Novel compounds and compositions as cathepsin S inhititors

Abstract

The present invention relates to novel selective cathepsin S 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  and X 2  are both methylene or X 1  is ethylene and X 2  is a bond;  
 
         R 1  is hydrogen and R 2  is cyano, hetero(C 5 )aryl or (C 1-4 )alkyl-substituted hetero(C 5 )aryl or both R 1  and R 2  are hydrogen, halo, (C 1-4 ) or —X 3 OR 9 , wherein X 3  and R 9  are as defined below, or R 1  and R 2  together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene; 
 R 3  is —CR═CHR 6  or —CR 7 ═NR 8 , wherein R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 2-6 )aryl, (C 5-12 )cycloalkenyl, hetero(C 5-12 )cycloalkenyl, (C 6-12 )aryl, hetero (C 6-12 )aryl, (C 9-12 )bicycloaryl or hetero(C 8-12 )bicycloaryl and R 7  and R 8  together with the atoms to which R 7  and R 8  are attached form hetero(C 5-12 )cycloalkenyl, hetero (C 6-2 )aryl or hetero(C 8-12 )bicycloaryl, wherein R 3  optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 9 R 9 , —X 3 OR 9 , X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10  and —X 3 C(O)R 10 , wherein X 3  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and  
 R 4  is —C(O)X 4 R 11  or —S(O) 2 X 4 R 11 , wherein X 4  is a bond, —O— or —NR 12 —, wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl optionally substituted by —OR 13 , SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , —NR 14 C(O)NR 13 R 14  or —NR 14 C(NR 14 )NR 13 R 14 , wherein R 13  is (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-1 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero (C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero (C 8-12 )bicycloaryl(C 0-3 )alkyl and R 14  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12- )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 6-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl( 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl substituted by —X 5 OR 15 , —X 5 SR 15 , —X 5 S(O)R 15 , —X 5 S(O) 2 R 15 , —X 5 C(O)R 15 , —X 5 C(O)OR 15 , —X 5 C(O)NR  15 R 16 , —X 5 NR 15 R 16 , —X 5 NR 16 C(O)R 15 , —X 5 NR 16 C(O)OR 15 , —X 5 NR 16 C(O)NR 15 R 16  or —X 5 NR 16 C(NR 16 )NR 15 R 16 , wherein X 5  is a bond or methylene, R 15  is (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(CO 3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substitutents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting, of (C 1-6 ), alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 5 NR 17 R 17 , —X 5 NR 17 C(O)OR 17 , —X 5 NR 17 C(O)NR 17 R 17 , —X 5 NR 17 C(NR 17 )NR 17 R  7 , —X 5 OR 17 , —X 5 SR 17 , —X 5 C(O)OR 17 , —X 5 C(O)NR  17 R 17 , —X 5 S(O) 2 NR  17 R 17 , —X 5 P(O)(OR 8 )OR 17 , —X 5 OP(O)(OR 8 )OR 17 , —X 5 NR 17 C(O)R 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18  and —X 5 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein X 5  is a bond or (C 1-6 )alkylene, R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
 
       
     
     
         2 . The compound of  claim 1  in which R 1  represents hydrogen and R 2  represents hydrogen, hetero(C 5 )aryl or (C 1-4 )alkyl-substituted hetero(C 5 )aryl or together with the carbon atom to which both R 1  and R 2  are attached form (C 3-5 )cycloalkylene or (C 5-6 )heterocycloalkylene; X 1  and X 2  are both methylene and R 3  represents (C 2-6 )alkenyl, (C 6-12 )aryl or hetero(C 5-12 )aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 9 R 9 , —X 3 OR 9 , —X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10  and X 3 C(O)R 10 , wherein X 3  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and R 4  is —C(O)X 4 R 11 , wherein X 4  is a bon, —O— or —NH— and R 11  is (C 1-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-10 )aryl(C 0-3 )alkyl or hetero(C 5-10 )aryl(C 0-3 )alkyl, wherein any heterocycloalkyl, aryl or heteroaryl group comprising R 1  optionally is substituted in the ring by —X 5 OR 17 , —X 5 NR 17 C(O)OR 17 , X 5 C(O)OR 17  or —X 5 C(O)R 18 ; and the N-Oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         3 . The compound of  claim 2  in which R 3  more preferably represents biphenyl, isooxazolyl, naphthyl, phenyl, pyridyl, thienyl or vinyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C 1-4 )alkyl, cyano, hallo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 9 R 9 , —X 3 OR 9 , —X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10  and —X 3 C(O)R 10 , wherein X 3  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         4 . The compound of  claim 3  in which R 3  is biphenyl-2-yl, 2,4-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 4-tert-butylphenyl, 2bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorphenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 1,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3.5-dimethylisooxaxol-4-yl, 3,5-dimethylphenyl, 2-fluoro-6-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2fluoro-6-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methyl-2-fluorophenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitropheyl, 2,3,4,5,6-pentafluorophenyl, phenyl, prop-2-en-1-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 3-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanyl-phenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl or 2,3,6-trifluorophenyl; and R 4  is 3-acetylbenzoyl, allyloxycarbonyl, 2-aminopyrid-3-ylcarbonyl, 6-aminopyrid-3-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, benzoyl, 4-benzoylbenzoylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, benofur-2-ylcarbonyl, biphenyl-4-ylcarbonyl, 4-bromobenzoyl, 3-bromothien-2-yl, tert-butoxycarbonyl, 3-tert-butoxycarbonyaminomethylbenzoyl, 4-tert-butoxycarbonylpiperazin-1-ylcarbonyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 3-chlorothienylcarbonyl, cyclopentylcarbonyl, 3,4-difluorobenzoyl, 3,4-dimethoxybenzoyl, dimethylcarbamoyl, 4-ethoxycarbonylpiperazin-1-ylcarbonyl, 4-fluorobenzoyl, 3-fluoro-4-methoxybenzoyl, fur-2-ylcarbonyl, fur-3-ylcarbonyl, 4-fur-2-ylcarbonylpiperazin-1-ylcarbonyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, 4-hydroxypyrid-3-yl, 6-hydroxypyrid-3-yl, 1H-indol-4-ylcarbonyl, isopropylcarbamoyl, isobutyloxycarbonyl, isopropyloxycarbonyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 3-methylbenzoyl, 5-methylthienylcarbonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, naphth-2-ylcarbonyl, naphth-2-ylsulfonyl, 3-phenozybenzoyl, 3-phenylacryloyl, phenylsulfonyl, pyrazin-2-ylcarbonyl, 3-ylacryl, pyrid-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, quinol-2-ylcarbonyl, quinol-3-ylcarbonyl, thien-2-ylcarbonyl, thien-3-ylcarbonyl, thien-2-ylsulfonyl, 4-trifluoromethoxybenzoyl or 4-trifluoromethylbenzoyl, and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         5 . The compound of  claim 3  in which X 1 , X 2  and R 3  along with the sulfonyl moiety to which X 1  and X 2  are attached together represent a group having the following formula:  
       
         
           
           
               
               
           
         
         in which n is 0, 1, 2, 4 or 5 and R 22  at each occurrence independently is selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 9 R 9 , —X 3 OR 9 , —X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10  and —X 3 C(O)R 10 , wherein X 3  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and R 4  is benzoyl, morpholin-4-ylcarbonyl, thien-2-yl, thien-3-yl, indol-4-yl and pyridin-4-yl, respectively, optionally substituted in the ring by 1 to 2 substituents selected from fluoro and methyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
       
     
     
         6 . The compound of  claim 5  in which n is 0, 1 or 2 and R 22  at each occurrence independently is selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —OR 9 , —SR 9  and —C(O)OR 9 , wherein R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         7 . The compound of  claim 6  in which R 22  at each occurrence independently is selected from a group consisting of (C 1-4 )alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         8 . The compound of  claim 7  in which at the first occurrence is attached at the ring carbon ortho or meta to the 1-position of the phenyl moiety; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         9 . The compound of  claim 8  selected from a group consisting of: 
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-isonicotinamide,  
 Pyridine-2-carboxylic acid-N—{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 Pyrazine-2-carboxylic acid-N—{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide,  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-6-hydroxy-nicotinamide;  
 2-Amino-N—{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide;  
 6-Amino-N—{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide;  
 3-Hydroxy-pyridine-2-carboxylic acid-N—{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 Morpholine-4-carboxylic acid-{(R)-1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2 [2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 Morpholine-4-carboxylic acid-{(R)-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 (R)—N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-2-(3,3-dimethyl-ureido)-propionamide;  
 {(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-carbamic allyl ester;  
 {(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-carbamic acid isopropyl ester;  
 {(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-carbamic acid isobutyl ester;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3,4-difluoro-benzamide;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-methyl-benzamide;  
 Thiophene-2-carboxylic acid-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 4-Bromo-N—{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-benzamide,  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-4-methoxy-benzamide;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-4-trifluoromethoxy-benzamide,  
 Naphthalene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 (E)-N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-phenyl-acrylamide;  
 5-Methyl-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 Biphenyl-4-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 1H-Indole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 Benzo[1,3]-dioxole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide  
 Benzo[b]thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-phenoxy-benzamide;  
 Quinoline-3-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-(1-phenyl-methanoyl)-benzamide;  
 4-Chloro-N—{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-benzamide;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-fluoro-4-methoxy-benzamide;  
 3Bromo-thiophene-2-carboxylic acid-N—{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 3-Chloro-benzo[b]thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 3-Chloro-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 N—{(R)-1-(Cyanomethyl-carbamoyl)-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-trifluoromethyl-benzamide;  
 (R)—N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-2-(naphthalene-2-sulfonylamino)-propionamide;  
 Cyclopentanecarboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 N-[1R-cyanomethylcarbamoyl-2-(3-trifluoromethoxybenzylsulfonyl)ethyl]benzamide;  
 N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]benzamide;  
 N-[1R-cyanomethylcarbamoyl-2-(2-trifluoromethoxybenzylsulfonyl)ethyl]benzamide;  
 N-[1R-cyanomethylcarbamoyl-2-(3-difluoromethoxybenzylsulfonyl]benzamide;  
 N-[1R-cyanomethylcarbamoyl-2 (2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1-cyanocyclopropylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
 
     
     
         10 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable excipient.  
     
     
         11 . A method for treating a disease in an animal in which inhibition cathepsin S can prevent, inhibit or ameliorate 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 derivative or individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt or solvate of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         12 . A compound of Formula II:  
       
         
           
           
               
               
           
         
         in which: 
 n is 1, 2, 3, 4 or 5;  
 R 1  is hydrogen and R 2  is cyano, hetero(C 5 )aryl or (C 1-4 )alkyl-substituted hetero(C 5 )aryl or both R 1 and R 2  are hydrogen, halo, (C 1-4 )alkyl or —X 3 OR 9 , wherein X 3  and R 9  are as defined below, or R 1  and R 2  together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene;  
 R 22  at the first occurrence is selected from a group consisting of nitro, —X 3 NR 9 R 9 , —X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10 , —X 3 C(O)R 10  and —X 3 OR 23 , wherein X 3  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl, R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 23  is halo-substituted (C 1-3 )alkyl and R 22  at each other occurrence, if present, independently is selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 9 R 9 , —X 3 OR 9 , —X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 (O)OR 9 , —X 3 S(O)R 10 ), —X 3 S(O) 2 R 10  and —X 3 C(O)R 10 , wherein X 3 , R 9  and R 10  are as defined above, and  
 R 4  is —C(O)X 4 R 11  or —S(O) 2 X 4 R 11 , wherein X 2  is a bond, —O— or —NR 12 , wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl optionally substituted by —OR 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , —NR 14 C(O)NR 13 R 14  or —NR 14 C(NR 14 )NR 13 R 14 , wherein R 13  is (C 1-3 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl and R 14  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl or (iii) (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalky(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 i)alkyl substituted by —X 5 OR 15 , —X 5 SR 15 , —X 5 S(O)R 15 , —X 5 S(O) 2 R 15 , —X 5 (O)R 15 , —X 5 C(O)OR 15 , —X 5 C(O)NR 15 R 16 , —X 5 NR 15 R 16 , —X 5 NR 16 C(O)R 15 , —X 5 NR 16 C(O)OR 15 , —X 5 NR 16 C(O)NR 15 R 16  or —X 5 NR 16 C(NR 16 )NR 15 R 16,  wherein X 5  is a bond or methylene, R 15  is (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-3 )alkyl, nitro, —X 5 NR 17 R 17 , —X 5 NR 17 C(O)OR 17 , —X 5 NR 17 C(O)NR 17 R 17 , —X 5 NR 17 C(NR 17 )NR 17 R 17 , —X 5 OR 17 , —X 5 SR 17 , —X 5 C(O)OR 17 , —X 5 C(O)NR 17 R 17 , —X 5 S(O) 2 NR 17 R 17 , —X 5 P(O)(OR 17 )OR  17 , —X 5 OP(O)(OR 17 )OR 17 , —X 5 NR 17 C(O)R 17 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18  and —X 5 C(O)R 15  and when occurring within an aliphatic moiety are radicals independently selected form a group consisting of cyano, halo, nitro, —NR 14 R 17 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —R 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein X 5  is a bond or (C 1-6 )alkylene, R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof, and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
 
       
     
     
         13 . The compound of  claim 12  in which n is 1 to 2, R 1  represents hydrogen and R 2  represents hydrogen, hetero (C 5 )aryl or (C 1-4 )alkyl-substituted hetero (C 5 ) or R 1  and R 2  together with the carbon atom to which both R 1  and R 2  are attached form (C 3-5 )cycloalkylene or (C 5-6 )heterocycloalkylene, R 3  at the first occurrence is selected from a group consisting of difluoromethoxy, trifluoromethoxy, trifluorosulfanyl and nitro and R 3  at the second occurrence, if present, is selected from a group consisting of (C 1-4 )alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl and R 4  is —C(O)X 1 R 11  or —S(O) 2 X 4 R 11 , wherein X 4  is a bond, —O— or —NR 12 —, wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (C 1-6 )alkyl, (C 1-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-10 )aryl(C 0-3 )alkyl, hetero(C 5-10 )aryl(C 0-3 )alkyl, hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl, or phenyl(C 0-3 )alkyl, wherein the phenyl is substituted by —X 5 OR 15  or —X 5 C(O)R 15 , wherein X 5  is a bond or methylene and R 15  is phenyl(C 0-3 )alkyl, wherein any aryl or heteroaryl group comprising R 4  optionally is substituted in the ring by 1 to 2 substituents selected from (C 1-6 )alkyl, halo, halo-substituted (C 1-3 )alkyl, —X 5 NR 17 R 17 and —X 5 OR 17 , wherein X 5  is a bond or (C 1-6 )alkylene, R 17  is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         14 . The compound of  claim 13  in which R 22  at the first occurrence is nitro or difluoromethoxy in the ortho or meta position and R 4  is allyloxycarbonyl, 2-aminopyridinylcarbonyl, benzo[1,3]dioxolylcarbonyl, benzothienzyl, benzoyl, 3-benzoylbenzoyl, 4-bromobenzoyl, 3-bromothienyl, biphenylylcarbonyl, 3-chlorobenzothienyl, 4-chlorobenzoyl, 3-chlorothienyl, cyclopentylcarbonyl, 3,4-difluorobenzoyl, dimethylcarbamoyl, 3,4-dimethoxybenzoyl, 4-fluorobenzoyl, 3-fluoro-4-hydroxybenzoyl, 2-hydroxypyridinylcarbonyl, 3-hydroxypyridinylcarbonyl, indolylcarbonyl, isobutyloxycarbonyl, isopropylcarbamoyl, isopropyloxycarbonyl, 4-methoxybenzoyl, methoxycarbonyl, 3-methylbenzoyl, 2-methylthienylcarbonyl, 4-methylvaleryl, morpholin-1-ylcarbonyl, naphthalenylcarbonyl, naphthalenylsulfonyl, phenoxycarbonyl, phenylacryloyl, phenylsulfonyl, pyrazinylcarbonyl, pyridinylcarbonyl, quinolyl, thienylcarbonyl, thienylsulfonyl, 4-trifluoromethoxybenzoyl or 4-trifluoromethylbenzoyl; and the N-oxides derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         15 . The compound of  claim 14  in which R 22  at the first occurrence is nitro or difluoromethoxy in the ortho position and R 4  is benzoyl, indolyl. morpholin-4-ylcarbonyl, thienylcarbonyl or pyridinylcarbonyl optionally substituted in the ring by 1 to 2 substituents selected from fluoro and methyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         16 . The compound of  claim 15  selected from a group consisting of: 
 N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]-morpholine-4-carboximide; 
 thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 thiophene-3-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 
 N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-4-fluoro-benzamide; 
 morpholine-4-carboxylic acid-{(R)-1-(4-cyano1-methyl-piperidin-4-ylcarbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 5-methyl-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 1H-indole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide;  
 
 N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-methyl-benzamide,  
 N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3,4-difluoro-benzamide;  
 N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-isonicotinamide;  
 N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-morpholine-4-carboxamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
 
     
     
         17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 12  in combination with a pharmaceutically acceptable excipient.  
     
     
         18 . A method for treating a disease in an animal in which inhibition of cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of  claim 12  or a N-oxide derivative or individual isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate of such of such compounds and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
     
         19 . The use of a compound of Formula II:  
       
         
           
           
               
               
           
         
         in which: 
 n is 1 2, 3, 4 or 5;  
 
         R 1  is hydrogen and R 2  is cyano, hetero(C 5 )aryl or (C 1-4 )alkyl-substituted hetero(C 5 )aryl or both R 1  and R 2  are hydrogen, halo, (C 1-4 )alkyl or —X 3 OR 9 , wherein X 3  and R 9  are as defined below, or R 1  and R 2  together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene;  
         R 22  at the first occurrence is selected from a group consisting of nitro, —X 3 NR 9 R 9 , —X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10 , —X 3 C(O)R 10  and —X 3 OR 23 , wherein X 3  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl, R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 23  is halo-substituted (C 1-3 )alkyl and R 22  at each other occurrence, if present, independently is selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 9 R 9 , —X 3 OR 9 , —X 3 SR 9 , —X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10  and —X 3 C(O)R 10 , wherein X 3 , R 9  and R 10  are as defined above; and  
         R 1  is —C(O)X 4 R 11  or —S(O) 2 X 4 R 11 , wherein X 2  is a bond, —O— or NR 12 —, wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl optionally substituted by —OR 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , —NR 14 C(O)NR 13 R 14  or —NR 11 C(NR 14 )NR 3 R 14 , wherein R 13  is (C 1-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl and R 14  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) C 3-12 )cycloalkyl (C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl or (iii) (C 1-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl substituted by —X 5 OR 15 , —X 5 SR 15 , —X 5 S(O)R 15 , —X 5 S(O) 2 R 15 , —X 5 (O)R 15 , —X 5 C(O)OR 15 , —X 5 (C(O)NR 15 R 16 , —X 5 NR 15 R 16 , —X 5 NR 16 C(O)R 15 , —X 5 NR 16 C(O)OR 15 , —X 5 NR 16 C(O)NR 15 R 16  or —X 5 NR 16 C(NR 16 )NR 15 R 16 , wherein X 5  is a bond or methylene, R 15  is (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-3 )alkyl, nitro, —X 5 NR 17 R 17 , —X 5 NR 17 C(O)OR 17 , —X 5 NR 17 C(O)NR 17 R 17 , —X 5 NR 17 C(NR 17 )NR 17 R 17 , —X   5 OR 17 , —X 5 SR 17 , —X 5 C(O)OR 17 , —X 5 C(O)NR 17 R 17 , —X 5 S(O) 2 NR 17 R 17 , —X 5 P(O)(OR 17 )OR 17 , —X 5 OP(O)(OR 17 )OR 17 , —X 5 NR 17 C(O)R 17 , —X 5 S(O)R 18 , X 5 S(O) 2 R 18  and —X 5 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 14 R 7 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein X 5  is a bond or (C 1-6 )alkylene, R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl; or a N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt or solvate of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; in the manufacture of a medicament for treating a disease in an animal in which cathepsin S activity contributes to the pathology and/or symptomatology of the disease.  
       
     
     
         20 . A process for preparing a compound of Formula:  
       
         
           
           
               
               
           
         
         in which: 
 X 1  and X 2  are both methylene or X 1  is ethylene and X 2  is a bond;  
 R 1  is hydrogen and R 2  is cyano, hetero(C 5 )aryl or (C 1-4 )alkyl-substituted hetero(C 5 )aryl or both R 1  and R 2  are hydrogen, halo, (C 1-4 )alkyl or —X 3 OR 9 , wherein X 3  and R 9  are as defined below, or R 1  and R 2  together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene;  
 R 3  is —CR 5 ═CHR 6  or CR 7 ═NR, wherein R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 2-6 )alkenyl, (C 5-12 )cycloalkenyl, hetero(C 5-12 )cycloalkenyl, (C 6-12 )aryl, hetero(C 6-12 )aryl, (C 9-12 )bicycloaryl or hetero(C 8-12 )bicycloaryl and R 7  and R 8  together with the atoms to which R 7  and R 8  are attached form hetero(C 5-12 )cycloalkenyl, hetero(C 6-12 )aryl or hetero(C 8-12 )bicycloaryl, wherein R 3  optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 9 R 9 , —X 3 OR 9 , —X 3 SR 9 , X 3 C(O)NR 9 R 9 , —X 3 C(O)OR 9 , —X 3 S(O)R 10 , —X 3 S(O) 2 R 10 and —X 3 C(O)R 10 ), wherein X 3  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 ); and  
 R 4  is —C(O)X 4 R 11  or —S(O) 2 X 4 R 11 , wherein X 4  is a bond, —O— or —NR 12 —, wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl optionally substituted by —OR 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , NR 14 C(O)NR 13 R 14  or —NR 14 C(NR 14 )NR 13 R 13 , wherein R 13  is (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl and R 14  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl or (iii) (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl substituted by —X 5 OR 15 , —X 5 SR 15 , —X 5 S(O)R 15 , —X 5 (O) 2 R 15 , —X 5 C(O)R 15 , —X 5 C(O)OR 15 , —X 5 C(O)NR 15 R 16 , —X 5 NR 15 R 16 , —X 5 NR 16 C(O)R 15 , —X 5 NR 16 C(O)OR 15 , —X 5 NR 16  C(O)NR 15 R 16  or —X 5 NR 16 C(NR 16 )NR 15 R 16 , wherein X 5  is a bond or methylene, R 15  is (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalky(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 5 NR 17 R 17 , —X 5 NR 17 C(O)OR 17 , —X 5 NR 17 C(O)NR 17 R 17 , —X 5 NR 17 C(NR 17 )NR 17 R 17 , —X 5 OR 17 , —X 5 SR 17 , —X 5 C(O)OR 17 , —X 5 C(O)NR 17 R 17 , —X 5 S(O) 2 NR 17 R 17 , —X 5 P(O)(OR 8 )OR 17 , —X 5 OP(O)(OR 8 )OR 17 , —X 5 NR 17 C(O)R 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18  and —X 5 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —N 17 C(O)OR 17 , —NR 17 C(O)NR 17  R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein X 5  is a bond or (C 1-6 )alkylene, R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof, and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; which processes comprises:  
 
         (A) reacting a compound of Formula 2:  
         
           
             
             
                 
                 
             
           
         
         with a compound of the formula NH 2 CR 1 R 2 CN, in which X 1 , X 2 , R 1 , R 2 , R 3  and R 4  are as defined in the Summary of the Invention for Formula I; or  
         (B) reacting a compound of Formula 3:  
         
           
             
             
                 
                 
             
           
         
         with a compound of the formula R 4 L, in which n is 0 or 2, L is a leaving, group and each X 1 , X 2 , R 1 , R 2 , R 3  and R 4  are as defined in the Summary of the Invention for Formula I, and then oxidizing when n is 0; or  
         (C) reacting a compound of Formula 4:  
         
           
             
             
                 
                 
             
           
         
         with a compound of formula NHR 13 R 14  or NHR 20 R 21  to provide a compound of Formula I in which R 4  is —C(O)NR 13 R 14  or C(O)NR 20 R 21 , respectively, wherein n is 0 or 2, R 20  and R 21  together with the nitrogen atom to which R 20  and R 21  are attached form hetero(C 5-12 )cycloalkyl and each X 1 , X 2 , R 1 , R 2 , R 3 , R 13  and R 14  are as defined in the Summary of the Invention for Formula I, and then oxidizing when n is 0; or  
         (D) reacting a Compound of Formula 5:  
         
           
             
             
                 
                 
             
           
         
         with a compound of R 1 X 2 L in which L is leaving group and each X 1 , X 2 , R 1 , R 2 , R 3  and R 4  are as defined in the Summary of the Invention for Formula I; and  
         (E) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;  
         (F) optionally converting a salt form of a compound of Formula I to non-salt form;  
         (G) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;  
         (H) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;  
         (I) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;  
         (J) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and  
         (K) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.