Methods of treatment using pyridinonyl pdk1 inhibitors

Abstract

The present invention provides pyridinonyl PDK1 inhibitors and methods of treating cancer using the same.

1 - 46 . (canceled) 
     
     
         47 . A compound selected from Table 2 or a pharmaceutically acceptable salt thereof. 
     
     
         48 . A pharmaceutical formulation comprising a compound of  claim 47 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         49 . A method for decreasing PDK1 catalytic activity, the method comprising:
 contacting a PDK1 with an effective amount of a compound of  claim 47 , or a pharmaceutically acceptable salt thereof.   
     
     
         50 . A method for selectively reducing PDK1-mediated phosphorylation of Akt relative to PDK1-mediated phosphorylation of PKC in a cell, the method comprising:
 contacting the cell with an effective amount of a compound of  claim 47 , or a pharmaceutically acceptable salt thereof.   
     
     
         51 . A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 47 , or a pharmaceutically acceptable salt thereof. 
     
     
         52 . A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of  claim 48 . 
     
     
         53 . A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         n is an integer from 2 to 3; 
         L 1  and L 2  are independently absent, —O—, —NH—, —S—, —S(O)—, S(O) 2 —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; 
         X is absent, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, 
         wherein if X is substituted or unsubstituted phenylene and L 1  is absent, then R 1  is not substituted or unsubstituted pyridinyl, substituted or unsubstituted benzo-oxazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted quinazolinyl, and 
         wherein if X is substituted or unsubstituted phenylene, then R 1  is not substituted or unsubstituted cyclohexyl; 
         R 1  is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, 
         wherein if R 1  is substituted or unsubstituted phenyl and X absent, then L 1  is not absent, and wherein if R 1  is substituted or unsubstituted phenyl, then X is not substituted or unsubstituted pyridinonyl, or substituted or unsubstituted imidazolyl; 
         each R 2  is halogen; 
         R 4 , R 5 , and R 6  are hydrogen; 
         R 7 , and R 8  are independently hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 3  is hydrogen, —OH, —CF 3 , —OR 10 , —C(O)R 12 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 3  is optionally attached to X thereby forming a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         each instance of R 10  is independently —C(O)R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         each instance of R 12  and R 15  is independently hydrogen, —NR 19 R 20 , —OR 21 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         each instance of R 13  is independently hydrogen, —C(O)R 15 , —S(O) 2 R 16 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         each instance of R 14 , R 19 , R 20  and R 21  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         each instance of R 16  is independently hydrogen, —NR 19 R 20 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.