Iap binding compounds

Abstract

IAP binding molecules and compositions including these are disclosed. The IAP binding molecules interact with IAPs (inhibitor of apoptosis proteins) in cells and may be used to modify apoptosis in cells treated with such molecules. Embodiments of these compounds have a K d of less that 0.1 micromolar. Methods of using these IAP binding molecules for therapeutic, diagnostic, and assay purposes are also disclosed.

1 - 7 . (canceled) 
     
     
         8 . The compound of  claim 26  or a pharmaceutically
 acceptable salt thereof that has a K d  for IAP of less than about 1 micromolar. 
 
     
     
         9 . The compound of  claim 26  or a pharmaceutically
 acceptable salt thereof where A 1  is H, methyl, or ethyl. 
 
     
     
         10 . The compound of  claim 26  or a pharmaceutically
 acceptable salt thereof where R 1a  is H; R 1b  is methyl or ethyl. 
 
     
     
         11 . The compound of  claim 26  or a pharmaceutically acceptable salt thereof where Y is an alkyl group of 1 to 10 carbon atoms, a branched alkyl group of 1 to 10 carbon atoms, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, hydroxy substituted versions of these groups. 
     
     
         12 . The compound of  claim 26  or a pharmaceutically acceptable salt thereof where Z 1a  and Z 1b  are independently an H, hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, or heteroaryloxy. 
     
     
         13 . The compound of  claim 26  or a pharmaceutically
 acceptable salt thereof where M is an alkyl or an alkylene of 1 to 5 carbon atoms. 
 
     
     
         14 . The compound of  claim 26  or a pharmaceutically
 acceptable salt thereof where R 10  is: 
 
       
         
           
           
               
               
           
         
         and R 3 , R′ 3 , R 4 , R 5 , R′ 5 , are each independently H, alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkoxy optionally substituted alkyl, cycloalkyl, alkylene, aryl, heteroaryl, halo, cyano, —(CH 2 ) p C(═O)OH, —(CH 2 ) p C(═O)O-alkyl, or —(CH 2 ) p C (═O)NH 2  and where p is independently the integer 0, 1, 2, or 3. 
       
     
     
         15 . The compound of  claim 26  or a pharmaceutically acceptable salt thereof where R 10  is anyone of structures (4a), (4b), (4c) or (4d): 
       
         
           
           
               
               
           
         
       
       where X 2  is a heteroatom and independently groups R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is H, halogen, alkyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups. 
     
     
         16 . The compound of  claim 26  or a pharmaceutically
 acceptable salt thereof where R 10  has the structure of formula (4a): 
 
       
         
           
           
               
               
           
         
       
       where X 2  is a heteroatom and independently groups R 11 , R 12 , or any of R 14-17  is H, or optional substituents including halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy independently R 11 , R 12 , or any of R 14-17  are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , R 12 , or any of R 14-17  are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups. 
     
     
         17 . The compound of  claim 26  or a pharmaceutically
 acceptable salt thereof that has a K d  for IAP of less than about 0.1 micromolar. 
 
     
     
         18 . (canceled) 
     
     
         19 . A method of treating cells comprising:
 administering to cells that have a proliferation disorder, an amount of the IAP binding compound of  claim 26  or a pharmaceutically acceptable salt thereof that reduces the cellular proliferation disorder in the sample of cells.   
     
     
         20 . The method of  claim 19  where the IAP binding compound or
 pharmaceutically acceptable salt thereof has an EC 50  of less than about 1 micromolar. 
 
     
     
         21 . The method of  claim 19  where the IAP binding compound or
 pharmaceutically acceptable salt thereof has an EC 50  of less than about 0.06 micromolar. 
 
     
     
         22 . The method of  claim 21  where the compound or pharmaceutically
 acceptable salt thereof has a K d  for IAP of less that about 0.1 micromolar. 
 
     
     
         23 . A compound of formula (2): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
         wherein: A 1  and A 2  are independently hydrogen, alkyl, aryl, or alkylaryl, R 1a  is H or a methyl; R 1b  is an alkyl or aryl; X 1  is —O—, —S—, —CH 2 —, or —NH—, and J is —CH—, or —N—, provided that when J is —N—, X 1  is —CH 2 —, or —NH—; Y is H, or an alkyl; Z is —OH, aryloxy, alkoxy, benzyloxy, benzyloxy, amino, arylamino, alkylamino, benzylamino; R 2  is a detectable label or is: 
       
       
         
           
           
               
               
           
         
         M is alkylene, alkenylene, alkynlene, heteroalkylene, heteroalkenylene, or heteroalkynlene, 
         G is selected from a bond, —O—; —N(R 2d )— where R 2d  is H, alkyl, cycloalkyl, or aryl; or —S(O) m — where m is 0, 1, or 2; 
         R 10  is cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl; and n is independently the integer 0, 1, 2, 3, 4, or 5. 
       
     
     
         24 . A compound of formula (3): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
         where A 1  is H, lower alkyl, or optionally-substituted lower alkyl; R 1a  and R 1b  are separately H, lower alkyl, optionally-substituted lower alkyl, lower alkylene, optionally substituted lower alkylene; or A 1  together with either R 1a  or R 1b  form an optionally substituted heterocycloalkyl of 3 to 6 atoms; 
         Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, hydroxy substituted versions of these groups, or Y together with Z, M, G, or R 10  forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Y is linked to Z, M, G, or R 10 ; 
         Z is H, alkyl, hydroxy, amino, alkylamino, diakylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy, or heteroaryloxy; or Z together with Y, M, G, or R 10  form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Z is linked to Y, M, G, or R 10 ; 
         M is an optionally-substituted alkyl, alkenyl, or alkynyl; an optionally-substituted alkyl, alkenyl, or alkynyl of 1 to 5 carbon atoms; an optionally-substituted alkylene, alkenylene, or alkynylene; or an optionally-substituted alkylene, alkenylene, or alkynylene of 1 to 5 carbon atoms; 
         G is a bond, a heteroatom, —(C═O)—; —S(O) t — where t=0, 1, or 2; —NR 18 —; —NCOR 18 —; or —NS(O) x R 18 — where x=0, 1, or 2, and R 18  is lower alkyl, optionally-substituted lower alkyl, or cycloalkyl or R 18  is contained within a carbocyclic, or heterocyclic ring containing 1 to 5 heteroatoms, where R 18  is linked to Z, M, or R 10 ; and 
         R 10  is an aryl, a heteroaryl, a fused aryl, a fused heteroaryl; or R 10  is any one of structures (4a), (4b), (4c) or (4d): 
       
       
         
           
           
               
               
           
         
         where X 2  is a heteroatom and independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is H, optionally-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; or independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z, M, G, R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17 . 
       
     
     
         25 . The compound of  claim 24 :
 or a pharmaceutically acceptable salt thereof   where A 1  is H, lower alkyl, or optionally-substituted lower alkyl; R 1a  and R 1b  are separately H, lower alkyl, optionally-substituted lower alkyl, lower alkylene, optionally substituted lower alkylene; or A 1  together with either R 1a  or R 1b  form an optionally substituted heterocycloalkyl of 3 to 6 atoms;   Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, hydroxy substituted versions of these groups, or Y together with Z, M, G, or R 10  forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Y is linked to Z, M, G, or R 10 ;   Z is H, alkyl, hydroxy, amino, alkylamino, diakylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy, or heteroaryloxy; or Z together with Y, M, G, or R 10  form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Z is linked to Y, M, G, or R 10 ;   M is an optionally-substituted alkyl, alkenyl, or alkynyl; an optionally-substituted alkyl, alkenyl, or alkynyl of 1 to 5 carbon atoms; an optionally-substituted alkylene, alkenylene, or alkynylene; or an optionally-substituted alkylene, alkenylene, or alkynylene of 1 to 5 carbon atoms;   G is a bond, a heteroatom, —(C═O)—; —S(O) t — where t=0, 1, or 2; —NR 18 —; —NCOR 18 —; or —NS(O) x R 18 — where x=0, 1, or 2, and Rig is lower alkyl, optionally-substituted lower alkyl, or cycloalkyl or Rig is contained within a carbocyclic, or heterocyclic ring containing 1 to 5 heteroatoms, where R 18  is linked to Z, M, or R 10 ; and   R 10  is any one of structures (4a), (4b), (4c) or (4d):   
       
         
           
           
               
               
           
         
         where X 2  is a heteroatom and independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is H, optionally-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; or independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z, M, G, R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17 . 
       
     
     
         26 . A compound of formula (5) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
         where A 1  is H, or lower alkyl, or A 1  and R 1b  together form a ring of 3-5 atoms; 
         R 1a  is H; R 1b  is lower alkyl, or together with A 1  forms a ring of 3 to 5 atoms; 
         Y is an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, hydroxy substituted versions of these groups, or Y together with Z 1a , Z 1b , or R 10  forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Y is linked to Z 1a , Z 1b , or R 10 ; 
         Z 1a  and Z 1b  are independently an H, hydroxy, amino, alkylamino, diakylamino, alkoxy, aryloxy, or heteroaryloxy; or Z 1a , Z 1b , together with Y or R 10  form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Z 1a  or Z 1b , is linked to Y or R 10 ; 
         M is an optionally-substituted alkyl or an optionally-substituted alkylene of 1 to 5 carbon atoms; 
         G is a bond, a heteroatom, —(C═O)—; —NR 18 —; —NCOR 18 —; or —NS(O) x R 18 — where x=0, 1, or 2, and R 18  is lower alkyl, optionally-substituted lower alkyl; and 
         R 10  is aryl, a heteroaryl, or R 10  is anyone of structures (4a), (4b), (4c) or (4d): 
       
       
         
           
           
               
               
           
         
         where X 2  is a heteroatom and independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z 1a , Z 1b , M, G, R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17 . 
       
     
     
         27 . The Compound of  claim 26   or a pharmaceutically acceptable salt thereof   where A 1  is H, or lower alkyl;   R 1a  is H; R 1b  is lower alkyl;   Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, hydroxy substituted versions of these groups;   Z 1a  and Z 1b  are independently an H, hydroxy, alkoxy, aryloxy, or heteroaryloxy;   M is an optionally-substituted alkyl or an optionally-substituted alkylene of 1 to 5 carbon atoms;   G is a bond, a heteroatom, or —NCOR 18 — and R 18  is lower alkyl, optionally-substituted lower alkyl; and   R 10  is anyone of structures (4a), (4b), (4c) or (4d):   
       
         
           
           
               
               
           
         
         where X 2  is a heteroatom and independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z 1a , Z 1b , M, G, R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17 . 
       
     
     
         28 . The compound of  claim 26   or a pharmaceutically acceptable salt thereof   where A 1  is H, or methyl;   R 1a  is H; R 1b  is methyl or ethyl;   Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, or hydroxy substituted versions of these groups;   Z 1a  and Z 1b  are independently an H, hydroxy, or alkoxy;   M is a methyl;   G is a bond; and   R 10  is aryl, a heteroaryl, or R 10  is any one of structures (4a) or (4b):   
       
         
           
           
               
               
           
         
         where X 2  is a heteroatom and independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17  are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z 1a , Z 1b , M, G, R 11 , R′ 11 , R 12 , any of R 13-17 , or any of R 14-17 . 
       
     
     
         29 . The compound of  claim 28  or a
 pharmaceutically acceptable salt thereof, in which R 10  is: 
 
       
         
           
           
               
               
           
         
       
     
     
         30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising a compound of  claim 24 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         32 . The pharmaceutical composition of  claim 31  comprising a compound of  claim 25 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         33 . A pharmaceutical composition comprising a compound of  claim 26 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         34 . The pharmaceutical composition of  claim 33  comprising a compound of  claim 27 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         35 . The pharmaceutical composition of  claim 33  comprising a compound of  claim 28 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         36 . The pharmaceutical composition of  claim 33  comprising a compound of  claim 29 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.