Pyrrolo Pyrimidines as Agents for the Inhibition of Cystein Proteases

Abstract

The invention provides compounds of Formula I or a pharmaceutically acceptable salt or ester thereof 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 compound of formula I, or a pharmaceutically acceptable salt or ester thereof 
     
       
         
         
             
             
         
       
       wherein 
       R is H, —R2, —OR2 or NR1R2, 
       wherein R1 is H, lower alkyl or C 3  to C 10  cycloalkyl, and 
       R2 is lower alkyl or C 3  to C 10  cycloalkyl, and 
       wherein R1 and R2 are independently, optionally substituted by halo, hydroxy, lower alkoxy, CN, NO 2 , or optionally mono- or di-lower alkyl substituted amino; 
       X is ═N 
       R13 is lower alkyl, C 3  to C 10  cycloalkyl or C 3 -C 10 cycloalkyl-lower alkyl, all of which are independently optionally substituted by halo, hydroxy, CN, NO 2  or optionally mono- or di-lower alkyl-substituted amino; and 
       R14 is H or optionally substituted (aryl, aryl-W—, aryl-lower alkyl-W—, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkyl-W—, N-heterocyclyl or N-heterocyclyl-W— (wherein N-heterocyclyl is as defined above), phthalimide, hydantoin, oxazolidinone, or 2,6-dioxo-piperazine), 
       wherein —W— is —O—, —C(O)—, —NH(R6)-, —NH(R6)—C(O)—, —NH(R6)—C(O)—O—, S(O)—, —S(O) 2 — or —S—, 
       wherein R14 is optionally substituted by R18 which represents from 1 to 10 substitutents selected from halo, hydroxy, CN, NO 2 , oxo, amido, carbonyl, sulphonamido, lower-alkyldioxymethylene, or optionally substituted (lower-alkoxy, lower-alkyl, lower-alkenyl, lower alkynyl, lower alkoxy carbonyl, optionally mono- or di-lower alkyl substituted amino, aryl, aryl-lower alkyl, aryl-lower alkenyl, aryloxy, aroyl, lower-alkylsulphonyl, arylsulphonyl, N-heterocyclyl, N-heterocyclyl-lower alkyl, heterocyclyl or R14 comprising aryl has aryl fused with a hetero-atom containing ring, and wherein R18 is optionally substituted by R19 which represents from 1 to 4 substitutents selected from halo, hydroxy, CN, NO 2  or oxo, or optionally substituted (lower-alkoxy, lower-alkyl, lower-alkoxy-lower-alkyl, C 3 -C 10 cycloalkyl, lower-alkoxy carbonyl, halo-lower alkyl, optionally mono- or di-lower alkyl substituted amino, aryl, aryloxy, aroyl (e.g. benzoyl), acyl (e.g. lower-alkyl carbonyl), lower-alkylsulphonyl, arylsulphonyl or N-heterocyclyl, or N-heterocyclyl-lower alkyl (wherein N-heterocyclyl is as defined above)), wherein R19 is optionally substituted by from 1 to 4 substitutents selected from halo, hydroxy, CN, NO 2 , oxo, optionally mono- or di-lower alkyl substituted amino, lower-alkyl, or lower-alkoxy; 
       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, NR6, O, S, S(O) or S(O) 2  and wherein the N-heterocyclyl is optionally fused in a bicyclic structure 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 , and wherein heterocyclyl denotes a ring having from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O) 2 , and 
       wherein R6 is H or optionally substituted (lower alkyl, carboxy, acyl, amido, aryl, S(O) or S(O) 2 ). 
     
   
   
       2 - 4 . (canceled) 
   
   
       5 . A pharmaceutical composition comprising a compound according to  claim 1 . 
   
   
       6 . A method of 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 according to  claim 1  to a patient in need thereof. 
   
   
       7 - 8 . (canceled)