Claims for Patent: 8,420,650

Summary for Patent: 8,420,650

Title:	Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
Abstract:	A compound having the structure set forth in Formula (I) and Formula (II): ##STR00001## wherein the substituents Y, Z, A, B, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.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 that are ameliorated by the inhibition of PARP activity.
Inventor(s):	Wang; Bing (San Jose, CA), Chu; Daniel (Santa Clara, CA)
Assignee:	BioMarin Pharmaceutical Inc. (Novato, CA)
Application Number:	13/077,785
Patent Claims:	1. A compound of Formula (I): ##STR00038## wherein: Y is a heteroaryl group optionally substituted with 1, 2, or 3 R.sub.6; Z is selected from the group consisting of: a) an aryl group optionally substituted with 1, 2, or 3 R.sub.6; b) a heteroaryl group optionally substituted with 1, 2, or 3 R.sub.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, (NR.sub.AR.sub.B)alkylene, (NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene, (NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene; R.sub.1, R.sub.2, and R.sub.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.sub.AR.sub.B, NR.sub.AR.sub.Balkylene, and (NR.sub.AR.sub.B)carbonyl; A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy, and alkoxyalkyl are optionally substituted with at least one substituent selected from the group consisting of OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; R.sub.A, and R.sub.B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R.sub.A and R.sub.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.sub.1-C.sub.6-alkyl)-, --NCO(C.sub.1-C.sub.6-alkyl)-, --N(aryl)-, --N(aryl-C.sub.1-C.sub.6-alkyl-)-, --N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-, --N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-, --N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or S(O).sub.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.sub.2-C.sub.10-alkenyl, C.sub.1-C.sub.10-alkoxy, C.sub.1-C.sub.10-alkoxy-C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-alkoxycarbonyl, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-alkylcarbonyl, C.sub.1-C.sub.10-alkylcarbonyloxy, C.sub.1-C.sub.10-alkylthio, C.sub.1-C.sub.10-alkylthio- C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, carboxy, cyano, formyl, C.sub.1-C.sub.10-haloalkoxy, C.sub.1-C.sub.10-haloalkyl, halogen, hydroxyl, C.sub.1-C.sub.10-hydroxyalkylene, mercapto, nitro, --NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)carbonyl; R.sub.4 and R.sub.5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR.sub.AR.sub.B)alkylene; and each R.sub.6 is selected from the group consisting of OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8heterocycloalkyl, C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl, C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C.sub.3-C.sub.8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene, (NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene, (NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 2. A compound of Formula (II): ##STR00039## wherein: Y is a heteroaryl group optionally substituted with 1, 2, or 3 R.sub.6; Z is an aryl group optionally substituted with 1, 2, or 3 R.sub.6; A and B are each independently selected from the group consisting of hydrogen, Br, Cl, F, I, OH, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy, and alkoxyalkyl are optionally substituted with at least one substituent selected from the group consisting of OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; R.sub.6 is selected from the group consisting of OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8heterocycloalkyl, C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl, C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C.sub.3-C.sub.8heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene, (NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene, (NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene; R.sub.2 is selected from the group consisting of hydrogen, Br, Cl, I, and F; R.sub.A, and R.sub.B are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and alkylcarbonyl; or R.sub.A and R.sub.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.sub.1-C.sub.6alkyl)-, --NCO(C.sub.1-C.sub.6alkyl)-, --NCO(C.sub.3-C.sub.8cycloalkyl)-, --N(aryl)-, --N(aryl-C.sub.1-C.sub.6alkyl-)-, --N(substituted-aryl-C.sub.1-C.sub.6alkyl-)-, --N(heteroaryl)-, --N(heteroaryl-C.sub.1-C.sub.6alkyl-)-, --N(substituted-heteroaryl-C.sub.1-C.sub.6alkyl-)-, and --S-- or S(O).sub.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.sub.2-C.sub.10-alkenyl, C.sub.1-C.sub.10-alkoxy, C.sub.1-C.sub.10-alkoxy-C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-alkoxycarbonyl, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-alkylcarbonyl, C.sub.1-C.sub.10-alkylcarbonyloxy, C.sub.1-C.sub.10-alkylthio, C.sub.1-C.sub.10-alkylthio-C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkynyl, carboxy, cyano, formyl, C.sub.1-C.sub.10-haloalkoxy, C.sub.1-C.sub.10-haloalkyl, halogen, hydroxyl, C.sub.1-C.sub.10-hydroxyalkylene, mercapto, nitro, --NR.sub.AR.sub.B, and --(NR.sub.AR.sub.B)carbonyl; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 3. The compound of claim 1 wherein R.sub.6 is hydroxyalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 4. The compound of claim 3 wherein the hydroxyalkylene is selected from the group consisting of CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2OH, CH(OH)CH.sub.3, CH(OH)CH.sub.2CH.sub.3, CH.sub.2CH(OH)CH.sub.3, and CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 5. The compound of claim 1 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.sub.6; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 6. The compound of claim 5 wherein the heteroaryl group is substituted with C.sub.1-C.sub.6alkyl selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 7. The compound of claim 1 wherein Z is an aryl group which is optionally substituted with 1, 2, or 3 R.sub.6; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 8. The compound of claim 7 wherein the aryl group is a phenyl group which is optionally substituted with 1, 2, or 3 R.sub.6; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 9. The compound of claim 8 wherein the phenyl group is substituted with 1, 2, or 3 R.sub.6 selected from the group consisting of Br, Cl, F, and I; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 10. The compound of claim 9 wherein the phenyl group is substituted with 1, 2, or 3 R.sub.6 selected from the group consisting of (NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene, (NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene, (NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 11. A compound selected from the group consisting of: 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; 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-dih- ydro-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]pht- halazin-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-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]phthala- zin-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-yl)-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]pht- halazin-3(7H)-one; 9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pht- halazin-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; 9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-d- e]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-dihydr- o-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; 8-(4-fluorophenyl)-9-(1,4,5-trimethyl-1H-imidazol-2-yl)-8,9-dihydro-2H-py- rido[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-pyri- do[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-2- H-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]phthal- azin-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-Fluorophenyl)-9-(4-methyl-4H-1,2,4-triazol-3-yl)-8,9-dihydro-2H-pyri- do[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-pyri- do[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; 9-(1-methyl-1H-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dih- ydro-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; 5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrid- o[4,3,2-de]phthalazin-3(7H)-one; and or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a phaimaceutically acceptable salt thereof. 12. 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-py- rido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py- rido[4,3,2-de]phthalazin-3(7H)-one; (8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-- 2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-- 2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p- yrido[4,3,2-de]phthalazin-3(7H)-one; (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p- yrido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih- ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih- ydro-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-methyl-1H-1,2,4- -triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4- -triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1 where Z is selected from the group consisting of: a) a phenyl group optionally substituted with 1, 2, or 3 R.sub.6; and b) an imidazole group optionally substituted with 1, 2, or 3 R.sub.6; and Y is an imidazole group optionally substituted with 1, 2, or 3 R.sub.6; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 14. The compound of claim 1 where Z is selected from the group consisting of a) a phenyl group optionally substituted with 1, 2, or 3 R.sub.6; and b) a triazole group optionally substituted with 1, 2, or 3 R.sub.6; and Y is a triazole group optionally substituted with 1, 2, or 3 R.sub.6; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof. 15. A pharmaceutical composition comprising a compound of claim 1, 11, or 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, binder or diluent.