Protease inhibitors

Abstract

This invention relates to treating an infection with a virus using protease inhibitors. Examples of the protease inhibitors include compounds of formula (I). Each variable is defined in the specification.

1 . A method for treating an infection with a virus, comprising administering to a subject in need thereof an effective amount of a compound of the formula (I); wherein 
       
         
           
           
               
               
           
         
         X is N(R a1 ), O, or CH 2 ; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; in which R a1  is H or C 1 -C 15  alkyl; 
         R 1  is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, C(O)R b1 , CO 2 R b1 , C(O)NR b1 R b2 , C(O)—N(R b1 )—OR b2 , C(S)R b1 , C(S)NR b1 R b2 , S(O)R b1 , SO 2 R b1 , S(O)NR b1 R b2 , S(O)—N(R b1 )—OR b2 , SO 2 NR b1 R b2 , or SO 3 R b1 ; in which each of R b1  and R b2 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         each of R 2  and R 3 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, OR c1 , SR c1 , or NR c1 R c2 ; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; in which each of R c1  and R c2 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         each of R 4  and R 5 , independently, is H, halogen, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         one of R 6  and R 7  is C 1 -C 15  alkyl substituted with C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; and the other of R 6  and R 7  is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         R 8  is H, halogen, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, OR d1 , or SR d1 ; in which R d1  is H and C 1 -C 15  alkyl; and 
         each of R 9  and R 10 , independently, is H, halogen, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, C(O)R e1 , CO 2 R e1 , C(O)NR e1 R e2 , C(O)—N(R e1 )—OR e2 , C(S)R e1 , C(S)NR e1 R e2 , CN, NO 2 , S(O)R e1 , SO 2 R e1 , S(O)NR e1 R e2 , S(O)—N(R e1 )—OR e2 , SO 2 NR e1 R e2 , SO 3 R e1 , PO(OR e1 )(OR e2 ), PO(R e1 )(R e2 ), PO(NR e1 R e2 )(OR e3), PO(NR   e1 R e2 )(NR e3 R e4 ), C(O)—N(R e1 )—NR e2 R e3 , or C(S)—N(R e1 )—NR e2 R e3 ; or R 8  and R 10 , taken together, are C 3 -C 20  cycloalkyl or C 3 -C 20  heterocycloalkyl; or R 9  and R 10 , taken together, are C 3 -C 20  cycloalkyl or C 3 -C 20  heterocycloalkyl; in which each of R e1 , R e2 , R e3 , and R e4 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; or any two of R e1 , R e2 , R e3 , and R e4 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; and 
         the virus is a coronavirus or a hepatitis C virus. 
       
     
     
         2 . The method of  claim 1 , wherein X is N(R a1 ) or O; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; R 1  is H, C(O)R b1 , CO 2 R b1 , C(O)NR b1 R b2 , C(S)NR b1 R b2 , or SO 2 R b1 ; each of R 2  and R 3 , independently, is H or C 1 -C 15  alkyl; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; each of R 4  and R 5 , independently, is H or C 1 -C 15  alkyl; one of R 6  and R 7  is C 1 -C 15  alkyl substituted with C 3 -C 20  heterocycloalkyl, and the other of R 6  and R 7  is H; R 8  is H; and each of R 9  and R 10 , independently, is H or CO 2 R c1 . 
     
     
         3 . The method of  claim 2 , wherein one of R 6  and R 7  is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 3 , wherein one of R 2  and R 3  is H or C 1 -C 15  alkyl optionally substituted with halogen, heteroaryl, aryl, OR c1 , SR c1 , OC(O)R c1 , CO 2 R c1 , C(O)NR c1 R c2 , NR c1 R c2 , N(R c1 )—CO 2 R c2 , N(R c1 )—C(O)R c2 , N(R c1 )—C(O)—NR c2 R c3 , N(R c1 )—SO 2 R c2 , SO 2 R c1 , or O—SO 2 —R c1 ; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; in which R c3  is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl. 
     
     
         5 . The method of  claim 4 , wherein one of R 4  and R 5  is H or C 1 -C 15  alkyl optionally substituted with halogen, aryl, OR f1 , SR f1 , CO 2 R f1 , C(O)NR f1 R f2 , SO 2 R f1 , SO 3 R f1 , or NR f1 R f2 ; in which each of R f1  and R f2 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl. 
     
     
         6 . The method of  claim 1 , wherein the coronavirus is a severe acute respiratory syndrome virus or a human coronavirus 229E. 
     
     
         7 . The method of  claim 1 , wherein the virus is a hepatitis C virus. 
     
     
         8 . A method for inhibiting a viral protease, comprising contacting the protease with an effective amount of a compound of the formula (I): wherein 
       
         
           
           
               
               
           
         
         X is N(R a1 ), O, or CH 2 ; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; in which R a1  is H or C 1 -C 15  alkyl; 
         R 1  is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, C(O)R b1 , CO 2 R b1 , C(O)NR b1 R b2 , C(O)—N(R b1 )—OR b2 , C(S)R b1 , C(S)NR b1 R b2 , S(O)R b1 , SO 2 R b1 , S(O)NR b1 R b2 , S(O)—N(R b1 )—OR b2 , SO 2 NR b1 R b2 , or SO 3 R b1 ; in which each of R b1  and R b2 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         each of R 2  and R 3 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, OR c1 , SR c1 , or NR c1 R c2 ; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; in which each of R c1  and R c2 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         each of R 4  and R 5 , independently, is H, halogen, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         one of R 6  and R 7  is C 1 -C 15  alkyl substituted with C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; and the other of R 6  and R 7  is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; 
         R 8  is H, halogen, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, OR d1 , or SR d1 ; in which R d1  is H and C 1 -C 15  alkyl; and 
         each of R 9  and R 10 , independently, is H, halogen, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, aryl, C(O)R e1 , CO 2 R e1 , C(O)NR e1 R e2 , C(O)—N(R e1 )—OR e2 , C(S)R e1 , C(S)NR e1 R e2 , CN, NO 2 , S(O)R e1 , SO 2 R e1 , S(O)NR e1 R e2 , S(O)—N(R e1 )—OR e2 , SO 2 NR e1 R e2 , SO 3 R e1 , PO(OR e1 )(OR e2 ), PO(R e1 )(R e2 ), PO(NR e1 R e2 )(OR e3 ), PO(NR e1 R e2 )(NR e3 R e4 ), C(O)—N(R e1 )—NR e2 R e3 , or C(S)—N(R e1 )—NR e2 R e3 ; or R 8  and R 10 , taken together, are C 3 -C 20  cycloalkyl or C 3 -C 20  heterocycloalkyl; or R 9  and R 10 , taken together, are C 3 -C 20  cycloalkyl or C 3 -C 20  heterocycloalkyl; in which each of R e1 , R e2 , R e3 , and R e4 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl; or any two of R e1 , R e2 , R e3 , and R e4 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; and 
         the viral protease is a coronaviral 3CL protease or a hepatitis C viral protease. 
       
     
     
         9 . The method of  claim 8 , wherein X is N(R a1 ) or O; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; R 1  is H, C(O)R b1 , CO 2 R b1 , C(O)NR b1 R b2 , C(S)NR b1 R b2 , or SO 2 R b1 ; each of R 2  and R 3 , independently, is H or C 1 -C 15  alkyl; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; each of R 4  and R 5 , independently, is H or C 1 -C 15  alkyl; one of R 6  and R 7  is C 1 -C 15  alkyl substituted with C 3 -C 20  heterocycloalkyl, and the other of R 6  and R 7  is H; R 8  is H; and each of R 9  and R 10 , independently, is H or CO 2 R c1 . 
     
     
         10 . The method of  claim 9 , wherein one of R 6  and R 7  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein one of R 2  and R 3  is H or C 1 -C 15  alkyl optionally substituted with halogen, heteroaryl, aryl, OR c1 , SR c1 , OC(O)R c1 , CO 2 R c1 , C(O)NR c1 R c2 , NR c1 R c2 , N(R c1 )—CO 2 R c2 , N(R c1 )—C(O)R c2 , N(R c1 )—C(O)—NR c2 R c3 , N(R c1 )—SO 2 R c2 , SO 2 R c1 , or O—SO 2 —R c1 ; or X and one of R 2  and R 3 , together with the atom or atoms to which they are bonded, are C 3 -C 20  heterocycloalkyl; in which R c3  is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl. 
     
     
         12 . The method of  claim 11 , wherein one of R 4  and R 5  is H or C 1 -C 15  alkyl optionally substituted with halogen, aryl, OR f1 , SR f1 , CO 2 R f1 , C(O)NR f1 R f2 , SO 2 R f1 , SO 3 R f1 , or NR f1 R f2 ; in which each of R f1  and R f2 , independently, is H, C 1 -C 15  alkyl, C 3 -C 20  cycloalkyl, C 3 -C 20  heterocycloalkyl, heteroaryl, or aryl. 
     
     
         13 . The method of  claim 8 , wherein the coronaviral 3CL protease is a severe acute respiratory syndrome viral 3CL protease or a human coronaviral 229E protease. 
     
     
         14 . The method of  claim 8 , wherein the viral protease is a hepatitis C viral protease. 
     
     
         15 . The method of  claim 1 , wherein the compound is one of compounds 5, 6, 8, 59, 89, 99, 102, 103, 105, 111, 112, 113, 114, 123, 124, 125, 128, 129, 133, 139, 141, and 143. 
     
     
         16 . The method of claim.  8 , wherein the compound is one of compounds 5, 6, 8, 59, 89, 99, 102, 103, 105, 111, 112, 113, 114, 123, 124, 125, 128, 129, 133, 139, 141, and 143. 
     
     
         17 . The method of  claim 1 , wherein the virus is a coronavirus. 
     
     
         18 . The method of  claim 8 , wherein the viral protease is a coronaviral 3CL protease. 
     
     
         19 . The method of  claim 17 , wherein the compound is one of compounds 5, 6, 8, 59, 89, 99, 102, 103, 105, 111, 112, 113, 114, 123, 124, 125, 128, 129, 133, 139, 141, and 143. 
     
     
         20 . The method of  claim 18 , wherein the compound is one of compounds 5, 6, 8, 59, 89, 99, 102, 103, 105, 111, 112, 113, 114, 123, 124, 125, 128, 129, 133, 139, 141, and 143. 
     
     
         21 . The method of  claim 1 , wherein the compound, is one of compounds 5, 6, 59, 102, 103, 105, 111, 112, 113, 114, 124, and 125. 
     
     
         22 . The method of  claim 8 , wherein the compound is one of compounds 5, 6, 59, 102, 103, 105, 111, 112, 113, 114, 124, and 125. 
     
     
         23 . The method of  claim 17 , wherein the compound is one of compounds 5, 6, 59, 102, 103, 105, 111, 112, 113, 114, 124, and 125. 
     
     
         24 . The method of  claim 18 , wherein the compound is one of compounds 5, 6, 59, 102, 103, 105, 111, 112, 113, 114, 124, and 125.