Di-fluoro containing compounds as cysteine protease inhibitors

1. A compound of Formula (I):

wherein:

R 1 and R 2 taken together with the carbon atom to which both R 1 and R 2 are attached form cycloalkylene optionally substituted with one or two R b independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, and aryloxycarbonyl;

wherein the aromatic or alicyclic ring in the groups attached to cycloalkylene is optionally substituted with one, two, or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxycarbonyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl;

R 3 is hydrogen or alkyl;

R 5 is hydrogen or alkyl;

R 6 is aryl, optionally substituted by one, two, or three R e independently selected from alkyl, halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, alkylsulfonyl, aminosulfonyl, or aminoalkyl, and further where the aromatic or alicyclic ring in R e is optionally substituted with one, two or three R f independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl;

R 7 is haloalkyl;

R 8 is hydrogen, alkyl, alkoxyalkyl or haloalkyl;

R 22 is cycloalkyl, cycloalkylalkyl, aryl or aralkyl, wherein the aromatic or alicyclic ring in R 22 is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl;

Y is -alkylene-, wherein the alkylene group is optionally substituted with one to six fluoro atoms; and

Z is a direct bond or -alkylene-, wherein the alkylene portion is optionally substituted with one to six fluoro atoms;

or, a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein R 1 and R 2 together with the carbon atom to which they are attached form cycloalkylene.

3. A compound according to claim 1 wherein R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropylene.

4. A compound according to claim 1 wherein R 7 is trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.

5. A compound according to claim 1 wherein R 3 , R 5 and R 8 are hydrogen; R 22 is aryl, aralkyl, cycloalkyl or cycloalkylalkyl; Y is -alkylene-; and Z is a direct bond.

6. A compound according to claim 1 selected from the following compounds, or a pharmaceutically acceptable salt thereof:

N-(1-cyanocyclopropyl)-4,4-difluoro-5-phenyl-2(S)-(2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)pentanamide;

N-(1-cyanocyclopropyl)-4,4-difluoro-4-phenyl-2(S)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)butanamide;

N-(1-cyanocyclopropyl)-4,4-difluoro-5-cyclopropyl-2(S)-(2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)pentanamide;

N-(1-cyanocyclopropyl)-4,4-difluoro-4-cyclopropyl-2(S)-(2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)butanamide;

N-(1-cyanocyclopropyl)-4,4-difluoro-4-cyclohexyl-2(S)-(2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)butanamide;

N-(1-cyanocyclopropyl)-5,5-difluoro-5′-cyclopropyl-2(S)-(2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)pentanamide;

N-(1-cyanocyclopropyl)-5,5-difluoro-5-phenyl-2(S)-(2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)pentanamide; or

N-(1-cyanocyclopropyl)-5,5-difluoro-6-phenyl-2(S)-(2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino)hexanamide.

7. A pharmaceutical composition comprising a compound of claim 1 in admixture with one or more suitable excipients.

8. The compound of claim 1 , wherein R 6 is phenyl or naphthyl optionally substituted with one, two or three groups independently selected from alkyl, halo, hydroxy, oxo, carboxy, cyano, nitro, cycloakyl, alkoxy, acyl or alkoxycarbonyl.

9. The compound of claim 1 , wherein R 6 is phenyl or naphthyl optionally substituted with one, two or three groups independently selected from methyl, ethyl, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano, nitro, cyclopropyl, methoxy, acetyl or methoxycarbonyl.

10. The compound of claim 1 , wherein R 6 is phenyl or naphthyl optionally substituted with one, two or three groups independently selected from methyl, fluoro, chloro, methoxy, acetyl or methoxycarbonyl.

11. The compound of claim 1 , wherein R 6 is phenyl optionally substituted with one, two or three groups independently selected from methyl, fluoro, chloro, methoxy, acetyl or methoxycarbonyl.

12. The compound of claim 1 , wherein R 6 is phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl.

13. The compound of claim 1 , wherein R 6 is 4-fluorophenyl.