petroleum ether: 1 / 30-1 / 10) to obtain a white solid 1-iso Propyl-5-bromo-1H-indole (0.8 g, yield 66%).

[0060] Step 2: 1-isopropyl-5-bromo-1H-indole (0.8g, 3.36mmol), bisboronic acid pinacol ester (1.02g, 4.0mmol), Pd(dppf)Cl 2 (0.25g, 0.34mmol), potassium acetate (0.66g, 6.72mmol) were added in 1,4-dioxane (15mL), N 2 Reaction at 80°C for 5h under protection. Concentrate the solvent to dryness, add H to the residue 2 O (50mL) / ethyl...

Embodiment 2

[0064] Compound (I-2) N-(5-(piperazin-1-yl)-pyridin-2-yl)-5-fluoro-4-(1-isopropyl-1H-indol-5-yl)pyrimidine -2-amine

[0065] The synthesis of compound I-2 is carried out according to the method of Example 1, and the starting materials are 1-isopropyl-5-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indole and 4-(6- Aminopyridin-3-yl)piperazine-1-carboxylate tert-butyl ester, after reacting in step 4 of Example 1, N-(5-(4-carboxylate tert-butyl ester-1-piperazinyl)-pyridine- 2-yl)-5-fluoro-4-(1-isopropyl-1H-indol-5-yl)pyrimidin-2-amine, the intermediate was de-BOC-protected with 3N hydrochloric acid ethyl acetate to give light Yellow solid target product N-(5-(piperazin-1-yl)-pyridin-2-yl)-5-fluoro-4-(1-isopropyl-1H-indol-5-yl)pyrimidine-2 - Amine hydrochloride (I-2). MS(m / z): 432[M+H] + . 1 H NMR (DMSO-d 6 ): δ: 11.65 (br, 1H), 9.70 (br, 2H), 8.77-8.76 (d, J=4.0Hz, 1H), 8.39 (s, 1H), 8.01-8.00 (d, J=4.0Hz, 1H), 7.96(s, 1H), 7.93(s, 1H), 7.85-7.83(d, J=8.0Hz, 1H), 7.76-7.74(d, J=8...

Embodiment 3

[0067] Compound (I-3) N-(5-(piperazin-1-yl)-pyridin-2-yl)-5-fluoro-4-(1-cyclopentyl-3-acetyl-1H-indole- 5-yl)pyrimidin-2-amine

[0068] The synthesis of compound I-3 is carried out according to the method in Example 1, and the starting material is 1-cyclopentyl-3-acetyl-5-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indole ( Synthetic method is similar to embodiment 1, and starting material is 2,4-dichloro-5-fluoropyrimidine and 1-cyclopentyl-3-acetyl-5-boronic acid pinacol ester-1H-indole (starting Starting materials are bromocyclopentane and 3-acetyl-5-bromo-1H-indole)) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The target product N-(5-(piperazin-1-yl)-pyridin-2-yl)-5-fluoro-4-(1-cyclopentyl-3-acetyl-1H-indole- 5-yl)pyrimidin-2-amine hydrochloride (I-3). MS(m / z): 500[M+H] + . 1 H NMR (DMSO-d 6 ): δ: 11.67 (br, 1H), 9.73 (br, 2H), 9.39 (s, 1H), 8.78 (s, 1H), 8.69-8.67 (d, J=8.0Hz, 1H), 8.00-7.97 ( m, 2H), 7.93(s, 1H), 7.72-7.69(m, 2H), 4.89-4.83(m, 1H), 3....

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Abstract

The present invention relates to a class of 2,4-disubstituted pyrimidine derivatives and their use as therapeutically effective cyclin-dependent protein kinase (CDK) inhibitors. Specifically, the present invention relates to a new 2,4-disubstituted pyrimidine derivative represented by general formula (I), and its pharmaceutical composition, as a selective CDK4 / 6 inhibitor in the prevention or treatment of CDK4 / 6 Uses in related diseases.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a 2,4-disubstituted pyrimidine derivative as a CDK inhibitor and its application. Background technique [0002] Cyclin-dependent protein kinase (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 promoting 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 cyclins in the G1 phase mainly include CDK2, CDK4 and CKD6. Cyclin D mainly binds to CDK4 and CKD6 and regulates the activity of the latter; cyclin E binds to CDK2 in the G1 / S phase, p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D471/04C07D487/04C07D473/00A61K31/52A61K31/506A61P35/00A61P35/02
CPCC07D401/14C07D471/04C07D473/00C07D487/04A61K31/506A61K31/52A61P35/00C07D471/14
Inventor 郑永勇金华周峰黄美花孟欣
Owner SHANGHAI XUNHE PHARMA TECH CO LTD