Tetracyclic benzamide derivatives and methods of use thereof

Abstract

The invention relates to Tetracyclic Benzamide Derivatives; compositions comprising a Tetracyclic Benzamide Derivative; and methods for treating or preventing an inflammatory disease, a reperfusion disease, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease, or cancer, comprising administering to a subject in need thereof an effective amount of a Tetracyclic Benzamide Derivative.

1 - 27 . (canceled)  
   
   
       28 . A method for treating an inflammatory disease, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))-, or —CH(NR 11 R 12 )— wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat the inflammatory disease.  
 
   
   
       29 - 35 . (canceled)  
   
   
       36 . A method for treating a reperfusion disease, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))-, or —CH(NR 11 R 12 )— wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat the reperfusion disease.  
 
   
   
       37 - 43 . (canceled)  
   
   
       44 . A method for treating or preventing diabetes, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))-, or —CH(NR 11 R 12 )— wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat or prevent the diabetes.  
 
   
   
       45 - 51 . (canceled)  
   
   
       52 . A method for treating cancer, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound of having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))-, or —CH(NR 11 R 12 )— wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat the cancer.  
 
   
   
       53 - 59 . (canceled)  
   
   
       60 . A method for treating renal failure, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))-, or —CH(NR 11 R 12 )— wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat the renal failure.  
 
   
   
       61 - 67 . (canceled)  
   
   
       68 . A method for treating a vascular disease, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))-, or —CH(NR 11 R 12 )— wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat the vascular disease.  
 
   
   
       69 - 75 . (canceled)  
   
   
       76 . A method for treating an ischemic condition, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))-, or —CH(NR 11 R 12 )— wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat the ischemic condition.  
 
   
   
       77 - 81 . (canceled)  
   
   
       82 . A method for treating a diabetic complication, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or hydrate of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 5  is O, NH or S;  
 R 6  is —H or C 1 -C 4  alkyl;  
 X is —C(O)—, —CH 2 —, —CH(halo)-, —(C(OH)((CH 2 ) n CH 3 ))—, —(C(OH)(aryl))- or —CH(NR 11 R 12 )—, wherein n is an integer ranging from 0-5;  
 R 11  and R 12  are independently -hydrogen or —C 1 -C 9  alkyl, or N, R 11  and R 12  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);  
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, halo-substituted-(C 1 -C 5  alkyl), —C 2 -C 10  alkenyl, —C 3 -C 8 -cycloalkyl, -aryl, —NH 2 , amino-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B;  
 A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4  alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;  
 B is —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), —C 3 -C 8  cycloalkyl, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , amino-substituted-(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), —(C 1 -C 5  alkyl)-(3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5  alkyl)-(7- to 10-membered bicyclic heterocycle), —(H 2 NC(O))-substituted aryl, —(H 2 NC(O))-substituted pyridyl, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2 , each of which is unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, halo-substituted-(C 1 -C 5  alkyl), HO-substituted-(C 1 -C 5  alkyl), amino-substituted-(C 1 -C 5  alkyl), -hydroxy, —NO 2 , —NH 2 , —CN, —NH(C 1 -C 5  alkyl), —N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, —(H 2 NC(O))-substituted(C 1 -C 5  alkyl), carboxy-substituted-(C 1 -C 5  alkyl), —C(O)OH, —C 1 -C 5 -alkylene-C(O)O—(C 1 -C 5  alkyl) or —C 1 -C 5  alkylene-OC(O)—(C 1 -C 5  alkyl); and  
 Z 1  and Z 2  are independently —H or —C 1 -C 10  alkyl, which 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 a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or a -nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z 1  and Z 2  are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),  
 in an amount effective to treat the diabetic complication.  
 
   
   
       83 . The method according to  claim 52 , wherein said method further comprises administering radiation therapy.