Inhibitors of iap

Abstract

The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds have the general formula (I): wherein Q, X 1 , X 2 , Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 2 , R 3 , R 3′ , R4, R 4′ , R 5 , R 6 , R 6′ , and n are as described herein.

1 - 19 . (canceled) 
     
     
         20 . A method for treating a disease or condition associated with the overexpression of an IAP in a mammal, comprising administering to said mammal an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 X 1  and X 2  are each independently O or S; 
 Y is a bond, (CR 7 R 7 ) n , O or S; 
 Z 1  is NR 8 , O, S, SO or SO 2 ; 
 Z 2 , Z 3  and Z 4  are independently CQ or N; 
 Q is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a carbocycle, a heterocycle; wherein one or more CH S , or CH groups of an alkyl is optionally replaced with —O—, —S—, —SO—, —S(O) 2 , —N(R 8 )—, —C(O)—, —C(O)—NR 8 —, —NR 8 —C(O)—, —SO 2 —NR 8 —, —NR 8 —SO 2 , —NR 8 —C(O)—NR 8 —, —NR 8 —C(NH)—NR 8 —, —NR 8 —C(NH)—, —C(O)—O— or —O—C(O)—; and an alkyl, carbocycle and heterocycle is optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heterocycle; 
 R 1  is H, OH or alkyl; or R 1  and R 2  together form a 5-8 member heterocycle; 
 R 2  is alkyl a carbocycle carbocyclylalkyl a heterocycle or heterocyclylalkyl each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, acyl, alkoxy, alkylthio, sulfonyl, amino and nitro, wherein said alkyl, acyl, alkoxy, alkylthio and sulfonyl are optionally substituted with hydroxy, mercapto, halogen, amino, alkoxy, hydroxyalkoxy and alkoxyalkoxy; 
 R 3  is H or alkyl optionally substituted with halogen or hydroxyl; or R 3  and R 4  to ether form a 3-6 heterocycle; 
 R 3 ′ is H, or R 3  and R 3 ′ together form a 3-6 carbocycle; 
 R 4  and R 4 ′ are independently H, hydroxyl, amino, alkyl, carbocycle, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy or heterocycloalkyloxycarbonyl; wherein each alkyl, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy and heterocycloalkyloxycarbonyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino and nitro; or R 4  and R 4 ′ to ether form a heterocycle; 
 R 5  is H or alkyl; 
 R 6  and R 6 ′ are each independently H, alkyl, aryl or aralkyl; 
 R 7  is H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle a heterocycle or —U—V; wherein U is —O—, —S—, —S(O)S O—N(R 8 )—, —C(O)—, —C(O)—NR 8 —, —NR 8 —C(O)—, —NR 8 —SO 2 —, —NR 8 —C(O)—NR 8 —, —NR 8 —C(NH)—NR 8 —, —NR R —C(NH)—, —C(O)—O— or —O—C(O)— and V is alkyl, a carbocycle or a heterocycle; and wherein one or more CH 2  or CH groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, S(O) 7 , —N(R 8 )—, —C(O)—, —C(O)—NR 8 —, —NR 8 —C(O)—NR 8 —, —C(O)—O— or —O—C(O)—; and an alkyl, carbocycle and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heterocycle; 
 R 8  is H, alkyl, a carbocycle or a heterocycle wherein one or more CH, or CH groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—, S(O) 7 , —N(R 8 ), or —C(O)—; and said alkyl, carbocycle and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heterocycle; and 
 n is 0 to 4. 
 
       
     
     
         21 . A method for treating cancer, comprising administering to said mammal an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 X 1  and X 2  are each independently O or S; 
 Y is a bond, (CR 2 R 7 ) n , O or S; 
 Z 1  is NR 8 , O, S, SO or SO 2 ; 
 Z 2 , Z 3  and Z 4  are independently CO or N; 
 Q is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a carbocycle, a heterocycle; wherein one or more CH 2  or CH groups of an alkyl is optionally replaced with —O—, —S—, S(O) 2 , —N(R 8 )—, —C(O)—, —C(O)—NR 8 —, —NR 8 —C(O)—, —SO 2 —NR 8 —, —NR 8 —C(O)—NR 8 —, —NR 8 —C(NH)—NR 8 —, —NR 8 —C(NH)—, —C(O)—O— or —O—C(O)—; and an alkyl, carbocycle and heterocycle is optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heterocycle; 
 R 1  is H, OH or alkyl; or R 1  and R 2  together form a 5-8 member heterocycle; 
 R 2  is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle or heterocyclylalkyl each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, acyl, alkoxy, alkylthio, sulfonyl, amino and nitro, wherein said alkyl, acyl, alkoxy, alkylthio and sulfonyl are optionally substituted with hydroxy, mercapto, halogen, amino, alkoxy, hydroxyalkoxy and alkoxyalkoxy; 
 R 3  is H or alkyl optionally substituted with halogen or hydroxyl; or R 3  and R 4  together form a 3-6 heterocycle; 
 R 3 ′ is H, or R 3  and R 3 ′ together form a 3-6 carbocycle; 
 R 4  and R 4 ′ are independently H, hydroxyl, amino, alkyl, carbocycle, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy or heterocycloalkyloxycarbonyl; wherein each alkyl, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy and heterocycloalkyloxycarbonyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino and nitro; or R 4  and R 4 ′ together form a heterocycle; 
 R 5  is H or alkyl; 
 R 6 , and R 6 ′ are each independently H, alkyl, aryl or aralkyl; 
 R 7  is H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle a heterocycle or —U—V; wherein U is —O—, —S—, —S(O)—, S(O) 2 —, —N(R 8 )—, —C(O)—, —C(O)—NR 8 —, —NR 8 —C(O)—, —SO 2 —NR 8 —, —NR 8 —SO 2 —, —NR 8 —C(O)—NR 8 —, —NR 8 —C(NH)—, —NR 8 —C(NH)—, —C(O)—O— or —O—C(O)— and V is alkyl, a carbocycle or a heterocycle; and wherein one or more CH 2  or CH groups of an alkyl is optionally replaced —S—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —C(O)—, —C(O)—NR 8 —, —NR 8 —C(O)—, —SO 2 —NR 8 —, —NR 8 SO 2 , —NR 8 —C(O)—NR 8 —, —C(O)—O— or —O—C(O)—; and an alkyl, carbocycle and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heterocycle; 
 R 8  is H, alkyl, a carbocycle or a heterocycle wherein one or more CH 2  or CH groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—, S(O) 2 , —N(R 8 ), or —C(O)—; and said alkyl, carbocycle and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heterocycle; and 
 
         n is 0 to 4.