Small molecule inhibitors of parp activity

Abstract

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 - 7 . (canceled) 
     
     
         8 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         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, 3 or 4. 
       
     
     
         9 - 13 . (canceled) 
     
     
         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 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 and 2-(1,2,3,4-tetrahydroquinolin-2-yl)-1H-benzo[d]imidazole-4-carboxamide. 
     
     
         16 . A compound of Formula (III) 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, 3 or 4. 
       
     
     
         17 - 21 . (canceled) 
     
     
         22 . The compound of  claim 16  wherein R 7  is H, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorobenzyl or phenylethyl. 
     
     
         23 . The compound of  claim 16  selected from 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 and 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)-1H-benzo[d]imidazole-4-carboxamide. 
     
     
         24 - 31 . (canceled) 
     
     
         32 . A pharmaceutical composition comprising a compound of  claim 8  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         33 . 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. 
     
     
         34 . A method of treating or lessening the severity of a disease, disorder or condition, which method comprises administering to a patient in need thereof an effective amount of a compound  claim 8  or a pharmaceutical composition thereof, wherein the disease, disorder or condition is selected from the group consisting of a dysproliferative disease, an inflammatory disease, rheumatoid arthritis, neovascularization of the eye as a consequence of diabetic retinopathy, muscular dystrophy, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke, traumatic head injury, spinal cord injury, cerebrovascular diseases; myocardial ischemia; atherosclerosis; peripheral vascular disease; cardiovascular diseases; diabetes; renal failure; pancreatitis; multiple sclerosis; neurodegenerative disease; Parkinsonism; Alzheimer disease; acceleration of wound healing; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, or other tissues or organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . The method of  claim 34  wherein the dysproliferative disease is cancer. 
     
     
         38 - 47 . (canceled) 
     
     
         48 . A pharmaceutical composition comprising a compound of  claim 16  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         49 . 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 16  or a pharmaceutical composition thereof. 
     
     
         50 . A method of treating or lessening the severity of a disease, disorder or condition which method comprises administering to a patient in need thereof an effective amount of a compound  claim 16  or a pharmaceutical composition thereof, wherein the disease, disorder or condition is selected from the group consisting of dysproliferative disease, an inflammatory disease, rheumatoid arthritis, neovascularization of the eye as a consequence of diabetic retinopathy, muscular dystrophy, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke, traumatic head injury, spinal cord injury, cerebrovascular diseases; myocardial ischemia; atherosclerosis; peripheral vascular disease; cardiovascular diseases; diabetes; renal failure; pancreatitis; multiple sclerosis; neurodegenerative disease; Parkinsonism; Alzheimer disease; acceleration of wound healing; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, or other tissues or organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus. 
     
     
         51 . The method of  claim 50  wherein the dysproliferative disease is cancer. 
     
     
         52 . A method of treating or lessening the severity of a disease, disorder or condition selected from the group consisting of a dysproliferative disease, an inflammatory disease, neovascularization of the eye as a consequence of diabetic retinopathy, muscular dystrophy, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; traumatic head injury, spinal cord injury, cerebrovascular diseases; myocardial ischemia; peripheral vascular disease; cardiovascular diseases; diabetes; renal failure; pancreatitis; multiple sclerosis; neurodegenerative disease; Parkinsonism; Alzheimer disease; acceleration of wound healing; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, or other tissues or organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus, comprising administering to a patient in need thereof an effective amount of a compound or a pharmaceutical composition thereof 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. 
       
     
     
         53 . The method of  claim 52  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. 
     
     
         54 . The method of  claim 52  wherein the compound or pharmaceutical composition thereof is 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. 
     
     
         55 . The method of  claim 52  wherein the proliferative disease is cancer. 
     
     
         56 . A method of treating or lessening the severity of a disease, disorder or condition selected from the group consisting of a dysproliferative disease, an inflammatory disease, neovascularization of the eye as a consequence of diabetic retinopathy, muscular dystrophy, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; traumatic head injury, spinal cord injury, cerebrovascular diseases; myocardial ischemia; peripheral vascular disease; cardiovascular diseases; diabetes; renal failure; pancreatitis; multiple sclerosis; neurodegenerative disease; Parkinsonism; Alzheimer disease; acceleration of wound healing; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, or other tissues or organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus, comprising administering to a patient in need thereof an effective amount of a compound or a pharmaceutical composition thereof of formula (IV): 
       
         
           
           
               
               
           
         
         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. 
       
     
     
         57 . The method of  claim 56  wherein R 7  is H, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorobenzyl or phenylethyl. 
     
     
         58 . The method of  claim 56  wherein the compound or pharmaceutical composition thereof is 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. 
     
     
         59 . The method of  claim 56  wherein the proliferative disease is cancer.