Inhibitors of glucocorticoid receptor

Abstract

The present invention relates generally to compositions and methods for treating cancer and hypercortisolism. Provided herein are substituted steroidal derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of glucocorticoid receptors. Furthermore, the subject compounds and compositions are useful for the treatment of cancer.

1 .- 55 . (canceled) 
     
     
         56 . A method for treating a hypercortisolism disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 ring A is heteroaryl, aryl, cycloalkyl, or heterocyclyl; 
 R 1  is —NR 4a R 5a ; 
 each R 2  is independently —NR 4 R 5 , optionally substituted alkylNR 4 R 5 , halo, —OR 6 , —OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, —C(O)R 6 , —C(O)OR 6 , —C(O)NR 4 R 5 , —OC(O)OR 6 , —OC(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , —S(O) 2 R 7 , —S(O)R 7 , —SR 7 , —NR 4 S(O) 2 NR 4 R 5 , —CN, —CO 2 H, or —NO 2 ; 
 or R 1  and R 2  on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heterocycle; 
 R 3  is optionally substituted C 2-8  alkyl, halo, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, —Si(R 6 ) 3 , —OR 6 , or —S(O) 2 R 7 ; 
 R 4a  is C 2-8  alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —S(O) 2 R 7 , —C(O)N(R 13 ) 2 , —C(O)R 6 , or —C(O)OR 6 ; 
 R 5a  is —H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —S(O) 2 R 7 , —C(O)N(R 13 ) 2 , —C(O)R 6 , or —C(O)OR 6 ; 
 or R 4a  and R 5a  are taken together with the N atom to which they are attached to form an optionally substituted heterocycle; 
 R 4  and R 5  are each independently —H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —S(O) 2 R 7 , —C(O)N(R 13 ) 2 , —C(O)R 6 , or —C(O)OR 6 ; 
 or R 4  and R 5  are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle; 
 each R 6  is independently optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; 
 R 7  is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; 
 R 8  and R 9  are each independently —H, optionally substituted alkyl, haloalkyl, halo, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —OH, —S(O) 2 R 7 , —C(O) 2 H, —C(O)R 6 , or —C(O)OR 6 ; 
 or R 8  and R 9  are taken together with the atom to which they are attached to form a substituted or unsubstituted ring containing 0-2 heteroatoms selected from the group consisting of —O—, —NH—, —NR 6 —, —S—, and —S(O) 2 —; 
 R 10  and R 11  are each independently —H, optionally substituted alkyl, halo, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —OH, —S(O) 2 R 7 , —C(O) 2 H, —C(O)R 6 , or —C(O)OR 6 ; 
 or R 10  and R 11  are taken together with the atom to which they are attached to form a substituted or unsubstituted ring containing 0-2 heteroatoms selected from the group consisting of —O—, —NH—, —NR 6 —, —S—, and —S(O) 2 —; 
 R 12  is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy, halo, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroalkyl; 
 each R 13  is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and 
 n is 0, 1, 2, 3, or 4. 
 
       
     
     
         57 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 12  is methyl. 
     
     
         58 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 12  is H. 
     
     
         59 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, ring A is monocyclic heteroaryl or monocyclic aryl. 
     
     
         60 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, ring A is phenyl. 
     
     
         61 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 4a  is C 2-8  alkyl. 
     
     
         62 . The method of  claim 61 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 4a  is ethyl, i-propyl, or t-butyl. 
     
     
         63 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 5a  is —H, optionally substituted alkyl, or haloalkyl. 
     
     
         64 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2. 
     
     
         65 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, each R 2  is independently —NR 4 R 5 , halo, —OR 6 , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, —S(O) 2 NR 4 R 5 , or —S(O) 2 R 7 . 
     
     
         66 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 3  is optionally substituted C 2-8  alkyl, haloalkyl, or optionally substituted carbocyclyl. 
     
     
         67 . The method of  claim 66 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 3  is CF 3 , t-butyl, or cyclopropyl. 
     
     
         68 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 3  is t-butyl. 
     
     
         69 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 8  and R 9  are —H. 
     
     
         70 . The method of  claim 56 , wherein in the compound of Formula (III), or a pharmaceutically acceptable salt thereof, R 10  and R 11  are each —H. 
     
     
         71 . The method of  claim 56 , wherein the compound of Formula (III), or a pharmaceutically acceptable salt thereof, has the structure of Formula (IIIa): 
       
         
           
           
               
               
           
         
       
     
     
         72 . A method for treating a hypercortisolism disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         73 . The method of  claim 56 , wherein the hypercortisolism disorder in the subject is refractory Cushing's syndrome.