Preparation of pyrazolyl-urea compounds as kinase inhibitors for treatment of inflammatory diseases.

Abstract

Provided are compds. of I and compns. thereof as inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) enzymes demonstrating antiinflammatory activity useful alone or in pharmaceutical combinations in the treatment of inflammatory diseases of the lung, eye, and intestine. Compds. of formula I [wherein Q is thienyl, Ph, or pyridinyl, any of which may be independently optionally substituted with OH, halo, C1-6alkyl, etc.; X is CH or N; Y is NR2R3 or (un)substituted 4-10 heterocycle linked through a heteroatom, etc.; R is C1-6alkyl, C2-6alkenyl, C1-6hydroxyalkyl, etc.; R1 is H, OH, halo, etc.; Ra and Rb together with the C-atoms to which they are attached form an optionally substituted fused Ph ring, or Ra and Rb independently represent H, halo, cyano, etc.; R2 or R3 each independently is H, C1-8alkyl, C0-6 alkylene aryl, etc.] or a pharmaceutically acceptable salt thereof including all stereoisomers and tautomers are claimed and exemplified. Thus, II was prepd. by the reaction of 3-amino-5-ethynyl-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide with III. Candidate compds. of I were assayed for enzyme inhibition activity against p38 MAPKα, c-Src, and Syk with II demonstrating IC50 values of 25 nM, 30 nM, and 370 nM, resp. [on SciFinder(R)]