Protease inhibitors

Abstract

Compounds of the formula wherein R 1 and R 2 are independently H, F or CH 3 ; or R 1 forms an ethynyl bond and R 2 is H or C 3 -C 8 cycloalkyl which is optionally substituted with one or two substituents independently selected from methyl, CF 3 , OMe or halo; R 3 is C 1 -C 3 alkyl or C 3 -C 8 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R 3 is C 3 -C 6 cycloalkyl it may alternatively be gem subsituted with fluoro; R 4 is methyl or fluoro; m is 0, 1 or 2; E is a bond, or thiazolyl, optionally substituted with methyl or fluoro; A 1 is CH or N, A 2 is CR 6 R7 or NR 8 , provided at least one of A 1 and A 2 comprises N; R 6 is H, C-C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl, or when A 2 is C, R 6 can also be C 1 -C 4 alkoxy or F; R 7 is H, C 1 -C 4 alkyl or F or a pharmaceutically acceptable salt, N-oxide or hydrate thereof, have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases:

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         2 . A process for the preparation of a compound of the formula 
       
         
           
           
               
               
           
         
       
       comprising the step of reacting a compound of the formula 
       
         
           
           
               
               
           
         
       
       with 4-methylpiperazine-1-carbothioic acid amide. 
     
     
         3 . The process according to  claim 2 , wherein the compound of formula 
       
         
           
           
               
               
           
         
       
       is prepared by reacting a compound of the formula 
       
         
           
           
               
               
           
         
       
       with bromine in acetic acid. 
     
     
         4 . The process according to  claim 3  wherein the compound of the formula 
       
         
           
           
               
               
           
         
       
       is prepared by reacting a compound of the formula 
       
         
           
           
               
               
           
         
       
       with potassium fluoride in the presence of 18-crown-6.