Compounds and compositions as cathepsin S inhibitors

1. A compound of Formula I

in which

R 1 is

R 6 and R 7 are independently hydrogen, C 1-6 alkyl, cyano-C 0-6 alkyl, C 3-12 cycloalkylC 0-4 alkyl and C 6-10 arylC 0-4 alkyl; or R 6 and R 7 together with the carbon atom to which R 6 and R 7 are attached form C 3-8 heterocycloalkyl or C 3-12 cycloalkyl;

wherein any alkyl of R 6 and R 7 can optionally have a methylene replaced with an atom or group chosen from O and S(O) 0-2 ; wherein any aryl, heterocycloalkyl or cycloalkyl of R 6 , R 7 or formed by the combination of R 6 and R 7 can be optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, —XC(O)OR 10 , —X(S(O) 0-2 R 10 , —XNRS(O) 0-2 R 10 and —XS(O) 0-2 NR 10 R 10 ; wherein X is a bond or C 1-4 alkylene; and R 10 is independently chosen from hydrogen and C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 3 and R 4 are independently hydrogen, C 1-6 alkyl, C 3-12 cycloalkylC 0-4 alkyl and C 6-10 arylC 0-4 alkyl; wherein any alkyl of R 3 and R 4 can optionally have a methylene replaced with an atom or group chosen from O and S(O) 0-2 ; wherein any aryl or cycloalkyl of R 3 and R 4 can optionally be substituted with 1 to 3 radicals independently chosen from halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl and halo-substituted-C 1-6 alkoxy;

R 5 is C 3-8 heterocycloalkyl; wherein any heterocycloalkyl of R 5 can be optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, —XC(O)OR 10 , —X(S(O) 0-2 R 10 , —XNR 10 S(O) 0-2 R 10 and —XS(O) 0-2 NR 10 R 10 ; wherein X is a bond or C 1-4 alkylene; and R 10 is independently chosen from hydrogen and C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of Formula Ia

in which

R 1 is

R 6 is hydrogen, C 1-6 alkyl, cyano-C 0-6 alkyl, C 3-12 cycloalkylC 0-4 alkyl and C 6-10 arylC 0-4 alkyl;

wherein any alkyl of R 6 can optionally have a methylene replaced with an atom or group chosen from O and S(O) 0-2 ; wherein any aryl or cycloalkyl of R 6 can be optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, —XC(O)OR 10 , —X(S(O) 0-2 R 10 , —XNRS(O) 0-2 R 10 and —XS(O) 0-2 NR 10 R 10 ; wherein X is a bond or C 1-4 alkylene; and R 10 is independently chosen from hydrogen and C 1-6 alkyl;

R 3 is hydrogen, C 1-6 alkyl, C 3-12 cycloalkylC 0-4 -alkyl and C 6-10 arylC 0-4 alkyl; wherein any alkyl of R 3 can optionally have a methylene replaced with an atom or group chosen from O and S(O) 0-2 ; wherein any aryl or cycloalkyl of R 3 can optionally be substituted with 1 to 3 radicals independently chosen from halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl and halo-substituted-C 1-6 alkoxy;

R 5 is C 3-8 heterocycloalkyl; wherein any heterocycloalkyl of R 5 can be optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, —XC(O)OR 10 , —X(S(O) 0-2 R 10 , —XNR 10 S(O) 0-2 R 10 and —XS(O) 0-2 NR 10 R 10 ; wherein X is a bond or C 1-4 alkylene; and R 10 is independently chosen from hydrogen and C 1-6 alkyl.

3. The compound of claim 1 , in which

R 2 and R 4 are both hydrogen;

R 6 is hydrogen, C 1-6 alkyl, cyano-C 0-6 alkyl, C 3-12 cycloalkylC 0-4 -alkyl and C 6-10 arylC 0-4 alkyl; wherein any alkyl of R 6 can optionally have a methylene replaced with an atom or group chosen from O and S(O) 0-2 ; wherein any aryl or cycloalkyl of R 6 can be optionally substituted with 1 to 3 radicals independently selected from halo;

R 7 is hydrogen; and

R 3 is C 1-6 alkyl, C 3-12 cycloalkylC 0-4 alkyl or C 6-10 arylC 0-4 -alkyl; wherein any alkyl of R 3 can optionally have a methylene replaced with an atom or group from O and S(O) 0-2 .

4. The compound of claim 3 , in which R 6 is hydrogen, methyl, ethyl propyl, isopropyl, cyclopropyl, cyanomethyl, 2-chloro-benzyloxymethyl, benzyloxymethyl, benzyloxyethyl, phenethyl or benzyl.

5. The compound of claim 3 , in which R 3 is selected from cyclohexyl-methyl, cyclopentyl-methyl, benzyl-sulfonyl-methyl, cyclohexyl-ethyl, phenyl, iso-butyl, t-butyl-methyl, cyclohexyl, benzyl, and phenethyl; and R 5 is chosen from morpholino, dimethylamino, piperidinyl and pyrrolidinyl.

6. The compound of claim 1 , wherein said compound is selected from:

(S)-1-tert-butoxycarbonyl-4-cyano-4-(1-cyclohexylmethyl-2-morpholin-4-yl-2-oxo-ethoxycarbonylamino)-piperidine,

(S)-4-cyano-4-(1-cyclohexylmethyl-2-morpholin-4-yl-2-oxo-ethoxycarbonylamino)-1-methyl-piperidine,

(1S)-cyclohexylmethyl-2-morpholin-4-yl-2-oxo-ethyl 2-(2-chloro-benzyloxy)-(1R)-cyano-ethyl carbamate,

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl (1S)-cyano-2-methyl-propyl carbamate,

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl (1S)-cyano-propyl carbamate,

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl 2-benzyloxy-(1R)-cyano-ethyl carbamate,

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl 3-benzyloxy-(1S)-cyano-propyl carbamate,

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl (1S)-cyano-3-phenyl-propyl carbamate,

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl (1S),2-dicyano-ethyl carbamate,

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl (1S)-cyano-2-phenyl-ethyl carbamate, and

(1S)-cyclohexylmethyl-2-(morpholin-4-yl)-2-oxo-ethyl cyanomethyl carbamate;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

8. A method for treating a disease associated with Cathepsin S activity, which method comprises administering to an animal a therapeutically effective amount of a compound of claim 1 .