Pyrazine derivatives

摘要

The invention relates to a compound of formula (I);
wherein R1 to R4 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament. In particular, the compound may be used as a preferential agonist of Cannabinoid Receptor 2.

主权项

1. A compound, selected from the group consisting of:
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide; 6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (cyano-dimethyl-methyl)-amide; 6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid [1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclobutyl]-amide; 6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 5-Azetidin-1-yl-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide; 6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid piperidin-1-ylamide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclobutyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-hydroxy-1,1-dimethyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclobutyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclobutyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-1-methyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid piperidin-1-ylamide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-2,2-dimethyl-propyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-cyclopropyl-2-hydroxy-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide; (S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-methylcarbamoyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-3-methyl-1-methylcarbamoyl-butyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide; 2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-methylcarbamoyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-3-methyl-1-methylcarbamoyl-butyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide; (S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-propionic acid methyl ester; (S)-3-Cyclopropyl-2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl ester; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(S)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(R)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(R)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide; (S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-pyridin-2-yl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(R)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-1-phenyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-3-methyl-1-(2,2,2-trifluoro-ethylcarbamoyl)-butyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-carbamoyl-(4-chloro-phenyl)-methyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (4-hydroxy-1,1-dimethyl-butyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1,1-dimethyl-3-pyridin-4-yl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1,1-dimethyl-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1,1-dimethyl-3-pyridin-4-yl-butyl)-amide; 1-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-cyclobutanecarboxylic acid methyl ester; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoylmethyl-2-methyl-propyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoylmethyl-2-methyl-propyl)-amide; (+)-6-Cyclopropylrnethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; (−)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 2-Cyclopropyl-2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl ester; (+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((1R,2S)-rel-2-carbamoyl-cyclohexyl)-amide; (−)-5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl)-amide; (+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl)-amide; 5-Cyclopropyl-6-cyclopropylinethoxy-pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide; (+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; (−)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl[1,2,4]oxadiazol-3-yl)-ethyl]amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-carbamoyl-2-methyl-propyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-carbamoyl-cyclohexyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (5-chloro-thiophen-2-yl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-methoxy-1,1-dimethyl-propyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbarnoyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbarnoyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (3-methoxy-1,1-dimethyl-propyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl)-amide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-carbamoyl-1,1-dimethyl-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-carbamoyl-1,1-dimethyl-ethyl)-amide; (S)-2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-4-methyl-pentanoic acid methyl ester; and 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1,1-dimethyl-3-phenyl-propyl)-amide.