Substituted triazine compound
An object of the present invention is to provide a pharmaceutical composition, particularly a compound suitable for preventing and/or treating an inflammatory disease and/or a neurodegenerative disease. The present inventors accomplished the present invention by conducting intensive studies to find a compound having an inhibitory effect on NLRP3 inflammasome activation, with the result that a substituted triazine compound is found to have the inhibitory effect on NLRP3 inflammasome activation. The substituted triazine compound of the present invention is expected to serve as a preventive and/or therapeutic drug for an inflammatory disease and/or a neurodegenerative disease.
1 . A compound of formula (I) or a salt thereof
wherein,
R 1 are the same or different from each other, and are C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, halogen, —O—C 1-6 alkyl, —O-halogeno-C 1-6 alkyl or cyano,
R 2 is C 1-6 alkyl, C 3-8 cycloalkyl, halogeno-C 1-6 alkyl, —O—C 1-6 alkyl, —N(C 1-6 alkyl) 2 or aryl,
R 3 is H or C 1-6 alkyl,
R 4 is C 1-6 alkyl substituted with the same or different one to four R 5 , —C 1-6 alkylene-(aryl optionally substituted with the same or different one to four R 6 ), —C 1-6 alkylene-(C 3-8 cycloalkyl optionally substituted with the same or different one to four R 7 ), —C 1-6 alkylene-(heteroaryl optionally substituted with the same or different one to four R 8 ), —C 1-6 alkylene-(4 to 7-membered saturated heterocyclyl optionally substituted with the same or different one to four R 9 ), C 3-8 cycloalkyl optionally substituted with the same or different one to four R 10 , heteroaryl optionally substituted with the same or different one to four R 11 , or a 4 to 7-membered saturated heterocyclyl optionally substituted with the same or different one to four R 12 ,
R 5 is —OR 13 , —NR 14 R 15 , halogen or cyano,
R 6 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen or cyano,
R 7 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen or cyano,
R 8 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen or cyano,
R 9 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen, cyano, oxo, —C(O)—C 1-6 alkyl or —S(O) 2 —C 1-6 alkyl,
R 10 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen or cyano,
R 11 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen or cyano,
R 12 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen, cyano, oxo, —C(O)—C 1-6 alkyl or —S(O) 2 —C 1-6 alkyl,
R 13 is H or C 1-6 alkyl,
R 14 and R 15 are the same or different from each other, and are H, C 1-6 alkyl or —C(O)—C 1-6 alkyl, and
n is an integer of 1 to 4, which represents the number of R 1 substituents.
2 . The compound or a salt thereof according to claim 1 , wherein the formula (I) is formula (Ia):
wherein,
R 1a is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, halogen, —O—C 1-6 alkyl, —O-halogeno-C 1-6 alkyl or cyano,
R 1b are the same or different from each other, and are C 1-6 alkyl, halogeno-C 1-6 alkyl or halogen,
R 2 is C 1-6 alkyl, C 3-8 cycloalkyl, halogeno-C 1-6 alkyl, —N(C 1-6 alkyl) 2 or aryl,
R 3 is H,
R 4 is C 1-6 alkyl substituted with the same or different one to four R 5 , —C 1-6 alkylene-(aryl optionally substituted with the same or different one to four R 6 ), —C 1-6 alkylene-(C 3-8 cycloalkyl optionally substituted with the same or different one to four R 7 ), —C 1-6 alkylene-heteroaryl, —C 1-6 alkylene-(4 to 7-membered saturated heterocyclyl optionally substituted with the same or different one to four R 9 ), C 3-8 cycloalkyl optionally substituted with the same or different one to four R 10 , heteroaryl or 4 to 7-membered saturated heterocyclyl optionally substituted with the same or different one to four R 12 ,
R 5 is —OR 13 , —NR 14 R 15 , halogen or cyano,
R 6 is —OR 13 ,
R 7 is —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 or —C 1-6 alkylene-NR 14 R 15 ,
R 9 is —C(O)—C 1-6 alkyl,
R 10 is C 1-6 alkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen or cyano,
R 12 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, —OR 13 , —NR 14 R 15 , —C 1-6 alkylene-OR 13 , —C 1-6 alkylene-NR 14 R 15 , halogen, cyano, oxo, —C(O)—C 1-6 alkyl or —S(O) 2 —C 1-6 alkyl,
R 13 is H or C 1-6 alkyl,
R 14 and R 15 are the same or different from each other, and are H, C 1-6 alkyl or —C(O)—C 1-6 alkyl, and
k is 0 or 1, which represents the number of R 1b substituents.
3 . The compound or a salt thereof according to claim 2 , wherein
R 1a is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 3-8 cycloalkyl, halogen, —O—C 1-6 alkyl or —O-halogeno-C 1-6 alkyl,
R 2 is C 1-6 alkyl or C 3-8 cycloalkyl,
R 4 is —C 1-6 alkylene-(C 3-8 cycloalkyl optionally substituted with the same or different one to four R 7 ), —C 1-6 alkylene-(4 to 7-membered saturated heterocyclyl optionally substituted with the same or different one to four R 9 ), C 3-8 cycloalkyl optionally substituted with the same or different one to four R 10 , or a 4 to 7-membered saturated heterocyclyl optionally substituted with the same or different one to four R 12 , and
k represents 0.
4 . The compound or a salt thereof according to claim 1 , wherein the compound is selected from the group consisting of
2-(3-{[(1R,2R)-2-hydroxycyclohexyl] amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy) phenol,
(3S,4R)-4-{[6-(4-chloro-2-hydroxyphenyl)-5-methyl-1,2,4-triazin-3-yl]amino}oxan-3-ol,
2-(5-cyclopropyl-3-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl) phenol,
2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol,
2-(3-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl) phenol,
2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl) phenol,
5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl) phenol,
2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl) phenol, and
2-[5-methyl-3-({[(2R)-morpholin-2-yl]methyl}amino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol.
5 . A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.
6 . The compound or a salt thereof according to claim 1 , wherein R 2 is C 1-6 alkyl.
7 . The compound or a salt thereof according to claim 1 , wherein R 4 is 4 to 7-membered saturated heterocyclyl optionally substituted with the same or different one to two R 12 .
8 . The compound or a salt thereof according to claim 7 , wherein R 4 is 4 to 7-membered saturated heterocyclyl optionally substituted with one R 12 .