Pyrrolidine 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 A, Q, X<SUB>1</SUB>, X<SUB>2</SUB>, Y, R<SUB>1</SUB>, R<SUB>2</SUB>, R<SUB>3</SUB>, R<SUB>4</SUB>, R<SUB>4</SUB>', R<SUB>5</SUB>, R<SUB>6</SUB>' and R<SUB>6</SUB>' are as described herein.

1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 A is a 5-member aromatic heterocycle incorporating 1 to 4 heteroartoms N, O or S and is optionally substituted with one or more R 7  and R 8  groups;  
 Q is H, 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)—, 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, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heterocycle;  
 X 1  and X 2  are each independently O or S;  
 Y is a bond, (CR 7 R 7 ) n , O or S; wherein n is 1 or 2 and R 7  is H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamino, alkoxy, aryloxy or aralkyloxy;  
 R 1  is H or R 1  and R 2  together form a 5-8 member ring;  
 R 2  is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle or heterocyclylalkyl each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, sulfonyl, amino and nitro;  
 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  in each instance is independently 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 —, —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 with —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 —, —NR 8 —C(NH)—, —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 salts and solvates thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein ring A has the general formula II or II′:  
       
         
           
           
               
               
           
         
         wherein Z, is NR 8 , O or S; and Z 2 , Z 3  and Z 4  are each independently N or CR 7 ;  
         wherein R 8  is H, alkyl or acyl; and R 7  is H, halogen, amino, hydroxyl, carboxyl, alkyl, haloalkyl or aralkyl.  
       
     
     
         3 . The compound of  claim 1 , wherein ring A and Q together are selected from the group consisting of IIa-IIz:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 8  is H, alkyl or acyl; and R 7  is H, halogen, amino, hydroxyl, carboxyl, alkyl, haloalkyl or aralkyl.  
       
     
     
         4 . The compound of  claim 1 , wherein Q is a carbocycle or heterocycle optionally substituted with halogen, amino, oxo, alkyl, a carbocycle or a heterocycle; wherein one or more CH 2  or CH groups of an alkyl is optionally replaced with —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 —, —NR 8 —C(NH)—, —C(O)—O— or —O—C(O)—; and wherein said alkyl, carbocycle or heterocycle is optionally substituted with halogen, amino, hydroxyl, mercapto, carboxyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, alkylthio, acyloxy, acyloxyalkoxy, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinyl, and alkylsulfinylalkyl.  
     
     
         5 . The compound of  claim 1 , wherein Q is a carbocycle or heterocycle selected from the group consisting of IIIa-IIIs:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein n is 1-4; T is O, S, NR 8  or CR 7 R 7 ; and W is O, NR 8  or CR 7 R 7 .  
       
     
     
         6 . The compound of  claim 1 , wherein R 1  is H.  
     
     
         7 . The compound of  claim 1 , wherein R 2  is alkyl, cycloalkyl or a heterocycle.  
     
     
         8 . The compound of  claim 1 , wherein R 2  is is selected from the group consisting of t-butyl, isopropyl, cyclohexyl, tetrahydropyran-4-yl, N-methylsulfonylpiperidin-4-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl (in which the S is in oxidized form SO or SO 2 ), cyclohexan-4-one, 4-hydroxycyclohexane, 4-hydroxy-4-methylcyclohexane, 1-methyl-tetrahydropyran-4-yl, 2-hydroxyprop-2-yl, but-2-yl, phenyl and 1-hydoxyeth-1-yl.  
     
     
         9 . The compound of  claim 1 , wherein R 3  is methyl.  
     
     
         10 . The compound of  claim 1 , wherein R 4  is H or methyl, and R 4 ′ is H.  
     
     
         11 . The compound of  claim 1 , wherein R 5  is H or methyl.  
     
     
         12 . The compound of  claim 1 , wherein R 6  and R 6 ′ are independently H or methyl.  
     
     
         13 . The compound of  claim 1 , wherein X 1  and X 2  are independently O.  
     
     
         14 . The compound of  claim 2 , wherein R 1  is H; R 2  is isopropyl, t-butyl, cyclohexyl or pyran; R 3  is methyl; R 4  is H or methyl, R 4 ′ is H; R 5  is H or methyl; and X 1  and X 2  are both O.  
     
     
         15 . A method of inducing apoptosis in a cell comprising introducing into said cell a compound of  claim 1 .  
     
     
         16 . A method of sensitizing a cell to an apoptotic signal comprising introducing into said cell a compound of  claim 1 .  
     
     
         17 . The method of  claim 16 , wherein said apoptotic signal is induced by contacting said cell with a compound selected from the group consisting of cytarabine, fludarabine, 5-fluoro-2′-deoxyuiridine, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, colcemid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, taxotere and mitomycin C or radiation.  
     
     
         18 . The method of  claim 16 , wherein said apoptotic signal is induced by contacting said cell with Apo2L/TRAIL.  
     
     
         19 . A method for inhibiting the binding of an IAP protein to a caspase protein comprising contacting said IAP protein with a compound of  claim 1 .  
     
     
         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  claim 1 .  
     
     
         21 . A method for treating cancer, comprising administering to said mammal an effective amount of a compound of  claim 1.