Small molecule inhibitors of PARP activity
Compounds and pharmaceutical compositions are provided that inhibit the activity of poly ADP-ribose synthetase (PARP). Such compounds are useful in the treatment of various diseases, conditions and injuries such as stroke, myocardial infarction, ischemia-perfusion injury in various organs, traumatic brain injury, atherosclerosis, inflammatory diseases and cancer.
1. A compound of Formula (I):
wherein R 1 is one or more H, hydroxy, halogen, cyano, OR 4 , nitro, NH 2 , NR 4 R 5 , NR 4 COR 5 , NR 4 SO 2 R 5 , CONR 4 R 5 , COOR 4 , SO 2 R 4 , alkynyl, optionally substituted aliphatic, alicyclic, heteroaliphatic, or heterocyclic;
R 2 is H, optionally substituted alkyl or cycloalkyl;
R 3 is H, COR 4 , CONR 4 R 5 , COOR 4 , SO 2 R 4 , optionally substituted alkyl, alkenyl, alkynyl, cyclolalkyl, heterocycloalkyl, aryl or heteroaryl;
R 4 and R 5 are independently selected from the group consisting of H, OH, NH 2 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
A and B joined together form a bicyclic ring wherein:
A is nonaromatic 4, 5, 6, 7 or 8-membered ring that contains 1 or 2 nitrogen atoms and optionally one sulfur or oxygen atom, where in the nonaromatic ring is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogen, cyano, OR 4 , nitro, NH 2 , NR 4 R 5 , NR 4 COR 5 , NR 4 SO 2 R 4 , CONR 4 R 5 , COOR 4 , SO 2 R 4 , alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and oxo; and
B is aryl or heteroaryl that is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogen, cyano, OR 4 , nitro, NH 2 , NR 4 R 5 , NR 4 COR 5 , NR 4 SO 2 R 5 , CONR 4 R 5 , COOR 4 , SO 2 R 4 , alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
2. The compound of claim 1 wherein R 1 is H, Cl or F.
3. The compound of claim 1 wherein R 2 is H, methyl or ethyl.
4. The compound of claim 1 wherein R 3 is H.
5. The compound of claim 1 wherein R 4 and R 5 are independently H, methyl or ethyl.
6. The compound of claim 1 wherein A and B taken together is indolin-2-yl, isoindolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, 1,2,3,4-tetrahydroquinolin-2-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-2-yl, 2,3,4,5-tetrahydro-1H-benzo[c]azepin-3-yl, 2,3,4,5-tetrahydro-1H-benzo[d]azepin-2-yl, 2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl, 1,2,3,4,5,6-hexahydrobenzo[b]azocin-2-yl, 1,2,3,4,5,6 hexahydrobenzo[c]azocin-3-yl, 1,2,3,4,5,6-hexahydrobenzo[d]azocin-2-yl, 1,2,3,4,5,6-hexahydrobenzo[c]azocin-1-yl or 1,2,3,4,5,6-hexahydrobenzo[d]azocin-4-yl.
7. The compound of claim 1 selected from benzyl 2-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)indoline-1-carboxylate; 2-(indolin-2-yl)-1H-benzo[d]imidazole-4-carboxamide; tert-butyl 2-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate; 2-(1,2,3,4-tetrahydroquinolin-2-yl)-1H-benzo[d]imidazole-4-carboxamide; benzyl 1-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)isoindoline-2-carboxylate; 2-(isoindolin-1-yl)-1H-benzo[d]imidazole-4-carboxamide; benzyl 1-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)-1H-benzo[d]imidazole-4-carboxamide; benzyl 3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; 2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide; benzyl 3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 2-(3-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide; tert-butyl
7-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; tert-butyl 7-amino-3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; tert-butyl (3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate and 2-(7-amino-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide.
8. The compound of Formula (IV) below:
wherein R 1 and R 6 are one or more H, hydroxy, halogen, cyano, OR 4 , nitro, NH 2 , NR 4 R 5 , NR 4 COR 5 , NR 4 SO 2 R 5 , CONR 4 R 5 , COOR 4 , SO 2 R 4 , alkynyl, optionally substituted aliphatic, alicyclic, heteroaliphatic or heterocyclic;
R 2 is H, optionally substituted alkyl or cycloalkyl;
R 3 and R 7 are independently selected from the group consisting of H, COR 4 , CONR 4 R 5 , COOR 4 , SO 2 R 4 , optionally substituted alkyl, alkenyl, alkynyl, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl;
R 4 and R 5 are independently selected from the group consisting of H, OH, NH2, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
n=0, 1, 2 or 3.
9. The compound of claim 8 wherein R 1 is H, Cl or F.
10. The compound of claim 8 wherein R 2 is H, methyl or ethyl.
11. The compound of claim 8 wherein R 3 is H.
12. The compound of claim 8 wherein R 4 and R 5 are independently H, methyl or ethyl.
13. The compound of claim 8 wherein R 6 is H or F.
14. The compound of claim 8 wherein R 7 is H, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorobenzyl or phenylethyl.
15. The compound of claim 8 selected from benzyl 3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; 2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide; benzyl 3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 2-(3-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide; tert-butyl 7-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; tert-butyl 7-amino-3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; tert-butyl (3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate and 2-(7-amino-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.
17. A method for inhibiting PARP activity in a patient or a biological sample, which method comprises administering to the patient or exposing the biological sample to an effective amount of a compound of claim 1 or a pharmaceutical composition thereof.
18. A method of treating or lessening the severity of a disease, disorder or condition selected from stroke, myocardial infarction, rheumatoid arthritis and atherosclerosis, which method comprises administering to a patient in need thereof an effective amount of a compound claim 1 or a pharmaceutical composition thereof.
19. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier, excipient or diluent.
20. A method for inhibiting PARP activity in a patient or a biological sample, which method comprises administering to the patient or exposing the biological sample to an effective amount of a compound of claim 8 or a pharmaceutical composition thereof.
21. A method of treating or lessening the severity of a disease, disorder or condition selected from stroke, myocardial infarction, rheumatoid arthritis and atherosclerosis, which method comprises administering to a patient in need thereof an effective amount of a compound of claim 8 or a pharmaceutical composition thereof.