(6S,9aS)-N-Benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-(methyl)-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound
AssigneesEisai R&D Management Co., Ltd., PRISM Pharma Co., Ltd.
InventorsSatoshi Inoue, Yuji Yamamoto, Kentaro Iso
Life of this patent
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Abstract
A compound represented by formula (1) or pharmaceutically acceptable salt thereof: wherein R1 is a C1-6 alkyl group; R2 and R3 are the same or different from each other and each is a hydrogen atom or a C1-6 alkyl group; X2, X3 and X4 are the same or different from each other and each is a hydrogen atom or a halogen atom; and X5 is a hydrogen atom or —P(═O)(OH)2 has a Wnt Pathway modulating activity.
Claims17
A compound represented by formula (1) or pharmaceutically acceptable salt thereof:
- wherein R1 is a C1-6 alkyl group;
- R2 and R3 are the same or different from each other and each is a hydrogen atom or a C1-6 alkyl group;
- X2, X3 and X4 are the same or different from each other and each is a hydrogen atom or a halogen atom;
- and X5 is a hydrogen atom or —P(═O)(OH)2.
A compound or pharmaceutically acceptable salt thereof selected from:
- (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-((3-((3S)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3R)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((5-fluoro-6-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-8-((6-(3-(4-(propan-2-yl)piperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((5-fluoro-6-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-8-((6-(3-(4-(propan-2-yl)piperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-8-((6-(3-(4-(propan-2-yl)piperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3S)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3S)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-3-((3R)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3S)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3R)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3S)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3R)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3R)-3,4-dimethylpiperazin-1-yl)azetidine-1-yl)-5-fluoropyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- 4-(((6S,9aS)-1-(benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)-3-fluorophenyl dihydrogen phosphate, and,
- 4-(((6S,9aS)-1-(benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate.
A compound or pharmaceutically acceptable salt thereof selected from:
- (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3S)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3R)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((5-fluoro-6-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-8-((6-(3-(4-(propan-2-yl)piperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3S)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-(3-((3S)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-8-((6-3-((3R)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3S)-4-ethyl-3-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
- 4-(((6S,9aS)-1-(benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)-3-fluorophenyl dihydrogen phosphate, and
- 4-(((6S,9aS)-1-(benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate.
(6S,9aS)-N-Benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide or a pharmaceutically acceptable salt thereof:
(6S,9aS)-N-Benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide or a pharmaceutically acceptable salt thereof:
(6S,9aS)-N-Benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide or a pharmaceutically acceptable salt thereof:
(6S,9aS)-N-Benzyl-8-((6-(3-((3S)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide or a pharmaceutically acceptable salt thereof:
(6S,9aS)-N-Benzyl-8-((6-(3-((3R)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en 1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide or a pharmaceutically acceptable salt thereof:
(6S,9aS)-N-Benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide or a pharmaceutically acceptable salt thereof:
4-(((6S,9aS)-1-(Benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)-3-fluorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof:
4-(((6S,9aS)-1-(Benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof:
Dependencies are inferred from the claim text.