Novel compounds and compositions as protease inhibitors

Abstract

The present invention relates to novel N-cyanomethyl amides which are 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: 
 R 1  is a group of Formula (a) or (b):  
                     
 wherein:  
 X 1  and X 2  independently are —C(O)— or —CH 2 S(O) 2 —;  
 R 5  and R 6  independently are hydrogen, (C 1-6 )alkyl or as defined below;  
 R 7  and R 8  independently are hydrogen or (C 1-6 )alkyl or as defined below;  
 R 9  and R 10  independently are (i) (C 1-6 )alkyl optionally substituted with cyano, halo, halo-substituted (C 1-3 )alkyl, nitro, —NR 12 R 12 , —NR 12 C(O)OR 12 , —NR 12 C(O)NR 12 R 12 , —NR 12 C(NR 12 )NR 12 R 12 , —OR 12 , —SR 12 , —C(O)OR 12 , —OC(O)R 12 , —C(O)NR 12 R 12 , —S(O) 2 NR 12 R 12 , —P(O)(OR 12 )OR 12 , —OP(O)(OR 12 )OR 12 , —NR 12 C(O)R 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , — 14 , —SR 14 , —S(O)R 14 , —S(O) 2 R 14 , —C(O)R 14 , —C(O)OR 14 , —OC(O)R 14 , —NR 14 R 15 , —NR 15 C(O)R 14 , —NR 15 C(O)R 14 , —C(O)NR 14 R 15 , —S(O) 2 NR 14 R 15 , —NR 15 C(O)NR 14 R 15  or —NR 15 C(NR 15 )NR 14 R 15 , wherein R 12  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 13  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 14  is (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 5-12 )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 15  is hydrogen or (C 1-6 )alkyl, and wherein within R 14  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 16 , —X 3 OR 16 , —X 3 SR 16 , —X 3 S(O)R 16 , —X 3 S(O) 2 R 16 , —X 3 C(O)R 16 , —X 3 C(O)OR 16 , —X 3 OC(O)R 16 , —X 3 NR 16 R 17 , —X 3 NR 17 C(O)R 16 , —X 3 NR 17 C(O)OR 16 , X 3 C(O)NR 16 R 17 , —X 3 S(O) 2 NR 16 R 17 , —X 3 NR 17 C(O)NR 16 R 17  or —X 3 NR 17 C(NR 17 )NR 16 R 17 , wherein X 3  is a bond or (C 1-6 )alkylene, R 16  is hydrogen or (C 1-6 )alkyl and R 17  is (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 5-12 )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) a group selected from (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 5-12 )aryl(C 0-6 )alkyl, (C 9-12 )polycycloaryl(C 0-6 )alkyl and hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 16 , —X 3 OR 16 , —X 3 SR 16 , —X 3 S(O)R 16 , —X 3 S(O) 2 R 16 , —X 3 C(O)R 16 , —X 3 C(O)OR 16 , —X 3 OC(O)R 16 , —X 3 NR 16 R 17 , —X 3 NR 17 C(O)R 16 , —X 3 NR 17 C(O)OR 16 , —X 3 C(O)NR 16 R 17 , —X 3 S(O) 2 NR 16 R 17 , —X 3 NR 17 C(O)NR 16 R 17  or —X 3 NR 17 C(NR 17 )NR 16 R 17 , wherein X 3 , R 16  and R 17  are as defined above; wherein within R 9  and/or R 10  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 3 NR 12 R 12 , —X 3 NR 12 C(O)OR 12 , —X 3 NR 12 C(O)NR 12 R 12 , —X 3 NR 12 C(NR 12 )NR 12 R 12 , —X 3 OR 12 , —X 13 SR 12 , —X 3 C(O)OR 2 , —X 3 C(O)NR 12 R 12 , —X 3 S(O) 2 NR 12 R 12 , —X 3 P(O)(OR 3 )OR 12 , —X 3 OP(O)(OR 3 )OR 12 , —X 3 NR 12 C(O)R 13 , —X 3 S(O)R 13 , —X 13 S(O) 2 R 13  and —X 3 C(O)R 13 , wherein X 3 , R 12  and R 13  are as defined above; or  
 R 9  together with R 7  and/or R 10  together with R 8  form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C 1-4 )alkyl or methylene; or  
 R 9  and R 5  together with the carbon atom to which both R 9  and R 5  are attached and/or R 10  and R 6  together with the carbon atom to which both R 10  and R 6  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene; and  
 R 11  is —X 4 X 5 R 18 , wherein X 4 is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 5  is a bond, —O— or —NR 19 —, wherein R 19  is hydrogen or (C 1-6 )alkyl, and R 18  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, halo-substituted (C 1-3 )alkyl, nitro, —NR 14 R 14 , —NR 14 C(O)OR 14 , —NR 14 C(o)NR 14 R 14 , —NR 14 C(NR 14 )NR 14 R 14 , —OR 14 , —SR 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —S(O) 2 NR 14 R 14 , —P(O)(OR 14 )OR 14 , —OP(O)(OR 14 )OR 14 , —NR 14 C(O)R 15 , —S(O)R 15 , —S(O) 2 R 15 , —C(O)R 15 , —OR 20 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 2 , — 20 R 21 , —NR 21  C(O)R 20 , NR 21 C(O)OR 20 , —NR 21 C(O)NR 20 R 21  or —NR 21 C(NR 21 )NR 20 R 21 , wherein R 14  and R 15  are as defined above, R 20  is (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 5-12 )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 21  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) (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, diphenyl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl, dihetero(C 5-6 )aryl(C 0-6 )alkyl, (C 9-2 )polycycloaryl(C 0-6 )alkyl or hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl wherein said cycloalkyl, heterocycloalkyl, aryl, diphenyl, heteroaryl, diheteroaryl, polycycloaryl or heterpolycycloaryl ring may be substituted by —R 22 , —X 3 OR 22 , —X 3 SR 22 , —X 3 S(O)R 22 , —X 3 S(O) 2 R 22 , —X 3 C(O)R 22 , —X 3 C(O)OR 22 , —X 3 C(O)NR 22 R 23 , —X 3 NR 22 R 23 , —X 3 NR 23 C(O)R 22 , —X 3 NR 23 C(O)OR 22 , —X 3 NR 23 S(O) 2 R 22 , —X 3 NR 23 C(O)NR 22 R 23  or —X 3 NR 23 C(NR 23 )NR 22 R 23 , wherein X 3  is as defined above, R 22  is (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 5-12 )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 23  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 11  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 3 NR 12 R 12 , —X 3 NR 12 C(O)OR 12 , —X 3 NR 12 C(O)NR 12 R 12 , —X 3 NR 12 C(NR 12 )NR 12 R 12 , —X 3 OR 12 , —X 3 SR 12 , —X 3 C(O)OR 12 , —X 3 C(O)NR 12 R 12 , —X 3 S(O) 2 NR 12 R 12 , —X 3 P(O)(OR 3 )OR 12 , —X 3 OP(O)(OR 3 )OR 12 , —X 3 NR 12 C(O)R 13 , —X 3 S(O)R 13 , X 3 S(O) 2 R 13  and —X 3 C(O)R 13 , wherein X 3 , R 12  and R 13  are as defined above;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3 is hydrogen, (C 1-6 )alkyl or as defined below;  
 R 4  is (i) cyano, —C(O)OR 12  or (C 1-6 )alkyl, wherein said alkyl optionally is substituted with cyano, halo, halo-substituted (C 1-3 )alkyl, nitro, —NR 12 R 12 , —NR 12 C(O)OR 12 , —NR 12 C(O)NR 12 R 12 , —NR 12 C(NR 12 )NR 12 R 12 , —OR 12 , —SR 12 , —C(O)OR 12 , —OC(O)R 12 , —C(O)NR 12 R 12 , —S(O) 2 NR 12 R 12 , —P(O)(OR 12 )OR 12 , —OP(O)(OR 12 )OR 12 , —NR 12 C(O)R 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —OR 14 , —SR 14 , —S(O)R 14 , —S(O) 2 R R   14 , —C(O)R 14 , —C(O)OR 14 , —OC(O)R 14 , —NR 14 R 15 , —NR 15 C(O)R 14 , —NR 15 C(O)OR 14 , —C(O)NR 14 R 15 , —S(O) 2 NR 14 R 15 , —NR 15 C(O)NR 14 R 15  or —NR 15 C(NR 15 )NR 14 R 15 , wherein R 12 , R 13  and R 14  are as defined above, or (ii) a group selected from (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 5-12 )aryl(C 0-6 )alkyl, (C 9-12 )polycycloaryl(C 0-6 )alkyl and hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 16 , —X 3 OR 16 , —X 3 SR 16 , —X 3 S(O)R 16 , —X 3 S(O) 2 R 16 , —X 3 C(O)R 16 , —X 3 C(O)OR 16 , —X 3 OC(O)R 16 , —X 3 NR 16 R 17 , —X 3 NR 17 C(O)R 16 , —X 3 NR 17 C(O)OR 16 , —X 3 C(O)NR 16 R 17 , —X 3 S(O) 2 NR 16 R 17 , —X 3 NR 17 C(O)NR 16 R 17  or —X 3 NR 17 C(NR 17 )NR 16 R 17 , wherein X 3 , R 16  and R 17  are as defined above; wherein within R 4  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 3 NR 12 R 12 , —X 3 NR 12 C(O)OR 12 , —X 3 NR 12 R 12 , —X 3 NR 12 C(NR 12 )NR 12 R 12 , —X 3 OR 12 , —X 3 SR 12 , —X 3 C(O)OR 12 , —X 3 C(O)NR 12 R 12 , —X 3 S(O) 2 NR 12 R 12 , —X 3 P(O)(OR 3 )OR 12 , —X 3 OP(O)(OR 3 )OR 12 , —X 3 NR 12 C(O)R 13 , —X 3 S(O)R 13 , —X 3 S(O) 2 R 13  and X 3 , R 12  and R 13  are as defined above; or  
 R 4  taken together with R 2  forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C 1-4 )alkyl or methylene; or  
 R 4  and R 3  taken together with the carbon atom to which both R 4  and R 3  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted 1 to 3 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 3 NR 12 R 12 , —X 3 NR 12 C(O)OR 12 , —X 3 NR 12 C(O)NR 12 R 12 , —X 3 NR 12 C(NR 12 )NR 12 R 12 , —X 3 OR 12 , —X 3 SR 12 , —X 3 C(O)OR 12 , —X 3 C(O)NR 12 R 12 , —X 3 S(O) 2 NR 12 R 12 , —X 3 P(O)(OR 3 )OR 12 , —X 3 OP(O)(OR 3 )OR 12 , —X 3 NR 12 C(O)R 13 , —X 3 S(O)R 13 , —X 3 S(O) 2 R 13  and —X 3 C(O)R 13 , wherein X 3 , R 12  and R 13  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: 
 R 1  is a group Formula (a), wherein within Formula (a): 
 X 1 is —C(O)—;  
 R 5  is hydrogen, (C 1-6 )alkyl or as defined below;  
 R 7  is hydrogen, (C 1-6 )alkyl or as defined below;  
 R 9  is (i) (C 1-6 )alkyl optionally substituted with halo-substituted (C 1-3 )alkyl, —OR 12 , or —NR 12 C(NR 12 )NR 12 R 12  wherein R 12  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, or (ii) (C 6-12 )aryl(C 0-6 )alkyl, or  
 
 R 9  taken together with R 7  forms trimethylene optionally substituted oxo, (C 1-4 )alkyl or methylene, or  
 R 9  and R 5  together with the carbon atom to which both R 9  and R 5  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene; and  
 R 11  is—X 4 X 5 R 18 , wherein X 4  is —C(O)—, X 5  is a bond, —O— or —S(O) 2 — and R 18  is (i) (C 1-6 )alkyl optionally substituted by —C(O)NR 20 R 21  or —NR 21 C(O)R 20 , wherein R 20  is (C 6-12 )aryl(C 0-6 )alkyl and R 21  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) (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 5-12 )aryl(C 0-6 )alkyl or hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl, wherein said heterocycloalkyl, aryl, heteroaryl or heteropolycycoaryl ring may be substituted by —R 22 , —X 3 OR 22 , —X 3 NR 22 R 23 , —X 3 NR 17 C(O)R 16 , —X 3 NR 23 C(O)OR 22 , —X 3 NR 23 S(O) 2 R 22 , —X 3 S(O) 2 R 22 , —X 3 C(O)R 22  or —X 3 NR 23 C(O)NR 22 R 23 , wherein X 3  is a bond or (C 1-6 )alkylene, R 22  is hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl and R 23  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 11  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 3 NR 12 R 12 , —X 3 NR 12 C(O)OR 12 , —X 3 NR 12 C(O)NR 12 R 12 , —X 3 NR 12 C(NR 12 )NR 12 R 12 , —X 3 OR 12 , —X 3 SR 12 , —X 3 C(O)OR 12 , —X 3 C(O)NR 12 R 12 , —X 3 S(O) 2 NR 12 R 12 , —X 3 P(O)(OR 3 )OR 12 , —X 3 OP(O)(OR 3 )OR 12 , —X 3 NR 12 C(O)R 13 , —X 3 S(O)R 13 , —X 3 S(O) 2 R 13  and —X 3 C(O)R 13 , wherein X 3  is a bond or (C 1-6 )alkylene, R 12  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 13  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 R 3  is hydrogen, (C 1-6 )alkyl or as defined together with R 4 ; and  
 R 4  is (i) hydrogen, cyano, —C(O)OR 12  or (C 1-6 )alkyl wherein said alkyl optionally is substituted with —C(O)OR 12 , —OC(O)R 12 , wherein R 12  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, or (ii) (C 6-10 )aryl(C 0-3 )alkyl or  
 R 4  taken together with R 2  forms trimethylene or  
 R 4  and R 3  taken together with the carbon atom to which both R 4  and R 3  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene, wherein said (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene optionally is substituted with (C 1-6 )alkyl; 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: 
 R 1  is a group Formula (a), wherein within Formula (a): 
 X 1 is —C(O)—;  
 R 5  is hydrogen or as defined together with R 9 ;  
 R 7  is hydrogen;  
 R 9  is (i) (C 1-6 )alkyl or  
 R 9  and R 5  together with the carbon atom to which both R 9  and R 5  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene; and  
 R 11  is—X 4 X 5 R 18 , wherein X 4  is —C(O)— and R 18  is (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl, wherein said aryl or heteroaryl ring may be substituted by —R 22 , X 3 OR 22 , X 3 NR 22 R 23 , —X 3 NR 17 C(O)R 16 , —X 3 NR 23 C(O)OR 22 , —X 3 NR 23 S(O) 2 R 22 , —X 3 S(O) 2 R 22 , —X 3 C(O)R 22  or —X 3 NR 23 C(O)NR 22 R 23 , wherein X 3  is a bond or (C 1-6 )alkylene, R 22  is hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl and R 23  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 11  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 3 NR 12 R 12 , —X 3 NR 12 C(O)OR 12 , —X 3 NR 12 C(O)NR 12 R 12 , —X 3 NR 12 C(NR 12 )NR 12 R 12 , —X 3 OR 12 , —X 3 SR 12 , —X 3 C(O)OR 12 , —X 3 C(O)NR 12 R 12 , —X 3 S(O) 2 NR 12 R 12 , —X 3 P(O)(OR 3 P(O)(OR 3 )OR 12 , —X 3 OP(O)(OR 3 )OR 12 , —X 3 NR 12 C(O)R 13 , —X 3 S(O)R 13 , —X 3 S(O) 2 R 13  and —X 3 C(O)R 13 , wherein X 3  is a bond or (C 1-6 )alkylene, R 12  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 13  is  
 
 (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 R 3  is hydrogen or as defined together with R 4 ; and  
 R 4  is (i) hydrogen or  
 R 4  and R 3  taken together with the carbon atom to which both R 4  and R 3  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene, wherein said (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene optionally is substituted with (C 1-6 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof; 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 1  is a group Formula (a), wherein within Formula (a): 
 X 1  is —C(O)—;  
 R 5  is hydrogen or as defined together with R 9 ;  
 R 7  is hydrogen;  
 R 9  is (i) (C 1-6 )alkyl or  
 R 9  and R 5  together with the carbon atom to which both R 9  and R 5  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene; and  
 R 11  is—X 4 X 5 R 18 , wherein X 4  is —C(O)— and R 18  is phenyl, wherein said phenyl ring may be substituted by —R 22 , —X 3 OR 22 , —X 3 NR 22 R 23 , —X 3 NR 17 C(O)R 16 , —X 3 NR 23 C(O)OR 22 , —X 3 NR 23 S(O) 2 R 22 , —X 3 S(O) 2 R 22 , —X 3 C(O)R 22  or —X 3 NR 23 C(O)NR 22 R 23 , wherein X 3  is a bond or (C 1-6 )alkylene, R 22  is hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl and R 23  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 11  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 3 NR 12 R 12 , —X 3 NR 12 C(O)OR 12 , —X 3 NR 12 C(O)NR 12 R 12 , —X 3 NR 12 C(NR 12 )NR 12 R 12 , —X 3 OR 12 , —X 3 SR 12 , —X 3 C(O)OR 12 , —X 3 C(O)NR 12 R 12 , —X 3 S(O) 2 NR 12 R 12 , —X 3 P(O)(OR 3 )OR 12 , —X 3 OP(O)(OR 3 )OR 12 , —X 3 NR 12 C(O)R 13 , —X 3 S(O)R 13 , —X 3 S(O) 2 R 13  and —X 3 C(O)R 13 , wherein X 3  is a bond or (C 1-6 )alkylene, R 12  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 13  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 
 R 3  is hydrogen or as defined together with R 4 ; and  
 R 4  is (i) hydrogen or  
 R 4  and R 3  taken together with the carbon atom to which both R 4  and R 3  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene, wherein said (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene optionally is substituted with (C 1-6 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         5 . The compound of  claim 4  which is selected from a group consisting of: 
 N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-3-[3-(3-morpholin-4-yl-propyl)-ureido]-benzamide; and  
 N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-3-(3-pyridin-2-yl-ureido)-benzamide;  
 N-[1S-(cyanomethyl-carbamoyl)-3-methyl-butyl]4-(3-pyridin-4-ylmethyl-ureido)-benzamide;  
 N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]4-(3-piperidin-4-yl-ureido)-benzamide;  
 N-[1-S-(dicyanomethyl-carbamoyl)-3-methyl-butyl]4-morpholin4-yl-benzamide;  
 4-dimethylamino-piperidine-1-carboxylic acid {4-[1-(cyanomethyl-carbamoyl)-3-methyl-butylcarbamoyl]-phenyl}-amide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)4-(4-methylpiperazin-1-yl)benzamide;  
 N-[1-cyanomethylcarbamoyl-3-methylbutyl4-(2-guanidinothiazol-4-yl)]benzamide;  
 {4-[1-S-(cyanomethyl-carbamoyl)-3-methyl-butylcarbamoyl]-phenyl}-carbamic acid 3-pyridin-4-yl-propyl ester; and  
 N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-4-{3-[2-(3H-imidazol-4-yl)-ethyl]ureido}-benzamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         6 . A compound of Formula II:  
       
         
           
           
               
               
           
         
       
       in which: 
 X 1  is selected from —C(O)—, —S(O)—, —C(S), —S(O) 2 — and —P(O) 2 —;  
 R 1  and R 2  independently are hydrogen or (C 1-6 )alkyl;  
 R 3  and R 4  independently are hydrogen or (C 1-6 )alkyl or R 3  and R 4  taken together with the carbon atom to which both R 3  and R 4  are attached form (C 3-8 )cycloalkylene;  
 R 5  and R 6  independently are hydrogen or (C 1-6 )alkyl or R 5  and R 6  taken together with the carbon atom to which both R 5  and R 6  are attached form (C 3-8 )cycloalkylene or (C 3-8 )heterocycloalkylene; and  
 R 7  is —X 2 X 3 R 9 , wherein X 2  is —C(O)—, —S(O)—, —C(S)—, —S(O) 2 — or —P(O) 2 —, X 3  is a bond, —O— or —NR 10 —, wherein R 10  is hydrogen or (C 1-6 )alkyl, and R 9  is (C 3-6 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-6 )cycloalkyl(C 0-6 )alkyl, phenyl(C 0-6 )alkyl or hetero(C 5-6 )aryl(C 0-6 )alkyl, wherein within R 9  said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —R 2 , —X 4 NR 11 R 12 , —X 4 NR 11 C(O)R 12 , —X 4 NR 11 C(O)OR 12 , —X 4 NR 11 C(O)NR 11 R 12 , —X 4 NR 11 C(NR 11 )NR 11 R 12 , —X 4 OR 12 , —X 4 SR 12 , —X 4 S(O)R 12 , —X 4 S(O) 2 R 12 , —X 4 C(O)R 12 , —X 4 C(O)OR 12 , —X 4 OC(O)R 12 , —X 4 C(O)NR 11 R 12 , —X 4 OC(O)NR 11 R 12 , —X 4 S(O) 2 NR 11 R 12 , —X 4 P(O)(OR 11 )OR 12  or —X 4 OP(O)(OR 11 )OR 12 , wherein X 4  is a bond or (C 1-6 )alkylene, R 11  at each occurrence is hydrogen or (C 1-6 )alkyl and R 12  is (C 3-6 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-6 )cycloalkyl(C 0-6 )alkyl, phenyl(C 0-6 )alkyl or hetero(C 5-6 )aryl(C 0-6 )alkyl, wherein within R 12  said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —R 13 , —X 4 NR 11 R 13 , —X 4 NR 11 C(O)R 13 , —X 4 NR 11 C(O)OR 13 , —X 4 NR 11 C(O)NR 11 R 13 , —X 4 NR 11 C(NR 11 )NR 11 R 13 , —X 4 OR 13 , —X 4 SR 13 , —X 4 S(O)R 13 , —X 4 S(O) 2 R 13 , —X 4 C(O)R 13 , —X 4 C(O)OR 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 11 R 13 , —X 4 OC(O)NR 11 R 13 , —X 4 S(O) 2 NR 11 R 13 , —X 4 P(O)(OR 11 )OR 13  or —X 4 OP(O)(OR 11 )OR 13 , wherein X 4  and R 11  are as defined above and R 13  is (C 3-6 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-6 )cycloalkyl(C 0-6 )alkyl, phenyl(C 0-6 )alkyl or hetero(C 5-6 )aryl(C 0-6 )alkyl, wherein within R 7  any alicyclic and aromatic rings 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 5 NR 14 R 14 , —X 5 NR 14 C(O)OR 14 , —X 5 NR 14 C(O)NR 14 R 14 , —X 5 NR 14 C(NR 14 )NR 14 R 14 , —X 5 OR 14 , —X 5 SR 14 , —X 5 C(O)OR 14 , —X 5 C(O)NR 14 R 14 , —X 5 S(O) 2 NR 14 R 14 , —X 5 P(O)(OR 5 )OR 14 , —X 5 OP(O)(OR 5 )OR 14 , —X 5 NR 14 C(O)R 15 , —X 5 S(O)R 15 , —X 5 S(O) 2 R 15  and —X 5 C(O)R 15 , wherein X 5  is a bond or (C 1-6 )alkylene, R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 15  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; and the pharrmaceutically acceptable salts thereof.  
 
     
     
         7 . The compound of  claim 6  in which: 
 X 1  is selected from —C(O)—;  
 R 1  and R 2  both are hydrogen;  
 R 3  is isobutyl and R 4  is hydrogen or R 3  and R 4  taken together with the carbon atom to which both R 3  and R 4  are attached form cyclopropylene or cyclohexylene;  
 R 5  and R 6  both are hydrogen or R 5  and R 6  taken together with the carbon atom to which both R 5  and R 6  are attached form cyclohexylene or (C 6 )heterocycloalkylene; and  
 R 7  is —X 2 X 3 R 9 , wherein X 2  is —C(O)—, X 3  is a bond and R 9  is phenyl, wherein within R 9  said phenyl is substituted by —R 12 , —X 4 NR 11 R 12 , —X 4 NR 11 C(O)R 12 , —X 4 NR 11 C(O)OR 12 , —X 4 NR 11 C(O)NR 11 R 12 , —X 4 NR 11 C(NR 11 )NR 11 R 12 , —X 4 OR 12 , —X 4 SR 12 , —X 4 S(O)R 12 , —X 4 S(O) 2 R 12 , —X 4 C(O)R 12 , —X 4 C(O)OR 12 , —X 4 OC(O)R 12 , —X 4 C(O)NR 11 R 12 , —X 4 OC(O)NR 11 R 12 , —X 4 S(O) 2 NR 11 R 12 , —X 4 P(O)(OR 11 )OR 12  or —X 4 OP(O)(OR 11 )OR 12 , wherein X 4  is a bond or (C 1-6 )alkylene, R 11  at each occurrence is hydrogen or (C 1-6 )alkyl and R 12  is hetero(C 3-6 )cycloalkyl(C 0-6 )alkyl, phenyl(C 0-6 )alkyl or hetero(C 5-6 )aryl(C 0-6 )alkyl, wherein within R 12  said heterocycloalkyl, phenyl or heteroaryl is substituted by —R 13 , —X 4 NR 11 R 13 , —X 4 NR 11 C(O)R 13 , —X 4 NR 11 C(O)OR 13 , —X 4 NR 11 C(O)NR 11 R 13 , —X 4 NR 11 C(NR 11 )NR 11 R 13 , —X 4 OR 13 , —X 4 SR 13 , —X 4 S(O)R 13 , —X 4 S(O) 2 R 13 , —X 4 C(O)R 13 , —X 4 C(O)OR 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 11 R 13 , —X 4 OC(O)NR 11 R 13 , —X 4 S(O) 2 NR 11 R 13 , —X 4 P(O)(OR 11 )OR 13  or —X 4 OP(O)(OR 11 )OR 13 , wherein X 4  and R 11  are as defined above and R 13  is (C 3-6 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-6 )cycloalkyl(C 0-6 )alkyl, phenyl(C 0-6 )alkyl or hetero(C 5-6 )aryl(C 0-6 )alkyl, wherein within R 7  any alicyclic and aromatic rings 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 5 NR 14 R 14 , —X 5 NR 14 C(O)OR 14 , —X 5 NR 14 C(O)NR 14 R 14 , —X 5 NR 14 C(NR 14 )NR 14 R 14 , —X 5 OR 14 , —X 5 SR 14 , —X 5 C(O)OR 14 , —X 5 C(O)NR 14 R 14 , —X 5 S(O) 2 NR 14 R 14 , —X 5 P(O)(OR 5 )OR 14 , —X 5 OP(O)(OR 5 )OR 14 , —X 5 NR 14 C(O)R 15 , —X 5 S(O)R 15 , —X 5 S(O) 2 R 15  and —X 5 C(O)R 15 , wherein X 5  is a bond or (C 1-6 )alkylene, R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 15  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; and the pharmaceutically acceptable salts thereof.  
 
     
     
         8 . The compound of  claim 7  selected from a group consisting of: 
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-pyrid-4-ylamino)thiazol4-ylbenzamide;  
 4-[3-(1-benzylpiperidin4-yl)ureido]-N-(1S-cyanomethylcarbamoyl-3-methylbutyl)benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-pyrid-4-ylthiazol-4-yl)benzamide;  
 4-[3-(1-benzylpyrrolidin-3S-yl)-3-methylureido]-N-(1S-cyanomethylcarbamoyl-3-methylbutyl)benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(4-pyrid-4-ylpiperazin-1-yl)benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(1-methylpyridin-4-ylamino)thiazol-4-yl]benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(1-methylpyridin-4-yl)thiazol-4-yl]benzamide;  
 N-[(S)-1-(Cyanomethyl-carbamoyl)-3-methyl-but-3-enyl]-4-[2-(pyridin-4-ylamino)-thiazol4-yl]-benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(1-allylpyrid-4-yl)thiazol-4-yl]benzamide;  
 N-(1S-Cyanomethylcarbamoyl-3-methylbutyl)-4-(2-piperidin4-ylaminothiazol-4-yl)benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-piperazin-1-ylthiazol-4-yl)benzamide;  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;  
 N-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-4-(2-piperazin-1-yl-thiazol4-yl)benzamide;  
 N-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;  
 N-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-4-(2-piperidin4-ylaminothiazol4-yl)benzamide;  
 N-(1-cyanomethylcarbamoylcyclohexyl)-4-(2-piperazin-1-ylthiazol-4-yl)benzamide;  
 N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[2-(piperidin-4-ylamino)-thiazol4-yl]-benzamide;  
 N-(1R-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-morpholin-4-ylthiazol-4-yl)benzamide;  
 N-(1-Cyanomethylcarbamoylcyclohexyl]-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;  
 N-[1-(4-cyanotetrahydropyran-4-ylcarbamoyl)cyclohexyl]-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;  
 N-(1-cyanomethylcarbamoylcyclohexyl)-4-(2-morpholin-4-ylthiazol-4-yl)benzamide;  
 N-(1-cyanomethylcarbamoylcyclohexyl)-4-(2-piperazin-1-ylmethylthiazol-4-yl)benzamide;  
 tert-butyl 4-(4-{4-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutylcarbamoyl]phenyl}thiazol-2-ylmethyl)piperazine-1-carboxylate;  
 N-[(S)-1-(1-Cyano-cyclopropylcarbamoyl)-3-methyl-butyl]-4-(2-piperazin-1-ylmethyl-thiazol-4-yl)-benzamide; and  
 N-(1S-cyanomethylcarbamoyl-3-methylbutyl]-4-(4-morpholin-4-ylmethylthiazol-2-ylamino)benzamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable excipient.  
     
     
         10 . The composition of  claim 9  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.  
     
     
         11 . The composition of  claim 10  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.  
     
     
         12 . The composition of  claim 11  wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.  
     
     
         13 . The composition of  claim 12  which comprises 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.  
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 6  in combination with a pharmaceutically acceptable excipient.  
     
     
         15 . The composition of  claim 14  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.  
     
     
         16 . The composition of  claim 15  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.  
     
     
         17 . The composition of  claim 16  wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.  
     
     
         18 . The composition of  claim 17  which comprises 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.  
     
     
         19 . 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 derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.  
     
     
         20 . The method of  claim 19  wherein the disease is osteoporosis.  
     
     
         21 . The method of  claim 20  wherein the animal is a human.  
     
     
         22 . The method of  claim 21  wherein the human is a post-menopausal woman.  
     
     
         23 . The method of  claim 22  wherein the cysteine protease is cathepsin K.  
     
     
         24 . 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 6;  or a N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.  
     
     
         25 . The method of  claim 24  wherein the disease is osteoporosis.  
     
     
         26 . The method of  claim 25  wherein the animal is a human.  
     
     
         27 . The method of  claim 26  wherein the human is a post-menopausal woman.  
     
     
         28 . The method of  claim 27  wherein the cysteine protease is cathepsin K.