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Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase

A solvate and CHF2 technology, applied in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc., can solve the problems of reducing the sensitivity and inefficiency of EGFR inhibitors

Inactive Publication Date: 2020-05-01
CS PHARMATECH LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The third and most common resistance mode is further mutations in EGFR, resulting in a double mutant receptor (dm-EGFR) that reduces its sensitivity to EGFR inhibitors
In general, these compounds are extremely potent inhibitors of mutant EGFR containing the T790M mutation, and are slightly less potent against wt EGFR and some other mutations

Method used

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  • Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase
  • Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase
  • Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase

Examples

Experimental program
Comparison scheme
Effect test

example

[0481]

[0482] A1-A4 junction site

[0483] Heteroarylamino linkage microdots

[0484] The following description can be used as A 1 Representative examples of 5,6-bicyclic azaaromatics, but the invention is not limited to these examples:

[0485]

[0486] linking site

[0487]

[0488]

[0489]

[0490] The following description can be used as A 1 、A 2 、A 3 or A 6 Representative examples of 5.X bicyclic azaaromatics, but the invention is not limited to these examples:

[0491] Junction

[0492] The following description can be used as A 3 Representative examples of 5.5 bicyclic azaaromatics, but the invention is not limited to these examples:

[0493]

[0494] linking site

[0495]

[0496] The following description can be used as A 4a or A 4b Representative examples of 6.5 bicyclic azaaromatics, but the invention is not limited to these examples:

[0497]

[0498] linking site

[0499] The following explains A...

example 1

[1313] Example 1. N-(5-((4-(3-(dimethylamino)-6-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrimidine-2- base)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[1314]

[1315] 2-Chloro-4-(N,N,6-trimethyl-pyrazolo[4,3-c]pyridin-3-amine-1-yl)pyrimidine (120mg, 0.42mmol, 1.0eq), N- (5-Amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (134 mg, 0.46 mmol, 1.1 eq) and 2-pentanol (2mL) and p-TsOH·H 2 O (87 mg, 0.46 mmol, 1.1 eq) was sealed in a 10 mL Schlenk tube. The mixture was stirred at 120 °C for 2 h. After completion, the mixture was cooled to RT and washed with saturated NaHCO 3 (10 mL) and DCM / MeOH (10 / 1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL x 2). Combine the organic layers with NaHCO 3 (20 mL x 2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N-(5-((4-(3-(dimethylamino)-6-methyl-1H- Pyrazolo[4,3-c]pyridin-1-yl)pyrimidin-2-yl)ami...

example 2

[1316] Example 2. N-(5-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-2-((2 -(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[1317]

[1318] To 2-chloro-4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidine (164mg, 0.58mmol, 1.0eq) and N-(5-amino-2 -((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (170mg, 0.58mmol, 1.0eq) in 2-pentanol (4mL) To the solution in , p-toluenesulfonic acid monohydrate (123 mg, 0.64 mmol, 1.1 eq) was added. The mixture was heated to 120° C. for 5 h in a 10 mL Schlenk tube. After cooling to RT, the mixture was poured into water (10 mL), extracted with DCM / MeOH=10:1 (10 mL×3), the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated and passed Silica column purification affords N-(5-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (48 mg, 15%). 1 H NMR (300MHz, DMSO-d 6 ):δ1...

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Abstract

The present invention provides compounds of Formula (I) or a subgeneric structure or species thereof, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, and methods and compositions for treating or ameliorating abnormal cell proliferative disorders, such as cancer, wherein A, R2, R3, R10, E1, E2, E3, Y, and Z are as defined herein.

Description

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 528,697, filed July 5, 2017, the contents of which are hereby incorporated by reference in their entirety for all purposes technical field [0002] The present invention relates to a compound of formula (I) or its subgenus structure or substance or its pharmaceutically acceptable salt ester, solvate and / or prodrug, and including these compounds or its pharmaceutically acceptable salt ester , a pharmaceutical composition of a solvate and / or a prodrug. The compounds and salts of the invention inhibit kinases, especially the epidermal growth factor receptor EGFR, and specific mutants thereof that are critical for the development of therapeutic resistance by EGFR inhibition therapy, and are useful in the treatment or amelioration of abnormal cell proliferative disorders, such as cancer . Background technique [0003] The present invention relates to biarylamine-based compounds useful as hig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/136A61K31/404C07D209/04C07D471/04
CPCA61K31/506A61P35/00C07D403/04C07D471/04C07D495/04A61K31/505C07D403/10
Inventor 宋运涛A.J.布里奇斯陈晓颀
Owner CS PHARMATECH LTD
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