Pyridazinone derivatives as PARP inhibitors

1. A compound of structural formula I:

wherein:

a is 0 or 1;

b is 0 or 1;

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

d is 1 or 2;

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

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

A is a 6 to 15 membered monocyclic, fused, bridged or spiro saturated heterocyclic ring containing two N atoms and zero or one O atom, substituted by one oxo group;

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

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

each of R 3 and R 4 is independently hydrogen, halogen, C 1-6 alkyl or haloC 1-6 alkyl;

each R 5 is independently cyano, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl or a ring which is: C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, oxetanyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 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 N atoms or a 7-10 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 R 6 ;

each R 6 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, —O(C═O)C 1-6 alkyl, —(C═O)OC 1-6 alkyl, NR a R b , CONR a R b , NR a COR b , S(O) r NR a R b , S(O) r R c , NR a S(O) r R c or a ring which is: C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 6-10 arylcarbonyl, C 6-10 aryloxycarbonyl, C 6-10 arylC 1-6 alkoxycarbonyl, 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, two or three groups independently selected from halogen, C 1-6 alkyl or haloC 1-6 alkyl;

r is 0, 1 or 2;

each of R a and R b is independently hydrogen, C 1-6 alkyl or a ring which is: C 3-10 cycloalkyl, C 6-10 aryl, 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 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from halogen, C 1-6 alkyl or haloC 1-6 alkyl;

R c is hydrogen or C 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, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ;

g is 2 or 3;

each of R 7 , R 8 , R 9 and R 10 is independently hydrogen, halogen, C 1-6 alkyl or haloC 1-6 alkyl;

R 11 is independently cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl or a ring which is: C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, oxetanyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 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 N atoms or a 7-10 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 R 6 ;

R 6 is as defined in claim 1 ;

or one R 7 together with one R 9 forms a bridge containing 1, 2, or 3 carbon atoms optionally substituted by one, two or three groups independently selected from halogen or C 1-6 alkyl;

or one R 9 and one R 10 together with the carbon atom to which they are attached form a spiro ring containing 3, 4, 5 or 6 carbon atoms optionally substituted by one, two or three groups independently selected from halogen, C 1-6 alkyl or haloC 1-6 alkyl;

or R 11 (CR 3 R 4 ) e together with)N—(CR 9 R 10 ) forms a 4 to 8 membered fused saturated heterocyclic ring containing one N atom, optionally substituted by one, two or three groups independently selected from halogen, C 1-6 alkyl or haloC 1-6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

3. A compound of claim 1 of formula III:

wherein:

a, b, c, R 1 and R 2 are as defined in claim 1 ;

h is 0, 1 or 2;

R 12 is C 1-6 alkyl or haloC 1-6 alkyl;

either:

R 13 is hydrogen or R 12 ;

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

each R 3 and R 4 is independently hydrogen, halogen, C 1-6 alkyl or haloC 1-6 alkyl; and

each R 11 is independently cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl or a ring which is: C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, oxetanyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 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 N atoms or a 7-10 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 R 6 ;

R 6 is as defined in claim 1 ;

or:

R 11 (CR 3 R 4 ) e and R 13 together with the N and C atoms to which they are attached form a fused 5, 6 or 7 membered saturated heterocyclic ring containing one N atom, optionally substituted by one, two or three groups independently selected from halogen, C 1-6 alkyl or haloC 1-6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

4. A compound of claim 1 of formula IV:

wherein:

a, b, c, e, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 ;

h is 0, 1 or 2;

R 12 is C 1-6 alkyl or haloC 1-6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

5. A compound of claim 1 of formula V:

wherein:

a, b, and R 1 are as defined in claim 1 ;

h is 0 or 1;

R 5 is C 3-10 cycloalkyl or C 6-10 aryl, optionally substituted by one, two or three groups independently selected from fluorine, chlorine or cyano;

R 12 is methyl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

6. A compound of claim 1 wherein c is 1 and R 2 is halogen.

7. A compound of claim 4 wherein R 5 is halogen, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, C 1-6 alkoxy, C 1-4 alkoxycarbonyl or a ring which is: phenyl, cyclohexyl, cyclopentyl, pyridinyl, naphthyl, thienyl, tetrahydropyranyl, bicyclo[1.1.1]pentyl, tetrahydronaphthalenyl, oxadiazolyl, cyclobutyl, quinolinyl, benzothienyl, thiazolyl, pyrimidinyl, tetrahydrofuranyl, dihydroindenyl, cycloheptyl, cyclopropyl, dihydrochromenyl, bicyclo[2.2.1]heptyl, oxaspiro[4.4]nonyl, oxaspiro[4.5]decyl, piperidinyl or imidazolyl; any of which rings being optionally substituted by one, two or three groups independently selected from R 6 .

8. A compound of claim 2 wherein:

each of R 7 , R 8 , R 9 and R 10 is independently hydrogen, halogen, C 1-6 alkyl or haloC 1-6 alkyl; and

R 11 is independently cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl or a ring which is: C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, oxetanyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 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 N atoms or a 7-10 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 R 6 .

9. A compound of claim 8 wherein R 6 is cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 1-6 alkylsulfonyl or C 6-10 aryl.

10. A compound of claim 1 selected from:

6-{4-Fluoro-3-[(3-oxo-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-{4-Fluoro-3-[(3-oxo-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethylpyridazin-3(2H)-one hydrochloride;

4-Ethyl-6-{4-fluoro-3-[(3-oxo-4-phenylpiperazin-1-yl)carbonyl]benzyl}pyridazin-3(2H)-one trifluoroacetate;

6-{3-[(4-Cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-ethylpyridazin-3(2H)-one trifluoroacetate;

3-{4-Fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(4-Fluoro-3-{[4-(4-fluorobenzyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2-Chlorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(3-Chloro-4-fluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(3,4-Difluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(3,5-Difluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(4-Chlorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2-Chlorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-Fluoro-3-({3-oxo-4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2-Chloro-4-fluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Ethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-{3-[(4-Butyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(3-{[4-(3,5-Dimethylbenzyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(4-Fluoro-3-{[4-(4-methoxybenzyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(2-phenylethyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(4-Fluoro-3-{[4-(3-methoxyphenyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(3-{[4-(3,5-Dimethylphenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

Methyl (4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-oxopiperazin-1-yl)acetate trifluoroacetate;

3-{3-[(4-Cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(3-{[4-(3,4-Difluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-3-oxo-4-(trifluoromethyl)-2,3-dihydropyridazin-1-ium trifluoroacetate;

3-{3-[(4-Cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-ethyl-5-methyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-{3-[(4-Cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5-ethyl-4-methyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-{3-[(4-Cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5-ethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-{4-Fluoro-3-[(3-oxo-4-pyridin-2-ylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethyl-6-oxo-1, 6-dihydropyridazin-1-ium trifluoroacetate;

6-{4-Fluoro-3-[(4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-3-oxo-4-(trifluoromethyl)-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cyclohexyl-3-oxo-1,4-diazepan-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cyclohexyl-2-methyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{4-Fluoro-3-[(4-isopropyl-5-oxo-1,4-diazepan-1-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

3-{3-[(4-Cyclohexyl-2,2-dimethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-{4-Fluoro-3-[(3-oxo-4-pyridin-3-ylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-{3-[(4-Cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate;

6-(4-Fluoro-3-{[4-(4-fluorophenyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

(1S,4S)-5-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-phenyl-2,5-diazabicyclo[2.2.1]heptan-3-one trifluoroacetate;

3-(3-{[4-(3,5-Dichlorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(4-Fluoro-3-{[4-(1-naphthyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(4-Fluoro-3-{[3-oxo-4-(2-thienyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(3,3,3-trifluoro-2-methylpropyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2,2-Difluoro-1-phenylethyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(tetrahydro-2H-pyran-3-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(4,4-Difluorocyclohexyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(3,3-Difluorocyclopentyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(4,4-Dimethylcyclohexyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(3,3-Dimethylcyclohexyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Bicyclo[1.1.1]pent-1-yl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-Fluoro-3-({4-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(3,3-Difluorocyclobutyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-Fluoro-3-({3-oxo-4-[(4-phenyltetrahydro-2H-pyran-4-yl)methyl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cyclobutyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-Fluoro-3-({4-[2,4,3-fluorophenyl)ethyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{4-Fluoro-3-[(3-oxo-4-quinolin-3-ylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethylpyridazin-3(2H)-one;

3-[4-Fluoro-3-({3-oxo-4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(3-{[4-(1-Benzothien-3-yl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(4-Fluoro-3-{[3-oxo-4-(1,3-thiazol-5-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-{4-Fluoro-3-[(3-oxo-4-pyrimidin-5-ylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-[4-Fluoro-3-({3-oxo-4-[5-(trifluoromethyl)pyridin-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(3-phenylcyclohexyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-Fluoro-3-({3-oxo-4-[(1R,2S)-2-phenylcyclohexyl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(4-phenylcyclohexyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(1,2,3,4-tetrahydronaphthalen-2-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2,3-Dihydro-1H-inden-2-yl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-Fluoro-3-{[3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-Cycloheptyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

3-(4-Fluoro-3-{[4-(3-thienyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-[4-fluoro-3-({(3R)-3-methyl-5-oxo-4-[(3S)-tetrahydrofuran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-[4-fluoro-3-({(3S)-3-methyl-5-oxo-4-[(3S)-tetrahydrofuran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-{3-[(3,3-Dimethyl-5-oxo-4-phenylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

3-[4-fluoro-3-(3-methyl-5-oxo-4-phenyl-piperazine-1-carbonyl)-benzyl]-4,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[(3S)-3-methyl-5-oxo-4-phenylpiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(4-fluoro-3-{[(3R)-3-methyl-5-oxo-4-phenylpiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

3-{4-fluoro-3-[4-(4-fluoro-phenyl)-3-methyl-5-oxo-piperazine-1-carbonyl]-benzyl}-4,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[(3S)-4-(4-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(4-fluoro-3-{[(3R)-4-(4-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

cis-3-{4-Fluoro-3-[4-(3-fluoro-cyclopentyl)-3-oxo-piperazine-1-carbonyl]-benzyl}-4,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-1-ium trifluoroacetate;

6-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-(pentafluoroethyl)pyridazin-3(2H)-one;

1-cyclopropyl-4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-1,4-diazepan-2-one;

6-{2-bromo-5-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-{4-fluoro-3-[(6-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{4-fluoro-3-[(cis-6-methyl-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

(6S,9aS)-2-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-6-methyloctahydro-4H-pyrido[1,2-a]pyrazin-4-one;

(6R,9aR)-2-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-6-methyloctahydro-4H-pyrido[1,2-a]pyrazin-4-one;

6-{4-fluoro-3-[(cis-6-methyl-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)carbonyl]benzyl}-3-oxo-4-(trifluoromethyl)-2,3-dihydropyridazin-1-ium trifluoroacetate;

(6S,9aS)-2-(2-fluoro-5-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl]methyl}benzoyl)-6-methyloctahydro-4H-pyrido[1,2-a]pyrazin-4-one;

(6R,9aR)-2-(2-fluoro-5-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl]methyl}benzoyl)-6-methyloctahydro-4H-pyrido[1,2-a]pyrazin-4-one;

(9aS)-2-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}octahydro-4H-pyrido[1,2-a]pyrazin-4-one trifluoroacetate;

(9aR)-2-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}octahydro-4H-pyrido[1,2-a]pyrazin-4-one trifluoroacetate;

2-(2-fluoro-5-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl]methyl}benzoyl)octahydro-4H-pyrido[1,2-a]pyrazin-4-one;

(9aS)-2-(2-fluoro-5-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl]methyl}benzoyl)octahydro-4H-pyrido[1,2-a]pyrazin-4-one;

(9aR)-2-(2-fluoro-5-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl]methyl}benzoyl)octahydro-4H-pyrido[1,2-a]pyrazin-4-one;

3-{3-[(4-cyclohexyl-2,2-dimethyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(3-{[4-(4-cyanophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-[4-fluoro-3-({4-[4-(methylsulfonyl)phenyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2,2-difluoro-1-pyridin-3-ylethyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-fluoro-3-({4-[(2-methyltetrahydrofuran-2-yl)methyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(3,4-dihydro-2H-chromen-3-yl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[3-oxo-4-(1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2,3-dihydro-1H-inden-1-yl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[3-({4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-3-oxopiperazin-1-yl}carbonyl)-4-fluorobenzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-cyclopentyl-3-methyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-fluoro-3-({3-oxo-4-[(3S)-tetrahydro-2H-pyran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-[4-fluoro-3-({3-oxo-4-[(3R)-tetrahydro-2H-pyran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

3-{3-[(4-ethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[4-(1-oxaspiro[4.4]non-3-yl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(4-fluoro-3-{[4-(1-oxaspiro[4.5]dec-3-yl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

(9aR)-2-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}octahydro-4H-pyrido[1,2-a]pyrazin-4-one;

(9aS)-2-{5-[(4,5-dimethyl-6-oxo-1,6-Dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}octahydro-4H-pyrido[1,2-a]pyrazin-4-one;

6-(4-fluoro-3-{[4-(1-methylcyclohexyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-fluoro-3-({4-[1-(methylsulfonyl)piperidin-4-yl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-fluoro-3-({3-oxo-4-[(3R)-tetrahydrofuran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-[4-fluoro-3-({3-oxo-4-[(3S)-tetrahydrofuran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3S)-4-cyclopentyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-cyclopentyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

3-(4-fluoro-3-{[4-(1-methyl-1H-imidazol-5-yl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(3-{[4-(2,4-dimethyl-1,3-thiazol-5-yl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-[3-({4-[2,2-difluoro-1-(4-fluorophenyl)ethyl]-3-oxopiperazin-1-yl}carbonyl)-4-fluorobenzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[3-oxo-4-(3-phenylcyclopentyl-piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[3-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-fluoro-3-({3-oxo-4-[(1R)-1-phenylethyl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[4-fluoro-3-({3-oxo-4-[(1S)-1-phenylethyl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2,2-difluoro-1R-phenylethyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(2,2-difluoro-1S-phenylethyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

3-{3-[(4-cyclohexyl-3-methyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-6-oxo-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-(3-{[4-(4,4-difluorocyclohexyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(3-{[4-(3,3-difluorocyclopentyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(3-{[4-(4,4-dimethylcyclohexyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(4-fluoro-3-{[3-methyl-5-oxo-4-(tetrahydro-2h-pyran-3-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(4-fluoro-3-{[3-methyl-5-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(3-{[4-(2,2-difluoro-1-phenylethyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

6-(3-{[4-(3,4-dihydro-2H-chromen-3-yl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate;

4-ethyl-6-(4-fluoro-3-{[3-oxo-4-(tetrahydro-2H-pyran-3-yl)piperazin-1-yl]carbonyl}benzyl)-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

4-ethyl-6-(4-fluoro-3-{[3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]carbonyl}benzyl)-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

3-(4-fluoro-3-{[(9aS)-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl]carbonyl}benzyl)-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-{4-fluoro-3-[(6-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)carbonyl]benzyl}-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-ethyl-3-methyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoro acetate;

6-(4-fluoro-3-{[4-(4-methoxybenzyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[3-methyl-5-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-[3-({4-[(1R,4S)-bicyclo[2.2.1]hept-2-yl]-3-methyl-5-oxopiperazin-1-yl}carbonyl)-4-fluorobenzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate;

3-(4-fluoro-3-{[3-oxo-4-(tetrahydro-2h-pyran-3-yl)piperazin-1-yl]carbonyl}benzyl)-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-(4-fluoro-3-{[3-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl]carbonyl}benzyl)-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

6-{3-[(4-ethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one;

4-ethyl-6-[4-fluoro-3-[{3-oxo-4-[(3S)-tetrahydro-2H-pyran-3-yl]piperazin-1-yl}carbonyl)benzyl]pyridazin-3(2H)-one;

4-ethyl-6-[4-fluoro-3-({3-oxo-4-[(3R)-tetrahydro-2H-pyran-3-yl]piperazin-1-yl}carbonyl)benzyl]pyridazin-3(2H)-one;

3-(4-fluoro-3-{[3-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]carbonyl}benzyl)-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

3-{3-[(4-ethyl-3-methyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-1-ium trifluoroacetate;

4-ethyl-6-(4-fluoro-3-{[3-oxo-4-(1,2,3,4-tetrahydronaphthalen-2-yl)piperazin-1-yl]carbonyl}benzyl)pyridazin-3(2H)-one;

6-{3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-3-oxo-4-(pentafluoroethyl)-2,3-dihydropyridazin-1-ium trifluoroacetate;

6-(4-fluoro-3-{[4-(3-fluorocyclopentyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-cyclopentyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one;

6-(3-{[(3S)-4-cyclopentyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one;

6-[4-fluoro-3-({3-oxo-4-[(3S)-tetrahydro-2H-pyran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4-(trifluoromethyl)pyridazin-3(2H)-one;

6-[4-fluoro-3-({3-oxo-4-[(3R)-tetrahydro-2H-pyran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4-(trifluoromethyl)pyridazin-3(2H)-one;

6-(3-{[(3S)-4-ethyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-5-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one;

6-(3-{[(3R)-4-ethyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-5-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one;

6-[4-fluoro-3-({(3S)-3-methyl-5-oxo-4-[(3S)-tetrahydrofuran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-[4-fluoro-3-({(3R)-3-methyl-5-oxo-4-[(3S)-tetrahydrofuran-3-yl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

4-ethyl-6-(4-fluoro-3-{[3-oxo-4-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazin-1-yl}carbonyl)benzyl]pyridazin-3(2H)-one;

4-ethyl-6-(4-fluoro-3-{[3-oxo-4-[(2R)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazin-1-yl}carbonyl)benzyl]pyridazin-3(2H)-one;

6-[4-Fluoro-3-({4-[(1S)-1-methylpropyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-(4-Fluoro-3-{[4-(2-methoxy-1-methylethyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-{3-[(4-Cyclobutyl-3-methyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-{3-[(4-Cyclobutyl-3-ethyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[4-(3-Chlorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

4-((2S)-4-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-methyl-6-oxopiperazin-1-yl)benzonitrile;

6-(3-{[4-(1-Ethylpropyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-[4-Fluoro-3-({4-[(1R)-1-methylpropyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-[4-Fluoro-3-({4-[(1S)-2-methoxy-1-methylethyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-(4-Fluoro-3-{[4-(2-methoxyethyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[4-(2-Ethoxyethyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(4-Fluoro-3-{[4-(2-isopropoxyethyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(4-Fluoro-3-{[4-(2-hydroxy-2-methylpropyl)-3-oxopiperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

4-((2S)-4-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-methyl-6-oxopiperazin-1-yl)-2-fluorobenzonitrile;

6-(3-{[(3R)-4-Cyclobutyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3S)-4-Cyclobutyl-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3S)-4-(3-Chlorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(3-Chlorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-[4-Fluoro-3-({4-[(1R)-2-methoxy-1-methylethyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-Cyclobutyl-3-ethyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3S)-4-Cyclobutyl-3-ethyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-[3-({4-[(1R)-1,2-Dimethylpropyl]-3-oxopiperazin-1-yl}carbonyl)-4-fluorobenzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-[3-({4-[(1S)-1,2-Dimethylpropyl]-3-oxopiperazin-1-yl}carbonyl)-4-fluorobenzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-{3-[(4-Cyclohexyl-3-ethyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-{3-[(4-Cyclopentyl-3-isobutyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-{3-[(4-Cyclopentyl-3-ethyl-5-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(4-Chloro-3-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[4-(3,3-Difluorocyclobutyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

4-((2R)-4-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-methyl-6-oxopiperazin-1-yl)benzonitrile;

6-(3-{[(3R)-4-(3-Chlorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

4-((2R)-4-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-methyl-6-oxopiperazin-1-yl)-2-fluorobenzonitrile;

6-[4-Fluoro-3-({3-oxo-4-[(1S)-2,2,2-trifluoro-1-methylethyl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(3S-Difluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(4-Chlorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(4-Fluoro-3-{[(3R)-3-methyl-5-oxo-4-(2-thienyl)piperazin-1-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(4-Chloro-2-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

5-((2R)-4-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-methyl-6-oxopiperazin-1-yl)-2-fluorobenzonitrile;

6-(3-{[(3R)-4-(3-Chloro-5-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(3-Chloro-4-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-[4-Fluoro-3-({3-oxo-4-[(1R)-2,2,2-trifluoro-1-methylethyl]piperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

4-((2R)-4-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-methyl-6-oxopiperazin-1-yl)-3-fluorobenzonitrile;

3-((2R)-4-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoyl}-2-methyl-6-oxopiperazin-1-yl)-5-fluorobenzonitrile;

6-(3-{[(3R)-4-(3,4-Difluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[4-(1-Cyclopropylethyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(5-Chloro-2-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(3-Chloro-2-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-Cyclopentyl-3-isopropyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3S)-4-(4-Chloro-3-fluorophenyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3S)-4-(3,3-Difluorocyclobutyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-(3-{[(3R)-4-(3,3-Difluorocyclobutyl)-3-methyl-5-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethylpyridazin-3(2H)-one;

6-{4-Fluoro-3-[(4-isopropyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-4,5-dimethylpyridazin-3(2H)-one;

6-[4-Fluoro-3-({4-[(trans)-3-fluorocyclopentyl]-3-oxopiperazin-1-yl}carbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one;

or a pharmaceutically acceptable salt, stereoisomer, free base or tautomer thereof.

11. 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.

12. A combination of a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof and an anti-cancer agent for simultaneous, separate or sequential administration.