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US 2014/0369959 A1Published application
4'-azido, 3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication
AssigneeHoffmann-La Roche Inc.
InventorsMark Smith, Francisco Xavier Talamas, Jing Zhang, Zhuming Zhang
Life of this patent
Estimating the term…
Abstract
The present invention relates to the use of nucleoside derivatives of formula (I) wherein the symbols are as the specification, and of pharmaceutically acceptable salts thereof and to pharmaceutical compositions containing such compounds.
Claims74
A compound Formula I
- wherein:
- R1 is H, lower haloalkyl, or aryl, wherein aryl is phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halo, lower haloalkyl, —N(R1a)2, acylamino, —SO2N(R1a)2, —COR1b, —SO2(R1c), —NHSO2(R1c), nitro or cyano;
- each R1a is independently H or lower alkyl;
- each R1b is independently —OR1a or —N(R1a)2;
- each R1c is lower alkyl;
- R2a and R2b are (i) independently H, lower alkyl, —(CH2)rN(R1a)2, lower hydroxyalkyl, —CH2SH, —(CH2)S(O)pMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-indol-4-yl)methyl, —(CH2)mC(═O)R1b, aryl and aryl lower alkyl, wherein aryl may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano;
- (ii) R2a is H and R2b and R4 together form (CH2)3;
- (iii) R2a and R2b together form (CH2)n;
- or, (iv) R2a and R2b both are lower alkyl;
- R3 is H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl;
- R4 is H, lower alkyl, or R2b and R4 together form (CH2)3;
- R5 is H, C(═O)R1c, C(═O)R1b, P(═O)(OR1)(OR1a), or P(═O)(OR1)(NR4R7);
- R6 is
- m is 0 to 3;
- n is 4 or 5;
- p is 0 to 2;
- and
- r is 1 to 6;
- or a pharmacologically acceptable salt thereof.
16 more elements
A compound selected from the group consisting of:
- (S)-2-{[(2R,3S,4S,5R)-2-Azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester;
- (S)-2-{[(2R,3S,4S,5R)-2-Azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid ethyl ester;
- (S)-2-[[(2R,3S,4S,5R)-2-Azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid ethyl ester;
- (S)-2-[[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester;
- (S)-2-[[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid benzyl ester;
- (S)-2-[[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid ethyl ester;
- (S)-2-{[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester;
- (S)-2-{[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-hydroxy-phosphorylamino}-propionic acid isopropyl ester;
- and
- (S)-2-[[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-propionyloxy-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester.
7 more elements
16-20. (canceled)
Dependencies are inferred from the claim text.