FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme poly(ADP-ribose)polymerase (PARP).

BACKGROUND OF THE INVENTION

The family of poly(ADP-ribose)polymerases (PARP) includes approximately 18 proteins, which all display a certain level of homology in their catalytic domain but differ in their cellular functions (Ame et al.,BioEssays,26(8), 882-893 (2004)). PARP-1 and PARP-2 are unique members of the family, in that their catalytic activities are stimulated by the occurrence of DNA strand breaks.

PARP has been implicated in the signaling of DNA damage through its ability to recognize and rapidly bind to DNA single or double strand breaks (D'Amours, et al.,Biochem. J.,342, 249-268 (1999)). It participates in a variety of DNA-related functions including gene amplification, cell division, differentiation, apoptosis, DNA base excision repair as well as effects on telomere length and chromosome stability (d'Adda di Fagagna, et al.,Nature Gen.,23(1), 76-80 (1999)).

SUMMARY OF THE INVENTION

Provided herein are compounds, compositions and methods for modulating the activity of PARP. Among the compounds that are provided herein, are compounds that are inhibitors of PARP. Also described herein is the use of such compounds, compositions and methods for the treatment of diseases, disorders or conditions associated with the activity of PARP.

In some embodiments, compounds provided herein have the structure of Formula (I) and Formula (II) and pharmaceutically acceptable salts, solvates, esters, acids and prodrugs thereof. In certain embodiments, provided herein are compounds having the structure of Formula (I) and Formula (II) that are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP).

Described herein are 8-B,Z-2-R4-4-R1-5-R2-6R3-7R5-9-A,Y-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one s, 8-B,Z-5-R2-9-A,Y-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one s, in which A, B, Z, Y, R1, R2, R3, R4and R5are further described herein. In certain embodiments, isomers including enantiomers and diastereoisomers, and chemically protected forms of compounds having a structure represented by Formula (I) and Formula (II) are also provided.

Formula (I) is as follows:


wherein:
Y and Z are each independently selected from the group consisting of:a) an aryl group optionally substituted with 1, 2, or 3 R6; wherein each R6is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C2-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;b) a heteroaryl group optionally substituted with 1, 2, or 3 R6;c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
R1, R2, and R3are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NRARB, NRARBalkylene, and (NRARB)carbonyl;
A and B are each independently selected from hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C5cycloalkyl, wherein B is not OH;
RA, and RBare independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RAand RBtaken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of —O—, —NH, —N(C1-C6-alkyl)-, —NCO(C1-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted-aryl-C1-C6-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-alkyl-)-, and —S— or S(O)q—, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with one or more substituents;
R4and R5are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRARB)alkylene;
and isomers, salts, solvates, chemically protected forms, and prodrugs thereof.

Formula (II) is as follows:


wherein:
Y is an aryl or heteroaryl group optionally substituted with at least one R6;
Z is an aryl group optionally substituted with at least one R6;
A and B are each independently selected from hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl, wherein B is not OH;
R6is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C2-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
R2is selected from hydrogen, Br, Cl, I, or F;
RA, and RBare independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C8cycloalkyl, and alkylcarbonyl; or RAand RBtaken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of —O—, —NH, —N(C1-C6alkyl)-, —NCO(C1-C6alkyl)-, —NCO(C3-C8cycloalkyl)-N(aryl)-, —N(aryl-C1-C6alkyl-)-, —N(substituted-aryl-C1-C6alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6alkyl-)-, —N(substituted-heteroaryl-C1-C6alkyl-)-, and —S— or S(O)q—, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with one or more substituents; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In certain embodiments are provided compounds of Formula (I) or a therapeutically acceptable salt thereof wherein R1, R2, R3are independently selected from a group consisting of hydrogen, alkyl, and halogen; R4is hydrogen and R5is selected from the group consisting hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRARB)alkylene; RA, and RBare independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RAand RBtaken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of —O—, —NH, —N(C1-C6-alkyl)-, —NCO(C1-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted-aryl-C1-C6-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-alkyl-)-, and —S— or S(O)q—, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with one or more substituents.

In one embodiment is a compound of Formula (I) wherein Y is an aryl group. In another embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group is substituted with at least one R6selected from Br, Cl, F, or I. In one embodiment R6is F. In one embodiment the phenyl group is substituted with at least one R6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene. In one embodiment R6is (NRARB)C1-C6alkylene. In another embodiment C1-C6alkyl is selected from methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet another embodiment C1-C6alkyl is methylene. In yet a further embodiment RAand RBare each independently hydrogen, C1-C6alkyl, or C3-C8cycloalkyl. In one embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one embodiment C1-C6alkyl is methyl. In another embodiment C1-C6alkyl is ethyl. In yet another embodiment C3-C8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In a further embodiment C3-C8cycloalkyl is cyclopropyl. In yet a further embodiment R6is hydroxyalkylene. In one embodiment hydroxyalkylene is selected from CH2OH, CH2CH2OH, CH2CH2CH2OH, CH(OH)CH3, CH(OH)CH2CH3, CH2CH(OH)CH3, and CH2CH2CH2CH2OH. In another embodiment RAand RBtaken together with the nitrogen to which they are attached form a 6 membered heterocycle ring having 1 heteroatom or hetero functionality selected from the group consisting of —O—, —NH, or —N(C1-C6alkyl). In yet another embodiment the hetero functionality is —N(C1-C6alkyl). In a further embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment Y is a heteroaryl group optionally substituted with at least one R6. In another embodiment the heteroaryl group is selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline, quinoline, and isoquinoline. In yet another embodiment the heteroaryl group is imidazole. In a further embodiment imidazole is substituted with C1-C6alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment the heteroaryl group is furan. In another embodiment the heteroaryl group is thiazole. In yet another embodiment the heteroaryl group is 1,3,4-oxadiazole. In a further embodiment heteroaryl group is substituted with C1-C6alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment Z is an aryl group. In another embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group is substituted with at least one R6selected from Br, Cl, F, or I. In a further embodiment R6is F. In yet a further embodiment R6is C1. In one embodiment the phenyl group is substituted with at least one R6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene. In another embodiment R6is (NRARB)C1-C6alkylene. In yet another embodiment C1-C6alkyl is selected from methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet a further embodiment C1-C6alkyl is methylene. In a further embodiment RAand RBare each independently hydrogen, C1-C6alkyl, or C3-C8cycloalkyl. In one embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In another embodiment C1-C6alkyl is methyl. In yet another embodiment RAand RBtaken together with the nitrogen to which they are attached form a 6 membered heterocycle ring having 1 heteroatom or hetero functionality selected from the group consisting of —O—, —NH, or —N(C1-C6alkyl). In a further embodiment the hetero functionality is —N(C1-C6alkyl). In one embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment Z is a heteroaryl group optionally substituted with at least one R6. In another embodiment the heteroaryl group is selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline, quinoline, and isoquinoline. In yet another embodiment the heteroaryl group is imidazole. In a further embodiment imidazole is substituted with C1-C6alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment the heteroaryl group is furan. In another embodiment the heteroaryl group is thiazole. In yet another embodiment the heteroaryl group is 1,3,4-oxadiazole. In a further embodiment heteroaryl group is substituted with C1-C6alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In another embodiment R2is hydrogen. In yet another embodiment R2is selected from F, Cl, Br, and I. In a further embodiment R2is F.

In one embodiment is a compound of Formula (I) wherein A is hydrogen. In another embodiment A is C1-C6alkyl. In a further embodiment, A is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH, NO2, CN, Br, Cl, F, and I. In a further embodiment A is methyl. In yet another embodiment, A is selected from F, Cl, Br, and I. In another embodiment, A is C3-C8cycloalkyl. In another embodiment, A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, A is substituted with OH, NO2, or CN. In a further embodiment, B is C1-C6alkyl. In a further embodiment, B is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH, NO2, CN, Br, Cl, F, and I. In one embodiment is a compound of Formula (I) wherein B is hydrogen. In a further embodiment B is methyl. In yet another embodiment, B is selected from F, Cl, Br, and I. In another embodiment, B is C3-C8cycloalkyl. In another embodiment, B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, A is substituted with OH, NO2, or CN. In a further embodiment, is a compound of Formula (I) wherein A is hydrogen and B is selected from Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl. In another embodiment, is a compound of Formula (I) wherein B is hydrogen and A is selected from Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl. In yet another embodiment, both A and B are hydrogen. In a further embodiment, both A and B are selected from Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl.

In one embodiment is a compound of Formula (II) wherein Y is an aryl group. In another embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group is substituted with at least one R6selected from Br, Cl, F, or I. In one embodiment R6is F. In one embodiment the phenyl group is substituted with at least one R6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene. In one embodiment R6is (NRARB)C1-C6alkylene. In another embodiment C1-C6alkyl is selected from methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet another embodiment C1-C6alkylene is methylene. In yet a further embodiment RAand RBare each independently hydrogen, C1-C6alkyl, or C3-C8cycloalkyl. In one embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one embodiment C1-C6alkyl is methyl. In another embodiment C1-C6alkyl is ethyl. In yet another embodiment C3-C8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In a further embodiment C3-C8cycloalkyl is cyclopropyl. In yet a further embodiment R6is hydroxyalkylene. In one embodiment hydroxyalkylene is selected from CH2OH, CH2CH2OH, CH2CH2CH2OH, CH(OH)CH3, CH(OH)CH2CH3, CH2CH(OH)CH3, and CH2CH2CH2CH2OH. In another embodiment RAand RBtaken together with the nitrogen to which they are attached form a 6 membered heterocycle ring having 1 heteroatom or hetero functionality selected from the group consisting of —O—, —NH, or —N(C1-C6alkyl). In yet another embodiment the hetero functionality is —N(C1-C6alkyl). In a further embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment Y is a heteroaryl group optionally substituted with at least one R6. In another embodiment the heteroaryl group is selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline, quinoline, and isoquinoline. In yet another embodiment the heteroaryl group is imidazole. In a further embodiment imidazole is substituted with C1-C6alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment the heteroaryl group is furan. In another embodiment the heteroaryl group is thiazole. In yet another embodiment the heteroaryl group is 1,3,4-oxadiazole. In a further embodiment heteroaryl group is substituted with C1-C6alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In one embodiment Z is an aryl group. In another embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group is substituted with at least one R6selected from Br, Cl, F, or I. In a further embodiment R6is F. In yet a further embodiment R6is Cl. In one embodiment the phenyl group is substituted with at least one R6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene. In another embodiment R6is (NRARB)C1-C6alkylene. In yet another embodiment C1-C6alkylene is selected from methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet a further embodiment C1-C6alkyl is methylene. In a further embodiment RAand RBare each independently hydrogen, C1-C6alkyl, or C3-C8cycloalkyl. In one embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In another embodiment C1-C6alkyl is methyl. In yet another embodiment RAand RBtaken together with the nitrogen to which they are attached form a 6 membered heterocycle ring having 1 heteroatom or hetero functionality selected from the group consisting of —O—, —NH, or —N(C1-C6alkyl). In a further embodiment the hetero functionality is —N(C1-C6alkyl). In one embodiment C1-C6alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C1-C6alkyl is methyl. In another embodiment R2is hydrogen. In yet another embodiment R2is selected from F, Cl, Br, and I. In a further embodiment R2is F.

In one embodiment is a compound of Formula (II) wherein A is hydrogen. In another embodiment A is C1-C6alkyl. In a further embodiment, A is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH, NO2, CN, Br, Cl, F, and I. In a further embodiment A is methyl. In yet another embodiment, A is selected from F, Cl, Br, and I. In another embodiment, A is C3-C8cycloalkyl. In another embodiment, A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, A is substituted with OH, NO2, or CN. In one embodiment is a compound of Formula (II) wherein B is hydrogen. In a further embodiment, B is C1-C6alkyl. In a further embodiment, B is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH, NO2, CN, Br, Cl, F, and I. In a further embodiment B is methyl. In yet another embodiment, B is selected from F, Cl, Br, and I. In another embodiment, B is C3-C8cycloalkyl. In another embodiment, B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, A is substituted with OH, NO2, or CN. In a further embodiment, is a compound of Formula (II) wherein A is hydrogen and B is selected from Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl. In another embodiment, is a compound of Formula (II) wherein B is hydrogen and A is selected from Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl. In yet another embodiment, both A and B are hydrogen. In a further embodiment, both A and B are selected from Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl.

In yet a further aspect is a compound selected from:


or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In yet another aspect is a compound selected from:


or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In yet another aspect is a compound selected from:


or a pharmaceutically acceptable salt, solvate or prodrug thereof

In yet a further embodiment is a compound selected from:


or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In yet a further embodiment is a compound selected from:(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, and(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect is a pharmaceutical composition comprising a compound of Formula (I) and Formula (II) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug and a pharmaceutically acceptable carrier, excipient, binder or diluent thereof.

In one aspect is a method of inhibiting poly(ADP-ribose)polymerase (PARP) in a subject in need of PARP inhibition comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) and Formula (II).

In another aspect is a method of treating a disease ameliorated by the inhibition of PARP comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I) and Formula (II).

In one embodiment the disease is selected from the group consisting of: vascular disease; septic shock; ischaemic injury; reperfusion injury; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis; secondary effects of diabetes; and acute treatment of cytoxicity following cardiovascular surgery.

In another aspect is a method of treating cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I) and Formula (II) in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.

In one embodiment the compound of Formula (I) and Formula (II) is administered simultaneously with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof. In another embodiment the compound of Formula (I) and Formula (II) is administered sequentially with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.

In yet another aspect is a method of treating a cancer deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair pathway, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I) and Formula (II).

In one embodiment the cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells. In another embodiment the cancer cells have a BRCA1 or BRCA2 deficient phenotype. In yet another embodiment the cancer cells are deficient in BRCA1 or BRCA2. In a further embodiment the subject is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway. In yet a further embodiment the subject is heterozygous for a mutation in BRCA1 and/or BRCA2. In one embodiment the cancer is breast, ovarian, pancreatic or prostate cancer. In another embodiment the treatment further comprises administration of ionizing radiation or a chemotherapeutic agent.

In one aspect is the use of a compound of Formula (I) and Formula (II) in the formulation of a medicament for the treatment of a poly(ADP-ribose)polymerase mediated disease or condition.

In another aspect is an article of manufacture, comprising packaging material, a compound of Formula (I) and Formula (II), and a label, wherein the compound is effective for modulating the activity of the enzyme poly(ADP-ribose)polymerase, or for treatment, prevention or amelioration of one or more symptoms of a poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polymerase-mediated disease or condition, wherein the compound is packaged within the packaging material, and wherein the label indicates that the compound, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, or a pharmaceutical composition comprising such a compound is used for modulating the activity of poly(ADP-ribose)polymerase, or for treatment, prevention or amelioration of one or more symptoms of a poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polymerase-mediated disease or condition.

