Glucocorticoid receptor agonist and immunoconjugates thereof

Abstract

Provided herein are glucocorticoid receptor agonist immunoconjugates, glucocorticoid receptor agonists, and methods of using the same, e.g., to treat autoimmune or inflammatory diseases.

1 - 23 . (canceled) 
     
     
         24 . A compound having Formula VII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  is selected from the group consisting of hydrogen and halo; 
 R 2  is selected from the group consisting of hydrogen, halo, and hydroxy; 
 R 3  is selected from the group consisting of —CH 2 OH, —CH 2 SH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, —SCH 2 CF 3 , —CH 2 OS(═O) 2 OH, hydroxy, —OCH 2 CN, —OCH 2 Cl, —OCH 2 F, —OCH 3 , —OCH 2 CH 3 , —SCH 2 CN, 
 
       
         
           
           
               
               
           
         
         R 3a  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 3b  is selected from the group consisting of C 1-4  alkyl and C 1-4  alkoxy; 
         R 3c  is selected from the group consisting of hydrogen, C 1-4  alkyl, —CH 2 OH, C 1-4  alkoxy, —CH 2 (amino), and —CH 2 CH 2 C(═O)OR 3f ; 
         R 3d  and R 3e  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 3f  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         X is selected from the group consisting of —(CR 4a R 4b )—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 5 —, —CH 2 S—, —CH 2 O—, —N(H)C(R 8a )(R 8b )—, —CR 4c —CR 4d —, —C≡C—, —N(R 5 )C(═O)—, and —OC(═O)—; or 
         X is absent; 
         t is 1 or 2; 
         Z is selected from the group consisting of ═CR 11a — and ═N—; 
         each R 4a  and R 4b  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; or 
         R 4a  and R 4b  taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; 
         R 4c  and R 4d  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 5  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 6a , R 6b , R 6c , and R 6d  are each independently selected from the group consisting of hydrogen, halo, C 1-4  alkyl, haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; 
         R 7a  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 7b  is selected from the group consisting of hydrogen, -L-H, -L-PG, 
       
       
         
           
           
               
               
           
         
       
       or
 R 7a  and R 7b  taken together with the nitrogen atom to which they are attached form: 
 
       or 
       
         
           
           
               
               
           
         
         R 7a  and R 7b  taken together with the nitrogen atom to which they are attached form a nitro group; 
         m is 1, 2, 3, 4, 5, or 6; 
         L is a linker; 
         PG is a protecting group; 
         R 9f  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 8a  and R 8b  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 11a  and R 11b  are independently selected from the group consisting of hydrogen, halo, C 1-4  alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; and 
            represents a single or double bond. 
       
     
     
         25 . A compound having Formula VII-A or Formula VII-B: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  is selected from the group consisting of hydrogen and halo; 
 R 2  is selected from the group consisting of hydrogen, halo, and hydroxy; 
 R 3  is selected from the group consisting of —CH 2 OH, —CH 2 SH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, —SCH 2 CF 3 , —CH 2 OS(═O) 2 OH, hydroxy, —OCH 2 CN, —OCH 2 Cl, —OCH 2 F, —OCH 3 , —OCH 2 CH, —SCH 2 CN, 
 
       
         
           
           
               
               
           
         
         R 3a  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 3b  is selected from the group consisting of C 1-4  alkyl and C 1-4  alkoxy; 
         R 3c  is selected from the group consisting of hydrogen, C 1-4  alkyl, —CH 2 OH, C 1-4  alkoxy, —CH 2 (amino), and —CH 2 CH 2 C(═O)OR 3f ; 
         R 3d  and R 3e  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 3f  is selected from the group consisting of hydrogen and C 1-4  alkyl; X is selected from the group consisting of —(CR 4a R 4b ) t —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 5 —, —CH 2 S—, —CH 2 O—, —N(H)C(R 8a )(R 8b )—, —CR 4c ═CR 4d —, —C≡C—, —N(R 5 )C(═O)—, and —OC(═O)—; or 
         X is absent; 
         t is 1 or 2; 
         Z is selected from the group consisting of ═CR 11a — and ═N—; 
         each R 4a  and R 4b  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; or 
         R 4a  and R 4b  taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; 
         R 4c  and R 4d  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 5  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 6a , R 6b , and R 6c  are each independently selected from the group consisting of hydrogen, halo, C 1-4  alkyl, haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; 
         R 7a  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 7b  is selected from the group consisting of hydrogen, -L-H, -L-PG, 
       
       
         
           
           
               
               
           
         
       
       or
 R 7a  and R 7b  taken together with the nitrogen atom to which they are attached form: 
 
       
         
           
           
               
               
           
         
       
       or
 R 7a  and R 7b  taken together with the nitrogen atom to which they are attached form a nitro group; 
 m is 1, 2, 3, 4, 5, or 6; 
 L is a linker; 
 PG is a protecting group; 
 R 9f  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
 R 8a  and R 8b  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
 R 11a  and R 11b  are independently selected from the group consisting of hydrogen, halo, C 1-4  alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; and 
    represents a single or double bond. 
 
     
     
         26 . The compound of  claim 24  or  25 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 7b  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         m is 1, 2, 3, 4, 5, or 6; and 
         R 10a  and R 10b  are each independently selected from the group consisting of hydrogen and optionally substituted C 1-6  alkyl. 
       
     
     
         27 . The compound of  claim 24  or  26 , or a pharmaceutically acceptable salt or solvate thereof, having Formula VIII-a: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of any one of  claims 24 - 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
    represents a double bond;   R 1  is selected from the group consisting of hydrogen and fluoro;   R 2  is selected from the group consisting of hydrogen and fluoro;   R 3  is selected from the group consisting of —CH 2 OH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, and   
       
         
           
           
               
               
           
         
         R 3d  and R 3e  are independently selected from the group consisting of hydrogen, methyl, and ethyl; 
         Z is ═CH—; 
         R 6a , R 6b , R 6c , and R 6d  are hydrogen; 
         R 7a  is hydrogen; 
         X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —CH 2 S—, and —N(H)CH 2 —; 
         R 9f  is hydrogen; and 
         R 11b  is hydrogen. 
       
     
     
         29 . The compound of any one of  claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b  is hydrogen. 
     
     
         30 . The compound of any one of  claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b  is R 7b -1. 
     
     
         31 . The compound of any one of  claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b  is R 7b -2, and PG is BOC. 
     
     
         32 . The compound of any one of  claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b  is R 7b -3. 
     
     
         33 . The compound of  claim 29 , or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds of Table VI. 
     
     
         34 . The compound of  claim 29 , or a pharmaceutically acceptable salt or solvate thereof, which is any one of the compounds of Table VII. 
     
     
         35 . The compound of  claim 33 , or a pharmaceutically acceptable salt or solvate thereof, which is: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 24 , or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds of Table VIII, wherein R 7b  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 24 , or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds of Table X. 
     
     
         38 . The compound of  claim 37 , or a pharmaceutically acceptable salt or solvate thereof, which is: 
       
         
           
           
               
               
           
         
       
     
     
         39 - 40 . (canceled)