Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency
View Patent ↗A compound having the structure set forth in Formula (I) and Formula (II): wherein the substituents Y, Z, A, B, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions associated with a PTEN deficiency that are ameliorated by the inhibition of PARP activity.
1. A method of polymerase (PARP) in a treating a disease associated with a PTEN deficiency ameliorated by the inhibition of PARP, wherein the disease associated with a PTEN deficiency is endometrial carcinoma, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I):
wherein:
Y and Z are each independently selected from the group consisting of:
a) an aryl group optionally substituted with 1, 2, or 3 R 6 ;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R 6 ; and
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, hetercarylcarbonyl alkylsulfnnyl, arylsulfonyl, heteroarylsulfonyl, (NR A R B )alkkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonyalkylene;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR A R B , NR A R B alkylene, and (NR A R B )carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl, wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, wherein B is not OH;
R A and R B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R A and R B taken together with the atom to which they are attached form a 3-10 membered hetrocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of —O—, —NH, —N(C 1 -C 6 -alkyl)-, —N(aryl)-, —NN(aryl-C 1 C 6 alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or S(O) q —, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 2 -C 10 -alkenyl, C 1 -C 10 -alkoxy-C 1 , -C 10 -alkyl, C 1 -C 10 -alkoxycarbonyl, C 1 -C 10 -alkyl, C 1 -C 10 -alkylcarbonyl, C 1 -C 10 -a 1 kylcarbonyloxy, C 1 -C 10 -alkylthio, C 1 -C 10 -alkylthio-C 1 -C 10-alkyl, C 2 -C 10 alkynyl, carboxy, cyano, formyl, C 1 -C 10 -haloalkoxy, C 1 -C 10 -haloalkyl, halogen, hydroxyl, C 1 -C 10 -hydroxyalkylene, mercapto, nitro, —NR A R B , and (NR A R B )carbonyl;
R 4 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR A R B )alkylene; and
each R 6 is selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 -cycloalkyalkyl, haloalkoxy, haloakyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroaryl thio, heteroarylalkylthio, heterocycloalkoxy, C 2 -C 8 heterocycloalkythio, C 3 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene; or
a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.
2. A method of treating a disease associated with a PTEN deficiency ameliorated by the inhibition of PARP, wherein the disease associated with a PTEN deficiency is eudometrial carcinoma, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (II):
wherein:
Y is an aryl or heteroaryl group optionally substituted. with 1, 2, or 3 R 6 ;
Z is an aryl group optionally substituted with 1, 2, or 3 R 6 ;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and aloxyalkyl, wherein C 1 -C 6 alkyl, C 3 -C 8 - cycloalkyl, alkoxy, and alkoxyalkyl are optionally substituted with at least one substituent selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 C 8 cycloalkyl, wherein B is not OH;
R 6 is selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C 3 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene;
R 2 is selected from the group consisting of hydrogen, Br, Cl, I, and F;
R A and R B are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and alkylcarbonyl; or R A and R B taken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetro functionalities seleted from the group consisting of —O—, —NH, —N(C 1 -C 6 alkyl)-, —NCO(C 1 -C 6 alkyl)-, —NCO(C 3 -C 8 cycloalkyl)- —N(aryl)-, —N(aryl-C 1 -C 6 alkyl-)-, —N(substitited-aryl-C 1 C 6 alkyl-)-, —N(heteroaryl)-, —N(heteroaryl -C 1 -C 6 alkyl-)-, —N(substituted-heteroaryl-C 1-C 6 alkyl-)-, and —S— or S(O) q -, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with 1, 2, 3, or 4 substitnents independently selected from C 2 -C 10 -alkenyl, C 1 -C 10 -alkoxy, C 1 -C 10 alkyl, C 1 -C 10 -alkoxycarbonyl, C 1 -C 10 alkyl, C 1 -C 10 -alkylcarbonyl, C 1 -C 10 -alkylcarbonyloxy, C 1 -C 10 -alkylthio, C 1 -C 10 -alkylthio-C 1 C 10 -alkyl, C 2 -C 10 -alkynyl, carboxy, cyano, formyl, C 1 C 10 -haloalkoxy, C 1 -C 10 -haloalkyl, halogen, hydroxyl, C 1 -C 10 -hydroxyalkylene, mercapto, nitro, —NR A R B , and —(NR A R B )carbonyl; or
a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt solvate, chemically protected form or prodrug thereof.
3. The method of claim 1 wherein Y is a heteroaryl group optionally substituted with 1, 2, or 3 R 6 .
4. The method of claim 3 wherein, the heteroaryl group is selected from the group consisting of 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; each of which is optionally substituted with 1, 2, or 3 R 6 .
5. The method of claim 4 wherein the heteroaryl group is substituted with C 1 -C 6 alkyl selected from the group consisting of methyl, ethyl n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.
6. The method of claim 5 wherein C 1 C 6 alkyl is methyl.
7. The method of claim 1 wherein Z is an aryl group which is optionally substituted with 1, 2, or 3 R 6 .
8. The method of claim 7 wherein the aryl group is a phenyl group which is optionally substituted with 1, 2, or 3 R 6 .
9. The method of any of claim 8 wherein the phenyl group is substituted with 1, 2, or 3 R 6 selected from the group consisting of Br, Cl, F, and I.
10. The method of claim 9 wherein R 6 is F.
11. The method of claim 1 wherein R 2 is selected from the group consisting of F, Cl, Br, and L.
12. The method of cairn 11 wherein R 2 is F.
13. A method of treating a disease associated with a PTEN deficiency ameliorated by the inhibition of PARP, wherein the disease associated with a PTEN deficiency is endometrial carcinoma, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound selected from the group consisting of:
8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phtalazin-3(7H)-one,
8,9bis(4-methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido [4,3,2-de]phtalazin-3(7H)-one,
8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H- pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-bi(3-((methylamino)methyl)phenyl)-8,9-dihydo)-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-bis(3-(4-(isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pthalazin-3(7H)-one,
9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8(4-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-(hydromethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
8(4((dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrdio[4,3,2-de]phthalazin-3(7H)-one,
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido [4,3,2-de]pthalazin-3(7H)-one,
9(3-(4-(cyclopropanecarbonyl)piprazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido [4,3,2-de]phthhalazin-3(7H)-one,
9-(3-((dimethylamino)methyl)phenyl)-8phenyl-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
8-(3-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro 2H pyrido[4,3,2 de]phthalazin 3(7H) one,
8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pthalazin-3(7H)-one,
9(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino(methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthatalin-3(7H)-one,
9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phemyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H-one,
9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin,4-yl)-8,9-dihyro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-((methylamino)methyl(phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((dimethylamimo)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
9-(3-(hydroxymethyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
9-(4-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-((dimethylaminio)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
9-(3-((methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-(hydroxymethyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-((methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
9-(3-(hydroxymethyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
5-fluoro-9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
5-fluoru-9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)- 8,9-dihydro -2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
5-fluoro-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one,
5-fluoro-9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one,
9-(3-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyiido[4,3,2-de]phthalazin-one,
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one,
5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-phenyl-,8,9-dihydro-2H-pyrido[4,3,2de]phthalazin-one,
5-fluoro-8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro -2H-pyrido[4,3,2-de]phthalazin-one,
7-methyl-8,9- diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
7-ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
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,
8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H) one,
8-phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(furan-3-yl)-8,9-dihydro-2H-pyrido[4,3,2de]phthalazin 3(7H)-one,
8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrdo[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalzin-3(7H)-one,
8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(1-methyl-1H--imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(1-ethyl-1H-imidazol-2-2yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-phenyl-9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(1-methyl-1H-imidazol-5-yl)8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phathalazin-3(7H)-one,
9-(3-((diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl)8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
9-(3-((4-methylpiperazin-1-yl) methyl)phenyl)-8-phenyl-8,9-dihydro-2H -pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(pyridin-2-yl))-8,9-dihydro-2H-pryido[4,3,2-de]phthalazin-3(7H)-one,
8-(4((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-bis(4-flurophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-bis(3-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin3(7H)-one,
8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
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,
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,
8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
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,
8-(4-fluorophenyl)-9-methyl-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-fluorophenyl)-9-(1,4,5-trimethy 1-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,3-triazol-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(1-methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-fluorophenyl)-9-(thiazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(1-ethyl-1H-imidazol-2-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one
8-(4-((4-ethyl-3-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-Fluorophenyl)-9-(4-methyl-4H-1,2,4-triazol-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
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,
8-(4-fluorophenyl)-9-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
5-chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8,9-bis(4-((dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((3,4-dimethylpiperazin-1-methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((3,5-dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(1-methyl-1H-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(quinolin-6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
8-(4-((dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((diethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((diethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-chlorophenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
5-fluoro-9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-((diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(4-(1-methylpyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(4-(pyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
8-(4-fluorophenyl)-9-methyl-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
9-(4-fluorophenyl)-8-(1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
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,
9-(4-fluorophenyl)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one,
8-(4-(azetidin-1-ylmethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, and
5-fluora-8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
14. A method of treating a disease associated with a PTEN deficiency ameliorated by the inhibition of PARP, wherein the disease associated with a PTEN deficiency is endometrial carcinoma, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I):
wherein
Y and Z are each independently selected from the group consisting of:
a) an aryl group optionally substituted with 1, 2, or 3 R 6 ;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R 5 ; and
c) a substituent independently selected from the group hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocyloalkylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (NR A R B )alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR A R B , NR A R B alkylene, and (NR A R B )carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cyclcoalkyl, alkoxy, and alkoxyalkyl, wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, wherein B is not OH;
R A and R B an independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R A and R B taken 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(C 1 -C 6 -alkyl)-, —NCO(C 1 -C 6 alkyl)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or S(O) q —,
wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 2 -C 10 -alkenyl, C 1 -C 10 -alkoxy, C 1 C 10 -alkoxy-C 1 -C 10 -alkyl, C 1 -C 10 -alkoxycarbonyl, C 1 -C 10 -alkyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 -alkylcarbonyloxy, C 1 -C 10 -alkylthio, C 1 -C 10 -alkylthio-C 1 -C 10 -alkyl, C 2 -C 10 -alkynyl, carboxy, cyano , formyl, C 1 C 10 -haloalkoxy, C 1 -C 10 -haloalkyl, halogen, hydroxyl, C l -C 10 -hydroxyalkylene, mercapto, nitro, —NR A R B , and (NR A R B )carbonyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR A R B )alkylene; and each R 6 is selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C 3 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A ,R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene; or a single isomer, stereoiosomer, or enantiomer, or mixture thereof;
or a pharmaceutically acceptable salt pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug, and a pharmaceutically acceptable carrier, excipient, binder or diluent thereof.
15. The method of claim 1 , wherein said administration is in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.
16. The method of claim 15 , wherein the compound
wherein
with 1, 2, or 3 R 6 ;
alkoxy, and the group consisting of OH,
wherein
selected from C 2 -C 10
or a single isomer, stereoisomer, or
is administered simultaneously with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.
17. The method of claim 15 , wherein the compound is administered sequentially with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.
18. A method of treating a cancer associated with a PTEN deficiency, wherein the cancer associated with a PTEN deficiency endometrial carcinoma, wherein said endometrial carcinoma is deficient in Homologous Recombination (HR) dependent DNA double strand break (DSD) repair pathway, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I);
wherein:
Y and Z are each independently selected from the group consisting of:
a) an aryl group optionally substituted with 1, 2, or 3 R 6 ;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R 6 ; and
c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarboaylalkyl, alkyl, alkalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (NR A R B )alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, akkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR A R B , NR A R B alkylene, and (NR A R B )carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl, wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, wherein B is not OH;
R A and R B are independently selected from the group of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R A and R B taken 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(C 1 -C 6 -alkyl)-, —NCO(C 1 -C 6 -alkyl)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or S(O) q -,
wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 2 -C 10 -alkenyl, C 1 -C 10-alkoxy, C 1 -C 10 -alkoxy-C 1-C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 -alkyl, C 1 -C 10 -alkylcarbonyl, C 1 -C 10 -alkycarbonyloxy, C 1 -C 10 -alkylthio, C 1 -C 10 -alkyl, C 2 -C 10 -alkynyl, carboxy, cyano, formyl, C 1 -C 10 -haloalkoxy, C 1 -C 10 -haloalkyl, halogen, hydroxyl, C 1 -C 10 -hydroxyalkylene, mercapto, nitro, —NR A R B , and (NR A R B )carbonyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR A R B )alkylene; and each R 6 is selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkexycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, halolkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy. C 3 -C 8 heterocycloalkylthio, heterocyclooxy, heterecyclothio, NH A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A RB)sulfonyl, and (NR A R B )sulfonylalkylene or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.
19. The method of claim 18 , wherein the endometrial carcinoma comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to cancer cells.
20. The method of claim 19 , wherein the endometrial carcinoma cancer cells have a PTEN deficient phenotype.
21. The method of claim 19 , wherein the endometrial carcinoma cancer cells are deficient in PTEN.
22. The method of claim 18 , wherein the endometrial carcinoma comprises one or more cancer cells deficient in protects involved in DNA DSB repair by HR.
23. The method of claim 22 , wherein the endometrial carcinoma cancel cells are deficient in ATM, Rad51, Rad52, Rad54, Rad50, MRE11, NBS1, XRCC2, XRCC3, cABL, RPA, CtIP, or MBC.
24. The method of claim 23 , wherein the endometrial carcinoma cancer cells are deficient in Rad51.
25. The method of claim 18 wherein a subject is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA PSB repair pathway.
26. The method of claim 18 wherein the subject is heterozygous for a mutation in PTEN.
27. The method of claim 18 wherein the treatment further comprises administration of ionizing radiation or a chemotherapeutic agent.
28. A method of treating a disease associated with a PTEN deficiency, wherein the disease associated with a PTEN deficiency is endometrial carcinoma, wherein said endometrial carcinoma is associated with an abrogated or reduced ability to control the phosphoinositide 3-kinase signaling pathway comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I):
wherein:
Y and Z arc each independently selected from the group consisting of:
a) an aryl group optionally substituted with 1, 2, or 3 R 6 ;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R 6 ; and
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, (NH A R B )alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR A R B , NR A R B alkylene, and (NR A R B )carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl, wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, wherein B is not OH;
R A and R B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcabbonyl, or R A and R B taken 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(C 1 -C 6 -alkyl)-, —NCO(C 1 C 6 -alkyl)-, —N(aryl)- —N(aryl-C 1 -C 6 -alkly-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or S(O) q -, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 2 -C 10 -alkenyl, C 1 -C 10 -alkoxy, C 1 -C 10 alkoxy-C 1 -C 10 -alkyl, C 1 -C 10 -alkoxycarbonyl, C 1 -C 10 -alkyl, C 1 -C 10 -alkylcarbonyl, C 1 -C 10 -alkylcarbonyloxy, C 1 -C 10 -alkylthio, C 1 -C 10 -alkylthio-C 1 -C 10 -alkyl, C 2 -C 10 -alkynyl, carboxy, cyano, formyl, C 1 -C 10 -haloalkoxy, C 1 -C 10 -haloalkyl, halogen, hydroxyl, C 1 -C 10 - hydroxyalkylene, mercapto, nitro, —NR A R B and (NR A R B )carbonyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene and (NR A R B )alkylene; and each R 6 is selected from the group consisting of CH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 2 -C, 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C 3 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.
29. A method of treating a disease associated with a PTEN deficiency, wherein the disease associated with a PTEN deficiency is endometrial carcinoma, wherein said endometrial carcinoma is due to abnormal regulation of centromere stability comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula. (I):
wherein:
Y and Z are each independently selected from the group consisting of:
a) an aryl group optionally substituted with 1, 2, or 3 R 6 ;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R 6 ; and
c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyearbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylakyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (NR A R B )alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene;
R 1 ,R 2 , and R 3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkomy, aloxycarbonyl, alkyl, cycloalkyl, alknyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR A R B , NR A R B alkylene, and (NR A R B )carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl, wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO 2 , CN, Br, CI, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, wherein B is not OH;
R A and R B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R A and R B taken 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(C 1 -C 6 -alkyl)-, —NCO(C 1 -C 6 -alkyl)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or S(O) q -, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkoxy-C 1 -C 10-alkyl, C 1 -C 10 -alkoxycarbonyl, C 1 -C 10 -alkyl, C 1 -C 10 -alkylcarbonyl, C 1 -C 10 -alkylcarbonyloxy, C 1 -C 10 -alkylthio, C 1 -C 10 -alkylthio-C 1 -C 10 alkyl, C 2 -C 10 -alkynyl, carboxy, cyano, fomyl, C 1 -C 10 -haloalkoxy, C 1 -C 10 -haloalkyl, halogen, hydroxyl, C 1 -C 10 -hydroxyalkylene, mercapto, nitro, —NR A R B , and (NR A R B )carbonyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR A R B )alkylene; and each R 6 is selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylthio, heterocycloalkoxy, C 3 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.
30. The method of claim 1 where Y and Z are each independently selected from the group consisting of:
a) a phenyl group optionally substituted with 1, 2, or 3 R 6 ; and
b) an imidazole group optionally substituted with 1, 2, or 3 R 6 ;
or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.
31. The method of claim 1 where Y and Z are each independently selected tram the group consisting of:
a) a phenyl group optionally substituted with 1, 2, or 3 R 6 ; and
b) a triazole group optionally substituted with 1, 2, or 3 R 6 ;
or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.
32. A method of treating a disease associated with a PTEN deficiency ameliorated by the inhibition of PARP, wherein the disease associated with a PTEN deficiency is endometrial carcinoma, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound selected from the group consisting of:
(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[1,3,2de]phthalazin-3(7H)-one,
(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[1,3,2de]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]phthatazn-3(7H)-one,
(8S,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidzol-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)-5-fluoro-8-(1-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)-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-imidazol-2-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]phthalazin-3(7H)-one,
(8S,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,
(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-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-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-triazol-5-yl)-8,9-dihydro-H-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,
(8R,9S)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, and
(8S,9R)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-4-fluorophenyl)-8,9-dihydro-2H-pyridoi[4,3,2-de]phthalazin-3(7H)-one, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
33. A method of treating a disease associated with a PTEN deficiency ameliorated by the inhibition of PARP, wherein the disease associated with a PTEN deficiency is endometrial carcinoma, comprising administering to a subject in need of treatment a therapeutically effective amount of 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 or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a pharmaceutically acceptable salt.
34. A method of treating astrocytoma; endometroid serous adenocarcinoma, endometroid clear cell adenocarcinoma, endometroid adenosquamous carcinoma, or mixed histology; and small cell comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I):
wherein:
Y and Z are each independently selected from the group consisting of:
a) an aryl group optionally substituted with 1, 2, or 3 R 6 ;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R 6 ; and
c) a substituent independently selected from the group consisting of hydrogen, alkonyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (NR A R B )alkylene, (NR A R B )carbonyl, (NR A R B )carbonaylkylene, (NR A R B )sulfonyl, and (NR A R B sulfonylalkylene;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, aloxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR A R B , NR A R B alkylene, and (NR A R B )carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl, wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, wherein B is not OH;
R A and R B are indepepdently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R A and R B taken together with the atom to which they are attached from a 3-10 membered heterocycle ring optionally haviug one to three heteroatoms or hetero functionalities seleted from the group consisting of —O—, —NH, —N(C 1 -C 6 alkyl)-, —NCO(C 1 -C 6 -alkyl)-, —N(arly)-, —N(aryl-C 1 -C 6 -alkyl-)-, —(substituted-aryl-C 1 C 6 alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or S(O) q -,
wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from C 2 -C 10 alkenyl, C 1 -C 10 -alkoxy, C 1 -C 10 -alkoxy-C 1 -C 10 -alkyl, C 1 -C 10 -alkoxycarbonyl, C 1 -C 10 -alkyl, C 1 -C 10 -alkylcarbonyl, C 1 -C 10 -alkylthio, C 1 -C 10 alkylthio-C 1 -C 10 alkyl, C 2 -C 10 -alkynyl, carboxy, cyano, formyl, C 1 -C 10 -haloalkoxy, C 1 -C 10 -haloalkyl, halogen, hydroxyl, C 1 -C 10 -hydroxyalkylene, mercapto, nitro, —NR A R B , and (NR A R B )carbonyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR A R B )alkylene: and
each R 6 is selected from the group consisting of OR, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 hetercoyeloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylakyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, hetetoaryl, heteroarylalkoxy, heteroaryloxy, heteroaryl thio, heteroarylalkylthio, heterocycloalkoxy, C 3 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonyalkylene; or
a single isomer, stereoisomer, or enantionier, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.
35. The method of claim 34 where Y and Z are each independently selected from the group consisting of:
a) a phenyl group optionally substituted with 1, 2, or 3 R 6 ; and
b) an imidazole group optionally substituted with 1, 2, or 3 R 6 ;
or a single isomer, stereoisomer, enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.
36. The method of claim 34 where Y and Z are each independently selected from the group consisting of:
a) a phenyl group optionally substituted with 1, 2, or 3 R 6 ; and
b) a triazole group optionally substituted with 1, 2, or 3 R 6 ;
or a single isoimer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.
37. The method of claim 34 comprising administering to the subject a therapeutically effective amount of 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 or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a pharmaceutically acceptable salt.
38. A method of treating a disease associated with a PTEN deficiency wherein the disease associated with a PTEN deficiency is endometrial carcinoma, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of 5-fluoro-8-(4-fluorophettyl)-9-(1-methyl-1H-1,2,4-triazol-5yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a pharmaceutically acceptable salt.