Cyanomethyl derivatives as cysteine protease inhibitors

1 . A compound of Formula (I):

wherein:

R 1 is a group of formula:

(xvii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl;

(xviii) 1-methyl-1H-thieno[2,3-c]pyrazol-5-yl where the 3-position of the pyrazole ring is substituted with alkyl, haloalkyl, or phenyl optionally substituted with alkyl, halo, haloalkyl, haloalkoxy, or alkoxy;

(xix) 4-(3,5-dimethyloxazol-4-yl)phenyl; or

(xx) 4-(5-carboxy-2-methylthiophen-3-yl)phenyl;

(xxi) biphen-4-yl;

(xxii) 4-alkoxycarbonylbiphen-4-yl;

(xxii) 4-carboxybiphen-4-yl;

(xxiii)

(xxiv) 4-(5-carboxy-2-halothiophen-3-yl)phenyl;

where:

Z a and Z b are independently —CX— or —N— and Z c is selected from —CH— and —N— provided that if an R 1 group contains Z a , Z b , and Z c simultaneously then, when Z c is —N—, then Z a is —N— or —CX— and Z b is —H—; and when Z b is —N— then both Z a and Z c cannot be —N— simultaneously;

Q is —NR— where R is hydrogen or alkyl, —O—, or —S—;

Q′ is —CH— or —N—;

X and Y are independently selected from hydrogen, halo, alkyl, alkoxy, haloalkyl, or haloalkoxy provided that both X and Y are not simultaneously hydrogen;

Z is hydrogen, halo, alkyl, alkoxy, haloalkyl, or haloalkoxy;

X a and X b are independently selected from alkyl, halo, alkoxy, haloalkyl, or haloalkoxy;

R 2 is selected from the group consisting of hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, methyl, ethyl, n-propyl, 2-propyl, 2-methylpropyl, 2-ethylbutyl, 3-methylbutyl, thiazolylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2,4,4-trimethylpentyl, 1-methylindol-3-ylmethyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 2-cyclohexylpropyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), benzyl (where the phenyl ring in the benzyl group is optionally substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino; or dialkylamino), heteroaryl(C 3-6 )alkyl, and 1-heteroaryl(C 3-6 )cycloalkylmethyl, and furthermore wherein the alkyl chain in the above groups is optionally substituted with one to six halo;

R 3 is hydrogen; or

R 2 and R 3 together with the carbon atom to which they are attached form (C 4-8 )-cycloalkylene, (C 4-8 )cycloalkenylene or spirocycloalkylene wherein said (C 4-8 )cycloalkylene, (C 4-8 )cycloalkenylene or spirocycloalkylene is optionally substituted with one or two alkyl, alkylidene, or alkenyl;

R 4 is hydrogen;

R 5 is hydrogen, alkyl or heteroaryl optionally substituted with alkyl, halo, haloalkyl, haloalkoxy, or alkoxy; or

R 4 and R 5 together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene;

R 6 and R 7 are independently selected from phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 8 is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 9 is halo, phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 10 is a branched alkyl chain of 4-6 carbon atoms or trifluoroalkoxy; and

each R 11 and R 12 are independently hydrogen or alkyl;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 wherein:

wherein:

R 1 is a group of formula:

(xvii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl;

(xviii) 1-methyl-3-trifluoromethyl-1H-thieno[2,3-c]pyrazol-5-yl;

(xix) 4-(3,5-dimethyloxazol-4-yl)phenyl; or

(xx) 4-(5-carboxy-2-methylthiophen-3-yl)phenyl;

where:

Z a is —CX— or —N— and Z b and Z c are independently selected from —CH— and —N— provided that if an R 1 group contains Z a , Z b , and Z c simultaneously then, when Z c is —N—, then Z a is —N— or —CX— and Z b is —CH—; and when Z b is —N— then both Z a and Z c cannot be —N— simultaneously;

Q is —NR— where R is hydrogen or alkyl, —O—, or —S—;

Q′ is —CH— or —N—;

X and Y are independently selected from hydrogen, halo, alkyl, alkoxy, haloalkyl, or haloalkoxy provided that both X and Y are not simultaneously hydrogen;

X a and X b are independently selected from alkyl, halo, alkoxy, haloalkyl, or haloalkoxy;

R 2 is selected from the group consisting of hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, methyl, ethyl, n-propyl, 2-propyl, 2-methylpropyl, 2-ethylbutyl, 3-methylbutyl, thiazolylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), benzyl (where the phenyl ring in the benzyl group is optionally substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino), heteroaryl(C 3-6 )alkyl, and 1-heteroaryl(C 3-6 )cycloalkylmethyl, and furthermore wherein the alkyl chain in the above groups is optionally substituted with one to six halo;

R 3 is hydrogen; or

R 2 and R 3 together with the carbon atom to which they are attached form (C 4-8 )cycloalkylene, (C 4-8 )cycloalkenylene or spirocycloalkylene wherein said (C 4-8 )cycloalkylene, (C 4-8 )cycloalkenylene or spirocycloalkylene is optionally substituted with one or two alkyl, alkylidene, or alkenyl;

R 4 is hydrogen;

R 5 is hydrogen or alkyl; or

R 4 and R 5 together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene;

R 6 and R 7 are independently selected from phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 8 and R 9 are independently selected from phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl; and

R 10 is a branched alkyl chain of 4-6 carbon atoms or trifluoroalkoxy;

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 or 2 wherein R 3 , R 4 and R 5 are hydrogen and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

4 . The compound of claim 1 or 2 wherein R 3 is hydrogen and R 4 and R 5 together with the carbon atom to which they are attached form cycloalkylene and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

5 . The compound of claim 1 or 2 wherein R 3 is hydrogen and R 4 and R 5 together with the carbon atom to which they are attached form cyclopropylene and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

6 . The compound of claim 1 or 2 wherein R 3 is hydrogen and R 4 and R 5 together with the carbon atom to which they are attached form heterocycloalkylene and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

7 . The compound of claim 1 or 2 wherein R 3 is hydrogen, R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino, and R 4 and R 5 together with the carbon atom to which they are attached form:

wherein R is hydrogen, alkyl, haloalkyl or cycloalkyl.

8 . The compound of claim 7 wherein R 4 and R 5 together with the carbon atom to which they are attached form:

wherein R is methyl, ethyl, 2,2,2-trifluoroethyl, or cyclopropyl.

9 . The compound of any of the claims 1 - 8 wherein R 2 is 2,6-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, 2(S)-phenylpropyl, 2(R)-phenylpropyl, 2-methylpropyl, 2-methyl-2-phenylpropyl, 2-phenylethyl, 2-phenylprop-2-enyl, benzyl, or thiazol-2-ylmethyl.

10 . The compound of any of the claims 1 - 8 wherein R 1 is:

(xvii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl;

(xix) 4-(3,5-dimethyloxazol-4-yl)phenyl; or

(xx) 4-(5-carboxy-2-methylthiophen-3-yl)phenyl;

wherein:

X is hydrogen, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

Y is chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

X a , and X b are independently selected from methyl, chloro, fluoro, methoxy, trifluoromethyl, or trifluoromethoxy;

R 6 is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 7 is 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, or 2-haloalkoxyphenyl;

R 8 is 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, or 2-haloalkoxyphenyl; and

R 9 is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl.

11 . The compound of claim 10 wherein R 2 is preferably selected from the group consisting of cyclohexyl, cycloheptyl, thiazol-2-ylmethyl, 2-ethylbutyl, pyrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 2-napth-1-ylpropyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-methyl-2-(2-methoxyphenyl)propyl, 2-(2-methoxyphenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-dimethylphenyl)propyl, benzyloxymethyl, 2-(2,4-dimethylphenyl)propyl, 2-(2,4-dichlorophenyl)-propyl, 2,6-difluorobenzyl, 2,5-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, and 2,3-difluorobenzyl.

12 . The compound of claim 10 wherein R 2 is 2,6-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, 2(S)-phenylpropyl, 2(R)-phenylpropyl, 2-methylpropyl, 2-methyl-2-phenylpropyl, 2-phenylethyl, 2-phenylprop-2-enyl, benzyl, or thiazol-2-ylmethyl.

13 . The compound of claim 10 , 11 or 12 wherein R 1 is 2′-chlorobiphen-4-yl, 3,2′-dichlorobiphen-4-yl, 2′,6′-dichlorobiphen-4-yl, 2′,6′-dimethylbiphen-4-yl, 2′-methylbiphen-4-yl, 2′-fluorobiphen-4-yl; 2-(2-methylphenyl)furan-5-yl, 2-(2-methoxyphenyl)furan-5-yl, 3-methoxy-2-(2-methylphenyl)thiophen-4-yl, 3-methoxy-2-(2-methoxyphenyl)thiophen-4-yl, 2,3-di(2-methoxyphenyl)thiophen-5-yl, 3,5-di(2-methoxyphenyl)phenyl, 3,5-di(3-methoxyphenyl)phenyl, 2,3-di(2-methylphenyl)thiophen-5-yl, 4-(2-methylphenyl)thiophen-2-yl, 4-(2-methoxyphenyl)thiophen-2-yl, 2′-chlorobiphen-3-yl, 2′-methyl-4-chlorobiphen-3-yl, 3,5-di(2-chlorophenyl)phenyl, 2,3-di(2-chlorophenyl)thiophen-5-yl, 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl, 2-(2,6-dichlorophenyl)furan-5-yl, 3-trifluoromethyl-1-methylthieno[2,3-c]pyrazol-5-yl, 2′-methoxybiphen-4-yl, 2′-trifluoromethylbiphen-4-yl, 2′-methyl-3-chlorobiphen-4-yl, 2-(2-chlorophenyl)pyridin-5-yl, 2-(2,6-dichlorophenyl)pyridin-5-yl, 2-(2-trifluoromethylphenyl)pyridin-5-yl, 4-(3-methylpyridin-2-yl)phenyl, 2-(2-chlorophenyl)-3-chloropyridin-5-yl, 2-(2,6-dichlorophenyl)-3-chloropyridin-5-yl, 4′-carboxy-2′-chlorobiphen-4-yl, 4′-carboxy-2′-fluorobiphen-4-yl, 4′-carboxy-2′-methylbiphen-4-yl, 5′-carboxy-2′-chlorobiphen-4-yl, 5′-carboxy-2′-methylbiphen-4-yl, 2-(4-carboxy-2-chlorophenyl)pyridin-5-yl, 2-(5-carboxy-2-chlorophenyl)pyridin-5-yl, 4-(5-carboxy-2-methylthiophen-3-yl)phenyl, 4-(3-methoxy-phenyl)thiophen-2-yl, 3-(2-chlorophenyl)isoxazol-5-yl, or 4-(3-methylpyridin-2-yl)phenyl, 4-(2-chlorophenyl)thiophen-2-yl, 3-chloro-2′-methylbiphen-4-yl, 1-oxo-2-(2,6-dichlorophenyl)pyridin-5-yl, 1-oxo-2-(2-methylphenyl)pyridin-5-yl, 4′-carboxy-2′-methylbiphen-4-yl, 1-oxo-3-chloro-2-(2-chlorophenyl)pyridin-5-yl, 3-chloro-2-(2-trifluoromethylphenyl)pyridin-S-yl, 3-chloro-2-(2-methylphenyl)pyridin-5-yl, 1-oxo-2-(2-chlorophenyl)pyridin-5-yl, 4′-carboxy-2′6′-dichlorobiphen-4-yl, or 4′-carboxy-3,2′-dichlorobiphen-4-yl.

14 . The compound of any of the claims 1 - 8 wherein R 1 is a group of formula:

where:

X is chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

Y is hydrogen;

X a , and X b are independently selected from methyl, chloro, fluoro, methoxy, trifluoromethyl, or trifluoromethoxy;

R 6 and R 7 are phenyl;

R 8 are independently selected from phenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 9 is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl; and

R 10 is a branched alkyl chain of 4-6 carbon atoms or trifluoroalkoxy.

15 . The compound of claim 14 wherein R 2 is preferably selected from the group consisting of cyclohexyl, cycloheptyl, thiazol-2-ylmethyl, 2-ethylbutyl, pyrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 2-napth-1-ylpropyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-methyl-2-(2-methoxyphenyl)propyl, 2-(2-methoxyphenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-dimethylphenyl)propyl, benzyloxymethyl, 2-(2,4-dimethylphenyl)propyl, 2-(2,4-dichlorophenyl)-propyl, 2,6-difluorobenzyl, 2,5-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, and 2,3-difluorobenzyl.

16 . The compound of claim 14 wherein R 2 is 2,6-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, 2(S)-phenylpropyl, 2(R)-phenylpropyl, 2-methylpropyl, 2-methyl-2-phenylpropyl, 2-phenylethyl, 2-phenylprop-2-enyl, benzyl, or thiazol-2-ylmethyl.

17 . The compound of claim 14 , 15 or 16 wherein R 1 is 4-trifluoromethoxyphenyl, 4-(2-butyl)phenyl, 3,5-diphenylphenyl, 2,3-diphenylthiophen-5-yl, 3,5-di(thiophen-3-yl)phenyl, 3,5-di(pyridin-4-yl)phenyl, 4-tert-butylphenyl, 2,3-di(furan-2-yl)thiophen-5-yl, 3,5-di(furan-2-yl)phenyl, 2,3-diphenylthiophen-5-yl, 4,5-diphenylthiazol-2-yl, or 3-methylbiphen-4-yl.

18 . The compound of claim 1 wherein R 3 , R 4 and R 5 are hydrogen and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

19 . The compound of claim 1 wherein R 3 is hydrogen and R 4 and R 5 together with the carbon atom to which they are attached form cycloalkylene and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

20 . The compound of claim 1 wherein R 3 is hydrogen and R 4 and R 5 together with the carbon atom to which they are attached form cyclopropylene and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

21 . The compound of claim 1 wherein R 3 is hydrogen and R 4 and R 5 together with the carbon atom to which they are attached form heterocycloalkylene and R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino.

22 . The compound of claim 1 wherein R 3 is hydrogen, R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-pyridin-2-ylpropyl, 2-methyl-2-pyridin-2-ylpropyl, 1-pyridin-2-ylcyclopropylmethyl, 1-pyridin-2-ylcyclobutylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy), and benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6 positions with groups independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino, and R 4 and R 5 together with the carbon atom to which they are attached form:

wherein R is hydrogen, alkyl, haloalkyl or cycloalkyl.

23 . The compound of claim 1 wherein R 4 and R 5 together with the carbon atom to which they are attached form:

wherein R is methyl, ethyl, 2,2,2-trifluoroethyl, or cyclopropyl.

24 . The compound of any of the claims 18 - 23 wherein R 2 is 2,6-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, 2(S)-phenylpropyl, 2(R)-phenylpropyl, 2-methylpropyl, 2-methyl-2-phenylpropyl, 2-phenylethyl, 2-phenylprop-2-enyl, benzyl, or thiazol-2-ylmethyl.

25 . The compound of any of the claims 18 - 23 wherein R 1 is:

(xvii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl;

(xix) 4-(3,5-dimethyloxazol-4-yl)phenyl; or

(xx) 4-(5-carboxy-2-methylthiophen-3-yl)phenyl;

wherein:

X is hydrogen, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

Y is chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

X a , and X b are independently selected from methyl, chloro, fluoro, methoxy, trifluoromethyl, or trifluoromethoxy;

R 6 is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 7 is 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, or 2-haloalkoxyphenyl;

R 8 is 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, or 2-haloalkoxyphenyl; and

R 9 is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl.

26 . The compound of claim 25 wherein R 2 is preferably selected from the group consisting of cyclohexyl, cycloheptyl, thiazol-2-ylmethyl, 2-ethylbutyl, pyrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 2-napth-1-ylpropyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-methyl-2-(2-methoxyphenyl)propyl, 2-(2-methoxyphenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-dimethylphenyl)propyl, benzyloxymethyl, 2-(2,4-dimethylphenyl)propyl, 2-(2,4-dichlorophenyl)-propyl, 2,6-difluorobenzyl, 2,5-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, and 2,3-difluorobenzyl.

27 . The compound of claim 25 wherein R 2 is 2,6-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, 2(S)-phenylpropyl, 2(R)-phenylpropyl, 2-methylpropyl, 2-methyl-2-phenylpropyl, 2-phenylethyl, 2-phenylprop-2-enyl, benzyl, or thiazol-2-ylmethyl.

28 . The compound of claim 26 wherein R 1 is 2′-chlorobiphen-4-yl, 3,2′-dichlorobiphen-4-yl, 2′,6′-dichlorobiphen-4-yl, 2′,6′-dimethylbiphen-4-yl, 2′-methylbiphen-4-yl, 2′-fluorobiphen-4-yl; 2-(2-methylphenyl)furan-5-yl, 2-(2-methoxyphenyl)furan-5-yl, 3-methoxy-2-(2-methylphenyl)thiophen-4-yl, 3-methoxy-2-(2-methoxyphenyl)thiophen-4-yl, 2,3-di(2-methoxyphenyl)thiophen-5-yl, 3,5-di(2-methoxyphenyl)phenyl, 3,5-di(3-methoxyphenyl)phenyl, 2,3-di(2-methylphenyl)thiophen-5-yl, 4-(2-methylphenyl)thiophen-2-yl, 4-(2-methoxyphenyl)thiophen-2-yl, 2′-chlorobiphen-3-yl, 2′-methyl-4-chlorobiphen-3-yl, 3,5-di(2-chlorophenyl)phenyl, 2,3-di(2-chlorophenyl)thiophen-5-yl, 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl, 2-(2,6-dichlorophenyl)furan-5-yl, 3-trifluoromethyl-1-methylthieno[2,3-c]pyrazol-5-yl, 2′-methoxybiphen-4-yl, 2′-trifluoromethylbiphen-4-yl, 2′-methyl-3-chlorobiphen-4-yl, 2-(2-chlorophenyl)pyridin-5-yl, 2-(2,6-dichlorophenyl)pyridin-5-yl, 2-(2-trifluoromethylphenyl)pyridin-5-yl, 4-(3-methylpyridin-2-yl)phenyl, 2-(2-chlorophenyl)-3-chloropyridin-5-yl, 2-(2,6-dichlorophenyl)-3-chloropyridin-5-yl, 4′-carboxy-2′-chlorobiphen-4-yl, 4′-carboxy-2′-fluorobiphen-4-yl, 4′-carboxy-2′-methylbiphen-4-yl, 5′-carboxy-2′-chlorobiphen-4-yl, 5′-carboxy-2′-methylbiphen-4-yl, 2-(4-carboxy-2-chlorophenyl)pyridin-5-yl, 2-(5-carboxy-2-chlorophenyl)pyridin-5-yl, 4-(5-carboxy-2-methylthiophen-3-yl)phenyl, 4-(3-methoxy-phenyl)thiophen-2-yl, 3-(2-chlorophenyl)isoxazol-5-yl, or 4-(3-methylpyridin-2-yl)phenyl, 4-(2-chlorophenyl)thiophen-2-yl, 3-chloro-2′-methylbiphen-4-yl, 1-oxo-2-(2,6-dichlorophenyl)pyridin-5-yl, 1-oxo-2-(2-methylphenyl)pyridin-5-yl, 4′-carboxy-2′-methylbiphen-4-yl, 1-oxo-3-chloro-2-(2-chlorophenyl)pyridin-5-yl, 3-chloro-2-(2-trifluoromethylphenyl)pyridin-5-yl, 3-chloro-2-(2-methylphenyl)pyridin-5-yl, 1-oxo-2-(2-chlorophenyl)pyridin-5-yl, 4′-carboxy-2′6′-dichlorobiphen-4-yl, or 4′-carboxy-3,2′-dichlorobiphen-4-yl.

29 . The compound of any of the claims 18 - 23 wherein R 1 is a group of formula:

where:

X is chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

Y is hydrogen;

X a , and X b are independently selected from methyl, chloro, fluoro, methoxy, trifluoromethyl, or trifluoromethoxy;

R 6 and R 7 are phenyl;

R 8 are independently selected from phenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;

R 9 is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl; and

R 10 is a branched alkyl chain of 4-6 carbon atoms or trifluoroalkoxy.

30 . The compound of claim 29 wherein R 2 is preferably selected from the group consisting of cyclohexyl, cycloheptyl, thiazol-2-ylmethyl, 2-ethylbutyl, pyrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 2-napth-1-ylpropyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-methyl-2-(2-methoxyphenyl)propyl, 2-(2-methoxyphenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-dimethylphenyl)propyl, benzyloxymethyl, 2-(2,4-dimethylphenyl)propyl, 2-(2,4-dichlorophenyl)-propyl, 2,6-difluorobenzyl, 2,5-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, and 2,3-difluorobenzyl.

31 . The compound of claim 30 wherein R 2 is 2,6-difluorobenzyl, 2,6-difluoro-4-methoxybenzyl, 2(S)-phenylpropyl, 2(R)-phenylpropyl, 2-methylpropyl, 2-methyl-2-phenylpropyl, 2-phenylethyl, 2-phenylprop-2-enyl, benzyl, or thiazol-2-ylmethyl.

32 . The compound of claim 30 wherein R 1 is 4-trifluoromethoxyphenyl, 4-(2-butyl)phenyl, 3,5-diphenylphenyl, 2,3-diphenylthiophen-5-yl, 3,5-di(thiophen-3-yl)phenyl, 3,5-di(pyridin-4-yl)phenyl, 4-tert-butylphenyl, 2,3-di(furan-2-yl)thiophen-5-yl, 3,5-di(furan-2-yl)phenyl, 2,3-diphenylthiophen-5-yl, 4,5-diphenylthiazol-2-yl, or 3-methylbiphen-4-yl.

33 . A pharmaceutical composition comprising a compound of any of the claims 1 - 33 pharmaceutically acceptable excipient.

34 . A method of treating a disease in a patient mediated by cathepsin B, K, L, F, and/or S which method comprises administering to said patient a pharmaceutical composition comprising a compound of any of the claims 1 - 33 and a pharmaceutically acceptable excipient.

35 . The method of claim 34 wherein the disease is Alzheimer's disease, a cardiovascular disease, a respiratory disease, osteroporosis, and an autoimmune disease.

36 . The method of claim 34 wherein the disease is asthma, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis.

37 . Use of a compound of any of the claims 1 - 33 in the preparation of a medicament for the treatment of a disease mediated by Cathepsin B, K, L, F, and/or S.