Cysteine protease inhibitors

Abstract

Compounds of the formula I wherein R 2a and R 2b are independently H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy, or R 2a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; R 3 is a C 5 -C 10 alkyl, optionally substituted with 1-3 substituents independently selected from halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy; or R 3 is a C 2 -C 4 alkyl chain with at least 2 chloro or 3 fluoro substituents; or R 3 is C 3 -C 7 cycloalkylmethyl, optionally substituted with 1-3 substituents independently selected from C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy; R 4 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino or; R 4 is Het or Carbocyclyl, either of which is optionally substituted with 1-3 substituents R 4 is Het, carbocyclyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy; n is 1, 2 or 3; for the use in the prophylaxis or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S.

1 . A compound of the formula IV: 
       
         
           
           
               
               
           
         
         wherein 
         Pg is an amino protecting group; 
         n is 2; and 
         R 2a  and R 2b  are independently H or F. 
       
     
     
         2 . A compound of the formula 2a: 
       
         
           
           
               
               
           
         
         wherein 
         Pg is an amino protecting group; 
         n is 2; 
         R 2a  and R 2b  are independently H or F; and 
         R 3  is 1-methylcyclopentylmethyl or 1-fluorocyclopentylmethyl. 
       
     
     
         3 . A compound of the formula 2b: 
       
         
           
           
               
               
           
         
         wherein 
         n is 2; 
         R 2a  and R 2b  are independently H or F; 
         R 3  is 1-methylcyclopentylmethyl or 1-fluorocyclopentylmethyl; and 
         R 4  is C 1 -C 6 alkyl C 1 -C 6 haloalkyl or C 3 -C 6 cycloalkyl, wherein C 3 -C 6 cycloalkyl is optionally substituted with methyl, CF 3  or one or two fluoro. 
       
     
     
         4 . A compound according to any one of  claims 1  to  3 , wherein Pg is Boc, CBz or Fmoc. 
     
     
         5 . A compound according to any one of  claims 1  to  3 , wherein R 2a  and R 2b  are both H. 
     
     
         6 . A compound having the formula IV-a: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A process for the preparation of a compound of formula III, 
       
         
           
           
               
               
           
         
         wherein 
         R 2a  and R 2b  are independently H or F; 
         R 3′  is CH 3  or F; 
         R 4  is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 6 cycloalkyl, wherein C 3 -C 6 cycloalkyl is optionally substituted with methyl, CF 3  or one or two fluoro, 
         comprising the step of oxidising the compound of formula 2b, 
       
       
         
           
           
               
               
           
         
         wherein 
         n is 2; and 
         R 3  is 1-methylcyclopentylmethyl or 1-fluorocyclopentylmethyl. 
       
     
     
         8 . The process according to  claim 7 , wherein the compound of formula 2b is prepared by a process comprising the step of removing the N-protecting group from a compound of formula 2a, followed by coupling of a P3 building block as outlined in the scheme: 
       
         
           
           
               
               
           
         
       
       wherein Pg is an amino protecting group and n, R 2a , R 2b , R 3  and R 4  are as defined in  claim 7 . 
     
     
         9 . The process according to  claim 8 , wherein the compound of formula 2a is prepared by a process comprising the step of removing the N-protecting group from a compound of formula IV, followed by coupling of a P2 building block as outlined in the scheme: 
       
         
           
           
               
               
           
         
       
       wherein Pg, n, R 2a , R 2b  and R 3  are as defined in  claim 8 . 
     
     
         10 . The process according to any one of  claims 7  to  9 , for the preparation of a compound of formula IIIc: 
       
         
           
           
               
               
           
         
       
       wherein R 2a  and R 2b  are H, R 3  is 1-fluorocyclopentylmethyl and R 4  is 1,1,1-trifluoro-2-methylpropan-2-yl. 
     
     
         11 . The process according to any one of  claims 7  to  9 , for the preparation of a compound of formula IIId: 
       
         
           
           
               
               
           
         
       
       wherein R 2a  and R 2b  are H, R 3  is 1-fluorocyclopentylmethyl and R 4  is 1,1-difluoroethyl. 
     
     
         12 . A process for the preparation of a compound of  claim 3 , comprising the step of removing the N-protecting group from the compound of formula 2a, followed by coupling of a P3 building block as outlined in the scheme: 
       
         
           
           
               
               
           
         
         wherein 
         Pg is an amino protecting group; 
         n is 2; 
         R 2a  and R 2b  are independently H or F; 
         R 3  is 1-methylcyclopentylmethyl or 1-fluorocyclopentylmethyl; 
         R 4  is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 6 cycloalkyl, wherein C 3 -C 6 cycloalkyl is optionally substituted with methyl, CF 3  or one or two fluoro. 
       
     
     
         13 . The process according to  claim 12 , wherein the compound of formula 2a is prepared by a process comprising the step of removing of the N-protecting group from the compound of formula IV, followed by coupling of a P2 building block as outlined in the scheme: 
       
         
           
           
               
               
           
         
         wherein Pg, n, R 2a , R 2b  and R 3  are as defined in  claim 12 . 
       
     
     
         14 . A process for the preparation of a compound of  claim 2  comprising the step of removal of the N-protecting group from the compound of formula IV, followed by coupling of a P2 building block as outlined in the scheme: 
       
         
           
           
               
               
           
         
         wherein Pg is an amino protecting group; 
         n is 2; 
         R 2a  and R 2b  are independently H or F; and 
         R 3  is 1-methylcyclopentylmethyl or 1-fluorocyclopentylmethyl.