Inhibitors of cysteine proteases and methods of use thereof

Abstract

The disclosure provides compounds, such as compounds of Formula II, with warheads and their use in treating medical diseases or disorders, such as viral infections. Pharmaceutical compositions and methods of making various compounds with warheads are provided. The compounds are contemplated to inhibit proteases, such as the 3C, CL- or 3CL-like protease.

What is claimed: 
     
         1 . A compound represented by: 
       
         
           
           
               
               
           
         
         wherein: 
         R 3a  is selected from 
       
       
         
           
           
               
               
           
         
       
       and a 4-10 membered heterocycle;
 X is selected from CH, C(CH 3 ), and N; 
 A is cyano; 
 R 3  is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle; 
 R 3b  is selected from hydrogen and C 1 -C 8 alkyl; 
 R 1a  is selected from the group consisting of C 1 -C 8 alkyl, —(C 1 -C 8 alkyl)-R 1 , —(C 1 -C 8 alkyl)-CN, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; 
 R 1  is selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; 
 R 1b  is selected from hydrogen and C 1 -C 8 alkyl; 
 R 2  is selected from the group consisting of —NHC(O)R B , —NHC(O)N(R B ) 2 , —NHC(O)C(R C ) 2 R B , —NHS(O) 2 R B , 4-10 membered heterocycle, C 6 -C 14 aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R 2  may optionally be substituted by one, two, or three substituents each selected from R x ; 
 R C  is independently selected, for each occurrence, from hydrogen and C 1 -C 8 alkyl; 
 R 1a  and R 2  may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C 3 -C 10 cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from R A ; 
 R B  is independently selected, for each occurrence, from the group consisting of C 1 -C 8 alkyl, C 2 -C 10 alkenyl, and C 2 -C 10 alkynyl; 
 R A  is independently selected, for each occurrence, from the group consisting of halogen, cyano, hydroxyl, oxo, SF 5 , —NH 2 , —O-phenyl, —O—(C 1 -C 8 alkyl)-phenyl, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH 3 ) 3 , —C(O)—(C 2 -C 10 alkenyl)-(C 6 -C 14 aryl), C 1 -C 8 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 8 heteroalkyl, C 1 -C 8 alkoxy, C 3 -C 10 cycloalkyl, —(C 1 -C 8 alkyl)-(C 6 -C 14 aryl), —(C 1 -C 8 alkyl)-(5-10 membered heteroaryl), C 6 -C 14 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; 
 R x  is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF 5 , cyano, —C(O)O(CH 3 ), —N(R y ) 2 , —N(R y )C(O)R y , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; and 
 R y  is independently selected, for each occurrence, from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —(C 1 -C 8 alkoxy)-(5-10 membered aryl) and C 3 -C 6 cycloalkyl. 
 
     
     
         2 . A compound represented by: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is selected from the group consisting of C 1 -C 8 alkyl, —(C 1 -C 8 alkyl)-R 1 , —(C 1 -C 8 alkyl)-CN, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; 
         R 1  is selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R 1  may optionally be substituted by one, two, or three substituents each selected from R A ; 
         R 1b  is selected from hydrogen and C 1 -C 8 alkyl; 
         R 2  is selected from the group consisting of —NHC(O)R B , —NHC(O)N(R B ) 2 , —NHC(O)C(R C ) 2 R B , —NHS(O) 2 R B , 4-10 membered heterocycle, C 6 -C 14 aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R 2  may optionally be substituted by one, two, or three substituents each selected from R x ; 
         R C  is independently selected, for each occurrence, from hydrogen and C 1 -C 8 alkyl; 
         R 1a  and R 2  may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C 3 -C 10 cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from R A ; 
         R B  is independently selected, for each occurrence, from the group consisting of C 1 -C 8 alkyl, C 2 -C 10 alkenyl, and C 2 -C 10 alkynyl, 
         R A  is independently selected, for each occurrence, from the group consisting of halogen, cyano, hydroxyl, oxo, SF 5 , —NH 2 , —O-phenyl, —O—(C 1 -C 8 alkyl)-phenyl, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH 3 ) 3 , —C(O)—(C 2 -C 10 alkenyl)-(C 6 -C 14 aryl), C 1 -C 8 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 8 heteroalkyl, C 1 -C 8 alkoxy, C 3 -C 10 cycloalkyl, —(C 1 -C 8 alkyl)-(C 6 -C 14 aryl), —(C 1 -C 8 alkyl)-(5-10 membered heteroaryl), C 6 -C 14 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; 
         R x  is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF 5 , cyano, —C(O)O(CH 3 ), —N(R y ) 2 , —N(R y )C(O)R y , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; and 
         R y  is independently selected, for each occurrence, from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —(C 1 -C 8 alkoxy)-(5-10 membered aryl) and C 3 -C 6 cycloalkyl.