Soft protease inhibitors and pro-soft forms thereof

Abstract

The invention provides compounds and methods for inhibiting proteases. One aspect of the invention features pro-soft inhibitors which react with an activating protease to release an active inhibitor moiety in proximity to a target protease. In certain instances, compounds inhibit proteasomes and/or post-proline cleaving enzymes (PPCE), such as dipeptidyl peptidase IV. The compounds of the invention provide a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.

1 - 64 . (canceled) 
     
     
         65 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by: 
       
         
           
           
               
               
           
         
         or a pharmaceutical acceptable salt thereof; wherein, independently for each occurrence: 
         R 1  represents hydrogen, a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog; 
         R 9a  represents hydrogen or alkyl; 
         R 9b  represents hydrogen or alkyl; 
         R 10  represents the side chain of a natural or non-natural amino acid; 
         R 11  represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, or the side chain of a natural or non-natural amino acid; and 
         Y 1  and Y 2 , independently, are OH, or a group capable of being hydrolyzed to a hydroxyl group, or Y 1  and Y 2  are connected via a ring having from 5 to 8 atoms in the ring structure which is capable of being hydrolyzed to two hydroxyl groups. 
       
     
     
         66 . The method of  claim 65 , wherein R 1  is H. 
     
     
         67 . The method of  claim 65 , wherein R 9b  is alkyl. 
     
     
         68 . The method of  claim 65 , wherein R 9b  is methyl. 
     
     
         69 . The method of  claim 65 , wherein Y 1  and Y 2  are OH. 
     
     
         70 . The method of  claim 69 , wherein R 9b  is alkyl. 
     
     
         71 . The method of  claim 69 , wherein R 9b  is methyl. 
     
     
         72 . The method of  claim 65 , wherein:
 R 1 , R 9a  and R 11  are hydrogen;   R 10  is —(CH 2 ( 2 CO 2 H;   R 9b  is methyl; and   Y 1  and Y 2  are each OH.   
     
     
         73 . The method of  claim 69 , wherein said compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         74 . The method of  claim 65 , wherein R 1  is a proline, glutamate, or alanine residue. 
     
     
         75 . The method of  claim 65 , wherein R 1  is an alanine residue. 
     
     
         76 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         77 . The method of  claim 76 , wherein the compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         78 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         79 . The method of  claim 65 , wherein the compound is a protease inhibitor. 
     
     
         80 . The method of  claim 79 , wherein the compound inhibits dipeptidyl peptidase VIII and IX with a Ki of 100 μM or greater. 
     
     
         81 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein, independently for each occurrence: 
         W represents —CN, —CH=NR 5 , 
       
       
         
           
           
               
               
           
         
         R 1  represents a C-terminally linked peptide or peptide analog which is a substrate for an activating enzyme; 
         R 3  represents a hydrogen or lower alkyl; 
         R 4  represents hydrogen, halogen, lower alkyl, lower alkenyl, or lower alkynyl; 
         R 5  represents independently for each occurrence H, alkyl, alkenyl, alkynyl, —C(X 1 )(X 2 )X 3 , —(CH 2 ) m —R 7 , —(CH 2 ) n —OH, —(CH 2 ) n —O-alkyl, —(CH 2 ) n —O-alkenyl, —(CH 2 ) n —O-alkynyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) n —SH, —(CH 2 ) n —S-alkyl, —(CH 2 ) n —S-alkenyl, —(CH 2 ) n —S-alkynyl, —(CH 2 ) n —S—(CH 2 ) m —R 7 , —C(O)C(O)NH 2 , or —C(O)C(O)OR′ 7 ; 
         R 6  represents independently for each occurrence a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; 
         R 7  represents independently for each occurrence hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; 
         R 8  represents hydrogen, —CH 3 , or —(CH 2 ) n —CH 3 ; 
         Y 1  and Y 2  are independently OH, or a group capable of being hydrolyzed to a hydroxyl group, or Y 1  and Y 2  are connected via a ring having from 5 to 8 atoms in the ring structure which is capable of being hydrolyzed to two hydroxyl groups; 
         R 10  represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, or the side chain of a natural or non-natural amino acid; 
         R 50  represents O or S; 
         R 51  represents N 3 , SH, NH 2 , NO 2  or —OR 7 ; 
         R 52  represents hydrogen, a lower alkyl, an amine, —OR 7 , or a pharmaceutically acceptable salt, or R 51  and R 52  taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; 
         X 1  represents a halogen; 
         X 2  and X 3  each represent a hydrogen or a halogen; 
         m is zero or an integer in the range of 1 to 8; and 
         n is an integer in the range of 1 to 8. 
       
     
     
         82 . The method of  claim 81 , wherein W is —B(Y 1 )(Y 2 ). 
     
     
         83 . The method of  claim 81 , wherein R 4  represents hydrogen or lower alkyl. 
     
     
         84 . The method of  claim 81 , wherein R 5  represents H or alkyl. 
     
     
         85 . The method of  claim 81 , wherein Y 1  and Y 2  are OH. 
     
     
         86 . The method of  claim 81 , wherein W is —B(OH) 2 . 
     
     
         87 . The method of  claim 81 , wherein said compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         88 . The method of  claim 87 , wherein R 4  represents hydrogen or lower alkyl. 
     
     
         89 . The method of  claim 81 , wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         90 . The method of  claim 81 , wherein the compound is selected from the group consisting of: