Isoquinoline derivatives and methods of use thereof

Abstract

The invention provides novel classes of Isoquinoline Derivatives. Pharmaceutical compositions and methods of making and using the compounds, are also described.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       wherein:
 R 5  is NH or S; 
 R 6  is —H or C 1 -C 4  alkyl; 
 X is —C(O)—, —CH 2 —, —CH(halo)-, —CH(OH)—(CH 2 ) n —, —CH(OH)-arylene-, —O—, —NH—, —S—, —CH(NR 11 R 12 )— or —N(SO 2 Y)—, wherein Y is —OH, —NH 2  or -alkylheterocycle and 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 heterocyclic amine; 
 R 1  is -hydrogen, -halo, —C 1 -C 10  alkyl, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5  alkyl), NO 2  or -A′-B′; 
 A′ is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —CO—, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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); 
 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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B; and at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  or R 10  is other than hydrogen; 
 A is —SO 2 —, —SO 2 N—H—, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine. 
 
     
     
         2 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       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)-, —CH(OH)—(CH 2 ) n —, —CH(OH)-arylene-, —O—, —NH—, —S—, —CH(NR 11 R 12 )— or —N(SO 2 Y)—, wherein Y is —OH, —NH 2  or -alkylheterocycle and 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 heterocyclic amine. 
 R 1  is -hydrogen, -halo, —C 1 -C 10  alkyl, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5  alkyl), NO 2  or -A′-B′; 
 A′ is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —CO—, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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); 
 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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B; and at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9  or R 10  is other than hydrogen; 
 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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine. 
 
     
     
         3 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       wherein:
 R 6  is —H or C 1 -C 4  alkyl; 
 R 1  is -hydrogen, -halo, —C 1 -C 10  alkyl, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5  alkyl), NO 2  or -A′-B′; 
 A′ is —SO 2 —, —SO 2 NH—, —NBCO—, —NHCONH—, —CO—, —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 11  alkenyl, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —NZ 1 Z 2 ; 
 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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5  alkyl), —OC(O)(C 1 -C 5  alkyl), NO 2  or -A-B; wherein at least one of R 1 , R 4  and R 10  is other than hydrogen; 
 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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —NZ 1 Z 2 ; 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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine. 
 
     
     
         4 . The compound of  claim 1  wherein R 5  is O, and R 6  is hydrogen. 
     
     
         5 . The compound of  claim 2  wherein R 5  is O, and R 6  is hydrogen. 
     
     
         6 . The compound of  claim 3  wherein R 5  is O, and R 6  is hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein either R 8  or R 9  but not both, is -A-B. 
     
     
         8 . The compound of  claim 7  wherein R 1 , R 2 , R 3 , R 4 , R 7 , and R 10  are hydrogen. 
     
     
         9 . The compound of  claim 1 , wherein R 9  is -A-B. 
     
     
         10 . The compound of  claim 1 , wherein R 9  is -A-B and R 8  is hydrogen. 
     
     
         11 . The compound of  claim 1 , wherein A is —SO 2 —, —SO 2 NH— or —NHCO—. 
     
     
         12 . The compound of  claim 1 , wherein R 9  is -A-B and B is —C 1 -C 8  alkyl, -heterocycle, —C 3 -C 8  carbocycle, -aryl, -alkylamino, -alkanol or -alkylheterocycle. 
     
     
         13 . The compound of  claim 1 , wherein A is —SO 2 — and B is —NZ 1 Z 2 , and Z 1  and Z 2  are independently hydrogen, or —C 1 -C 5  alkyl, unsubstituted or substituted with -halo, -hydroxy or —NZ 3 Z 4 : wherein Z 3  and Z 4  are independently -hydrogen, —C 1 -C 5  alkyl, unsubstituted or substituted with one or more of -halo; -hydroxy or —NH 2 , or wherein N, Z 1  and Z 2 , taken together, form a heterocyclic amine. 
     
     
         14 . The compound of  claim 13 , wherein Z 1  and Z 2  are —(CH 2 ) n D; wherein n is an integer ranging from 1-5, and D is hydrogen, hydroxy, heterocyclic amine or —NZ 3 Z 4 ; wherein Z 3  and Z 4  are independently hydrogen, methyl or ethyl. 
     
     
         15 . The compound of  claim 13 , wherein B is a heterocycle, unsubstituted or substituted with methyl, ethyl or -alkanol. 
     
     
         16 . The compound of  claim 13 , wherein Z 1  is hydrogen and Z 2  is —(CH 2 ) n  NZ 3 Z 4 , wherein n is 2 or 3, and Z 3  and Z 4  are independently methyl or ethyl, or, taken together, NZ 3 Z 4  form a heterocyclic amine. 
     
     
         17 . The compound of  claim 1  wherein X is —C(O)—, —CH(OH)—, —CH(Br)-, —CH 2 — or —CH(NR 11 R 12 )— wherein R 11  and R 12  are hydrogen, —C 1 -C 9  alkyl, or NR 11 R 12 , taken together, form a heterocycle. 
     
     
         18 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       wherein:
 X is —CH 2 — or —O—; 
 R 2  and R 3  are independently -hydrogen, -halo, -alkylhalo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 3  alkyl, —NO 2 , —NH 2 , —CONH 2 , —C(O)OH, —OC(O)—C 1 -C 5  alkyl or —C(O)O—C 1 -C 5  alkyl; 
 R 8  and R 9  are independently -hydrogen or -A-B; 
 A is —SO 2 —, —SO 2 NH— or —NHCO—; and 
 B is —C 1 -C 3  alkyl, —NZ 1 Z 2 , -heterocycle or -alkylamino, each unsubstituted or substituted with one or more of -alkanol, -alkylamino, -aminoalkyl, -aminodialkyl or -heterocycle, each unsubstituted or substituted with —C 1 -C 10  alkyl or -alkanol; and 
 Z 1  and Z 2  are independently -hydrogen or —C 1 -C 8  alkyl, which is unsubstituted or substituted with one or more of -hydroxy or —NZ 3 Z 4 , where Z 3  and Z 4  are independently —H or —C 1 -C 3  alkyl, which is unsubstituted or substituted with one or more of -hydroxy or —NH 2 , or N, Z 3  and Z 4  are taken together to a heterocyclic amine, or N, Z 1  and Z 2  are taken together to form a heterocyclic amine. 
 
     
     
         19 . The compound of  claim 18 , wherein A is —SO 2 — and B is —NZ 1 Z 2 . 
     
     
         20 . The compound of  claim 19 , wherein Z 1  and Z 2  are independently hydrogen, or —C 1 -C 5  alkyl, unsubstituted or substituted with hydroxy or —NZ 3 Z 4 , or, taken together, —NZ 1 Z 2  form a heterocyclic amine. 
     
     
         21 . The compound of  claim 20 , wherein Z 3  and Z 4  are independently hydrogen, or —C 1 -C 3  alkyl, unsubstituted or substituted with hydroxy or —NH 2 , or, taken together, NZ 3 Z 4  form a heterocyclic amine. 
     
     
         22 . The compound of  claim 21 , wherein the heterocyclic amine is selected from the group consisting of an unsubstituted piperidine, piperazine or morpholine group, or a piperazine, pyrrolidine or imidazole group which can be unsubstituted or substituted with —N—(C 1 -C 5  alkyl) or —N—C(O)(C 1 -C 5  alkyl). 
     
     
         23 . The compound of  claim 20 , wherein either NZ 1 Z 2  or NZ 3 Z 4  is a heterocycle, unsubstituted or substituted with —C 1 -C 5  alkyl, -alkanol or -alkylamino. 
     
     
         24 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 1  in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell. 
     
     
         25 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 2  in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell. 
     
     
         26 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 3  in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell. 
     
     
         27 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 18  in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell. 
     
     
         28 . The method of  claim 24  wherein the cell is an in vivo cell. 
     
     
         29 . The method of  claim 25  wherein the cell is an in vivo cell. 
     
     
         30 . The method of  claim 26  wherein the cell is an in vivo cell. 
     
     
         31 . The method of  claim 27  wherein the cell is an in vivo cell. 
     
     
         32 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of  claim 1  in an amount sufficient to treat or prevent the inflammatory disease. 
     
     
         33 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of  claim 2  in an amount sufficient to treat or prevent the inflammatory disease. 
     
     
         34 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of  claim 3  in an amount sufficient to treat or prevent the inflammatory disease. 
     
     
         35 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of  claim 18  in an amount sufficient to treat or prevent the inflammatory disease. 
     
     
         36 . The method of  claim 32 , wherein said 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. 
     
     
         37 . The method of  claim 33 , wherein said 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. 
     
     
         38 . The method of  claim 34 , wherein said 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. 
     
     
         39 . The method of  claim 35 , wherein said 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. 
     
     
         40 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 1  in an amount sufficient to treat or prevent the reperfusion disease. 
     
     
         41 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 2  in an amount sufficient to treat or prevent the reperfusion disease. 
     
     
         42 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 3  in an amount sufficient to treat or prevent the reperfusion disease. 
     
     
         43 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 18  in an amount sufficient to treat or prevent the reperfusion disease. 
     
     
         44 . The method of  claim 40 , wherein the reperfusion disease is stroke or myocardial infarction. 
     
     
         45 . The method of  claim 41 , wherein the reperfusion disease is stroke or myocardial infarction. 
     
     
         46 . The method of  claim 42 , wherein the reperfusion disease is stroke or myocardial infarction. 
     
     
         47 . The method of  claim 43 , wherein the reperfusion disease is stroke or myocardial infarction. 
     
     
         48 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 1  in an amount sufficient to treat or prevent diabetes or the diabetic complication. 
     
     
         49 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 2  in an amount sufficient to treat or prevent diabetes or the diabetic complication. 
     
     
         50 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 3  in an amount sufficient to treat or prevent diabetes or the diabetic complication. 
     
     
         51 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 18  in an amount sufficient to treat or prevent diabetes or the diabetic complication. 
     
     
         52 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 1  in an amount sufficient to treat or prevent the reoxygenation injury. 
     
     
         53 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 2  in an amount sufficient to treat or prevent the reoxygenation injury. 
     
     
         54 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 3  in an amount sufficient to treat or prevent the reoxygenation injury. 
     
     
         55 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of  claim 18  in an amount sufficient to treat or prevent the reoxygenation injury. 
     
     
         56 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of  claim 1  and a pharmaceutically acceptable carrer. 
     
     
         57 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         58 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         59 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of  claim 18  and a pharmaceutically acceptable carrier. 
     
     
         60 . The compound or pharmaceutically acceptable salt or hydrate of  claim 18 , wherein either R 8  is hydrogen and R 9  is -A-B, or R 8  is -A-B and R 9  is hydrogen. 
     
     
         61 . A method for making a compound of formula 13 
       
         
           
           
               
               
           
         
         wherein 
         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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine, 
       
       comprising contacting a compound of formula 11a 
       
         
           
           
               
               
           
         
       
       with a compound of formula 12 
       
         
           
           
               
               
           
         
         wherein
 R b  is —Cl, —Br, —I, —OMs, —OTs or —OTf, 
 
       
       in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 13. 
     
     
         62 . A method for making a compound of formula 22 
       
         
           
           
               
               
           
         
       
       wherein
 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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine, 
 
       comprising contacting a compound of formula 21 
       
         
           
           
               
               
           
         
         wherein
 R c  is C 1 -C 3  alkyl, 
 
       
       with a compound of formula 20 
       
         
           
           
               
               
           
         
         wherein
 each occurrence of R a  is independently C 1 -C 3  alkyl; and 
 R b  is —Cl, —Br, —I, —OMs, —OTs or —OTf, 
 
       
       in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 22. 
     
     
         63 . A method for making a compound of formula 37 
       
         
           
           
               
               
           
         
         wherein 
         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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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 11  alkyl, —C 2 -C 11  alkenyl, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 11  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine, 
       
       comprising contacting a compound of formula 36 
       
         
           
           
               
               
           
         
         wherein
 R c  is C 1 -C 3  alkyl, 
 
       
       with a compound of formula 11a or a compound of formula 20 
       
         
           
           
               
               
           
         
         wherein
 each occurrence of R a  is independently C 1 -C 3  alkyl; and 
 R b  is —Cl, —Br, —I, —OMs, —OTs or —OTf, 
 
       
       in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 37. 
     
     
         64 . A method for making a compound of formula 40 
       
         
           
           
               
               
           
         
         wherein 
         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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido , -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine, 
       
       comprising contacting a compound of formula 39 
       
         
           
           
               
               
           
         
       
       with a compound of formula 11 or formula 20 
       
         
           
           
               
               
           
         
         wherein
 each occurrence of R a  is independently C 1 -C 3  alkyl; 
 R b  is —Cl, —Br, —I, —OMs, —OTs or —OTf; and 
 R d  is —H or —Br, 
 
       
       in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 40. 
     
     
         65 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       wherein
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , W and R 10  are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5  alkyl), —C 1 -C 10  alkyl, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 11  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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine. 
 
     
     
         66 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       wherein:
 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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido , -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine. 
 
     
     
         67 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       wherein
 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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine. 
 
     
     
         68 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable hydrate or salt thereof, 
       wherein
 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, -alkylhalo, —C 2 -C 10  alkenyl, —C 3 -C 8  carbocycle, -aryl, —NH 2 , -alkylamino, —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, -heterocycle, —C 3 -C 8  carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5  alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5  alkyl), —C(O)O-phenyl or —C(NH)NH 2  any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5  alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —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 an unsubstituted or substituted heterocyclic amine; or N, Z 1  and Z 2  are taken together to form a heterocyclic amine.