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Substituted 2-aminopyridine inhibitor for protein kinase

A technology of alkyl and phenyl, which is applied in the direction of medical preparations containing active ingredients, compounds of Group 5/15 elements of the periodic table, drug combinations, etc., and can solve problems such as drug resistance

Inactive Publication Date: 2014-08-06
CHIA TAI TIANQING PHARMA GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although people have studied a large number of compounds with inhibitory activity on protein kinases, and some protein kinase inhibitors have been marketed for anti-tumor treatment, drug resistance will occur

Method used

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  • Substituted 2-aminopyridine inhibitor for protein kinase
  • Substituted 2-aminopyridine inhibitor for protein kinase
  • Substituted 2-aminopyridine inhibitor for protein kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0466] Example 1: 4-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)-5-(2-methoxy-4-(piperazin-1-yl)phenyl)- 2-aminopyridine

[0467]

[0468] General synthesis method:

[0469]

[0470] Step 1: 2-Chloro-4-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)pyridine

[0471]

[0472] 1-(2-chloropyridin-4-yl)-3-(dimethylamino)prop-2-en-1-one (2.11g, 10mmol), 3-chloro-4-fluorophenylhydrazine (1.61g, 10mmol), a few drops of glacial acetic acid and water (1mL) were added to ethanol (50mL), refluxed for 1.5 hours, the solvent was spin-dried, ethyl acetate and water were added, extracted, the organic phase was dried, purified by silica gel column chromatography, and 2-chloro- 4-(1-(3-Chloro-4-fluorophenyl)-1H-pyrazol-5-yl)pyridine (2.50 g), yield: 81%. MS m / z [ESI]: 308.0 [M+1].

[0473] Step 2: 4-(1-(3-Chloro-4-fluorophenyl)-1H-pyrazol-5-yl)-N-(dibenzylidene)-2-aminopyridine

[0474]

[0475] 2-Chloro-4-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)pyridine ((2.0g, 6.5mmol)...

Embodiment 2

[0488] Example 2: 4-(1-(4-fluorophenyl)-1H-pyrazol-5-yl)-5-(2-methoxy-4-(piperazin-1-yl)phenyl)- 2-aminopyridine hydrochloride

[0489]

[0490] Step 1: 2-Chloro-4-(1-(4-fluorophenyl)-1H-pyrazol-5-yl)pyridine

[0491]

[0492] Referring to the method of step 1 in Example 1, 4-fluorophenylhydrazine was used instead of 3-chloro-4-fluorophenylhydrazine to obtain the target compound with a yield of 86%. MS m / z [ESI]: 274.0 [M+1].

[0493] Step 2: 4-(1-(4-Fluorophenyl)-1H-pyrazol-5-yl)-N-(dibenzylidene)-2-aminopyridine

[0494]

[0495] With reference to the method of step 2 in Example 1, replace 2-chloro-4-(1-(3 -Chloro-4-fluorophenyl)-1H-pyrazol-5-yl)pyridine to obtain the target compound, yield: 56%. MS m / z [ESI]: 419.2 [M+1].

[0496] Step 3: 4-(1-(4-fluorophenyl)-1H-pyrazol-5-yl)-2-aminopyridine

[0497]

[0498] Referring to the method of step 3 in Example 1, replace 4 with 4-(1-(4-fluorophenyl)-1H-pyrazol-5-yl)-N-(dibenzylidene)-2-aminopyridine -(1-(3-chlo...

Embodiment 3

[0508] Example 3: 4-(1-(3-fluorophenyl)-1H-pyrazol-5-yl)-5-(2-methoxy-4-(piperazin-1-yl)phenyl)- 2-aminopyridine hydrochloride

[0509]

[0510] Step 1: 2-Chloro-4-(1-(3-fluorophenyl)-1H-pyrazol-5-yl)pyridine

[0511]

[0512] Referring to the method of step 1 in Example 1, using 3-fluorophenylhydrazine instead of 3-chloro-4-fluorophenylhydrazine, the target compound was obtained with a yield of 79%. MS m / z [ESI]: 274.0 [M+1].

[0513] Step 2: 4-(1-(3-Fluorophenyl)-1H-pyrazol-5-yl)-N-(dibenzylidene)-2-aminopyridine

[0514]

[0515] With reference to the method of step 2 in Example 1, replace 2-chloro-4-(1-(3 -Chloro-4-fluorophenyl)-1H-pyrazol-5-yl)pyridine to obtain the target compound, yield: 69%. MS m / z [ESI]: 419.2 [M+1].

[0516]Step 3: 4-(1-(3-Fluorophenyl)-1H-pyrazol-5-yl)-2-aminopyridine

[0517]

[0518] Referring to the method of step 3 in Example 1, replace 4 with 4-(1-(3-fluorophenyl)-1H-pyrazol-5-yl)-N-(dibenzylidene)-2-aminopyridine -(1-(3-chlo...

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Abstract

The invention discloses a substituted 2-aminopyridine inhibitor for protein kinase, and concretely relates to 2-aminopyridine derivatives with protein kinase inhibition activity, a preparation method thereof, and pharmaceutical compositions thereof, and the invention also discloses application of the compounds and the pharmaceutical compositions thereof to treat diseases related to protein kinase.

Description

technical field [0001] The present invention generally relates to novel 2-aminopyridine derivatives with protein kinase inhibitory activity, their preparation methods, pharmaceutical compositions, and the use of such compounds and their pharmaceutical compositions for treating diseases related to protein kinases. Background technique [0002] Cancer and cardiovascular disease are two major diseases that seriously threaten human health and life. Cancer, in particular, has seen a rapid increase in morbidity and mortality in recent years, surpassing cardiovascular disease as the number one killer of human health. [0003] The proliferation, apoptosis, and metastasis of tumors are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside cells. An important class of molecules in these signaling pathways are protein kinases. The abnormality of protein kinase activity is not only directly related to tumors, but also the ma...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D213/74C07D401/06C07D401/14C07D213/73C07F9/6558A61K31/496A61K31/675A61K31/4545A61K31/506A61P35/00
CPCC07D401/04C07D213/73C07D213/74C07D401/06C07D401/14C07F9/65583
Inventor 校登明许新合刘希杰胡远东于洪灏刘志华彭勇孙颖慧罗鸿孔繁胜韩永信孙键
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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