Fused Ring Azadecalin Glucocorticoid Receptor Modulators

Abstract

The present invention provides a novel class of fused ring azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 L 1  and L 2  are members independently selected from a bond, —O—, —S—, S(O)—, —S(O 2 )—, —C(O)—, —C(O)O—, —C(O)NH—, substituted or unsubstituted alkylene, and substituted or unsubstituted heteroalkylene; 
 the dashed line b is optionally a bond; 
 the ring A is a member selected from substituted or unsubstituted 5 to 6 membered heterocycloalkyl, and substituted or unsubstituted heteroaryl; 
 R 1  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR 1A , —NR 1C R 1D , —C(O)NR 1C R 1D , —C(O)OR 1A , wherein
 R 1A  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 R 1C  and R 1D  are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
 wherein R 1C  and R 1D  are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen, and 
 
 
 R 2  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —S(O 2 )R 2A , —S(O 2 )NR 2B R 2C , and ═NOR 2D , wherein
 R 2A , R 2B , R 2C , and R 2D  are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
 
 
     
     
         2 . The compound of  claim 1 , wherein A is a member selected from:
 unsubstituted 5 to 6 membered heterocycloalkyl comprising at least one heteroatom selected from N, O and S;   substituted 5 to 6 membered heterocycloalkyl comprising 1 to 3 substituents and at least one ring heteroatom selected from N, O and S;   unsubstituted aryl comprising at least one heteroatom selected from N, O and S; and   substituted aryl comprising 1 to 3 substituents and at least one ring heteroatom selected from N, O and S.   
     
     
         3 . The compound of  claim 1 , wherein A is a member selected from substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, and substituted or unsubstituted pyrazinyl. 
     
     
         4 . The compound of  claim 1 , wherein A is a substituted or unsubstituted pyrazolyl. 
     
     
         5 . The compound of  claim 1 , wherein A is substituted with a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, —NR 3A R 3B , and —OR 3C , wherein
 R 3A  and R 3B  are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl, wherein
 R 3A  and R 3B  are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and 
 
 R 3C  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
 
     
     
         6 . The compound of  claim 5 , wherein A is substituted with a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
     
     
         7 . The compound of  claim 1  having the formula 
       
         
           
           
               
               
           
         
         wherein,
 the dashed ring represents unsaturated, partially saturated, or fully saturated bonds within ring E; 
 Z 1  is a member selected from —NR 5 —, ═N—, —O—, and —S—, wherein
 R 5  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; 
 
 Z 2  is a member selected from —CR 6A R 6B —, ═CR 6A —, —C(O)—, —NR 6C —, ═N—, —O—, —CR 6A R 6B —NR 6C —, ═CR 6A —NR 6C —, —CR 6A R 6B —N═, and ═CR 6A —N═, wherein
 R 6C  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
 R 6A  and R 6B  are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, —NR 6A1 R 6A2 , and —OR 6A3 , wherein
 R 6A1  and R 6A2  are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein 
  R 6A1  and R 6A2  are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and 
 R 6A3  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
 wherein R 6A  and R 6C  are optionally joined together to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom; 
 
 
 Z 3  is a member selected from —CR 7A R 7B —, ═CR 7A —, —C(O)—, —NR 7C —, ═N—, —O—, and —S—, wherein 
 R 7C  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl, 
 R 7A  and R 7B  are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, —NR 7A1 R 7A2 , and —OR 7A3 , wherein
 R 7A1  and R 7A2  are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein
 R 7A1  and R 7A2  are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and 
 
 R 7A3  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 
 wherein R 5  is optionally joined with R 6A  or R 6C  to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom; 
 wherein R 7A  is optionally joined with R 6A  or R 6C  to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom; and 
 wherein R 7C  is optionally joined with R 6A  or R 6C  to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom. 
 
       
     
     
         8 . The compound of  claim 7 , wherein
 Z 1  is —NR 5 —;   Z 2  is ═N—; and   Z 3  is ═CR 7A —.   
     
     
         9 . The compound of  claim 8 , wherein
 R 7A  is hydrogen; and   R 5  is a member selected from hydrogensubstituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl.   
     
     
         10 . The compound of  claim 7 , wherein R 5  has the formula: 
       
         
           
           
               
               
           
         
         wherein,
 R 5A  is a member selected from hydrogen, halogen, —OR 5A1 , —NR 5A2 R 5A3 , —S(O 2 )NR 5A2 R 5A3 , —CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein
 R 5A1  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and 
 R 5A2  and R 5A3  are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 
 m is an integer from 0 to 10; and 
 n is an integer from 1 to 5. 
 
       
     
     
         11 . The compound of  claim 10 , wherein
 n is 1;   m is 0 or 1; and   R 5A1 , R 5A2  and R 5A3  are hydrogen.   
     
     
         12 . The compound of  claim 7 , wherein
 Z 1  is —NR 5 —;   Z 2  is ═CR 6A —; and   Z 3  is ═N—.   
     
     
         13 . The compound of  claim 12 , wherein R 5  is a member selected from hydrogen and substituted or unsubstituted aryl. 
     
     
         14 . The compound of  claim 8 , wherein R 5  and R 7A  are hydrogen and b is a bond. 
     
     
         15 . The compound of  claim 1 , wherein R 1  is a member selected from substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
     
     
         16 . The compound of  claim 1 , wherein R 1  has the formula: 
       
         
           
           
               
               
           
         
         wherein,
 q is an integer selected from 1 to 5; 
 R 1B  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NR 1B1 R 1B2 , —OR 1B3 , and —C(O)NR 1B4 R 1B5  wherein
 R 1B1  and R 1B2  are members independently selected from hydrogen, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl, wherein R 1B1  and R 1B2  are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and 
 R 1B3  is a member selected from
 hydrogen, 
 substituted or unsubstituted heteroalkyl comprising a nitrogen, 
 substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, 
 substituted or unsubstituted heteroaryl comprising a ring nitrogen, and 
 alkyl substituted with a substituted or unsubstituted heteroalkyl comprising a nitrogen, substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, and substituted or unsubstituted heteroaryl comprising a ring nitrogen; and 
 
 
 R 1B4  and R 1B5  are members independently selected from
 hydrogen, 
 substituted or unsubstituted heteroalkyl comprising a nitrogen, 
 substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, 
 substituted or unsubstituted heteroaryl comprising a ring nitrogen, and 
 alkyl substituted with a substituted or unsubstituted heteroalkyl comprising a nitrogen, substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, and substituted or unsubstituted heteroaryl comprising a ring nitrogen, wherein
 R 1B4  and R 1B5  are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises a heteroatom. 
 
 
 
       
     
     
         17 . The compound of  claim 16 , wherein
 q is an integer selected from 1 to 3;   R 1B  is a member selected from hydrogen, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl, and substituted or unsubstituted heteroaryl.   
     
     
         18 . The compound of  claim 16 , wherein R 1  has the formula: 
       
         
           
           
               
               
           
         
         wherein,
 R 1B  is a member selected from hydrogen, —NR 1B1 R 1B2 , —OR 1B3 , substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
 
       
     
     
         19 . The compound of  claim 16 , wherein R 1B  is a member selected from —C(O)NR 1B4 R 1B5  and substituted or unsubstituted heteroaryl comprising a ring nitrogen, wherein
 R 1B4  and R 1B5  are members independently selected from
 hydrogen, 
 substituted or unsubstituted heteroalkyl comprising a nitrogen, 
 substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, 
 substituted or unsubstituted heteroaryl comprising a ring nitrogen, and 
 alkyl substituted with a substituted or unsubstituted heteroalkyl comprising a nitrogen, substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, and substituted or unsubstituted heteroaryl comprising a ring nitrogen, wherein
 R 1B4  and R 1B5  are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises a heteroatom. 
 
 
 
     
     
         20 . The compound of  claim 19 , wherein R 1B1 , R 1B2 , R 1B3 , R 1B4  and R 1B5  are members independently selected from hydrogen and a substituted or unsubstituted ring, wherein said ring optionally comprises a nitrogen atom and at least one additional ring heteroatom. 
     
     
         21 . The compound of  claim 1 , wherein R 2  is a member selected from substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
     
     
         22 . The compound of  claim 1 , R 2A , R 2B , R 2C , and R 2D  are members independently selected from substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
     
     
         23 . The compound of  claim 1 , R 2  has the formula: 
       
         
           
           
               
               
           
         
         wherein,
 R 2G  is a member selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 J is a substituted or unsubstituted ring selected from substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 t is an integer from 0 to 5; and 
 X is a member selected from a bond, —S(O 2 )—, and —S(O 2 )N 2I —, wherein
 R 2I  is a member selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl. 
 
 
       
     
     
         24 . The compound of  claim 23 , wherein
 R 2G  is a member selected from hydrogen, substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;   J is a substituted or unsubstituted ring selected from substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;   t is 1; and   R 2I  is hydrogen.   
     
     
         25 . The compound of  claim 23 , wherein R 2G  is a branched or unbranched (C 1 -C 10 )alkyl. 
     
     
         26 . The compound of  claim 23 , wherein X is —S(O 2 )—. 
     
     
         27 . The compound of  claim 1 , wherein L 1  and L 2  are members independently selected from a bond and unsubstituted (C 1 -C 6 ) alkylene. 
     
     
         28 . The compound of  claim 1 , wherein
 the dashed line b is a bond;   R 1  is substituted or unsubstituted benzyl; and   R 2  has the formula:   
       
         
           
           
               
               
           
         
         wherein,
 R 2G  is a member selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
 J is a substituted or unsubstituted ring selected from substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
 t is an integer fro 0 to 5, and 
 X is —S(O 2 )—; 
 
         L 1  is a bond; and 
         L 2  is a bond. 
       
     
     
         29 . A method of treating a disorder or condition through modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of the compound of one of  claims 1 - 28 . 
     
     
         30 . A method of treating a disorder or condition through antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of the compound of one of  claims 1 - 28 . 
     
     
         31 . A method of modulating a glucocorticoid receptor including the steps of contacting a glucocorticoid receptor with an effective amount of the compound of one of  claims 1 - 28  and detecting a change in the activity of the glucocorticoid receptor. 
     
     
         32 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of one of  claims 1 - 28 .