Pyrazole derivatives as p38 MAP inhibitors

摘要

Compounds of formula (I):;wherein R1, R2, J, Q, V, X, Y and Z are defined herein are disclosed. The compounds are inhibitors of the family of p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), particularly the alpha sub-type thereof, and of Syk kinase and the Src family of tyrosine kinases. The compounds may be used in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, in particular inflammatory diseases of the lung, such as asthma and COPD, as well as those of the gastrointestinal tract, such as ulcerative colitis and Crohn's disease and of the eye, such as uveitis.

主权项

1. A compound of formula (I):wherein:
R1 represents C1-6 alkyl, C1-6 hydroxyalkyl, C0-2 alkylene-C3-8 cycloalkyl optionally substituted by C1-3 alkyl, halo substituted C1-6 alkyl or a 4-6 membered heterocycle optionally substituted with C1-3 alkyl, Q represents thienyl, phenyl, pyridine or pyridone, each optionally substituted by 1to 3 substituents independently selected from the group consisting of hydroxyl, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, OC2-6alkyleneORA, OC2-6 alkyleneOC2-6 alkyleneORA, OC2-6alkyleneNRARA C1-6 alkylene-5-10 membered heterocycle, and C0-3 alkylene-O—C1-6 alkylene-5-10 membered heterocycle, RA represents H or C1-3 alkyl, R2 represents H, C1-3 alkyl, C1-3 alkoxy or halo, J represents CH or N, V represents CR2 or N, X represents S, N, NR3, CR4, C═O, O, CR5R6, or —OCR5R6-thereby forming a six membered ring, Y represents O, N, NR7, CR8, C═O, SOn or CR9R10, Z represents O, S, N, NR11, C═O, CR12, CR12R13, or —OCR12R13-thereby forming a six membered ring, R3 represents H, C1-3 alkyl or C1-6 alkylene-5-10 membered heterocycle, R4 represents H, hydroxyl, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-3 haloalkyl, C0-6 alkyleneNR14R15 or C1-6 alkylene-5-10 membered heterocycle, wherein each alkylene group or alkyl group optionally bears 1oxo substituent and optionally one or two carbons in the alkylene chain or alkyl chain is replaced by a heteroatom selected from the group consisting of O,N, NR14 and S(O)p, R5 represents H or C1-3 alkyl, R6 represents H or C1-3 alkyl, R7 represents H, C1-3 alkyl or C1-6 alkylene-5-10 membered heterocycle, R8 represents H, hydroxyl, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-3 haloalkyl, C0-6 alkyleneNR14R15 or C1-6 alkylene-5-10 membered heterocycle, wherein each alkylene group or alkyl group optionally bears 1oxo substituent and optionally one or two carbons in the alkylene chain or alkyl chain is replaced by a heteroatom selected from the group consisting of O, N, NR14 and S(O)p, R9 represents H or C1-3 alkyl, R10 represents H or C1-3 alkyl, R11 represents H, C1-3 alkyl or C1-6 alkylene-5-10 membered heterocycle, R12 represents H, hydroxyl, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-3 haloalkyl, C0-6 alkyleneNR14R15 or C1-6 alkylene-5-10 membered heterocycle, wherein each alkylene group or alkyl group optionally bears 1oxo substituent and optionally one or two carbons in the alkylene chain or alkyl chain is replaced by a heteroatom selected from the group consisting of O N, NR14 and S(O)p, R13 represents H or C1-3 alkyl, R14 represents H or C1-3 alkyl, R15 represents H or C1-3 alkyl, a dashed bond represents, as required by valency, a double or single bond, n represents 0, 1 or 2, P represents 0, 1 or 2, with the proviso that when Z represents —OCR12R13-then X represents S, N, NR3, CR4, C═O, O or CR5R6;or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.