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 chosen from 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 the group consisting of 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 8 is C 5-10 heterarylC 0-4 alkyl;

wherein any heteraryl of R 8 can be optionally substituted by 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, halo-substituted-C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteraryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl; and

R 2 is chosen from hydrogen and C 1-6 alkyl;

R 3 and R 4 are independently chosen from 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; optionally substituted with 1 to 3 radicals independently selected from the group consisting of 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, hydrate, solvate, isomer or prodrug thereof.

2. The compound of claim 1 of Formula Ia

in which

R 1 is formula (a)

R 6 is chosen from 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 the group consisting of 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 8 is C 5-10 heterarylC 0-4 alkyl;

wherein any heteroaryl, of R 8 can be optionally substituted by 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, halo-substituted-C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteraryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl; and

R 3 is chosen from 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 from C 3-8 heterocycloalkyl; wherein any heterocycloalkyl of R 5 can be optionally substituted with 1 to 3 radicals independently selected from the group consisting of 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 chosen from 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;

R 8 is C 5-10 heteraryl optionally substituted by 1 to 3 radicals independently chosen from halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 6-10 aryl, C 5-10 heteraryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl; and

R 9 is C 1-6 alkyl;

R 3 is chosen from 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 ;

R 5 is C 3-8 heterocycloalkyl.

4. The compound of claim 3 , in which R 6 is selected from the group consisting of hydrogen, methyl, ethyl propyl, isopropyl, cyclopropyl, cyanomethyl, 2-chloro-benzyloxymethyl, benzyloxymethyl, benzyloxyethyl, phenethyl and benzyl.

5. The compound of claim 3 , in which R 8 is benzooxazol-2-yl, benzothiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl and oxazolo[5,4-b]pyridin-2-yl; wherein any heteroaryl of R 8 is optionally substituted by 1 to 3 radicals independently chosen from halo, ethyl, phenyl, cyclopropyl and trifluoromethyl.

6. 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, piperidinyl and pyrrolidinyl.

7. The compound of claim 6 , selected from the group consisting of 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxo-ethyl carbamate, 2-phenylmethanesulfonyl-(1R)-(morpholine-4-carbonyl)ethyl 2-(benzoxazol-2-yl)-(1S)-methyl-2-oxo-ethyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(5-ethyl-[1,2,4]oxadiazole-3-carbonyl)propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(5-phenyl-[1,2,4]oxadiazole-3-carbonyl)propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl 4-oxo-tetrahydro-furan-(3S)-yl carbamate, (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, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl 2-(benzoxazol-2-yl)-(1S)-methyl-2-oxo-ethyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(benzoxazole-2-carbonyl)-butyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl 2-(5-fluoro-benzoxazol-2-yl)-(1S)-methyl-2-oxo-ethyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl 2-(6-fluoro-benzoxazol-2-yl)-(1S)-methyl-2-oxo-ethyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(benzoxazole-2-carbonyl)-2-methyl-propyl carbamate, 2-cyclopentyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(benzothiazole-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(benzothiazole-2-carbonyl)-ethyl carbamate, 2-phenylmethanesulfonyl-(1R)-(morpholine-4-carbonyl)ethyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, 3-cyclohexyl-(1S)-(morpholine-4-carbonyl)propyl (1S)-(benzoxazole-2-carbonyl)-ethyl carbamate, 3-cyclohexyl-(1S)-(morpholine-4-carbonyl)propyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, (1S)-(morpholine-4-carbonyl)-1-phenyl-methyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, 3,3-dimethyl-(1S)-(morpholine-4-carbonyl)-butyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)-methyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, (1S)-cyclohexylmethyl-2-oxo-2-(piperidin-1-yl)-ethyl (1S)-(benzoxazole-2-carbonyl)-ethyl carbamate, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)-ethyl 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxo-ethyl carbamate, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)-ethyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)-ethyl (1S)-(benzoxazole-2-carbonyl)-butyl carbamate, 2 cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(6-fluoro-benzoxazole-2-carbonyl)-propyl carbamate, 2-cyclopentyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(6-fluoro-benzoxazole-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(oxazolo[5,4-b]pyridine-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-cyclopropyl-2-(6-fluoro-benzoxazol-2-yl)-2-oxo-ethyl carbamate, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl (1S)-(6-fluoro-benzoxazole-2-carbonyl)-ethyl carbamate, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl (1S)-(6-fluoro-benzoxazole-2-carbonyl)-propyl carbamate, 2 cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(6-fluoro-benzoxazole-2-carbonyl)-butyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(5-cyclopropyl-[1,2,4]oxadiazole-3-carbonyl)-propyl carbamate, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl (1S)-(benzoxazole-2-carbonyl)-butyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(6-methyl-benzoxazole-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(5-chloro-benzoxazole-2-carbonyl)-propyl carbamate, (1S)-(morpholine-4-carbonyl)-2-phenyl-ethyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, (1S)-(morpholine-4-carbonyl)-3-phenyl-ethyl (1S)-(benzoxazole-2-carbonyl)-propyl carbamate, (JS)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)-ethyl fluoro-benzoxazole-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (JS)-(5-trifluoromethyl-[1,2,4]oxadiazole-3-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(7-fluoro-benzoxazole-2-carbonyl)-propyl carbamate, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(5-fluoro-benzoxazole-2-carbonyl)-butyl carbamate; (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)-ethyl fluoro-benzoxazole-2-carbonyl)-propyl carbamate; 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1S)-(3-cyclopropyl-[1,2,4]oxadiazole-5-carbonyl)-propyl carbamate; 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl (1R)-(5-cyclopropyl-[1,2,4]oxadiazole-3-carbonyl)-propyl carbamate; [1-(benzooxazole-2-carbonyl)-propyl]-carbamic acid 3-methyl-1-(morpholine-4-carbonyl)-butyl ester; (S,S)-(2-benzooxazol-2-yl-1-methyl-2-oxo-ethyl)-carbamic acid 3-methyl-1-(morpholine-4-carbonyl)-butyl ester; (S,S)-[1-(5-cyclopropyl-[1,2,4]oxadiazole-3-carbonyl)-propyl]-carbamic acid 3,3-dimethyl-1-(pyrrolidine-1-carbonyl)-butyl ester; and (S,S)-[1-(5-cyclopropyl-[1,2,4]oxadiazole-3-carbonyl)-propyl]-carbamic acid 3,3-dimethyl-1-(morpholine-4-carbonyl)-butyl ester.

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

9. A method for treating a disease in an animal in which inhibition of Cathepsin S activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of claim 1 .