| 摘要 |
The instant invention relates to a novel compound representing a substituted phosphoramidic acid—a (2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl aryl phosphoramidate of formula 1 or a (S)-(2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl aryl phosphoramidate of formula 2, or a pharmaceutically acceptable salt, a hydrate, a crystalline form or a stereoisomer thereof, as defined in the specification.;The novel compound is used for a pharmaceutical composition with at least one pharmaceutically acceptable excipient as well as with an inosine 5 monophosphate dehydrogenase inhibitor, HCV protease NS3 inhibitor, HCV protease NS3/4A inhibitor, and RNA polymerase NS5A inhibitor. The novel compound is useful as a viral polymerase HCV NS5B inhibitor and can be used for treating a disease caused by hepatitis C virus (HCV). |
| 主权项 |
1. A compound selected from a (2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl aryl phosphoramidate of formula 1 or a (5)-(2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl aryl phosphoramidate of formula 2, or a pharmaceutically acceptable salt, a hydrate, a crystalline form or a stereoisomer thereof, wherein: R1 is (i) hydrogen, (CH3)2[(CH3)3C]Si, a C2-C6acyl, optionally substituted with NR5R6 group, wherein R5 and R6 are independently hydrogen or a C1-C4 alkyl; or (ii) 1-pyrrole-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl; R2 and R3 are F; or R3 is CH3 and R2 is F or OH; R4 is hydrogen or methyl; Ar is a phenyl, a pyridyl or a naphthyl, wherein phenyl, pyridyl or naphthyl are optionally substituted with at least one of C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, F, Cl, Br, I, nitro, cyano, or —N(C1-3 alkyl)2; Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4-(4-amino-2-oxo-2H-pyrimidin-1-yl), in which amino group is optionally substituted with 1-pyrrole-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or radical C(O)R8, wherein R8 is (i) a C1-C4alkyl, optionally substituted with NR6R7 group, wherein R6 and R7 are independently hydrogen or C1-C4 alkyl; or (ii) a C1-3 alkoxy optionally substituted with a phenyl; X is O or N—R9, wherein R9 is a C1-C4alkyl, optionally substituted with OH or OCH3; n=1, 2 or 3. |
