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Certain protein kinase inhibitors

A compound and alkyl technology, applied in the field of treatment of hyperproliferative diseases, can solve the problems of low inhibitor activity, toxicity, short half-life, etc.

Active Publication Date: 2018-11-09
FOCHON BIOSCIENCES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CDK4 / 6 inhibitors have been reported in the literature, such as WO2010020675 and WO2012064805, many inhibitors have low activity, short half-life or toxicity

Method used

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  • Certain protein kinase inhibitors
  • Certain protein kinase inhibitors
  • Certain protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0400] 1-cyclopentyl-N,N-dimethyl-6-((5-(piperazin-1-yl)pyrimidin-2-yl)amino)-1H-pyrrole[3,2-c]pyrrole Pyridine-2-carboxamide (1)

[0401]

[0402] tert-Butyl 4-(2-aminopyrimidin-5-yl)piperazine-1-carboxylate (1a)

[0403] 2-Amino-5-bromopyrimidine (3.5g, 20.1mmol), N-Boc-piperazine (8.2g, 44.1mmol), sodium tert-butoxide (3.3g, 34.4mmol), three (dibenzylidene acetone ) Dipalladium 0.92g, 1.0mmol) and 2-di-tert-butylphosphine-2'-(N,N-dimethylamino)biphenyl (1.37g, 4.0mmol) were added in toluene (150mL) and mixed and stirred, Heated to 110°C under protection to react overnight. The reaction system was cooled to room temperature and filtered with Celite on a Buchner funnel, and the filtrate was concentrated. The residue was dissolved with 0.5N hydrochloric acid (200 mL) and extracted with ethyl acetate (2×100 mL). The aqueous phase was basified with sodium hydroxide, adjusted to pH 4 and extracted with dichloromethane (3 x 150 mL). The combined organic layers were dr...

Embodiment 2

[0409] 1-cyclopentyl-N,N-dimethyl-6-((5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)amino)-1H-pyrrole[3, 2-c]pyridine-2-carboxamide (2)

[0410]

[0411] To 1-cyclopentyl-N,N-dimethyl-6-((5(piperazin-1-yl)pyrimidin-2-yl)amino)-1H-pyrrole[3,2-c at 0°C ]Pyridine-2-carboxamide (1) (11 mg, 0.025 mmol) in 1,2-dichloroethane (3 mL) was added formaldehyde (37% aqueous solution, 10 μ L), sodium triacetoxyborohydride (54 mg, 0.25mmol), and then reacted at this temperature for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2 x 30 mL). Dry over anhydrous sodium sulfate and concentrate. The residue was purified by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol 15:1) to give 1-cyclopentyl-N,N-dimethyl-6-((5-(4-methylpiperazine -1-yl)pyrimidin-2-yl)amino)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (2). MS-ESI(m / z):449[M+1] + .

Embodiment 3

[0413] 1-cyclopentyl-6-((5-(4-ethylpiperazin-1-yl)pyrimidin-2-yl)amino)-N,N-dimethyl-1H-pyrrole[3, 2-c]pyridine-2-carboxamide (3)

[0414]

[0415]To 1-cyclopentyl-N,N-dimethyl-6-((5-(piperazin-1-yl)pyrimidin-2-yl)amino)-1H-pyrrole[3,2- c] To a solution of pyridine-2-carboxamide (1) (8.2mg, 0.019mmol) in 1,2-dichloroethane (3mL) was added acetaldehyde (40% aqueous solution, 10μL), sodium triacetoxyborohydride (40mg, 0.19mmol), and then reacted at this temperature for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2×30 mL). Dry over anhydrous sodium sulfate and concentrate. The residue was purified by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol 15:1) to give 1-cyclopentyl-6-((5-(4-ethylpiperazin-1-yl)pyrimidine-2 -yl)amino)-N,N-dimethyl-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (3). MS-ESI(m / z):463[M+1] + .

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Abstract

Provided are certain CDK4 / 6 inhibitors, pharmaceutical compositions, and methods of use thereof.

Description

[0001] This application claims priority from US Provisional Application 62 / 271,311, the entire contents of which are incorporated herein by reference in their entirety. technical field [0002] The present invention relates to a class of compounds or pharmaceutically acceptable salts capable of inhibiting CDK4 / 6 kinase activity, and as medicines for treating hyperproliferative diseases, such as cancer and inflammation. Background technique [0003] Hyperproliferative diseases such as cancer and inflammation attract the academic community to provide effective treatments for them. And in this regard, efforts have been made to identify and target specific mechanisms that play a role in proliferative diseases. [0004] Tumor development is closely related to gene variation and abnormal regulation of cyclin-dependent kinase (CDK) and its regulatory proteins, suggesting that CDK inhibitors may be effective anticancer therapies. [0005] CDKs are serine / threonine protein kinases t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D493/04C07D495/04A61K31/4355A61K31/4365A61K31/437A61P35/00
CPCC07D471/04C07D495/04A61P35/00A61P17/06A61P17/00A61P13/08A61P9/10A61P3/10A61P27/02A61P11/06A61P37/06A61P11/00C07D487/04C07D493/04A61K45/06A61K31/4545A61K31/496A61K31/506A61K31/5377A61K2300/00
Inventor 赵兴东李同双张华杰李志福刘滨刘启洪谭锐容悦杨理君陈志方谭浩瀚姜立花刘研新令狐莉林敏孙婧王为波
Owner FOCHON BIOSCIENCES LTD
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