Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis

Abstract

Peptido and peptidomimetic compounds of the formula: wherein the formula variables are as defined in the disclosure, advantageously inhibit or block the biological activity of the picornaviral 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picornaviruses, such as RVP. Intermediates and synthetic methods for preparing such compounds are also provided.

1 . A compound of the formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 Y is —N(R y )—, —C(R y )(R y )—, or —O—, where each R y  is independently H or lower alkyl;  
 R 1  is H, F, an alkyl group, OH, SH, or an O-alkyl group;  
 R 2  and R 3  are each independently H;  
                     
 where n is an integer from 0 to 5, A 1  is CH or N, A 2  and each A 3  are independently selected from C(R 41 )(R 41 ), N(R 41 ), S, S(O), S(O) 2 , and 0, and A 4  is NH or NR 41 , where each R 41  is independently H or lower alkyl, provided that no more than 2 heteroatoms occur consecutively in the ring formed by A 1 , A 2 , (A 3 ) n , A 4  and C═O; and provided that at least one of R 2  and R 3  is  
                     
 R 5  and R 6  are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;  
 R 7  and R 8  are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR 17 , —SR 17 , —NR 17 R 18 , NR 19 NR 17 R 18 , or —NR 17 OR 18 , where R 17 , R 18 , and R 19  are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;  
 R 9  is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S, or R 9  is  
                     
 where R 2  is  
                     
 and  
 Z and Z 1  are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R 21 , —CO 2 R 21 , —CN, —C(O)NR 21 ,R 22 , —C(O)NR 21 OR 22 , —C(S)R 21 , —C(S)NR 21 R 22 , —NO 2 , —SOR 21 , —SO 2 R 21 , —SO 2 NR 21 R 22 , —SONR 21 )(OR 22 ), —SONR 21 , —SO 3 R 21 , —PO(OR 21 ) 2 , —PO(R 21 )(R 22 ), —PO(NR 21 R 22 )(OR 23 ), PO(NR 21 R 22 )(NR 23 R 24 ), —C(O)NR 21 NR 22 R 23 , or —C(S)NR 21 NR 22 R 23 , where R 21 , R 22 , R 23 , and R 24  are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or any two of R 21 , R 22 , R 23 , and R 24 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z, are not both H;  
 or Z 1  and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group;  
 or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group;  
 or a prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate thereof.