Cysteine Protease Inhibitors

Abstract

A compound of the formula II wherein one of R 1 and R 2 is halo and the other is H or halo; R 3 is C 1 -C 4 straight or branched chain, optionally fluorinated, alkyl; R 4 is H; or R 3 together with R 4 and the adjoining backbone carbon defines: a spiro-C 5 -C 7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; or optionally bridged with a methylene group; or a C 4 -C 6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(═O) 2 ; where Ra is H, C 1 -C 4 alkyl or CH 3 C(═O); R 5 is independently selected from H or methyl; E is —C(═O)—, —S(═O) m —, —NR 5 S(═O) m —, —NR 5 C(═O)—, —OC(═O)—, R 6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle; m is independently 0, 1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.

1 .- 28 . (canceled) 
     
     
         29 . A method of treatment of disorders mediated by cathepsin K comprising administering to a patient in need of thereof an effective amount of a compound of formula II 
       
         
           
           
               
               
           
         
         wherein 
         one of R 1  and R 2  is halo and the other is H or halo; 
         R 3  is C 1 -C 5  straight or branched chain, optionally fluorinated, alkyl; 
         R 4  is H; or 
         R 3  together with R 4  defines
 a spiro-C 5 -C 7  cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C 1 -C 4  alkyl or C 1 -C 4  haloalkyl; or optionally bridged with a methylene group: or 
 a C 4 -C 6  saturated heterocycle having a hetero atom selected from
 O, NRa, S, S(═O) 2 ; 
 
 
         R 5  is independently selected from H or methyl; 
         E is —C(═O)—, —S(═O) m —, —NR 5 S(═O) m —, —NR 5 C(═O)—, —OC(═O)—, 
         R 6  is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle wherein the or each ring has 4, 5 or 6 ring atoms and 0 to 3 hetero atoms selected from S, O and N and wherein the optional substituents comprise 1 to 3 members selected from R 7 ; 
         R 7  is independently selected from halo, oxo, nitrile, nitro, C 1 -C 4  alkyl, —XNRaRb, —XNRbR 9 , —NRbC 1 -C 4 alkylR 9 , NH 2 CO—, X—R 9 , X—O—R 9 , O—X—R 9 , X—C(═O)R 9 , X—(C═O)NRaR 9 , X—NRbC(═O)R 9 , X—NHSO m R 9 , X—S(═O) m R 9 , X—C(═O)OR 9 , X—NRbC(═O)OR 9 ; 
         R 9  is independently H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, phenyl, any of which is optionally substituted with R 10 ; 
         R 10  is independently selected from hydroxy, XR 9 , —XNRaRb, —XNRbR 9 , —NRbC 1 -C 4 alkylR 9 , nitro, cyano, carboxy, oxo, C 1 -C 4  alkyl, C 1 -C 4 -alkoxy, C 1 -C 4  alkanoyl, carbamoyl; 
         X is independently a bond or C 1 -C 4  alkyl; 
         Ra is independently H, C 1 -C 4  alkyl or CH 3 C(═O); 
         Rb is independently H, or C 1 -C 4  alkyl 
         m is independently 0, 1 or 2; 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         30 . The method according to  claim 29 , wherein the disorder is selected from the group consisting of:
 osteoporosis,   gingival diseases such as gingivitis and periodontitis,   Paget's disease,   hypercalcaemia of malignancy   metabolic bone disease   diseases characterised by excessive cartilege or matrix degradation, such as osteoarthritis and rheumatoid arthritis.   bone cancers including neoplasia, and   pain.