Novel compounds and compositions as cathepsin 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 compound of Formula I:  
     
       
         
         
             
             
         
       
     
     in which: 
 X 1  is —C(R 1 )(R 2 )X 2  or —X 3 ;  
 X 2  is cyano, —CHO, —C(R 7 )(R 8 )R 5 , —C(R 7 )(R 8 )CF 3 , —C(R 7 )(R 8 )CF 2 CF 2 R 9 —CH═CHS(O) 2 R 5 , —C(R 7 )(R 8 )CF 2 C(O)NR 5 R 6 , —C(R 7 )(R 8 )C(R 7 )(R 8 )NR 5 R 6 , —C(R 7 )(R 8 )C(R 7 )(R 8 )OR 5 , —C(R 7 )(R 8 )CH 2 OR 5 , —C(R 7 )(R 8 )CH 2 N(R 6 )SO 2 R 5 , —C(R 7 )(R 8 )C(R 7 )(R 8 )N(R 6 )(CH 2 ) 2 OR 6 , —C(R 7 )(R 8 )C(R 7 )(R 8 )N(R 6 )(CH 2 ) 2 NR 6  or —C(R 7 )(R 8 )C(R 7 )(R 8 )R 5 ; wherein R 5  is (C 1-4 )alkyl, (C 6-10 )aryl(C 0-6 )alkyl, hetero(C 4-10 )aryl(C 0-6 )alkyl, (C 4-10 )cycloalkyl(C 0-6 )alkyl or hetero(C 4-10 )cycloalkyl(C 0-6 )alkyl; R 6  is hydrogen or (C 1-6 )alkyl; R 7  is hydrogen or (C 1-4 )alkyl and R 8  is hydroxy or R 7  and R 8  together form oxo; R 9  is hydrogen, halo, (C 1-4 )alkyl, (C 5-10 )aryl(C 0-6 )alkyl or hetero(C 5-10 )aryl(C 0-6 )alkyl;  
 X 3  represents a group of Formula (a):  
                     
 in which n is 1 or 2, z is 0 or 1, X 5  is selected from NR 10 , S or O, wherein R 10  is hydrogen or (C 1-6 )alkyl, and X 6  is O, S or NR 11 , wherein R 11  is selected from hydrogen, (C 1-6 )alkyl, —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 S(O) 2 R 14 , —R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 C(O)NR 12 R 15  and —X 4 S(O) 2 NR 12 R 15 , in which X 4  is a bond or (C 1-6 )alkylene; R 12  at each occurrence independently is hydrogen or (C 1-6 )alkyl; R 13  is hydrogen, (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl, R 14  is (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl and R 15  is (C 3-10 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-10 )cycloalkyl(C 0-3 )alkyl, (C 6-10 )aryl(C 0-6 )alkyl, hetero(C 5-10 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl;  
 wherein within X 1  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R 20  selected from —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 15 R 12 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 ; and wherein X 1  and R 20  may be substituted further with 1 to 5 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14  wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above;  
 R 1  and R 2  are both fluoro; or  
 R 1  is hydrogen or (C 1-6 )alkyl and R 2  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, cyano, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14 , —X 4 S(O) 2 R 14 , —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 15 R 12 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 , wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above; or R 1  and R 2  taken together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or hetero(C 3-8 )cycloalkylene; wherein R 2 , said cycloalkylene and said heterocycloalkylene may be substituted further with 1 to 3 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4  SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13  and R 14  are as defined above;  
 R 3  and R 4  are independently —C(R 16 )(R 17 )X 7 , wherein R 16  and R 17  are hydrogen, (C 1-6 )alkyl or fluoro, or R 16  is hydrogen and R 17  is hydroxy and X 7  is selected from —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14 , —X 4 S(O) 2 R 14 , —R 15 , X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 15 R 12 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 2 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 , wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above;  
 wherein within one of R 3  or R 4  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R 21  selected from —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 12 R 15 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 , wherein X 4 , R 12  and R 15  are as defined above; and wherein each of R 3 , R 4  and R 21  may be substituted further with 1 to 5 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13  and R 14  are as defined above; provided that only one bicyclic ring structure is present within each of R 3  or R 4 ; and provided that when X 2  is cyano and X 7  within one of R 3  or R 4  is —X 4 C(O)R 13  or —X 4 C(O)R 15 , wherein X 4  is a bond, then X 7  within the other of R 3  or R 4  is limited to —X 4 SR 15 , —X 4 S(O)R 15  and —X 4 S(O) 2 R 15 , wherein R 15  is (C 6-10 )aryl(C 1-6 )alkyl substituted with 1 to 5 radicals or hetero(C 5-10 )aryl(C 0-6 )alkyl optionally substituted with 1 to 5 radicals, wherein said radicals are independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13  and R 14  are as defined above, provided that the radical is not selected from only halo when R 15  is (C 6-10 )aryl(C 1-6 )alkyl; and provided that when X 2  is cyano then X 7  within R 3  and R 4  is not —X 4 C(O)NR 12 R 12 , —X 4 C(O)NR 15 R 12  or —X 4 C(O)NR 18 R 19 , wherein X 4  is a bond and R 18  and R 19  together with the nitrogen atom to which they are attached form hetero(C 3-10 )cycloalkyl or hetero(C 5-10 )aryl;  
 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: 
 X 1  is —C(R 1 )(R 2 )X 2  or —X 3 ;    X 2  is cyano, —CHO, —C(O)R 5 , —C(O)CF 3 , —C(O)CF 2 CF 2 R 9 —CH═CHS(O) 2 R 5 , —C(O)CF 2 C(O)NR 5 R 6 , —C(O)C(O)NR 5 R 6 , —C(O)C(O)OR 5 , —C(O)CH 2 OR 5 , —C(O)CH 2 N(R 6 )SO 2 R 5 , —C(O)C(O)N(R 6 )(CH 2 ) 2 OR 6 , —C(O)C(O)N(R 6 )(CH 2 ) 2 NR 6  or —C(O)C(O)R 5 , wherein R 5  is (C 1-4 )alkyl, (C 6-10 )aryl(C 0-6 )alkyl, hetero(C 4-10 )aryl(C 0-6 )alkyl, (C 4-10 )cycloalkyl(C 0-6 )alkyl or hetero(C 4-10 )cycloalkyl(C 0-6 )alkyl, R 6  is hydrogen or (C 1-6 )alkyl and R 9  is halo;    X 3  represents a group of Formula (b):                          in which n is 1 or 2, z is 0 or 1, X 6  is O or NR 11 , wherein R 11  is selected from hydrogen, (C 1-6 )alkyl, —X 4 OC(O)R 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 S(O) 2 R 14 , —R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 C(O)NR 12 R 15  and —X 4 S(O) 2 NR 12 R 15 , in which X 4  is a bond or (C 1-6 )alkylene; R 12  at each occurrence independently is hydrogen or (C 1-6 )alkyl; R 13  is hydrogen, (C 1-4 )alkyl or halo-substituted(C 1-6 )alkyl, R 14  is (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl and R 15  is (C 3-10 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-10 )cycloalkyl(C 0-3 )alkyl, (C 6-10 )aryl(C 0-6 )alkyl, hetero(C 5-10 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl;    wherein within X 1  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R 15  and —X 4 C(O)R 15 ; and wherein X 1  may be substituted further with 1 to 3 radicals independently selected from (C 1-6 )alkyl, halo-substituted(C 1-4 )alkyl, —X 4 NR 12 R 12 , —X 4 OR 13  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above;    R 1  and R 2  are both fluoro; or    R 1  is hydrogen or (C 1-6 )alkyl and R 2  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, —X 4 OR 13  and —R 15 ; or R 1  and R 2  taken together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or hetero(C 3-8 )cycloalkylene; wherein R 2  may be substituted further with (C 1-6 )alkyl; wherein X 4 , R 13  and R 15  are as defined above;    R 3  and R 4  are independently —C(R 16 )(R 17 )X 7 , wherein R 16  and R 17  are hydrogen, (C 1-6 )alkyl or fluoro, or R 16  is hydrogen and R 17  is hydroxy and X 7  is selected from —X 4 SR 13 , —X 4 C(O)R 13 , —X 4 C(O)NR 12 R 12 , —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15  and —X 4 C(O)NR 15 R 12 , wherein X 4 , R 12 , R 13  and R 15  are as defined above;    wherein within one of R 3  or R 4  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 12 R 15 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 , wherein X 4 , R 12  and R 15  are as defined above; and wherein each of R 3  and R 4  may be substituted further with 1 to 5 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13  and R 14  are as defined above;    wherein within one of R 3  and R 4  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R 15  and —X 4 OR 15 ; and wherein each of R 3  or R 4  may be substituted further by 1-5 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, —X 4 NR 12 C(O)OR 12 , —X 4 OR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above;    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.    
   
   
       3 . A compound of  claim 2  in which R 3  and R 4  are independently —CH 2 X 7 , wherein X 7  is selected from X 4 SR 13 , —X 4 C(O)R 13 , —X 4 C(O)NR 12 R 12 , —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15  and —X 4 C(O)NR 15 R 12 , wherein X 4  is a bond or (C 1-6 )alkylene, R 12  at each occurrence independently is hydrogen or (C 1-6 )alkyl, R 13  is hydrogen, (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl, R 14  is (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl and R 15  is (C 3-10 )cycloalkyl(C 0-6 )alkyl, (C 3-10 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-10 )cycloalkyl(C 0-3 )alkyl, (C 6-10 )aryl(C 0-6 )alkyl, hetero(C 5-10 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl; wherein within R 3  and R 4  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R 15  and —X 4 OR 15 , wherein X 4  and R 15  are as defined above; and wherein R 3  and R 4  may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, —X 4 NR 12 C(O)OR 12 , —X 4 OR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13  and —X 4 S(O) 2 R 14 , wherein X 4 R 12 , R 13  and R 14  are as defined above; 
 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 . A compound of  claim 3  in which R 3  is selected from 5-bromo-thiophen-2-ylmethyl, 3-cyclohexylpropyl, 2-cyclohexylpropyl, 2-cyclopentylpropyl, 3-phenylpropyl, 3-(2-difluoromethoxy)phenylpropyl, 2-phenylcyclopropylmethyl, 2,2-difluoro-3-phenylpropyl, 1-benzylcyclopropylmethy, 2-tetrahydro-pyran-4-ylethyl, 1-isobutylcyclopropylmethyl, thiophen-2-ylmethyl, tetrahydro-pyran-4-ylmethyl, cyclopropylmethylsulfanylmethyl, 2,2-dimethyl-3-phenylpropyl, 4-methyl-[[1,2,5]thiadiazol-3-ylmethylsulfonylmethyl, 3-methyl-[1,2,4]thiadiazol-3-ylmethylsulfonylmethyl, thiophen-3-ylmethylsulfonylmethyl, 3-methoxy-5-methyl-isoxazol-4-ylmethylsulfonylmethyl, 2,4-dimethyl-thiazol-5-ylmethylsulfonylmethyl, 2-methyl-oxazol-4-ylmethylsulfonylmethyl, 2-methyl-thiazol-4-ylmethylsulfonylmethyl, [1,2,3]thiadiazol-4-ylmethylsulfonylmethyl, 3-methyl-[1,2,4]thiadiazol-5-ylmethylsulfonylmethyl, 4-methyl-[1,2,5]thiadiazol-3-ylmethylsulfonylmethyl, thiophen-3-ylmethylsulfonylmethyl, tetrahydro-pyran-4-yloxymethyl, piperidin-1-ylcarbonyl, thiophene-2-sulfonylmethyl, 3-chloro-2-fluoro-benzylsulfonylmethyl, benzenesulfonylmethyl, benzylsulfonylmethyl, 2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl, 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl, 2-benzylsulfonyl-ethyl, oxy-pyridin-2-ylmethylsulfonylmethyl, prop-2-ene-1-sulfonylmethyl, 4-methoxy-benzylsulfonylmethyl, p-tolylmethylsulfonylmethyl, 4-chloro-benzylsulfonylmethyl, o-tolylmethylsulfonylmethyl, 3,5-dimethyl-benzylsulfonylmethyl, 4-trifluoromethyl-benzylsulfonylmethyl, 4-trifluoromethoxy-benzylsulfonylmethyl, 2-bromo-benzylsulfonylmethyl, pyridin-2-ylmethylsulfonylmethyl, pyridin-3-ylmethylsulfonylmethyl, pyridin-4-ylmethylsulfonylmethyl, naphthalen-2-ylmethylsulfonylmethyl, 3-methyl-benzylsulfonylmethyl, 3-trifluoromethyl-benzylsulfonylmethyl, 3-trifluoromethoxy-benzylsulfonylmethyl, 4-fluoro-2-trifluoromethoxy-benzylsulfonylmethyl, 2-fluoro-6-trifluoromethyl-benzylsulfonylmethyl, 3-chloro-benzylsulfonylmethyl, 2-fluoro-benzylsulfonylmethyl, 2-trifluoro-benzylsulfonylmethyl, 2-cyano-benzylsulfonylmethyl, 4-tert-butyl-benzylsulfonylmethyl, 2-fluoro-3-methyl-benzylsulfonylmethyl, 3-fluoro-benzylsulfonylmethyl, 4-fluoro-benzylsulfonylmethyl, 2-chloro-benzylsulfonylmethyl, 2,5-difluoro-benzylsulfonylmethyl, 2,6-difluoro-benzylsulfonylmethyl, 2,5-dichloro-benzylsulfonylmethyl, 3,4-dichloro-benzylsulfonylmethyl, 2-(11,1-difluoro-methoxy)-benzylsulfonylmethyl, 2-cyano-benzylsulfonylmethyl, 3-cyano-benzylsulfonylmethyl, 2-trifluoromethoxy-benzylsulfonylmethyl, 2,3-difluoro-benzylsulfonylmethyl, 2,5-difluoro-benzylsulfonylmethyl, biphenyl-2-ylmethylsulfonylmethyl, cyclohexylmethyl, 3-fluoro-benzylsulfonylmethyl, 3,4-difluoro-benzylsulfonylmethyl, 2,4-difluoro-benzylsulfonylmethyl, 2,4,6-trifluoro-benzylsulfonylmethyl, 2,4,5-trifluoro-benzylsulfonylmethyl, 2,3,4-trifluoro-benzylsulfonylmethyl, 2,3,5-trifluoro-benzylsulfonylmethyl, 2,5,6-trifluoro-benzylsulfonylmethyl, 2-chloro-5-trifluoromethylbenzylsulfonylmethyl, 2-methyl-propane-1-sulfonyl, 2-fluoro-3-trifluoromethylbenzylsulfonylmethyl, 2-fluoro-4-trifluoromethylbenzylsulfonylmethyl, 2-fluoro-5-trifluoromethylbenzylsulfonylmethyl, 4-fluoro-3-trifluoromethylbenzylsulfonylmethyl, 2-methoxy-benzylsulfonylmethyl, 3,5-bis-trifluoromethyl-benzylsulfonylmethyl, 4-difluoromethoxy-benzylsulfonylmethyl, 2-difluoromethoxy-benzylsulfonylmethyl, 3-difluoromethoxy-benzylsulfonylmethyl, 2,6-dichloro-benzylsulfonylmethyl, biphenyl-4-ylmethylsulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethylsulfonylmethyl, 5-chloro-thiophen-2-ylmethylsulfonylmethyl, 2-[4-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[2-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[3-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(2-trifluoromethoxy-benzenesulfonyl)-ethyl, (cyanomethyl-methyl-carbamoyl)-methyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-benzenesulfonyl-ethyl, isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, cyclohexylmethylsulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2-trifluoromethyl-benzylsulfanylmethyl, phenylsulfanyl-ethyl and cyclopropylmethylsulfonylmethyl; 
 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 . A compound of  claim 4  in which R 4  is selected from 2-trifluorobenzylsulfonylmethyl, 3-phenylsulfanylpropyl, 4-chlorobenzylsulfonylmethyl, thiophen-2-ylsulfonylmethyl, benzylsulfonylmethyl, 4-methylbenzylsulfonylmethyl, 2-phenylsulfonylethyl, 2-pyridin-2-ylsulfonylethyl, 2-pyridin-4-ylsulfonylethyl, 2-benzylsulfonylethyl, 2-(3-difluoromethoxyphenylsulfonyl)ethyl, naphthalen-2-ylmethylsulfonylmethyl, pyridin-2-ylmethylsulfonylmethyl, 3-methylbenzylsulfonylmethyl, 3-trifluoromethylbenzylsulfonylmethyl, 3-difluoromethoxybenzylsulfonylmethyl, 3-chlorobenzylsulfonylmethyl, 3-fluorobenzylsulfonylmethyl, 4-fluorobenzylsulfonylmethyl, 3-cyanobenzylsulfonylmethyl, 4-cyanobenzylsulfonylmethyl, 3,4-difluorobenzylsulfonylmethyl, benzylsulfonylmethyl, N-cyanomethyl-N-methylcarbamoylmethyl, 3-bromobenzyl, 4-phenylbutyl, 2,2-difluoro-3-phenylpropyl, 4′-methylsulfonylaminobiphenyl-3-ylmethyl, 4′-ethoxycarbonylaminobiphenyl-3-ylmethyl, 4-methylpiperazin-1-ylcarbonylmethyl, 1-fluoro-2-(4-methylpiperazin-1-yl)-2-oxoethyl, 1-hydroxy-4-methylpiperazin-1-yl-2-oxoethyl, 1-hydroxy-2-morpholin-4-yl-2-oxoethyl, 1-hydroxy-2-oxo-2-pyrrolidin-1-yl-ethyl, 1-fluoro-2-oxo-2-pyrrolidin-1-yl-ethyl, 1-fluoro-2-isopropylamino-2-oxoethyl, 1-hydroxy-2-isopropylamino-2-oxoethyl, 1-fluoro-2-oxo-2-piperazin-1-ylethyl, thiophen-3-ylmethylsulfonylmethyl, 4-methyl-[1,2,5]thiadiazol-3-ylmethylsulfonylmethyl, 3-methoxy-5-methyl-isoxazol-4-ylmethylsulfonylmethyl, 2,4-dimethyl-thiazol-5-ylmethylsulfonylmethyl, 2-methyl-oxazol-4-ylmethylsulfonylmethyl, 2-methyl-thiazol-4-ylmethylsulfonylmethyl, 2-([1,2,3]thiadiazol-4-ylmethylsulfonyl)-ethyl, 2-(3-methyl-[1,2,4]thiadiazol-5-ylmethylsulfonyl)-ethyl, 2-oxo-2-phenyl-ethyl, 2-morpholin-4-yl-2-oxo-ethyl, 2-benzenesulfonyl-ethyl, 2-naphthalen-2-yl-2-oxo-ethyl, 2-benzo[1,3]dioxol-5-yl-2-oxo-ethyl, 2-benzo[b]thiophen-2-yl-2-oxo-ethyl, 2-biphenyl-4-yl-2-oxo-ethyl, 4-benzylsulfonylmethyl, 2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-oxo-2-(4-phenoxy-phenyl)-ethyl, 2-(4-hydroxy-phenyl)-2-oxo-ethyl, benzylcarbamoyl-methyl, 4-acetyl-piperazine-1-carboxylic acid ethyl ester, cyclohexylcarbamoylmethyl, 2-(3-Chloro-benzo[b]thiophen-2-yl)-2-oxo-ethyl, benzenesulfonylmethyl, 2-oxo-2-thiophen-2-yl-ethyl, 2-oxo-2-thiophen-3-yl-ethyl, naphthalene-2-sulfonylmethyl, 2-(5-methyl-thiophen-2-yl)-2-oxo-ethyl, 2-(3-chloro-thiophen-2-yl)-2-oxo-ethyl, 5-methyl-thiophene-2-sulfonylmethyl, phenylcarbamoylmethyl, (5,6,7,8-tetrahydro-naphthalen-1-ylcarbamoyl)-methyl, (4-carbamoyl-phenylcarbamoyl)-methyl, (3-carbamoyl-phenylcarbamoyl)-methyl, (butyl-methyl-carbamoyl)-methyl, biphenyl-4-ylmethyl, 2-oxo-2-p-tolyl-ethyl, 2-(3-fluoro-4-methoxy-phenyl)-2-oxo-ethyl, 2-(4-chloro-phenyl)-2-oxo-ethyl, 2-(4-methoxy-phenyl)-2-oxo-ethyl, 2-oxo-2-(4-trifluoromethoxy-phenyl)-ethyl, 2-(3,4-difluoro-phenyl)-2-oxo-ethyl, 2-(3,4-dimethoxy-phenyl)-2-oxo-ethyl, 2-(4-fluoro-phenyl)-2-oxo-ethyl, 5-methyl-2-oxo-hexyl, 3,5-dimethyl-benzylsulfonylmethyl, 4-trifluoromethyl-benzylsulfonylmethyl; 4-trifluoromethoxy-benzylsulfonylmethyl, isopropylcarbamoyl-methyl, 4-dimethylcarbamoylmethyl, pyridin-4-ylcarbamoylmethyl, pyridin-4-ylmethylsulfonylmethyl, pyridin-3-ylmethylsulfonylmethyl, 3,4-dichloro-benzylsulfonylmethyl, pyridin-3-ylcarbamoylmethyl, 4-methoxy-benzylsulfonylmethyl, 4-chloro-benzylsulfonylmethyl, thiophene-2-sulfonylmethyl, benzylsulfonylmethyl, p-tolylmethylsulfonylmethyl, 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl, 2-benzylsulfonyl-ethyl, 2-[3-(11,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, naphthalen-2-ylmethylsulfonylmethyl, pyridin-2-ylmethylsulfonylmethyl, m-tolylmethylsulfonylmethyl, 3-trifluoromethyl-benzylsulfonylmethyl, 3-trifluoromethoxy-benzylsulfonylmethyl, 3-chloro-benzylsulfonylmethyl, 3-fluoro-benzylsulfonylmethyl, 4-fluoro-benzylsulfonylmethyl, 3-cyano-benzylsulfonylmethyl, 4-cyano-benzylsulfonylmethyl, 3,4-difluoro-benzylsulfonylmethyl, (cyanomethyl-methyl-carbamoyl)-methyl, 3-bromo-benzyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-(4′-chloro-biphenyl-4-yl)-2-oxo-ethyl, biphenyl-3-ylmethyl, 2-(11,1-difluoro-methoxy)-benzylsulfonylmethyl, 2-(4-methylsulfonylamino-phenyl)-2-oxo-ethyl, 2-oxo-2-piperidin-1-yl-ethyl, 2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl, 2-trifluoromethyl-benzylsulfonylmethyl, 4-fluoro-3-trifluoromethyl-benzylsulfonylmethyl, 4-carboxy-benzylsulfonylmethyl, 3,5-bis-trifluoromethyl-benzylsulfonylmethyl, 4-(, 1-difluoro-methoxy)-benzylsulfonylmethyl, 3-(1,1-difluoro-methoxy)-benzylsulfonylmethyl, 5-chloro-thiophen-2-ylmethylsulfonylmethyl, 2-[4-(1,1-difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-phenylsulfanyl-ethyl, benzylsulfanylmethyl, 2-trifluoromethyl-benzylsulfanylmethyl, 2-trifluoromethoxy-benzylsulfanylmethyl, 2-cyclohexyl-ethyl and isobutylsulfanylmethyl; 
 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 R 1  is hydrogen or (C 1-6 )alkyl and R 2  is hydrogen, —X 4 OR 13 , hetero(C 5-10 )aryl(C 0-6 )alkyl, (C 5-10 )aryl(C 0-6 )alkyl or (C 1-6 )alkyl; or R 1  and R 2  taken together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or hetero(C 3-8 )cycloalkylene; wherein the cycloalkylene or heterocycloalkylene are optionally substituted with 1 to 3 (C 1-6 )alkyl radicals; 
 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 1  is hydrogen or methyl and R 2  is methoxymethyl, methoxyethyl, methyl, ethyl, propyl, butyl, phenethyl, hiophen-2-yl or 5-methyl-furan-2-yl; or R 1  and R 2  taken together with the carbon atom to which both R 1  and R 2  are attached form cyclopropyl, tetrahydro-pyran-4-yl or 1-methyl-piperidin-4-yl; 
 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  of Formula I(a):  
     
       
         
         
             
             
         
       
     
     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 the group consisting of 3-biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide; 3-biphenyl-4-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide; 3-(3-bromo-phenyl)-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide; N-cyanomethyl-3-(3-cyano-benzylsulfonyl)-2-benzylsulfonyl-methyl-propionamide; N-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfanylmethyl]-3-benzylsulfanyl-propionamide; N-cyanomethyl-3-(2-trifluoromethyl-benzylsulfanyl)-2-(2-trifluoro-methyl-benzylsulfanylmethyl)-propionamide; N-cyanomethyl-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide; N-cyanomethyl-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide; N-cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfanyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfanylmethyl]-propionamide; 3-benzylsulfanyl-2-benzylsulfanylmethyl-N-cyanomethyl-propionamide; N-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide; N-cyanomethyl-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide; 4-benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N-cyanomethyl-butyramide; N-cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfonyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-propionamide; N-cyanomethyl-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide; N-cyanomethyl-3-(2-methyl-propane-1-sulfonyl)-2-(2-methyl-propane-1-sulfonylmethyl)-propionamide; N-cyanomethyl-3-(2-methyl-thiazol-4-ylmethylsulfonyl)-2-benzyl-sulfonylmethyl-propionamide; 3-biphenyl-3-yl-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzyl-sulfonylmethyl]-propionamide; (3′-{2-(cyanomethyl-carbamoyl)-3-[2-(1,1-difluoro-methoxy)-benzyl-sulfonyl]-propyl}-biphenyl-4-yl)-carbamic acid ethyl ester; N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-(4′-methylsulfonylamino-biphenyl-3-yl)-propionamide; 3-(3-bromo-phenyl)-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-phenyl-methylsulfonylmethyl]-propionamide; N-cyanomethyl-2-((E)-3-phenyl-allyl)-3-benzylsulfonyl-propionamide; and N-cyanomethyl-3-benzylsulfonyl-2-(3-phenyl-propyl)-propionamide; 
 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 . The compound of  claim 7  of Formula I(b):  
     
       
         
         
             
             
         
       
     
     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.  
   
   
       11 . The compound of  claim 10  in which R 5  is 1H-benzoimidazol-2-yl, benzooxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, benzothiazol-2-yl, 5-phenyl-[1,3,4]oxadiazol-2-yl, 4-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl, 5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl, 5-pyridazin-3-yl-[1,3,4]oxadiazol-2-yl, pyrimidin-2-yl, pyridazin-3-yl, 3-phenyl-[1,2,4]oxadiazol-5-yl, 5-methoxymethyl-[1,3,4]oxadiazol-2-yl, 5-ethyl-[1,3,4]oxadiazol-2-yl, 1,3,4]thiadiazol-2-yl, benzyloxycarbonyl, benzyloxydicarbonyl, phenyldicarbonyl, 5-methyl-[1,3,4]thiadiazol-2-yl, 5-trifluoromethyl-[1,3,4]oxadiazol-2-yl, 5-methyl-[1,3,4]oxadiazol-2-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, 5-phenyl-[1,2,4]oxadiazol-3-yl, 5-thiophen-3-yl-[1,2,4]oxadiazol-3-yl, 5-trifluoromethyl-[1,2,4]oxadiazol-3-yl, 3-methyl-[1,2,4]oxadiazol-5-yl or 3-pyrazin-2-yl; 
 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.    
   
   
       12 . The compound of  claim 11  selected from the group consisting of N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-(2-methoxy-benzenesulfonyl)-2-[2-(2-methoxy-benzenesulfonyl)-ethyl]-butyramide; 4-Benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-butyramide; (R)—N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-2-cyclohexylmethyl-3-benzylsulfonyl-propionaminde; N—[(S)-1-(1-benzothiazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-cyclohexyl-2-cyclohexylmethyl-propionamide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-{(S)-1-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl]-propyl}-butyramide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide; 4-Morpholin-4-yl-4-oxo-N-[1-(2-oxo-2-phenyl-acetyl)-pentyl]-2-benzylsulfonylmethyl-butyramide; N-(1,1-Dimethyl-2-oxazolo[4,5-b]pyridin-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide; N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide; N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide; N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-piperidin-1-yl-butyramide; 4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide; N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 4-Oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-3-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; 2-Cyclohexylmethyl-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide; 2-Cyclohexylmethyl-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide; N-(2-Benzooxazol-2-yl-1-methoxymethyl-2-oxo-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-butyramide; 2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide; 2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 2-(2-Difluoromethoxy-benzylsulfonylmethyl)-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-(2-difluoromethoxy-benzyl-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; 
 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, 1-(benzooxazole-2-carbonyl)-propyl]-amide; (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide; 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, (S)-1-(5-phenyl-[1,2,4]oxadiazole-3-carbonyl)-propyl]-amide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide; (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-cabonyl)-propyl]-butyramide; 4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide; N-(1,1-Dimethyl-2-oxazol-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-4-Isopropyl-N-1-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-2-benzylsulfonylmethyl-succinamide; 2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide; 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide; 2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide; N-[1-(Benzooxazole-2-carbonyl)-butyl]-2-benzylsulfonyl-3-(tetrahydro-pyran-4-yloxymethyl)-propionamide; N-[1-(Benzooxazole-2-carbonyl)-butyl]-3-ethanesulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide; N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-cyclopropylmethylsulfonyl-methyl-4-morpholin-4-yl-4-oxo-butyramide; 2-Cyclopropylmethylsulfonylmethyl-N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide; N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid {(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-amide; 2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide; 2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide; 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, (S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl}-amide; N-[(1S)-1-(Benzooxazol-2-yl-hydroxy-methyl)-3-phenyl-propyl]-2-cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyramide; (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, 1-(benzoxazole-2-carbonyl)-propyl]-amide; (R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid, 1-(benzoxazole-2-carbonyl)-propyl]-amide; and 4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-cyclopropyl]-4-oxo-2-benzylsulfonyl methyl-butyramide; 
 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 7  of Formula I(c):  
     
       
         
         
             
             
         
       
     
     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 5  is phenyl; 
 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.    
   
   
       15 . The compound of  claim 14  selected from the group consisting of N—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide and N-(3-benzenesulfonyl-1-phenethyl-allyl)-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide; 
 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 7  of Formula I(d):  
     
       
         
         
             
             
         
       
     
     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 . The compound of  claim 16  in which R 5  is phenyl and R 6  is hydrogen; 
 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.    
   
   
       18 . The compound of  claim 17  namely N-(3-benzenesulfonylamino-2-oxo-propyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; 
 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.    
   
   
       19 . The compound of  claim 7  of Formula I(e):  
     
       
         
         
             
             
         
       
     
     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.  
   
   
       20 . The compound of  claim 19  in which R 5  and R 6  is 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.    
   
   
       21 . The compound of  claim 20  in which one X 7  is morpholine-4-carbonyl and the other is benzylsulfonyl, R 1  is hydrogen and R 2  is ethyl, namely (S)-2,2-difluoro-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-3-oxo-hexanoic acid dimethylamide; 
 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.    
   
   
       22 . The compound of  claim 7  of Formula I(f):  
     
       
         
         
             
             
         
       
     
     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.  
   
   
       23 . The compound of  claim 22  in which R 5  is methyl, benzyl, phenethyl, cyclohexyl, methoxyethyl, dimethylaminoethyl, tetrahydro-pyran-4-yl, 1-methylsulfonyl-piperidin-4-yl, 4-methyl-piperazin-1-yl, morpholin-4-ylethyl, pyridin-2-yl, pyridin-2-ylmethyl or oxazol-2-ylmethyl; R 6  is hydrogen or methyl; or R 5  and R 6  together with the nitrogen atom to which both R 5  and R 6  are attached form morpholine-4-yl, pyrrolidin-1-yl, 4-dimethylamino-piperazin-1-yl, 4-hydroxy-piperazin-1-yl, 4-pyridin-2-yl-piperazin-1-yl, 4-benzoyl-piperazin-1-yl or 3-oxo-piperazin-1-yl; 
 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.    
   
   
       24 . The compound of  claim 23  selected from the group consisting of N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide and N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; 
 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.    
   
   
       25 . The compound of  claim 7  of Formula I(g):  
     
       
         
         
             
             
         
       
     
     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.  
   
   
       26 . The compound of  claim 25  in which X 3  is 1-benzoyl-4-oxo-pyrrolidin-3-yl, 4-oxo-pyrrolidin-3-yl-1-carboxylic acid tert-butyl ester, 2-methyl-4-oxo-tetrahydro-furan-3-yl, 2-ethyl-4-oxo-tetrahydro-furan-3-yl, 4-oxo-tetrahydro-furan-3-yl, 2-acetoxy-4-oxo-azetidin-3-yl, 1-isopropyl-3-oxo-azepan-4-yl, 3-oxo-azepan-4-yl-1-carboxylic acid benzyl ester, 3-oxo-azepan-4-yl-1-carboxylic acid tert-butyl ester, 1-benzoyl-3-oxo-azepan-4-yl, 1-isobutyryl-3-oxo-azepan-4-yl, 3-oxo-1-(propane-2-sulfonyl)-azepan-4-yl, 1-benzenesulfonyl-3-oxo-azepan-4-yl, 1-benzenesulfonyl-3-oxo-piperidin-4-yl, 1-benzenesulfonyl-4-oxo-pyrrolidin-3-yl, 1-benzoyl-3-oxo-piperidin-4-yl or 3-oxo-tetrahydro-pyran-4-yl; 
 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.    
   
   
       27 . The compound of  claim 23  selected from the group consisting of 3-Hydroxy-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-azepane-1-carboxylic acid tert-butyl ester; 4-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester; 3-Hydroxy-4-[2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-azepane-1-carboxylic acid tert-butyl ester; 4-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic acid tert-butyl ester; 4-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-oxo-azepane-1-carboxylic acid tert-butyl ester; 4-[2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-3-oxo-azepane-1-carboxylic acid tert-butyl ester; N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; 3-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester; 4-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic acid benzyl ester; and acetic acid (2S,3S)-3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-4-oxo-azetidin-2-yl ester; 
 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.    
   
   
       28 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable excipient.  
   
   
       29 . A method for treating a disease in an animal in which inhibition of Cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomology 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.  
   
   
       30 . The use of a compound of  claim 1  in the manufacture of a medicament for treating a disease in an animal in which Cathepsin S activity contributes to the pathology and/or symptomology of the disease.  
   
   
       31 . A process for preparing a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     in which: 
 X 1  is —C(R 1 )(R 2 )X 2  or —X 3 ;  
 X 2  is cyano, —CHO, —C(R 7 )(R 8 )R 5 , —C(R 7 )(R 8 )CF 3 , —C(R 7 )(R 8 )CF 2 CF 2 R 9 —CH═CHS(O) 2 R 5 , —C(R 8 )CF 2 C(O)NR 5 R 6 , —C(R 7 )(R 8 )C(R 7 )(R 8 )NR 5 R 6 , —C(R 7 )(R 8 )C(R 7 )(R 8 )OR 5 , —C(R 7 )(R 8 )CH 2 OR 5 , —C(R 7 )(R 8 )CH 2 N(R 6 )SO 2 R 5 , —C(R 7 )(R 8 )C(R 7 )(R 8 )N(R 6 )(CH 2 ) 2 OR 6 , —C(R 7 )(R 8 )C(R 7 )(R 8 )N(R 6 )(CH 2 ) 2 NR 6  or —C(R 7 )(R 8 )C(R 7 )(R 8 )R 5 ; wherein R 5  is (C 1-4 )alkyl, (C 6-10 )aryl(C 0-6 )alkyl, hetero(C 4-10 )aryl(C 0-6 )alkyl, (C 4-10 )cycloalkyl(C 0-6 )alkyl or hetero(C 4-10 )cycloalkyl(C 0-6 )alkyl; R 6  is hydrogen or (C 1-6 )alkyl; R 7  is hydrogen or (C 1-4 )alkyl and R 8  is hydroxy or R 7  and R 8  together form oxo; R 9  is hydrogen, halo, (C 1-4 )alkyl, (C 5-10 )aryl(C 0-6 )alkyl or hetero(C 5-10 )aryl(C 0-6 )alkyl;  
 X 3  represents a group of Formula (a):  
                     
 in which n is 1 or 2, z is 0 or 1, X 5  is selected from NR 10 , S or O, wherein R 10  is hydrogen or (C 1-6 )alkyl, and X 6  is O, S or NR 11 , wherein R 11  is selected from hydrogen, (C 1-6 )alkyl, —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 S(O) 2 R 14 , —R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 C(O)NR 12 R 15  and —X 4 S(O) 2 NR 12 R 15 , in which X 4  is a bond or (C 1-6 )alkylene; R 12  at each occurrence independently is hydrogen or (C 1-6 )alkyl; R 13  is hydrogen, (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl, R 14  is (C 1-6 )alkyl or halo-substituted(C 1-6 )alkyl and R 15  is (C 3-10 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-10 )cycloalkyl(C 0-3 )alkyl, (C 6-10 )aryl(C 0-6 )alkyl, hetero(C 5-10 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl;  
 wherein within X 1  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R 20  selected from —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 15 R 12 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 ; and wherein X 1  and R 20  may be substituted further with 1 to 5 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 2 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14  wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above;  
 R 1  and R 2  are both fluoro; or  
 R 1  is hydrogen or (C 1-6 )alkyl and R 2  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, cyano, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4  SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14 , —X 4 S(O) 2 R 14 , —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 15 R 12 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 , wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above; or R 1  and R 2  taken together with the carbon atom to which both R 1  and R 2  are attached form (C 3-8 )cycloalkylene or hetero(C 3-8 )cycloalkylene; wherein R 2 , said cycloalkylene and said heterocycloalkylene may be substituted further with 1 to 3 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13  and R 14  are as defined above;  
 R 3  and R 4  are independently —C(R 16 )(R 17 )X 7 , wherein R 16  and R 17  are hydrogen, (C 1-6 )alkyl or fluoro, or R 16  is hydrogen and R 17  is hydroxy and X 7  is selected from —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14 , —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 15 R 12 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(NR 12 )NR 15 R 12 , wherein X 4 , R 12 , R 13 , R 14  and R 15  are as defined above;  
 wherein within one of R 3  or R 4  any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R 21  selected from —R 15 , —X 4 OR 15 , —X 4 SR 15 , —X 4 S(O)R 15 , —X 4 S(O) 2 R 15 , —X 4 C(O)R 15 , —X 4 C(O)OR 15 , —X 4 OC(O)R 15 , —X 4 NR 15 R 12 , —X 4 NR 12 C(O)R 15 , —X 4 NR 12 C(O)OR 15 , —X 4 C(O)NR 12 R 15 , —X 4 S(O) 2 NR 15 R 12 , —X 4 NR 12 S(O) 2 R 15 , —X 4 NR 12 C(O)NR 15 R 12  and —X 4 NR 12 C(N 12 )NR 15 R 12 , wherein X 4 , R 12  and R 15  are as defined above; and wherein each of R 3 , R 4  and R 21  may be substituted further with 1 to 5 radicals independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , —X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13  and R 14  are as defined above; provided that only one bicyclic ring structure is present within each of R 3  or R 4 ; and provided that when X 2  is cyano and X 7  within one of R 3  or R 4  is —X 4 C(O)R 13  or —X 4 C(O)R 15 , wherein X 4  is a bond, then X 7  within the other of R 3  or R 4  is limited to —X 4 SR 15 , —X 4 S(O)R 15  and —X 4 S(O) 2 R 15 , wherein R 15  is (C 6-10 )aryl(C 1-6 )alkyl substituted with 1 to 5 radicals or hetero(C 5-10 )aryl(C 0-6 )alkyl optionally substituted with 1 to 5 radicals, wherein said radicals are independently selected from (C 1-6 )alkyl, cyano, halo, halo-substituted(C 1-4 )alkyl, nitro, —X 4 NR 12 R 12 , —X 4 NR 12 C(O)R 12 , —X 4 NR 12 C(O)OR 12 , —X 4 NR 12 C(O)NR 12 R 12 , X 4 NR 12 C(NR 12 )NR 12 R 12 , —X 4 OR 13 , —X 4 SR 13 , —X 4 C(O)OR 12 , —X 4 C(O)R 13 , —X 4 OC(O)R 13 , —X 4 C(O)NR 12 R 12 , —X 4 S(O) 2 NR 12 R 12 , —X 4 NR 12 S(O) 2 R 13 , —X 4 P(O)(OR 12 )OR 12 , —X 4 OP(O)(OR 12 )OR 12 , —X 4 S(O)R 14  and —X 4 S(O) 2 R 14 , wherein X 4 , R 12 , R 13  and R 14  are as defined above, provided that the radical is not selected from only halo when R 15  is (C 6-10 )aryl(C 1-6 )alkyl; and provided that when X 2  is cyano then X 7  within R 3  and R 4  is not —X 4 C(O)NR 12 R 12 , —X 4 C(O)NR 15 R 12  or —X 4 C(O)NR 18 R 19 , wherein X 4  is a bond and R 18  and R 19  together with the nitrogen atom to which they are attached form hetero(C 3-10 )cycloalkyl or hetero(C 5-10 )aryl;  
 and the corresponding N-oxides, and their prodrugs, and their protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds of formula I and their N-oxides and their prodrugs, and their protected derivatives, individual isomers and mixtures of isomers thereof; which process comprises:  
 (A) reacting a compound of Formula 2:  
                     
 with a compound of the formula NH 2 CR 1 R 2 X 2 , in which 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 2 with a compound of the formula NH 2 X 3 , in which X 3 , R 3  and R 4  are as defined in the Summary of the Invention for Formula I; or  
 (C) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;  
 (D) optionally converting a salt form of a compound of Formula I to non-salt form;  
 (E) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;  
 (F) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;  
 (G) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;  
 (H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and  
 (I) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.