Quinolin-4-one and 4-oxodihydrocinnoline derivatives as inhibitors of poly(ADP-ribose) polymerase (PARP)

1. A compound of formula I:

wherein:

a is 0, 1, 2, 3 or 4;

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

c is 0 or 1;

d is 0 or 1;

e is 0 or 1;

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

g is 0 or 1;

X is N or CH;

Y is phenyl, a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from 0, N and S, but not more than one of which is O or S, or a 6 membered unsaturated heterocycle containing 1, 2, 3 or 4 nitrogen atoms;

Z is C or SO;

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

each R 2 is independently hydroxy, halogen, cyano, nitro, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;

R 3 is hydrogen or C 1-6 alkyl;

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

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

R 7 is azetidinyl optionally substituted by one or more groups independently selected from A-(CR 8 R 9 ) q R 10 ;

each A is independently a direct bond, O, (CH 2 ) s (C═O) t , (C═O)NR 11 , NR 11 (C═O), (C═O)O, O(C═O), (C═S)NR 11 , NR 11 or S(O) r ;

each q is independently 0, 1, 2, 3, or 4;

r is 0, 1 or 2;

s is 0, 1, 2 or 3;

t is 1 or 2;

each of R 8 and R 9 is independently hydrogen, hydroxy, halogen, C 1-6 alkyl or haloC 1-6 alkyl;

each R 10 is independently hydroxy, oxo, cyano, halogen, nitro, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, (C 1-6 alkylcarbonyl)amino or a ring which is: C 3-10 cycloalkyl; C 6-10 aryl; azetidinyl; a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three atoms 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 7-13 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 or more groups independently selected from R 12 ;

R 11 is hydrogen or R 10 ;

each R 12 is independently hydroxy, oxo, cyano, halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, —O(C═O)C 1-6 alkyl, —O(C═O)OC 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, (C 1-6 alkylsulfonyl)amino, C 6-10 aryl, C 1-6 arylC 1-6 alkyl, 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 or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; any of which rings being optionally substituted by one or more groups independently selected from halogen, C 1-6 alkyl and haloC 1-6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

2. A compound of claim 1 of formula II:

wherein:

a, b, c, d, e, f, g, X, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1 ;

Y is phenyl or a 6 membered unsaturated heterocycle containing 1, 2, 3 or 4 nitrogen atoms;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

3. A compound of claim 2 wherein Y is phenyl and each of c, d, e, f and g is 0.

4. A compound of claim 2 wherein:

Y is phenyl;

b is 1;

each of c, d, e, f and g is 0; and

R 7 is azetidinyl optionally substituted by one or more groups independently selected from A-(CR 8 R 9 ) q R 10 .

5. A compound of claim 1 of formula III:

wherein:

a, b, q, A, R 1 , R 2 , R 8 , R 9 and R 10 are as defined in claim 1 ;

Y is phenyl or a 6 membered unsaturated heterocycle containing 1, 2, 3 or 4 nitrogen atoms;

w is 0, 1, 2, 3 or 4;

B is azetidinyl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

6. A compound of claim 5 wherein:

Y is phenyl;

A is a direct bond, CO or COO; and

R 10 is oxo, halogen, C 1-6 alkyl, haloC 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 3-7 cycloalkyl, C 6-10 aryl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three atoms independently selected from N, O and S or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; any of which rings being optionally substituted by one or more groups independently selected from R 12 ;

R 12 is as defined in claim 1 .

7. 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.

8. A method of treating cardiovascular diseases, which method comprises administration to a patient in need thereof of an effective amount of a compound of claim 1 or a composition comprising a compound of claim 1 .

9. A compound selected from:

1-[3-(8-aza-1-azoniaspiro[4.5]dec-8-ylcarbonyl)-4-fluorobenzyl]-4-oxo-1,4-dihydroquinolinium bis(trifluoroacetate);

1-[4-fluoro-3-({4-[2-(4-fluorobenzyl)prolyl]piperazin-1-yl}carbonyl)benzyl]quinolin-4(1H)-one;

1-[3-(8-aza-1-azoniaspiro[4.5]dec-8-ylcarbonyl)-4-fluorobenzyl]-4-oxo-1,4-dihydrocinnolin-1-ium bis(trifluoroacetate);

1-[3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl]quinolin-4(1H)-one;

1-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}quinolin-4(1H)-one;

1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)quinolin-4(1H)-one;

1-[3-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-4-fluorobenzyl]quinolin-4(1H)-one;

1-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]quinolin-4(1H)-one;

1-[3-(2,6-diazaspiro[3.5]non-2-ylcarbonyl)-4-fluorobenzyl]quinolin-4(1H)-one;

1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl]quinolin-4(1H)-one;

1-(4-fluoro-3-{[4-(2-methylprolyl)piperazin-1-yl]carbonyl}benzyl)quinolin-4(1H)-one;

1-(4-fluoro-3-{[4-(3,3,3-trifluoro-N,N-dimethylalanyl)piperazin-1-yl]carbonyl}benzyl)quinolin-4(1H)-one;

(2R)-2-[(4-{2-fluoro-5-[(4-oxoquinolin-1(4H)-yl)methyl]benzoyl}piperazin-1-yl)carbonyl]-2-methylazetidinium trifluoroacetate;

1-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(3-ethyl-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-2-ium-7(8H)-yl)carbonyl]-4-fluorobenzyl}-4-oxo-1,4-dihydrocinnolin-1-ium bis(trifluoroacetate);

1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

8-fluoro-1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-ethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-8-hydroxycinnolin-4(1H)-one;

1-{4-fluoro-3-[(3-oxo-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4-oxo-1,4-dihydroquinolinium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-oxo-1,4-dihydroquinolinium trifluoroacetate;

1-(4-fluoro-3-{[4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydroquinolinium trifluoroacetate;

1-(4-fluoro-3-{[1-(2,2,2-trifluoroethyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(3-{[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]cinnolin-4(1H)-one;

2-(4-{2-fluoro-5-[(4-oxocinnolin-1(4H)-yl)methyl]benzoyl}piperazin-1-yl)pyrimidin-1-ium trifluoroacetate;

1-{4-fluoro-3-[(3-oxo-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{4-fluoro-3-[(4-isobutyrylpiperazin-1-yl)carbonyl]benzyl}-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(4-fluoro-3-{[4-(trifluoroacetyl)piperazin-1-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{4-fluoro-3-[(4-{[(2S)-2-(4-fluorobenzyl)pyrrolidinium-2-yl]carbonyl}piperazin-1-yl)carbonyl]benzyl}-4-oxo-1,4-dihydrocinnolin-1-ium bis(trifluoroacetate); 1-{4-fluoro-3-[(4-{[(2R)-2-methylazetidin-2-yl]carbonyl}piperazin-1-yl)carbonyl]benzyl}cinnolin-4(1H)-one;

1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl]cinnolin-4(1H)-one;

1-[3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl]cinnolin-4(1H)-one;

1-(4-fluoro-3-{[3-(pentafluoroethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(3-{[4-(2-chlorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(3-{[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(3-{[4-(2-chloro-4-fluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(3-{[4-(3,4-difluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(3-{[3-[(dimethylamino)methyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-4-fluorobenzyl)cinnolin-4(1H)-one;

1-{3-[(3-cyclobutyl-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)carbonyl]-4-fluorobenzyl}-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(3-tert-butyl-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)carbonyl]-4-fluorobenzyl}-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(4-fluoro-3-{[3-(2,2,2-trifluoroethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(4-fluoro-3-{[4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}benzyl)cinnolin-4(1H)-one;

5-fluoro-1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl]-5-fluorocinnolin-4(1H)-one;

6-fluoro-1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-6-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-6-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl]-6-fluorocinnolin-4(1H)-one;

7-fluoro-1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-7-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-7-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl]-7-fluorocinnolin-4(1H)-one;

1-{3-[(4-cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-8-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-8-fluoro-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl]-8-fluorocinnolin-4(1H)-one;

1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-7-methoxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-7-methoxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-7-methoxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl]-7-methoxycinnolin-4(1H)-one;

1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-8-hydroxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-8-hydroxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-(3-{[4-(2-chloro-4-fluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-8-hydroxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-8-hydroxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

1-{4-fluoro-3-[(4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)carbonyl]benzyl}-8-hydroxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate; and

1-{4-fluoro-3-[(6-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)carbonyl]benzyl}-8-hydroxy-4-oxo-1,4-dihydrocinnolin-1-ium trifluoroacetate;

and other pharmaceutically acceptable salts, free bases and tautomers thereof.