Spiro-substituted pyrrolopyrimidines

Abstract

The invention provides compounds of formula I or a pharmaceutically acceptable salt or ester thereof formula I wherein the symbols have the meaning as defined in the description. Said compounds are inhibitors of cathepsin K and/or cathepsin S and are useful for the treatment of diseases and medical conditions in which cathepsin K and or cathepsin S is implicated, e.g. various disorders including neuropathic pain, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis and tumours.

1 . A compound of formula I, or a pharmaceutically acceptable salt or ester thereof: 
     
       
         
         
             
             
         
       
     
     wherein E is a radical of formula a or formula b 
     
       
         
         
             
             
         
       
     
     wherein
 A is CH 2 , CH 2 —CH 2  or C═O; 
 
     
       
         
         
             
             
         
       
       B is CH 2 , C═O or 
       D is CH 2 , or C═O; 
       G is CH 2 , CH 2 C═O or CH 2 —CH 2 ; 
       J is CH 2 , C═O or CH 2 —CH 2 ; 
       M is CH 2  or NH; 
       Q is H, lower alkyl, hydroxy substituted lower alkyl, optionally substituted aryl lower alkyl, lower alkyl sulfonyl, carbocyclic aryl lower alkyl, lower alkoxy-substituted carbocyclic aryl lower alkyl, halo-substituted carbocyclic aryl lower alkyl, N-heterocyclyl-substituted lower alkyl, lower alkoxy substituted carbocyclic aryl, amino carbonyl, cycloalkyl amino carbonyl, N-heterocyclyl substituted lower alkyl carbonyl, halo-substituted carbocyclic aryl lower alkyl, lower alkoxy carbonyl, or lower alkyl carbonyl; and 
       R is lower alkyl, para-chlorophenylethyl, cyclohexylethyl, dimethylbutyl, difluorocyclohexylethyl, cyclopentylethyl or cycloheptylethyl. 
     
   
   
       2 . A compound of formula I-(i) or a pharmaceutically acceptable salt or ester thereof 
     
       
         
         
             
             
         
       
     
     wherein
 Q-i is H, lower alkyl, hydroxyl-substituted lower alkyl, N-heterocyclyl substituted lower alkyl, mono or di-substituted aryl lower alkyl, lower alkoxy substituted carbocyclic aryl lower alkyl; 
 and 
 R is as defined in  claim 1 . 
 
   
   
       3 . (canceled) 
   
   
       4 . A compound of formula I-(iii) or a pharmaceutically acceptable salt or ester thereof 
     
       
         
         
             
             
         
       
     
     wherein
 B-iii is CH 2 ; 
 G-iii is CH 2 CH 2 ; 
 J-iii is CH 2 CH 2 ; 
 Q-iii is H, cycloalkyl amino carbonyl, amino carbonyl, lower alkoxy substituted carbocyclic aryl, lower alkyl carbonyl, carbocyclic aryl lower alkyl or N-heterocyclyl substituted lower alkyl carbonyl; and 
 R is as defined in  claim 1 . 
 
   
   
       5 . A compound of  claim 1 , wherein R is R1 which is lower alkyl. 
   
   
       6 . A compound of  claim 1 , wherein R is R2 which is para-chlorophenylethyl, cyclohexylethyl, dimethylbutyl, difluorocyclohexylethyl, cyclopentylethyl or cycloheptylethyl. 
   
   
       7 . A compound of  claim 1 , wherein R is R5 which is 2,2-dimethyl-propyl. 
   
   
       8 . A compound of  claim 1 , wherein R is R6 which is 3,3-dimethyl-butyl. 
   
   
       9 . A compound of formula I-(iv) or a pharmaceutically acceptable salt or ester thereof 
     
       
         
         
             
             
         
       
     
     wherein
 R3 is (8-lower alkyl-carbonyl)-2,8-diaza-spiro[4.5]dec-2-ylmethyl, (8-lower alkyl-sulfonyl)-2,8-diaza-spiro[4.5]dec-2-ylmethyl, (8-aryl-lower alkyl)-2,8-diaza-spiro[4.5]dec-2-ylmethyl, 
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       R4 is para-chlorophenylmethyl, cyclohexylmethyl, dimethylpropyl, difluorocyclohexylmethyl, cyclopentylmethyl or cycloheptylmethyl; and 
       Q is as defined in  claim 1 . 
     
   
   
       10 - 11 . (canceled) 
   
   
       12 . A pharmaceutical composition comprising an excipient and a compound according to  claim 1  as an active ingredient. 
   
   
       13 . A method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K and/or cathepsin S is implicated, comprising administering an effective amount of a compound according to  claim 1  to the patient. 
   
   
       14 . (canceled) 
   
   
       15 . A process for the preparation of a compound of  claim 1  comprising coupling a compound of 
     formula II 
     
       
         
         
             
             
         
       
     
     wherein Q is defined in  claim 1 , 
     with a compound of formula III 
     
       
         
         
             
             
         
       
     
     wherein X is a halo and R is defined in  claim 1 ; and recovering the resulting compound in free base, or in a pharmaceutically acceptable salt or ester thereof.