Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
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 that are ameliorated by the inhibition of PARP activity.
1. A compound of Formula (I):
wherein:
Y is selected from the group consisting of:
a) an aryl group optionally substituted with 1, 2, or 3 R 6 ; and
b) 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 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;
Z is 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, (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 cycloalkyl, alkoxy, and alkoxyalkyl, 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 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 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-, —S—, and 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 -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 OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, (C 3 -C 8 cycloalkyl)alkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, (3-8 membered heterocycloalkyl)thio, heterocyclooxy, 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 thereof.
2. A compound of Formula (II):
wherein:
Y is an aryl 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 alkoxyalkyl, 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, 3-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, (C 3 -C 8 cycloalkyl)alkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, (3-8 membered heterocycloalkyl)thio, heterocyclooxy, 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 hetero functionalities selected 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(substituted-aryl-C 1 -C 6 alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 alkyl-)-, —S—, and 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 -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 thereof.
3. The compound of claim 1 wherein Y is an aryl group which is optionally substituted with 1, 2, or 3 R 6 ; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
4. The compound of claim 3 wherein Y is a phenyl group which is optionally substituted with 1, 2, or 3 R 6 ; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
5. The compound of claim 4 wherein Y is a phenyl group substituted with 1, 2, or 3 R 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.
6. The compound of claim 4 wherein Y is a phenyl group substituted with 1, 2, or 3 R 6 selected from the group consisting of (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 thereof.
7. The compound of claim 6 wherein R 6 is (NR A R B )C 1 -C 6 alkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
8. The compound of claim 7 wherein R A and R B are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
9. The compound of claim 7 wherein (NR A R B ) is azetidine, pyrrolidine, piperidine or morpholine; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
10. The compound of claim 1 wherein R 6 is hydroxyalkylene; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
11. The compound of claim 10 wherein the hydroxyalkylene is selected from the group consisting of CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(OH)CH 3 , CH(OH)CH 2 CH 3 , CH 2 CH(OH)CH 3 , and CH 2 CH 2 CH 2 CH 2 OH; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
12. The compound of claim 7 wherein R A and R B taken together with the nitrogen to which they are attached form a 6 membered heterocycle ring having 1 heteroatom or hetero functionality selected from the group consisting of —O—, —NH, and —N(C 1 -C 6 alkyl); or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
13. The compound of claim 1 wherein Z is an aryl group which is optionally substituted with 1, 2, or 3 R 6 ; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
14. The compound of claim 13 wherein Z is a phenyl group which is optionally substituted with 1, 2, or 3 R 6 ; or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
15. The compound of claim 14 wherein Z is a phenyl group substituted with 1, 2, or 3 R 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.
16. The compound of claim 15 wherein Z is a phenyl group substituted with 1, 2, or 3 R 6 selected from the group consisting of (NR A R B )C l -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 thereof.
17. A compound selected from the group consisting of:
8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
8,9-bis(4-methylamino)methyl)phenyl-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-bis(3-((methylamino)methyl)phenyl)-8,9-dihydro-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]phthalazin-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-(hydroxymethyl)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-pyrido[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]phthalazin-3(7H)-one;
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-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]phthalazin-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]phthalazin-3(7H)-one;
9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl)-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-dihydro-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-((dimethylamino)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-((dimethylamino)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-fluoro-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-pyrido[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[4,3,2-de]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;
8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[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]phthalazin-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-(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-ypmethyl)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-pyrido[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-fluorophenyl)-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;
8,9-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]phthalazin-3(7H)-one;
8-(4-(azetidin-1-ylmethyl)phenyl)-9-(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-ethylpiperazin-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-((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-yl)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-(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;
9-(4-fluorophenyl)-8-(1H-imidazol-2-yl)-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-fluoro-8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-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 thereof.
18. A compound selected from the group consisting of (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-pyrido[4,3,2-de]phthalazin-3(7H)-one; or a pharmaceutically acceptable salt thereof.
19. 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 6 ; and
b) an imidazole group optionally substituted with 1, 2, or 3 R 6 ;
and Y is a phenyl group optionally substituted with 1, 2, or 3 R 6 ;
or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
20. 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 6 ; and
b) a triazole group optionally substituted with 1, 2, or 3 R 6 ;
and Y is a phenyl group optionally substituted with 1, 2, or 3 R 6 ;
or a single isomer, stereoisomer, or enantiomer, or mixture thereof, optionally as a salt thereof.
21. A compound of formula (3):
where
R is alkyl;
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 alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, 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 cycloalkyl, alkoxy, and alkoxyalkyl, 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 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 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, —S—, and S(O) q —, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with one or more substituents;
R 5 is 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, 3-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, (C 3 -C 8 cycloalkyl)alkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, (3-8 membered heterocycloalkyl)thio, heterocyclooxy, 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 salt thereof.
22. A pharmaceutical composition comprising a compound of claim 1 , 17 , or 18 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, excipient, binder or diluent thereof.
23. A method of making a compound of claim 1 comprising
a) reacting an intermediate with hydrazine, wherein the intermediate is of the following formula (3):
where R is alkyl; and
b) optionally resolving individual isomers.