Proline compounds as Granzyme B inhibitors

摘要

Proline compounds as Granzyme B inhibitors, compositions that include the compounds, and methods for using the compounds. Methods for treating cutaneous scleroderma, epidermolysis bullosa, radiation dermatitis, alopecia areata, and discoid lupus erythematosus are provided.

主权项

1. A compound selected from the group consisting of
3-{[(1S,2S)-2-methyl-1-({2-oxo-2-[(2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethyl)carbamoyl]pyrrolidin-1-yl]ethyl}carbamoyl)butyl]carbamoyl}-propanoic acid; 4-(R)-tert-Butoxy-1-[2-[(2S,3S)-3-methyl-2-(2-phenylacetylamido)pentanamido]-acetyl]-pyrrolidine-2-(S)-carboxylic acid (1H-[1,2,3]triazol-4-ylmethyl)-amide; 4-(R)-benzyloxy-1-[2-[(2S,3S)-3-methyl-2-(2-phenylacetylamido)pentanamido]-acetyl]-pyrrolidine-2-(S)-carboxylic acid (1H-[1,2,3]triazol-4-ylmethyl)-amide; (2S,4S)—N-((2H-tetrazol-5-yl)methyl)-1-(2-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)acetyl)-4-phenylpyrrolidine-2-carboxamide; (2S,4S)—N-((2H-tetrazol-5-yl)methyl)-4-cyclohexyl-1-(2-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)acetyl)pyrrolidine-2-carboxamide; 3-{[(1S,2S)-1-({2-[(2S,4S)-4-cyclohexyl-2-[(2H-1,2,3,4-tetrazol-5-ylmethyl)carbamoyl]pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)-2-methylbutyl]carbamoyl}propanoic acid; 5-(((2S,3S)-1-((2-(2S,4S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-cyclohexylpyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-5-oxopentanoic acid; 4-(((S)-2-((2-((2S,4S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-cyclohexylpyrrolidin-1-yl)-2-oxoethyl)amino)-1-cyclopentyl-2-oxoethyl)amino)-4-oxobutanoic acid; 4-(((S)-1-((2((2S,4S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-cyclohexylpyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2-((2S,4S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2-((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((3R,5S)-5-(((2H-tetrazol-5-yl)methyl)carbamoyl)-1-(2-((2S,3S)-2-(3-carboxypropanamido)-3-methylpentanamido)acetyl)pyrrolidin-3-yl)oxy)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2-((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-acetoxypyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3 S)-1-((2((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-((3-aminopropanoyl)oxy)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid hydrochloride; 4-(((2S,3S)-1-((2((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-phenoxypyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-(phenylthio)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2((2S,4S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-phenoxypyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2((2S,4S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-(phenylthio)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-(phenylsulfinyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2-((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-(phenylsulfonyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; (2S,4R)—N-((2H-tetrazol-5-yl)methyl)-4-(4-fluorobenzyl)-1-(2-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)acetyl)pyrrolidine-2-carboxamide; 4-(((2S,3S)-1-((2((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-(2-phenylacetoxy)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-(benzoyloxy)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-(((2S,3S)-1-((2((2S,4R)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)-4-((3,3-dimethylbutanoyl)oxy)pyrrolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid; (2S,5R)—N-((2H-tetrazol-5-yl)methyl)-1-(2-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)acetyl)-5-phenylpyrrolidine-2-carboxamide; and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof.