Indazole-substituted epidermal growth factor receptor (EGFR) inhibitor and application thereof

A technology of isomers and solvates, applied in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc., can solve the lack of selectivity, affect patient compliance, and change the ATP affinity of the EGFR kinase region And other issues

Active Publication Date: 2017-05-31
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since methionine occupies a larger space than threonine, it forms steric hindrance and changes the affinity of ATP in the kinase region of EGFR, making EGFR-TKI small molecule drugs unable to effectively block EGFR activation signals, leading to drug resistance production
At the same time, the first-generation EGFR inhibitors lack the selectivity between wild-type EGFR and mutant EGFR, and commonly have side effects such as rash and diarrhea, which affect patient compliance

Method used

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  • Indazole-substituted epidermal growth factor receptor (EGFR) inhibitor and application thereof
  • Indazole-substituted epidermal growth factor receptor (EGFR) inhibitor and application thereof
  • Indazole-substituted epidermal growth factor receptor (EGFR) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0144] Example 1A N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1H-indazol-1-yl)pyrimidine Synthesis of -2-amino)phenyl)acrylamide

[0145]

[0146] Step a 2-Chloro-4-(1H-indazol-1-yl)pyrimidine

[0147]

[0148] In a 250mL reaction flask, add 2,4-dichloropyrimidine (14.9g, 100mmol), after 50mL of DMF dissolves, add cesium carbonate (50g, 152mmol), add dropwise 30mL of indazole (11.8g , 100mmol) DMF solution, after the dropwise addition, react at room temperature for 1h, after the reaction, pour into ice water, filter with suction, wash the filter cake with 50mL water, dry and purify by column chromatography to obtain the title compound.

[0149] ESI-Ms m / z: 231.1 [M+H].

[0150] Step b Synthesis of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indazol-1-yl)pyrimidin-2-amine

[0151]

[0152] In a 250mL reaction flask, add 2-chloro-4-(1H-indazol-1-yl)pyrimidine (16.3g, 70mmol) and 4-fluoro-2-methoxy-5-nitroaniline obtained in step a (13.0g, 70mmol) and...

Embodiment 1B

[0167] Example 1B N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1H-indazol-2-yl)pyrimidine Synthesis of -2-amino)phenyl)acrylamide

[0168]

[0169] Synthesis of step a 2-chloro-4-(1H-indazol-2-yl)pyrimidine

[0170]

[0171] In a 250mL reaction flask, add 2,4-dichloropyrimidine (14.9g, 100mmol), after 50mL of DMF dissolves, add cesium carbonate (50g, 152mmol), add dropwise 30mL of indazole (11.8g , 100mmol) DMF solution, after the dropwise addition, react at room temperature for 1h, after the reaction, pour into ice water, filter with suction, wash the filter cake with 50mL water, dry and purify by column chromatography to obtain the title compounds respectively.

[0172] ESI-Ms m / z: 231.1 [M+H].

[0173] Step b Synthesis of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indazol-2-yl)pyrimidin-2-amine

[0174]

[0175] In a 250mL reaction flask, add 2-chloro-4-(1H-indazol-2-yl)pyrimidine (16.3g, 70mmol) and 4-fluoro-2-methoxy-5-nitroaniline obtained in ...

Embodiment 2A

[0190] Example 2A N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(5-chloro-4-(1H-indazole-1 Synthesis of -yl)pyrimidine-2-amino)phenyl)acrylamide

[0191]

[0192] Starting from 4-fluoro-2-methoxy-5-nitroaniline, 2,4,5-trichloropyrimidine, indazole, N,N,N'-trimethylethylenediamine and allyl chloride , The title compound was prepared according to the method of Example 1A.

[0193] 1 H NMR (300MHz, DMSO-d 6 )δ10.01(s,1H),9.06(s,1H),8.60(s,1H),8.45(s,1H),8.32(s,1H),8.00(d,1H),7.89(d,1H ),7.44-7.26(m,2H),7.00(s,1H),6.53(d,1H),6.24(d,1H),5.79(d,1H),3.80(s,3H),3.04-2.91( m,2H), 2.65(s,3H), 2.49-2.37(m,2H), 2.20(s,6H).

[0194] ESI-Ms m / z: 521.2 [M+H].

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Abstract

The invention specifically relates to an indazole-substituted EGFR inhibitor, a pharmaceutical composition containing the inhibitor, and application of the inhibitor or the pharmaceutical composition as a drug for prevention and/or treatment of cancers, belonging to the field of medical chemistry. The inhibitor presents good EGFR inhibitory activity, especially good inhibitory effect on mutant EGFR, and is expected to become a drug with specific curative effect and small side effect on treatment of tumors resistant to drugs due to EGFR mutation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of epidermal growth factor receptor inhibitors with an indazole substituted structure, a pharmaceutical composition containing the inhibitor, and the use of the inhibitor or the pharmaceutical composition as cancer treatment drugs. Background technique [0002] Epidermal Growth Factor Receptor (EGFR) is the expression product of the proto-oncogene C-erbB-1 and is one of the members of the EGFR family. The EGFR family includes four members: EGFR (HER-1), ERBB2 (HER-2), ERBB3 (HER-3) and ERBB4 (HER-4). It has been shown that EGFR overexpression or mutations generally cause tumors. EGFR mutations lead to continuous activation of EGFR, enhanced function of autocrine loop, disruption of receptor downregulation mechanism, and activation of abnormal signaling pathways, which play an important role in tumor progression. [0003] EGFR-tyrosine kinase inhibitor (EGFR...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/506A61P35/00
CPCC07D403/04
Inventor 王勇张小猛赵立文
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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