Inhibitors of cysteine proteases and methods of use thereof

Abstract

Certain anti-viral compounds, pharmaceutical compositions, and methods related thereto are disclosed.

1 . A compound of Formula A or pharmaceutically acceptable or physiological salts thereof: 
       
         
           
           
               
               
           
         
         wherein X in each occurrence is independently selected from O and S; 
         wherein Y is selected from a bond, O, CH 2 , and NR b ; 
         wherein A is a warhead, which is independently selected from 
       
       
         
           
           
               
               
           
         
         wherein R a  is selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 10  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, and wherein R a  can optionally be substituted with one or more Rat; 
         wherein each R a1  is independently selected from halo, oxo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl, 5-10 membered heteroaryl, C 1 -C 8  alkyl and C 1 -C 8  alkoxy, wherein any two R a1  can be combined with the atoms to which they are attached to form a C 3-10  cycloalkyl or heterocycle or C 5-10  aryl or 5-10 membered heteroaryl, and wherein each R a1  can optionally be substituted by one or more substituents, each independently selected from halo, cyano and C 1 -C 6  alkyl; 
         wherein R c  is selected from H, C 1 -C 6  alkyl, C 1 -C 6  branched alkyl, C 2 -C 6  alkylene, C 2 -C 6  branched alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, wherein R c  can optionally be substituted with one or more substituents, each independently selected from halo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy; 
         wherein R b  or R m  in each occurrence is independently selected from H, C 1 -C 3  alkyl, aryl, carbonyl, —S(O) 2 —CH 3 , —(C═O)—CH 3 , —(C═O)—CF 3 , C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl and 5-6 membered heteroaryl, and wherein each R b  or R m  can optionally be substituted with one or more substituents, each independently selected from halo, C 1 -C 6  alkyl and C 1 -C 6  alkoxy; and 
         wherein R a  and R b  can fuse to form a ring, with the proviso that the compound of Formula A is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1  or pharmaceutically acceptable or physiological salts thereof, having a structure of Formula C, 
       
         
           
           
               
               
           
         
         wherein R a  is selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, and wherein R g  can optionally be substituted with one or more Rat; 
         wherein each R a1  is independently selected from halo, oxo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl, 5-10 membered heteroaryl, C 1 -C 8  alkyl and C 1 -C 8  alkoxy, wherein any two R a1  can be combined with the atoms to which they are attached to form a C 3-10  cycloalkyl or heterocycle or C 5-10  aryl or 5-10 membered heteroaryl, and wherein each R a1  can optionally be substituted by one or more substituents, each independently selected from halo, cyano and C 1 -C 6  alkyl; 
         wherein R c  is selected from H, C 1 -C 6  alkyl, C 1 -C 6  branched alkyl, C 2 -C 6  alkylene, C 2 -C 6  branched alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 1f  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, and wherein R c  can optionally be substituted with one or more substituents, each independently selected from halo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy; 
         wherein R b  or R m  in each occurrence is independently selected from H, C 1 -C 3  alkyl, aryl, carbonyl, —S(O) 2 —CH 3 , —(C═O)—CH 3 , —(C═O)—CF 3 , C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl and 5-6 membered heteroaryl, and wherein each R b  or R m  can optionally be substituted with one or more substituents, each independently selected from halo, C 1 -C 6  alkyl and C 1 -C 6  alkoxy; and 
         wherein R a  and R b  can fuse to form a ring. 
       
     
     
         3 . The compound of  claim 2  or a pharmaceutically acceptable salt thereof,
 wherein R c  is 
 
       
         
           
           
               
               
           
         
         wherein each of the above structures can be optionally substituted with one or more R d , 
         wherein each R d  is independently selected from H, halo, CF 3 , cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy, 
         wherein any two R d  can be combined with the atom to which they are attached to form a C 3-10  cycloalkyl or heterocyclyl or C 5-10  aryl or 5-10 membered heteroaryl, and 
         wherein each R d  is optionally substituted with one or more halo. 
       
     
     
         4 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein the C 5 -C 10  aryl and 5-10 membered heteroaryl in each occurrence is independently selected from 
       
         
           
           
               
               
           
         
         wherein each of the above structures can optionally substituted with one or more R e , 
         wherein each R is independently selected from H, halo, OH, CF 3 , oxo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 3 -C 10  cycloalkyl, and C 3 -C 10  heterocycle, 
         wherein any two R e  can be combined with the atoms to which they are attached to form a C 3-10  cycloalkyl or heterocyclyl or C 5-10  aryl or 5-10 membered heteroaryl, and 
         wherein each R e  is optionally substituted with one or more halo. 
       
     
     
         5 . A pharmaceutical composition, comprising:
 the compound of  claim 1  or a pharmaceutically acceptable or physiological salt thereof; and   a pharmaceutically acceptable carrier.   
     
     
         6 . A method of treating or preventing a virus infection in a subject, comprising:
 administering to the subject an effective amount of the compound of  claim 1  or a pharmaceutically acceptable or physiological salt thereof.   
     
     
         7 . The method of  claim 6 , where the virus infection is an infection of SARS-CoV-2 or a variant thereof. 
     
     
         8 . A compound of Formula B or pharmaceutically acceptable or physiological salts thereof: 
       
         
           
           
               
               
           
         
         wherein X in each occurrence is independently selected from O and S; 
         wherein Y is selected from a bond, O, CH 2 , and NR b ; 
         wherein A is a warhead, which is independently selected from 
       
       
         
           
           
               
               
           
         
         wherein R a  is selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, and wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, and wherein R a  can optionally be substituted with one or more R a1 ; 
         wherein each R a1  is independently selected from halo, oxo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl, 5-10 membered heteroaryl, C 1 -C 8  alkyl and C 1 -C 8  alkoxy, wherein any two R a1  can be combined with the atoms to which they are attached to form a C 3-10  cycloalkyl or heterocycle or C 5-10  aryl or 5-10 membered heteroaryl, and wherein each R a1  may optionally be substituted by one or more substituents, each independently selected from halo, cyano and C 1 -C 6  alkyl; 
         wherein R c  is selected from H, C 1 -C 6  alkyl, C 1 -C 6  branched alkyl, C 2 -C 6  alkylene, C 2 -C 6  branched alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, wherein each R c  can optionally be substituted with one or more substituents, each independently selected from halo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy; 
         wherein R b  or R m  in each occurrence is independently selected from H, C 1 -C 3  alkyl, aryl, carbonyl, —S(O) 2 —CH 3 , —(C═O)—CH 3 , —(C═O)—CF 3 , C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl and 5-6 membered heteroaryl, and wherein each R b  or R m  can optionally be substituted with one or more substituents, each independently selected from halo, C 1 -C 6  alkyl and C 1 -C 6  alkoxy; and 
         wherein R a  and R b  can fuse to form a ring. 
       
     
     
         9 . The compound of  claim 8  or pharmaceutically acceptable or physiological salts thereof, having a structure of Formula D 
       
         
           
           
               
               
           
         
         wherein R a  is selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, and wherein R a  can optionally be substituted with one or more R a1 ; 
         wherein each R a1  is independently selected from halo, oxo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  Spiro alkyl, C 5 -C 10  aryl, 5-10 membered heteroaryl, C 1 -C 8  alkyl and C 1 -C 8  alkoxy, wherein any two R a1  can be combined with the atoms to which they are attached to form a C 3-10  cycloalkyl or heterocycle or C 5-10  aryl or 5-10 membered heteroaryl; and wherein each R a1  can optionally be substituted by one or more substituents, each independently selected from halo, cyano and C 1 -C 6  alkyl; 
         wherein R c  is selected from H, C 1 -C 6  alkyl, C 1 -C 6  branched alkyl, C 2 -C 6  alkylene, C 2 -C 6  branched alkylene, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, heterocycle, C 4 -C 10  bridged alkyl, C 5 -C 12  spiro alkyl, C 5 -C 10  aryl and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, and wherein R c  can optionally be substituted with one or more substituents, each selected from halo, cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy; 
         wherein R b  or R m  in each occurrence is independently selected from H, C 1 -C 3  alkyl, aryl, carbonyl, —S(O) 2 —CH 3 , —(C═O)—CH 3 , —(C═O)—CF 3 , C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl and 5-6 membered heteroaryl, and wherein each R b  or R m  can optionally be substituted with one or more substituents, each independently selected from halo, C 1 -C 6  alkyl and C 1 -C 6  alkoxy; and 
         wherein R a  and R b  can fuse to form a ring. 
       
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof,
 wherein R c  is   
       
         
           
           
               
               
           
         
         wherein each of the above structures can be optionally substituted with one or more R d , 
         wherein each R d  is independently selected from H, halo, CF 3 , cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 5  alkyl and C 1 -C 5  alkoxy, 
         wherein any two R d  can combined with the atom to which they are attached to form a C 3-10  cycloalkyl or heterocyclyl or C 5-10  aryl or 5-10 membered heteroaryl, and 
         wherein each R d  is optionally substituted with one or more halo. 
       
     
     
         11 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl and heterocycle in each occurrence is independently selected 
       
         
           
           
               
               
           
         
       
       from
 wherein n=1, 2, 3, 4, 5 or 6, 
 wherein Z is selected from CH 2 , NH, O and S, 
 wherein each of the above structures can optionally substituted with one or more R f , 
 wherein each R f  is independently selected from H, halo, CF 3 , cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy, 
 wherein any two R f  can be combined with the atom to which they are attached to form a C 3-10  cycloalkyl or heterocyclyl or C 5-10  aryl or 5-10 membered heteroaryl, and 
 wherein each R f  is optionally substituted with one or more halo. 
 
     
     
         12 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein the C 4 -C 10  bridged alkyl in each occurrence is independently selected from 
       
         
           
           
               
               
           
         
         wherein Z is CH 2 , NH or O; 
         wherein each of the above structures can optionally substituted with one or more R g , 
         wherein each R g  is independently selected from H, halo, CF 3 , cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy, 
         wherein any two R g  can be combined with the atom to which they are attached to form a C 3-10 cycloalkyl or heterocyclyl or C 5-10  aryl or 5-10 membered heteroaryl, and 
         wherein each R g  is optionally substituted with one or more halo. 
       
     
     
         13 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein the spiro alkyl in each occurrence is independently selected from 
       
         
           
           
               
               
           
         
         wherein Z is CH 2 , NH, or O, 
         wherein n=0, 1, 2, 3, 4, 5, or 6, 
         wherein each of the above structures can optionally substituted with one or more R h , 
         wherein each R h  is independently selected from H, halo, CF 3 , cyano, SF 5 , —NR m R m , —NR m (C═O)R m , —S(O) 2 —R m , C 1 -C 8  alkyl and C 1 -C 8  alkoxy, 
         wherein any two R h  can combined with the atom to which they are attached to form a C 3-10  cycloalkyl or heterocyclyl or C 5-10  aryl or 5-10 membered heteroaryl, and 
         wherein each R h  is optionally substituted with one or more halo. 
       
     
     
         14 . A pharmaceutical composition, comprising:
 the compound of  claim 8  or a pharmaceutically acceptable or physiological salt thereof; and   a pharmaceutically acceptable carrier.   
     
     
         15 . A method of treating or preventing a virus infection in a subject, comprising:
 administering to the subject an effective amount of the compound of  claim 8  or a pharmaceutically acceptable or physiological salt thereof.   
     
     
         16 . The method of  claim 15 , where the virus infection is an infection of SARS-CoV-2 or a variant thereof. 
     
     
         17 .- 20 . (canceled)