Novel compounds and compositions as protease inhibitors

Abstract

The present invention relates to novel cysteine protease inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.

We claim:  
     
         1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 X 1  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 X 2  and X 3  independently are —C(O)— or —CH 2 S(O) 2 —;  
 R 7  and R 8  are independently (i) (C 1-6 )alkyl optionally substituted with cyano, halo, nitro, —NR 10 R 10 , —NR 10 C(O)OR 10 , —NR 10 C(O)NR 10 R 10 , —NR 10 C(NR 10 )NR 10 R 10 , —OR 10 , —SR 10 , —C(O)OR 10 , —C(O)NR 10 R 10 , —S(O) 2 NR 10 R 10 , —P(O)(OR 10 )OR 10 , —OP(O)(OR 10 )OR 10 , —NR 10 C(O)R 11 , —S(O)R 11 , —S(O) 2 R 11 , —C(O)R 11 , —OR 12 , —SR 2 , —S(O)R 12 , —S(O) 2 R 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —NR 12 R 13 , —NR 13 C(O)R 12 , —NR 13 C(O)OR 12 , —C(O)NR 12 R 13 , —S(O) 2 NR 12 R 13 , —NR 13 C(O)NR 12 R 13  or —NR 13 C(NR 13 )NR 12 R 13 , wherein R 10  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 11  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 12  is (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl or hetero(C 5-2 )aryl(C 0-3 )alkyl and R 13  is hydrogen or (C 1-6 )alkyl, and wherein within R 12  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 14 , —X 4 OR 4 , —X 4 SR 14 , —X 4 S(O)R 4 , —X 4 S(O) 2 R 14 , —X 4 C(O)R 14 , —X 4 C(O)OR 14 , —X 4 OC(O)R 14 , —X 4 NR 15 , —X 4 NR 15 C(O)R 14 , —X 4 NR 15 C(O)OR 14 , X 4 C(O)NR 14 R 15 , —X 4 S(O) 2 NR 14 R 15 , —X 4 NR 15 C(O)NR 14 R 15  or —X 4 NR 15 C(NR 15 )NR 14 R 15 , wherein X 4  is a bond or (C 1-6 )alkylene, R 14  is hydrogen or (C 1-6 )alkyl and R 15  is (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-2 )aryl(C 0-6 )alkyl, hetero(C 5-2 )aryl(C 0-6 )alkyl, (C 9-12 )polycycloaryl(C 0-6 )alkyl or hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl, or (ii) (C 3-12 )cycloalkyl(C 0-3 )alkyl, heterocyclo(C 3-12 )alkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )polycycloaryl(C 0-3 )alkyl or hetero(C 8-12 )polycycloaryl(C 0-3 )alkyl, wherein within R 15  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 14 , —X 4 OR 4 , —X 4 SR 14 , —X 4 S(O)R 14 , —X 4 S(O) 2 R 14 , —X 4 C(O)R 14 , X 4 C(O)OR 14 , —X 4 OC(O)R 14 , —X 4 NR 14 R 15 , —X 4 NR 15 C(O)R 14 , —X 4 NR 15 C(O)OR 14 , —X 4 C(O)NR 14 R 15 , —X 4 S(O) 2 NR 14 R 15 , —X 4 NR 15 C(O)NR 14 R 15  or —X 4 NR 15 C(NR 15 )NR 14 R 15 , wherein X 4 , R 14  and R 15  are as defined above; wherein within R 7  and/or R 8  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 10 R 10 , —X 4 NR 10 C(O)OR 10 , —X 4 NR 10 C(O)NR 10 R 10 , —X 4 NR 10 C(NR 10 )NR 10 R 10 , —X 4 OR 10 , —X 4 SR 10 , —X 4 C(O)OR 10 , —X 4 C(O)N 10 R 10 , —X 4 S(O) 2 NR 10 R 10 , —X 4 P(O)(OR 4 )OR 10 , —X 4 OP(O)(OR 4 )OR 10 , —X 4 NR 10  C(O)R 11 , —X 4 S(O)R 11 , —X 4 S(O) 2 R 11  and —X 4 C(O)R 11 , wherein X 4  is a bond or (C 1-6 )alkylene and R 10  and R 11  are as defined above, or  
 R 7  taken together with R 5  and/or R 8  taken together with R 6  forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; 
 R 9  at each occurrence is hydrogen or (C 1-6 )alkyl; and  
 R 5  and R 6  are independently hydrogen, (C 1-6 )alkyl or as defined above; and  
 
 R 1  is —X 6 X 7 R 16 , wherein X 6  is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 17  wherein R 17  is hydrogen or (C 1-6 )alkyl, and R 16  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, nitro, —NR 10 R 10 , —NR 10 C(O)OR 10 , —NR 10 C(O)NR 10 R 10 , —NR 10 C(NR 10 )NR 10 R 10 , —OR 10 , —SR 10 , —C(O)OR 10 , —C(O)NR 10 R 10 , —S(O) 2 NR 10 R 10 , —P(O)(OR 10 )OR 10 , —OP(O)(OR 10 )OR 10 , —NR 10 C(O)R 11 , —S(O)R 11 , —S(O) 2 R 11 , —C(O)R 11 , —OR 18 , —SR 18 , —S(O)R 18 , —S(O) 2 R 18 , —C(O)R 18 , —C(O)OR 18 , —C(O)NR 18 R 19 , —NR 18 R 19 , —NR 19 C(O)R 18 , —NR 19 C(O)OR 18 , —NR 19 C(O)NR 18 R 19  or —NR 19 C(NR 19 )NR 18 R 19 , wherein R 10  and R 11  are as defined above, R 18  is (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-2 )cycloalkyl(C 0-6 )alkyl, (C 6-2 )aryl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl, (C 9-12 )polycycloaryl(C 0-6 )alkyl or hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl and R 19  at each occurrence independently is hydrogen or (C 1-6 )alkyl, and wherein within R 18  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 14 , —X 4 OR 14 , —X 4 SR 14 , —X 4 S(O)R 14 , —X 4 S(O) 2 R 14 , —X 4 C(O)R 14 , —X 4 C(O)OR 14 , —X 4 OC(O)R 14 , —X 4 NR 14 R 15 , —X 4 NR 15 C(O)R 14 , —X 4 NR 15 C(O)OR 14 , —X 4 C(O)NR 14 R 15 , —X 4 S(O) 2 NR 14 R 15 , —X 4 NR 15 C(O)NR 14 R 15  or —X 4 NR 15 C(NR 15 )NR 14 R 15 , wherein X 4 , R 14  and R 15  are as defined above, or (ii) (C 3-14 )cycloalky](C 0-6 )alkyl, hetero(C 3-14 )cycloalkyl(C 0-6 )alkyl, (C 6-14 )aryl(C 0-6 )alkyl, diphenyl(C 0-6 )alkyl, hetero(C 5-14 )aryl(C 0-6 )alkyl, heterodi(C 5-6 )aryl(C 0-6 )alkyl, (C 9-12 )polycycloaryl(C 0-6 )alkyl or hetero(C 9-14 )polycyclo(C 8-14 )aryl(C 0-6 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 14 , —X 4 OR 14 , —X 4 SR 14 , —X 4 S(O)R 14 , —X 4 S(O) 2 R 14 , —X 4 C(O)R 14 , —X 4 C(O)OR 14 , —X 4 OC(O)R 14 , —X 4 NR 14 R 15 , —X 4 NR 15 C(O)R 14 , —X 4 NR 15 C(O)OR 4 , —X 4 C(O)NR 14 R 15 , —X 4 S(O) 2 NR 14 R 15 , —X 4 NR 15 C(O)NR 14 R 15  or —X 4 NR 15 C(NR 15 )NR 14 R 15 , wherein X 4 , R 14  and R 15  are as defined above; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 10 R 10 , —X 4 NR 10 C(O)OR 10 , —X 4 NR 10 C(O)NR 10 R 10 , —X 4 NR 10 C(NR 10 )NR 10 R 10 , —X 4 OR 10 , —X 4 SR 10 , —X 4 C(O)OR 10 , —X 4 C(O)NR 10 R 10 , —X 4 S(O) 2 NR 10 R 10 , —X 4 P(O)(OR 4 )OR 10 , —X 4 OP(O)(OR 4 )OR 10 , —X 4 NR 10 C(O)R 11 , —X 4 S(O)R 11 , —X 4 S(O) 2 R 11  and —X 4 C(O)R 1 , wherein X 4 , R 10  and R 11  are as defined above; or when X 1  is a divalent group of formula (a) or (b) then R 1  may also represent hydrogen;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is hydrogen or (C 1-6 )alkyl wherein said alkyl optionally is substituted with —OR 20 , NR 21 C(O)OR 20 , —C(O)NR 20 R 21 , —S(O) 2 R 20 , wherein R 20  is (C 0-6 )alkyl or (C 6-10 )aryl(C 0-6 )alkyl and R 21  is hydrogen or (C 1-6 )alkyl, or (ii) (C 6-10 )aryl(C 1-6 )alkyl or (C 5-10 )heteroaryl(C 1-6 )alkyl or  
 R 3  taken together with R 2  forms trimethylene, tetramethylene or phenylene -1,2-dimethylene, optionally substituted with hydroxy or oxo; wherein within R 3  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 10 R 10 , —X 4 NR 10 C(O)OR 10 , —X 4 NR 10 C(O)NR 10 R 10 , —X 4 NR 10 C(NR 10 )NR 10 R 10 , —X 4 OR 10 , —X 4 SR 10 , —X 4 C(O)OR 10 , —X 4 C(O)NR 10 R 10 , —X 4 S(O) 2 NR 10 R 10 , —X 4 P(O)(OR 4 )OR 10 , —X 4 OP(O)(OR 4 )OR 10 , —X 4 NR 10 C(O)R 11 , —X 4 S(O)R 11 , —X 4 S(O) 2 R 11  and —X 4 C(O)R 11 , wherein X 4 , R 10  and R 11  are as defined above; and  
 R 4  is nitromethyl, 1-hydroxy-1-methylethyl or —CH 2 OR 22 , wherein R 22  is hydrogen, (C 1-6 )alkyl, (C 6-12 )aryl(C 6 )alkyl, hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl, (C 1-6 )alkylcarbonyl or (C 6-12 )arylcarbonyl wherein within R 22  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 10 R 10 , —X 4 NR 10 C(O)OR 10 , —X 4 NR 10 C(O)NR 10 R 10 , —X 4 NR 10 C(NR 10 )NR 10 R 10 , —X 4 OR 10 , —X 4 SR 10 , —X 4 C(O)OR 10 , —X 4 C(O)NR 10 R 10 , —X 4 S(O) 2 NR 10 R 10 , —X 4 P(O)(OR 4 )OR 10 , —X 4 OP(O)(OR 4 )OR 10 , —X 4 NR 10 C(O)R 11 , —X 4 S(O)R 11 , —X 4 S(O) 2 R 11  and —X 4 C(O)R 11 , wherein X 4 , R 10  and R 11  are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1  in which: 
 X 1  is a bond or a divalent group of Formula (a) wherein within Formula (a): 
 R 5  is hydrogen or together with R 7  forms phenylene-1,2-dimethylene; and  
 R 7  is (i) (C 1-6 )alkyl optionally substituted with —OR 10 , —C(O)OR 10 , —C(O)NR 10 R 10 , wherein R 10  at each occurrence independently is hydrogen or (C 1-6 )alkyl or (ii) (C 6-12 )aryl(C 0-3 )alkyl, cyclo(C 3-12 )alkyl(C 0-3 )alkyl or (C 6-12 )aryl(C 0-3 )alkyl or (iii) together with R 5  is phenylenedimethylene; wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 10 R 10 , —X 4 NR 10 C(O)OR 10 , —X 4 NR 10 C(O)NR 10 R 10 , —X 4 NR 10 C(NR 10 )NR 10 R 10 , —X 4 OR 10 , —X 4 SR 10 , —X 4 C(O)OR 10 , —X 4 C(O)NR 10 R 10 , —X 4 S(O) 2 NR 10 R 10 , —X 4 P(O)(OR 4 )OR 10 , —X 4 OP(O)(OR 4 )OR 10 , —X 4 NR 10 C(O)R 11 , —X 4 S(O)R 11 , —X 4 S(O) 2 R 11  and —X 4 C(O)R 11 , wherein X 4  is a bond or (C 1-6 )alkylene, R 10  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 11  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 
 R 1  is —X 6 X 7 R 16 , wherein X 6  is —C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 17 —, wherein R 17  is hydrogen or (C 1-6 )alkyl, and R 16  is (i) (C 1-6 )alkyl optionally substituted with —C(O)OR 10 , —NR 10 R 10  or —NR 10 C(O)OR 10 , wherein R 10  at each occurrence independently is hydrogen or (C 1-6 )alkyl or (ii) hetero(C 3-14 )cycloalkyl(C 0-6 )alkyl, (C 6-14 )aryl(C 0-6 )alkyl, diphenyl(C 0-6 )alkyl, or hetero(C 5-14 )aryl(C 0-6 )alkyl; wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 10 R 10 , —X 4 NR 10 C(O)OR 10 , —X 4 NR 10 C(O)NR 10 R 10 , —X 4 NR 10 C(NR 10 )NR 10 R 10 , —X 4 OR 10 , —X 4 SR 10 , —X 4 C(O)OR 10 , —X 4 C(O)NR 10 R 10 , —X 4 S(O) 2 NR 10 R 10 , —X 4 P(O)(OR 4 )OR 10 , —X 4 OP(O)(OR 4 )OR 10 , —X 4 NR 10 C(O)R 11 , —X 4 S(O)R 11 , —X 4 S(O) 2 R 11  and —X 4 C(O)R 11 , wherein X 4 , R 10  and R 11  are as defined above;  
 R 2  is hydrogen;  
 R 3  is (i) hydrogen or (C 1-6 )alkyl optionally substituted with —OR 20 , —NR 21 C(O)OR 20 , —C(O)(O)NR 20 R 20 , —S(O) 2 R 20 , wherein R 20  is (C 0-6 )alkyl or (C 0-10 )aryl(C 0-6 )alkyl and R 21  is hydrogen or (C 1-6 )alkyl, or (ii) (C 6-10 )aryl(C 1-6 )alkyl or (C 5-10 )heteroaryl(C 1-6 )alkyl or (ii) together with R 2  forms trimethylene or phenylene -1,2-dimethylene; wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 10 R 10 , —X 4 NR 10 C(O)OR 10 , —X 4 NR 10 C(O)NR 10 R 10 , —X 4 NR 10 C(NR 10 )NR 10 R 10 , —X 4 OR 10 , —X 4 SR 10 , —X 4 C(O)OR 10 , —X 4 C(O)NR 10 R 10 , —X 4 S(O) 2 NR 10 R 10 , —X 4 P(O)(OR 4 )OR 10 , —X 4 OP(O)(OR 4 )OR 10 , —X 4 NR 10 C(O)R 11 , —X 4 S(O)R 11 , —X 4 S(O) 2 R 11  and —X 4 C(O)R 11 , wherein X 4 , R 10  and R 11  are as defined above; and  
 R 4  is nitromethyl, 1-hydroxy-1-methylethyl or —CH 2 OR 22 , wherein R 22  is hydrogen, (C 1-6 )alkyl, (C 6-2 )aryl(C 0-6 )alkyl, heteropolycyclo(C 8-2 )aryl(C 0-6 )alkyl, (C 1-6 )alkylcarbonyl or (C 6-12 )arylcarbonyl, wherein within R 4  any aromatic ring present may be substituted further by 1 to 3 radicals independently selected from halo, —OR 10 , —C(O)NR 10 R 10 , —S(O) 2 NR 10 R 10  or —X 4 NR 10 R 10 , wherein X 4 , R 10  and R 11  are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         3 . The compound of  claim 2  in which: 
 within Formula (a): 
 R 5  is hydrogen or as defined below; and  
 R 7  is (i) butyl, ethyl, methyl, 1-methylethyl, 1-methylpropyl or 2-methylpropyl optionally substituted with —OR 10 , —C(O)OR 10 , —NR 10 , —NR 10 C(O)OR 10  or —C(O)NR 10 R 10 , wherein R 10  is hydrogen or (C 1-6 )alkyl, or (ii) benzyl, benzyoxycarbonylmethyl, biphenyl-4-ylmethyl, cyclohexyl, cyclohexylmethyl, naphth-2-ylmethyl, phenylcarbamoylmethyl or phenylethyl or (iii) together with R 5  is phenylenedimethylene; wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 3 radicals independently selected from nitro and amino;  
 
 R 1  is hydrogen, acetyl, 3-aminobenzoyl, 4-aminobutyryl, 3-aminopropionyl, 6-aminohexanoyl, 3-aminomethylbenzoyl, 4-aminomethylbenzoyl, benzoyl, benzylcarbamoyl, 4-benzyloxybenzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, 3-tert-butoxycarbonylaminobenzoyl, 4-tert-butoxycarbonylaminobutyryl, 6-tert-butoxycarbonylaminohexanoyl, 3-tert-butoxycarbonylaminomethylbenzoyl, 4-tert-butoxycarbonylaminomethylbenzoyl, 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, 1-tert-butoxycarbonylpyrrolidin-2-ylcarbonyl, 3-carbamoylbenzoyl, 3-cyanobenzoyl, dibenzofur-2-ylsulfonyl, 3-[N′,N″-di(tert-butoxycarbonyl)guanidino]benzoyl, 4-dimethylaminobenzoyl, 2,2-dimethylpropionyl, 3-diphenylpropionyl, 3-fluorobenzoyl, 3-guanidinobenzoyl, 3-hydroxybenzoyl, 1H-indol-3-ylacetyl, 3-methoxycarbonylbenzoyl, 3-methoxycarbonylpropionyl, 3-methoxyphenylcarbamoyl 4-methylpiperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, naphth-1-ylcarbonyl, naphth-2-ylcarbonyl naphth-2-ylsulfonyl, 3-nitrophenylacetyl, phenoxyacetyl, phenylcarbamoyl, 3-phenylpropionyl, piperidin-4-ylcarbonyl, 1-piperidin-1-ylpiperidin-1-ylcarbonyl, pyrid-3-ylacetyl, pyrid-4-ylacetyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrazinylcarbonyl or 3-ureidobenzoyl;  
 R 2  is hydrogen or as defined below;  
 R 3  is hydrogen, benzyl, 2-benzyloxyethyl, 4-benzyloxycarbonylaminobutyl, benzyloxymethyl, butyl, 2-(4-hydroxyphenyl)ethyl, 1H-indol-3-ylmethyl, 4-methoxybenzyl, methyl, 2-methylsulfonylethyl, 2-methylpropyl, phenethyl, 2-phenylcarbamoylethyl or together with R 2  forms tetramethylene or phenylenedimethylene; and  
 R 4  is acetoxymethyl, benzo[1,3]dioxol-5-yloxy, benzyloxymethyl, 4-carbamoylphenoxymethyl, 4-chlorophenoxymethyl, 2,5-dichlorobenzoyloxymethyl, 2,6-dichlorobenzoyloxymethyl, 3-dimethylaminophenoxymethyl, ethoxymethyl, hydroxymethyl, 1-hydroxy-1-methylethyl, 4-(1H-imidazol-1-yl)phenoxymethyl, methoxymethyl, 3-methoxyphenoxymethyl, 4-methoxyphenoxymethyl, 4-sulfamoylphenoxymethyl or phenoxymethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         4 . The compound of  claim 3  in which R 5  is hydrogen and R 7  is butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or naphth-2-ylmethyl; R 1  is 3-aminobenzoyl, 3-aminomethylbenzoyl, 4-aminomethylbenzoyl, benzoyl, benzylcarbamoyl, benzyloxycarbonyl, tert-butoxycarbonyl, 3-tert-butoxycarbonylaminobenzoyl, 4-tert-butoxycarbonylaminomethylbenzoyl, 3-[N′,N″-di(tert-butoxycarbonyl)guanidino]benzoyl, 4-dimethylaminobenzoyl, 3-guanidinobenzoyl 4-methylpiperazin-1-ylcarbonyl, naphth-1-ylcarbonyl, naphth-2-ylcarbonyl or piperidin-4-ylcarbonyl; R 2  is hydrogen; R 3  is hydrogen, 4-benzyloxycarbonylaminobutyl, butyl or phenethyl; and R 4  is benzyloxymethyl, hydroxymethyl, 2,5-dichlorobenzoyloxymethyl, ethoxymethyl, 1-hydroxy-1-methylethyl or phenoxymethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
     
     
         5 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with one or more pharmaceutically acceptable excipient(s).  
     
     
         6 . The composition of  claim 5  which further comprises one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effective amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof.  
     
     
         7 . The composition of  claim 6  wherein the bisphosphonic acid is selected from the group consisting of 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy -3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene -1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy -2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof.  
     
     
         8 . The composition of  claim 7  wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.  
     
     
         9 . The composition of  claim 8  which comprises 1,1-dichloromethylene -1,1-diphosphonate monosodium trihydrate.  
     
     
         10 . A method of treating a disease in an animal in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of  claim 1;  or a N-oxide derivatives, prodrug derivative, protected derivative, individual isomer and mixtures of isomers; or pharmaceutically acceptable salt thereof.  
     
     
         11 . The method of  claim 10  wherein the disease is osteoporosis.  
     
     
         12 . The method of  claim 11  wherein the animal is a human.  
     
     
         13 . The method of  claim 12  wherein the human is a post-menopausal woman.  
     
     
         14 . The method of  claim 13  wherein the cysteine protease is cathepsin K.  
     
     
         15 . The method of  claim 10  in which the cysteine protease is cathepsin S.  
     
     
         16 . The method of  claim 15  in which the disease is an autoimmune disorder, allergic disorder, allogeneic immune response, a disorder involving excessive elastolysis, cardiovascular disorders or a disorder involving fibril formation.  
     
     
         17 . The method of  claim 16  in which the disorder is selected from juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ transplant or tissue graft rejections, chronic obstructive pulmonary disease, bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities, plaque rupture, atheroma and systemic amyloidosis.  
     
     
         18 . A process for preparing a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 X 1  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 X 2  and X 4  independently are —C(O)— or —S(O) 2 —,  
 X 3  is —CHR 7 —, —CH 2 CHR 7 — or —CHR 7 CH 2 — and X 5  is —CHR 8 —, —CH 2 CHR 8 — or —CHR 8 CH 2 —, wherein: 
 R 7  and R 8  are independently (i) (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl optionally substituted with —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —C(O)R 9 , —C(O)OR 9 , —NR 9 R 10 , —NR 10 C(O)OR 9 , —C(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , —NR 10 C(O)NR 9 R 10  or —NR 10 C(NR 10 )NR 9 R 10 , wherein R 9  is hydrogen, (C 1-6 )alkyl, cyclo(C 3-12 )alkyl(C 0-3 )alkyl, heterocyclo(C 3-2 )alkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl or hetero(C 5-12 )aryl(C 0-3 )alkyl and R 10  is hydrogen or (C 1-6 )alkyl, or (ii) cyclo(C 3-12 )alkyl(C 0-3 )alkyl, heterocyclo(C 3-12 )alkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, polycyclo(C 9-12 )aryl(C 0-3 )alkyl or heteropolycyclo(C 8-12 )aryl(C 0-3 )alkyl optionally substituted with —R 11 , —X 6 OR 11 , —X 6 SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —C(O)R 11 , —C(O)OR 11 , —X 6 NR 11 R 12 , —X 6 NR 12 C(O)OR 11 , —C(O)NR 11 R 12 , —S(O) 2 NR 11 R 12 , —NR 12 C(O)NR 11 R 12  or —NR 12 C(NR 12 )NR 11 R 12 , wherein X 6  is a bond or methylene, R 11  is cyclo(C 3-12 )alkyl(C 0-3 )alkyl, heterocyclo(C 3-12 )alkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alky), polycyclo(C 9-12 )aryl(C 0-3 )alkyl or heteropolycyclo(C 8-12 )aryl(C 0-3 )alkyl and R 12  is hydrogen or (C 1-6 )alkyl, or (iii) together with R 5  or R 6 , respectively, when X 3  is —CHR 7 — and/or X 5  is —CHR 8 —, forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R 7  and/or R 8  are optionally independently substituted with halo, nitro, cyano, (C 1-6 )alkyl, halo-substituted(C 1-6 )alkyl, —OR 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 13 , S(O)NR 3 R 13 , —X 6 NR 13 R 13 , X 6 NR 13 C(O)OR 13 , —X 6 NR 13 C(O)NR 13 R 13  or —X 6 NR 13 C(NR 13 NR 13 R 13 , wherein X 6  is as defined above and each R 13  independently is hydrogen or (C 1-6 )alkyl; and  
 R 5  and R 6  are independently hydrogen, (C 1-6 )alkyl or as defined above; and  
 
 R 1  is hydrogen or —X 7 X 8 R 14 , wherein X 7  is —C(O)— or —S(O) 2 —, X 8  is a bond, —O— or —NR 15 —, wherein R 15  is hydrogen or (C 1-6 )alkyl, and R 14  is (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl optionally substituted with —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —C(O)R 9 , —C(O)OR 9 , —NR 9 R 10 , —NR 10 C(O)OR 9 , —C(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , —NR 10 C(O)NR 9 R 10  or —NR 10 C(NR 10 )NR 9 R 10 , wherein R 9  and R 10  are as defined above, or (ii) (C 3-14 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-14 )cycloalkyl(C 0-6 )alkyl, (C 6-14 )aryl(C 0-6 )alkyl, diphenyl(C 0-6 )alkyl, hetero(C 5-14 )aryl(C 0-6 )alkyl, heterodi(C 5-6 )aryl(C 0-6 )alkyl, polycyclo(C 9-14 )aryl(C 0-6 )alkyl or heteropolycyclo(C 8-14 )aryl(C 0-6 )alkyl optionally substituted with —R 11 , —X 6 OR 11 , —X 6 SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —C(O)R 11 , —C(O)OR 11 , —X 6 NR 11 R 12 , —X 6 NR 12 C(O)OR 11 , —C(O)NR 11 R 12 , —S(O) 2 NR 11 R 12 , —NR 12 C(O)NR 11 R 12  or —NR 12 C(NR 12 )NR 11 R 12 , wherein X 6 , R 11  and R 12  are as defined above; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R 1  optionally independently are substituted with halo, nitro, cyano, (C 1-6 )alkyl, halo-substituted(C 1-6 )alkyl, —OR 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 13 , —S(O) 2 NR 13 R 13 , —X 6 NR 3 R 13 , —X 6 NR 13 C(O)OR 13 , —X 6 NR 13 C(O)NR 13 R 13  or —X 6 NR 13 C(NR 13 NR 13 R 13 , wherein X 6  and R 13  are as defined above;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is (i) hydrogen or (C 1-6 )alkyl optionally substituted with —OR 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 R 16 , wherein R 16  is (C 0-6 )alkyl or (C 6-10 )aryl(C 0-6 )alkyl and R 17  is hydrogen or (C 1-6 )alkyl, or (ii) (C 6-10 )aryl(C 1-6 )alkyl or (C 5-10 )heteroaryl(C 1-6 )alkyl or (iii) together with R 2  forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R 3  optionally independently are substituted with halo, nitro, cyano, optionally halo-substituted(C 1-6 )alkyl, —OR 13 , —C(O)OR 13 , —C(O)NR 13 R 13 , —X 6 NR 13 R 13 , —X 6 NR 13 C(O)NR 13 R 13  and —X 6 NR 13 C(NR 13 )NR 13 R 13 , wherein X 6  and R 13  are as defined above; and  
 R 4  is nitromethyl, 1-hydroxy-1-methylethyl or —CH 2 OR 8 , wherein R 18  is hydrogen, (C 1-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, heteropolycyclo(C 8-12 )aryl(C 0-6 )alkyl, (C 1-6 )alkylcarbonyl or (C 6-12 )arylcarbonyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R 4  optionally independently are substituted with halo, nitro, cyano, (C 1-6 )alkyl, halo-substituted(C 1-6 )alkyl, —OR 13 , —C(O)R 13 , —C(O)O R   13 , —C(O)NR 13 R 13 , —S(O) 2 NR 13 R 13 , —X 6 NR 13 R 13 , —X 6 NR 13 C(O)OR 13 , —X 6 NR 13 C(O)NR 13 R 13  or —X 6 NR 13 C(NR 13 Nk 13 R 13 , wherein X 6  and R 3  are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof; which process comprises: 
 (A) reacting a compound of Formula 2:  
                     
 with a compound of the formula LX 1 R 21 , in which L is a leaving group, R 20  is —NO 2  or —OR 22 , wherein R 22  is a hydroxy protecting group or optionally substituted (C 1-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, heteropolycyclo(C 8-12 )aryl(C 0-6 )alkyl, (C 1-6 )alkylcarbonyl or (C 6-12 )arylcarbonyl, R 21  is R 1  or a protecting group and each X 1 , R 1 , R 2  and R 3  are as defined above, and then removing one or more protective groups if necessary to provide a compound of Formula I in which R 4  is nitromethyl or —CH 2 OR 17 ;  
 (B) reacting a compound of Formula 3:  
                     
 with a compound of the formula LCH 2 OR 22 , in which L is a leaving group, R 22  is a hydroxy protecting group or optionally substituted (C 1-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, heteropolycyclo(C 8-12 )aryl(C 0-6 )alkyl, (C 1-6 )alkylcarbonyl or (C 6-12 )arylcarbonyl, R 20  is R 1  or a protecting group and each X 1 , R 1 , R 2 , R 3  and R 17  are as defined above, and then removing one or more protective groups if necessary to provide a compound of Formula I in which R 4  is —CH 2 OR 17 ;  
 (C) oxidizing a compound of Formula 4:  
                     
 in which R 2  is R 1  or a protecting group and each X 1 , R 1 , R 2  and R 3  are as defined above, and then deprotecting if necessary to provide a compound of Formula I in which R 4  is 1-hydroxy -1-methylethyl;  
 (D) reacting a compound of Formula 5:  
                     
 with nitromethane, in which R 21  is R 1  or a protecting group and each X 1 , R 1 , R 2  and R 3  are as defined above, and then deprotecting if necessary to provide a compound of Formula I in which R 4  is nitromethyl;  
 (E) optionally dealkylating a compound of Formula I in which R 4  is —CH 2 OR 18 , wherein R 18  is (C 1-6 )alkyl or (C 6-12 )aryl(C 1-6 )alkyl to provide a compound of Formula I in which R 18  is hydrogen;  
 (F) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;  
 (G) optionally converting a salt form of a compound of Formula I to non-salt form;  
 (H) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;  
 (I) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;  
 (K) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and  
 (L) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.  
 
 
     
     
         19 . A process for preparing a compound of Formula UI:  
       
         
           
           
               
               
           
         
       
       which process comprises hydrogenating a compound of Formula 9:  
       
         
           
           
               
               
           
         
       
       in which R 1  is peptidyl, R 2  is hydrogen or (C 1-6 )alkyl, R 3  is an amino acid side chain and R 4  is (C 1-6 )alkyl or (C 6-12 )aryl(C 1-6 )alkyl, in the presence of a catalytic amount of 20% palladium hydroxide on carbon.  
     
     
         20 . The process of  claim 19  in which the hydrogenation is effected with an excess amount of cyclohexene and in a 1:2 mixture of cyclohexene:ethanol.  
     
     
         21 . The process of  claim 20  for preparing an individual (R)- or (S)-isomer of the compound of Formula II.