Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin K inhibitory activity for the treatment of inflammations and other diseases

Abstract

The invention provides compounds of formula I or a pharmaceutically acceptable salt or ester thereof (I), wherein the symbols have meaning as defined, which are inhibitors of cathepsin K and find use pharmaceutically for treatment of diseases and medical conditions in which cathepsin K is implicated, e.g., various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumors.

1 . A method for treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof  
     
       
         
         
             
             
         
       
     
     wherein 
 R is H, —R4, —OR4 or NR3R4,  
 wherein R3 is H, lower alkyl or C 3  to C 10  cycloalkyl, and  
 R4 is lower alkyl or C 3  to C 10  cycloalkyl,  
 wherein R3 and R4 are independently, optionally substituted by halo, hydroxy, lower alkoxy, CN, NO 2 , or optionally mono- or di-lower alkyl substituted amino;  
 R1 is —CO—NR5R6, —NH—CO—R5, —CH 2 —NH—C(O)—R5, —CO—R5, —S(O)—R5, —S(O) 2 —R5, —CH 2 —CO—R5 or —CH 2 —NR5R6,  
 wherein  
 R5 is aryl, aryl-lower alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl,  
 R6 is H, aryl, aryl-lower alkyl, aryl-lower-alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, or  
 wherein R5 and R6 together with the nitrogen atom to which they attached are joined to form an N-heterocyclyl group,  
 wherein N-heterocyclyl denotes a saturated, partially unsaturated or aromatic nitrogen containing heterocyclic moiety attached via a nitrogen atom thereof having from 3 to 8 ring atoms optionally containing a further 1, 2 or 3 heteroatoms selected from N, NR7, O, S, S(O) or S(O) 2  wherein R7 is H or optionally substituted (lower alkyl, carboxy, acyl (including both lower alkyl acyl, e.g. formyl, acetyl or propionyl, or aryl acyl, e.g. benzoyl), amido, aryl, S(O) or S(O) 2 ), and wherein the N-heterocyclyl is optionally fused in a bicyclic structure, e.g. with a benzene or pyridine ring, and wherein the N-heterocyclyl is optionally linked in a spiro structure with a 3 to 8 membered cycloalkyl or heterocyclic ring wherein the heterocyclic ring has from 3 to 10 ring members and contains from 1 to 3 heteroatoms selected from N. NR6, O, S, S(O) or S(O) 2  wherein R6 is as defined above), and  
 wherein heterocyclyl denotes a ring having from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, NR7, O, S, S(O) or S(O) 2  wherein R7 is as defined above), and  
 wherein R5 and R6 are independently, optionally substituted by one or more groups, e.g. 1-3 groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or NO 2 , or optionally substituted (optionally mono- or di-lower alkyl substituted amino, lower alkoxy, aryl, aryl-lower alkyl, N-heterocyclyl or N-heterocyclyl-lower alkyl) wherein the optional substitution comprises from 1 to 3 substituents selected from halo, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-carbonyl CN, NO 2 , optionally mono- or di-lower alkyl substituted amino, N-heterocyclyl or N-heterocyclyl-lower alkyl or optionally mono- or di-lower alkyl substituted amino;  
 R2 is is independently H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl), and  
 wherein R2 is optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN, NO 2 , or optionally mono- or di-lower alkyl substituted amino.  
 
   
   
       2 - 12 . (canceled)