IAP Inhibitors

Abstract

Smac mimetics that inhibit IAPs.

1 . The compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         Z 1  and Z 2  are each independently CH or N; 
         R 1  is H or optionally substituted hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 
         R 2  and R 2 ′ are each independently H or optionally substituted alkyl, cycloalkyl, or heterocycloalkyl; or when R 2 ′ is H then R 2  and R 1  can together form an aziridine or azetidine ring; 
         R 3  and R 4  are each independently H or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or, R 3  and R 4  are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O; 
         R 5  and R 6  are each independently H or optionally substituted hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R 5  and R 6  are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O; 
         M is a bond or an optionally substituted alkylene group of 1 to 5 carbon atoms; 
         G is a bond, a heteroatom, —(C═O)—, —S(O) n —, —NR 8 —, —NCOR 8 —, or —NS(O) n R 8 —, where R 8  is lower alkyl, optionally-substituted lower alkyl or C 3-8  cycloalkyl; 
         R 7  is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein R 7  is substituted with -L1-R 10  and is optionally further substituted; 
         L1 is a covalent bond or optionally substituted C 1-6  alkylene; 
         R 10  is an optionally substituted 5-, 6-, or 7-membered heterocycloalkyl with at least one N or O atom in the ring or R 10  is heteroaryl with at least one N atom in the ring; 
         each n can be the same or different and is 0, 1, or 2; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 - 16 . (canceled) 
     
     
         17 . A compound of  claim 1  having Formula IV: 
       
         
           
           
               
               
           
         
         wherein 
         Z 1 a, Z 2 a, Z 1 b, and Z 2 b are independently CH or N; 
         R 1 a and R 1 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and when R 2 a′ is H then R 2 a and R 1 a can together form an aziridine or azetidine ring and when R 2 b′ is H then R 2 b and R 1 b can together form an aziridine or azetidine ring; 
         R 2 a, R 2 a′, and R 2 b and R 2 b′ are independently H or optionally substituted alkyl, cycloalkyl, or heterocycloalkyl; or when R 2 a′ is H then R 2 a and R 1 a can together form an aziridine or azetidine ring and when R 2 b′ is H then R 2 b and R 1 b can together form an aziridine or azetidine ring; 
         R 3 a, R 3 b, R 4 a and R 4 b are independently H or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or, R 4 a and R 3 a, or R 4 b and R 3 b, or both, are carbon atoms linked by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O; 
         R 5 a, R 6 a, R 5 b, and R 6 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R 5 a and R 6 a or R 5 b and R 6 b, or both, are carbon atoms linked by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O; 
         n can be the same or different in each usage and is 0, 1, or 2; 
         Xa is —O—, —N(La—R 10 a)-, —S—, optionally-substituted —C(La—R 10 a)=CH—, —C(O)—O—, —C(O)—N(La—R 10 a)-, —N═C(La—R 10 a)-; 
         Xb is —O—, —N(Lb-R 10 b)-, —S—, optionally-substituted —C(Lb-R 10 b)=CH—, —C(O)—O—, —C(O)—N(Lb-R 10 b)-, —N═C(Lb-R 10 b)-, provided that if Xb is —O—, —S—, or —C(O)—O—, then Xa is —N(La—R 10 a)-, optionally-substituted —C(La—R 10 a)=CH—, —C(O)—N(La—R 10 a)-, or —N═C(La—R 10 a)-, and if Xa is —O—, —S—, or —C(O)—O—, then Xb is —N(Lb-R 10 b)-, optionally-substituted —C(Lb-R 10 b)=CH—, —C(O)—N(Lb-R 10 b)-, or —N═C(Lb-R 10 b)-; 
         La and Lb are independently a covalent bond or C 1 -C 4  alkylene; 
         R 10 a and R 10 b are independently an optionally substituted 5-, 6-, or 7-membered heterocycloalkyl with at least one N or O atom in the ring or heteroaryl with at least one N atom in the ring provided that one but not both of R 10 a and R 10 b can be —H or absent; 
         Wa and Wb are together a Linker. 
       
     
     
         18 - 37 . (canceled) 
     
     
         38 . A method of treating a disease associated with the overexpression of IAP in an individual comprising administering to said individual an effective amount of a compound of  claim 1 . 
     
     
         39 . A method of treating cancer comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         40 . A pharmaceutical composition comprising: a compound selected from a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         41 . The composition of  claim 40  further comprising a second chemotherapeutic agent. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled)