KINASE INHIBITORS

摘要

There are provided compounds of formula I,;;wherein:

Y represents NR2R3;

one of R2 and R3 represents —[C2-4 alkylene-O]1-12—[C2-4 alkylene]-R2a and the other of R2 and R3 has a meaning given in the description; and

R, R1, R2a, Ra, Rb, Q, X and Y have meanings given in the description,

which compounds have antiinflammatory activity (e.g., through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

主权项

1. A compound of formula (I): wherein: Q represents thienyl, phenyl or pyridinyl, either of which may optionally bear 1 to 3 substituents independently selected from, hydroxyl, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, NH2, N(H)—C1-6 alkyl, N(C1-6 alkyl)2, -L-P(O)R′R″, C1-6 alkylene-5-10 membered heterocycle and C0-3 alkylene-O—C0-6 alkylene-5-10 membered heterocycle; L is a direct bond or C1-2 alkylene; R′ represents C1-4 alkyl; R″ represents C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy or hydroxy; or R′ and R″ together combine to form C3-6 n-alkylene, wherein one CH2 of said n-alkylene group is optionally replaced by O, N(H) or N(C1-4 alkyl); X represents CH or N, Y represents NR2R3; R is
C1-6 alkyl,C2-6 alkenyl,C1-6 hydroxyalkyl,C1-6 haloalkyl,C1-6 alkyl substituted by C2-3 alkynyl, C1-3 alkoxy or cyano,C0-2 alkylene-C3-8 cycloalkyl optionally substituted with C1-3 alkyl, a 4-5 membered heterocycle optionally substituted with C1-3 alkyl orSi(R1a)(R1b)(R1c); R1a and R1b independently represent C1-4 alkyl or C3-6 cycloalkyl, or R1a and R1b together combine to form C2-6 alkylene; R1c represents C1-2 alkyl; Ra and Rb, together with the C-atoms to which they are attached, form a fused phenyl ring that is optionally substituted by one or more substituents selected from C1-3 alkyl, C1-3 haloalkyl, cyano and halo, or one of Ra and Rb represents H, halo, cyano, C1-3 alkyl or C1-3 haloalkyl and the other independently represents halo, cyano, C1-3 alkyl or C1-3 haloalkyl or Ra and Rb together represent C3-5 n-alkylene, which alkylene group is optionally substituted by one or more methyl substituents and/or which alkylene group optionally contains one C—C double bond between two C-atoms of the n-alkylene chain; R1 is selected from hydrogen, OH, halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C0-3 alkylene-C3-6 cycloalkyl, C0-3 alkylene-O—C1-3 alkylene-C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C0-3 alkylene-SO2C1-3alkyl, C0-3 alkylene-SO2NR4R5, and C0-3 alkylene-NR6R7 and C0-3 alkylene-NCOR6R7; one of R2 and R3 represents —[C2-4 alkylene-O]1-12—[C2-4 alkylene]-R2a and the other of R2 and R3 is selected from H, C1-8 alkyl, C0-6 alkylene aryl, C0-6 alkylene heteroaryl, —[C2-4 alkylene-O]0-12—[C2-4 alkylene]-R2a, C0-6 alkylene-4-10 membered heterocycle, and C0-3 alkylene-O—C0-6 alkylene-4-10 membered heterocycle with the proviso that when the said heterocycle is linked through nitrogen there are at least two C-atoms in the alkylene chain that links that nitrogen atom to the essential O atom of the substituent, wherein independently each alkyl or alkylene group optionally bears 1 oxo substituent, and optionally one or two carbon atoms in the alkyl or alkylene chain may each be replaced by a heteroatom selected from O, N or S(O)p, such that when said alkyl or alkylene comprises an amine said amino group is a tertiary amine, wherein each 4-10 membered heterocycle is optionally substituted by 1 or 2 groups independently selected from halo, OH, C1-6 alkyl, C1-4 haloalkyl, C0-3 alkylene-O—C0-6 alkyl, C0-3 alkylene-O—C1-3 haloalkyl, C0-6 alkylene aryl, C0-3 alkylene-O—C0-3 alkylene aryl, C0-6 alkylene heteroaryl, C0-3 alkylene-O—C0-3 alkylene heteroaryl, C(O)C1-6 alkyl, SO2NR8R9, and C0-3 alkylene-NR8R9, C0-3 alkylene-NR8SO2R9 and C0-3 alkylene-NR8C(O)R9; R2a represents OR2b or N(R2c) R2d; R2b to R2d independently represent H or C1-4 alkyl optionally substituted by one or more halo atoms, or R2C and R2d together represent
C3-6 n-alkylene,C4-5 n-alkylene interrupted between C2 and C3 by —O— or —N(R2e)— orC6 n-alkylene interrupted between C2 and C3, or between C3 and C4, by —O— or —N(R2e)—,any of which n-alkylene groups are optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C1-4 alkyl and C1-4 alkoxy; R2e represents H or C1-6 alkyl optionally substituted by one or more substituents selected from halo and hydroxy; R4 is H or C1-4 alkyl; R5 is H or C1-4 alkyl, R6 is H or C1-4 alkyl, C(O)C1-3alkyl and SO2C1-3 alkyl; R7 is H or C1-4 alkyl, C(O)C1-3alkyl and SO2C1-3 alkyl; R8 is H or C1-4 alkyl, and R9 is H or C1-4 alkyl, p is 0, 1 or 2 or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.