# US 8,541,403 B2 · Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency

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- Number: US 8,541,403 B2
- Document ID: US8541403B2
- Status: Granted
- Kind: B2
- Application number: 13/020,619
- Filed: 2011-02-03
- Published: 2011-08-04
- Granted: 2013-09-24
- Earliest claimed: 2010-02-03
- Assignees: Biomarin Pharmaceutical Inc.
- Applicants: Daniel Chu; Bing Wang; Ying Feng; Yuqiao Shen; Leonard Edwin Post
- Inventors: Daniel Chu; Bing Wang; Ying Feng; Yuqiao Shen; Leonard Edwin Post
- Web page: https://patentgrep.com/patent/US8541403B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 487/06: Peri-condensed systems
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A compound having the structure set forth in Formula (I) and Formula (II): wherein the substituents Y, Z, A, B, R1, R2, R3, R4 and R5 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.

## Claims

### Claim 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 R6;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R6; 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, (NRARB)alkkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonyalkylene;
R1, R2, and R3 are 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 the group consisting of hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl, wherein B is not OH;
RA and RB are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RA and RB 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(C1-C6-alkyl)-, —N(aryl)-, —NN(aryl-C1C6alkyl-)-, —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 1, 2, 3, or 4 substituents independently selected from C2-C10-alkenyl, C1-C10-alkoxy-C1, -C10-alkyl, C1-C10-alkoxycarbonyl, C1-C10-alkyl, C1-C10-alkylcarbonyl, C1-C10-a1kylcarbonyloxy, C1-C10-alkylthio, C1-C10-alkylthio-C1-C10-alkyl, C2-C10alkynyl, carboxy, cyano, formyl, C1-C10 -haloalkoxy, C1-C10-haloalkyl, halogen, hydroxyl, C1-C10-hydroxyalkylene, mercapto, nitro, —NRARB, and (NRARB)carbonyl;
R4 and R6 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRARB)alkylene; and
each R6 is selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1 C6alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8-cycloalkyalkyl, haloalkoxy, haloakyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroaryl thio, heteroarylalkylthio, heterocycloalkoxy, C2-C8heterocycloalkythio, C3-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARB)C 1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene; or
a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.

### Claim 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 R6;
Z is an aryl group optionally substituted with 1, 2, or 3 R6;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and aloxyalkyl, wherein C1-C6alkyl, C3-C8- cycloalkyl, alkoxy, and alkoxyalkyl are optionally substituted with at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3C8cycloalkyl, wherein B is not OH;
R6 is selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C3-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
R2 is selected from the group consisting of hydrogen, Br, Cl, I, and F;
RA and RB are independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C8cycloalkyl, and alkylcarbonyl; or RA and RB 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(C1-C6alkyl)-, —NCO(C1-C6alkyl)-, —NCO(C3-C8cycloalkyl)- —N(aryl)-, —N(aryl-C1-C6alkyl-)-, —N(substitited-aryl-C1C6alkyl-)-, —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 1, 2, 3, or 4 substitnents independently selected from C2-C10-alkenyl, C1-C10-alkoxy, C1-C10alkyl, C1-C10-alkoxycarbonyl, C1-C10 alkyl, C1-C10-alkylcarbonyl, C1-C10-alkylcarbonyloxy, C1-C10-alkylthio, C1-C10-alkylthio-C1C10-alkyl, C2-C10-alkynyl, carboxy, cyano, formyl, C1C10-haloalkoxy, C1-C10-haloalkyl, halogen, hydroxyl, C1-C10-hydroxyalkylene, mercapto, nitro, —NRARB, and —(NRARB)carbonyl; or
a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt solvate, chemically protected form or prodrug thereof.

### Claim 3 (depends on 1)

The method of claim 1 wherein Y is a heteroaryl group optionally substituted with 1, 2, or 3 R6.

### Claim 4 (depends on 3)

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 R6.

### Claim 5 (depends on 4)

The method of claim 4 wherein the heteroaryl group is substituted with C1-C6alkyl selected from the group consisting of methyl, ethyl n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

### Claim 6 (depends on 5)

The method of claim 5 wherein C1C6alkyl is methyl.

### Claim 7 (depends on 1)

The method of claim 1 wherein Z is an aryl group which is optionally substituted with 1, 2, or 3 R6.

### Claim 8 (depends on 7)

The method of claim 7 wherein the aryl group is a phenyl group which is optionally substituted with 1, 2, or 3 R6.

### Claim 9 (depends on 8)

The method of any of claim 8 wherein the phenyl group is substituted with 1, 2, or 3 R6 selected from the group consisting of Br, Cl, F, and I.

### Claim 10 (depends on 9)

The method of claim 9 wherein R6 is F.

### Claim 11 (depends on 1)

The method of claim 1 wherein R2 is selected from the group consisting of F, Cl, Br, and L.

### Claim 12

The method of cairn 11 wherein R2 is F.

### Claim 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.

### Claim 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 R6;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R5; 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, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
R1, R2, and R3 are 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 the group consisting of hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cyclcoalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl, wherein B is not OH;
RA and RB an independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RA and RB 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(C1-C6-alkyl)-, —NCO(C1-C6alkyl)-, —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 1, 2, 3, or 4 substituents independently selected from C2-C10-alkenyl, C1-C10-alkoxy, C1C10-alkoxy-C1-C 10-alkyl, C1-C10-alkoxycarbonyl, C1-C10-alkyl, C1-C10alkylcarbonyl, C1-C10-alkylcarbonyloxy, C1-C10-alkylthio, C1-C10-alkylthio-C1-C10-alkyl, C2-C10-alkynyl, carboxy, cyano , formyl, C1C10-haloalkoxy, C1-C10-haloalkyl, halogen, hydroxyl, Cl-C10-hydroxyalkylene, mercapto, nitro, —NRARB, and (NRARB)carbonyl;
R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRARB)alkylene; and each R6 is selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C3-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR ARB, (NRARB)C1-C6alkylene, (NRA,RB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)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.

### Claim 15 (depends on 1)

The method of claim 1, wherein said administration is in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.

### Claim 16 (depends on 15)

The method of claim 15, wherein the compound
wherein
with 1, 2, or 3 R6;
alkoxy, and the group consisting of OH,
wherein
selected from C2-C10
or a single isomer, stereoisomer, or
is administered simultaneously with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.

### Claim 17 (depends on 15)

The method of claim 15, wherein the compound is administered sequentially with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.

### Claim 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 R6;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R6; 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, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
R1, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, akkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NRARB, NRARBalkylene, and (NRARB)carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl, wherein B is not OH;
RA and RB are independently selected from the group of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RA and RB 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(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 1, 2, 3, or 4 substituents independently selected from C2-C10-alkenyl, C1-C10-alkoxy, C1-C10-alkoxy-C1-C10alkyl, C1-C10alkoxycarbonyl, C1-C10-alkyl, C1-C10-alkylcarbonyl, C1-C10-alkycarbonyloxy, C1-C10-alkylthio, C1-C10-alkyl, C2-C10-alkynyl, carboxy, cyano, formyl, C1-C10-haloalkoxy, C1-C10-haloalkyl, halogen, hydroxyl, C1-C10-hydroxyalkylene, mercapto, nitro, —NRARB, and (NRARB)carbonyl;
R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRARB)alkylene; and each R6 is selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkexycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylalkyl, haloalkoxy, halolkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy. C3-C8heterocycloalkylthio, heterocyclooxy, heterecyclothio, NHARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.

### Claim 19 (depends on 18)

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.

### Claim 20 (depends on 19)

The method of claim 19, wherein the endometrial carcinoma cancer cells have a PTEN deficient phenotype.

### Claim 21 (depends on 19)

The method of claim 19, wherein the endometrial carcinoma cancer cells are deficient in PTEN.

### Claim 22 (depends on 18)

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.

### Claim 23 (depends on 22)

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.

### Claim 24 (depends on 23)

The method of claim 23, wherein the endometrial carcinoma cancer cells are deficient in Rad51.

### Claim 25 (depends on 18)

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.

### Claim 26 (depends on 18)

The method of claim 18 wherein the subject is heterozygous for a mutation in PTEN.

### Claim 27 (depends on 18)

The method of claim 18 wherein the treatment further comprises administration of ionizing radiation or a chemotherapeutic agent.

### Claim 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 R6;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R6; 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, (NHARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
R1, R2, and R3 are 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 the group consisting of hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl, wherein B is not OH;
RA and RB are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcabbonyl, or RA and RB 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(C1-C6-alkyl)-, —NCO(C1C6-alkyl)-, —N(aryl)- —N(aryl-C1-C6-alkly-)-, —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 1, 2, 3, or 4 substituents independently selected from C2-C10-alkenyl, C1-C10-alkoxy, C1-C10alkoxy-C1-C10-alkyl, C1-C10-alkoxycarbonyl, C1-C10-alkyl, C1-C10-alkylcarbonyl, C1-C10-alkylcarbonyloxy, C1-C10-alkylthio, C1-C10-alkylthio-C1-C10-alkyl, C2-C10-alkynyl, carboxy, cyano, formyl, C1-C10-haloalkoxy, C1-C10-haloalkyl, halogen, hydroxyl, C1-C10- hydroxyalkylene, mercapto, nitro, —NRARB and (NRARB)carbonyl;
R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene and (NRARB)alkylene; and each R6 is selected from the group consisting of CH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C2-C,6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C3-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.

### Claim 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 R6;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R6; 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, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
R1,R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkomy, aloxycarbonyl, alkyl, cycloalkyl, alknyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NRARB, NRARBalkylene, and (NRARB)carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO2, CN, Br, CI, F, I, C1-C6alkyl, and C3-C8cycloalkyl, wherein B is not OH;
RA and RB are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RA and RB 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(C1-C6-alkyl)-, —NCO(C1-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted-aryl-C1-C6-)-, —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 1, 2, 3, or 4 substituents independently selected from C2-C10alkenyl, C1-C10alkoxy, C1-C10-alkoxy-C1-C10-alkyl, C1-C10-alkoxycarbonyl, C1-C10-alkyl, C1-C10-alkylcarbonyl, C1-C10-alkylcarbonyloxy, C1-C10-alkylthio, C1-C10-alkylthio-C1-C10alkyl, C2-C10-alkynyl, carboxy, cyano, fomyl, C1-C10-haloalkoxy, C1-C10-haloalkyl, halogen, hydroxyl, C1-C10-hydroxyalkylene, mercapto, nitro, —NRARB, and (NRARB)carbonyl;
R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRARB)alkylene; and each R6 is selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylthio, heterocycloalkoxy, C3-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.

### Claim 30 (depends on 1)

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 R6; and
b) an imidazole group optionally substituted with 1, 2, or 3 R6;
or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.

### Claim 31 (depends on 1)

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 R6; and
b) a triazole group optionally substituted with 1, 2, or 3 R6;
or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.

### Claim 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.

### Claim 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.

### Claim 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 R6;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R6; 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, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonaylkylene, (NRARB)sulfonyl, and (NRARBsulfonylalkylene;
R1, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, aloxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NRARB, NRARBalkylene, and (NRARB)carbonyl;
A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, alkoxy, and alkoxyalkyl are independently optionally substituted with at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, and C3-C8cycloalkyl, wherein B is not OH;
RA and RB are indepepdently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RA and RB 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(C1-C6alkyl)-, —NCO(C1-C6-alkyl)-, —N(arly)-, —N(aryl-C1-C6-alkyl-)-, —(substituted-aryl-C1C6alkyl-)-, —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 0, 1, 2, 3, or 4 substituents independently selected from C2-C10alkenyl, C1-C10-alkoxy, C1-C10-alkoxy-C1-C10-alkyl, C1-C10-alkoxycarbonyl, C1-C10-alkyl, C1-C10-alkylcarbonyl, C1-C10-alkylthio, C1-C10alkylthio-C1-C10alkyl, C2-C10-alkynyl, carboxy, cyano, formyl, C1-C10-haloalkoxy, C1-C10-haloalkyl, halogen, hydroxyl, C1-C10-hydroxyalkylene, mercapto, nitro, —NRARB, and (NRARB)carbonyl;
R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRARB)alkylene: and
each R6 is selected from the group consisting of OR, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, C3-C8hetercoyeloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, C3-C8cycloalkylakyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, hetetoaryl, heteroarylalkoxy, heteroaryloxy, heteroaryl thio, heteroarylalkylthio, heterocycloalkoxy, C3-C8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonyalkylene; or
a single isomer, stereoisomer, or enantionier, or mixture thereof, optionally as a salt, solvate, chemically protected form or prodrug thereof.

### Claim 35 (depends on 34)

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 R6; and
b) an imidazole group optionally substituted with 1, 2, or 3 R6;
or a single isomer, stereoisomer, enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.

### Claim 36 (depends on 34)

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 R6; and
b) a triazole group optionally substituted with 1, 2, or 3 R6;
or a single isoimer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt, or chemically protected form thereof.

### Claim 37 (depends on 34)

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.

### Claim 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.