Heterocycle substituted amide and sulfur amide derivatives as histone deacetylase (hdac) inhibitors

1. A compound of formula I:

wherein:

p is 0, 1, 2 or 3;

q is 1, 2, 3 or 4;

t is 0 or 1;

X is C or S═O;

Y is R 2 , (C═S)R 2 , (C═O)R 2 , (C═S)NR X R 2 or (C═O)NR X R 2 ;

Het is a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, but not more than one of which is O or S;

optionally substituted by one or more groups independently chosen from cyano, halogen, hydroxy, oxido, oxo, nitro, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 6-10 aryl;

R 1 is naphthyl optionally substituted by one or more groups independently chosen from cyano, halogen, nitro, oxo, hydroxy, oxido, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylcarbonyl, N(R a ) 2 , SO 2 N(R b ) 2 and N(R b )SO 2 R b ;

R 2 is R 9 or R 10 ;

R 3 is hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkoxy, C 3-10 cycloalkyl, haloC 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, nitro, N(R c ) 2 , C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 6-10 arylC 1-6 alkoxy; 4, 5 or 6 membered saturated or partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally bridged by a C 1-4 alkyl group; 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, but not more than one of which is O or S; 6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; or a 7-13 membered saturated, partially saturated or unsaturated heterocycle containing heteroatoms independently selected from N, O or S; any of which rings being optionally substituted by one or more groups independently chosen from R d ;

R 4 , R 5 and R 7 are independently selected from hydrogen and C 1-6 alkyl;

R 6 and R 8 are independently hydrogen, C 1-6 alkyl, a 5 or 6 membered saturated or partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S or a 6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; each of which rings being optionally substituted by one or more groups independently chosen from halogen, nitro, amino, cyano, oxo, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-10 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl; or

R 6 and R 8 together represent an oxo group;

R 9 is hydrogen, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl or C 1-6 alkoxy;

R 10 is C 6-10 aryl, C 6-10 arylC 1-6 alkyl, a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, but not more than one of which is O or S, or a 6 membered unsaturated heterocycle containing 1, 2, or 3 heteroatoms independently selected from N and O; optionally substituted by one or more groups independently chosen from cyano, halogen, hydroxy, oxo, oxido, nitro, N(R c ) 2 , C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CON(R b ) 2 , NR b COR b , SO 2 N(R b ) 2 , NR b SO 2 R b , C 6-10 aryl, 5 or 6 membered saturated or partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, but not more than one of which is O or S, 6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogen atoms and a 7-10 membered saturated, partially saturated or unsaturated heterocycle containing heteroatoms independently selected from N, O or S;

each R a is independently selected from hydrogen, C 1-6 alkyl, C 6-10 aryl, C 1-6 alkylcarbonyl and C 6-10 arylcarbonyl;

each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5 or 6 membered saturated or partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O or S, optionally bridged by a C 1-4 alkyl group; 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, but not more than one of which is O or S; or a 6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; any of which rings may be optionally substituted by one or more groups independently chosen from halogen, hydroxy, amino, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy;

each R c is independently selected from hydrogen and C 1-6 alkyl;

each R d is halogen, hydroxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkylcarbonyl, haloC 1-6 alkylcarbonyloxy, C 1-6 alkoxy, haloC 1-6 alkoxy, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, nitro, oxo, SO 2 N(R e ) 2 , NR e SO 2 R e , N(R e ) 2 , C 6-10 aryl, C 6-10 arylC 1-6 alkyl, 5 or 6 membered saturated or partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O or S, optionally bridged by a C 1-4 alkyl group; 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, but not more than one of which is O or S; or a 6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; any of which rings may be optionally substituted by one or more groups independently chosen from halogen, hydroxy, amino, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and halo C 1-6 alkoxy;

each R e is independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, carboxy or C 1-6 alkyloxycarbonyl; and

each R x is independently selected from hydrogen and C 1-6 alkyl;

provided that when Y is R 2 then R 9 is not hydrogen or C 1-6 alkyl; and

when Y is (C═O)R 2 then R 9 is not hydroxy or C 1-6 alkoxy;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

2. The compound according to claim 1 wherein:

Y is R 10 , (C═S)R 2 , (C═O)R 10 , (C═S)NR x R 2 or (C═O)NR x R 2 ;

or a pharmaceutically acceptable salt, stereoisomer or tautomer therof.

3. The compound according to claim 1 wherein Y is (C═O)NR x R 2 .

4. The compound according to claim 1 of formula III:

wherein:

R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , X, Y, p and t are as defined in claim 2 ;

A represents CH or N;

B represents NR f , O or S;

Z represents N or CR g ;

R f represents hydrogen or C 1-6 alkyl; and

R g represents hydrogen, C 1-6 alkyl or C 6-10 aryl optionally substituted by up to two groups selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl or haloC 1-6 alkoxy;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

5. The compound according to claim 1 of formula V:

wherein R 1 , R 3 , R 6 , R 8 , Y and p are as defined in claim 2 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

6. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier.