Inhibitors of iap

Abstract

Novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies and have the general formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described herein.

1 .- 22 . (canceled) 
     
     
         23 . A method for inhibiting the binding of an IAP protein to a caspase protein comprising a combination therapy of contacting said IAP protein with a compound according to formula I and applying a further therapy to the IAP protein: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . A method for treating a disease or condition associated with the overexpression of an IAP in a mammal, comprising a combination therapy of administering to said mammal an effective amount of a compound according to formula I and applying a further therapy to said mammal: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . A method of inducing apoptosis in a cell comprising a combination therapy of introducing into said cell a compound according to formula I and applying a further therapy to said cell: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . A method of sensitizing a cell to an apoptotic signal comprising a combination therapy of introducing into said cell a compound according to formula I and applying a further therapy to said cell: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . A method for treating cancer, comprising a combination therapy of administering to said mammal an effective amount of a compound according to formula I and applying a further therapy to said mammal: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The method according to  claim 23 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
         29 . The method according to  claim 23 , wherein R 1  is cyclohexyl. 
     
     
         30 . The method according to  claim 23 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method according to  claim 24 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method according to  claim 25 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method according to  claim 26 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method according to  claim 27 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method according to  claim 24 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
         36 . The method according to  claim 24 , wherein R 1  is cyclohexyl. 
     
     
         37 . The method according to  claim 25 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
         38 . The method according to  claim 25 , wherein R 1  is cyclohexyl. 
     
     
         39 . The method according to  claim 26 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
         40 . The method according to  claim 26 , wherein R 1  is cyclohexyl. 
     
     
         41 . The method according to  claim 27 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
         42 . The method according to  claim 27 , wherein R 1  is cyclohexyl. 
     
     
         43 . The method according to  claim 23 , wherein said further therapy is radiation therapy. 
     
     
         44 . The method according to  claim 24 , wherein said further therapy is radiation therapy. 
     
     
         45 . The method according to  claim 25 , wherein said further therapy is radiation therapy. 
     
     
         46 . The method according to  claim 26 , wherein said further therapy is radiation therapy. 
     
     
         47 . The method according to  claim 27 , wherein said further therapy is radiation therapy. 
     
     
         48 . The method according to  claim 23 , wherein said further therapy is contacting the IAP protein with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
         49 . The method according to  claim 24 , wherein said further therapy is administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
         50 . The method according to  claim 25 , wherein said further therapy is contacting the cell with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
         51 . The method according to  claim 26 , wherein said further therapy is contacting the cell with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
         52 . The method according to  claim 27 , wherein said further therapy is administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes.