Kinase inhibitors

A compound of formula I,

• wherein:
• R1A represents
• C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, which latter four groups are optionally substituted by one or more substituents selected from C1-2 alkyl, halo, hydroxy, —OP(O)(OH)2 and C1-2 alkoxy,
• H, halo, cyano,
• phenyl or Het1, which latter two groups are optionally substituted with one or more substituents selected from C1-2 alkyl and C1-2 alkoxy,
• or R1A and R1B together represent a structural fragment selected from the following
• wherein the wavy lines represent the points of attachment to the phenyl ring;
• A represents O, S or N(RA2);
• RA1 represents H, C1-4 alkyl or hydroxy;
• RA2 represents H or C1-4 alkyl;
• R1B represents —NRXS(O)2RY1, —C(O)NRXRY, H, halo, cyano, —C1-4 alkylene-CN, —C1-4 alkylene-OH, —NRXRX1, —C(O)ORX, —S(O)2NRXRY, —NRXC(O)RY, —NRX2S(O)2NRXRY, —NRXP(O)RY1RY2, —NRXC(O)ORY1 or Het1 optionally substituted with one or more substituents selected from halo, hydroxy, C1-2 alkyl and C1-2 alkoxy;
• RX and RX1 independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from halo, hydroxy, —OP(O)(OH)2 and C1-2 alkoxy, or RX and RX1 together represent C3-6 n-alkylene or C4-5 n-alkylene interrupted between C2 and C3 by —O— or —N(RX2)—, or RX1 represents Het1 optionally substituted with one or more substituents selected from halo, hydroxy, C1-2 alkyl and C1-2 alkoxy;
• RY, RY1 and RY2 independently represent C1-6 alkyl, C3-7 cycloalkyl, phenyl, benzyl, Het1 or Het2, which latter six groups are optionally substituted by one or more substituents selected from C1-2 alkyl, halo, hydroxy, —OP(O)(OH)2, C1-2 alkoxy, C(O)OH, C(O)O—(C1-4 alkyl) and —N(Ra)(Rb), and/or which Het2 group is substituted with one or more oxo groups,
• or RY represents H,
• or RX and RY together represent C3-6 n-alkylene or C4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O)n— or —N(RX2)—;
• Ra and Rb independently represent H, methyl or —C(Rc)(Rd)—C1-3 alkyl, the C1-3 alkyl portion of which latter group is optionally substituted by one or more hydroxy substituents,
• or Ra and Rb together represent C3-6 n-alkylene or C4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O)m— or —N(RX2);
• Rc and Rd independently represent H or methyl;
• each RX2 independently represents H or C1-4 alkyl;
• R1c and R1E independently represent H, halo, cyano or methyl;
• provided that at least one of R1A, R1B, R1C and R1E is other than H;
• R1D represents trimethylsilyl, C2-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, phenyl, Het1 or Het2, which latter seven groups are optionally substituted by one or more substituents selected from C1-2 alkyl, halo, cyano, hydroxy, —OP(O)(OH)2 and C1-2 alkoxy;
• R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from C1-3 alkyl, C1-3 haloalkyl, cyano and halo,
• or one of R2 and R3 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 R2 and R3 together combine to form C3-5 alkylene or C3-5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from C1-3 alkyl, C1-3 haloalkyl, cyano and halo;
• X1 represents N or CH;
• L represents a direct bond or C1-2 alkylene;
• X2 represents CRZ or N;
• X3 represents CR5b or N;
• RZ represents H, halo, cyano, hydroxy, C1-3 alkyl or C1-3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
• R4 represents
• -Q1-[C(R6c)(R6d)—(CH2)0-1CH2—Z]1-12—CH2(CH2)0-1CH2—R6a,
• -Q2-C(R6c)(R6d)—[C1-5 alkylene]-R6a, which C1-5 alkylene group is optionally substituted by oxo and/or by one or more R6e,
• -Q3-[C1-4 alkylene]0-1-Hetx1, which C1-4 alkylene group is optionally substituted by oxo and/or by one or more R6e and which Hetx1 group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C3-6 cycloalkyl, C1-3 alkoxy and —[C(O)]0-1—C1-4 alkyl, the C1-4 alkyl part of which latter group is optionally substituted by one or more R6e,
• -Q22-[C1-4 alkylene]0-1-phenyl, which C1-4 alkylene group is optionally substituted by oxo and/or by one or more R6e, and which phenyl group is substituted by —[C(O)]0-1—C1-4 alkyl, the C1-4 alkyl part of which latter group is optionally substituted by one or more R6e, and which phenyl group is optionally further substituted by one or more substituents selected from halo, hydroxy, oxo, C3-6 cycloalkyl and C1-3 alkoxy,
• —S(O)pR6b,
• —[C1-4 alkylene]0-1-CO2H,
• Hetx2 which Hetx2 group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C1-3 alkyl and C1-3 alkoxy,
• —COR6b,
• —CH2OH,
• —CH2OP(O)(OH)2 or
• -Q4-P(O)(OR9)(R7);
• Z represents, independently upon each occurrence, O, C(O)N(R8) or N(R8)C(O);
• R5a and R5b independently represent C1-3 alkoxy or C1-3 alkyl, which latter two groups are optionally substituted by one or more halo atoms, or R5a and R5b independently represent —N(Re)(Rf), C2-3 alkynyl, H, cyano, —C(O)NH2, hydroxy, halo or —S(O)0-2—C1-3 alkyl;
• R6a represents OR7a, —S(O)0-2R7aa, N(R7b)R7c or CO2H;
• R6b represents C1-8 alkyl, C3-8 cycloalkyl, phenyl, Het1 or Het2, which latter five groups are optionally substituted by one or more substituents selected from halo, hydroxy, —OP(O)(OH)2, C1-3 alkyl, C1-3 alkoxy, —C1-3 alkylene-R6e and CO2H,
• or R6b represents —C1-4 alkylene-Het3, which Het3 group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C3-6 cycloalkyl, C1-3 alkoxy and —[C(O)]0-1—C1-3 alkyl, which C1-3 alkyl group is optionally substituted by one or more R6e,
• or, when p is 1 or 2, R6b may alternatively represent OH,
• or, when p is 2, R6b may alternatively represent —N(R7b)R7c or —N(R7b)—C(O)—R7c;
• R6e represents, independently upon each occurrence, halo, hydroxy, —OP(O)(OH)2, C1-3 alkoxy, —N(Rg)(Rh) or —CO2H;
• R7a to R7c independently represent H or C1-4 alkyl optionally substituted by one or more halo atoms or by —CO2H,
• or R7a represents P(O)(OH)2 or Het3, which latter group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C3-6 cycloalkyl, C1-3 alkoxy and —[C(O)]0-1—C1-3 alkyl, which C1-3 alkyl group is optionally substituted by one or more R6e,
• or R7b and/or R7c represents —[Ca alkylene]-[Cb alkylene]-OR7d,
• or R7b and R7c together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic and which heterocyclic group contains one N atom (the atom to which R7b and R7c are attached) and, optionally, one or more further heteroatoms selected from O, S and N, and which heterocyclic group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C1-4 alkyl, C1-4 alkoxy and C1-4 hydroxyalkyl;
• a and b independently represent an integer selected from 1, 2 and 3, wherein the sum of a and b is 2, 3 or 4;
• R7d represents H or C1-4 alkyl optionally substituted by one or more halo atoms;
• R7aa represents —C(R7d)(R7e)—C1-3 alkylene-OH or C1-4 alkyl optionally substituted by one or more halo atoms or by —CO2H;
• Q1, Q2, Q22 and Q3 independently represent —C(O)N(R8)—, —O— or —S(O)2N(R8)—, or Q1, Q2 and
• Q22 independently represent S(O)q;
• Q4 represents a direct bond or C1-3 alkylene;
• n, m, p and q independently represent 0, 1 or 2;
• R6c, R6d, Re, Rg, Rh and R8 independently represent H or methyl,
• or R6c and R6d independently represent hydroxymethyl;
• R7 represents H, hydroxy, C1-4 alkyl, C1-4 alkoxy, C3-7 cycloalkyl or phenyl, which latter four groups are optionally substituted by one or more substituents selected from halo, OH, C1-3 alkyl and C1-3 alkoxy;
• R9 represents H or C1-4 alkyl, which latter group is optionally substituted by one or more halo atoms or by phenyl, which phenyl group is optionally substituted by one or more substituents selected from halo, OH, C1-3 alkyl and C1-3 alkoxy;
• Hetx1 and Hetx2 independently represent Het1a or Het3;
• Het1 and Het1a represent, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S;
• and
• Het2 and Het3 represent, independently upon each occurrence, a 4- to 9-membered heterocyclic group that is fully saturated or partially unsaturated, and is monocyclic or is fused or bridged bicyclic, which group contains one or more heteroatoms selected from N, O and S;
• or a pharmaceutically acceptable salt thereof.