Tetracyclic amino and carboxamido compounds and methods of use thereof

Abstract

The present invention relates to Tetracyclic Amino Compounds and Tetracyclic Carboxamido Compounds, compositions comprising an effective amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and methods for treating or preventing an inflammatory disease, a reperfusion injury, diabetes, a diabetic complication, reoxygenation injury resulting from organ transplantation, an ischemic condition, Parkinson's disease, renal failure, a vascular disease, a cardiovascular disease, or cancer, comprising administering to a subject in need thereof an effective amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.

1 - 25 . (canceled) 
     
     
         26 . A method for treating cancer, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 26 , wherein the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, skin cancer, brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer. 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 26 , further comprising the administration of an effective amount of another anticancer agent. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 30 , wherein the other anticancer agent is temozolomide, procarbazine, dacarbazine, interleukin-2, irinotecan, or a combination thereof. 
     
     
         33 - 35 . (canceled) 
     
     
         36 . The method of  claim 28 , wherein the cancer is brain cancer or melanoma. 
     
     
         37 . The method of  claim 36 , wherein the brain cancer is metastatic brain cancer or a glioma. 
     
     
         38 . The method of  claim 37 , wherein the glioma is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma or glioblastoma multiforme. 
     
     
         39 . (canceled) 
     
     
         40 . A method for treating renal failure, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 40 , wherein the renal failure is chronic renal failure or acute renal failure. 
     
     
         43 . (canceled) 
     
     
         44 . A method for treating a reperfusion injury, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 44 , wherein the reperfusion injury is stroke or myocardial infarction. 
     
     
         47 . (canceled) 
     
     
         48 . A method for treating an inflammatory disease, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         49 . (canceled) 
     
     
         50 . The method of  claim 48 , wherein the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock. 
     
     
         51 . (canceled) 
     
     
         52 . A method for treating or preventing diabetes, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, C 1 -C 6  alkyl, or -phenyl, wherein the C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         53 . (canceled) 
     
     
         54 . The method of  claim 52 , wherein the diabetes is type I diabetes or type II diabetes. 
     
     
         55 . (canceled) 
     
     
         56 . A method for treating an ischemic condition, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         57 . (canceled) 
     
     
         58 . The method of  claim 56 , wherein the ischemic condition is stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric ischemia, ischemic heart disease, intestinal ischemia, limb ischemia, acute cardiac ischemia, stroke, or cerebral ischemia. 
     
     
         59 . (canceled) 
     
     
         60 . A method for treating reoxygenation injury resulting from organ transplantation, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         61 . (canceled) 
     
     
         62 . A method for treating Parkinson's disease, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         63 . (canceled) 
     
     
         64 . A method for treating a vascular disease, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         65 . (canceled) 
     
     
         66 . The method of  claim 64 , wherein the vascular disease is peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema or lipedema. 
     
     
         67 . (canceled) 
     
     
         68 . A method for treating a diabetic complication, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         69 . (canceled) 
     
     
         70 . A method for treating a cardiovascular disease, comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 one of the R 1 , R 2 , R 3  and R 4  groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H; 
 
       R 5  and R 6  are independently —H, —C 1 -C 6  alkyl, or -phenyl, wherein the —C 1 -C 6  alkyl, or -phenyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H or —C 1 -C 5  alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3  and Z 4  are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; or N, R 5  and R 6  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, hydroxy, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5  alkyl), —OC(O)—(C 1 -C 5  alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, or —C 1 -C 10  alkyl; and
 n is an integer ranging from 2 to 6 
 
       to a subject in need thereof. 
     
     
         71 . (canceled) 
     
     
         72 . The method of  claim 70 , wherein the cardiovascular disease is chronic heart failure, atrial fibrillation, supraventricular tachycardia, atrial flutter or paroxysmal atrial tachycardia. 
     
     
         73 - 82 . (canceled) 
     
     
         83 . The method of  claim 26 , wherein the cancer is colon cancer or cancer of the central nervous system, further comprising administering an effective amount of a DNA alkylating agent or a topoisomerase inhibitor. 
     
     
         84 . The method of  claim 44 , wherein the reperfusion injury is a reperfusion injury resulting from cardiopulmonary bypass, resulting from aortic aneurysm repair surgery, resulting from carotid endarteretcomy surgery, or resulting from hemorrhagic shock. 
     
     
         85 . The method of  claim 84 , wherein said carotid endarterectomy surgery is angioplasty. 
     
     
         86 . The method of  claim 68 , wherein the diabetic complication is diabetic nephropathy, diabetic retinopathy, diabetic neuropathy or diabetic cardiomyopathy. 
     
     
         87 . The method of  claim 26 , wherein the cancer is a metastatic malignant melanoma, a malignant melanoma, or glioblastoma multiforme, further comprising administering an effective amount of a DNA alkylating agent. 
     
     
         88 . The method of  claim 26 , wherein the cancer is a adenocarcinoma, lung cancer, fibrosarcoma, breast cancer, squamous cell carcinoma or cervical cancer, further comprising administering an effective amount of a radiation.