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A kind of alkyne compound, preparation method and application thereof

A technology of compounds and enantiomers, applied in the application field of drug preparation, can solve the problems of side effects limiting the clinical application of drugs, no inhibitory activity, etc.

Active Publication Date: 2021-04-23
BEIJING SCITECH MQ PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The second-generation CML drugs Dasatinib, Nilotinib, and Bosutinib have broad activity on Imatinib-resistant and intolerant patients, but they have no inhibitory activity on BCR-ABL T315I kinase mutation
Its severe side effects limit the clinical application of the drug

Method used

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  • A kind of alkyne compound, preparation method and application thereof
  • A kind of alkyne compound, preparation method and application thereof
  • A kind of alkyne compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0181] 1‐methyl‐N‐(4‐((4‐methylpiperazine‐1‐)methyl)phenyl)‐7‐(pyridine‐3‐ethynyl)‐1H‐indole‐2‐carboxamide preparation

[0182] Step 1) Preparation of 7-bromo-1-methyl-N-(4-((4-methylpiperazine-1-)methyl)phenyl)-1H-indole-2-formamide

[0183]

[0184] 7-bromo-1-methyl-1H-indole-2-carboxylic acid (2.5g, 10mmol), 4-((4-methylpiperazine-1-)methyl)amine (2.0g, 10mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (3.8g, 10mmol) dissolved in N,N-dimethylformaldehyde Add diethylisopropylamine (1.65mL, 10mmol) to the amide, stir until the reaction is complete, extract with ethyl acetate and water, concentrate the organic phase, and perform column chromatography to obtain 3.1 g of the target compound with a yield of 70%. 1 H NMR (400MHz, DMSO-d 6 )δ10.48(s,1H),7.76–7.68(m,3H),7.53–7.49(m,1H),7.27(d,J=8.4Hz,2H),7.23(s,1H),7.04(t ,J=7.7,7.7Hz,1H),4.28(s,3H),3.43(s,2H),2.48–2.27(m,8H),2.19(s,3H); MS:441[M+H] + .

[0185] Step 2) 1‐methyl‐N‐(...

Embodiment 2

[0192] 1‐methyl‐N‐(4‐((4‐methylpiperazine‐1‐)methyl)‐3‐(trifluoromethyl)phenyl)‐7‐(pyridine‐3‐ethynyl)‐1H ‐Indole‐2‐carboxamide preparation

[0193] Step 1) 7‐bromo‐1‐methyl‐N‐(4‐((4‐methylpiperazine‐1‐)methyl)‐3‐(trifluoromethyl)phenyl)‐1H‐indole‐ Preparation of 2‐formamide

[0194]

[0195] 7-Bromo-1-methyl-1H-indole-2-carboxylic acid (2.5g, 10mmol), 4-((4-methylpiperazine-1-)methyl)-3-(trifluoromethyl ) aniline (2.73g, 10mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (3.8g, 10mmol) Add diethylisopropylamine (1.65mL, 10mmol) to N,N-dimethylformamide, stir until the reaction is complete, extract with ethyl acetate and water, concentrate the organic phase, and column chromatography to obtain 3.6 grams of product , yield 70%. 1 H NMR (400MHz, DMSO-d 6 )δ10.74(s,1H),8.22(s,1H),8.05–7.99(m,1H),7.77–7.69(m,2H),7.53(d,J=7.5Hz,1H),7.30(s ,1H),7.05(t,J=7.7,7.7Hz,1H),4.30(s,3H),3.57(s,2H),2.47–2.23(m,8H),2.17(s,3H); MS: 509[M+H] ...

Embodiment 3

[0203] N‐(4‐((4‐methylpiperazine‐1‐)methyl)‐3‐(trifluoromethyl)phenyl)‐7‐(pyrimidine‐5‐ethynyl)‐1H‐indole‐2 ‐ Formamide preparation

[0204] Step 1) of 7‐bromo‐N‐(4‐((4‐methylpiperazine‐1‐)methyl)‐3‐(trifluoromethyl)phenyl)‐1H‐indole‐2‐carboxamide preparation

[0205]

[0206]7-Bromo-1H-indole-2-carboxylic acid (1) (2.4g, 10mmol), 4-((4-methylpiperazine-1-)methyl)-3-(trifluoromethyl)aniline N , into N-dimethylformamide, add diethylisopropylamine (1.65mL, 10mmol), stir until the reaction is complete, extract with ethyl acetate and water, concentrate the organic phase, and column chromatography to obtain 3.5 grams of product, yield rate of 70%. 1 H NMR (400MHz, DMSO-d 6 )δ11.67(s,1H),10.65(s,1H),8.23(d,J=2.1Hz,1H),8.10–8.02(m,1H),7.80–7.70(m,2H),7.55–7.45 (m,2H),7.06(t,J=7.8Hz,1H),3.58(s,2H),2.49–2.24(m,8H),2.18(s,3H); MS:495[M+H] + .

[0207] Step 2) N‐(4‐((4‐methylpiperazine‐1‐)methyl)‐3‐(trifluoromethyl)phenyl)‐7‐((trimethylsilyl)ethynyl)‐ Preparation of 1H‐indole...

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Abstract

The present invention belongs to the field of chemical medicine, in particular to compounds of formula (I) or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, as well as pharmaceutical compositions containing these compounds and these compounds or compositions in Application in pharmaceutical preparation. Such compounds and their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs can be used for the treatment or prevention of many different cancers and other diseases.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a class of compounds with BCR-ABL kinase inhibitory activity or pharmaceutically acceptable salts, isomers, solvates, crystal forms or prodrugs thereof, and pharmaceutical compositions containing these compounds And the application of these compounds or compositions in medicine preparation. Background technique [0002] Tumor is the abnormal signal transduction of cells under the action of various carcinogenic factors, and a certain cell in some tissues loses its normal growth regulation, resulting in the disorder of cell apoptosis and continuous proliferation of cells, which in turn leads to the cloning of new organisms. formed by sexual growth. Tumor cells have the ability to grow autonomously after losing their normal growth regulation functions, and the tumor can continue to grow even after the growth of oncogenic factors stops. Clinically, tumors can be divided...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/06C07D403/06C07D471/04C07D487/04C07D403/14A61K31/496A61K31/506A61K31/5025A61K31/519A61K31/437A61P35/00A61P37/02A61P35/02A61P27/02A61P17/06A61P19/02A61P9/10A61P17/00A61P1/16A61P1/00A61P11/00
CPCC07D401/06C07D403/06C07D403/14C07D471/04C07D487/04
Inventor 张强张宏波周利凯冯守业杨海龙王中祥
Owner BEIJING SCITECH MQ PHARMA LTD
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