PDK-1/Akt signaling inhibitors

Abstract

A new class of phosphoinositide-dependent kinase-1 (PDK-1) inhibitors of formula I: wherein X is selected from the group consisting of alkyl and haloalkyl; Ar is an aryl radical selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl; and wherein Ar is optionally substituted with one or more radicals selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, azido, C 1 -C 4 azidoalkyl, aryl, akylaryl, haloaryl, haloalkylaryl, and combinations thereof; and R is selected from the group consisting of nitrile, acetonitrile, ethylnitrile, propylnitrile, carboxamide, amidine, tetrazole, oxime, hydrazone, acetamidine, aminoacetamide, guanidine, and urea. Also provided are methods of using the compounds for the treatment and prevention of cancer in humans.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
         wherein  
         X is selected from the group consisting of alkyl and haloalkyl;  
         Ar is selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl;  
         R is selected from the group consisting of —CN, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN —CONH 2    
         
           
             
             
                 
                 
             
           
         
         or metabolites or pharmaceutically acceptable salts thereof:  
       
     
     
         2 . The compound of  claim 1  wherein X is C 1  to C 4  haloalkyl.  
     
     
         3 . The compound of  claim 2  wherein X is CF 3 .  
     
     
         4 . The compound of  claim 1 , wherein Ar is substituted at any substitutable position with one or more radicals selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, azido, C 1 -C 4  azidoalkyl, aryl, akylaryl, haloaryl, haloalkylaryl, and combinations thereof.  
     
     
         5 . The compound of  claim 1  wherein Ar is selected from the group consisting of 2-naphthyl, 4-biphenyl, 9-anthryl, 2-fluorenyl, 4-azidophenyl, 4-azidomethylphenyl, 4-(2-azidoethyl)phenyl, 4-(3-azidopropyl)phenyl, 4-(4-azidobutyl)phenyl, 4-(4-azidophenyl)phenyl, 4-(4-azidomethylphenyl)phenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-(2-bromoethyl)phenyl, 4-(3-bromopropyl)phenyl, 4-(4-bromobutyl)phenyl, 4-(trifluoromethyl)phenyl, 4-(4-methylphenyl)phenyl, 4-(4-bromomethylphenyl)phenyl, 4-(4-butylphenyl)phenyl, 4-(4-tert-butylphenyl)phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-(4-chlorophenyl)phenyl, 4-(3,5-dichlorophenyl)phenyl, 4-(2,3-dichlorophenyl)phenyl, 4-(3,5-dimethylphenyl)phenyl, 4-(2,4,5-trichlorophenyl)phenyl, 4-(4-trifluoromethylphenyl)phenyl, 2-phenanthrenyl, 3-indolyl, 2-pyrrolyl, and 4-(benzyl)phenyl.  
     
     
         6 . The compound of  claim 5  wherein Ar is selected from the group consisting of 4-(2-bromoethyl)phenyl, 4-(3-bromopropyl)phenyl, 4-(2-azidoethyl)phenyl; 4-(3-azidopropyl)phenyl, 4-butylphenyl, 4-t-butylphenyl, 2-naphthalenyl, 3-indolyl, 4-biphenylyl, 4′-chloro[1,1′-biphenyl]-4-yl, 3′,5′-dichloro[1,1′-biphenyl]-4-yl, 2′,3′-dichloro[1,1′-biphenyl]-4-yl, 4′-methyl[1,1′-biphenyl]-4-yl, 4′-trifluoromethyl[1,1′-biphenyl]-4-yl, 4′-bromomethyl[1,1′-biphenyl]-4-yl, 3′,5′-dimethyl[1,1′-biphenyl]-4-yl, 4′-butyl[1,1′-biphenyl]-4-yl, 4′-tert-butyl[1,1′-biphenyl]-4-yl, 4-(phenylmethyl)phenyl, 9H-fluoren-2-yl, 9-anthracenyl, 2-phenanthrenyl, 9-phenanthrenyl.  
     
     
         7 . The compound of  claim 6  wherein Ar is 2-phenanthrenyl.  
     
     
         8 . The compound of  claim 1  wherein R is selected from aminoacetamide and guanidine.  
     
     
         9 . The compound of  claim 1  wherein X is CF 3 , Ar is 2-phenanthrenyl, and R is selected from aminoacetamide and guanidine.  
     
     
         10 . A compound of formula 2  
       
         
           
           
               
               
           
         
         X is selected from the group consisting of alkyl and haloalkyl;  
         R is selected from the group consisting of —CN, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN —CONH 2    
         
           
             
             
                 
                 
             
           
         
         or metabolites or pharmaceutically acceptable salts thereof.  
       
     
     
         11 . The compound of  claim 10  wherein X is C 1  to C 4  haloalkyl.  
     
     
         12 . The compound of  claim 11  wherein X is CF 3 .  
     
     
         13 . The compound of  claim 10  wherein R is selected from aminoacetamide and guanidine. or a pharmaceutically acceptable salt thereof.  
     
     
         14 . A compound of formula III:  
       
         
           
           
               
               
           
         
         X is selected from the group consisting of alkyl and haloalkyl;  
         R is selected from the group consisting of —CN, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN —CONH 2    
         
           
             
             
                 
                 
             
           
         
         or metabolites or pharmaceutically acceptable salts thereof.  
       
     
     
         15 . The compound of  claim 14  wherein X is C 1  to C 4  haloalkyl.  
     
     
         16 . The compound of  claim 15  wherein X is CF 3 .  
     
     
         17 . The compound of  claim 14  wherein R is selected from aminoacetamide and guanidine. or a pharmaceutically acceptable salt thereof.  
     
     
         18 . A compound of formula IV:  
       
         
           
           
               
               
           
         
       
       or metabolites or pharmaceutically acceptable salts thereof.  
     
     
         19 . A compound of formula V  
       
         
           
           
               
               
           
         
       
       or metabolites or pharmaceutically acceptable salts thereof.  
     
     
         20 . A method of inducing apoptosis in unwanted rapidly proliferating cells, the method comprising the step of contacting a therapeutically effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
         wherein  
         X is selected from the group consisting of alkyl and haloalkyl;  
         Ar is selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl;  
         R is selected from the group consisting of —CN, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN —CONH 2    
         
           
             
             
                 
                 
             
           
         
         or metabolites or pharmaceutically acceptable salts thereof, with the rapidly proliferating cells.  
       
     
     
         21 . The method of  claim 20 , wherein the rapidly proliferating cells are cancer cells, wherein the cancer cells are selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.  
     
     
         22 . The method of  claim 20  wherein the compound is selected from compounds IV and V  
       
         
           
           
               
               
           
         
       
       or a combination thereof, or metabolites or pharmaceutically acceptable salts thereof.  
     
     
         23 . A method for treating, inhibiting, or delaying the onset of cancer, wherein the cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer, in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of formula I:  
       
         
           
           
               
               
           
         
         wherein  
         X is selected from the group consisting of alkyl and haloalkyl;  
         Ar is selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl;  
         R is selected from the group consisting of —CN, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN —CONH 2    
         
           
             
             
                 
                 
             
           
         
         or metabolites or pharmaceutically acceptable salts thereof, to the subject in need of such treatment.  
       
     
     
         24 . The method of  claim 23  wherein the compound is selected from compounds IV and V  
       
         
           
           
               
               
           
         
       
       or a combination thereof, or metabolites or pharmaceutically acceptable salts thereof.  
     
     
         25 . The method of  claim 23  wherein the subject is a human.  
     
     
         26 . A method for preventing restenosis in a subject that has undergone an angioplasty or stent procedure, the method comprising administering a therapeutically effective amount of a compound of formula I:  
       
         
           
           
               
               
           
         
         wherein  
         X is selected from the group consisting of alkyl and haloalkyl;  
         Ar is selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl;  
         R is selected from the group consisting of —CN, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN —CONH 2    
         
           
             
             
                 
                 
             
           
         
         or metabolites or pharmaceutically acceptable salts thereof, to the subject in need of such treatment.