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Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases

A technology of compounds and oxides, applied in disease states or diseases, in the field of new compounds with kinase inhibitory or regulatory activities, which can solve the problems of not disclosing the activity of CDK kinases or GSK kinases

Inactive Publication Date: 2009-03-04
ASTEX THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0071] WO 03 / 035065 (Aventis) discloses a large class of benzimidazole derivatives as protein kinase inhibitors, but it does not disclose their activity on CDK kinases or GSK kinases

Method used

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  • Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases
  • Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases
  • Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1016] 5-cyano-2-methoxy-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazole -2-yl)-1H-pyrazol-4-yl)-benzamide

[1017] 1A. Synthesis of (3,4-Dinitro-phenyl)-morpholin-4-yl-methanone (methanone)

[1018]

[1019] A mixture of 3,4-dinitrobenzoic acid (10.0 g) and thionyl chloride (30 ml) was heated under reflux for 2 hours, cooled to ambient temperature and excess thionyl chloride was removed by azeotroping with toluene. The residue was taken up in THF (100ml) and morpholine (4.1ml) and Et were simultaneously added to the mixture at 0°C 3 N (7.2ml). The mixture was stirred for 3 hours, water (100 ml) was added thereto, and then extracted with EtOAc. The organic part was washed with brine and dried (MgSO 4 ) And concentrate it under vacuum. The residue was recrystallized from MeOH to obtain (3,4-dinitro-phenyl)-morpholin-4-yl-methanone (8.23 g) as a yellow solid.

[1020] ( 1 H NMR(300MHz, DMSO-d 6 )δ 8.3(d, 1H), 8.3(s, 1H), ...

Embodiment 2

[1042] 6-Methyl-imidazo[2.1-b]thiazole-5-carboxylic acid [3-(5-morpholin-4-ylmethyl- Synthesis of 1H-benzimidazol-2-yl)-1H-pyrazol-4-yl)-amide

[1043]

[1044] The 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid (Bionet) (61mg, 0.33mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazole-2- A mixture of -1H-pyrazol-4-ylamine (100mg, 0.33mmol), EDC (77mg, 0.39mmol) and HOAt (54mg, 0.39mmol) was stirred in DMF (3ml) at 80°C for 1 hour, It was then stirred at ambient temperature for 20 hours. The mixture was reduced in vacuo and the residue was partitioned between EtOAc and saturated NaHCO. The organic part was washed with brine and dried (MgSO 4 ) And decrement it under vacuum. The residue was purified by preparative LC / MS to obtain 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzimidazole) -2-yl)-1H-pyrazol-4-yl]-amide (29 mg). (Alkaline LC / MS: R t 2.56[M+H] + 463).

Embodiment 3

[1046] 2-cyano-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)- Synthesis of 1H-pyrazol-4-yl]-acetamide

[1047]

[1048] The cyano-acetic acid (23mg, 0.28mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (70%, A mixture of 100 mg, 0.23 mmol), TBTU (89 mg, 0.28 mmol) and DMF (2 ml) was stirred at 25°C overnight. Then, the mixture was evaporated in vacuo. Purification by flash column chromatography, eluting with DCM-6% MeOH / DCM, gave 2-cyano-N-[3-(5-morpholin-4-ylmethyl-1H-) as a yellow solid. Benzimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide (65 mg, 77%). (LC / MS (acid method / final compound): R t 4.61, [M+H] + 366).

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Abstract

The invention provides a compound of the formula (I): or a salt, solvate, tautomer or N-oxide thereof, wherein M is selected from a group D1 and a group D2: and R', E, A and X are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds, processes for making the compounds and the use of the compounds in the prophylaxis or treatment of a disease state mediated by a CDK kinase, GSK-3 kinase or Aurora kinase.

Description

Technical field [0001] The present invention relates to a pyrazole compound that inhibits or modulates the activity of Cyclin-dependent kinase (CDK), glycogen synthase kinase (GSK) and Aurora kinase, which is used in the treatment or prevention of the kinase-mediated The application in guided disease states or disorders, and new compounds with kinase inhibitory or regulatory activity. Pharmaceutical compositions and novel chemical intermediates containing the compounds are also provided. Background technique [0002] Protein kinases constitute a large family of structurally related enzymes responsible for controlling a wide range of signal transduction processes in cells (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). These kinases can be divided into families by their phosphorylated substrates (eg, protein-tyrosine, protein-serine / threonine, lipid, etc.). Sequence motifs that are generally equivalent to each of these kina...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D513/04C07D407/14A61K31/4184A61P35/00
Inventor V·贝尔迪尼M·G·卡尔A·L·吉尔S·霍沃德E·F·纳瓦罗G·特里瓦撒D·C·里斯M·文科维克P·G·怀亚特
Owner ASTEX THERAPEUTICS LTD
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