Novel Compounds and compositions as protease inhibitors

Abstract

The present invention relates to novel alkanoyl-substituted heterocyclic derivatives 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: 
 A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1  is a ring member carbon atom and each ring member atom other than X 1  is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;  
 n is 0, 1, 2 or 3;  
 X 1  is ═C— or —CH—;  
 X 2  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 X 3  and X 4  independently are —C(O)— or —CH 2 S(O) 2 — 
 R 9  and R 10  independently are hydrogen, (C 1-6 )alkyl or as defined below;  
 R 11  at each occurrence independently is hydrogen or (C 1-6 )alkyl;  
 R 12 and R 13  independently are (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17 , wherein R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 15  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, halo, (C 1-6 )alkyl or R 16  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 9-2 )polycycloaryl(C 0-6 )alkyl or hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl and R 17  is hydrogen or (C 1-6 )alkyl, and wherein within R 16  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 9 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5  is a bond or (C 1-6 )alkylene, R 18  is hydrogen or (C 1-6 )alkyl and R 19  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 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5 , R 18  and R 19  are as defined above; wherein within R 12  and/or R 13  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 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 14 ) OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; or  
 R 12  together with R 9  and/or R 13  together with R 10  form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, oxo, —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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and  
 R 1  is —X 6 X 7 R 20 , wherein X 6  is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 21 —, wherein R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, 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 22 , —SR 22 , —S(O)R 22 , —S(O) 2 R 22 , —C(O)R 22 , —C(O)OR 22 , —C(O)NR 22 R 23 , —NR 22 R 23 , —NR 23 C(O)R 22 , —NR 23 C(O)OR 22 , —NR 23 C(O)NR 22 R 23  or —NR 23 C(NR 23 )NR 22 R 23 , wherein R 14  and R 15  are 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 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl and R 23  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, (C 9-2 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl or (iii) (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 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —R 24 , —X 5 OR 24 , —X 5 SR 24 , —X 5 S(O)R , —X 5 S(O) 2 R 24 , —X 5 C(O)R 24 , —X 5 C(O)OR 24 , —X 5 C(O)NR 24 R 25 , —X 5 NR 24 R 25 , —X 5 NR 25 C(O)R 24 , —X 5 NR 25 C(O)OR 24 , —X 5 NR 25 C(O)NR 24 R 25  or —X 5 NR 25 C(NR 25 )NR 24 R 25 , wherein X 5  is as defined above, R 24  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 and R 25  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; or when X 2  is a divalent group of formula (a) or (b) then R 1  may also represent hydrogen, carboxy, oxalo or carbamoyl;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, nitro, —SR 26 , —C(O)OR 26 , —C(O)NR 26 R 26 , —P(O)(OR 26 )OR 26 , —OP(O)(OR 26 )OR 26 , —S(O)R 27 , —S(O) 2 R 27  or —C(O)R 27 , wherein R 26  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 27  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, or (ii) (C 5-6 )cycloalkyl(C 2-3 )alkyl, hetero(C 3-6 )cycloalkyl(C 2-3 )alkyl, (C 6-12 )aryl(C 2-3 )alkyl or hetero(C 5-6 )aryl(C 2-3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above, provided that when R 3  is unsubstituted (C 1-5 )alkyl and R 4  is hydrogen or unsubstituted (C 1-5 )alkyl, then X 2  may not represent (i) a bond when R 1  is —C(O)R 20 , —C(O) 2 R 20  or —S(O) 2 R 20  in which R 20  is (C 1-6 )alkyl, phenyl(C 1-4 )alkyl, phenyl, (C 3-7 )cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, (C 1-4 )alkylamino, (C 1-4 )dialkylamino, carboxy or (C 1-4 )alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C 1-4 )alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R 12  is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R 9  and R 12  form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; 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 or (C 3-8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 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 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 4 , —X 5 S(O) 2 NR 14 R 14 , —X 5 P(O)(OR 14 )OR 14 , —X 5 OP(O)(OR 14 )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 5 , wherein X 5 , R 14  and R 15  are as defined above;  
 R 4  is hydrogen, (C 1-6 )alkyl or as defined above;  
 R 5  is hydrogen and R 6  is hydroxy or R 5  and R 6  together form oxo;  
 R 7  is a group selected from cyano, halo, nitro, —R 29 , —X 5 NR 29 R 30 , —X 5 NR 30 C(O)OR 29 , —X 5 NR 30 C(O)NR 29 R 30 , —X 5 NR 30 C(NR 30 )NR 29 R 30 , —X 5 OR 29 , —X 5 SR 29 , —X 5 C(O)OR 29 , —X 5 C(O)NR 29 R 30 , —X 5 S(O) 2 NR 29 R 30 , —X 5 P(O)(OR 30 )OR 29 , —X 5 OP(O)(OR 29 )OR 29 , —X 5 NR 30 C(O)R 31 , —X 5 S(O)R 31 , —X 5 S(O) 2 R 31  and —X 5 C(O)R 31 , wherein X 5  is as defined above, R 29  is hydrogen or —R 31 , R 30  at each occurrence is hydrogen or (C 1-6 )alkyl and R 31  is (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl, wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and  
 R 8  at each occurrence independently is 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  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.; but excluding compounds selected from the group consisting of ((S)-1-{(S)-1-[(S)-1-(1-bnzooxazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester, {1-[1-(1-1H-imidazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester, [(S)-3-methyl-1-((S)-3-methyl-1-{1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanoyl}-butylcarbamoyl)-butyl]-carbamic acid benzyl ester; {(S)-1-[(S)-1-(1H-imidazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester, ((S)-1-{(S)-1-[1-(1-benzyl-1H-imidazol-2-yl)-methanoyl]-3-methyl-butylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester, {(S)-1-[(S)-1-(1-1H-imidazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester, 3-{[1-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-4-pyridin-3-yl-butyric acid ethyl ester, 4-furan-2-yl-4-oxo-3-[1-(4-trifluoromethyl-phenyl)-methanoyl]-amino}-butyric acid ethyl ester 3-(2-methyl-propanoylamino)-4-oxo-4-thiophen-2-yl-butyric acid ethyl ester, 4-oxo-4-thiophen-2-yl-3-[(1-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 4-(5-bromo-thiophen-2-yl)-3-{[1-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-butyric acid ethyl ester, 3-{[1-(4-chloro-phenyl)-methanoyl]-amino}-4-(5-methyl-thiophen-2-yl)-4-oxo-butyric acid ethyl ester, 4-oxo-4-thiophen-3-yl-3-[(1-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 3-{[1-(4-methoxy-phenyl)-methanoyl]-amino}-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester, 3-{[1-(3,4-dichloro-phenyl)-methanoyl]-amino}-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester, 4-fluoro-N-[1-(1-thiophen-3-yl-methanoyl)-propyl]-benzamide, 4-[1-(4-fluoro-phenyl)-methanoyl]-amino)-5-oxo-5-thiophen-3-yl-pentanoic acid ethyl ester and 3-{[1-(4-fluoro-phenyl)-methanoyl]-amino}-2-methyl-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester.  
 
     
     
         2 . The compound of  claim 1  in which X 2  is a bond or a divalent group of Formula (a).  
     
     
         3 . The compound of  claim 2  in which: 
 A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R 7  and optionally substituted with a group R 8 , wherein R 7  is hydrogen, halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl, nitro or phenyl, R 8  at each occurrence independently is halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl, nitro or trifluoromethyl;  
 X 1  is ═C—;  
 X 2  is a bond or a divalent group of Formula (a), wherein within Formula (a) R 9  is hydrogen, R 11  is hydrogen or methyl and R 12  is (i) (C 1-6 )alkyl substituted with —SR 14 , —S(O)R 14  or —S(O) 2 R 14 , wherein R 14  is (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl or (ii) (C 3-12 )cycloalkyl(C 0-6 )alkyl or (C 6-12 )aryl(C 0-6 )alkyl; wherein within R 12  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 5 NR 14 R 14 , —X 5 NR 14 C(O)R 14 , —X 5 NR 14 C(O)NR 14 R 14 , —X 5 NR 4 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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;  
 R 1  is —X 6 X 7 R 20 , wherein X 6  is —C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 21 —, wherein R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by —C(O)OR 14  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 or hetero(C 5-12 )aryl(C 0-6 )alkyl or (iii) (C 3-6 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-6 )cycloalkyl, phenyl phenyl(C 0-6 )alkyl or hetero(C 5-6 )aryl(C 0-6 )alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —X 5 OR 24 , —X 5 C(O)R 24 , X 5 C(O)OR 24 , X 5 C(O)NR 24 R 25 , —X 5 NR 24 R 25 , —X 5 NR 25 C(O)R 24 , —X 5 NR 25 C(O)OR 24 , —X 5 NR 25 C(O)NR 24 R 25  or —X 5 NR 25 C(NR 25 )NR 24 R 25 , wherein X 5  is a bond or (C 1-6 )alkylene, R 24  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 and R 25  is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 substituents independently selected from (C 1-6 )alkyl, halo, halo-substituted (C 1-4 )alkyl, —OR 14  and —C(O)OR 14  wherein R 14  is as defined above, or when X 2  is a divalent group of formula (a) then R 1  may be, but is not limited to, hydrogen or oxalo;  
 R 2  is hydrogen;  
 R 3  is hydrogen, (C 1-6 )alkyl (optionally substituted with cyano, halo, nitro, —SR 24 , —C(O)OR 24 , —C(O)NR 24 R 24 , —P(O)(OR 24 )OR 24 , —OP(O)(OR 24 )OR 24 , —S(O)R 25 , —S(O) 2 R 25  or —C(O)R 25 , wherein R 24  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 25  is halo, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl) or (C 6-12 )aryl(C 2-3 )alkyl, wherein said aryl optionally is substituted further with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 and R 14  and R 15  are as defined above, or R 3  and R 4  or R 3  and R 4  taken together with the carbon atom to which both R 3  and R 4  are attached form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene;  
 R 4  is hydrogen or as defined above; and  
 R 5  and R 6  together form oxo; and he 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: 
 A is benzoxazol-2-yl substituted by R 7 , wherein R 7  is hydrogen, halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl or nitro and R 8  at each occurrence independently is halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl, nitro or trifluoromethyl;  
 X 2  is a bond or a divalent group of Formula (a), wherein within Formula (a) X 3  is —C(O)—, R 11  is hydrogen and R 12  is a group having the following formula:  
                     
 in which q is 0, 1, 2, 4 or 5 and R 33  at each occurrence independently is selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 5 NR 14 R 14 , —X 5 OR 14 , —X 5 SR 14 , —X 5 C(O)NR 14 R 14 , —X 5 C(O)OR 14 , —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 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 15  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl;  
 R 1  is selected from a group consisting of acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, 1-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclo[2.2.1]hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di(2-methoxyethyl)carbamoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, 1H-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, 2-morpholin-4-ylethylcarbonyl, naphth-1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl;  
 R 3  is selected from hydrogen, (C 1-4 )alkyl, phenyl(C 2-3 )alkyl or (C 1-4 )alkylsulfonyl(C 2-4 )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 3-6 )cycloalkylene;  
 R 4  is hydrogen or as defined above; 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  in which q is 0, 1 or 2, R 1  is morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl, R 3  is methyl, ethyl, n-propyl, n-butyl, 2-methylsulfonylethyl or phenyethyl or R 3  and R 4  taken together with the carbon atom to which both R 3  and R 4  are attached form cyclobutylene and R 33  at each occurrence independently is (C 1-4 )alkyl, cyano, halo, halo-subsituted (C 1-4 )alkyl, nitro, —OR 14 , —SR 14  or —C(O)OR 14 , wherein R 14  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
     
     
         6 . The compound of  claim 5  in which R 33  at each occurrence independently is selected from a group consisting of (C 1-4 )alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
     
     
         7 . The compound of  claim 6  in which within Formula (a) R 12  is benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
     
     
         8 . A compound of Formula II:  
       
         
           
           
               
               
           
         
       
       in which: 
 A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1  is a ring member carbon atom and each ring member atom other than X 1  is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom;  
 n is 0, 1, 2 or 3;  
 X 1  is ═C— or —CH—;  
 X 8  is (C 1-2 )alkylene;  
 R 1  is hydrogen, carboxy, oxalo, carbamoyl or —X 6 X 7 R 20 , wherein X 6  is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 21 —, wherein R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, 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 22 l , —SR   22 , —S(O)R 22 ,  13  S(O) 2 R 22 , —C(O)R 22 , —C(O)OR 22 , —C(O)NR 22 R 23 , —NR 22 R 23 , —NR 23 C(O)R 22 , —NR 23 C(O)OR 22 , —NR 23 C(O)NR 22 R 23  or —NR 23 C(NR 23 )NR 22 R 23 , wherein R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 15  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 22  is (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-2 )aryl(C 0-6 )alkyl, hetero(C 5-2 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0 O 6 )alkyl and R 23  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, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl or (iii) (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 1-6 )alkyl substituted by —X 5 OR 24 , —X 5 SR 24 , —X 5 S(O)R 24 , —X 5 S(O) 2 R 24 , —X 5 C(O)R 24 , —X 5 C(O)OR 24 , —X 5 C(O)NR 24 R 25 , —X 5 NR 24 R 25 , —X 5 NR 25 C(O)R 24 , —X 5 NR 15 C(O)OR 24 , —X 5 NR 25 C(O)NR 24 R 25  or —X 5 NR 25 C(NR 25 )NR 24 R 25 , wherein X 5  is a bond or (C 1-6 )alkylene, R 24  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 and R 25  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 R 14  and R 15  are as defined above;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17 , wherein R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 15  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 16  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 17  is hydrogen or (C 1-6 )alkyl, and wherein within R 16  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5  is as defined above, R 18  is hydrogen or (C 1-6 )alkyl and R 19  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 1-2 )polycycloaryl(C 0-6 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5 , R 18  and R 19  are as defined above; wherein within R 12  and/or R 13  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 5 NR 14 R 14 , —X 5 NR 14 C(O)OR 4 , —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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above, 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 or (C 3-8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above;  
 R 4  is hydrogen, (C 1-6 )alkyl or as defined above;  
 R 5  is hydrogen and R 6  is hydroxy or R 5  and R 6  together form oxo;  
 R 7  is a group selected from cyano, halo, nitro, —R 29 , —X 5 NR 29 R 30 , —X 5 NR 3 C(O)OR 29 , —X 5 NR 30 C(O)NR 19 R 30 , —X 5 NR 30 (NR 30 )NR 29 R 30 , —X 5 OR 29 , —X 5 SR 29 , —X 5 C(O)OR 29 , —X 5 C(O)NR 29 R 30 , —X 5 S(O) 2 NR 29 R 30 , —X 5 P(O)(OR 30 )OR 29 , —X 5 OP(O)(OR 29 )OR 29 , —X 5 NR 30 C(O)R 31 , —X 5 S(O)R 31 , —X 5 S(O) 2 R 31  and —X 5 C(O)R 31 , wherein X 5  is as defined above, R 29  is hydrogen or —R 31 , R 30  at each occurrence is hydrogen or (C 1-6 )alkyl and R 31  is (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl, wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and  
 R 8  at each occurrence independently is 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above;  
 R 9  is hydrogen or (C 1-6 )alkyl; and  
 R 32  is (C 1-8 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl, (C 9-12 )polycycloaryl(C 0-6 )alkyl, or hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl, wherein within R 30  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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  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.  
 
     
     
         9 . The compound of  claim 8  in which: 
 A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R 7  and optionally substituted with a group R 8 , wherein R 7  is hydrogen, halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl, nitro or phenyl, R 8  at each occurrence independently is halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl, nitro or trifluoromethyl;  
 X 1  is ═C— 
 X 8  is methylene or ethylene;  
 R 1  is —X 6 X 7 R 20 , wherein X 6  is —C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 21 —, R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by —C(O)OR 14  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 or hetero(C 5-12 )aryl(C 0-6 )alkyl or (iii) (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 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —X 5 OR 24 , —X 5 C(O)R 24 , —X 5 C(O)OR 24 , —X 5 C(O)NR 24 R 25 , —X 5 NR 24 R 25 , —X 5 NR 25 C(O)R 24 , —X 5 NR 25 C(O)OR 24 , —X 5 NR 25 C(O)NR 24 R 25  or —X 5 NR 25 C(NR 25 )NR 24 R 25 , wherein X 4  is a bond or (C 1-6 )alkylene, R 24  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 and R 25  is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 substituents independently selected from (C 1-6 )alkyl, halo, halo-substituted (C 1-4 )alkyl, OR 14  and —C(O)OR 14  wherein R 14  is as defined above, or when X 2  is a divalent group of formula (a) then R 1  may be, but is not limited to, hydrogen or oxalo;  
 R 2 and R 9  each are hydrogen;  
 R 3  is hydrogen, (C 1-6 )alkyl (optionally substituted with cyano, halo, nitro, —SR 24 , —C(O)OR 24 , —C(O)NR 24 R 24 , —P(O)(OR 24 )OR 24 , —OP(O)(OR 24 )OR 24 , —S(O)R 25 , —S(O) 2 R 25  or —C(O)R 25 , wherein R 24  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 25  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl) or (C 6-12 )aryl(C 2-3 )alkyl, wherein said aryl optionally is substituted further with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above, or R 3  and R 4  taken together with the carbon atom to which both R 3  and R 4  are attached form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene;  
 R 4  is hydrogen or as defined above;  
 R 5  and R 6  together form oxo; and  
 R 32  is —X 9 R 34 , wherein X 9  is methylene when X 8  is methylene or is a bond when X 8  is ethylene, R 34  is —CR 35 CHR 36  or —CR 37 NR 38 , wherein R 35  and R 36  together with the atoms to which R 35  and R 36  are attached form (C 2-6 )alkenyl, (C 5-12 )cycloalkenyl, hetero(C 5-12 )cycloalkenyl, (C 6-12 )aryl, hetero(C 6-12 )aryl, (C 9-12 )bicycloaryl or hetero(C 8-12 )bicycloaryl and R 37  and R 38  together with the atoms to which R 37  and R 38  are attached form hetero(C 5-12 )cycloalkenyl, hetero(C 6-12 )aryl or hetero(C 8-12 )bicycloaryl, wherein within R 34  said cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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, (Cl  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.  
 
     
     
         10 . The compound of  claim 9  in which: 
 A is benzooxazol-2-yl, wherein R 7  is hydrogen, halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl or nitro and R 8  at each occurrence independently is halo, (C 1-4 )alkoxy, (C 1-4 )alkoxycarbonyl, nitro or trifluoromethyl;  
 —X 8 S(O) 2 R 32  is a group having the following formula:  
                     
 in which q is 0, 1, 2, 4 or 5 and R 33  at each occurrence independently is selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 5 NR 4 R 14 , —X 5 OR 14 , —X 5 SR 14 , —X 5 C(O)NR 14 R 14 , —X 5 C(O)OR 14 , —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 1-2 )alkylene, R 14  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 15  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl;  
 R 1  is selected from a group consisting of acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, 1-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclo[2.2.1]hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di(2-methoxyethyl)carbamoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, 1H-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, 2-morpholin-4-ylethylcarbonyl, naphth-1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl;  
 R 3  is selected from hydrogen, (C 1-4 )alkyl, phenyl(C 2-3 )alkyl or (C 1-4 )alkylsulfonyl(C 2-4 )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 3-6 )cycloalkylene;  
 R 4  is hydrogen or as defined above; and  
 R 34  is (C 6-12 )aryl or hetero(C 5-12 )aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 5 NR 14 R 14 , —X 5 R 14 , —X 5 SR 14 , —X 5 C(O)NR 14 R 14 , —X 5 C(O)OR 14 , —X 5 S(O)R 15 , —X 5 S(O) 2 R 15 , and —X 5 C(O)R 15 , wherein X 5 , R 14  and R 15  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.  
 
     
     
         11 . The compound of  claim 10  in which q is 0, 1 or 2, R 1  is morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl, R 3  is ethyl, butyl, 2-methylsulfonylethyl, phenethyl or propyl and —X 11 S(O) 2 R 32  is benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, cyclohexylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
     
     
         12 . The compound of  claim 11  selected from a group consisting of: 
 N-[1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethyl]morpholine-4-carboxamide;  
 methyl 1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethylcarbamate;  
 N-(1S-benzooxazol-2-ylcarbonylbutyl)-2R-methylsulfonylamino-3-benzylsulfonylpropionamide;  
 N-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2R-(3,3-dimethylureido)-3-(2-methoxybenzylsulfonyl)propionamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-(2-methoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-benzylsulfonylethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-chlorobenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethylcarbamate;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonylethyl]morpholine-4-carboxyamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(3,5-dimethylisoxazol-4-ylmethylsulfonylethyl]isonicotinamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-nitrobenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-pyridin-2-ylmethylsulfonylethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-o-tolylmethylsulfonylethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-trifluoromethylbenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-benzylsulfonylethyl]nicotinamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-benzylsulfonylethyl]pyrazine-2-carboxamide;  
 N-[R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-chlorobenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-cyanobenzylsulfonyl)ethyl]isonicotinamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]isonicotinamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)-2-benzyl sulfonylethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(6-methylpyrid-2-ylmethylsulfonyl)ethyl]isonicotinamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-nitrobenzylsulfonyl)ethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-pyrid-2-ylmethylsulfonylethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-o-tolylmethylsulfonylethyl]morpholine-4-carboxamide;  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-trifluoromethylbenzylsulfonyl)ethyl]tetrahydropyran-4-carboxamide;  
 tetrahydropyran-4-yl 1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-benzylsulfonylethylcarbamate; and  
 N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-cyanobenzylsulfonyl)ethyl]piperidine-4-carboxamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1 , or a N-oxide derivative, prodrug derivative, individual isomer, mixture of isomers, or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.  
     
     
         14 . 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 Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1  is a ring member carbon atom and each ring member atom other than X 1  is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;  
 n is 0, 1, 2 or 3;  
 X 1  is ═C— or —CH—;  
 X 2  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 X 3  and X 4  independently are —C(O)— or —CH 2 S(O) 2 — 
 R 9  and R 10  independently are hydrogen, (C 1-6 )alkyl or as defined below;  
 R 11  at each occurrence independently is hydrogen or (C 1-6 )alkyl;  
 R 12  and R 13  independently are (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17 , wherein R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 15  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 16  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 17  is hydrogen or (C 1-6 )alkyl, and wherein within R 16  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5  is a bond or (C 1-6 )alkylene, R 18  is hydrogen or (C 1-6 )alkyl and R 19  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 8-2 )polycycloaryl(C 0-6 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5 , R 18  and R 19  are as defined above; wherein within R 12  and/or R 13  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 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6  is a bond or (C 1-6 )alkylene and R 14  and R 15  are as defined above; or  
 R 12  together with R 9  and/or R 13  together with R 10  form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; and  
 R 1  is —X 7 X 8 R 20 , wherein X 7  is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 8  is a bond, —O— or —NR 21 —, wherein R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, 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 22 , —SR 22 , —S(O)R 22 , —S(O) 2 R 22 , —C(O)R 22 , —C(O)OR 22 , —C(O)NR 22 R 23 , —NR 22 R 23 , —NR 23 C(O)R 22 , —NR 23 C(O)OR 22 , —NR 23 C(O)NR 22 R 23  or —NR 23 C(NR 23 )NR 22 R 23 , wherein R 14  and R 15  are 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 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl and R 23  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, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl or (iii) (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 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —X 9 OR 24 , —X 9 SR 24 , —X 9 S(O)R 24 , —X 9 S(O) 2 R 24 , —X 9 C(O)R 24 , —X 9 C(O)OR 24 , —X 9 C(O)NR 24 R 25 , —X 9 NR 24 R 25 , —X 9 NR 25 C(O)R 24 , —X 9 NR 25 C(O)OR 24 , —X 9 NR 25 C(O)NR 24 R 25  or —X 9 NR 25 C(NR 25 )NR 24 R 25 , wherein X 9  is a bond or (C 1-6 )alkylene, R 24  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 and R 25  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6 , R 14  and R 15  are as defined above; or when X 2  is a divalent group of formula (a) or (b) then R 1  may also represent hydrogen, carboxy, oxalo or carbamoyl;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, nitro, —SR 26 , —C(O)OR 26 , —C(O)NR 26 R 26 , —P(O)(OR 26 )OR 26 , —OP(O)(OR 26 )OR 26 , —S(O)R 27 , —S(O) 2 R 27  or —C(O)R 27 , wherein R 26  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 27  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, or (ii) (C 5-6 )cycloalkyl(C 2-3 )alkyl, hetero(C 3-6 )cycloalkyl(C 2-3 )alkyl, (C 6-12 )aryl(C 2-3 )alkyl or hetero(C 5-6 )aryl(C 2-3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 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 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14   14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6 , R 14  and R 15  are as defined above, provided that when R 3  is unsubstituted (C 1-5 )alkyl and R 4  is hydrogen or unsubstituted (C 1-5 )alkyl, then X 2  may not represent (i) a bond when R 1  is —C(O)R 20 , —C(O) 2 R 20  or —S(O) 2 R 20  in which R 20  is (C 1-6 )alkyl, phenyl(C 1-4 )alkyl, phenyl, (C 3-7 )cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, (C 1-4 )alkylamino, (C 1-4 )dialkylamino, carboxy or (C 1-4 )alkoxycarbonyl, or naphth-1-yl of naphth-2-yl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C 1-4 )alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R 12  is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R 9  and R 12  form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; 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 or (C 3-8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above;  
 R 4  is hydrogen, (C 1-6 )alkyl or as defined above;  
 R 5  is hydrogen and R 6  is hydroxy or R 5  and R 6  together form oxo;  
 R 7  is a group selected from cyano, halo, nitro, —R 29 , —X 10 NR 29 R 30 , —X 10 NR 30 C(O)OR 29 , —X 10 NR 30 C(O)NR 29 R 30 , —X 10 NR 30 C(NR 30 )NR 29 R 30 , —X 10 OR 29 , —X 10 SR 29 , —X 10 C(O)OR 29 , —X 10 C(O)NR 29 R 30 , —X 10 S(O) 2 NR 29 R 30 , —X 10 P(O)(OR 30 )OR 29 , —X 10 OP(O)(OR 29 )OR 29 , —X 10 NR 30 C(O)R 31 , —X 10 S(O)R 31 , —X 10 S(O) 2 R 31  and —X 10 C(O)R 31 , wherein X 10  is a bond or (C 1-6 )alkylene, R 29  is hydrogen or —R 31 , R 30  at each occurrence is hydrogen or (C 1-6 )alkyl and R 31  is (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl, wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6 , R 14  and R 15  are as defined above; and  
 R 1  at each occurrence independently is selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6 , R 14  and R 15  are as defined above; or a N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers; or a pharmaceutically acceptable salt thereof.  
 
     
     
         15 . The method of  claim 14  in which the cysteine protease is cathepsin S.  
     
     
         16 . The method of  claim 15  in which the disease is an autoimmune disorder, allergic disorder, allogeneic immune response, a disorder involving excessive elastolysis, cardiovascular disorders or a disorder involving fibril formation.  
     
     
         17 . The method of  claim 16  in which the disorder is selected from juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ transplant or tissue graft rejections, chronic obstructive pulmonary disease, bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities, plaque rupture, atheroma and systemic amyloidosis.  
     
     
         18 . A method for 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 8;  or a N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers; or a pharmaceutically acceptable salt thereof.  
     
     
         19 . The method of  claim 18  in which the cysteine protease is cathepsin S.  
     
     
         20 . The method of  claim 19  in which the disease is an autoimmune disorder, allergic disorder, allogeneic immune response, a disorder involving excessive elastolysis, cardiovascular disorders or a disorder involving fibril formation.  
     
     
         21 . The method of  claim 19  in which the disorder is selected from juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ transplant or tissue graft rejections, chronic obstructive pulmonary disease, bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities, plaque rupture, atheroma and systemic amyloidosis.  
     
     
         22 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1  is a ring member carbon atom and each ring member atom other than X 1  is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;  
 n is 0, 1, 2 or 3,  
 X 1  is ═C— or —CH—;  
 X 2  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1  is a ring member carbon atom and each ring member atom other than X 1  is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing,5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;  
 n is 0, 1, 2 or 3;  
 X 1  is ═C— or —CH—;  
 X 2  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 X 3  and X 4  independently are —C(O)— or —CH 2 S(O) 2 —;  
 R 9  and R 10  independently are hydrogen, (C 1-6 )alkyl or as defined below;  
 R 11  at each occurrence independently is hydrogen or (C 1-6 )alkyl;  
 R 12  and R 13  independently are (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17 , wherein R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 15  (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 16  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 17  is hydrogen or (C 1-6 )alkyl, and wherein within R 16  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5  is a bond or (C 1-6 )alkylene, R 18  is hydrogen or (C 1-6 )alkyl and R 19  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 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5 , R 18  and R 19  are as defined above; wherein within R 12  and/or R 13  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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; or  
 R 12  together with R 9  and/or R 13  together with R 10  form trimethylene, tetramethylene or phenylene-1,2-dimethylene, , optionally substituted with 1 to 3 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, oxo, —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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and  
 R 1  is —X 6 X 7 R 20 , wherein X 6  is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 21 —, wherein R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, 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 22 , —SR 22 , —S(O)R 22 , —S(O) 2 R 22 , —C(O)R 22 , —C(O)R 22 , —C(O)NR 22 R 23 , —NR 22 R 23 , —NR 23 C(O)R 22 , —NR 23 C(O)OR 22 , —NR 23 C(O)NR 22 R 23  or —NR 23 C(NR 23 )NR 22 R 23 , wherein R 14  and R 15  are 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 )bicycloaryl(C 0-6 )alkyl or hetero(C 8- 2 )bicycloaryl(C 0-6 )alkyl and R 23  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 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by —R 24 , —X 5 OR 24 , —X 5 SR 24 , —X 5 S(O )R 24 , —X 5 S(O) 2 R 24 , —X 5 C(O)R 24 , —X 5 C(O)OR 24 , —X 5 C(O)NR 24 R 25 , —X 5 NR 24 R 25 , —X 5 NR 25 C(O)R 24 , —X 5 NR 25 C(O)OR 24 , —X 5 NR 25 C(O)NR 24 R 25  or —X 5 NR 25 C(NR 25 )NR 24 R 25 , wherein X 5  is as defined above, R 24  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 )bicycloaryl(C 0-6 )alkyl hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl and R 25  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 5 NR 14 R 14 , —X 5 NR 14 C(O)OR 14 , —X 5 NR 41 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 14 )OR 14 , —X 5 OP(O)(OR 14 )OR 14 , —X 5 NR 14 C(O)R 15 , —X 5 S(O)R 14 , —X 5 S(O) 2 R 15  and —X 5 C(O)R 15 , wherein X 5 , R 14  and R 15  are as defined above; or when X 2  is a divalent group of formula (a) or (b) then R 1  may also represent hydrogen, carboxy, oxalo or carbamoyl;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, nitro, —SR 24 , —C(O)OR 24 , —C(O)NR 24 R 24 , —P(O)(OR 24 )OR 24 , —OP(O)(OR 24 )OR 24 , —S(O)R 25 , —S(O) 2 R 25  or —C(O)R 25 , wherein R 24  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 25  (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, or (ii) (C 5-6 )cycloalkyl(C 2-3 )alkyl, hetero(C 3-6 )cycloalkyl(C 2-3 )alkyl, (C 6-12 )aryl(C 2-3 )alkyl or hetero(C 5-6 )aryl(C 2-3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above, provided that when R 3  is unsubstituted (C 1-5 )alkyl and R 4  is hydrogen or unsubstituted (C 1-5 )alkyl, then X 2  may not represent (i) a bond when R 1  is —C(O)R 20 , —C(O) 2 R 20  or —S(O) 2 R 20  in which R 20  is (C 1-6 )alkyl, phenyl(C 1-4 )alkyl, phenyl, C 3-7 )cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, (C 1-4 )alkylamino, (C 1-4 )dialkylamino, carboxy or (C 1-4 )alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C 1-4 )alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R 12  is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R 9  and R 12  form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; 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 or (C 3-8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above;  
 R 4  is hydrogen, (C 1-6 )alkyl or as defined above;  
 R 5  is hydrogen and R 6  is hydroxy or R 5  and R 6  together form oxo;  
 R 7  is a group selected from cyano, halo, nitro, —R 29 , —X 5 NR 29 R 30 , —X 5 NR 30 C(O)OR 29 , —X 5 NR 30 C(O)NR 29 R 30 , —X 5 NR 30 C(NR 30 )NR 29 R 30 , —X 5 OR 29 , —X 5 SR 29 , —X 5 C(O)OR 29 , —X 5 C(O)NR 29 R 30 , —X 5 S(O) 2 NR 29 R 30 , —X 5 P(O)(OR 30 )OR 29 , —X 5 OP(O)(OR 29 )OR 29 , —X 5 NR 30 C(O)R 20 , —X 5 S(O)R 20 , —X 5 S(O) 2 R 20 , —X 5 C(O)R 20  and —C(O)NR 42 CHR 43 C(O)OR 29 , wherein X 5  and R 20  are as defined as above, R 29  is hydrogen or —R 20 , wherein R 20  is defined as above, R 30  at each occurrence is hydrogen or (C 1-6 )alkyl, R 42  is hydrogen, (C 1-6 )alkyl or together with R 43  forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo, and R 43  is as defined above or is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17  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 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5 , R 14 , R 15 , R 16 , R 17 , R 18  and R 19  are as defined above; wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and  
 R 8  it each occurrence independently is selected from (C 1-6 )alkyl, halo-substituted (C 1-4 )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 14 )OR 14 , —X 5 OP(O)(OR 14 )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  (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 phannaceutically acceptable salts thereof.  
 
     
     
         23 . The compound of  claim 22  in which: 
 A is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, 1H-indol-5-yl, pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, 1-methyl-1H-imidazol-2-yl, 1-benzyl-1H-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, 1H-benzoimidazol-2-yl, 1,1-dioxo-1H-1λ 6 -benzo[b]thien-2-yl, quinol-3-yl, [1,3]dioxolan-2-yl, naphtho[2,3-d]oxazol-2-yl, naphtho[1,2-d]oxazol-2-yl and naphtho[2,1-d]oxazol-2-yl, each substituted by a group R 7  and optionally substituted with a group R 8 , wherein R 7  is halo, nitro, —R 29 , —OR 29 , —C(O)R 20 , —C(O)OR 29 , —S(O) 2 NR 29 R 30 , —C(O)NR 29 R 30  or —C(O)NHCHR 43 C(O)OR 29 , wherein R 20  is (C 1-6 )alkyl, (C 3-12 )Cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, diphenyl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl or hetero(C 8-12 )polycycloaryl(C 0-6 )alkyl and R 29  is hydrogen or —R 20 , wherein R 20  is defined as above, wherein said heterocycloalkyl may be substituted with (C 6-12 )aryl(C 0-3 )alkyl, R 30  at each occurrence is hydrogen or (C 1-6 )alkyl and R 43  is (C 1-6 )alkyl, and R 8  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-4 )alkyl; wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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  (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 X 2  is a bond or a divalent group of Formula (a) or (b), wherein within Formula (a) X 3 is —C(O)—, R 9  is hydrogen, R 11  is hydrogen or methyl, and R 12  is (C 1-6 )alkyl,  
 R 1  is hydrogen or —X 6 X 7 R 20 , wherein X 6  is —C(O)— or —S(O) 2 —, X 7  is a bond or —O— and R 20  is (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, —C(O)OR 14 , —X 5 NR 14 R 14  and —X 5 NR 14 C(O)OR 14 , 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  (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 R 2  is hydrogen;  
 R 3  is (C 1-6 )alkyl or (C 6-10 )aryl(C 1-3 )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 3-6 )alkylene;  
 R 4  is hydrogen or (C 1-6 )alkyl or as defined above; and  
 R 5  and R 6  preferably together form oxo; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         24 . The compound of  claim 23  in which: 
 A oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, naphtho[2,3-d]oxazol-2-yl, naphtho[1,2-d]oxazol-2-yl or naphtho[2,1-d]oxazol-2-yl, each substituted by a group R 7  and optionally substituted with a group R 8 , wherein R 7  is halo, —R 29 , —C(O)R 20 , —C(O)OR 29 , —C(O)NR 29 R 30  or —S(O) 2 NR 29 R 30 , wherein R 20  is (C 1-6 )alkyl, (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;  
 X 2  is a divalent group of Formula (a), wherein within Formula (a) X 3  is —C(O)—, R 9  and R 11  each are hydrogen and R 12  is isobutyl, sec-butyl or isopropyl;  
 R 1  is select from acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, tert-butoxycarbonyl, tert-butyryl, 4-tert-butoxycarbonylpiperazin-1-ylcarbonyl, 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, hydrogen, 4-methylpiperazin-1-ylcarbonyl, methylsulfonyl, 4-methylvaleryl, 3-morpholin-4-ylpropionyl, naphth-2-ylmethyl, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl and pyrid-3-ylcarbonyl, wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 3 radicals independently selected from 3-aminomethyl and 3-tert-butoxycarbonylaminomethyl;  
 R 3  is phenethyl or R 3  and R 4  taken together with the carbony atom to which both R 3  and R 4  are attached form cyclopropylene; and  
 R 4  is hydrogen or methyl or as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         25 . The compound of  claim 24  in which 
 A is selected from oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl or naphtho[1,2-d]oxazol-2-yl, each substituted by a group R 7  and optionally substituted with a group R 8 , particularly wherein R 7  is adamantan-1-ylmethylcarbamoyl, benzyl, benzylcarbamoyl, benzyl (methyl)carbamoyl, 1-benzyloxycarbonyl -3-methylbutylcarbamoyl, 4-benzylpiperidin-1-carbonyl, tert-butyl, chloro, 2,3-dihydroindol-1-ylcarbonyl, 3,4-dihydro-1H-isoquinol-2-ylcarbonyl, 3,4-dihydro-1H-quinol-1-ylcarbonyl, diphenylmethylcarbamoyl, fur-2-ylmethylcarbamoyl, hydrogen, 2-(1H-indol-3-yl)ethylcarbamoyl, methoxy, methoxycarbonyl, methyl, 3-methylbutylcarbamoyl, methylcarbamoyl, 1-methylethylcarbamoyl, naphth-1-ylmethylcarbonyl, nitro, phenyl, phenylcarbamoyl, 2-phenylcyclopropylcarbamoyl, 1-phenylethylcarbamoyl, sulfamoyl, trifluoromethyl, phenethylcarbamoyl, 3-phenylpropylcarbamoyl, piperid-1-ylcarbonyl, pyrid-2-ylmethylcarbamoyl, pyrid-3-ylmethylcarbamoyl, pyrid-4-ylmethylcarbamoyl and pyrrolidin-1-ylcarbonyl and R 8  is methyl  
 X 2  is a divalent group of Formula (a), wherein within Formula R 12  is isopropyl;  
 R 3  is phenethyl; and  
 R 4  is hydrogen; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.  
 
     
     
         26 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 22  in combination with one or more pharmaceutically acceptable excipient(s).  
     
     
         27 . The composition of  claim 26  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.  
     
     
         28 . The composition of  claim 27  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.  
     
     
         29 . The composition of  claim 28  wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.  
     
     
         30 . The composition of  claim 29  which comprises 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.  
     
     
         31 . 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 Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1  is a ring member carbon atom and each ring member atom other than X 1  is a carbon atom or a heteroatom, With the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;  
 n is 0, 1, 2 or 3;  
 X 1  is ═C— or —CH—;  
 X 2  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 X 3  and X 4  independently are —C(O)— or —CH 2 S(O) 2 — 
 R 9  and R 10  independently are hydrogen, (C 1-6 )alkyl or as defined below;  
 R 11  at each occurrence independently is hydrogen or (C 1-6 )alkyl;  
 R 12  and R 13  independently are (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17 , wherein R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 15  (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 16  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 17  is hydrogen or (C 1-6 )alkyl, and wherein within R 16  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X OC(O)R   18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5  is a bond or (C 1-6 )alkylene, R 18  is hydrogen or (C 1-6 )alkyl and R 19  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 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5 , R 18  and R 19  are as defined above; wherein within R 12  and/or R 13  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 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6  is a bond or (C 1-6 )alkylene and R 14  and R 15  are as defined above; or  
 R 12  together with R 9  and/or R 13  together with R 10  form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; and  
 R 1  is —X 7 X 8 R 20 , wherein X 7  is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 8  is a bond, —O— or —NR 21 —, wherein R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, 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 22 , —SR 22 , —S(O)R 22 , —S(O) 2 R 22 , —C(O)R 22 , —C(O)OR 22 , —C(O)NR 22 R 23 , —NR 22 R 23 , —NR 23 C(O)R 22 , —NR 23 C(O)OR 22 , —NR 23 C(O)NR 22 R 23  or —NR 23 C(NR 23 )NR 22 R 23 , wherein R 14  and R 15  are 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 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl and R 23  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 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by —X 9 OR 24 , —X 9 SR 24 , —X 9 S(O)R 24 , —X 9 S(O) 2 R 24 , —X 9 C(O)R 24 , —X 9 C(O)OR 24 , —C(O)NR 24 R 25 , —X 9 NR 24 R 25 , —X 9 NR 25 C(O)R 24 , —X 9 NR 25 C(O)OR 24 , —X 9 NR 25 C(O)NR 24 R 25  or —X 9 NR 25 C(NR 25 )NR 24 R 25 , wherein X 9  is a bond or (C 1-6 )alkylene, R 24  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 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl and R 25  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6  is a bond or (C 1-6 )alkylene and R 14  and R 15  are as defined above; or when X 2  is a divalent group of formula (a) or (b) then R 1  may also represent hydrogen, carboxy, oxalo or carbamoyl;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, nitro, —SR 24 , —C(O)OR 24 , —C(O)NR 24 R 24 , —P(O)(OR 24 )OR 24 , —OP(O)(OR 24 )OR 24 , —S(O)R 25 , —S(O) 2 R 25  or —C(O)R 25 , wherein R 24  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 25  (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, or (ii) (C 5-6 )cycloalkyl(C 2-3 )alkyl, hetero(C 3-6 )cycloalkyl(C 2-3 )alkyl, (C 6-12 )aryl(C 2-3 )alkyl or hetero(C 5-6 )aryl(C 2-3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 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 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6 , R 14  and R 15  are as defined above, 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 or (C 3-8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 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 5 NR 14 C(O)OR 14 , —X 5 NR 14 C(O)NR 14 R 14 , —X 5 NR 14 C(R 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)(R 14 )OR 14 , —X 5 O(O)(OR 14 )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 , R 14  and R 15  are as defined above;  
 R 4  is hydrogen, (C 1-6 )alkyl or as defined above;  
 R 5  is hydrogen and R 6  is hydroxy or R 5  and R 6  together form oxo;  
 R 7  is a group selected from cyano, halo, nitro, —R 29 , —X 10 NR 19 R 30 , —X 10 NR 30 C(O)OR 29 , —X 10 NR 30 C(O)NR 29 R 30 , —X 10 NR 30 C(NR 30 )NR 29 R 30 , —X 10 OR 29 , —X 10 SR 29 , —X 10 C(O)OR 29 , —X 10 C(O)NR 19 R 30 , —X 10 S(O) 2 NR 29 R 30 , —X 10 P(O)(OR 30 )OR 29 , —X 10 OP(O)(OR 29 )OR 29 , —X 10 NR 30 C(O)R 20 , —X 10 S(O)R 20 , —X 10 S(O) 2 R 20 , —X 10 C(O)R 20  and —C(O)NR 42 CHR 43 C(O)OR 29 , wherein X 10  is a bond or (C 1-6 )alkylene, wherein R 20  is defined as above, R 29  is hydrogen or —R 20 , wherein R 20  is defined as above, R 30  at each occurrence is hydrogen or (C 1-6 )alkyl, R 42  is hydrogen, (C 1-6 )alkyl or together with R 43  forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo, and R 43  is as defined above or is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 51 , —OR 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17  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 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 18 R 19 , wherein X 5 , R 14 , R 15 , R 16 , R 17 , R 18  and R 19  are as defined above; wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , X 6 C(O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6 , R 14  and R 15  are as defined above; and  
 R 8  at each occurrence independently is selected from (C 1-6 )alkyl, halo-substituted (C 1-4 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 6 NR 14 R 14 , —X 6 NR 14 C(O)OR 14 , —X 6 NR 14 C(O)NR 14 R 14 , —X 6 NR 14 C(NR 14 )NR 14 R 14 , —X 6 OR 14 , —X 6 SR 14 , —X 6 C((O)OR 14 , —X 6 C(O)NR 14 R 14 , —X 6 S(O) 2 NR 14 R 14 , —X 6 P(O)(OR 14 )OR 14 , —X 6 OP(O)(OR 14 )OR 14 , —X 6 NR 14 C(O)R 15 , —X 6 S(O)R 15 , —X 16 S(O) 2 R 15  and —X 6 C(O)R 15 , wherein X 6  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  (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl; or an N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomer; or a pharmaceutically acceptable salts thereof.  
 
     
     
         32 . The method of  claim 31  wherein the disease is osteoporosis.  
     
     
         33 . The method of  claim 32  wherein the animal is a human.  
     
     
         34 . The method of  claim 33  wherein the human is a post-menopausal woman.  
     
     
         35 . The method of  claim 34  wherein the cysteine protease is cathepsin K.  
     
     
         36 . A process for making a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1  is a ring member carbon atom and each ring member atom other than X 1  is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;  
 n is 0, 1, 2 or 3;  
 X 1  is ═C— or —CH—;  
 X 2  is a bond or a divalent group of Formula (a) or (b):  
                     
 wherein:  
 X 3  and X 4  independently are —C(O)— or —CH 2 S(O) 2 — 
 R 9  and R 10  independently are hydrogen, (C 1-6 )alkyl or as defined below;  
 R 11  at each occurrence independently is hydrogen or (C 1-6 )alkyl;  
 R 12  and R 13  independently are (i) (C 1-6 )alkyl optionally substituted with cyano, halo, 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 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —C(O)R 16 , —C(O)OR 16 , —OC(O)R 16 , —NR 16 R 17 , —NR 17 C(O)R 16 , —NR 17 C(O)OR 16 , —C(O)NR 16 R 17 , —S(O) 2 NR 16 R 17 ,  13  NR 17 C(O)NR 16 R 17  or —NR 17 C(NR 17 )NR 16 R 17 , wherein R 14  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, R 15 is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, halo, (C 1-6 )alkyl or R 16  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 5-2 )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 17  is hydrogen or (C 1-6 )alkyl, and wherein within R 16  said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5  is a bond or (C 1-6 )alkylene, R 18  is hydrogen or (C 1-6 )alkyl and R 19  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 18 , —X 5 OR 18 , —X 5 SR 18 , —X 5 S(O)R 18 , —X 5 S(O) 2 R 18 , —X 5 C(O)R 18 , —X 5 C(O)OR 18 , —X 5 OC(O)R 18 , —X 5 NR 18 R 19 , —X 5 NR 19 C(O)R 18 , —X 5 NR 19 C(O)OR 18 , —X 5 C(O)NR 18 R 19 , —X 5 S(O) 2 NR 18 R 19 , —X 5 NR 19 C(O)NR 18 R 19  or —X 5 NR 19 C(NR 19 )NR 18 R 19 , wherein X 5 , R 18  and R 19  are as defined above; wherein within R 12  and/or R 13  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, 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; or  
 R 12  together with R 9  and/or R 13  together with R 10  form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, oxo, —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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and  
 R 1  is —X 6 X 7 R 20 , wherein X 6  is —C(O)—, —C(O)C(O)— or —S(O) 2 —, X 7  is a bond, —O— or —NR 2 —, wherein R 21  is hydrogen or (C 1-6 )alkyl, and R 20  is (i) (C 1-6 )alkyl optionally substituted by cyano, halo, nitro, —NR 14 R 14 , —NR 14 C(O)OR 14 , —NR 14 C(O)NR 14 R 14 , —NR 14 C(NR 4 )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 22 , —SR 22 , —S(O)R 22 , —S(O) 2 R 22 , —C(O)R 22 , —C(O)OR 22 , —C(O)NR 22 R 23 , —NR 22 R 23 , —NR 23 C(O)R 22 , —NR 23 C(O)OR 22 , —NR 23 C(O)NR 22 R 23  or —NR 23 C(NR 23 )NR 22 R 23 , wherein R 14  and R 15  are 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 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl and R 23  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, (C 9-12 )bicycloaryl(C 0-6 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-6 )alkyl or (iii) (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 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —R 24 , —X 5 OR 24 , —X 5 SR 24 , —X 5 S(O)R 24 , —X 5 S(O) 2 R 24 , —X 5 C(O)R 24 , —X 5 C(O)OR 24 , —X 5 C(O)NR 24 R 25 , —X 5 NR 24 R 25 , —X 5 NR 25 C(O)R 24 , —X 5 NR 25 C(O)OR 24 , —X 5 NR 25 C(O)NR 24 R 25  or —X 5 NR 25 C(NR 25 )NR 24 R 25 , wherein X 5  is as defined above, R 24  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 and R 25  at each occurrence independently is hydrogen or (C 1-6 )alkyl; wherein within R 1  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; or when X 2  is a divalent group of formula (a) or (b) then R 1  may also represent hydrogen, carboxy, oxalo or carbamoyl;  
 R 2  is hydrogen or (C 1-6 )alkyl;  
 R 3  is (i) (C 1-6 )alkyl optionally substituted with cyano, halo, nitro, —SR 26 , —C(O)OR 26 , —C(O)NR 26 R 26 , —P(O)(OR 26 )OR 26 , —OP(O)(OR 26 )OR 26 , —S(O)R 27 , —S(O) 2 R 27  or C(O)R 27 , wherein R 26  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 27  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl, or (ii) (C 5-6 )cycloalkyl(C 2-3 )alkyl, hetero(C 3-6 )cycloalkyl(C 2-3 )alkyl, (C 6-12 )aryl(C 2-3 )alkyl or hetero(C 5-6 )aryl(C 2-3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above, provided that when R 3  is unsubstituted (C 1-5 )alkyl and R 4  is hydrogen or unsubstituted (C 1-5 )alkyl, then X 2  may not represent (i) a bond when R 1  is —C(O)R 20 , —C(O) 2 R 20  or —S(O) 2 R 20  in which R 20  is (C 1-6 )alkyl, phenyl(C 1-4 )alkyl, phenyl, (C 3-7 )cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, (C 1-4 )alkylamino, (C 1-4 )dialkylamino, carboxy or (C 1-4 )alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C 1-4 )alkyl, perfluoro(C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C 1-4 )alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R 12  is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R 9  and R 12  form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; 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 or (C 3-8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 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 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , and R 15  are as defined above;  
 R 4  is hydrogen, (C 1-6 )alkyl or as defined above;  
 R 5  is hydrogen and R 6  is hydroxy or R 5  and R 6  together form oxo;  
 R 7  is a group selected from cyano, halo, nitro, —R 29 , —X 5 NR 29 R 30 , —X 5 NR 30 C(O)OR 29 , —X 5 NR 30 C(O)NR 29 R 30 , —X 5 NR 30 C(NR 30 )NR 29 R 30 , —X 5 OR 29 , —X 5 SR 29 , —X 5 C(O)OR 29 , —X 5 C(O)NR 29 R 30 , —X 5 S(O) 2 NR 29 R 30 , —X 5 P(O)(OR 30 )OR 29 , —X 5 OP(OR 29 )OR 29 , —X 5 NR 30 C(O)R 31 , —X 5 S(O)R 31 , —X 5 S(O) 2 R 31  and —X 5 C(O)R 31 , wherein X 5  is as defined above, R 29  is hydrogen or —R 31 , R 30  at each occurrence is hydrogen or (C 1-6 )alkyl and R 31  is (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 3-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl, wherein within R 7  any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and  
 R 8  at each occurrence independently is 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 14 )OR 14 , —X 5 OP(O)(OR 14 )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 , R 14  and R 15  are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.; which process comprises: 
 (A) reacting an organometallic compound of Formula 2:  
                     
 with a compound of Formula 3:  
 wherein n, A, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 7  and R 8  are as above, to give a compound of Formula I in which R 5  and R 6  together form oxo; or  
 (B) reacting a compound of Formula 4:  
                     
 with a compound of Formula 5(a) or 5(b):  
                     
 wherein the dashed line represents an optional bond and B is a monocyclic radical containing 5 to 6 ring member atoms or a fused polycyclic radical containing 8 to 11 ring member atoms, wherein each ring, contains 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom and n, R 1 , R 2 , R 3 , R 4 , R 7  and R 8  are as defined above, to give a compound of Formula I in which the ring comprised by X 1  is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, respectively, R 5  is hydrogen and R 6  is hydroxy or  
 (C) reacting a compound of Formula 6:  
                     
 with a compound of the formula R 1 X 2 OY, wherein Y is hydrogen or or an activating group and n, A, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 7  and R 8  are as defined above to give a compound of Formula I in which R 5  is hydrogen and R 6  is hydroxy; or  
 (D) reacting a compound of Formula 7:  
                     
 or a protected derivative thereof, with R 39 OH, wherein R 39  is —X 6 X 7 R 20  and n, A, X 1 , X 2 , X 7 , X 8 , R 2 , R 3 , R 4 , R 6 , R 7  and R 20  are as defined above, and deprotecting if necessary to give a compound of Formula I in which R 1  is —X 6 X 7 R 20 ,  
 (E) optionally oxidizing a compound of Formula I in which R 5  is hydrogen and R 6  is hydroxy to give a compound of Formula I in which R 5  and R 6  together form oxo;  
 (F) optionally oxidizing a compound of Formula I in which A is optionally substituted 4,5-dihydroxyoxazol-2-yl to give a compound of Formula I in which A is optionally substituted oxazol-2-yl;  
 (G) optionally converting a compound of Formula I in which R 7  is —C(O)OH to a compound of Formula I in which R 7  is methoxycarbonyl;  
 (H) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;  
 (I) optionally converting a salt form of a compound of Formula I to non-salt form;  
 (J) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;  
 (K) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;  
 (L) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and  
 (M) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.