Iap binding compounds

Abstract

Compounds that bind cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The compounds are mimetics of the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABOLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these compounds for therapeutic, diagnostic and assay purposes.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is methyl, ethyl, n-propyl, isopropyl, or ethenyl; 
 R 1a  is H or methyl; 
 X is —O—, —S—, CH 2 —, or —NH—, and J is —CH— or —N—, provided that when J is —N—, X is —CH 2 — or —NH—; 
 Y is H, methyl, ethyl, n-propyl, or isopropyl; 
 R 2  is: 
 
       
       
         
           
           
               
               
           
         
         
           R 2a  is aryl, cycloalkyl optionally substituted aralkyl, or cycloalkylalkyl; 
           R 2b  is H or alkyl; 
           M is: 
         
       
       
         
           
           
               
               
           
         
         
           Ar is: 
         
       
       
         
           
           
               
               
           
         
         
           R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each independently H, methyl, ethyl, n-propyl, isopropyl halo, cyano, —(CH 2 ) p —C(═O)OH, —(CH 2 ) p —C(═O)O-alkyl, —(CH 2 ) p —C(═O)NH 2 ; 
           n and p are each independently the integer 0, 1, 2, or 3, and the sum of (n+p) is the integer 2 or 3; 
           provided that at least one of R 3 , R 4 , and R 5 , or at least two of R 6 , R 7 , R 8 , and R 9  are each independently H, methyl, ethyl, n-propyl, isopropyl, halo, or cyano; 
           provided that when one or more of R 3  and R 5  is isopropyl, R 4  is other than isopropyl; 
           provided that when R 4  is isopropyl, R 3  and R 5  are each independently other than isopropyl; 
           provided that when R 8  is isopropyl, R 9  is other than isopropyl; and 
           provided that when R 1a  is H, X is —NH—, J is —CH—, Y is H, methyl or isopropyl, and R 2  is: 
         
       
       
         
           
           
               
               
           
         
         
           R 1  is ethenyl; 
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1 , of formula L wherein R 1  is methyl. 
     
     
         3 . A compound according to  claim 1 , of formula I, wherein R 1a  is H. 
     
     
         4 . A compound according to  claim 1 , of formula L wherein Y is H, methyl, or isopropyl. 
     
     
         5 . A compound according to  claim 4 , of formula I, wherein Y is isopropyl. 
     
     
         6 . A compound according to  claim 1 , of formula I, wherein Ar is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound according to  claim 6 , of formula L, wherein one of R 3 , R 4 , and R 5  is —(CH 2 ) p —C(═O)OH, —CH 2 ) p —C(═O)O-alkyl, —(CH 2 ) p —C(═O)NH 2 . 
     
     
         8 . A compound according to  claim 7 , of formula I, wherein p is the integer 0. 
     
     
         9 . A compound according to  claim 7 , of formula I, wherein one of R 3 , R 4 , and R 5  is —(CH 2 ) p —C(═O)OH or —(CH 2 ) p —C(═O)O-alkyl. 
     
     
         10 . A compound according to  claim 9 , of formula L wherein p is the integer 0. 
     
     
         11 . A compound according to  claim 9 , of formula I, wherein one of R 3 , R 4 , and R 5  is —(CH 2 ) p —C(═O)OH. 
     
     
         12 . A compound according to  claim 11 , of formula L wherein p is the integer 0. 
     
     
         13 . A compound according to  claim 1 , of formula L wherein the sum of (n+p) is the integer 2. 
     
     
         14 . A compound according to  claim 1 , of formula I, wherein M is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound according to  claim 1 , of formula I, wherein Ar is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound according to  claim 1  of formula I wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound according to  claim 16 , of formula I, wherein R 2a  is optionally substituted aralkyl. 
     
     
         18 . A compound according to  claim 16 , of formula L wherein R 2a  is phenyl, cyclohexyl, alpha-naphthylmethyl, beta-naphthylmethyl, benzyl, phenylethyl, or cyclohexylmethyl. 
     
     
         19 . A compound according to  claim 17 , of formula L wherein R 2a  is optionally substituted benzyl. 
     
     
         20 . A compound according to  claim 19 , of formula I, wherein said benzyl is substituted with one or more alkyl, halo, aryl, carboxy, alkoxycarbonyl, or aroyl, or combinations thereof. 
     
     
         21 - 43 . (canceled) 
     
     
         44 . A pharmaceutical composition comprising the compound of  claim 1 . 
     
     
         45 . (canceled) 
     
     
         46 . A diagnostic or assay agent comprising a detectable form of the compound of  claim 1 . 
     
     
         47 . (canceled)