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 and hypercortisolism.

1 .- 58 . (canceled) 
     
     
         59 . A method of treating cancer in a subject, wherein the cancer expresses glucocorticoid receptor (GR), the method comprising administering to the subject a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —NR 3 S(O) 2 R 6 , —NR 3 S(O) 2 NR 3 R 4 , -alkylNR 3 S(O) 2 R 6 , -alkylNR 3 S(O) 2 NR 3 R 4 , —NR 3 S(O)R 6 , —Oaralkyl, —C(O)NR 3 R 4 , —OC(O)OR 5 , —C(O)OR 5 , —OC(O)NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 6 , or —S(O)R 6 ; 
 R 3  and R 4  are each independently —H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, —S(O) 2 R 6 , —C(O)N(R 10 ) 2 , —C(O)R 5 , or —C(O)OR 5 ; 
 or R 3  and R 4  attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle; 
 R 5  is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; 
 R 6  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 7  and R 8  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, —OR 5 , —NR 3 R 4 , —C(O)NR 3 R 4 , —CN, —S(O) 2 R 6 , —C(O) 2 H, —C(O)R 5 , or —C(O)OR 5 ; 
 or R 7  and R 8  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 —; and 
 each R 10  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. 
 
     
     
         60 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof,
 R 1  is —NR 3 S(O) 2 R 6 , —NR 3 S(O) 2 NR 3 R 4 , -alkylNR 3 S(O) 2 R 6 , -alkylNR 3 S(O) 2 NR 3 R 4 , —C(O)NR 3 R 4 , —S(O) 2 NR 3 R 4 , or —S(O) 2 R 6 ;   R 3  and R 4  are each independently —H, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, —C(O)N(R 10 ) 2 , or —S(O) 2 R 6 ;   or R 3  and R 4  attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted 3-, 4-, 5-, or 6-membered heterocycle;   R 5  is optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;   R 6  is optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;   R 7  and R 8  are each independently —H, optionally substituted alkyl, fluoroalkyl, halo, —OR 5 , —NR 3 R 4 , —C(O)NR 3 R 4 , —CN, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl;   or R 7  and R 8  are taken together with the atom to which they are attached to form a substituted or unsubstituted 3-, 4-, 5-, or 6-membered ring containing 0-2 heteroatoms selected from the group consisting of —O—, —NH—, —NR 6 —, —S—, and —S(O) 2 —; and   each R 10  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.   
     
     
         61 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1  is —NR 3 S(O) 2 R 6 , —C(O)NR 3 R 4 , —S(O) 2 NR 3 R 4 , or —S(O) 2 R 6 . 
     
     
         62 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1  is —NR 3 S(O) 2 R 6  or —S(O) 2 NR 3 R 4 . 
     
     
         63 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 3  and R 4  are each independently —H, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —C(O)N(R 10 ) 2 , or —S(O) 2 R 6 . 
     
     
         64 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 3  and R 4  are each independently —H, alkyl, or —S(O) 2 R 6 . 
     
     
         65 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof,
 R 3  and R 4  attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-, 5-, or 6-membered ring heterocycle containing 0-3 heteroatoms selected from —O—, —NH—, —NR 5 —, —S—, and —S(O) 2 —, and   R 5  is alkyl.   
     
     
         66 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6  is alkyl, carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heterocyclyl. 
     
     
         67 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6  is C 1-6  alkyl, C 3-6  carbocyclyl, optionally substituted phenyl, optionally substituted benzyl, or optionally substituted heterocyclyl. 
     
     
         68 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 7  and R 8  are each independently —H, alkyl, or carbocyclyl. 
     
     
         69 . The method of  claim 59 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 7  and R 8  are —H. 
     
     
         70 . The method of  claim 59 , wherein the cancer is chemo-resistant cancer. 
     
     
         71 . The method of  claim 59 , wherein the cancer is non-small cell lung cancer, triple negative breast cancer, ovarian cancer, castration resistant prostate cancer, or doubly resistant prostate cancer. 
     
     
         72 . The method of  claim 71 , wherein the cancer is non-small cell lung cancer. 
     
     
         73 . The method of  claim 71 , wherein the cancer is triple negative breast cancer. 
     
     
         74 . The method of  claim 71 , wherein the cancer is ovarian cancer. 
     
     
         75 . The method of  claim 71 , wherein the cancer is castrate resistant prostate cancer. 
     
     
         76 . The method of  claim 59 , further comprising administering one or more additional therapeutic agents to the subject. 
     
     
         77 . The method of  claim 76 , wherein the one or more additional therapeutic agents is one or more androgen receptor signaling inhibitors. 
     
     
         78 . The method of  claim 76 , wherein the one or more additional therapeutic agents is one or more chemotherapeutic agents.