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Pyridine derivative as well as preparation method and application thereof

A compound, selected technology, applied in organic chemistry methods, drug combinations, pharmaceutical formulations, etc., can solve problems such as small side effects

Pending Publication Date: 2021-10-29
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The remarkable achievements in the development of other members of the JAK kinase family have made TYK2 a research hotspot. Although there are no drugs for this target on the market, several compounds are already in the clinical stage, and TYK2 is finally in the history of protein kinases. debut
Most notably, BMS-986165, a TYK2 inhibitor developed by BMS for the treatment of psoriasis, is currently in phase 3 clinical trials in patients with moderate to severe plaque psoriasis. The primary end point of efficacy is achieved, the side effects are small, and it has a high degree of safety and efficacy, but there is still huge room for improvement, and it is still necessary to continue research and development of new TYK2 inhibitors

Method used

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  • Pyridine derivative as well as preparation method and application thereof
  • Pyridine derivative as well as preparation method and application thereof
  • Pyridine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] N-(5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridine-2- base) cyclopropanecarboxamide

[0157]

[0158] first step

[0159] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinic acid

[0160] 4,6-Dichloronicotinic acid 1a (6.0g, 31.25mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b ( 5.80g, 28.41mmol, synthesized according to the literature J.Med.Chem.2019,62,20,8973-8995) was dissolved in 50mL N,N-dimethylacetamide, cooled in an ice-water bath, and slowly added bistrimethylsilyl Lithium amide solution (1.0M / THF, 60 mL). After the addition, it was naturally raised to room temperature and reacted for 4 hours. Add water to quench, concentrate under reduced pressure to remove most of tetrahydrofuran and water, add hydrochloric acid (6.0M) dropwise to the remaining solution until the pH value is 1-2, a large amount of white solid precipitates, filter, and wash the filter cake with water several ti...

Embodiment 2

[0176] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridine-2- base) cyclopropanecarboxamide

[0177]

[0178] first step

[0179] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl ) propan-1-one

[0180] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl )amino)-N-methylnicotinamide 1d (3.0g, 7.45mmol) was dissolved in 75mL of tetrahydrofuran, cooled in an ice-water bath, slowly added ethylmagnesium bromide solution (1.0M / THF, 22mL), raised to room temperature for reaction 2 Hour. After the reaction, cool in an ice-water bath, quench the reaction solution with water, extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated brine (50mL), dry with anhydrous sodium sulfate, filter, and reduce pressure Concentrate, and the obtained residue is purified by silica gel column chromatography (eluent: B system) to obtain 1-(6-chloro-4...

Embodiment 3

[0187] N-(5-(cyclopropanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridine -2-yl)cyclopropanecarboxamide

[0188]

[0189] first step

[0190](6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)( Cyclopropyl)methanone

[0191] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl )amino)-N-methylnicotinamide 1d (1.0g, 2.48mmol) was dissolved in 20mL of tetrahydrofuran, cooled in an ice-water bath, slowly added cyclopropylmagnesium bromide solution (1.0M / THF, 7.5mL), and raised to room temperature React for 3 hours. After the reaction, cool in an ice-water bath, quench the reaction solution with water, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (20mL), dry with anhydrous sodium sulfate, filter, and reduce pressure Concentrate, and the obtained residue is purified by silica gel column chromatography (eluent: B system...

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Abstract

The invention relates to a pyridine derivative, a preparation method thereof and an application of the pyridine derivative in medicine. Specifically, the present invention relates to a pyridine derivative represented by general formula (I), a preparation method and a pharmaceutically acceptable salt thereof, and a use thereof as a therapeutic agent, especially as a tyrosine kinase 2 (TYK2) inhibitor, the definition of each substituent in the general formula (I) being the same as the definition in the specification.

Description

technical field [0001] The present invention relates to a new pyridine derivative, its preparation method, pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a tyrosine kinase 2 (TYK2) inhibitor. Background technique [0002] Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase that belongs to the Janus kinase family (JAKS). JAKS includes JAK1, JAK2, JAK3 and TYK2 subtypes. These four family members consist of 1100 amino acids and have High degree of homology, can be divided into 7 homology domains (JH): JH1 is a highly conserved kinase region with catalytic activity; JH2 is a kinase-like region, which is the unique difference between JAK kinase and other tyrosine kinases , this region has no catalytic activity, but can regulate the activity of JH1; JH3-JH4 is the SH2 domain, which can specifically recognize and bind activated tyrosine residues; JH5-JH7 is the FERM domain, which is relatively Conserved, regulates the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D405/14C07D401/14C07D213/75C07D403/12A61P35/00A61P35/02A61K31/4439A61K31/444A61K31/44A61K31/501A61K31/506
CPCC07D401/12C07D405/14C07D401/14C07D213/75C07D403/12A61P35/00A61P35/02C07B2200/07
Inventor 周梦光张盼盼林文成林凌志颜孙力李亚洲叶成施正政钱文建胡泰山陈磊
Owner ZHEJIANG HISUN PHARMA CO LTD
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