Thiophene and Thiazole Substituted trifluoroethanone Derivatives as Histone Deacetylase (Hdac) Inhibitors

A compound of formula I:

• wherein:
• each of the (X═O) linked group and trifluoroacetyl group is independently substituted on any carbon ring atom;
• A is CH or N;
• D is CH;
• X is C or S═O;
• R1 is hydrogen, C1-6alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, C6-10aryl, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, or a 7-10 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;
• any of which rings being optionally substituted by one or more groups independently selected from halogen, cyano, C1-6alkyl, C1-6alkoxy, mercaptoC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, amino, C1-6alkylamino and di(C1-6alkyl)amino;
• or
• R1 together with —(CH2)b—N—(CR2R3)aW forms a 4 membered saturated heterocycle containing one N atom or a 5, 6 or 7 membered saturated heterocycle containing one, two or three N atoms and zero or one O atom;
• the ring being optionally fused to a C3-10cycloalkyl ring, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a phenyl ring, a 5 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;
• optionally substituted at a carbon ring atom by a 5 or 6 membered spiro ring containing zero, one or two heteroatoms independently selected from N, O or S which ring is optionally fused to a phenyl ring;
• or optionally bridged by one or two C1-4alkyl groups;
• any of which rings being optionally substituted by one or more groups independently selected from L-R4;
• each L is independently a direct bond, (CH2)d or C═O;
• R2 and R3 are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, C6-10aryl, a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S;
• a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;
• or a 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S;
• or
• R2 and R3 together with the carbon atom to which they are attached form a C3-7cycloalkyl group, >C═O or >C═CH;
• W is halogen, C1-6alkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkoxy, S(O)r(CH2)cR5;
• or a ring which is:
• C3-5cycloalkyl;
• a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S;
• a 6-13 membered saturated, partially saturated or unsaturated hydrocarbon ring;
• a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S;
• a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;
• or a 7-15 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;
• any of which alkyl groups or rings being optionally substituted by one or more groups independently selected from R6;
• each R4 is independently halogen;
• cyano;
• hydroxy;
• oxo;
• C1-6alkyl;
• haloC1-6alkyl;
• C1-6alkoxy;
• mercaptoC1-6alkyl;
• haloC1-6alkoxy;
• C1-6alkylcarbonyl;
• C1-6alkoxycarbonyl;
• nitro;
• N(Ra)2;
• N(Ra)CON(Ra)2;
• N(Ra)CO(C1-6alkyl);
• N(Ra)CO2(C1-6alkyl);
• S(O)r(CH2)cR5;
• or a ring which is:
• C3-10cycloalkyl;
• C6-10aryl;
• C6-10arylC1-6alkyl;
• C6-10aryloxyC1-6alkyl;
• C6-10arylcarbonyl;
• a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S;
• a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S;
• a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;
• or a 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S;
• any of which alkyl groups or rings being optionally substituted by one or more groups independently selected from cyano, oxo, hydroxy, halogen, C1-6alkyl, C1-6alkoxy, mercaptoC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms and C6-10aryl, any of which rings being optionally substituted by one or more groups independently selected from halogen, C1-6alkyl, C1-6alkoxy and haloC1-6alkyl;
• R5 is C1-6alkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, C6-10aryl, C6-10aryloxy, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, or a 7-10 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;
• any of which alkyl or alkenyl groups or rings being optionally substituted by one or more groups independently selected from halogen, cyano, oxo, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy, N(Ra)2, —C1-6alkylN(Ra)2, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C6-10aryl and C6-10aryloxy rings, the rings being optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl and haloC1-6alkyl;
• each R6 is independently halogen, cyano, oxo, hydroxy, C1-6alkyl, C1-6alkoxy, mercaptoC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl;
• C1-6alkoxycarbonyl;
• nitro;
• N(Ra)2;
• CON(Ra)2;
• N(Ra)CON(Ra)2;
• N(Ra)CO(C1-6alkyl);
• N(Ra)CO2(C1-6alkyl);
• S(O)r(CH2)cR5, O(C1-10alkyl)N(Ra)COR7;
• or a ring which is:
• C3-7cycloalkyl, C6-10aryl, C6-10arylC1-6alkyl, C6-10aryloxyC1-6alkyl, C6-10aryloxy, C6-10arylcarbonyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S;
• any of which rings being optionally substituted by one or more groups independently selected from halogen, C1-6alkyl and C1-6alkoxy;
• R7 is C1-6alkoxy or C1-6alkyl optionally substituted by halogen or a 7-10 membered saturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, the ring being optionally substituted by one or more groups independently selected from halogen, hydroxy, oxo, C1-6alkyl and C1-6alkoxy;
• each Ra is independently hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C6-10aryl or C6-10arylcarbonyl;
• a is zero, one, two, three, four, five or six;
• b is zero, one, two, three or four;
• c is zero, one, two, three or four;
• each d is independently one, two, three or four;
• and
• r is zero, one or two;
• or a pharmaceutically acceptable salt thereof.