Compounds and uses thereof

Abstract

The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.

1 . A compound having the structure of Formula I:
   A-L-B   Formula I,
   wherein   A is   
       
         
           
           
               
               
           
         
         wherein
 A 1  is a bond between A and L; 
 R 4  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl 
 R 5  is H, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, or optionally substituted C 6 -C 10  aryl; 
 R 6a  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
 R 6b  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or R 6a  and R 6b , together with the carbon atoms to which each is attached, combine to form optionally substituted C 6 -C 10  aryl or optionally substituted C 2 -C 9  heteroaryl; 
 
         B is 
       
       
         
           
           
               
               
           
         
         wherein
 A 2  is a bond between B and L; 
 v1 is 0, 1, 2, 3, 4, or 5; 
 R A5  is H, optionally substituted C 1 -C 5  alkyl, or optionally substituted C 1 -C 5  heteroalkyl; 
 each R J1  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
 J A  is absent, O, optionally substituted amino, optionally substituted C 1 -C 5  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; and 
 J is absent, optionally substituted C 3 -C 10  carbocyclylene, optionally substituted C 6 -C 10  arylene, optionally substituted C 2 -C 9  heterocyclylene, or optionally substituted C 2 -C 9  heteroarylene, optionally substituted amino, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; and 
 
         L is
   A 1 -(E 1 )-(F 1 )—(C 3 ) m -(F 2 ) o1 -A 2 ,   Formula IId
 
 
         wherein 
         A 1  is a bond between L and A; 
         A 2  is a bond between B and L; 
         each of m and o1 is, independently, 0 or 1; 
         O, S, NR N , optionally substituted C 1-10  alkylene, optionally substituted C 2-10  alkenylene, optionally substituted C 2-10  alkynylene, optionally substituted C 2 -C 10  polyethylene glycol, or optionally substituted C 1-10  heteroalkylene; 
         R N  is H, optionally substituted C 1-4  alkyl, optionally substituted C 2-4  alkenyl, optionally substituted C 2-4  alkynyl, optionally substituted C 2-6  heterocyclyl, optionally substituted C 6-12  aryl, or optionally substituted C 1-7  heteroalkyl; 
         C 3  is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and 
         each of F 1  and F 2  is, independently, optionally substituted C 3 -C 10  carbocyclylene, optionally substituted C 2-10  heterocyclylene, optionally substituted C 6 -C 10  arylene, or optionally substituted C 2 -C 9  heteroarylene, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 - 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein E 1  is 
       
         
           
           
               
               
           
         
       
       where a is 0, 1, 2, 3, 4, or 5. 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 18 , wherein E 1  is 
       
         
           
           
               
               
           
         
       
     
     
         21 - 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , wherein each of F 1  and F 2  is, independently, optionally substituted C 3 -C 10  carbocyclylene. 
     
     
         32 - 38 . (canceled) 
     
     
         39 . The compound of  claim 1 , wherein each of F 1  and F 2  is, independently, optionally substituted C 2 -C 6  heterocyclylene. 
     
     
         40 . (canceled) 
     
     
         41 . The compound of  claim 39 , wherein the C 2 -C 6  heterocyclylene is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         q1 is 0, 1, 2, 3, or 4; 
         q2 is 0, 1, 2, 3, 4, 5, or 6; 
         q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
         each Rh is, independently,  2 H, halogen, optionally substituted C 1 -C 6  alkyl, OR i2 , or NR i3 R i4 ; or two R h  groups, together with the carbon atom to which each is attached, combine to form optionally substituted C 3 -C 10  carbocyclyl or optionally substituted C 2 -C 9  heterocyclyl; or two Rh groups, together with the carbon atoms to which each is attached, combine to form optionally substituted C 3 -C 10  carbocyclyl or optionally substituted C 2 -C 9  heterocyclyl; 
         R i1  is H or optionally substituted C 1 -C 6  alkyl; 
         R i2  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 6  carbocyclyl; 
       
     
     
         42 - 50 . (canceled) 
     
     
         51 . The compound of  claim 39 , wherein each of F 1  and F 2  is, independently, 
       
         
           
           
               
               
           
         
       
     
     
         52 . The compound of  claim 39 , wherein F 1  is 
       
         
           
           
               
               
           
         
       
     
     
         53 . The compound of  claim 39 , wherein F 2  is 
       
         
           
           
               
               
           
         
       
     
     
         54 - 77 . (canceled) 
     
     
         78 . The compound of  claim 1 , wherein m is 0. 
     
     
         79 - 80 . (canceled) 
     
     
         81 . The compound of  claim 1 , wherein o1 is 1. 
     
     
         82 - 116 . (canceled) 
     
     
         117 . The compound of  claim 1 , wherein v1 is 0. 
     
     
         118 - 119 . (canceled) 
     
     
         120 . The compound of  claim 1 , wherein R A5  is H. 
     
     
         121 - 128 . (canceled) 
     
     
         129 . The compound of  claim 1 , wherein J is optionally substituted C 3 -C 10  carbocyclylene or optionally substituted C 6 -C 10  arylene. 
     
     
         130 - 186 . (canceled) 
     
     
         187 . The compound of  claim 1 , wherein R 4  is H. 
     
     
         188 - 199 . (canceled) 
     
     
         200 . The compound of  claim 1 , wherein R 5  is H, 
       
         
           
           
               
               
           
         
       
     
     
         201 . The compound of  claim 200 , wherein R 5  is H or 
       
         
           
           
               
               
           
         
       
     
     
         202 - 204 . (canceled) 
     
     
         205 . The compound of  claim 1 , wherein R 8a  is H, F, cyano, 
       
         
           
           
               
               
           
         
       
     
     
         206 - 208 . (canceled) 
     
     
         209 . The compound of  claim 1 , wherein R 6b  is H, F, cyano, 
       
         
           
           
               
               
           
         
       
     
     
         210 - 300 . (canceled) 
     
     
         301 . A compound having the structure of any one of compounds D1-D259 in Table 1A, D260-D371 in Table 1B, D372-D476 in Table 1D, DD1-DD10 in Table 1C, and DD11-DD16 in Table 1E. 
     
     
         302 - 305 . (canceled) 
     
     
         306 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         307 . A method of inhibiting the level or activity of BRD9 in a cell, the method involving contacting the cell with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         308 . (canceled) 
     
     
         309 . The method of  claim 307 , wherein the cell is a cancer cell. 
     
     
         310 . The method of  claim 309 , wherein the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma, non-small cell lung cancer, stomach cancer, or breast cancer. 
     
     
         311 . The method of  claim 310 , wherein the cancer is a sarcoma. 
     
     
         312 . (canceled) 
     
     
         313 . The method of  claim 311 , wherein the sarcoma is synovial sarcoma. 
     
     
         314 . A method of treating a BAF complex-related disorder, an SS18-SSX fusion protein-related disorder, or a BRD9-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         315 - 317 . (canceled) 
     
     
         318 . A method of treating a cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         319 . (canceled) 
     
     
         320 . The method of  claim 318 , wherein the cancer is a sarcoma. 
     
     
         321 . (canceled) 
     
     
         322 . The method of  claim 320 , wherein the sarcoma is synovial sarcoma. 
     
     
         323 . (canceled) 
     
     
         324 . A method of treating infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         325 - 327 . (canceled) 
     
     
         328 . The compound of  claim 20 , wherein
 each of R 4 , R 6a , and R 6b  is   
       
         
           
           
               
               
           
         
         R 5  is H; 
         v1 is 0; 
         R A5  is H; 
         J A  is amino; 
         J is optionally substituted C 6 -C 10  arylene; 
         m is 0; 
         o1 is 1; 
         F 1  is 
       
       
         
           
           
               
               
           
         
       
       and
 F 2  is