Novel Compounds and Compositions as Cathepsin S Inhibitors

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.

1 . A method for treating a disease in an animal in which Cathepsin S 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 Formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X 1  and X 2  are both methylene or X 1  is ethylene and X 2  is methylene or a bond;  
 R 3  is —CR 5 ═CHR 6 , —CR 5 (CR 6   3 ) 2 , —CR 7 ═NR 8 , or (C 3-12 )cycloalkyl, wherein R 5  and R 6  are independently hydrogen or (C 1-4 )alkyl or R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )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 3-12 )cycloalkyl, hetero(C 5-12 )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 4 NR 9 R 9 , —X 4 OR 9 , —X 4 SR 9 , —X 4 C(O)NR 9 R 9 , —X 4 C(O)OR 9 , —X 4 S(O)R 10 , —X 4 S(O) 2 R 10  and —X 4 C(O)R 10 , wherein X 4  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 5 R 11  or —S(O) 2 X 5 R 11 , wherein X 5  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 0-3 )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 s 6 )aryl(C 0-3 )alkyl substituted by —X 6 OR 15 , —X 6 SR 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15 , —X 6 C(O)R 15 , —X 6 C(O)OR 15 , —X 6 C(O)NR 15 R 16 , —X 6 NR 15 R 16 , —X 6 NR 16 C(O)R 15 , —X 6 NR 16 C(O)OR 1  5, —X 6 NR 16 C(O)NR 15 R 16 , —X 6 NR 16 C(O)OR 1  6, —X 6 NR 16 C(NR 16 )NR 15 R 16 , wherein X 6  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, nitro, halo-substituted (C 1-3 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 SR 17 , —X 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 p(O)(OR 18 )OR 17 , —X 6 OP(O)(OR 18 )OR 17 , —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 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 6  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;  
 R 20  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl;  
 R 23  is selected from hydrogen, (C 1-6 )alkyl, alkoxy(C 1-3 )alkyl, halo(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl and hetero(C 5-12 )aryl(C 0-6 )alkyl optionally substituted with amino, —NHC(O)R 15  or —R 15  wherein R 15  is as described above; and  
 R 24  is selected from hydrogen or (C 1-6 )alkyl; or  
 R 23  and R 24  taken together with the carbon atom to which both R 23  and R 24  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene;  
 X 3  is selected from group (a), (b) or (c);  
                     
 wherein X is O and Y is N;  
 R 25  is selected from hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-13 )aryl(C 0-6 )alkyl, —X 4 NHR 15 , —X 4 S(O) 2 R 26  or —X 4 C(O)R 17 NR 17 C(O)R 17  wherein R 15 , R 17  and X 4  are as described above;  
 R 26  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl and hetero(C 8-12 )-bicycloaryl(C 0-3 )alkyl;  
 wherein R 25  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 1-13 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 C(O)R 17 , —X 6 OR 5 , —X 6 SR 17 , —X 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 P(O)(OR 8 )OR 1  7, —X 6 OP(O)(OR 8 )OR 1  7, —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 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 R 15 , R 17 , R 18  and X 6  are as described above; or  
 a derivative of said compound selected from the group consisting of N-oxide derivatives, prodrug derivatives, protected derivatives, isomers, and mixtures of isomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound or said derivative.  
 
   
   
       2 . The method of  claim 1  wherein: 
 X 1  and X 2  are both methylene or X 1  is ethylene and X 2  is a bond;    R 3  is —CR 5 ═CHR 6 , —CR 5 (CR 6   3 ) 2 , —CR 7 ═NR 8 , or (C 3-12 )cycloalkyl, wherein R 5  and R 6  are independently hydrogen or (C 1-4 )alkyl or R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 3-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl or (C 9-12 )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 )aryl;    wherein within R 3  any cycloalkyl, aryl, heteroaryl or bicycloaryl group may be substituted with 1 to 5 radicals independently selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, —X 4 OR 9  and —X 4 C(O)OR 9 , wherein X 4  is a bond or (C 1-2 )alkylene and R 9  at each occurrence independently is (C 1-3 )alkyl and halo-substituted (C 1-3 )alkyl;    R 4  is —C(O)X 5 R 11  or —S(O) 2 X 5 R 11 , wherein X 5  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 or (ii) 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) hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl or phenyl(C 0-3 )alkyl substituted by —X 6 OR 15 , —X 6 C(O)R 15  or —X 6 NR 16 C(O)OR 16 , wherein X 6  is a bond or methylene, R 15  is 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 within R 4  any alicyclic or aromatic ring system may be substituted with 1 to 5 radicals independently selected from a group consisting of (C 1-16 )alkyl, halo, —X 6 NR 17 R 17 , —X 6 OR 17 , —X 6 C(O)OR 17 , —X 6 NC(O)R 16  and —X 6 C(O)R 18 , wherein 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;    R 20  is hydrogen or(C 1-6 )alkyl;    R 23  is (C 1-6 )alkyl or (C 6-12 )aryl(C 0-6 )alkyl;    R 24  is hydrogen or (C 1-6 )alkyl;    X 3  is                          wherein X is O, Y is N and R 25  is selected from hydrogen, halo(C 1-3 )alkyl, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-13 )aryl(C 0-6 )alkyl, wherein within R 25  any alicyclic or aromatic ring system may be substituted with 1 to 5 radicals independently selected from (C 1-6 )alkyl and halo-substituted (C 1-3 )alkyl.    
   
   
       3 . The method of  claim 2  wherein R 3  is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, vinyl, 2-difluoromethoxyphenyl, 1-oxy-pyridin-2-yl, 4-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl, 3,5-dimethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-bromophenyl, naphthalen-2-yl, 3,4-dichlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 2,3,4,5,6-pentafluoro-phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-cyano-phenyl, 2-trifluoromethylphenyl, 4-tert-butyl-phenyl, 3-chlorophenyl, 4-bromophenyl, 2-fluoro-3-chloro-phenyl, 2-fluoro-3-methyl-phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 3-bromophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2-trifluoromethoxyphenyl, 2,3-difluorophenyl, biphenyl, 2-bromo-5-fluoro-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 2-chloro-5-trifluoromethylphenyl, 2,4-bis-trifluoromethylphenyl, 2,5,6-trifluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2,3,5-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-methoxyphenyl, 3,5-bis-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2,6-dichlorophenyl, 4-carboxyphenyl, cyclohexyl, cyclopropyl, isopropyl, thiophen-2-yl, 5-chloro-thiophen-2-yl and 3,5-dimethyl-isoxazol-4-yl.  
   
   
       4 . The method of  claim 3  wherein R 4  is benzoyl, morpholine-4-carbonyl, acetyl, furan-3-carbonyl, 2-methoxy-benzoyl, 3-methoxy-benzoyl, naphthalene-2-carbonyl, benzo[1,3]dioxole-5-carbonyl, 3-pyridin-3-yl-acryloyl, benzofuran-2-carbonyl, furan-2-carbonyl, tert-butoxy-carbonyl, biphenyl-4-carbonyl, quinoline-2-carbonyl, quinoline-3-carbonyl, 3-acetyl-benzoyl, 4-phenoxy-benzoyl, 3-hydroxy-benzoyl, 4-hydroxy-benzoyl, pyridine-3-carbonyl, 3-(tert-butoxycarbonylamino-methyl)-benzoyl, 4-carbonyl-piperazine-1-carboxylic acid tert-butyl ester, 4-carbonyl-piperazine-1-carboxylic acid ethyl ester, 4-(furan-2-carbonyl)-piperazine-1-carbonyl, pyridine-4-carbonyl, 1-oxy-pyridine-4-carbonyl, 1-oxy-pyridine-3-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl, 4-benzoyl-benzoyl, 5-methyl-thiophene-2-carbonyl, 3-chloro-thiophene-2-carbonyl, 3-bromo-thiophene-2-carbonyl, 4-chloro-benzoyl, 3-flouro-4-methoxy-benzoyl, 4-methoxy-benzoyl, 4-triflouromethoxy-benzoyl, 3,4-diflouro-benzoyl, 4-fluoro-benzoyl, 3,4-dimethoxy-benzoyl, 3-methyl-benzoyl, 4-bromo-benzoyl, 4-triflouromethyl-benzoyl, 3-benzoyl-benzoyl, cyclopentane-carbonyl, benzo[b]thiophene-2-carbonyl, 3-chloro-benzo[b]thiophene-2-carbonyl, benzenesulfonyl, naphthalene-2-sulfonyl, 5-methyl-thiophene-2-sulfonyl, thiophene-2-sulfonyl, formamyl-methyl ester, 4-methyl-pentanoyl, formamyl-isobutyl ester, formamyl-monoallyl ester, formamyl-isopropyl ester, N,N-dimethyl-formamyl, N-isopropyl-formamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-yl-formamyl, 3-phenyl-acryloyl, 1H-indole-5-carbonyl, pyridine-2-carbonyl, pyrazine-2-carbonyl, 3-hydroxy-pyridine-2-carbonyl, 2-amino-pyridine-3-carbonyl, 2-hydroxy-pyridine-3-carbonyl, 6-amino-pyridine-3-carbonyl, 6-hydroxy-pyridine-3-carbonyl, pyridazine-4-carbonyl, 3-phenoxy-benzoyl and 1-oxo-1,3-dihydro-isoindole-2-carbonyl.  
   
   
       5 . The method of  claim 4  wherein R 25  is tert-butyl, cyclopropyl, ethyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, thienyl or trifluoromethyl.  
   
   
       6 . The method of  claim 2 , wherein R 3  is —CR 5 ═CHR 6  wherein R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 6-12 )aryl, optionally 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, —X 4 OR 9  and —X 4 C(O)OR 9 , wherein X 4  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl.  
   
   
       7 . The method of  claim 6  wherein R 3  is phenyl or 2-difluoromethoxyphenyl.  
   
   
       8 . The method of  claim 2  wherein R 3  is —CR 5 (CR 6   3 ) 2  wherein R 5  is hydrogen and R 6  is (C 1-4 )alkyl.  
   
   
       9 . The method of  claim 8  wherein R 3  is —CH(CH 3 ) 2 .  
   
   
       10 . The method of  claim 2  wherein R 3  is (C 3-12 )cycloalkyl.  
   
   
       11 . The method of  claim 10  wherein R 3  is cyclopropyl.  
   
   
       12 . The method of  claim 5 , wherein X 3  is  
     
       
         
         
             
             
         
       
     
   
   
       13 . The method of  claim 5 , wherein X 31  is  
     
       
         
         
             
             
         
       
     
   
   
       14 . The method of  claim 5 , wherein X3 is  
     
       
         
         
             
             
         
       
     
   
   
       15 . The method of  claim 2  wherein R 4  is —C(O)X 5 R 11  wherein X 5  is a bond and R 11  is hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl.  
   
   
       16 . The method of  claim 15  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 2  wherein R 20  is hydrogen, R 23  is (C 1-6 )alkyl, R 24  is hydrogen, R 25  is tert-butyl, cyclopropyl, ethyl, phenyl, pyridin-3-yl, pyridin-4-yl, thien-3-yl or trifluoromethyl.  
   
   
       18 . The method of  claim 1  selected from the group consisting of: 
 morpholine-4-carboxylic acid {2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-[1,1-dimethyl-2-oxo-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-ethylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {2-phenylmethanesulfonyl-1-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-pentylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-[1-(5-pyridin-3-yl-[1,3,4]oxadiazole-2-carbonyl)-pentylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid [1-[1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide;    morpholine-4-carboxylic acid {2-(2-methyl-propane-1-sulfonyl)-1-[1-(3-thiophen-2-yl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid [1-[1-(3-tert-butyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide;    morpholine-4-carboxylic acid {2-cyclopropylmethanesulfonyl-1-[1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {(R)-2-cyclopropylmethanesulfonyl-1-[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid [(1-[(1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide;    {(R)-2-(2-methyl-propane-1-sulfonyl)-1-[(S)-1-(5-thiophen-3-yl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {(R)-1-[(S)-1-(3-tert-butyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-2-cyclopropylmethanesulfonyl-ethyl}-amide;    morpholine-4-carboxylic acid {(R)-2-(2-methyl-propane-1-sulfonyl)-1-[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {(R)-1-[(S)-1-(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide;    morpholine-4-carboxylic acid {(R)-1-[(S)-1-(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide;    morpholine-4-carboxylic acid {2-cyclopropylmethanesulfonyl-1-[1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {2-cyclopropylmethanesulfonyl-1-[1-(3-ethyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {2-cyclopropylmethanesulfonyl-1-[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {2-(2-methyl-propane-1-sulfonyl)-1-[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid [1-[1-(3-ethyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide;    morpholine-4-carboxylic acid {2-phenylmethanesulfonyl-1-[1-(3-phenyl-[1,2,4]oxadiazole-5-carbonyl)-propylcarbamoyl]-ethyl}-amide;    morpholine-4-carboxylic acid {1-[1-(3-ethyl-[1,2,4]oxadiazole-5-carbonyl)-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide;    morpholine-4-carboxylic acid {1-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide;    morpholine-4-carboxylic acid {1-[1-(5-tert-butyl-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide; and    morpholine-4-carboxylic acid {2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-[1,1-dimethyl-2-oxo-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-ethylcarbamoyl]-ethyl}-amide.    
   
   
       19 . A method for manufacturing a pharmaceutical composition using a compound of  claim 1  for treating a disease in an animal in which Cathepsin S activity contributes to the pathology and/or symptomology of the disease.