Heterocycle substituted ketone derivatives as histone deacetylase (HDAC) inhibitors

1. A compound of formula I:

wherein:

b is 0, 1, 2, 3, 4 or 5;

q is 1, 2, 3 or 4;

Y is C═O, (C═O)NR 7 , O(C═O)NR 7 or (CH 2 ) a O;

a is 0, 1, 2 or 3;

Het is imidazolyl, oxazolyl, thienyl, thiazolyl or pyrazolyl optionally substituted by one or more groups independently chosen from cyano, halogen, hydroxy, 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 hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 6-10 aryl, 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from O, N 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 8-10 membered unsaturated or partially saturated heterocycle containing heteroatoms independently selected from O, N and S; any of which rings being optionally substituted by one or more groups independently chosen from cyano, halogen, nitro, oxo, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, carboxy, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylcarbonyl and N(R a ) 2 wherein R a is independently selected from hydrogen, C 1-6 alkyl, C 6-10 aryl, C 1-6 alkylcarbonyl and C 6-10 arylcarbonyl;

R 2 is C 1-6 alkyl;

R 3 is hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-10 cycloalkyl, haloC 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, nitro, N(R d ) 2 wherein R d is independently selected from hydrogen, C 1-6 alkyl and C 1-6 alkylcarbonyl; 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 b ;

R 4 is hydrogen or C 1-6 alkyl; or

R 5 and R 6 are independently hydrogen or C 1-6 alkyl;

R 7 is hydrogen or C 1-6 alkyl;

each R b 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 c ) 2 , N(R c ) 2 wherein R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, carboxy and C 1-6 alkoxycarbonyl, or 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 haloC 1-6 alkoxy;

or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound of claim 1 of formula II:

wherein:

b, q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined in claim 1 ;

one of A and B is N and the other CH;

R e is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

3. The compound of claim 1 wherein Y is C═O, (C═O)NH, (C═O)NMe, O(C═O)NH, O or (CH 2 )O.

4. The compound of claim 1 of formula III:

wherein:

Y 1 is (C═O) or (C═O)NR 7 ;

R 1 , R 2 , R 3 , R 5 , R 6 , b and q are as defined in claim 1 ;

one of A and B is N and the other CH;

R 4 is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

5. The compound of claim 1 wherein R 1 is an optionally substituted ring selected from C 6-10 aryl, a 5 membered unsaturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, but not more than one of which is O or S, a 6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogen atoms, or a 8, 9 or 10 membered unsaturated or partially saturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S.

6. The compound of claim 1 wherein:

R 3 is hydrogen, dimethylamino, phenyl, naphthyl, pyrrolidinyl, piperidinyl, azoniabicyclo[2.2.1]heptanyl, azoniabicyclo[2.2.2]octanyl, piperazinyl, morpholinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyridinyl, indolyl, benzothienyl, benzothiadiazolyl, benzoxadiazolyl, dihydrobenzofuryl, dihydrothiazolopyrimidinyl, isoquinolyl, dihydrobenzodioxinyl, dihydrobenzoxazinyl, tert-butoxy, cyclopentyl, methyl, trifluoromethyl, methoxy, diethylamino, hydroxy, benzimidazolyl, benzofuranyl, triazolopyrimidinyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, quinolinyl, benzisoxazolyl, benzotriazolyl, tetrahydrobetacarbolinyl, dihydroisoindolyl, tetrahydronaphthyridinyl, tetrazolyl, benzyloxy, thiomorpholinyl, azetidinyl, tetrahydroquinolinyl, acetylamino, triazolyl, thiazolidinyl or amino; any of which rings being optionally substituted by one or more groups independently chosen from R b ; and

R b is halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, carboxy, C 1-6 alkoxycarbonyl, nitro, aminosulfonyl, (C 1-6 alkylcarbonyl)amino, morpholinyl, piperazinyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, oxo, haloC 1-6 alkyl, phenyl, pyrrolidinyl or benzyl; any of which rings being optionally substituted by one or more groups independently chosen from C 1-6 alkyl and haloC 1-6 alkyl.

7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof and a pharmaceutically acceptable carrier.