IP Library › Patent Application 10525114

Patent Application

App. No. 10/525,114

Protease inhibitors

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Patent No.: US None
App. No.: 10/525,114

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Abstract

This invention relates 4-amino-azepan-3-ones of formula (I) which are useful as protease inhibitors, particularly of cathepsin S, and as such are useful for preventing a number of diseases amongst which are atherosclerotic lesions and pulmonary diseases such as asthma and allergic reactions.

Claims (203)

1 . A method for treating a disease by inhibiting cathepsin S comprising administering at least one compound of Formula I neat or in a pharmaceutically acceptable formulation in an effective amount to a mammal in need thereof, wherein Formula I comprises:

wherein:

R 1 is

R 2 is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, R 9 C(O)—, R 9 C(S)—, R 9 SO 2 —, R 9 OC(O)—, R 9 R 11 NC(O)—, R 9 R 11 NC(S)—, R 9 (R 11 )NSO 2 —

R 3 is H or substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkylC 0-6 alkyl, C 4-7 cycloalkenylC 0-6 alkyl, C 5-8 bicycloalkylC 0-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, HetC 0-6 alkyl, ArC 0-6 alkyl, Ar—ArC 0-6 alkyl, Ar-HetC 0-6 alkyl, Het-ArC 0-6 alkyl, or Het-HetC 0-6 alkyl;

R 4 is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, R 5 C(O)—, R 5 C(S)—, R 5 SO 2 —, R 5 NSO 2 —, R 5 OC(O)—, R 5 R 12 NC(O)—, or R 5 R 12 NC(S)—;

R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, Ar—ArC 0-6 alkyl, Ar-HetC 0-6 alkyl, Het-ArC 0-6 alkyl, Het-HetC 0-6 alkyl, or Het-C 0-6 alkyl;

R 6 is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, R 10 C(O)—, R 10 C(S)—, R 10 SO 2 —, R 10 OC(O)—, R 10 R 13 NC(O)—, or R 10 R 13 NC(S)—;

R 8 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, HetC 0-6 alkyl or ArC 0-6 alkyl;

R 9 is C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl or Het-C 0-6 alkyl;

R 10 is C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl or Het-C 0-6 alkyl;

R 11 is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R 12 is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R 13 is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R′ is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R″ is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R′″ is C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

X is CH 2 , S, or O;

Z is C(O) or CH 2 ; or

a pharmaceutically acceptable salt, hydrate or solvate thereof.

2 . The method of claim 1 wherein, in Formula I:

R 1 is

R 2 is R 9 SO 2 R 9 OC(O)—, or R 9 C(O)—;

R 3 is C 5-7 cycloalkylC 1-2 alkyl, C 4-5 cycloalkenylC 1-2 alkyl, C 5-8 bicycloalkylC 1-2 alkyl or Ar-HetC 0-6 alkyl;

R 4 is R 5 C(O)—, or R 5 SO 2 —;

R 5 is unsubstituted or substituted furanyl, tetrahydrofuranyl, morpholinyl, pyrrolyl, piperazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrazolo[5,1-c]pyrimidinyl, triazolyl, pyrazinyl, imadazolyl, benzofuranyl, thiophenyl, furo[3,2-b]-pyridine-2-yl, phenyl, pyridinyl, thieno[3,2-b]thiopheneyl, or unsubsituted or C 1-2 alkylsubstituted pyrazolo[5,1-c]triazinyl;

R 9 is HetC 0-6 alkyl, ArC 0-6 alkyl, or C 1-6 alkyl;

R′ is H, C 1-6 alkyl;

R″ is H or C 1-6 alkyl; and

R′″ is C 1-6 alkyl.

3 . The method of claim 1 wherein in Formula I,

R 1 is

R 2 is R 9 SO 2 R 9 OC(O)—, or R 9 C(O)—;

R 3 is cyclopentylmethyl, cyclopentylethyl, cyclopentenylmethyl, cyclopentenylethyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, 2-cyclohexylprop-1-yl, cyclohexylethyl, cycloheptylmethyl, 7,7-dimethylbicyclo[2.2.1]hept-1-ylmethyl, or indol-2-ylmethyl;

R 4 is R 5 C(O)— or R 5 SO 2 —

R 5 is furan-2-yl, furan-3-yl, 2-methylfuran-3-yl, 2,4-dimethylfuran-3-yl, 5-phenylfuran-2-yl, 5-(2-chlorophenyl)furan-2-yl, 5-(3-chlorophenyl)furan-2-yl, 5-(4-chlorophenyl)furan-2-yl, 5-(4-fluorophenyl)furan-2-yl, 5-(4-hydroxyphenyl)furan-2-yl, 5-(3-trifluoromethylphenyl)furan-2-yl, 5-(4-trifluoromethylphenyl)furan-2-yl, 5-(3-trifluoromethylphenyl)furan-2-yl, 5-(4-methylphenyl)furan-2-yl, 5-(4-acetylphenyl)furan-2-yl, or 5-trifluoromethylfuran-2-yl;

tetrahydrofuran-2-yl or tetrahydrofuran-3-yl

N-morpholinyl;

pyrrol-2-yl;

piperzin-1-yl or 4-methylpeperzin-1-yl;

1H-pyrazol-2-yl, 1H-pyrazol-4-yl, 1-methyl-2H-pyrazol-2-yl, 2-methyl-2H-pyrazol-2-yl, 1-methyl-2H-pyrazol-3-yl or 2-methyl-2H-pyrazol-3-yl;

isoxazol-5-yl, 3-methylisoxazol-4-yl, 5-methylisoxazol-3-yl, 5-methylisoxazol-4-yl, or 3,5-dimethylisoxazol-4-yl;

thiazol-2-yl, 2-methylthiazol-2-yl, 2,4-dimethylthiazol-5-yl, 2-(2,3-dihydrobenzo[1,4]dioxin-2-yl)thiazol-4-yl, or 4-methyl-2-phenylthiazol-5-yl;

4,7-dimethylpyrazolo[5,1-c]triazin-3-yl;

2-methyl-2H-pyrazol-2-yl;

2,7-dimethylpyrazol[5,1-c]pyrimidin-6-yl;

3-phenyl-3H-{1,2,3]triazol-3-yl;

pyrazin-2-yl or 5-methylpyrazin-2-yl;

1-H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl or 1-methyl-1H-imidazol-2-yl;

benzofuran-2-yl, 5,6-dimethoxybenzofuran-2-yl, or 5-(2-morpholin-4-yl-ethoxy)benzofuran-2-yl;

thiophene-3-yl, or thiophen-2-yl, 5-pyridin-2-ylthiophen-2-yl, 5-methylthiophenyl 3-methylthiophen-2-yl; or 3-ethoxythiophen-2-yl;

furo[3,2-b]-pyridine-2-yl or 3-methylfuro[3,2-b]pyridin-2-yl;

phenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, or 4-acetylphenyl;

pyridin-2-yl; or

thieno[3,2-b]thiophen-2-yl or 5-isoxazol-3-ylthiophen-2-yl;

R 9 is pyridin-2-yl, 1-oxypyridin-2-yl, phenyl, furan-2-yl or methyl;

R′ is H;

R″ is H or C 1-6 alkyl; and

R′″ is methyl.

4 . The method according to claim 1 wherein Formula I has the structure:

and groups R 1 -R 13 , X, Z, R′, R″ and R′″ are the same as defined in claim 1 .

5 . The method according to claim 1 wherein the compound of Formula I is

morpholine 4-carboxylic acid {(S)-2-[1-methylcyclopentyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(L)-2-[1-methylcyclopentyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(S)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(L)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-carboxylic acid {(S)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-carboxylic acid {(L)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-carboxylic acid {(S)-2-[4-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-carboxylic acid {(S)-2-[homocyclopentyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(S)-2-[homocyclopentyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-carboxylic acid {(S)-2-[cycloheptyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(S)-2-[cycloheptyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-carboxylic acid {(S)-2-[cyclopentenyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-carboxylic acid {(S)-2-[tryptophanyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(S)-2-(7,7-dimethyl-bicyclo[2.2.1]hepty-1-yl)-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-2H-pyrazole-3-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

1H-pyrazole-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

1-methyl-1H-pyrrole-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

isoxazole-5-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

thiazole-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-trifluoromethyl-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

1H-pyrazole-4-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

tetrahydrofuran-3-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

4,7-dimethyl-pyrazolo[5,1-c][1,2,4]triazine-3-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2,7-dimethyl-pyrazolo[5,1-a]pyrimidine-6-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

3-phenyl-3H-[1,2,3]triazole-4-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-thiazole-4-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

N-{(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-2-pyrazol-1-yl-benzamide;

4-methyl-2-phenyl-thiazole-5-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(4-chloro-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(2-chloro-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(4-fluoro-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(4-methoxy-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-phenyl-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(4-trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(3-chloro-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(4-methylphenyl)furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(4-acetyl-phenyl)-furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

4-methyl-piperazine-1-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

piperazine-1-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(S)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-meyhanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(L)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-methanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-thiazole-4-carboxylic acid {(S)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-meyhanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-thiazole-4-carboxylic acid {(L)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-methanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(S)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-meyhanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

morpholine 4-carboxylic acid {(L)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-methanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-thiazole-4-carboxylic acid {(S)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-meyhanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-thiazole-4-carboxylic acid {(L)-2-[1-methylcyclohexyl-1-(4S,7R)-7-methyl-3-oxo-1-(1-pyridin-2-yl-methanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

6 . The method of claim 1 wherein the inhibition of cathepsin S effects treatment or prevention of an autoimmune disease; treatment or prevention of a disease caused by the formation of atherosclerotic lesions and complications arising therefrom; and diseases requiring inhibition, for therapy, of a class II MHC-restricted immune response, inhibition of an asthmatic response, inhibition of an allergic response, inhibition of immune response against a transplanted organ or tissue, or inhibition of elastase activity in atheroma.

7 . A compound of Formula II

wherein:

R 1 is:

R 4 is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, R 5 C(O)—, R 5 C(S)—, R 5 SO 2 —, R 5 NSO 2 —, R 5 OC(O)—, R 5 R 12 NC(O)—, or R 5 R 12 NC(S)—;

R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, Ar—ArC 0-6 alkyl, Ar-HetC 0 6 alkyl, Het-ArC 0-6 alkyl, Het-HetC 0-6 alkyl, or Het-C 0-6 alkyl;

R 6 is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, R 10 C(O)—, R 10 C(S)—, R 10 SO 2 —, R 10 OC(O)—, R 10 R 13 NC(O)—, or R 10 R 13 NC(S)—;

R 8 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, HetC 0-6 alkyl or ArC 0-6 alkyl;

R 9 is C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl or Het-C 0-6 alkyl;

R 10 is C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl or Het-C 0-6 alkyl;

R 11 is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R 12 is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R 13 is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R′ is H, C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

R″ is C 1-6 alkyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl;

X is CH 2 , S, or O;

Z is C(O) or CH 2 ; or

a pharmaceutically acceptable salt, hydrate or solvate thereof.

8 . A compound of Formula I according to claim 7 wherein:

R 1 is

R 2 is R 9 SO 2 , R 9 OC(O)—, R 9 C(O)— or C 1-6 alkyl;

R 3 is C 5-7 cycloalkylC 1-2 alkyl, C 4-5 cycloalkenylC 1-2 alkyl, C 5-8 bicycloalkylC 1-2 alkyl or Ar-HetC 0-6 alkyl;

R 4 is R 5 C(O)—, or R 5 SO 2 —;

R 9 is Het-C 0-6 alkyl, ArC 0-6 alkyl or C 1-6 alkyl;

R′ is H, C 1-6 alkyl; and

R″ is H or C 1-6 alkyl.

9 . A compound of Formula II according to claim 8 wherein:

R 1 is

R 2 is R 9 SO 2 R 9 OC(O)—, or R 9 C(O)—;

R 4 is R 5 C(O)— or R 5 SO 2 —

tetrahydrofuran-2-yl or tetrahydrofuran-3-yl

N-morpholinyl;

pyrrol-2-yl;

piperzin-1-yl or 4-methylpeperzin-1-yl;

1H-pyrazol-2-yl, 1H-pyrazol-4-yl, 1-methyl-2H-pyrazol-2-yl, 2-methyl-2H-pyrazol-2-yl, 1-methyl-2H-pyrazol-3-yl or 2-methyl-2H-pyrazol-3-yl;

isoxazol-5-yl, 3-methylisoxazol-4-yl, 5-methylisoxazol-3-yl, 5-methylisoxazol-4-yl, or 3,5-dimethylisoxazol-4-yl;

thiazol-2-yl, 2-methylthiazol-2-yl, 2,4-dimethylthiazol-5-yl, 2-(2,3-dihydrobenzo[1,4]dioxin-2-yl)thiazol-4-yl, or 4-methyl-2-phenylthiazol-5-yl;

4,7-dimethylpyrazolo[5,1-c]triazin-3-yl;

2-methyl-2H-pyrazol-2-yl;

2,7-dimethylpyrazol[5,1-c]pyrimidin-6-yl;

3-phenyl-3H-{1,2,3]triazol-3-yl;

pyrazin-2-yl or 5-methylpyrazin-2-yl;

1-H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl or 1-methyl-1H-imidazol-2-yl;

benzofuran-2-yl, 5,6-dimethoxybenzofuran-2-yl, or 5-(2-morpholin-4-yl-ethoxy)benzofuran-2-yl;

thiophene-3-yl, or thiophen-2-yl, 5-pyridin-2-ylthiophen-2-yl, 5-methylthiophenyl 3-methylthiophen-2-yl; or 3-ethoxythiophen-2-yl;

furo[3,2-b]-pyridine-2-yl or 3 -methylfuro[3,2-b]pyridin-2-yl;

phenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, or 4-acetylphenyl;

pyridin-2-yl; or

thieno[3,2-b]thiophen-2-yl or 5-isoxazol-3-ylthiophen-2-yl;

R 9 is pyridin-2-yl, phenyl, furan-2-yl or methyl;

R′ is H; and

R″ is H or C 1-6 alkyl.

10 . A compound of Formula II according to claim 7 wherein:

furan-2-carboxylic acid {(S)-2-homocyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-2-carboxylic acid {(S)-2-tryptophanyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-trifluoromethyl-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[(s)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2,4-dimethyl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[(s)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-methyl-pyrazine-2-carboxylic acid {(S)-2-cyclohexyl-1-[(s)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

1-methyl-1H-imidazole-2-carboxylic acid {(S)-2-cyclohexyl-1-[(s)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

1H-pyrazole-4-carboxylic acid {(S)-2-cyclohexyl-1-[(s)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

4-methyl-2-phenyl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[(s)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2,5-dimethyl-furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

isoxazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-methyl-isoxazole-3-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-methyl-isoxazole-4-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

3-methyl-isoxazole-4-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-2H-pyrazole-3-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

pyrazine-2-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

thiazole-2-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

2-methyl-thiazole-4-carboxylic acid {(S)-2-cyclohexyl-1-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

(S)-3-cyclohexyl-N-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-2-(thiophene-2-sulfonylamino)-propionamide;

(S)-3-cyclohexyl-2-(1-methyl-1H-imdiazole-4-sulfonylamino)-N-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-propionamide;

(S)-3-cyclohexyl-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-propionamide;

(S)-3-cyclohexyl-2-(furan-2-sulfonylamino)-N-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-propionamide;

(S)-3-cyclohexyl-N-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-2-(pyridine-2-sulfonylamino)-propionamide;

(S)-3-cyclohexyl-2-(morpholine-4-sulfonylamino)-N-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-propionamide;

(S) -3-cyclohexyl-2-(5-isoxazol-3-yl-thiophene-2-sulfonylamino)-N-[(S)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-propionamide;

4-{(S)-3-cyclopentyl-2-[(1-furan-2-yl-methanoyl)-amino]-propanoylamino}-3-oxo-azepane-1-carboxylic acid benzyl ester;

furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]ethyl}-amide;

furan-2-carboxylic acid [(S)-2-cyclopentyl-1-(1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-ethyl]-amide;

furan-2-carboxylic acid [(S)-1-(1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-2-cyclopentyl-ethyl]-amide

furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[1-(1-furan-2-yl-methanoyl)-3-oxo-azepan-4-ylcarbamoyl]-ethyl}-amide;

furan-2-carboxylic acid {(S)-2-cyclopentyl-1-[3-oxo-1-(1-phenyl-methanoyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; or

piperazine-1-carboxylic acid {(S)-2-cyclopentyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; or

a pharmaceutically acceptable salt, hydrate or solvate thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 17, 2005

From: BONDINELL, WILLIAM E.; HALL, RALPH F.; JIN, QI; KERNS, JEFFREY K.; NIE, HONG; WIDDOWSON, KATHERN L.

To: SMITHKLINE BEECHAM CORPORATION

Reel/Frame 015913/0979 →