Tricyclic derivatives as inhibitors of poly(ADP-ribose) polymerase (PARP)

1. A compound of formula I:

wherein:

a is 0, 1, 2 or 3;

b is 1 or 2;

each c is independently 0, 1, 2, 3, 4, 5 or 6;

each d is independently 0 or 1;

each e is independently 0 or 1;

each f is independently 0 or 1;

each g is independently 0, 1, 2, 3, 4, 5 or 6;

each h is independently 0 or 1;

j is 0, 1, 20r 3;

A is either C or CH as the case may be; one of B, D and E is N and the others are independently N or either C or CH as the case may be, provided that when D is N then at least one of B and E is N;

each of R 1 and R 2 is independently hydrogen or C 1-6 alkyl;

each R 3 is independently hydroxy, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;

each of R 4 , R 5 , R 7 and R 8 is independently hydrogen, C 1-6 alkyl or halo C 1-6 alkyl;

each of R 6 and R 9 is independently hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl;

each R 10 is independently hydrogen, hydroxy, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxycarbonyl, carboxy, nitro or a ring which is: C 6-10 aryl; C 6-10 aryloxy; C 6-10 arylcarbonyl; C 3-10 cycloalkyl; oxetanyl; azetidinyl; a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three 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 N atoms; or a 7-15 membered unsaturated, partially saturated or saturated 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, two or three groups independently selected from (CH 2 ) x R 11 ;

each x is independently 0, 1, 2, 3, 4, 5 or 6;

each R 11 is independently hydroxy, oxo, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxycarbonyl, carboxy, NR a R b , CONR a R b , S(O) r R c or a ring which is: C 6-10 aryl; C 6-10 arylC 1-6 alkyl; oxetanyl; azetidinyl; a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing one, two or three 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, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, amino, C 1-6 alkylamino and di(C 1-6 alkyl)amino;

each of R a and R b is independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, S(O) r R c or S(O) r N(R d ) 2 ; or

R a and R b together with the N atom to which they are attached form an azetidinyl ring or a 5, 6 or 7 membered saturated or partially saturated heterocycle containing one, two or three N atoms and zero or one O atom, the ring being optionally substituted by one, two or three groups independently selected from hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl and haloC 1-6 alkyl;

r is 0, 1 or 2;

R c is C 1-6 alkyl, C 6-10 aryl, oxetanyl, azetidinyl, 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, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl and haloC 1-6 alkyl;

each R d is independently hydrogen or C 1-6 alkyl;

Y is C 6-10 aryl, a 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, a 6 membered unsaturated heterocycle containing 1, 2 or 3 N atoms or a 7-10 membered unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

2. A compound of claim 1 of formula III:

wherein all other variables are as defined in claim 1 ;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

3. A compound of claim 1 of formula IV:

wherein all other variables are as defined in claim 1 ;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

4. A compound of claim 1 of formula V:

wherein all other variables are as defined in claim 1 ;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

5. A compound of claim 4 wherein Y is phenyl.

6. A compound of claim 4 wherein a is 0 or 1 and R 3 is haloC 1-6 alkyl or halogen.

7. A compound of claim 4 wherein R 10 is hydroxy, C 1-6 alkyl, C 1-6 alkoxy, nitro or a ring which is: azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three heteroatoms independently selected from N, O and S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7 to 10 membered saturated or partially saturated 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, two or three groups independently selected from (CH 2 ) x R 11 .

8. A compound of claim 4 wherein x is O and R 11 is C 1-6 alkyl.

9. A compound of claim 4 wherein R 10 is methyl, isopropyl, diazoniaspiro[4.5]decanyl, methylpiperidinyl, ethoxy, nitro, hydroxy, pyridinyl, pyrrolidinyl, azetidinyl, methylpiperazinyl or piperidinyl.

10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in association with a pharmaceutically acceptable carrier.

11. A compound according to claim 1 which is selected from:

N-Methyl[4-(6-oxo-3,4,5,6-tetrahydro-2H-azepino[5,4,3-cd]indazol-2-yl)phenyl]methanaminium trifluoroacetate;

N,N-Dimethyl[4-(6-oxo-3,4,5,6-tetrahydro-2H-azepino[5,4,3-cd]indazol-2-yl)phenyl]methanaminium trifluoroacetate;

N 2 ,N 2 -Dimethyl-N-[4-(1-oxo-1,2,3,4-tetrahydroazepino[3,4,5-hi]indolizin-5-yl)phenyl]glycinamide;

3-[4-(8-Fluoro-6-oxo-3,4,5,6-tetrahydro-2H-azepino[5,4,3-cd]indazol-2-yl)phenyl]piperidinium trifluoroacetate;

8-fluoro-2-{4-[(3R)-piperidin-3-yl]phenyl}-2,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one;

8-fluoro-2-{4-(3S)-piperidin-3-yl]phenyl}-2,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one;

2-[4-(6-oxo-3,4,5,6-tetrahydro-2H-azepino[5,4,3-cd]indazol-2-yl)benzyl]-2,7-diazoniaspiro[4.5]decane bis(trifluoroacetate);

[4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-2H-azepino[5,4,3-cd]indazol-2-yl)phenyl]-N,N-dimethylmethanaminium trifluoroacetate;

5-phenyl-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one;

ethyl 4-(1-oxo-1,2,3,4-tetrahydroazepino[3,4,5-hi]indolizin-5-yl)benzoate;

5-(4-nitrophenyl)-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one;

5-[4-(hydroxymethyl)phenyl]-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one;

N-[4-(1-oxo-1,2,3,4-tetrahydroazepino[3,4,5-hi]indolizin-5-yl)phenyl]nicotinamide;

N-[4-(1-oxo-1,2,3,4-tetrahydroazepino[3,4,5-hi]indolizin-5-yl)phenyl]pyridine-2-carboxamide;

N-[4-(1-oxo-1,2,3,4-tetrahydroazepino [3,4,5-hi]indolizin-5-yl)phenyl]-2-pyrrolidin-1-ylacetamide;

1-methyl-N-[4-(1-oxo-1,2,3,4-tetrahydroazepino[3,4,5-hi]indolizin-5-yl)phenyl]piperidine-4-carboxamide;

3-({[4-(1-oxo-1,2,3,4-tetrahydroazepino[3,4,5-hi]indolizin-5-yl)phenyl]amino}carbonyl)azetidinium chloride;

(3S)-1-methyl-N-[4-(1-oxo-1,2,3,4-tetrahydroazepino [3,4,5-hi]indolizin-5-yl)phenyl]piperidine-3-carboxamide;

(3R)-1-methyl-N-[4-(1-oxo-1,2,3,4-tetrahydroazepino [3,4,5-hi]indolizin-5-yl)phenyl]piperidine-3-carboxamide;

(2S)-1-methyl-N-[4-(1-oxo-1,2,3,4-tetrahydroazepino [3,4,5-hi]indolizin-5-yl)phenyl]piperidine-2-carboxamide;

(2R)-1-methyl-N-[4-(1-oxo-1,2,3,4-tetrahydroazepino [3,4,5-hi]indolizin-5-yl)phenyl]piperidine-2-carboxamide;

5-{4-[(dimethylamino)methyl]phenyl}-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one;

5-{4-[(methylamino)methyl]phenyl}-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one;

5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one;

5-{4-[(isopropylamino)methyl]phenyl}-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one; and

5-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3,4-dihydroazepino[3,4,5-hi]indolizin-1(2H)-one;

and pharmaceutically acceptable salts, free bases and tautomers thereof.