US 8,999,987 B2Granted

Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)

AssigneeBiomarin Pharmaceutical Inc.

InventorsBing Wang, Daniel Chu

Life of this patent

Estimating the term…

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 that are ameliorated by the inhibition of PARP activity.

Claims23

Dependent claims

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 R6;
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, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
Z is 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, (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-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, 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 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-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-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 C2-C10-alkenyl, C1-C10-alkoxy, 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-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, 3-8 membered heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, (C3-C8cycloalkyl)alkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, (3-8 membered heterocycloalkyl)thio, heterocyclooxy, 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 thereof.

16 more elements

A compound of Formula (II):

wherein:
Y is an aryl 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 alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, 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 C3-C8cycloalkyl, wherein B is not OH;
R6 is selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, (C3-C8cycloalkyl)alkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, (3-8 membered heterocycloalkyl)thio, heterocyclooxy, 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 hetero functionalities selected from the group consisting of —O—, —NH, —N(C1-C6alkyl)-, —NCO(C1-C6alkyl)-, —NCO(C3-C8cycloalkyl)-, —N(aryl)-, —N(aryl-C1-C6alkyl-)-, —N(substituted-aryl-C1-C6alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6alkyl-)-, —N(substituted-heteroaryl-C1-C6alkyl-)-, —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 C2-C10-alkenyl, C1-C10-alkoxy, 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-C10-alkyl, C2-C 10-alkynyl, carboxy, cyano, formyl, C1-C10-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 thereof.

7 more elements

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.

108 more elements

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 R6;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R6;
and
c) a substituent independently selected from the group consisting of alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, 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-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, 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 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-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-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;
R5 is 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, 3-8 membered heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, (C3-C8cycloalkyl)alkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, (3-8 membered heterocycloalkyl)thio, heterocyclooxy, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
or a salt thereof.

12 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/787,496Filed 6 Mar 2013 · continuation
Priority: 6 Aug 2008
Published: US 2013/0190306 A125 Jul 2013
Granted: 7 Apr 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

A61K 31/5025
Pyridazines; Hydrogenated pyridazines: ortho- or peri-condensed with heterocyclic ring systems
A61K 31/282
Compounds containing heavy metals: platinum compounds
A61K 31/4745
Ortho- or peri-condensed with heterocyclic ring systems: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
A61K 31/495
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with two or more nitrogen atoms as the only ring…

Family

Application61/086,687Us provisional application · filed 6 Aug 2008
Application61/151,036Us provisional application · filed 9 Feb 2009
Application61/173,088Us provisional application · filed 27 Apr 2009
Application12/510,096Parent of this continuation · filed 27 Jul 2009
Application13/077,785Parent of this continuation · filed 31 Mar 2011
US 8,012,976 B2Parent of this continuation · filed 6 Sep 2011
US 2013/0190306 A1Pre-grant publication · published 25 Jul 2013
US 8,420,650 B2Parent of this continuation
US 2010/0035883 A1Published application
US 2011/0237581 A1Published application
US 8,999,987 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

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 R6;
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, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylalkylene, (NRARB)sulfonyl, and (NRARB)sulfonylalkylene;
Z is 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, (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-C8cycloalkyl, alkoxy, and alkoxyalkyl, wherein C1-C6alkyl, C3-C8cycloalkyl, 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 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-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-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 C2-C10-alkenyl, C1-C10-alkoxy, 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-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, 3-8 membered heterocycloalkyl, C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyl, aryl, arylalkyl, (C3-C8cycloalkyl)alkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, (3-8 membered heterocycloalkyl)thio, heterocyclooxy, 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 thereof.

16 more elements

Facts

Application

13/787,496Filed 6 Mar 2013 · continuation

Priority

6 Aug 2008

Published

US 2013/0190306 A125 Jul 2013

Granted

7 Apr 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

A61K 31/5025
Pyridazines; Hydrogenated pyridazines: ortho- or peri-condensed with heterocyclic ring systems
A61K 31/282
Compounds containing heavy metals: platinum compounds
A61K 31/4745
Ortho- or peri-condensed with heterocyclic ring systems: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
A61K 31/495
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with two or more nitrogen atoms as the only ring…

Family

Application61/086,687Us provisional application · filed 6 Aug 2008

Application61/151,036Us provisional application · filed 9 Feb 2009

Application61/173,088Us provisional application · filed 27 Apr 2009

Application12/510,096Parent of this continuation · filed 27 Jul 2009

Application13/077,785Parent of this continuation · filed 31 Mar 2011

US 8,012,976 B2Parent of this continuation · filed 6 Sep 2011

US 2013/0190306 A1Pre-grant publication · published 25 Jul 2013

US 8,420,650 B2Parent of this continuation

US 2010/0035883 A1Published application

US 2011/0237581 A1Published application

US 8,999,987 B2This patent

From the US filing history. Foreign family members aren’t listed.