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Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives useful as cdk inhibitors

A C3-C10, compound technology, applied in the field of compounds that inhibit selective transcription cyclin-dependent kinase activity, can solve problems such as unsuccessful

Active Publication Date: 2021-10-08
奥瑞基尼肿瘤学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Confusingly, despite numerous attempts by the industry to find cell cycle-dependent changes in CDK7 kinase activity, they have been unsuccessful

Method used

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  • Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives useful as cdk inhibitors
  • Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives useful as cdk inhibitors
  • Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives useful as cdk inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0390] Example 1: Synthesis of 1-acryloyl-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1 ,3,5]triazin-4-yl)amino)methyl)phenyl)piperidine-3-carboxamide (Compound 1).

[0391]

[0392] To a solution of 1-acryloylpiperidine-3-carboxylic acid (0.086 g, 0.47 mmol, Intermediate 12) in cooled DMF (4 mL) was added successively HATU (0.22 g, 0.59 mmol) at a temperature of 0 °C, DIPEA (0.2 mL, 1.18 mmol) and N4-(3-aminobenzyl)-8-isopropyl-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a] [1,3,5]Triazine-2,4-diamine (0.15 g, 0.39 mmol, Intermediate 33). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with ice water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phases were washed with concentrated brine in Na 2 SO 4 Drying on celite, filtration and concentration gave a crude residue. Final...

Embodiment 2

[0399] Example 2: Synthesis of 1-acryloyl-N-(3-(((2-(((3R,4R)-3-fluoropiperidin-4-yl)amino)-8-isopropylpyrazolo[1,5- a] [1,3,5]Triazin-4-yl)amino)methyl)phenyl)pyrrolidine-3-carboxamide (Compound 14).

[0400] step 1: Synthesis of tert-butyl(3R,4R)-4-((4-((3-(1-acryloylpyrrolidine-3-carboxamido)benzyl) Amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-3-fluoropiperidine-1-carboxylate.

[0401]

[0402] To a solution of 1-acryloylpyrrolidine-3-carboxylic acid (0.05 g, 0.30 mmol, Intermediate 10) in cooled DMF (2 mL) was added successively HATU (0.11 g, 0.30 mmol) at a temperature of 0 °C, DIPEA (0.07mL, 0.40mmol) and tert-butyl(3R,4R)-4-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a] [1,3,5]Triazin-2-yl)amino)-3-fluoropiperidine-1-carboxylate (0.1 g, 0.20 mmol, intermediate 38). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water and diluted with ethyl acetate. The aqueous layer was separa...

Embodiment 3

[0408] Example 3: Synthesis of 1-acryloyl-N-(3-(((8-isopropyl-2-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrazolo[1,5- a] [1,3,5]Triazin-4-yl)amino)methyl)phenyl)piperidine-2-carboxamide (Compound 16).

[0409] step 1: Synthesis of tert-butyl-2-((3-(((8-isopropyl-2-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyridine Azolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)carbamoyl)piperidine-1-carboxylate.

[0410]

[0411] To a solution of 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.13 g, 0.577 mmol) in cooled DMF (10 mL) was added sequentially HATU (0.26 g, 0.68 mmol) at a temperature of 0 °C, DIPEA (0.2 mL, 1.04 mmol) and (S)-N4-(3-aminobenzyl)-8-isopropyl-N2-(tetrahydro-2H-pyran-3-yl)pyrazolo[1, 5-a] [1,3,5]triazine-2,4-diamine (0.2 g, 0.524 mmol, intermediate 34). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethy...

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Abstract

The present invention provides substituted pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives of formula (I), which have therapeutic Efficacy, especially as a selective transcriptional CDK inhibitor, including CDK7, CDK9, CDK12, CDK13 and CDK18 inhibitors, especially represented by transcriptional CDK7 inhibitors, where X, ring A, ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 6 , m, n and p have the meanings given in the description, and the pharmaceutically acceptable salts of the compound of formula (I) can be used for treating and preventing diseases or conditions related to selective transcription of CDK suffered by mammals. The present invention also illustrates how to prepare compounds comprising at least one substituted pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives of formula (I) Compounds and pharmaceutical preparations of substances or pharmaceutically acceptable salts or stereoisomers thereof.

Description

[0001] This application claims the benefit of Indian Provisional Patent Application (Application No: 1128 / CHE / 2015) filed March 9, 2015, the contents of which are hereby incorporated by reference. [0002] field of invention [0003] The present invention relates to compounds that inhibit the activity of selective transcriptional cyclin-dependent kinases (CDKs), said CDKs include CDK7, CDK9, CDK12, CDK13 and CDK18, especially represented by transcriptional cyclin-dependent kinase-7 (CDK7) . The invention also provides pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions to treat diseases or conditions associated with selectively transcribed CDKs. [0004] Background of the invention [0005] One of the most important and fundamental processes in biology is cell division mediated by the cell cycle. This process ensures that offspring cells with specific biological functions are produced under controlled condition...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/437A61K31/53A61P31/00A61P35/00
CPCA61K45/06C07D487/04A61K31/53A61P29/00A61P31/00A61P35/00A61P35/02A61P43/00
Inventor 苏姗塔·萨玛吉代尔拉姆鲁·波杜涂拉须伯汗杜·慕克吉拉杰夫·高斯瓦米
Owner 奥瑞基尼肿瘤学有限公司
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