Nova Patents
IL217228A

Nucleoside phosphoramidate prodrugs of 2'-deoxy-2'-fluoro-2'-c-methyluridine

Abstract

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Term

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27 claims: 2 independent, 25 dependent

  1. 1
    217228/3 Claims 1. A compound or its stereoisomer thereof selected from among (S)-2-{[(2R,3R,4R55R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -propionic acid methyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -3-methyl-butyric acid methyl ester;(S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyric acid methyl ester;(S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid methyl ester;(S)-2-{[(2R,3R,4R>5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -propionic acid ethyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -(naphthalen-1 -yloxy)-phosphorylamino}-propionic acid benzyl ester;{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-acetic acid methyl ester;(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid methyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -(naphthalen-1 -yloxy)-phosphorylamino}-propionic acid methyl ester;(S)-l-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryl}-pyrrolidine-2-carboxylic acid methyl ester;(S)-2- {[(2R,3R,4R,5R)-5 -(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -propionic acid butyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid benzyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino}-propionic acid methyl ester;(S)-2 - { (4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5 -(2,4-dioxo-3,4-dihydro-2H- pyrimidin-1 -yl)-4-fluoro-3 -hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] - phosphorylamino}-propionic acid methyl ester;698 217228/3 (S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R>5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino} -propionic acid methyl ester;(S)-2-{[(2R,3R,4R55R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -propionic acid sec-butyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino}-propionic acid butyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino}-propionic acid ethyl ester;(S)-2 - {[(2R,3R,4R,5R)-5 -(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino}-propionic acid isopropyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino}-propionic acid benzyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino}-propionic acid isopropyl ester;(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid benzyl ester;(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid butyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -p-tolyloxy-phosphorylamino } -propionic acid isopropyl ester;(S)-2- {[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3 -hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino}-propionic acid butyl ester;(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4Rj5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid ethyl ester;(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid isopropyl ester;(S)-2-{[(2R,3R,4R>5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino}-propionic acid benzyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3- hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid pentyl ester;699 217228/3 (S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3 -hydroxy-4-methy l-tetrahydro-iuran-2-y lmethoxy] -phosphorylamino}-propionic acid isopropyl ester;(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid butyl ester;(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid ethyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionic acid butyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo- 3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionic acid benzyl ester;(S)-2- {[(2R,3R,4R,5R)-5 -(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyric acid methyl ester;(S)-2- {[(2R,3R,4R,5R)-5 -(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid 4-fluoro-benzyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid 3-methyl-butyl ester;(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid ethyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid cyclohexyl ester;(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid butyl ester;(S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionic acid isopropyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino}-propionic acid cyclohexyl ester;(S)-2-{[(2R,3R,4R>5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-bromo-phenoxy)-phosphorylamino} -propionic acid cyclohexyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3- hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyric acid isopropyl ester;700 217228/3 (S)-2-{[(2R,3R,4R>5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyric acid cyclohexyl ester;(S)-2-{[(2R,3R,4R;5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino}-butyric acid cyclohexyl ester;(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4 R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-butyric acid isopropyl ester;(S)-2- {[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid 2,2-difluoro-ethyl ester;(S)-2- {[(2R,3R,4R,5R)-5 -(2,4-Dioxo- 3,4-dihydro-2H-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid 2,2,2-trifluoro-l-trifluoromethyl-ethyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -propionic acid 2-fluoro-1 -fluoromethyl-ethyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo- 3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid cyclopropyl methyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -butyric acid cyclopentyl ester;(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H -pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(3,4-dichloro-phenoxy)-phosphorylamino}-propionic acid benzyl ester;and (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino } -propionic acid 2-fluoro-ethyl ester.
  2. 4
    A compound selected from among (S)-methyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;(S)-methyl 2-(((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;methyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)acetate;methyl 2-(((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)acetate;(S)-isopropyl 2-(((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;(S)-isopropyl 2-(((S)-(4-chlorophenoxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoate;(S)-isopropyl 2-(((R)-(4-chlorophenoxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3 -hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoate;(S)-cyclohexyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;(S)-cyclohexyl 2-(((R)-(((2R,3R,4R>5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;(S)-cyclohexyl 2-(((S)-(((2R,3R,4R>5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(4-fluorophenoxy)phosphoryl)amino)propanoate;and (S)-cyclohexyl 2-(((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(4-fluorophenoxy)phosphoryl)amino)propanoate.
Independent claims2