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(Substituted phenyl) (substituted pyrimidine) amino derivative as well as preparation method and pharmaceutical application thereof

A technology of substituents and alkyl groups, which is applied in the field of preparation of tumor drugs, can solve the problems of limited clinical effectiveness of drugs, rashes and diarrhea in patients, and restrictions on the dosage of second-generation EGFR inhibitors, etc.

Pending Publication Date: 2021-07-16
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinically, simultaneous inhibition of wild-type EGFR can lead to rashes and diarrhea in patients, which limits the dose of second-generation EGFR inhibitors, so that the plasma concentration of the drug is not enough to inhibit T790M, making the clinical effectiveness of this class of drugs subject to greater restrictions

Method used

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  • (Substituted phenyl) (substituted pyrimidine) amino derivative as well as preparation method and pharmaceutical application thereof
  • (Substituted phenyl) (substituted pyrimidine) amino derivative as well as preparation method and pharmaceutical application thereof
  • (Substituted phenyl) (substituted pyrimidine) amino derivative as well as preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0402] N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1- Methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide (compound 1)

[0403] N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1, 7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

[0404]

[0405]

[0406] The first step: 5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1 -Methyl-1,7-diazaspiro[4.4]nonan-7-yl)-1-nitrobenzene (1B)

[0407] 5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro [4.4]nonan-7-yl)-1-nitrobenzene

[0408] 5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitro phenylbenzene (intermediate 5) (0.3g, 0.72mmol), 1-methyl-1,7-diazaspiro[4.4]nonane (1A) (0.15g, 10.8mmol) and N,N-diiso Propylethylamine (ie DIPEA) (0.28g, 2.17mmol) was added to N,N-dimethylformamide (3mL), and microwaved at 140°C for 1.5 ...

Embodiment 2

[0422] (S)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2 -(1-Methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide (compound 2)

[0423] (S)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1- methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

[0424]

Embodiment 3

[0426](R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2 -(1-Methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide (Compound 3)

[0427] (R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1- methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

[0428]

[0429] The split method of embodiment 2 and embodiment 3 is as follows:

[0430] Take N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1 -Methyl-1, 7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide (compound 1) (100mg) is used for resolution, and the preparation conditions are: Instrument GX-281C0630, (0.1 %diethylamine+n-hexane) / isopropanol=70 / 30, 10.0mL / min, 254nm, column temperature 40°C (AD-H 20*250mm 5um H-37); two optical isomers were obtained: iso Conformant 1 (peak 1, 50mg, yellow solid, ee%=100%, t=33.97min), isomer 2 (peak 2, 50mg, yellow solid, ee%=100%, t=40.78min).

[0431] Isomer 1

[0432] 1 H NMR (400M...

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Abstract

The invention provides a (substituted phenyl) (substituted pyrimidine) amido derivative as shown in a general formula (I) defined in the description, an optical isomer thereof, a pharmaceutically acceptable salt or eutectic, a preparation method thereof, and application thereof in preparation of tumor drugs. The general formula is a compound (I).

Description

[0001] This application is a divisional application with the application number 201580023470.2, the application date is August 25, 2015, and the title of the invention is a (substituted phenyl) (substituted pyrimidine) amino derivative, its preparation method and pharmaceutical use. technical field [0002] The present invention relates to a kind of (substituted phenyl) (substituted pyrimidine) amino derivatives described in general formula (I) and its optical isomers, pharmaceutically acceptable salts or co-crystals, as well as preparation methods and in Use in the preparation of tumor medicines. Background technique [0003] With the advent of industrialization, environmental pollution and changes in lifestyle, the incidence of cancer continues to rise. At present, cancer has become the main killer threatening human life and health. According to the report of the International Cancer Research Center (IARC), there were 12.66 million new cancer cases and 7.56 million deaths...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D403/04C07D471/04C07D403/14C07D405/14A61K31/506A61K31/5377A61P35/00
CPCA61K31/506C07D401/04C07D239/42C07D471/04
Inventor 魏用刚李瑶张国彪邱关鹏胡仕红陈雷李升张黔
Owner SICHUAN HAISCO PHARMA CO LTD
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