Peptide-containing alpha-ketoamide cysteine and serine protease inhibitors

Abstract

This invention relates to peptide-containing α-ketoamide inhibitors of cysteine and serine proteases, methods for making these compounds, and methods for using the same.

1 . A compound having the Formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Q has the formula G-B-(CHR 4 ) v  where R 4  is independently H or alkyl having from 1 to 4 carbons;  
 v is 0;  
 B is selected from the group consisting of —C(═O)—, —OC(═O)—, —S—, —SO—, —S(O) 2 — and a bond;  
 M is a carbon atom;  
 G is selected from the group consisting of H, a blocking group, lower alkyl, lower alkenyl, aryl having from about 6 to about 14 carbons, and arylalkyl having from about 7 to about 15 carbons, said alkyl and arylalkyl groups being optionally substituted with one or more J groups;  
 J is selected from the group consisting of halogen, CN, nitro, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, halogenated alkyl, aryloxyalkyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, arylalkyl, arylalkyloxy, arylsulfonyl, heteroarylsulfonyl, alkoxycarbonyl, alkoxyalkyl, acyl, alkoxy, hydroxy, carboxy, hydroxyalkyl, amino, alkylamino, and aminoalkyl, said amino group or said amino group of said aminoalkyl or alkylamino group being optionally substituted with an acyl group, an alkoxy group, or with 1 to 3 aryl, lower alkyl, cycloalkyl, or alkoxyalkyl groups; and said aryl, heteroaryl, heterocycloalkyl, and heteroalkyl groups being further optionally substituted by a J 1  group;  
 J 1  is selected from the group consisting of halogen, CN, nitro, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, halogenated alkyl, aryloxyalkyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, arylalkyl, arylalkyloxy, arylsulfonyl, heteroarylsulfonyl, alkoxycarbonyl, alkoxyalkyl, acyl, alkoxy, hydroxy, carboxy, hydroxyalkyl, amino, alkylamino, and aminoalkyl, said amino group or said amino group of said aminoalkyl or alkylamino group being optionally substituted with an acyl group, an alkoxy group, or with 1 to 3 aryl, lower alkyl, cycloalkyl, or alkoxyalkyl groups; and said aryl, heteroaryl, heterocycloalkyl, and heteroalkyl groups being further optionally substituted by a J 2  group;  
 J 2  is selected from a group consisting of halogen, CN, nitro, lower alkyl, halogenated alkyl, alkylthio, alkylsulfonyl, alkoxycarbonyl, alkoxyalkyl, acyl, alkoxy, hydroxy, carboxy, hydroxyalkyl, amino, alkylamino, and aminoalkyl;  
 each Aaa is independently an amino acid;  
 n is 0 or 1;  
 R 1  is selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, alkoxyalkyl, and a side chain of a naturally occurring amino acid in the R or S configuration, said alkyl, arylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups;  
 R 2  is benzyl;  
 R 3  is selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, alkoxyalkyl, a side chain of a naturally occurring amino acid in the R or S configuration, C(═O)R 7 , S(═O) 2 R 7 , a blocking group, and said alkyl, arylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups;  
 R 7  is selected from the group consisting of aryl having from about 6 to about 14 carbons, heteroaryl having from about 5 to about 14 ring atoms, arylalkyl having from about 7 to about 15 carbons, alkyl having from 1 to about 10 carbons, said aryl, heteroaryl, arylalkyl and alkyl groups being optionally substituted with one or more J groups, heteroalkyl having from 2 to about 7 carbons, alkoxy having from about 1 to about 10 carbons, and amino optionally substituted with 1 or more alkyl groups;  
 q is 0 or 1;  
 Z is C(═O)C(═O)NH—X-A 1 -K;  
 X is a bond;  
 A 1  is lower alkylene;  
 K is N(R 10 )SO 2 R 8  or SO 2 N(R 8 )(R 10 );  
 R 8  is thiophene, said thiophene being substituted with one or more J groups;  
 R 10  is selected from the group consisting of H and lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The compound of  claim 1  wherein n is 0, q is 1, B is a bond, and G is H.  
   
   
       3 . The compound of  claim 1  wherein R 1  is the sidechain of a naturally occurring amino acid.  
   
   
       4 . The compound of  claim 1  wherein R 3  is —S(═O) 2 R 7 .  
   
   
       5 . The compound of  claim 1  wherein A 1  is —CH 2 —CH 2 —, —CH 2 —CH(CH 3 )— or —CH 3 (CH)—CH 2 —.  
   
   
       6 . The compound of  claim 1  wherein R 1  is a serine sidechain, which is optionally capped with a benzyl group.  
   
   
       7 . The compound of  claim 6  wherein M is a carbon atom in the D configuration.  
   
   
       8 . The compound of  claim 1  wherein R 7  is methyl.  
   
   
       9 . The compound of  claim 1  wherein n is 0, q is 1, R 1  is the side chain of an amino acid in the D- or L-configuration, R 3  is S(═O) 2 R 7 , G is H and B is a bond.  
   
   
       10 . The compound of  claim 1  wherein R 1  is a serine side chain in the D-configuration in which the hydroxyl group is capped with benzyl and R 7  is methyl.  
   
   
       11 . The compound of  claim 1  wherein n and q are each 0; B is (C═O); and G is phenyl or lower alkyl, said phenyl or lower alkyl groups being optionally substituted with one or more J groups.  
   
   
       12 . A composition for inhibiting a serine protease or a cysteine protease comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       13 . A method for inhibiting a serine protease or a cysteine protease comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of  claim 1.