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.

What is claimed is: 
     
         1 . A compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 ring A is a 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. 
 
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is hydrogen, alkyl, haloalkyl, hydroxy, halo, carbocyclyl, or heteroalkyl. 
     
     
         3 . The compound of  claim 1  or  2  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 12  is C 1-6  alkyl or hydrogen. 
     
     
         4 . The compound of any one of  claims 1 - 3  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 12  is methyl. 
     
     
         5 . The compound of any one of  claims 1 - 3  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 12  is H. 
     
     
         6 . The compound of any one of  claims 1 - 5  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring A is monocyclic heteroaryl or monocyclic aryl. 
     
     
         7 . The compound of any one of  claims 1 - 6  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 
     
     
         8 . The compound of any one of  claims 1 - 7  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring A is phenyl. 
     
     
         9 . The compound of any one of  claims 1 - 8  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4a  is C 2-8  alkyl. 
     
     
         10 . The compound of any one of  claims 1 - 8  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4a  is C 3-6  alkyl. 
     
     
         11 . The compound of any one of  claims 1 - 8  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4a  is C 2-4  alkyl. 
     
     
         12 . The compound of any one of  claims 1 - 8  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4a  is ethyl, i-propyl, or t-butyl. 
     
     
         13 . The compound of any one of  claims 1 - 12  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 5a  is —H, optionally substituted alkyl, or haloalkyl. 
     
     
         14 . The compound of any one of  claims 1 - 12  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 5a  is —H or alkyl. 
     
     
         15 . The compound of any one of  claims 1 - 12  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 5a  is C 1-6  alkyl. 
     
     
         16 . The compound of any one of  claims 1 - 8  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4a  and R 5a  are taken together with the N atom to which they are attached to form an optionally substituted heterocycle. 
     
     
         17 . The compound of of  claim 16  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4a  and R 5a  are taken together with the N atom to which they are attached to form an optionally substituted pyrrolidinyl, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted piperidinyl, or an optionally substituted piperazinyl. 
     
     
         18 . The compound of any one of  claims 1 - 17  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, or 2. 
     
     
         19 . The compound of any one of  claims 1 - 18  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0. 
     
     
         20 . The compound of any one of  claims 1 - 18  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 1. 
     
     
         21 . The compound of any one of  claims 1 - 20  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein 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 . 
     
     
         22 . The compound of any one of  claims 1 - 21  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is optionally substituted C 2-8  alkyl, haloalkyl, or optionally substituted carbocyclyl. 
     
     
         23 . The compound of any one of  claims 1 - 22  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is C 4-8  alkyl, haloalkyl, or optionally substituted carbocyclyl. 
     
     
         24 . The compound of any one of  claims 1 - 23  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is CF 3 , t-butyl, or cyclopropyl. 
     
     
         25 . The compound of any one of  claims 1 - 23  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is C 4-8  alkyl. 
     
     
         26 . The compound of  claim 25  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is t-butyl. 
     
     
         27 . The compound of any one of  claims 1 - 23  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is haloalkyl. 
     
     
         28 . The compound of  claim 26  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is CF 3 . 
     
     
         29 . The compound of any one of  claims 1 - 23  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is optionally substituted carbocyclyl. 
     
     
         30 . The compound of  claim 29  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is cyclopropyl. 
     
     
         31 . The compound of any one of  claims 1 - 30  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 8  and R 9  are each independently —H, alkyl, or carbocyclyl. 
     
     
         32 . The compound of any one of  claims 1 - 31  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 8  and R 9  are —H. 
     
     
         33 . The compound of any one of  claims 1 - 32  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10  and R 11  are each independently —H, C 1-6  alkyl, halo, C 1-6  alkoxy, or —OH. 
     
     
         34 . The compound of any one of  claims 1 - 33  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10  and R 11  are each —H. 
     
     
         35 . The compound of any one of  claims 1 - 32  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10  and R 11  are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring. 
     
     
         36 . The compound of any one of  claims 1 - 35  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4  and R 5  are each independently —H, C 1-6  alkyl, or —S(O)R 7 . 
     
     
         37 . The compound of any one of  claims 1 - 35  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4  and R 5  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 additionally containing 0-3 heteroatoms selected from the group consisting of —O—, —NH—, —NR 6 —, —S—, and —S(O) 2 —. 
     
     
         38 . The compound of any one of  claims 1 - 37  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 6  is alkyl, carbocyclyl, or fluoroalkyl. 
     
     
         39 . The compound of any one of  claims 1 - 38  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 7  is alkyl, carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heterocyclyl. 
     
     
         40 . The compound of any one of  claims 1 - 39  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound has the structure of Formula (IIIa): 
       
         
           
           
               
               
           
         
       
     
     
         41 . A compound of  claim 1 , wherein the compound is selected from 
       or a pharmaceutically acceptable salt, solvate, or pro drug thereof 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         42 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof 
     
     
         43 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 42 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         44 . A method for treating or preventing cancer in a subject, the method comprising administering a therapeutically effective amount of a compound of any one of  claims 1 - 42 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to the subject in need thereof. 
     
     
         45 . A method of reducing incidences of cancer recurrence, the method comprising administering to a subject in cancer remission a therapeutically effective amount of a compound of any one of  claims 1 - 42  or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
     
     
         46 . A method for treating a chemo-resistant cancer in a subject, the method comprising administering a therapeutically effective amount of a compound of any one of  claims 1 - 42  or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to the subject in need thereof. 
     
     
         47 . The method of any one of  claims 43 - 46 , wherein the cancer is triple negative breast cancer, high grade serous ovarian cancer, castration resistant prostate cancer, or doubly resistant prostate cancer. 
     
     
         48 . The method of any one of  claims 43 - 46 , wherein the cancer is non-small cell lung cancer. 
     
     
         49 . The method of any one of  claims 43 - 46 , further comprising administering a second therapeutic agent to the subject. 
     
     
         50 . The method of  claim 49 , wherein the second therapeutic agent is an androgen receptor inhibitor. 
     
     
         51 . The method of  claim 50 , wherein the androgen receptor inhibitor is 3,3′-diindolylmethane (DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidal antiandrogens, turosteride, or any combinations thereof. 
     
     
         52 . The method of  claim 49 , wherein the second therapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin, camptothecin, topotecan, or any combinations thereof. 
     
     
         53 . The method of  claim 49 , wherein the second therapeutic agent is an anti-PD-1 agent or an anti-PD1 agent. 
     
     
         54 . A method for treating a hypercortisolism disease or disorder in a subject, the method comprising administering a therapeutically effective amount a compound of any one of  claims 1 - 42 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to the subject in need thereof. 
     
     
         55 . The method of  claim 54 , wherein the hypercortisolism disease or disorder is refractory Cushing's syndrome.