Hetereoaryl nitrile derivatives

compound of formula I, or a pharmaceutically acceptable salt or ester thereof

• In which
• R is H, —R2,—OR2 or NR1R2,
• wherein R1 is H, lower alkyl or C3 to C10 cycloalkyl, and
• R2 is lower alkyl or C3 to C10 cycloalkyl, and
• wherein R1 and R2 are independently, optionally substituted by halo, hydroxy, lower alkoxy, CN, NO2, or optionally mono- or di-lower alkyl substituted amino;
• X is ═N— or ═C(Z)-,
• wherein Z is H, —R4,—C≡C—CH2—R5, C(P)═C(Q)-R3,
• wherein
• P and Q independently are H, lower alkyl or aryl,
• R3 is aryl, aryl-lower alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl,
• wherein R3 is independently, optionally substituted by one or more groups, e.g. 1-3 groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or NO2, or optionally substituted (optionally mono- or di-lower alkyl substituted amino, aryl, aryl-lower alkyl, N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein the optional substitution comprises from 1 to 3 substituents selected from halo, hydroxy, lower alkoxy, CN, NO2, or optionally mono- or di-lower alkyl substituted amino)),
• R4 is H, aryl, aryl-lower alkyl, aryl-lower-alkenyl, C3-C10cycloalkyl, C3-C10cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, and wherein
• R5 is aryl, aryl-lower alkyl, aryloxy, aroyl or N-heterocyclyl as defined above, and wherein R5 is optionally substituted by R7 which represents from 1 to 5 substituents selected from halo, hydroxy, CN, NO2 or oxo, or optionally substituted (lower-alkoxy, lower-alkyl, aryl, aryloxy, aroyl, lower-alkylsulphonyl, arylsulphonyl, optionally mono- or di-lower alkyl substituted amino, or N-heterocyclyl, or N-heterocyclyl-lower alkyl, wherein N-heterocyclyl denotes a saturated, partially unsaturated or aromatic nitrogen containing heterocyclic moiety attached via a nitrogen atom thereof having from 3 to 8 ring atoms optionally containing a further 1, 2 or 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O)2 wherein R6 is H or optionally substituted (lower alkyl, carboxy, acyl (including both lower alkyl acyl, e.g. formyl, acetyl or propionyl, or aryl acyl, e.g. benzoyl), amido, aryl, S(O) or S(O)2), and wherein the N-heterocyclyl is optionally fused in a bicyclic structure, e.g. with a benzene or pyridine ring, and wherein the N-heterocyclyl is optionally linked in a spiro structure with a 3 to 8 membered cycloalkyl or heterocyclic ring wherein the heterocyclic ring has from 3 to 10 ring members and contains from 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O )2 wherein R6 is as defined above), and
• wherein heterocyclyl denotes a ring having from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O)2 wherein R6 is as defined above), and and
• wherein R7 is optionally substituted by from 1 to 3 substituents selected from halo, hydroxy, optionally mono- or di- lower-alkyl substituted amino, lower-alkyl carbonyl, lower-alkoxy or lower-alkylamido;
• Y is —NR8R9,
• wherein
• R8 is H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl),
• wherein R8 is optionally substituted by R10 which represents from 1 to 4 substituents selected from halo, hydroxy, CN, NO2, —O—C(O)—, optionally substituted (lower-alkyl, C3-C10cycloalkyl, lower-alkoxy, lower-alkenyl, lower-alkynyl, optionally mono- or di-lower alkyl-substituted amino or N-heterocyclyl (as defined above),
• wherein R10 is optionally substituted by R11 which represents from 1 to 4 substituents selected from halo, hydroxy, CN, NO2, oxo, optionally substituted (optionally mono- or di-lower alkyl-substituted amino, lower alkyl, optionally-lower alkyl substituted COOH, sulphinyl, sulphonyl, or N-heterocyclyl (as defined above))
• wherein R11 is optionally substituted by R12 which represents from 1 to 4 substituents selected from halo, hydroxy, CN, NO2, oxo, hydroxy lower alkyl, C3-C10cycloalkyl, optionally lower alkyl-substituted carboxy, hydroximine, or N-heterocyclyl as defined above, and
• wherein
• R9 is independently H, or optionally substituted (lower alkyl, aryl, aryl-lower alky, C3-C10cycloalkyl, C3-C10cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl), and
• wherein R9 is optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN, NO2, or optionally mono- or di-lower alkyl substituted amino;
• or Z and Y together with the carbon atoms to which they are attached are joined to provide a compound of formula I selected from,
• wherein
• R is as defined above;
• R15 is lower-alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl-lower alkyl, NR20R21-lower alkyl-, where
• T is —O— or a direct bond;
• R16 is NR20R21-lower alkyl- or R4, both as defined above,
• R20 is H, optionally substituted (lower alkyl, aryl, C3-C10cycloalkyl, lower alkoxy lower alkyl C3-C10cycloalkyl-lower alkyl or aryl lower alkyl),
• R21 is optionally substituted (lower alkyl, aryl, C3-C10cycloalkyl, lower alkoxy lower alkyl, C3-C10cycloalkyl-lower alkyl or aryl-lower alkyl), or
• R20 and R21 form an N-heterocyclyl ring as hereinbefore defined,
• and wherein R20 or R21 are independently optionally substituted by R23 which which represents from 1 to 3 substituents selected from halo, hydroxy, CN, NO2, oxo, optionally mono- or di-lower alkyl substituted amino, or optionally substituted (lower-alkoxy, lower-alkyl, lower alkoxy carbonyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, aryloxy, aroyl, alkylsulphonyl, arylsulphonyl or N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein N-heterocyclyl is as defined above));
• A is —CH═ or —C(O)—, B is —C═ or —N—, D is —CH═ or —C(O)— and E is —CH═ or —N(R1) (where R1is as defined above).