WO2016015638A1 - 丙型肝炎病毒抑制剂及其应用 - Google Patents

丙型肝炎病毒抑制剂及其应用 Download PDF

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WO2016015638A1
WO2016015638A1 PCT/CN2015/085380 CN2015085380W WO2016015638A1 WO 2016015638 A1 WO2016015638 A1 WO 2016015638A1 CN 2015085380 W CN2015085380 W CN 2015085380W WO 2016015638 A1 WO2016015638 A1 WO 2016015638A1
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group
alkyl
amino
acyl
hydroxy
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PCT/CN2015/085380
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English (en)
French (fr)
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王勇
赵立文
张先
毕胜
高毅平
陈宏雁
王德忠
南阳
张仓
李玉秀
张迪
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南京圣和药业股份有限公司
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Publication of WO2016015638A1 publication Critical patent/WO2016015638A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides

Definitions

  • the invention belongs to the field of medical chemistry, and particularly relates to a compound having a good hepatitis C virus inhibitory effect, a preparation method thereof, a composition containing the same, and the compound or composition as a therapeutic drug for hepatitis C virus infectious diseases. the use of.
  • Hepatitis C virus (HCV) infection is a worldwide disease. The number of chronically infected people worldwide has exceeded 200 million, and the infection rate in China is 3.2%, ranking the top three in the world.
  • the clinical manifestations of hepatitis C virus infection are diverse, ranging from inflammation to cirrhosis and liver cancer.
  • Chronic hepatitis C can also be associated with certain extrahepatic manifestations, including rheumatoid arthritis, dry conjunctival keratitis, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and delayed onset Skin porphyria, etc., may be caused by abnormal immune response in the body.
  • Hepatitis C cirrhosis decompensation there may be various complications, such as ascites abdominal infection, upper gastrointestinal bleeding, hepatic encephalopathy, liver and kidney syndrome, liver failure and other performance.
  • HCV belongs to the Flaviviridae virus, which is similar in gene structure to the other two genera of the Flaviviridae, the genus Pestivirus and Flavivirus.
  • standard methods of treating HCV infection are interferon and a combination of interferon and ribavirin.
  • interferons had significant side effects such as pan-like symptoms, weight loss, and fatigue, while interferon and ribavirin combination therapy produced considerable Side effects, including hemolysis, anemia, and fatigue.
  • drugs developed for the treatment of HCV infection include protease inhibitors, thiazolidine derivatives, thiazolidine and n-benzoanilide, phenanthrenequinone, helicase inhibitor, nucleoside polymerase inhibitor and colloidal Toxins, antisense phosphorothioate oligonucleotides, inhibitors of IRES-dependent translation, ribozymes, and nucleoside analogs, and the like.
  • nucleoside phosphate compounds for the treatment of Flaviviridae viruses, especially HCV infections, is an important research and development direction in the field.
  • WO 2006/065335 discloses a fluorinated pyrrolo[2,3,d]pyrimidine nucleoside compound which inhibits HCV virus.
  • US 2006/0241064 discloses nucleoside compounds for the treatment of viral infections caused by Flaviviridae family viruses such as HCV.
  • WO 2008/121634 discloses nucleoside phosphoramidate compounds for use in the treatment of viral infections in mammals.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof.
  • a further object of the present invention is to provide a composition comprising a compound of the formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline and pharmaceutically acceptable carrier thereof, and A compound of the formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate thereof or a combination of crystals and another antiviral agent.
  • a further object of the present invention is to provide a compound of the formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystallization thereof, and a method for the treatment and/or prevention of hepatitis C virus infection and Use of a compound of formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, for the manufacture of a medicament for the treatment and/or prevention of a viral infection.
  • the present invention provides the following technical solutions:
  • the invention provides a compound of Formula I, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof:
  • R 1 is selected from the group consisting of H, alkyl and haloalkyl
  • R 2 is selected from the group consisting of H and halogen
  • R 3 is selected from the group consisting of H, OH, and alkoxy
  • R 4 is selected from the group consisting of H and alkyl, wherein the alkyl group is optionally selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halogen, hydroxy, amino, nitro, cyano Substituting one or more groups of an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a sulfonyl group, a sulfinyl group, a fluorenyl group, an aryl group, and a heteroaryl group;
  • R 5 is selected from the group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally selected from alkyl, cycloalkyl, heterocycle Alkyl, alkoxy, alkylamino, halogen, hydroxy, amino, nitro, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl, sulfinyl, decyl, aryl and heteroaryl Substituted by one or more groups;
  • Cy 1 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are optionally selected from the group consisting of halogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, Substituting one or more groups of an alkylamino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a nitro group, a cyano group;
  • Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from halogen, Hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, nitrate Substituting one or more groups in the cyano group;
  • Cy 1 is an aryl group
  • Cy 2 is not hydrogen or an aryl group
  • the compound of the formula I of the present invention is not the following compound:
  • R 1 is selected from H, C 1-6 alkyl, halo C 1-6 alkyl, R 2 is selected from H, fluoro, chloro, bromo, and R 3 is selected from H, OH.
  • R 1 is selected from H, C 1-3 alkyl
  • R 2 is selected from fluoro, chloro
  • R 3 is selected from H, OH.
  • R 4 is selected from H, C 1-6 alkyl
  • R 5 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, wherein said alkyl and cycloalkyl Optionally selected from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl Substituting one or more groups of a sulfinyl group, a fluorenyl group, an aryl group, and a heteroaryl group.
  • R 4 is selected from H, C 1-3 alkyl
  • R 5 is selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein said alkyl and naphthenic
  • the group may be selected from a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 3-8 heterocycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, a halogen, a hydroxyl group, an amino group.
  • R 4 is selected from H, C 1-3 alkyl
  • R 5 is selected from C 1-3 alkyl and C 3-6 cycloalkyl, wherein said alkyl and naphthenic
  • the group may be selected from C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, halogen, hydroxy, amino Substituting one or more groups of nitro, cyano, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, sulfonyl, sulfinyl, decyl, phenyl and heteroaryl .
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring, heteroaryl group, heterocycloalkyl group, and hetero
  • the cycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1 Substituting one or more groups of the -6 alkylamino acyl group, the nitro group, and the cyano group.
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a heteroaryl group, a C 3-8 heterocycloalkyl group, and a C 3-8 heterocycloalkenyl group, wherein the benzene ring is hetero
  • the aryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, Halogen C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, amino, C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 Substituting one or more groups of an alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a nitro group, and a
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a heteroaryl group, a C 3-6 heterocycloalkyl group, and a C 3-6 heterocycloalkenyl group, wherein the benzene ring is hetero
  • the aryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, Halogen C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, amino, C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 Substituting one or more groups of an alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a nitro group, and a
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from a five- or six-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having at least one N atom
  • the benzene is The cyclo, 5- or 6-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkane Substituting one or more groups of a acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamin
  • Cy 1 is selected from the group consisting of benzene rings
  • Cy 2 is selected from 5- or 6-membered heteroaryl, heterocycloalkyl, and heterocycloalkenyl groups having 1-3 N atoms
  • a benzene ring, a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkyne , C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-
  • One or more groups of 6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano are substituted.
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from a five- or six-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having only one S atom
  • the phenyl ring, five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 Substituting one or more groups of an alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a six-membered heteroaryl group having 1 N atom, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring and the heterocyclic group are Or a heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkane Substituting one or more groups of a acyl group, an amino acyl group, a C 1-6 alkylamino acyl group,
  • Cy 1 is selected from the group consisting of benzene rings
  • Cy 2 is selected from the group consisting of a five-membered heteroaryl group having only one S atom, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring
  • the heteroaryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1- Substituting one or more groups of a 6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a nitro
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a 5-membered heteroaryl group having 2 N atoms, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring is hetero
  • the aryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, Halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 Substituting one or more groups of an alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a nitro
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a five-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having one N atom and one sulfur atom
  • a benzene ring, a heteroaryl group, a heterocycloalkyl group or a heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino Substituting one or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a five-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having one N atom and one oxygen atom
  • a benzene ring, a heteroaryl group, a heterocycloalkyl group or a heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino Substituting one or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, and an isoxazole.
  • Cy 1 is selected from the group consisting of a benzene ring
  • Cy 2 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, and an isoxazole.
  • the inventors of the present invention unexpectedly found that the compound of the present invention has very excellent antiviral activity when Cy 2 in the formula I is in the para or meta position of Cy 1 .
  • Cy 1 is selected from the group consisting of naphthalene rings, heteroaryl groups
  • Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein the naphthalene ring
  • the aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, Substituting one or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a nitro group, and a
  • Cy 1 is selected from the group consisting of naphthalene rings, heteroaryl groups
  • Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, C 3-8 heterocycloalkyl, and C 3-8 heterocycloalkenyl.
  • naphthalene ring, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2 - 4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C Substituting one or more groups of 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano.
  • Cy 1 is selected from the group consisting of naphthalene rings, heteroaryl groups
  • Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, C 3-6 heterocycloalkyl, and C 3-6 heterocycloalkenyl.
  • naphthalene ring, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-6 cycloalkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, amino, C 1-3 alkylamino, C Substituting one or more groups of 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, nitro, cyano.
  • Cy 1 is selected from a five- or six-membered heterocyclic ring containing at least one N atom, wherein the five- or six-membered heterocyclic ring having at least one N atom is optionally Selected from halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano One or more groups are substituted and Cy 2 is hydrogen.
  • Cy 1 is selected from a five- or six-membered heterocyclic ring containing only one S atom of benzene, wherein the five- or six-membered heterocyclic ring in which the benzene contains only one S atom is optionally Selected from halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano One or more groups are substituted and Cy 2 is hydrogen.
  • Cy 1 is selected from a benzene 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein the benzo five or six member contains 1, 2 or 3
  • the heteroaryl ring of the nitrogen atom is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkane Oxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino
  • Cy 2 is hydrogen.
  • Cy 1 is selected from the group consisting of a benzo-5-membered heteroaryl ring containing 1 or 2 nitrogen atoms, wherein the benzo-5-membered heteroaryl ring having 1 or 2 nitrogen atoms is optionally Selected from halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano One or more groups are substituted and Cy 2 is hydrogen.
  • Cy 1 is selected from the group consisting of a benzo-5-membered heteroaryl ring containing 1 nitrogen atom and 1 oxygen atom, wherein the benzoquinone contains 1 nitrogen atom and 1 oxygen atom.
  • the heteroaryl ring is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitrate One or more groups in the cyano group are substituted, and Cy 2 is hydrogen.
  • Cy 1 is selected from the group consisting of a five-membered heteroaryl ring containing only one S atom, wherein the five-membered heteroaryl ring containing only one S atom of the benzene is optionally selected from Halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy
  • Cy 1 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a triazole ring, Thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzoazepine ring, benzoxane ring, benzothiazepine, benzodiazepine, benzene And a dioxane, a benzodithioheterocycle, a benzoxazepine, a benzothiazepine, and the Cy 2 is selected from the group consisting of hydrogen, a benzene ring, a furan
  • Cy 1 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a triazole ring, Thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzofuran ring, benzopyrrole ring, benzothiophene ring, benzimidazole ring, benzopyrazole ring, a benzothiazole ring, a benzisothiazole ring, a benzoxazole ring, a benzisoxazole ring, a benzotriazole ring, a benzothiadiazole ring
  • the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof:
  • R a1 is selected from the group consisting of heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, alkyl, alkenyl Alkyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylacyl, alkoxyacyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, decyl, nitro Substituting one or more groups in the cyano group;
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkyl acyl, alkoxyacyl, aminoacyl, alkylaminoacyl, sulfonate Acyl, sulfinyl, decyl, nitro and cyano; or
  • R a1 , R a2 together with the carbon atom to which they are attached constitute a heteroaryl, heterocycloalkyl or heterocycloalkenyl group;
  • R a3 , R a4 , R a5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkyl acyl, alkoxy acyl, Aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, decyl, nitro, cyano;
  • R 1 , R 2 , R 3 , R 4 and R 5 have the definitions in the formula I.
  • the compound of formula Ia according to the present invention or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, in which R 1 is selected from H, C 1-6 alkyl And halogenated C 1-6 alkyl, preferably selected from H and C 1-3 alkyl; R 2 is selected from H, fluorine, chlorine and bromine, preferably selected from fluorine and chlorine; R 3 is selected from H and OH; 4 is selected from the group consisting of H and C 1-6 alkyl, wherein the alkyl group is optionally selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 Alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, nitro, cyano, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, Substituting one or more
  • the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from C 4-8 heteroaryl And a C 4-8 heterocycloalkyl group and a C 4-8 heterocycloalkenyl group, wherein said heteroaryl group, heterocycloalkyl group and heterocycloalkenyl group are optionally selected from the group consisting of halogen, hydroxy, amino, C 1- 6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Oxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, dec
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 , R a2 together with the carbon atom to which they are attached constitute a C 4-8 heteroaryl group, a C 4-8 heterocycloalkyl group or a C 4-8 heterocycloalkenyl group.
  • the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from at least one N atom five- or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl group optionally substituted selected from halogen, hydroxy, amino, C 1- 6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Oxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro,
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 , R a2 together with the carbon atom to which they are attached constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing at least one N atom.
  • the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from 1-3 N a five- or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group of the atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogen C 1- 6 alkoxy, C 1-6 alkyla
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 , R a2 together with the carbon atom to which they are attached constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group having from 1 to 3 N atoms.
  • the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of only one S atom five- or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl group optionally substituted selected from halogen, hydroxy, amino, C 1- 6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Oxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 , R a2 together with the carbon atom to which they are attached constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing only one S atom.
  • the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of one N atom a heteroaryl, heterocycloalkyl and heterocycloalkenyl group, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro, cyano Sub
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano.
  • the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 , R a2 and the carbon to which they are attached
  • the atoms together constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing one N atom, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from Halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, Sub
  • the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of 2 N atoms a five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl,
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 and R a2 together with the carbon atom to which they are attached constitute a five-membered heteroaryl group, heterocycloalkyl group or heterocycloalkenyl group having two N atoms.
  • the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of 1 N atom and a five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group of one sulfur atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogen C 1- 6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 and R a2 together with the carbon atom to which they are attached constitute a five-membered heteroaryl group, heterocycloalkyl group or heterocycloalkenyl group containing one N atom and one sulfur atom.
  • the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of 1 N atom and a five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group of one oxygen atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogen C 1- 6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 and R a2 together with the carbon atom to which they are attached constitute a five-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group having one N atom and one oxygen atom.
  • the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from only one S atom Five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkane , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro, cyano
  • R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
  • R a1 and R a2 together with the carbon atom to which they are bonded constitute a five-membered heteroaryl group, heterocycloalkyl group or heterocycloalkenyl group having only one S atom.
  • the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H, methyl, ethyl, N-propyl or isopropyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl Base, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl or benzyl, R a1 is selected from furan ring, pyrrole ring , thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring,
  • the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H or methyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, positive Butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl or benzyl, R a1 is selected from furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, Thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring,
  • the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H, methyl, ethyl, N-propyl or isopropyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or benzyl, R a1 , R a2 together with the carbon atom to which they are attached constitute a benzodiazepine, benzo Oxyheterocyclic ring, benzothiazepine, benzodiazepine, benzodioxane, benzodithioheterocycle,
  • the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H, methyl, ethyl, N-propyl or isopropyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or benzyl, R a1 , R a2 together with the carbon atom to which they are attached constitute a benzofuran ring, benzopyrrole Ring, benzothiophene ring, benzimidazole ring, benzopyrazole ring, benzothiazole ring, benzisothiazo
  • the compound of formula Ia of the invention is not the following:
  • the present invention provides the following specific compounds:
  • the invention provides a process for the preparation of a compound of formula I according to the invention, which process comprises the steps of:
  • R 1 , R 2 , R 3 , R 4 , R 5 , Cy 1 , Cy 2 are as defined in the above formula I.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I or Ia of the present invention.
  • the invention provides a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the invention and comprises a compound, stereoisomer, pharmaceutically acceptable salt of the invention A hydrate, solvate or crystalline pharmaceutical composition for treating and/or preventing a liver disease caused by a hepatitis C virus.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula I or Ia, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal, and further comprising a composition selected from the group consisting of One or more additional anti-HCV therapeutics: HCV NS3 protease inhibitor, HCV NS5B RNA-dependent RNA polymerase inhibitor, nucleoside analog, interferon alpha, pegylated interferon, ribavi Lin, L-Weiline, Veramididine, TLR7 agonist, TLR9 agonist, cyclophilin inhibitor, alpha glucosidase inhibitor, NS5A inhibitor and NS3 helicase inhibitor.
  • HCV NS3 protease inhibitor HCV NS5B RNA-dependent RNA polymerase inhibitor
  • nucleoside analog nucleoside analog, interferon alpha, pegylated interferon, ribavi Lin, L-Wei
  • the compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I and Ia of the present invention may be prepared by mixing with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical preparation suitable for oral or parenteral administration suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, such as by infusion or bolus injection, by absorption through the epithelium or skin mucosa (eg, oral mucosa or rectum, etc.) Apply. Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
  • the present invention provides a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I and Ia of the present invention or a pharmaceutical composition of the present invention for treating a Flaviviridae virus
  • a method of infecting a subject comprising administering to the subject a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of formula I and Ia or comprising formula I and Ia
  • a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline pharmaceutical composition is administered in an amount effective to reduce the viral load of the virus in the subject.
  • the invention provides a method for the treatment and/or prevention of an RNA virus, such as a Flaviviridae viral infection, comprising administering to a subject in need of such treatment a compound of the invention, a stereoisomer thereof, pharmaceutically acceptable a salt, hydrate, solvate or crystal or a pharmaceutical composition thereof.
  • the invention provides a method of inhibiting an RNA virus, such as a Flaviviridae virus infection, comprising hydrating the virus with a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, The substance, solvate or crystal or a pharmaceutical composition thereof is contacted.
  • Flaviviridae virus refers to any virus of the Flaviviridae family, including those that infect humans and non-human animals, such as flaviviruses, plague viruses, and hepatitis C virus.
  • the compounds and compositions of the invention are particularly useful for the therapeutic and/or prophylactic treatment of HCV.
  • the invention provides a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I and Ia of the invention for use in preventing or treating a viral infection, especially yellow Use of a virus-infected disease, and in the preparation of a medicament for preventing and/or treating a viral infection, particularly in the preparation of a medicament for preventing and/or treating an HCV viral infection, such as an HCV viral hepatitis disease.
  • diseases are acute hepatitis C, chronic hepatitis C, and a mixed infection of hepatitis C and hepatitis B or hepatitis D.
  • the invention provides methods for treating and/or preventing a viral infection, the method comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention or a stereoisomer thereof A pharmaceutically acceptable salt, hydrate, solvate or crystal or a pharmaceutical composition of the invention.
  • the compound of the present invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystallization thereof or a pharmaceutical composition of the present invention can be administered to a mammal in need thereof to inhibit the virus and prevent progression of the disease.
  • the method or use of treating and/or preventing a viral infection further comprises administering to the individual a compound of formula I of the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate thereof, , solvates or crystals or pharmaceutical compositions containing same, and are administered a compound of formula I of the invention
  • the at least one other compound having anti-HCV activity is administered before, after or simultaneously with the stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof or the pharmaceutical composition containing the same.
  • At least one of the other compounds is an interferon or ribavirin.
  • the interferon is selected from the group consisting of interferon alpha 2B, PEGylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
  • at least one of the other compounds is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, interfering RNA, antisense RNA, imiquimod, ribavirin, 5'-inosine monophosphate dehydrogenase inhibitor, amantadine and rimantadine.
  • At least one of the other compounds is effective to inhibit the function of a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV NS5B protein, HCV entry, HCV assembly, HCV release, HCV NS3/4A protein and IMPDH.
  • a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV NS5B protein, HCV entry, HCV assembly, HCV release, HCV NS3/4A protein and IMPDH.
  • stereoisomer refers to an isomer produced by the different arrangement of atoms in a molecule in space. These include cis and trans isomers, enantiomers and conformational isomers. All stereoisomers are within the scope of the invention. Individual stereoisomers of the compounds of the invention may be substantially free of other isomers or may be admixed, for example, as a racemate, or with all other stereoisomers.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt of a compound of the invention formed with an acid, such as, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid or the like.
  • an acid such as, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid or the like.
  • solvate refers to a form of a compound of the invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the invention, the solvate is preferably a hydrate.
  • crystalline refers to the various solid forms formed by the compounds described herein, including crystalline forms, amorphous forms.
  • alkyl refers to a straight or branched saturated hydrocarbon group, preferably a hydrocarbon group of 6 or less carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2,2-Methylbutyl and 2,3-dimethylbutyl.
  • C 1-6 alkyl refers to a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to a straight or branched saturated hydrocarbon group containing from 1 to 4 carbon atoms.
  • haloalkyl refers to an alkyl group substituted with at least one halogen atom.
  • cycloalkyl refers to a cyclic saturated hydrocarbon group, preferably a hydrocarbon group of 8 carbon atoms or less.
  • C 3-8 cycloalkyl refers to a cyclic saturated hydrocarbon group containing from 3 to 8 carbon atoms.
  • C 3-6 cycloalkyl refers to a straight or branched saturated hydrocarbon group containing from 3 to 6 carbon atoms.
  • alkoxy refers to -O-alkyl
  • halogen means fluoro, chloro, bromo, iodo.
  • alkylamino refers to -NH-alkyl or -N-(alkyl)(alkyl).
  • alkyl acyl refers to -C(O)-alkyl.
  • aminoacyl refers to -C (O) -NH 2
  • alkylamino group refers to -C (O) -NH- or a group -C (O) -N- (alkyl) (alkyl ).
  • sulfonyl refers to -S(O) 2 -alkyl
  • sulfinyl refers to -S(O)-alkyl
  • aryl refers to an aromatic hydrocarbon group containing one or more benzene rings. Suitable aryl groups include phenyl, naphthyl.
  • heteroaryl refers to an aromatic group in which at least one carbon atom of the aryl group is replaced by a hetero atom.
  • the hetero atom is O, S, N.
  • the heteroaryl groups described herein include, but are not limited to, pyridinyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl , tetrazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • heterocycloalkyl refers to a saturated cyclic group containing at least one heteroatom, wherein the heteroatom is N, O or S.
  • heterocyclenyl refers to an unsaturated cyclic group containing at least one heteroatom, wherein the heteroatom is N, O or S.
  • Step 2 (2S)-2-(((4-(3-fluoropyridin-2-yl)phenyloxy)(((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)propionic acid isopropyl preparation
  • the product obtained in step 1 is 4-(3-fluoropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
  • Step 2 (2S)-2-((4-(2-Fluoropyridin-4-yl)phenyloxy)(((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)propionic acid isopropyl preparation
  • Step 2 (2S)-2-(((4-(Pyridin-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3, Preparation of 4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester
  • step 1 The product obtained in step 1 is 4-(pyridin-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
  • the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
  • the title compound was obtained by the same procedure as in the step 1 of Example 1 from the crude product of 4-bromo-1-methyl-1H-pyrazole-3-carboxylate and 4-hydroxyphenylboronic acid.
  • the product obtained in the step 3 is 4-(1-methyl-3-cyano-1H-pyrazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • Step 2 (2S)-2-(((4-(Pyridin-3-yl)phenyloxy)(((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)propionic acid isopropyl ester
  • step 1 The product obtained in step 1 is 4-(pyridin-3-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
  • the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
  • the product obtained in step 1 is 4-(5-fluoropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
  • Step 2 (2S)-2-(((4-(2-chloropyridin-4-yl)phenyloxy)(((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)propionic acid isopropyl ester
  • step 2 The product obtained in step 2 is 4-(5-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • step 2 The product obtained in step 2 is 5-hydroxy-1-methyl-1H-indole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
  • the product obtained in the step 2 is 2-fluoro-4-(1-methyl-1H-pyrazol-3-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • step 1 4-bromo-5-methylthiazole and 5g of NBS in a 250mL single-mouth bottle, add 80mL of carbon tetrachloride to dissolve, reflux reaction for 2h, after the reaction is finished, cool to room temperature, concentrate, column layer
  • the title compound was purified by chromatography.
  • step 3 4-bromo-5-hydroxymethylthiazole in a 100 mL single-mouth bottle, add 30 mL of dichloromethane to dissolve, add 1.5 g of chlorochromic acid pyridine (PCC) in portions, add, and react at room temperature for 3 h. After the reaction is completed, it is concentrated and purified by column chromatography to give the title compound.
  • PCC chlorochromic acid pyridine
  • step 6 4-(thiazol-5-carbazin-4-yl)phenol in a 100 ml single-mouth bottle, add 10 mL of THF, add 8 mL of pyridine and 8 mL of trifluoroacetic anhydride, and react at room temperature for 12 h. After completion, it was cooled to room temperature, concentrated and purified by column chromatography.
  • step 7 The product obtained in step 7 is 4-(5-cyanothiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the product obtained in the step 2 is 6-hydroxy-3-methylbenzo[d]isoxazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2.
  • the target compound was obtained by the same procedure as in the steps 2 and 3 of Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • step 1 4-(thiazol-4-yl)phenol in a 100 mL single-mouth bottle, add 50 mL of dichloromethane to dissolve, add 0.75 g of NCS, add the mixture, and react at room temperature for 12 h. After the reaction is finished, concentrate. Purification by column chromatography gave the title compound.
  • the product obtained in step 2 is 4-(5-chlorothiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
  • Step 2 (2S)-2-(((4-(3,5-Dimethylisoxazol-4-yl)phenyloxy)(((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) Isopropyl propionate
  • step 1 The product obtained in step 1 is 4-(3,5-dimethylisoxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R).
  • the target compound was obtained by the same procedure as in Example 2, Steps 2 and 3, using -2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • the product obtained in the first step is 4-(4-chloro-1-methyl-1H-pyrazol-3-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the product obtained in the step 3 is 4-(5-methyloxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'.
  • Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • step 2 The product obtained in step 2 is N-methyl-4-hydroxyindole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
  • the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
  • step 3 The product obtained in step 3 is 4-(oxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using '-fluoro-2'-methyluridine as a starting material.
  • Step 2 (2S)-2-((4-(5-Fluorothiazol-4-yl)phenyloxy)(((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)propionic acid isopropyl preparation
  • step 1 The product obtained in step 1 is 4-(5-fluoro-thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • step 1 2-fluoro-4-(thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • step 1 The product obtained in step 1 is 4-(thien-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
  • the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
  • the product obtained in the first step is 3-fluoro-4-(thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • Step 2 (2S)-2-(((3-Methyl-4-(thiazol-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-di) Oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoic acid isopropyl ester
  • step 1 3-methyl-4-(thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2' Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • Step 2 (2S)-2-(((3-Methyl-4-(1-methyl-1H-imidazol-4-yl)phenyloxy)(((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) isopropyl propionate
  • the product obtained in the first step is 3-methyl-4-(1-methyl-1H-imidazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • Step 2 (2S)-2-(((4-(3-chloropyridin-2-yl)phenyloxy)(((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)propionic acid isopropyl preparation
  • the product obtained in the first step is 3-chloro-2-(4-hydroxyphenyl)pyridine, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • Step 2 (2S)-2-(((4-(5-chloropyridin-2-yl)phenyloxy)(((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)propionic acid isopropyl preparation
  • the product obtained in step 1 is 4-(5-chloropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
  • Step 2 (2S)-2-((4-(5-Chloropyridin-2-yl)-3-methylphenyloxy)(((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)propyl Isopropyl acrylate
  • Step 2 (2S)-2-((4-(3-Fluoropyridin-2-yl)-3-methylphenyloxy)(((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)propyl Isopropyl acrylate
  • step 4 The product obtained in step 4 is 4-(5-chlorooxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the product obtained in the first step is 3-fluoro-4-(1-methyl-1H-imidazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2)
  • the target compound was obtained by the same procedure as in the steps 2 and 3 of Example 1, using 'R)-2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • step 1 The product obtained in step 1 is 4-(2-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • step 1 The product obtained in step 1 is 4-(5-chloro-2-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R).
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • the product obtained in the first step of Example 40 was 4-(5-chloro-2-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2' R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the product obtained in the second step of Example 18 was 4-(5-chlorothiazol-4-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'.
  • Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the product obtained in the first step of Example 2 was 4-(3-fluoropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2'R)-2'.
  • Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the product obtained in step 1 is 4-(3-methylthiophen-2-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
  • the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
  • Step 1 of Example 49 The product obtained in Step 1 of Example 49 was 4-(3-methylthiophen-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)- Using 2'-deoxy-2'-fluoro-2'-methyluridine as a starting material, the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • step 1 The product obtained in step 1 is 4-(5-methylthien-2-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
  • the target compound was obtained by the same procedure as in Example 1 using -2'-fluoro-2'-methyluridine as a starting material.
  • the product obtained in the step 1 of Example 51 was 4-(5-methylthien-2-yl)phenol, phosphorus oxychloride, isopropyl ester of L-alanine, pentafluorophenol and (2'R)- Using 2'-deoxy-2'-fluoro-2'-methyluridine as a starting material, the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • Step 51 of Example 51 The product obtained in Step 51 of Example 51 was 4-(5-methylthien-2-yl)phenol, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2'R)-2.
  • the target compound was obtained by the same procedure as in the steps 2 and 3 of Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • the product obtained in the first step of Example 26 is 4-(thien-2-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy- Using 2'-fluoro-2'-methyluridine as a starting material, the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the product obtained in the first step of Example 26 is 4-(thien-2-yl)phenol, phosphorus oxychloride, and L-alanine neopentyl ester.
  • the hydrochloride salt, pentafluorophenol and (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine were used as starting materials, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
  • the Huh7 1b cell line was provided by Shanghai WuXi PharmaTech Development Co., Ltd. as a Huh7 cell line containing the HCV 1b replicon with a stable luciferase (Luc) reporter. It cloned the HCV non-structural protein gene, neo (G418 resistance) and luciferase reporter gene into pBR vector by gene recombination technology. The vector carrying the HCV replicon was then transfected into huh7 cells, and by G418 resistance screening, the HCV replicon was stably replicated and the related protein and luciferase were stably expressed in huh7 cells. This cell model is used for in vitro screening of anti-HCV compounds.
  • the anti-HCV activity of the compounds was determined by examining the level of chemiluminescence of the luciferase luminescent substrate. See Lohmann V, et al. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science. 285 (5424): 110-113.
  • each compound was formulated into a mother liquor in DMSO, and then diluted to a total concentration of 10 ⁇ M in DMEM containing 0.5% DMSO as a compound, and diluted 3 times, total 10 For each concentration, the compounds were separately added to the 96-well plate using a POD 810 fully automated microplate pretreatment system (LabCyte, USA); an ineffective control group (complete culture medium containing 0.5% DMSO instead of the compound) and 100 were set up. % effective control group (only complete culture medium containing 0.5% DMSO);
  • Bright-Glo assay 100 ⁇ l of luciferase luminescent substrate Bright-Glo was added to each well, and the fluorescence signal value was measured within 5 minutes using a chemiluminescence detection system EnVision (PerkinElmer, USA), and the obtained data was used for compound viability calculation.
  • CPD Fluorescence signal value of compound pore
  • CPD chemiluminescence signal value of compound pore
  • the experimental results show that the compound of the present invention has an EC 50 of between about 0.05 ⁇ M and 1 ⁇ M and has a very good ability to inhibit HCV virus. Some data are shown in Table 2.
  • Example 20 0.0783 Example 21 0.173 Example 22 0.104 Example 23 0.265 Example 24 0.055 Example 25 0.204 Example 26 0.019 Example 27 0.169 Example 28 0.142 Example 31 0.103 Example 32 0.174 Example 33 0.130 Example 34 0.196 Example 35 0.051 Example 36 0.146 Example 42 0.065 Example 46 0.055 Example 49 0.049 Example 50 0.063 Example 51 0.018 Example 52 0.021 Example 53 0.097 Example 54 0.020 Example 55 0.032 Example 56 0.028 Example 57 0.030
  • the current best anti-HCV drug sofosbuvir has an EC 50 value of 0.102 ⁇ M for gene type 1b in the HCV replicon assay, see http://www.gilead. Com/ ⁇ /media/Files/pdfs/medicines/liver-disease /sova ldi/sovaldi_pi.pdf .
  • the compounds of the invention have anti-HCV viral activity comparable to or superior to sofosbuvir.
  • the compound of the present invention prepared in the above examples was used, and a 10 mM mother liquid was prepared in DMSO, and then diluted to 1000 nM in a DMEM complete medium containing 0.5% DMSO, and then diluted 3 times in total for a total of 8 concentrations.
  • Huh 7.5.1 cells provided by Shanghai WuXi PharmaTech Development Co., Ltd.
  • the J399EM (HCV genotype 2a) virus a full-length HCV mutant transfected with EGFP (enhanced green fluorescent protein), has the same infectious ability as the JFH-1 wild type, and passes through the NS5A region. Inserting the EGFP coding sequence into the domain, the fluorescence of the NS5A-EGFP fusion protein can be directly observed in infected cells, and provided by Shanghai WuXi PharmaTech Development Co., Ltd.
  • Huh 7.5.1 Cell preparation Huh 7.5.1 cells in log phase were collected, resuspended in DMEM complete medium, seeded in 96-well plates (7 ⁇ 10 3 cells / well), placed at 37 ° C Incubate overnight in a 5% CO 2 incubator;
  • Drug treatment The compounds of the present invention were separately added to a 96-well plate, and the compounds were always at a concentration of 1000 nM, and each compound was double-replicated, 3 times diluted, a total of 8 concentrations, and a final concentration of DMSO of 0.5%; Ineffective control group (complete culture medium containing 0.5% DMSO instead of compound) and 100% effective control group (added to virus-free cells);
  • Viral infection J399EM virus supernatant was added to a 96-well plate at a concentration of 0.2 MOI per well. It was then placed in a 37 ° C, 5% CO 2 incubator for 3 days.
  • Inhibition% (RLU s -RLU c )/(RLU V -RLU c ) ⁇ 100
  • RLU V indicates the chemiluminescence intensity of the virus control group (complete culture medium containing 0.5% DMSO instead of compound)
  • RLU S indicates the chemiluminescence intensity of the corresponding compound treatment group
  • RLU C indicates the cell control group (cells without virus infection) Chemiluminescence intensity
  • Cytotoxicity assay The cell and compound treatment methods were the same as above, but the medium was replaced with the virus and added to the experimental plate. After culturing for 3 days at 37 ° C in a 5% CO 2 incubator, the cell viability assay reagent Alamar Blue was added, and the Fluorescence signal value was detected by a spectrophotometer. The data obtained were used for the calculation of compound cytotoxicity with the formula:
  • Viability% RFU S /RFU M ⁇ 100
  • RFU M represents the fluorescence intensity of the vehicle control group (complete culture medium containing 0.5% DMSO instead of the compound), and RFU S represents the fluorescence intensity of the corresponding compound treatment group;
  • EC 50 values for the compounds of the present invention is substantially between 40nM-150nM, CC 50 were greater than 1000nM, e.g. EC compound of Example 20 50 53.4nM, CC 50> 1000nM.
  • EC 50 values of the compounds of this invention is smaller, e.g. EC 50 Example 26 is 9.3nM, CC 50> 1000nM. From this, it can be seen that the compound of the present invention has excellent antiviral activity, has small cytotoxicity, and is safe.
  • the inventors of the present invention have found that the compound of the present invention has a good plasma protein binding rate and is suitable for medicine, and has a very good clinical application prospect. While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

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Abstract

本发明属于医药化学领域，具体涉及一类具有良好丙型肝炎病毒抑制效果的化合物，其制备方法，含有该化合物的组合物，以及所述化合物或组合物作为丙型肝炎病毒感染性疾病治疗药物的用途。本发明的化合物表现出优异的抗病毒活性，同时具有小的细胞毒性，安全性好，且血浆蛋白结合率良好，适于成药，具有非常好的临床应用前景。

Description

丙型肝炎病毒抑制剂及其应用 技术领域
本发明属于医药化学领域，具体涉及一类具有良好丙型肝炎病毒抑制效果的化合物，其制备方法，含有该化合物的组合物，以及所述化合物或组合物作为丙型肝炎病毒感染性疾病治疗药物的用途。
背景技术
丙型肝炎病毒(HCV)感染是世界范围内流行的疾病，全球慢性感染者已超过2亿，中国感染率为3.2％，位列世界前三。丙型肝炎病毒感染的临床表现多样，轻至炎症，重至肝硬化、肝癌。慢性丙型肝炎还可以并发某些肝外表现，包括类风湿性关节炎、干燥性结膜角膜炎、扁平苔藓、肾小球肾炎、混合型冷球蛋白血症、B细胞淋巴瘤和迟发性皮肤卟啉症等，可能是机体异常免疫反应所致。丙肝肝硬化失代偿期时，可以出现各种并发症，如腹水腹腔感染，上消化道出血，肝性脑病，肝肾综合征，肝衰竭等表现。
HCV属于黄病毒科肝病毒属病毒，其与黄病毒科中的另外两个属即瘟病毒属和黄病毒属的基因结构相似。目前，治疗HCV感染的标准方法有干扰素以及干扰素和利巴韦林联合疗法。不过，仅50％的治疗者对该方法有反应，且干扰素具有明显的副作用，例如流行性感冒样症状、体重减低以及疲乏无力，而干扰素和利巴韦林联合疗法则产生相当大的副作用，包括溶血、贫血症和疲乏等。
另外，已开发的用于治疗HCV感染的药物包括蛋白酶抑制剂、噻唑烷衍生物、噻唑烷和N-苯甲酰苯胺、菲醌、解旋酶抑制剂、核苷聚合酶抑制剂和胶霉毒素、反义硫代磷酸酯寡核苷酸、依赖于IRES的翻译的抑制剂、核酶以及核苷类似物等。
目前，核苷磷酸酯类化合物用于治疗黄病毒科病毒尤其是HCV感染是本领域的重要研发方向。WO 2006/065335公开了一种抑制HCV病毒的氟化吡咯并[2,3,d]嘧啶核苷化合物。US 2006/0241064公开了用于治疗黄病毒科家族病毒如HCV引起的病毒感染的核苷化合物。WO 2008/121634公开了用于治疗哺乳动物病毒性感染的核苷氨基磷酸酯化合物。
尽管存在上述公开，目前仍然非常需要用于治疗和/或预防HCV感染的有效化合物。
发明内容
本发明的一个目的是提供用于治疗和/或预防丙型肝炎病毒感染的通式I所示的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶：
Figure PCTCN2015085380-appb-000001
本发明的另一个目的是提供制备本发明的通式I的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶的方法。
本发明的再一个目的是提供包含本发明的通式I的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶和药效可接受的载体的组合物以及包含本发明的通式I的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶和另一种抗病毒药的组合物。
本发明的还一个目的是提供本发明的通式I的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶治疗和/或预防丙型肝炎病毒感染的方法以及本发明的通式I的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶在制备用于治疗和/或预防病毒感染的药物中的应用。
针对上述发明目的，本发明提供以下技术方案：
第一方面，本发明提供通式I所示的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶：
Figure PCTCN2015085380-appb-000002
其中：
R1选自H、烷基和卤代烷基；
R2选自H和卤素；
R3选自H、OH和烷氧基；
R4选自H和烷基，其中所述烷基任选被选自烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；
R5选自H、烷基、环烷基、芳基和杂芳基，其中所述烷基、环烷基、芳基和杂芳基任选被选自烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、 氨基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；
Cy1选自芳基和杂芳基，其中所述的芳基和杂芳基任选被选自卤素、羟基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、硝基、氰基中的一个或多个基团取代；
Cy2选自氢、芳基、杂芳基、杂环烷基和杂环烯基，其中所述的芳基、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、烷基、烯基、炔基、环烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、硝基、氰基中的一个或多个基团取代；
条件是Cy1为芳基时，Cy2不为氢或芳基，且本发明通式I的化合物不是以下化合物：
(2S)-2-(((4-(1,2,3-噻二唑-4-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((2-(喹喔啉-5-基)苯-1-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-(噻唑-2-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-(噻唑-5-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-氟-2-甲基-1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((3-甲氧羰基甲基-苯并呋喃-7-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-氧代-2-苯基-4H-苯并吡喃-6-基)氧 基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((喹喔啉-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-氧代-2-苯基苯并二氢吡喃-7-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-((((4-(1H-1,2,4-***-1-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-(嘧啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((S)-((4-氟-1,2-二甲基-1H-吲哚-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-((((6-氟-3-甲基苯并[d]异噁唑-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-((((6-氟苯并[c][1,2,5]噻二唑-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；和
(2S)-2-(((4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯。
在一些优选的实施方案中，R1选自H、C1-6烷基、卤代C1-6烷基，R2选自H、氟、氯、溴，R3选自H、OH。
在另一些优选的实施方案中，R1选自H、C1-3烷基，R2选自氟、氯，R3选自H、OH。
在一些优选的实施方案中，R4选自H、C1-6烷基，R5选自C1-6烷基和C3-8环烷基，其中所述的烷基和环烷基任选被选自烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、 磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代。
在另一些优选的实施方案中，R4选自H、C1-3烷基，R5选自C1-6烷基和C3-6环烷基，其中所述的烷基和环烷基可以被选自C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代。
在另一些优选的实施方案中，R4选自H、C1-3烷基，R5选自C1-3烷基和C3-6环烷基，其中所述的烷基和环烷基可以被选自C1-3烷基、C3-6环烷基、C3-6杂环烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基和杂芳基中的一个或多个基团取代。
在一些优选的实施方案中，Cy1选自苯环，Cy2选自杂芳基、杂环烷基和杂环烯基，其中所述的苯环、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯环，Cy2选自杂芳基、C3-8杂环烷基和C3-8杂环烯基，其中所述的苯环、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、C1-3烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、氨基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯环，Cy2选自杂芳基、C3-6杂环烷基和C3-6杂环烯基，其中所述的苯环、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、C1-3烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、氨基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯环，Cy2选自至少含有一个N原子的五元或六元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、五元或六元杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯环，Cy2选自含有1-3个N原子的五 元或六元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、五元或六元杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯环，Cy2选自仅含有1个S原子的五元或六元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、五元或六元杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在一些具体的实施方案中，Cy1选自苯环，Cy2选自含有1个N原子的六元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些具体的实施方案中，Cy1选自苯环，Cy2选自仅含有1个S原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些具体的实施方案中，Cy1选自苯环，Cy2选自含有2个N原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些具体的实施方案中，Cy1选自苯环，Cy2选自含有1个N原子和1个硫原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些具体的实施方案中，Cy1选自苯环，Cy2选自含有1个N原子和1个 氧原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯环，Cy2选自呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环，其中所述的呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯环，Cy2选自呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环，其中所述的呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代，且Cy2在Cy1的对位或间位。
在一些优选的实施方案中，根据本发明的通式I的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Cy2在Cy1的对位或间位。本发明的发明人意料不到地发现，当通式I中的Cy2在Cy1的对位或间位，本发明的化合物具有非常优异的抗病毒活性。
在另一些优选的实施方案中，Cy1选自萘环、杂芳基，Cy2选自氢、芳基、杂 芳基、杂环烷基和杂环烯基，其中所述的萘环、芳基、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自萘环、杂芳基，Cy2选自氢、芳基、杂芳基、C3-8杂环烷基和C3-8杂环烯基，其中所述的萘环、芳基、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。在另一些优选的实施方案中，Cy1选自萘环、杂芳基，Cy2选自氢、芳基、杂芳基、C3-6杂环烷基和C3-6杂环烯基，其中所述的萘环、芳基、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、C1-3烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、氨基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自苯并至少含有一个N原子的五元或六元杂环，其中所述苯并至少含有一个N原子的五元或六元杂环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代，且Cy2为氢。在另一些优选的实施方案中，Cy1选自苯并仅含有一个S原子的五元或六元杂环，其中所述苯并仅含有一个S原子的五元或六元杂环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代，且Cy2为氢。
在一些具体的实施方案中，Cy1选自苯并五元或六元含1、2或3个氮原子的杂芳环，其中所述苯并五元或六元含1、2或3个氮原子的杂芳环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代，且Cy2为氢。
在另一些具体的实施方案中，Cy1选自苯并五元含1或2个氮原子的杂芳环，其中所述苯并五元含1或2个氮原子的杂芳环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基 氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代，且Cy2为氢。
在另一些具体的实施方案中，Cy1选自苯并五元含1个氮原子和1个氧原子的杂芳环，其中所述苯并五元含1个氮原子和1个氧原子的杂芳环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代，且Cy2为氢。
在另一些具体的实施方案中，Cy1选自苯并仅含1个S原子的五元杂芳环，其中所述苯并仅含1个S原子的五元杂芳环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代，且Cy2为氢。
在另一些优选的实施方案中，Cy1选自呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环，Cy2选自氢、苯环、呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环，其中所述的苯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在另一些优选的实施方案中，Cy1选自呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并呋喃环、苯并吡咯环、苯并噻吩环、苯并咪唑环、苯并吡唑环、苯并噻唑环、苯并异噻唑环、苯并噁唑环、苯并异噁唑环、苯并三氮唑环、苯并噻二唑环、苯并噁二唑环、苯并吡啶环、苯并嘧啶环、苯并吡嗪环、苯并哒嗪环，Cy2为氢，其中所述的Cy1任选被选自卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷 基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代。
在一些优选的实施方案中，本发明提供通式Ia所示的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶：
Figure PCTCN2015085380-appb-000003
其中：
Ra1选自杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、烷基、烯基、炔基、环烷基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、烷基酰基、烷氧基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、烷基酰基、烷氧基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成杂芳基、杂环烷基或杂环烯基；
Ra3、Ra4、Ra5独立地选自氢、卤素、羟基、氨基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、烷基酰基、烷氧基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基；
R1、R2、R3、R4、R5具有通式I中的定义。
在一些实施方案中，根据本发明的通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中R1选自H、C1-6烷基和卤代C1-6烷基，优选选自H和C1-3烷基；R2选自H、氟、氯和溴，优选选自氟和氯；R3选自H和OH；R4选自H和C1-6烷基，其中所述烷基任选被选自C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代，优选地，R4选自H和C1-3烷基，其中所述烷基任选被选自C1-3烷基、C3-6环烷基、C3-6杂环烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟 基、氨基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；和R5选自H、C1-6烷基、C3-8环烷基和芳基，其中所述的烷基、环烷基和芳基任选被选自C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代，优选地，R5选自H、C1-3烷基、C3-6环烷基和芳基，其中所述的烷基任选被选自C1-3烷基、C3-6环烷基、C3-6杂环烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代。
在一些优选的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自C4-8杂芳基、C4-8杂环烷基和C4-8杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成C4-8杂芳基、C4-8杂环烷基或C4-8杂环烯基。
在另一些优选的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自至少含有一个N原子的五元或六元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成至少含有一个N原子的五元或六元杂芳基、杂环烷基或杂环烯基。在另一些优选的实施方案中，本发明提供通式Ia 的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自含有1-3个N原子的五元或六元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成含有1-3个N原子的五元或六元杂芳基、杂环烷基或杂环烯基。
在另一些优选的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自仅含有一个S原子的五元或六元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成仅含有一个S原子的五元或六元杂芳基、杂环烷基或杂环烯基。
在一些具体的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自含有1个N原子的六元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；和
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基。
在另一些具体的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1、Ra2与它们连接的碳原子一起构成含有1个N原子的五元或六元杂芳基、杂环烷基或杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代。
在另一些具体的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自含有2个N原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成含有2个N原子的五元杂芳基、杂环烷基或杂环烯基。
在另一些具体的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自含有1个N原子和1个硫原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成含有1个N原子和1个硫原子的五元杂芳基、杂环烷基或杂环烯基。
在另一些具体的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自含有1个N原子和1 个氧原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成含有1个N原子和1个氧原子的五元杂芳基、杂环烷基或杂环烯基。
在另一些具体的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自仅含有1个S原子的五元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基中的一个或多个基团取代；
Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
Ra1、Ra2与它们连接的碳原子一起构成仅含有1个S原子的五元杂芳基、杂环烷基或杂环烯基。
在一些优选的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中R1为H、甲基、乙基、正丙基或异丙基，R2为F，R3为OH，R4选自H、甲基、乙基、正丙基或异丙基，R5选自甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、环戊基或苄基，Ra1选自呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环，其中所述的Ra1任选被选自卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代；Ra2、Ra3、Ra4、Ra5独立 地选自氢、卤素、羟基、氨基、烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷基氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基。
在一些优选的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中R1为H或甲基，R2为F，R3为OH，R4选自H、甲基、乙基、正丙基或异丙基，R5选自甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、环戊基或苄基，Ra1选自呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并呋喃环、苯并吡咯环、苯并噻吩环、苯并咪唑环、苯并吡唑环、苯并噻唑环、苯并异噻唑环、苯并噁唑环、苯并异噁唑环、苯并三氮唑环、苯并噻二唑环、苯并噁二唑环、苯并吡啶环、苯并嘧啶环、苯并吡嗪环、苯并哒嗪环，其中所述的Ra1任选被选自卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代；Ra2、Ra3、Ra4、Ra5独立地选自氢、卤素、羟基、氨基、烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷基氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基。
在一些优选的实施方案中，本发明提供通式Ia的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中R1为H、甲基、乙基、正丙基或异丙基，R2为F，R3为OH，R4选自H、甲基、乙基、正丙基或异丙基，R5选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或苄基，Ra1、Ra2与它们连接的碳原子一起构成苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环，其中所述的苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环任选被选自卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代；Ra3、Ra4、Ra5独立地选自氢、卤素、羟基、氨基、烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷基氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基。
在一些优选的实施方案中，本发明提供通式Ia的化合物或其立体异构体、 药学可接受的盐、水合物、溶剂合物或结晶，其中R1为H、甲基、乙基、正丙基或异丙基，R2为F，R3为OH，R4选自H、甲基、乙基、正丙基或异丙基，R5选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或苄基，Ra1、Ra2与它们连接的碳原子一起构成苯并呋喃环、苯并吡咯环、苯并噻吩环、苯并咪唑环、苯并吡唑环、苯并噻唑环、苯并异噻唑环、苯并噁唑环、苯并异噁唑环、苯并三氮唑环、苯并噻二唑环、苯并噁二唑环、苯并吡啶环、苯并嘧啶环、苯并吡嗪环、苯并哒嗪环，其中所述的苯并呋喃环、苯并吡咯环、苯并噻吩环、苯并咪唑环、苯并吡唑环、苯并噻唑环、苯并异噻唑环、苯并噁唑环、苯并异噁唑环、苯并三氮唑环、苯并噻二唑环、苯并噁二唑环、苯并吡啶环、苯并嘧啶环、苯并吡嗪环、苯并哒嗪环任选被选自卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基、氰基中的一个或多个基团取代；Ra3、Ra4、Ra5独立地选自氢、卤素、羟基、氨基、烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷基氨基酰基、磺酰基、亚磺酰基、巯基、硝基、氰基。
在上述优选的实施方案中，本发明通式Ia的化合物，不是以下化合物：
(2S)-2-(((4-(1,2,3-噻二唑-4-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((2-(喹喔啉-5-基)苯-1-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-(噻唑-2-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-(噻唑-5-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-氟-2-甲基-1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基) 氨基)丙酸异丙酯；
(2S)-2-(((3-甲氧羰基甲基-苯并呋喃-7-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-氧代-2-苯基-4H-苯并吡喃-6-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((喹喔啉-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-氧代-2-苯基苯并二氢吡喃-7-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-((((4-(1H-1,2,4-***-1-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((4-(嘧啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-(((S)-((4-氟-1,2-二甲基-1H-吲哚-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-((((6-氟-3-甲基苯并[d]异噁唑-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
(2S)-2-((((6-氟苯并[c][1,2,5]噻二唑-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；和
(2S)-2-(((4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯。
本发明提供了以下具体化合物：
Figure PCTCN2015085380-appb-000004
Figure PCTCN2015085380-appb-000005
Figure PCTCN2015085380-appb-000006
Figure PCTCN2015085380-appb-000007
Figure PCTCN2015085380-appb-000008
另一方面，本发明提供本发明的通式I化合物的制备方法，该方法包括以下步骤：
Figure PCTCN2015085380-appb-000009
a)式(1)的化合物在碱性条件下与三氯氧磷反应，制得式(2)的化合物；
b)式(2)的化合物与式(3)的化合物反应制得式(4)的化合物；
c)式(4)的化合物与五氟苯酚反应制得式(5)的化合物；
d)式(5)的化合物与式(6)的化合物反应制得通式(I)的化合物。
其中，R1、R2、R3、R4、R5、Cy1、Cy2如以上通式I中所定义。
第三方面，本发明提供药物组合物，其包含本发明的通式I或Ia所示化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶。
在一些实施方案中，本发明提供本发明的化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶及包含本发明的化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶的药物组合物，所述化合物或药物组合物用于治疗和/或预防由丙型肝炎病毒引起的肝脏疾病。
在一些实施方案中，本发明提供药物组合物，其包含通式I或Ia所示化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，还包含选自下列组成的一种或多种另外的抗HCV治疗剂：HCV NS3蛋白酶抑制剂、HCV NS5B RNA依赖性RNA聚合酶抑制剂、核苷类似物、干扰素α、聚乙二醇化的干扰素、利巴韦林、左旋韦林、韦拉米啶、TLR7激动剂、TLR9激动剂、亲环蛋白抑制剂、α葡萄糖苷酶抑制剂、NS5A抑制剂和NS3解螺旋酶抑制剂。
可以将本发明的通式I和Ia所示化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径 施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
第四方面，本发明提供本发明的通式I和Ia所示化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或本发明的药物组合物治疗黄病毒科病毒感染的受治疗者的方法，包括向所述受治疗者施用通式I和Ia的化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或者包含通式I和Ia的化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶的药物组合物，以有效减少所述受治疗者中所述病毒的病毒载量的量施用。在一个实施方案中，本发明提供用于治疗和/或预防RNA病毒例如黄病毒科病毒感染的方法，包括向需要此治疗的个体给予本发明的化合物、其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或其药物组合物。在另一个实施方案中，本发明提供抑制RNA病毒例如黄病毒科病毒感染的方法，包括使所述病毒与治疗有效量的本发明的化合物、其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或其药物组合物接触。
“黄病毒科病毒”是指黄病毒科的任何病毒，包括感染人和非人动物的那些病毒，例如黄病毒、鼠疫病毒和丙型肝炎病毒。本发明的化合物和组合物可特别用于治疗和/或预防性治疗HCV。
另一方面，本发明提供本发明的通式I和Ia所示化合物、立体异构体、药学可接受的盐、水合物、溶剂合物或结晶用于预防或治疗病毒性感染，尤其是黄病毒感染疾病的应用，以及在制备预防和/或治疗病毒性感染疾病的药物中的应用，特别是在制备预防和/或治疗HCV病毒感染，如HCV病毒性肝炎疾病的药物中的应用。该类疾病的实例有急性丙型肝炎、慢性丙型肝炎以及丙型肝炎和乙型肝炎或丁型肝炎的混合感染。
在一些实施方案中，本发明提供用于治疗和/或预防病毒性感染的方法，所述方法包括向有此需要的个体给予治疗和/或预防有效量的本发明的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或本发明的药物组合物。可以向有需要的哺乳动物给予本发明的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或本发明的药物组合物以抑制病毒，阻止病程进展。
在另一些实施方案中，所述治疗和/或预防病毒性感染的方法或用途还包括向所述个体给予本发明的式I的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或含有它们的药物组合物，且在给予本发明的式I的化合物 或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或含有它们的药物组合物之前、之后或同时给予至少一种具有抗HCV活性的其它化合物。
在一些实施方案中，所述其它化合物中的至少一种为干扰素或利巴韦林。在一些具体的实施方案中，所述干扰素选自干扰素α2B、PEG化的干扰素α、同感干扰素、干扰素α2A和成淋巴细胞样干扰素τ。在另一些实施方案中，所述其它化合物中的至少一种选自白细胞介素2、白细胞介素6、白细胞介素12、干扰RNA、反义RNA、咪喹莫特、利巴韦林、5’-单磷酸肌苷脱氢酶抑制剂、金刚烷胺和金刚乙胺。在另一些实施方案中，所述其它化合物中的至少一种可有效抑制靶标的功能以治疗HCV感染，所述靶标选自HCV金属蛋白酶、HCV丝氨酸蛋白酶、HCV聚合酶、HCV解旋酶、HCV NS4B蛋白、HCV NS5B蛋白、HCV进入、HCV组装、HCV释出、HCV NS3/4A蛋白和IMPDH。
术语定义
除非另外定义，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围。本发明的化合物的单独立体异构体可基本上不含其它异构体或可以混合成例如外消旋体，或者与所有其它的立体异构体混合。
术语“药学可接受的盐”是指本发明所述的化合物与酸形成的药学上可接受的盐，所述的酸例如可选自，但不限于：磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂合物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂合物的特殊形式，其中与水发生配位。在本发明范围内，溶剂合物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。
术语“烷基”是指直链或支链的饱和烃基，优选6个碳原子以下的烃基。烷基的实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、2,2-甲基丁基和2,3-二甲基丁基。术语“C1-6烷基”是指含有1-6个碳原子的直链或支链的饱和烃基。术语“C1-4烷基”是指含有1-4个碳原子的直链或支链的饱和烃基。
术语“卤代烷基”是指至少被一个卤素原子取代的烷基。
术语“环烷基”是指环状的饱和烃基，优选8个碳原子以下的烃基。术语“C3-8环烷基”是指含有3-8个碳原子的环状饱和烃基。术语“C3-6环烷基”是指含有3-6个碳原子的直链或支链的饱和烃基。
术语“烷氧基”是指-O-烷基。
术语“卤素”是指氟、氯、溴、碘。
术语“烷基氨基”是指-NH-烷基或-N-(烷基)(烷基)。
术语“烷基酰基”是指-C(O)-烷基。
术语“氨基酰基”是指-C(O)-NH2，术语“烷氨基酰基”是指-C(O)-NH-烷基或-C(O)-N-(烷基)(烷基)。
术语“磺酰基”是指-S(O)2-烷基，术语“亚磺酰基”是指-S(O)-烷基。
术语“芳基”是指含有一个或多个苯环的芳烃基团。合适的芳基包括苯基、萘基。
术语“杂芳基”是指芳基中至少有一个碳原子被杂原子替代的芳香性基团。所述的杂原子为O、S、N。例如，本文所述杂芳基包括但不限于吡啶基、吡唑基、噁唑基、噻唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻唑基、咪唑基、***基、四唑基、噁二唑基、噻二唑基、嘧啶基、哒嗪基、吡嗪基和三嗪基。
术语“杂环烷基”是指至少含有一个杂原子的饱和环状基团，其中杂原子为N、O或S。
术语“杂环烯基”是指至少含有一个杂原子的不饱和环状基团，其中杂原子为N、O或S。
具体实施方式
下面结合实施例对本发明作进一步详细阐述，但本发明不限于这些实施例。本发明使用的试剂和原料均为商购所得。
实施例1 (2S)-2-(((4-(吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000010
步骤1 4-(吡啶-2-基)苯酚的制备
称取1.38g 4-羟基苯硼酸(10mmol)，1.58g 2-溴吡啶(10mmol)，0.4g[1,1'-双(二苯基磷)二茂铁]二氯化钯(Pd(dppf)Cl2,0.5mmol)和9g碳酸铯(30mmol)于250mL的茄形瓶中，加入50mL 1,4-二氧六环和5mL水，氩气保护下90℃反应1.5h，反应结束后，加入100mL乙酸乙酯和50mL饱和氯化钠水溶液萃取，收集有机相，用饱和氯化钠水溶液洗涤(3×50mL)，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化得标题化合物。
LC-MS m/z:[M+H]+＝172。
步骤2 2-(((五氟苯氧基)(4-(吡啶-2-基)苯氧基)磷酰基)氨基)丙酸异丙酯的制备
量取0.32mL三氯氧磷于反应瓶中，加入5mL无水四氢呋喃，-60℃下滴加10mL溶解有342mg步骤1所得物4-(吡啶-2-基)苯酚和0.42mL三乙胺的无水四氢呋喃溶液，滴毕，升温到25℃反应2h，然后于-60℃下加入334mg丙氨酸异丙酯盐酸盐，搅拌10min后滴加5mL溶解有1.05mL三乙胺的无水四氢呋喃，滴加完毕，缓慢升温到-5℃，加入5mL溶解有0.385g五氟苯酚和0.42mL三乙胺的无水四氢呋喃液体，滴加完毕，室温反应30分钟，反应结束后，柱层析纯化得到标题化合物。
步骤3 (2S)-2-(((4-(吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
称取260mg(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷(1mmol)于反应瓶中，密封，氩气保护下注射10mL无水四氢呋喃(THF)，0℃注射10mLt-BuMgCl溶液(1M，于THF中)，室温反应3h后，注射10mL溶有600mg步骤2所得物2-(((五氟苯氧基)(4-(吡啶-2-基)苯氧基)磷酰基)氨基)丙酸异丙酯的四氢呋喃溶液，25℃反应16h，反应完毕后，加入15mL 2N HCl溶液淬灭反应，乙酸乙酯萃取，有机相用饱和碳酸氢钠溶液洗涤，干燥，减压浓缩，柱层析纯化，得标题化合物。1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),8.64-8.65(m,1H),8.08-8.11(m,2H),7.93-7.95(m,2H),7.56-7.59(m,1H),7.32-7.35(m,3H),6.12-6.16(m,2H),5.84-5.87(m,1H),5.58(m,1H),4.87-4.89(m,1H),4.36-4.38(m,1H),4.26-4.28(m,1H),4.01(m,1H),3.82-3.84(m,2H),1.26-1.29(m,6H),1.13-1.16(m,6H)。
LC-MS m/z:[M+H]+＝607。
实施例2 (2S)-2-(((4-(3-氟吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4- 二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000011
步骤1 4-(3-氟吡啶-2-基)苯酚的制备
以4-羟基苯硼酸和2-溴-3-氟吡啶为原料，同实施例1步骤1的方法得到标题化合物。
LC-MS m/z:[M+H]+＝190。
步骤2 (2S)-2-(((4-(3-氟吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(3-氟吡啶-2-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),8.53-8.54(m,1H),7.92-7.95(m,2H),7.83-7.86(m,1H),7.54-7.57(m,1H),7.45-7.47(m,1H),7.33-7.35(m,2H),6.19-6.23(m,1H),6.07-6.15(m,1H),5.91-5.93(m,1H),5.57-5.60(m,1H),4.87-4.90(m,1H),4.41-4.46(m,1H),4.30-4.30(m,1H),4.05(m,1H),3.79-3.82(m,2H),1.20-1.27(m,6H),1.13-1.17(m,6H)。
LC-MS m/z:[M+H]+＝625。
实施例3 (2S)-2-(((4-(2-氟吡啶-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000012
步骤1 4-(2-氟吡啶-4-基)苯酚的制备
以4-羟基苯硼酸和2-氟-4-溴吡啶为原料，同实施例1步骤1的方法制得标题化 合物。
LC-MS m/z:[M+H]+＝190。
步骤2 (2S)-2-(((4-(2-氟吡啶-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(2-氟吡啶-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),8.28-8.30(m,1H),7.89-7.92(m,2H),7.68-7.70(m,1H),7.55-7.58(m,1H),7.52(m,1H),7.36-7.39(m,2H),6.11-6.19(m,1H),5.98-6.05(m,1H),5.84-5.86(m,1H),5.54-5.56(m,1H),4.81-4.90(m,1H),4.37-4.39(m,1H),4.26-4.28(m,1H),3.89-4.01(m,1H),3.83-3.85(m,2H),1.22-1.29(m,6H),1.14-1.16(m,6H)。
LC-MS m/z:[M+H]+＝625。
实施例4 (2S)-2-(((4-(吡啶-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000013
步骤1 4-(吡啶-4-基)苯酚的制备
以4-羟基苯硼酸和4-溴吡啶为原料，同实施例1步骤1的方法制得标题化合物。LC-MS m/z:[M+H]+＝172。
步骤2 (2S)-2-(((4-(吡啶-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(吡啶-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.52(s,1H),8.61-8.62(m,2H),7.82-7.84(m,2H),7.67-7.68(m,2H),7.36-7.37(m,1H),7.32-7.34(m, 2H),6.19-6.21(m,1H),6.13-6.16(m,1H),5.90-5.91(m,1H),5.56-5.58(m,1H),4.83-4.86(m,1H),4.30-4.31(m,1H),4.26-4.29(m,1H),4.01-4.05(m,1H),3.82-3.84(m,2H),1.26-1.28(m,6H),1.13-1.15(m,6H)。
LC-MS m/z:[M+H]+＝607。
实施例5 (2S)-2-(((4-(1-甲基-1H-吡唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000014
步骤1 4-(1-甲基-1H-吡唑-4-基)苯酚
以4-羟基苯硼酸和1-甲基-4-溴-1H-吡唑为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝175。
步骤2 (2S)-2-(((4-(1-甲基-1H-吡唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(1-甲基-1H-吡唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),8.06(s,1H),7.79(m,1H),7.52-7.58(m,3H),7.15-7.17(m,2H),6.00-6.06(m,2H),5.86-5.88(m,1H),5.55-5.60(m,1H),4.83-4.90(m,1H),4.38-4.42(m,1H),4.27-4.29(m,1H),4.03-4.06(m,1H),3.81-3.83(m,3H),3.78-3.81(m,2H),1.20-1.28(m,6H),1.14-1.17(m,6H)。
LC-MS m/z:[M+H]+＝610。
实施例6 (2S)-2-(((4-(1-甲基-1H-吡唑-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000015
步骤1 4-(1-甲基-1H-吡唑-3-基)苯酚
以4-羟基苯硼酸和3-溴-1-甲基-1H-吡唑为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝175。
步骤2 (2S)-2-(((4-(1-甲基-1H-吡唑-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(1-甲基-1H-吡唑-3-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),8.06(s,1H),7.79(m,1H),7.52-7.58(m,3H),7.15-7.17(m,2H),6.00-6.06(m,2H),5.86-5.88(m,1H),5.55-5.60(m,1H),4.83-4.90(m,1H),4.38-4.42(m,1H),4.27-4.29(m,1H),4.03-4.06(m,1H),3.81-3.83(m,3H),3.78-3.81(m,2H),1.20-1.28(m,6H),1.14-1.17(m,6H)。
LC-MS m/z:[M+H]+＝610。
实施例7 (2S)-2-(((4-(1-甲基-3-甲氨基羰基-1H-吡唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000016
步骤1 4-溴-1-甲基-1H-吡唑-3-甲酸甲酯
称取4.10g 4-溴-1-甲基-1H-吡唑-3-羧酸(20mmol)于250mL的茄形瓶中，加入100ml甲醇，0-4℃下，缓慢加入5ml二氯亚砜，常温下反应结束后，加入500mL乙酸乙酯和250mL饱和氯化钠水溶液萃取，收集有机相，水洗3遍，无水硫酸钠来干燥，过滤，浓缩，柱层析纯化得到标题化合物。
LC-MS m/z:[M+H]+＝219。
步骤2 4-(1-甲基-3-甲氧基羰基-1H-吡唑-4-基)苯酚
以步骤1所得物4-溴-1-甲基-1H-吡唑-3-甲酸甲酯和4-羟基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝233。
步骤3 4-(1-甲基-3-甲氨基羰基-1H-吡唑-4-基)苯酚
称取2.33g步骤2所得物4-(1-甲基-3-甲氧基羰基-1H-吡唑-4-基)苯酚(10mmol)于250mL的茄形瓶中，加入100ml甲氨水溶液和10ml甲醇，常温下反应，反应结束后，加入500mL乙酸乙酯，250mL饱和氯化钠水溶液萃取，收集有机相，水洗3遍，无水硫酸钠来干燥，过滤，浓缩，柱层析纯化得标题化合物。LC-MS m/z:[M+H]+＝232。
步骤4 (2S)-2-(((4-(1-甲基-3-甲氨基羰基-1H-吡唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤3所得物4-(1-甲基-3-甲氨基羰基-1H-吡唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.45(s,1H),8.03-8.04(m,1H),7.95(m,1H),7.53-7.56(m,3H),7.11-7.14(m,2H),6.06-6.10(m,2H),5.88-5.98(m,1H),5.56-5.59(m,1H),4.85-4.87(m,1H),4.38-4.39(m,1H),4.25-4.29(m,1H),4.02-4.04(m,1H),3.81-3.87(m,3H),3.72-3.78(m,2H),2.86-2.70(m,3H),1.21-1.26(m,6H),1.13-1.16(m,6H)。
LC-MS m/z:[M+H]+＝667。
实施例8 (2S)-2-(((4-(1-甲基-3-氰基-1H-吡唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000017
步骤1 1-甲基-3-氨基酰基-4-溴-1H-吡唑的制备
取4.10g 4-溴-1-甲基-1H-吡唑-3-羧酸(20mmol)、2.14g氯化铵(40mmol)、 15.2g HATU(40mmol)和6.98ml DIPEA(40mmol)于250mL的茄形瓶中，加入100ml DMF，常温下反应12h，反应结束后，加入500mL乙酸乙酯和250mL饱和氯化钠水溶液萃取，收集有机相，水洗3遍，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得标题化合物。
LC-MS m/z:[M+H]+＝204。
步骤2 1-甲基-3-氰基-4-溴-1H-吡唑的制备
称取2.03g步骤1所得物1-甲基-3-氨基酰基-4-溴-1H-吡唑(10mmol)于250mL的茄形瓶中，加入100ml吡啶，0-4℃下，缓慢加入30ml三氯氧磷，常温下反应12h，反应结束后，加入饱和碳酸钠水溶液中和，再加入500mL乙酸乙酯和250mL饱和氯化钠水溶液萃取，收集有机相，水洗3遍，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得标题化合物。
LC-MS m/z:[M+H]+＝186。
步骤3 4-(1-甲基-3-氰基-1H-吡唑-4-基)苯酚
以4-羟基苯硼酸和步骤2所得物1-甲基-3-氰基-4-溴-1H-吡唑为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝200。
步骤4 (2S)-2-(((4-(1-甲基-3-氰基-1H-吡唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤3所得物4-(1-甲基-3-氰基-1H-吡唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),8.03-8.09(m,1H),7.61-7.62(m,2H),7.55-7.57(m,1H),7.33-7.34(m,2H),6.09-6.11(m,1H),6.04-6.07(m,1H),5.98-6.00(m,1H),5.54-5.56(m,1H),4.83-4.88(m,1H),4.38-4.40(m,1H),4.24-4.27(m,1H),4.01-4.03(m,1H),3.82-3.84(m,3H),3.81(m,2H),1.23-1.27(m,6H),1.15-1.15(m,6H)。LC-MS m/z:[M+H]+＝635。
实施例9 (2S)-2-(((4-(吡啶-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000018
步骤1 4-(吡啶-3-基)苯酚的制备
在100mL单口瓶中加入1g 3-溴吡啶(6.4mmol)、0.96g对羟基苯硼酸(7.0mmol)、2.6g碳酸钾(21mmol)、0.45g PdCl2(PPh3)2(0.65mmol)、15mL水和30mL 1,4-二氧六环，氮气保护下，80℃反应2h，反应结束后，冷却至室温，过滤，浓缩，加乙酸乙酯和水萃取，收集有机相，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得标题化合物。
1HNMR((300MHz,DMSO-d6)δppm:9.67(s,1H),8.82(s,1H),8.49(d,1H),7.99(d,1H),7.65-7.54(m,2H),7.46-7.42(m,1H),6.88(d,2H)。
LC-MS m/z:[M+H]+＝172。
步骤2 (2S)-2-(((4-(吡啶-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物4-(吡啶-3-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),8.87(s,1H),8.56(d,1H),8.05(d,1H),7.74(d,2H),7.59-7.46(m,2H),7.35(d,2H),6.20-6.00(m,2H),5.90(d,1H),5.58(d,1H),4.90-4.82(m,1H),4.43(m,1H),4.31(m,1H),4.05(m,1H),3.84-3.78(m,2H),1.28-1.20(m,6H)，1.17-1.14(m,6H)。
LC-MS m/z:[M+H]+＝607。
实施例10 (2S)-2-(((4-(5-氟吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000019
步骤1 4-(5-氟吡啶-2-基)苯酚的制备
以2-溴-5-氟吡啶和4-羟基苯硼酸为原料，同实施例9步骤1的方法制得标题化合物。
1HNMR((300MHz,CDCl3-d6)δppm:8.50(s,1H),7.82(d,2H),7.64(m,1H),7.46(m,1H),6.90(d,2H),7.53(s,1H)。
步骤2 (2S)-2-(((4-(5-氟吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物4-(5-氟吡啶-2-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),8.64(d,1H),8.04(d,3H),7.80(m,1H),7.56(d,1H),7.33(d,2H),6.15-6.07(m,2H),5.84(d,1H),5.56(d,1H),4.90-4.83(m,1H),4.43(m,1H),4.27(m,1H),4.01(m,1H),3.88-3.78(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝625。
实施例11 (2S)-2-(((4-(2-氯吡啶-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000020
步骤1 4–(2-氯吡啶-4-基)苯酚的制备
以2-氯-4-溴吡啶和对羟基苯硼酸为原料，同实施例9步骤1的方法制得标题化合物。
1HNMR((300MHz,CDCl3-d6)δppm:8.50(s,1H),7.82(d,2H),7.64(m,1H),7.46(m,1H),6.90(d,2H),7.53(s,1H)。
LC-MS m/z:[M+H]+＝206。
步骤2 (2S)-2-(((4-(2-氯吡啶-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物4-(2-氯吡啶-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),8.46(d,1H),7.92(m,3H),7.42(d,1H),7.62-7.56(m,1H),7.37(d,2H),6.20-5.99(m,2H),5.86(d,1H),5.54(d,1H),4.88-4.81(m,1H),4.39(m,1H),4.27(m,1H),4.04(m,1H),3.89-3.81(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝641。
实施例12 (2S)-2-(((4-(5-甲基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000021
步骤1 4-溴-5甲基噻唑的制备
在100mL单口瓶中加入1g 5-甲基噻唑(10mmol),1.8g N-溴代丁二酰亚胺(10mmol)和30mL二氯甲烷，室温反应12h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤2 4-(5-甲基噻唑-4-基)苯酚的制备
以步骤1所得物4-溴-5-甲基噻唑和对羟基苯硼酸为原料，同实施例9步骤1的方法制得标题化合物。
1HNMR((300MHz,CDCl3-d6)δppm:8.65(s,1H),7.52(d,2H),6.88(d,2H),2.57(s,3H)。步骤3 (2S)-2-(((4-(5-甲基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤2所得物4-(5-甲基噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),7.89(d,2H),7.58(m,2H),7.33(d,2H),6.18-5.98(m,2H),5.86(d,1H),5.57(d,1H),4.88-4.81(m,1H),4.39(m,1H),4.27(m,1H),4.04(m,1H),3.89-3.81(m,2H),2.50(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝627。
实施例13 (2S)-2-(((1-甲基-1H-吲唑-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000022
以5-羟基-1-甲基-1H-吲唑、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),7.99(s,1H),7.63(d,1H),7.54(d,2H),7.26(d,1H),6.18-5.98(m,2H),5.86(d,1H),5.57(d,1H),4.88-4.81(m,1H),4.39(m,1H),4.27(m,1H),4.04(m,1H),3.99(s,3H),3.89-3.81(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝584。
实施例14 (2S)-2-(((1-甲基-1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000023
步骤1 5-甲氧基-1-甲基-1H-吲哚的制备
称取5g 5-甲氧基-1H-吲哚(0.034mol)于500mL的单口瓶中，加入200mL DMF溶解，0-4℃下加入2.7g氢化钠(0.068mol)，加毕搅拌0.5h后，滴加4.4g硫酸二甲酯(0.035mol)，加毕，室温反应0.5h，反应结束后，冰浴下加水淬灭，过滤，干燥，得到标题化合物。
步骤2 5-羟基-1-甲基-1H-吲哚的制备
称取0.7g步骤1所得物5-甲氧基-1-甲基-1H-吲哚(4.34mmol)于100mL单 口瓶中，加入20mL二氯甲烷溶解，-30℃下滴加0.52g三溴化硼(21mmol)，加毕，室温搅拌12h，反应结束后，冰浴下加二氯甲烷稀释，加水淬灭，萃取，干燥，浓缩，柱层析纯化得标题化合物。
步骤3 (2S)-2-(((1-甲基-1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤2所得物5-羟基-1-甲基-1H-吲哚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),8.37(d,1H),7.55-7.34(m,3H),7.02(d,1H),6.36(d,1H),6.04-5.85(m,3H),5.48(d,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,5H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝583。
实施例15 (2S)-2-(((2-氟-4-(1-甲基-1H-吡唑-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000024
步骤1 4-(1-甲基-1H-吡唑-3-基)苯酚的制备
以1-甲基-3-溴-1H-吡唑和4-羟基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝175。
步骤2 2-氟-4-(1-甲基-1H-吡唑-3-基)苯酚的制备
称取1.71g步骤1所得物4-(1-甲基-1H-吡唑-3-基)苯酚、3.54g 1-氯甲基-4-氟-1,4-二氮双环[2.2.2.]辛烷双氟硼酸盐(selectfluor)于100mL的茄形瓶中，加入50mL三氟乙酸，60℃反应12h，反应结束后，调节反应液pH值至7左右，加入100mL乙酸乙酯和50mL饱和氯化钠水溶液萃取，水洗3遍，收集有机相，无水硫酸钠来干燥，过滤，浓缩，柱层析纯化得标题化合物。
LC-MS m/z:[M+H]+＝193。
步骤3 (2S)-2-(((2-氟-4-(1-甲基-1H-吡唑-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤2所得物2-氟-4-(1-甲基-1H-吡唑-3-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),7.70-7.73(m,2H),7.60-7.66(m,2H),7.44-7.47(m,1H),6.67(s,1H),6.21-6.24(m,1H),6.19-6.20(m,1H),5.86-5.89(m,1H),5.56-5.59(m,1H),4.81-4.90(m,1H),4.38-4.42(m,1H),4.27-4.28(m,1H),4.01-4.06(m,1H),3.81-3.84(m,3H),3.78-3.80(m,2H),1.27-1.29(m,6H),1.14-1.16(m,6H)。
LC-MS m/z:[M+H]+＝628。
实施例16 (2S)-2-(((4-(5-氰基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000025
步骤1 4-溴-5-甲基噻唑的制备
称取15g 5-甲基噻唑于500mL的单口瓶中，加入250mL二氯甲烷溶解，分批加入27g NBS，加毕，室温反应12h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤2 4-溴-5-溴甲基噻唑的制备
称取5g步骤1所得物4-溴-5-甲基噻唑和5g NBS于250mL的单口瓶中，加入80mL四氯化碳溶解，回流反应2h，反应结束后，冷却至室温，浓缩，柱层析纯化得标题化合物。
步骤3 4-溴-5-羟甲基噻唑的制备
称取2g步骤2所得物4-溴-5-溴甲基噻唑，3.2g碳酸钾于100ml的单口瓶中，加入50mL 1,4-二氧六环和20mL水中溶解，90℃反应1h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤4 4-溴-5-甲酰基噻唑的制备
称取1g步骤3所得物4-溴-5-羟甲基噻唑于100mL的单口瓶中，加入30mL二氯甲烷溶解，分批加入1.5g氯铬酸吡啶(PCC)，加毕，室温反应3h，反应结束后，浓缩，柱层析纯化得到标题化合物。
步骤5 4-(5-甲酰基噻唑-4-基)苯酚的制备
以步骤4所得物4-溴-5-甲酰基噻唑和4-羟基苯硼酸为原料，同实施例9步骤1的方法得到标题化合物。
步骤6 4-(噻唑-5-甲醛肟-4-基)苯酚
称取1g步骤5所得物4-(5-甲酰基噻唑-4-基)苯酚、0.51g盐酸羟胺和0.6g乙酸钠于100mL的单口瓶中，加入30mL乙醇和5mL水溶解，回流反应1h，反应结束后，冷却至室温，浓缩，柱层析纯化得标题化合物。
步骤7 4-(5-氰基噻唑-4-基)苯酚的制备
称取1g步骤6所得物4-(噻唑-5-甲醛肟-4-基)苯酚于100ml的单口瓶中，加入10mL THF溶解后，加入8mL吡啶和8mL三氟乙酸酐，室温反应12h，反应结束后，冷却至室温，浓缩，柱层析纯化得标题化合物。
步骤8 (2S)-2-(((4-(5-氰基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤7所得物4-(5-氰基噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),8.74(d,1H),8.05(d,2H),7.02(d,1H),7.54(d,1H),7.41(d,2H),6.22(m,1H),6.17(m,1H),5.85(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。LC-MS m/z:[M+H]+＝638。
实施例17 (2S)-2-(((3-甲基苯并[d]异噁唑-6-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000026
步骤1 (Z)-1-(2,4-二羟基苯基)乙酮肟的制备
称取5g 1-(2,4-二羟基苯基)乙酮于100mL的单口瓶中，加入50mL乙醇溶解后，加入2.3g盐酸羟胺，2.7g乙酸钠和5mL水，回流反应2h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤2 6-羟基-3-甲基苯并[d]异噁唑的制备
称取1g二氯二氰基苯醌(DDQ)、1.2g PPh3于100mL的单口瓶中，加入30mL二氯甲烷搅拌溶解后，滴加30mL溶解有0.5g步骤1所得物(Z)-1-(2,4-二羟基苯基)乙酮肟的二氯甲烷溶液，室温反应0.5h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤3 (2S)-2-(((3-甲基苯并[d]异噁唑-6-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤2所得物6-羟基-3-甲基苯并[d]异噁唑、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.49(s,1H),7.63(d,1H),7.53(d,2H),7.19(d,1H),6.10-6.07(m,2H),5.84(m,1H),5.54(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),2.56(s,3H),1.29-1.22(m,6H),1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝585。
实施例18 (2S)-2-(((4-(5-氯噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000027
步骤1 4-(噻唑-4-基)苯酚的制备
以4-溴噻唑和4-羟基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝178。
步骤2 4-(5-氯噻唑-4-基)苯酚的制备
称取1g步骤1所得物4-(噻唑-4-基)苯酚于100mL的单口瓶中，加入50mL二氯甲烷溶解后，加入0.75g NCS，加毕，室温反应12h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤3 (2S)-2-(((4-(5-氯噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤2所得物4-(5-氯噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),9.13(s,1H),7.92(d,2H),7.57(d,1H),7.35(d,2H),6.17-6.07(m,2H),5.85(m,1H),5.56(m,1H)4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝647。
实施例19 (2S)-2-(((4-(3,5-二甲基异噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000028
步骤1 4-(3,5-二甲基异噁唑-4-基)苯酚的制备
以4-溴-3,5-二甲基异噁唑和对羟基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
步骤2 (2S)-2-(((4-(3,5-二甲基异噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物4-(3,5-二甲基异噁唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.49(s,1H),7.57(s,1H),7.39(d,2H),7.31(d,2H),6.00-6.11(m,2H),5.85(s,1H),5.51(m,1H),4.83-4.89(m,1H), 4.39(m,1H),4.27(m,1H),4.02(m,1H),3.83-3.87(m,2H),2.38(s,3H),2.21(s,3H),1.23-1.28(m,6H),1.14-1.16(m,6H)。
LC-MS m/z:[M+H]+＝625。
实施例20 (2S)-2-(((4-(4-氯-1-甲基-1H-吡唑-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000029
步骤1 4-(4-氯-1-甲基-1H-吡唑-3-基)苯酚
Figure PCTCN2015085380-appb-000030
称取0.5g实施例15步骤1制备的4-(1-甲基-1H-吡唑-3-基)苯酚(2.9mmol)、0.385gNCS(2.9mmol)于50mL的茄形瓶中，加入5mL THF和5mL CH3CN，50℃反应3h，反应结束后，加入100mL乙酸乙酯和50mL饱和氯化钠水溶液萃取，水洗3遍，然后收集有机相，无水硫酸钠来干燥，过滤，浓缩，柱层析纯化得标题化合物。
LC-MS m/z:[M+H]+＝209。
步骤2 (2S)-2-(((4-(4-氯-1-甲基-1H-吡唑-3-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(4-氯-1-甲基-1H-吡唑-3-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),8.02(s,1H),7.78-7.80(m,2H),7.56-7.57(m,1H),7.29-7.31(m,2H),6.00-6.09(m,2H),5.82-5.84(m,1H),5.57-5.58(m,1H),4.83-4.88(m,1H),4.37-4.40(m,1H),4.24-4.26(m,1H),4.00-4.03(m,1H),3.80-3.86(m,5H),1.23-1.29(m, 6H),1.14-1.15(m,6H)。
LC-MS m/z:[M+H]+＝644。
实施例21 (2S)-2-(((4-(5-甲基噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000031
步骤1 2-溴-1-(4-甲氧基苯基)-1-丙酮的制备
Figure PCTCN2015085380-appb-000032
称取1g 1-(4-甲氧基苯基)-1-丙酮(6.1mmol)、1.2g对甲苯磺酸一水合物(6.1mmol)和1.1g NBS(6.1mmol)于100mL的单口瓶中，加入30mL乙腈溶解，回流反应4h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤2 4-(4-甲氧基苯基)-5-甲基噁唑的制备
Figure PCTCN2015085380-appb-000033
称取1g步骤1所得物2-溴-1-(4-甲氧基苯基)-1-丙酮(4.4mmol)于100mL的单口瓶中，加入2mL甲酰胺和20mL DMF，回流反应2h。反应结束后，浓缩，将浓缩液倒入冰水中，乙酸乙酯萃取，干燥，过滤，浓缩，柱层析纯化得标题化合物。
步骤3 4-(5-甲基噁唑-4-基)苯酚的制备
Figure PCTCN2015085380-appb-000034
称取0.4g步骤2所得物4-(4-甲氧基苯基)-5-甲基噁唑(1.7mmol)于100mL的单口瓶中，加入20mL二氯甲烷溶解，冰浴下滴加8mL溶解有8mmol三溴化硼的二氯甲烷溶液，加毕，室温反应12h，原料结束后，冰浴下加水淬灭，二氯甲烷萃取，干燥，过滤，浓缩，柱层析纯化得标题化合物。
步骤4 (2S)-2-(((4-(5-甲基噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤3所得物4-(5-甲基噁唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),8.28(s,1H),7.68(d,2H),7.56(d,1H),7.31(d,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.31(m,2H),2.50(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝611。
实施例22 (2S)-2-(((1-甲基-1H-吲哚-4-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000035
步骤1 N-甲基-4-甲氧基吲哚
称取1.47g 4-甲氧基吲哚(10mmol)，1.38g碳酸钾(10mmol)于250mL的茄形瓶中，加入100mL丙酮溶解后，缓慢加入2.84g碘甲烷(20mmol)，室温反应，反应结束后，向反应液中加入100mL乙酸乙酯和50mL饱和氯化钠水溶液萃取，水洗3遍，然后收集有机相，用无水硫酸钠来干燥，过滤，浓缩，柱层析纯化得标题化合物。
LC-MS m/z:[M+H]+＝162。
步骤2 N-甲基-4-羟基吲哚
以步骤1所得物N-甲基-4-甲氧基吲哚为原料，同实施例14步骤2的方法制得标题化合物。
LC-MS m/z:[M+H]+＝148。
步骤3 (2S)-2-(((1-甲基-1H-吲哚-4-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤2所得物N-甲基-4-羟基吲哚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.47(s,1H),7.46-7.48(m,1H),7.31-7.32(m,1H),7.25-7.27(m,1H),7.05-7.11(m,1H),6.95-6.97(m,1H),6.49-6.50(m,1H),5.96-6.04(m,2H),5.83-5.85(m,1H),5.33-5.35(m,1H),4.82-4.90(m,1H),4.35-4.41(m,1H),4.20-4.28(m,1H),3.88-4.00(m,1H),3.84-3.87(m,2H),3.78-3.82(m,3H),1.20-1.27(m,6H),1.14-1.16(m,6H)。
LC-MS m/z:[M+H]+＝583。
实施例23 (2S)-2-(((4-(噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000036
步骤1 2-溴-1-(4-甲氧基苯基)乙酮的制备
称取1g 1-(4-甲氧基苯基)乙酮(6.7mmol)，1.5g对甲苯磺酸一水合物(6.7mmol)和1.2g NBS(6.7mmol)于100mL的单口瓶中，加入30mL乙腈溶解，回流反应4小时，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤2 4-(4-甲氧基苯基)噁唑的制备
称取1g步骤1所得物2-溴-1-(4-甲氧基苯基)乙酮(4.4mmol)于100mL的单口瓶中，加入2mL甲酰胺和20mL DMF，回流反应2h，原料结束后，浓缩，将反应液倒入冰水中，乙酸乙酯萃取，干燥，过滤，浓缩，柱层析纯化得标题化合物。
步骤3 4-(噁唑-4-基)苯酚的制备
称取0.4g步骤2所得物4-(4-甲氧基苯基)噁唑(2.3mmol)于100mL的单口瓶中，加入20mL二氯甲烷溶解后，冰浴下加入8mL三溴化硼的二氯甲烷溶液(1.0 mol/L,8mL)，加毕，室温反应24h，反应结束后，冰浴下加水淬灭，二氯甲烷萃取，干燥，过滤，浓缩，柱层析纯化得标题化合物。
步骤4 (2S)-2-(((4-(噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤3所得物4-(噁唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.51(s,1H),8.59(s,1H),8.45(s,1H),7.78(d,2H),7.56(d,1H),7.31(d,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。LC-MS m/z:[M+H]+＝597。
实施例24 (2S)-2-(((4-(5-氟噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000037
步骤1 4-(5-氟-噻唑-4-基)苯酚的制备
称取3g实施例18步骤1所得物4-(噻唑-4-基)苯酚(16mmol)，6.0g 1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(16mmol)于100mL的单口瓶中，加入50mL 1,4-二氧六环溶解，回流反应12h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤2 (2S)-2-(((4-(5-氟噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(5-氟-噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.51(s,1H),8.75(s,1H),7.84(d, 2H),7.56(d,1H),7.35(d,2H),6.17-6.05(m,2H),5.86(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝631。
实施例25 (2S)-2-(((2-氟-4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000038
步骤1 2-氟-4-(噻唑-4-基)苯酚的制备
称取3g 4-(噻唑-4-基)苯酚(0.017mol)，6.0g 1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(Selectfluor,0.017mol)于250mL的单口瓶中，加入30mL三氟乙酸，95℃反应3h，反应完全后，浓缩，加水和乙酸乙酯萃取，干燥，过滤，浓缩，柱层析纯化得标题化合物。
步骤2 (2S)-2-(((2-氟-4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物2-氟-4-(噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.50(s,1H),9.21(s,1H),8.25(s,1H),7.96-7.81(m,2H),7.66-7.56(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),1.29-1.22(m,6H),1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝631。
实施例26 (2S)-2-(((4-(噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000039
步骤1 4-(噻吩-2-基)苯酚的制备
称取3g 4-羟基苯硼酸(22mmol)，3g 2-溴-噻吩(18mmol)，7.5g碳酸钾(55mmol),1.2g PdCl2(PPh3)2(1.7mmol)于250mL的单口瓶中，加入50mL 1,4-二氧六环和10mL水,氮气保护下95℃反应3h，反应结束后，浓缩，加水和乙酸乙酯萃取，干燥，过滤，浓缩，柱层析纯化得标题化合物。
步骤2 (2S)-2-(((4-(噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.50(s,1H),7.66-7.56(m,3H),7.42-7.22(m,2H),7.26(d,2H),7.12(m,1H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),,1.29-1.22(m,6H)，1.16-1.14(m,6H)。LC-MS m/z:[M+H]+＝612。
实施例27 (2S)-2-(((3-氟-4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000040
步骤1 3-氟-4-(噻唑-4-基)苯酚的制备
以4-羟基-2-氟苯硼酸、4-溴-噻唑为原料，同实施例26步骤1的方法制得标题化合物。
步骤2 (2S)-2-(((3-氟-4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4- 二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物3-氟-4-(噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.49(s,1H),9.23(s,1H),8.17(m,1H),8.13(s,1H),7.55(d,1H),7.30-7.19(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),1.29-1.22(m,6H),1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝631。
实施例28 (2S)-2-(((3-甲基-4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000041
步骤1 3-甲基-4-(噻唑-4-基)苯酚的制备
以4-羟基-2-甲基苯硼酸和4-溴噻唑为原料，同实施例26步骤1的方法制得标题化合物。
步骤2 (2S)-2-(((3-甲基-4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物3-甲基-4-(噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.51(s,1H),9.19(s,1H),7.80(s,1H),7.60(d,2H),7.17(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),2.39(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝627。
实施例29 (2S)-2-(((3-甲基-4-(1-甲基-1H-咪唑-4-基)苯基氧 基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000042
步骤1 3-甲基-4-(1-甲基-1H-咪唑-4-基)苯酚的制备
以4-羟基-2-甲基苯硼酸和4-溴-N-甲基咪唑为原料，同实施例26步骤1的方法制得标题化合物。
步骤2 (2S)-2-(((3-甲基-4-(1-甲基-1H-咪唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物3-甲基-4-(1-甲基-1H-咪唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),7.80-7.31(m,4H),7.07(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),3.71(s.3H),3.54(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝624。
实施例30 (2S)-2-(((4-(1-甲基-1H-咪唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000043
步骤1 4-(1-甲基-1H-咪唑-4-基)苯酚的制备
以4-羟基苯硼酸和4-溴-N-甲基咪唑为原料，同实施例26步骤1的方法制得标题化合物。
步骤2 (2S)-2-(((4-(1-甲基-1H-咪唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(1-甲基-1H-咪唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.510(s,1H),7.72-7.58(m,5H),7.20(m,2H),6.04-6.00(m,2H),5.89(m,1H),5.58(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),3.68(s,3H),1.28-1.22(m,6H),1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝610。
实施例31 (2S)-2-(((4-(3-氯吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000044
步骤1 3-氯-2-(4-羟基苯基)吡啶的制备
称取1.38g 4-羟基苯硼酸(10mmol)，1.91g 2-溴-3-氯吡啶(10mmol)，0.4g[1,1'-双(二苯基磷)二茂铁]二氯化钯(0.5mmol)，9g碳酸铯(30mmol)于250mL的茄形瓶中，加入50mL 1,4-二氧六环和5mL水，氮气保护下90℃反应1.5h，反应结束后，加入100mL乙酸乙酯和50mL饱和氯化钠水溶液萃取，水洗3遍，然后收集有机相，用无水硫酸钠来干燥，过滤，浓缩，柱层析纯化得标题化合物。LC-MS m/z:[M+H]+＝206。
步骤2 (2S)-2-(((4-(3-氯吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物3-氯-2-(4-羟基苯基)吡啶、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.47(s,1H),8.61-8.62(m,1H), 8.02-8.05(m,1H),7.69-7.72(m,2H),7.56-7.59(m,1H),7.41-7.45(m,1H),7.32-7.35(m,2H),6.14-6.17(m,1H),6.05-6.09(m,1H),5.84-5.98(m,1H),5.57-5.60(m,1H),4.83-4.91(m,1H),4.38-4.43(m,1H),4.25-4.29(m,1H),4.01-4.05(m,1H),3.80-3.89(m,2H),1.22-1.29(m,6H),1.15-1.17(m,6H)。
LC-MS m/z:[M+H]+＝641。
实施例32 (2S)-2-(((4-(5-氯吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000045
步骤1 4-(5-氯吡啶-2-基)苯酚的制备
以4-羟基苯硼酸和2-溴-5-氯吡啶为原料，同实施例31步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝206。
步骤2 (2S)-2-(((4-(5-氯吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(5-氯吡啶-2-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.47(s,1H),8.68(m,1H),8.08-8.11(m,1H),7.82-7.85(m,1H),7.55-7.59(m,1H),7.48-7.53(m,1H),7.31-7.35(m,2H),7.15-7.20(m,1H),6.07-6.14(m,2H),5.99(m,1H),5.57-5.60(m,1H),4.85-4.89(m,1H),4.37-4.41(m,1H),4.26-4.28(m,1H),4.01(m,1H),3.80-3.87(m,2H),1.22-1.29(m,6H),1.13-1.16(m,6H)。
LC-MS m/z:[M+H]+＝641。
实施例33 (2S)-2-(((4-(5-氯吡啶-2-基)-3-甲基苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基 -4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000046
步骤1 4-(5-氯吡啶-2-基)-3-甲基苯酚的制备
以2-甲基-4-羟基苯硼酸和2-溴-5-氯吡啶为原料，同实施例31步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝220。
步骤2 (2S)-2-(((4-(5-氯吡啶-2-基)-3-甲基苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物4-(5-氯吡啶-2-基)-3-甲基苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),8.69(m,1H),7.54-7.57(m,2H),7.39-7.42(m,1H),7.14-7.17(m,2H),6.05-6.12(m,2H),5.85(m,1H),5.54-5.57(m,1H),4.82-4.91(m,1H),4.36-4.42(m,1H),4.21-4.27(m,2H),3.90-4.01(m,1H),3.82-3.88(m,2H),2.30(m,3H),1.21-1.29(m,6H),1.14-1.16(m,6H)。
LC-MS m/z:[M+H]+＝655。
实施例34 (2S)-2-(((4-(3-氟吡啶-2-基)-3-甲基苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000047
步骤1 4-(3-氟吡啶-2-基)-3-甲基苯酚的制备
以2-甲基-4-羟基苯硼酸和2-溴-3-氟吡啶为原料，同实施例31步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝204。
步骤2 (2S)-2-(((4-(3-氟吡啶-2-基)-3-甲基苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
以步骤1所得物4-(3-氟吡啶-2-基)-3-甲基苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),8.53(m,1H),8.13(m,1H),7.79-7.86(m,1H),7.50-7.57(m,1H),7.31-7.34(m,1H),7.15-7.20(m,2H),6.06-6.13(m,2H),5.84(m,1H),5.58-5.60(m,1H),4.85-4.89(m,1H),4.39(m,1H),4.28(m,1H),4.03(m,1H),3.83-3.85(m,2H),2.15(m,3H),1.22-1.29(m,6H),1.15-1.17(m,6H)。
LC-MS m/z:[M+H]+＝639。
实施例35 (2S)-2-(((4-(5-氯噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000048
步骤1 2-溴-1-(4-甲氧基苯基)乙酮的制备
以1-(4-甲氧苯基)乙酮为原料，同实施例21步骤1的方法制得标题化合物。步骤2 4-(4-甲氧基苯基)噁唑的制备
以步骤1所得物2-溴-1-(4-甲氧基苯基)乙酮和甲酰胺为原料，同实施例21步骤2的方法制得标题化合物。
LC-MS m/z:[M+H]+＝176。
步骤3 5-氯-4-(4-甲氧基苯基)噁唑的制备
称取3.0g步骤2所得物4-(4-甲氧基苯基)噁唑(0.0171mol)于100ml的单口瓶中，加入30mL乙腈溶解后，加入2.29g NCS(0.0171mol)，室温反应2h，反应结束后，浓缩，柱层析纯化得到标题化合物。
LC-MS m/z:[M+H]+＝210。
步骤4 4-(5-氯噁唑-4-基)苯酚的制备
称取1.3g步骤3所得物5-氯-4-(4-甲氧基苯基)噁唑(6.22mmol)于50mL 的单口瓶中，加入15mL甲磺酸溶解后，加入3.71g DL-Met(24.8mmol)，加毕，60℃反应24h，反应结束后，冷却，倒入冰水，乙酸乙酯萃取(50mL x 6)，干燥，过滤，浓缩，柱层析纯化得标题化合物。
1H NMR(300MHz,DMSO-d6)δppm:9.76(s,1H),8.48(s,1H),7.69(d,2H),6.88(d,2H)。
LC-MS m/z:[M+H]+＝196。
步骤5 (2S)-2-(((4-(5-氯噁唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤4所得物4-(5-氯噁唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),8.55(s,1H),7.87(d,2H),7.56(d,1H),7.37(d,2H),5.90-6.20(m,2H),5.85(d,1H),5.57(d,1H),4.77-4.92(m,1H),4.20-4.45(m,2H),3.95-4.10(m,1H),3.70-3.95(m,2H),1.18-1.40(m,6H),1.15(d,6H)。
LC-MS m/z:[M+H]+＝631。
实施例36 (2S)-2-(((4-(3-氯吡啶-2-基)-3-甲基苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000049
步骤1 4-(3-氯吡啶-2-基)-3-甲基苯酚的制备
以2-溴-3-氯吡啶和4-羟基-2-甲基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝220。
步骤2 (2S)-2-(((4-(3-氯吡啶-2-基)-3-甲基苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(3-氯吡啶-2-基)-3-甲基苯酚、三氯氧磷、L-丙氨酸异丙 酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得标题化合物。
1HNMR(300MHz,DMSO-d6)δppm:11.48(s,1H),8.61(d,1H),8.01(d,1H),7.58(d,1H),7.46(d,1H),7.23-7.02(m,3H),6.20-5.90(m,3H),5.58(m,1H),4.88-4.83(m,1H),4.39-4.26(m,2H),4.01-3.98(m,1H),3.90-3.78(m,2H),2.04(s,3H),1.29-1.22(m,6H),1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝655。.
实施例37 (2S)-2-(((4-(5-氯-1-甲基-1H-咪唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000050
步骤1 4-(5-氯-1-甲基-1H-咪唑-4-基)苯酚的制备
称取0.81g实施例30步骤1所得物4-(1-甲基-1H-咪唑-4-基)苯酚(5.14mmol)，0.62g NCS(5.14mmol)于100mL的单口瓶中，加入20mL乙腈溶解，回流反应1h，反应结束后，浓缩，柱层析纯化得标题化合物。
步骤2 (2S)-2-(((4-(5-氯-1-甲基-1H-咪唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(5-氯-1-甲基-1H-咪唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.51(s,1H),8.40(s,1H),7.84(d,2H),7.56(d,1H),7.35(d,2H),6.17-6.05(m,2H),5.86(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),3.62(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝644。
实施例38 (2S)-2-(((3-氟-4-(1-甲基-1H-咪唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000051
步骤1 3-氟-4-(1-甲基-1H-咪唑-4-基)苯酚
以4-溴-1-甲基-1H-咪唑和2-氟-4-羟基苯硼酸为原料，同实施例26步骤1的方法制得标题化合物。
步骤2 (2S)-2-(((3-氟-4-(1-甲基-1H-咪唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物3-氟-4-(1-甲基-1H-咪唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝628。
实施例39 (2S)-2-(((4-(2-甲基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000052
步骤1 4-(2-甲基噻唑-4-基)苯酚的制备
以2-甲基-4-溴噻唑和4-羟基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝192。
步骤2 (2S)-2-(((4-(2-甲基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(2-甲基噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝627。
实施例40 (2S)-2-(((4-(5-氯-2-甲基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000053
步骤1 4-(5-氯-2-甲基噻唑-4-基)苯酚的制备
以实施例39步骤1所得物4-(2-甲基噻唑-4-基)苯酚为原料，同实施例37步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝226。
步骤2 (2S)-2-(((4-(5-氯-2-甲基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯的制备
以步骤1所得物4-(5-氯-2-甲基噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝661。
实施例41 (2S)-2-(((4-(5-氯-2-甲基噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
Figure PCTCN2015085380-appb-000054
以实施例40步骤1所得物4-(5-氯-2-甲基噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸甲酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝633。
实施例42 (2S)-2-(((4-(5-氯-噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
Figure PCTCN2015085380-appb-000055
以实施例18步骤2所得物4-(5-氯噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸甲酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),9.13(s,1H),7.92(d,2H),7.56(d,1H),7.35(d,2H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),3.58(s,3H),1.28-1.22(m,6H)。
LC-MS m/z:[M+H]+＝619。
实施例43 (2S)-2-(((4-(5-氯噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸乙酯
Figure PCTCN2015085380-appb-000056
以实施例18步骤2所得物4-(5-氯噻唑-4-基)苯酚、三氯氧磷、L-丙氨酸乙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝633。
实施例44 (2S)-2-(((4-(3-氟吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
Figure PCTCN2015085380-appb-000057
以实施例2步骤1所得物4-(3-氟吡啶-2-基)苯酚、三氯氧磷、L-丙氨酸甲酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝597。
实施例45 (2S)-2-(((4-(3-氟吡啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸乙酯
Figure PCTCN2015085380-appb-000058
以实施例2步骤1所得物4-(3-氟吡啶-2-基)苯酚、三氯氧磷、L-丙氨酸乙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝611。
实施例46 (2S)-2-(((苯并[b]噻吩-4-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000059
以4-羟基苯并噻吩、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.49(s,1H),7.84-7.78(m,2H),7.51(d,2H),7.37-7.30(m,2H),6.20-6.02(m,2H),5.88(m,1H),5.43(m,1H),4.86(m,1H),4.43-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),1.28-1.22(m,6H),1.14-1.12(m,6H)。
LC-MS m/z:[M+H]+＝586。
实施例47 (2S)-2-(((苯并[b]噻吩-4-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
Figure PCTCN2015085380-appb-000060
以4-羟基苯并噻吩、三氯氧磷、L-丙氨酸甲酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝558。
实施例48 (2S)-2-(((3-甲基苯并[b]噻吩-4-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000061
以3-甲基-4-羟基苯并噻吩、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
LC-MS m/z:[M+H]+＝600。
实施例49 (2S)-2-(((4-(3-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
Figure PCTCN2015085380-appb-000062
步骤1 4-(3-甲基噻吩-2-基)苯酚的制备
以2-溴-3-甲基噻吩和4-羟基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝191。
步骤2 (2S)-2-(((4-(3-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
以步骤1所得物4-(3-甲基噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸甲酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.50(s,1H),7.57(s,1H),7.46-7.43(m,3H),7.30(d,2H),7.00(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),3.60(s,3H),2.24(s,3H),1.28-1.22(m,6H)。
LC-MS m/z:[M+H]+＝598。
实施例50 (2S)-2-(((4-(3-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯
Figure PCTCN2015085380-appb-000063
以实施例49步骤1所得物4-(3-甲基噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.50(s,1H),7.57(s,1H),7.46-7.43(m,3H),7.30(d,2H),7.00(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H), 4.88-4.83(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),2.26(s,3H),1.28-1.22(m,6H),1.17-1.14(m,6H)。
LC-MS m/z:[M+H]+＝626。
实施例51 (2S)-2-(((4-(5-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
Figure PCTCN2015085380-appb-000064
步骤1 4-(5-甲基噻吩-2-基)苯酚的制备
以2-溴-5-甲基噻吩和4-羟基苯硼酸为原料，同实施例1步骤1的方法制得标题化合物。
LC-MS m/z:[M+H]+＝191。
步骤2 (2S)-2-(((4-(5-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
以步骤1所得物4-(5-甲基噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸甲酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.51(s,1H),7.59-7.55(m,3H),7.25-7.21(m,3H),6.81(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),3.30(s,3H),2.46(s,3H),1.29-1.22(m,6H)。
LC-MS m/z:[M+H]+＝598。
实施例52 (2S)-2-(((4-(5-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯酯
Figure PCTCN2015085380-appb-000065
以实施例51步骤1所得物4-(5-甲基噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸异丙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),7.59-7.55(m,3H),7.25-7.22(m,3H),6.80(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.88-4.83(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),2.46(s,3H),1.28-1.22(m,6H),1.16-1.14(m,6H)。
LC-MS m/z:[M+H]+＝626。
实施例53 (2S)-2-(((4-(5-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸乙酯
Figure PCTCN2015085380-appb-000066
以实施例51步骤1所得物4-(5-甲基噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸乙酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),7.55-7.57(m,3H),7.21-7.25(m,3H),6.80-6.81(m,1H),6.60-6.61(m,1H),5.98-6.04(m,1H),5.83-5.86(m,1H),5.55-5.58(m,1H),4.34-4.40(m,1H),4.20-4.26(m,1H),3.90-3.93(m,1H),3.85-3.88(m,2H),3.58(m,2H),2.45-2.49(m,3H),1.21-1.29(m,9H)。
LC-MS m/z:[M+H]+＝612。
实施例54 (2S)-2-(((4-(噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸乙酯
Figure PCTCN2015085380-appb-000067
以实施例26步骤1所得物4-(噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸乙酯盐 酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(300MHz,DMSO-d6)δppm:11.50(s,1H),7.65(d,2H),7.58-7.52(m,2H),7.45(d,1H),7.25(d,2H),7.13-7.10(m,1H),6.14-6.06(m,2H),5.85-5.82(m,1H),5.58-5.55(m,1H),4.40-4.36(m,1H),4.26-4.22(m,1H),4.07-4.00(m,3H),3.89-3.81(m,2H),1.29-1.23(m,6H),1.16-1.11(t,3H)。
LC-MS m/z:[M+H]+＝598。
实施例55 (2S)-2-(((4-(噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸甲酯
Figure PCTCN2015085380-appb-000068
以实施例26步骤1所得物4-(噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸甲酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.48(s,1H),7.66(d,2H),7.58-7.51(m,2H),7.46(d,1H),7.26(d,2H),7.13(m,1H),6.15-6.00(m,2H),5.87(m,1H),5.56(m,1H),4.41-4.37(m,1H),4.28-4.21(m,1H),4.05(m,1H),4.01-3.80(m,2H),3.60(s,3H),1.29-1.17(m,6H)。
LC-MS m/z:[M+H]+＝584。
实施例56 (2S)-2-(((4-(噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸新戊酯
Figure PCTCN2015085380-appb-000069
以实施例26步骤1所得物4-(噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸新戊酯 盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.51(s,1H),7.65(d,2H),7.58-7.51(m,2H),7.45(d,1H),7.26(d,2H),7.14-7.11(m,1H),6.17-6.00(m,2H),5.86(d,1H),5.58(d,1H),4.40-4.21(m,2H),4.05-3.98(m,1H),3.93-3.85(m,3H),3.64(m,1H),1.31-1.21(m,6H)，0.86(s,9H)。
LC-MS m/z:[M+H]+＝640。
实施例57 (2S)-2-(((4-(3-甲基噻吩-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸新戊酯
Figure PCTCN2015085380-appb-000070
以实施例49步骤1所得物4-(3-甲基噻吩-2-基)苯酚、三氯氧磷、L-丙氨酸新戊酯盐酸盐、五氟苯酚和(2'R)-2'-脱氧-2'-氟-2'-甲基尿苷为原料，同实施例1步骤2和3的方法，制得目标化合物。
1H NMR(500MHz,DMSO-d6)δppm:11.50(s,1H),7.58(d,1H),7.45(m,3H),7.30(d,2H),7.00(d,1H),6.17-6.02(m,2H),5.87(m,1H),5.56(m,1H),4.40-4.21(m,2H),4.05-3.98(m,1H),3.93-3.85(m,3H),3.64(m,1H),2.26(s,3H),1.31-1.23(m,6H)，0.87(s,9H)。
LC-MS m/z:[M+H]+＝654。
药理活性评价
实验例1本发明的化合物在HCV复制子***中的抗病毒活性检测
1.实验材料
1.1试剂：
表1试剂列表
Figure PCTCN2015085380-appb-000071
Figure PCTCN2015085380-appb-000072
1.2 Huh7 1b细胞系：
Huh7 1b细胞系由上海药明康德新药开发有限公司提供，为包含带有稳定的荧光素酶(Luc)报告子的HCV 1b复制子的Huh7细胞系。其通过基因重组技术将HCV非结构蛋白基因、neo(G418抗性)及荧光素酶报告基因克隆入pBR载体构建。然后将携带有HCV复制子的载体转染入huh7细胞，通过G418抗性筛选，HCV复制子可稳定复制且相关蛋白和荧光素酶在huh7细胞内稳定表达。该细胞模型用于抗HCV化合物体外筛选。通过检查荧光素酶发光底物的化学发光水平而测定化合物的抗HCV的活性。参见Lohmann V,et al.1999.Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.Science.285(5424):110-113.
2.实验方法：
1)化合物准备：使用本发明以上实施例制备的化合物，每个化合物用DMSO配制成母液，然后用含0.5％DMSO的DMEM完全培养液稀释至10μM作为化合物起始终浓度，3倍稀释，共10个浓度，用POD 810全自动微孔板预处理***(LabCyte公司，美国)将化合物分别加入到96孔板中；同时设立无效作用对照组(含0.5％DMSO的完全培养液代替化合物)和100％有效作用对照组(只加入含0.5％DMSO的完全培养液)；
2.1细胞准备：收集对数期的Huh7 1b细胞，用DMEM完全培养液重悬后，接种到96孔板中，每孔125μl，8×103个细胞/孔，置于37℃、5％CO2培养箱培养细胞72小时；
2.2细胞活力检测：每孔加30μl细胞生长荧光滴定检测试剂，37℃、5％CO2培养箱培养细胞1小时，分光光度仪上检测荧光信号值，所得数据用于化合物细胞毒性计算；
2.3 Bright-Glo检测：每孔加100μl荧光素酶发光底物Bright-Glo，5分钟内用化学发光检测***EnVision(PerkinElmer公司，美国)检测荧光信号值，所得数据用于化合物活力计算。
2.4数据处理：使用如下公式将所得数据转换为细胞活力百分比(Viability％)：
Figure PCTCN2015085380-appb-000073
CPD：化合物孔的荧光信号值
HPE(Hundred percent effect):100％有效作用对照荧光信号值
ZPE(Zero percent effect):无效作用对照荧光信号值使用如下公式将原始数据处理为抑制百分数(Inhibition％)：
Figure PCTCN2015085380-appb-000074
CPD：化合物孔的化学发光信号值
HPE(Hundred percent effect):100％有效作用化学发光信号值
ZPE(Zero percent effect):无效作用化学发光信号值
将抑制百分数导入GraphPad Prism进一步处理得出对应曲线和EC50值。
实验结果表明，本发明化合物的EC50在约0.05μM-1μM之间，具有非常好的抑制HCV病毒的能力。部分数据见表2。
表2
实施例编号 EC50(μM) 实施例编号 EC50(μM)
实施例1 0.3266 实施例2 0.1312
实施例3 0.3912 实施例4 1.188
实施例5 0.4984 实施例6 0.4834
实施例9 0.665 实施例10 0.1498
实施例11 0.695 实施例12 0.240
实施例13 0.772 实施例14 0.380
实施例15 0.523 实施例17 0.443
实施例18 0.062 实施例19 0.557
实施例20 0.0783 实施例21 0.173
实施例22 0.104 实施例23 0.265
实施例24 0.055 实施例25 0.204
实施例26 0.019 实施例27 0.169
实施例28 0.142 实施例31 0.103
实施例32 0.174 实施例33 0.130
实施例34 0.196 实施例35 0.051
实施例36 0.146 实施例42 0.065
实施例46 0.055 实施例49 0.049
实施例50 0.063 实施例51 0.018
实施例52 0.021 实施例53 0.097
实施例54 0.020 实施例55 0.032
实施例56 0.028 实施例57 0.030
如Gilead公司的官方网站上所公布的，目前最好的抗HCV药物sofosbuvir(GS7977)在HCV复制子测定中对基因1b型的EC50值为0.102μM，具体参见http://www.gilead.com/～/media/Files/pdfs/medicines/liver-disease/sova ldi/sovaldi_pi.pdf。本发明的化合物具有与sofosbuvir相当或更优的抗HCV病毒活性。
实验例2本发明的化合物对HCV细胞感染模型(Cell-culture-derived infectious HCV，HCVcc)的抗病毒活性检测
1实验材料
1.1化合物
本实验例使用以上实施例制备的本发明的化合物，用DMSO配制成10mM母液后，用含0.5％DMSO的DMEM完全培养液稀释至1000nM，然后依次3倍稀释，共8个浓度。
1.2细胞
Huh 7.5.1细胞，由上海药明康德新药开发有限公司提供。
1.3病毒
J399EM(HCV genotype 2a)病毒，即转染了EGFP(增强型绿色荧光蛋白)的HCV全长突变株，与JFH-1野生型具有相同的感染能力，同时通过在NS5A区 域***EGFP编码序列，可以直接在感染细胞内观察NS5A-EGFP融合蛋白荧光，由上海药明康德新药开发有限公司提供。
1.4试剂
Figure PCTCN2015085380-appb-000075
2实验方法
2)Huh 7.5.1细胞准备：收集对数期的Huh 7.5.1细胞，用DMEM完全培养液重悬后，接种于96孔板中(7×103个细胞/孔)，置于37℃、5％CO2培养箱中培养过夜；
3)药物处理：将本发明化合物分别加入到96孔板中，化合物起始终浓度均为1000nM，每个化合物做双复孔，3倍稀释，共8个浓度，DMSO终浓度0.5％；同时设立无效作用对照组(含0.5％DMSO的完全培养液代替化合物)和100％有效作用对照组(加入无病毒感染的细胞)；
4)病毒感染：将J399EM病毒上清以每孔MOI 0.2的浓度加入96孔板中。随后置于37℃、5％CO2培养箱中培养3天。
5)抗病毒活性测定：培养结束后，每孔加入荧光素酶发光底物，用化学发光检测***Envision检测Luminescence信号值，所得数据用于化合物抑制HCV活性计算，计算公式为：
Inhibition％＝(RLUs-RLUc)/(RLUV-RLUc)×100
其中，RLUV表示病毒对照组(含0.5％DMSO的完全培养液代替化合物)的化学发光强度，RLUS表示对应化合物处理组的化学发光强度，RLUC表示细胞对照组(无病毒感染的细胞)的化学发光强度；
6)细胞毒性测定：细胞和化合物处理方法同以上步骤，但以培养基替代病毒加 入实验板中。同样条件37℃，5％CO2培养箱中培养3天后，加入细胞活力检测试剂Alamar Blue，用分光光度仪检测Fluorescence信号值。所得数据用于化合物细胞毒性计算，计算公式为：
Viability％＝RFUS/RFUM×100
其中，RFUM表示溶媒对照组(含0.5％DMSO的完全培养液代替化合物)的荧光强度，RFUS表示对应化合物处理组的荧光强度；
7)数据处理：将抑制百分数、细胞活力百分数分别导入GraphPad Prism软件进行数据处理，得出化合物对应的曲线及其对HCV的抑制活性(EC50)和细胞毒性(CC50)数值。
实验结果显示，本发明的化合物的EC50值基本上在40nM-150nM之间，CC50均大于1000nM，例如实施例20的化合物的EC50为53.4nM，CC50>1000nM。部分本发明的化合物的EC50值更小，例如实施例26的EC50为9.3nM，CC50>1000nM。由此可见，本发明的化合物具有优异的抗病毒活性，同时具有小的细胞毒性，安全性好。
另外，本发明的发明人发现，本发明的化合物具有良好的血浆蛋白结合率，适于成药，具有非常好的临床应用前景。尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。

Claims (12)

  1. 通式I所示的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶：
    Figure PCTCN2015085380-appb-100001
    其中：
    R1选自H、烷基和卤代烷基；
    R2选自H和卤素；
    R3选自H、OH和烷氧基；
    R4选自H和烷基，其中所述烷基任选被选自烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；
    R5选自H、烷基、环烷基、芳基和杂芳基，其中所述烷基、环烷基、芳基和杂芳基任选被选自烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；
    Cy1选自芳基和杂芳基，其中所述的芳基和杂芳基任选被选自卤素、羟基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、硝基和氰基中的一个或多个基团取代；
    Cy2选自氢、芳基、杂芳基、杂环烷基和杂环烯基，其中所述的芳基、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、硝基和氰基中的一个或多个基团取代；
    条件是Cy1为芳基时，Cy2不为氢或芳基，且所述化合物不是以下化合物：(2S)-2-(((4-(1,2,3-噻二唑-4-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((2-(喹喔啉-5-基)苯-1-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙 酯；
    (2S)-2-(((4-(噻唑-2-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((4-(噻唑-5-基)苯-1-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((4-氟-2-甲基-1H-吲哚-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((3-甲氧羰基甲基-苯并呋喃-7-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；(2S)-2-(((4-氧代-2-苯基-4H-苯并吡喃-6-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((喹喔啉-5-基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((4-氧代-2-苯基苯并二氢吡喃-7-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-((((4-(1H-1,2,4-***-1-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((4-(嘧啶-2-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-(((S)-((4-氟-1,2-二甲基-1H-吲哚-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-((((6-氟-3-甲基苯并[d]异噁唑-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；
    (2S)-2-((((6-氟苯并[c][1,2,5]噻二唑-5-基)氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代 -3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯；和
    (2S)-2-(((4-(噻唑-4-基)苯基氧基)(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰基)氨基)丙酸异丙酯。
  2. 根据权利要求1所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中R1选自H、C1-6烷基和卤代C1-6烷基；R2选自H、氟、氯和溴；R3选自H和OH；R4选自H和C1-6烷基，其中所述烷基任选被选自C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；和R5选自C1-6烷基和C3-8环烷基，其中所述的烷基任选被选自C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代。
  3. 根据权利要求1所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Cy1选自苯环，Cy2选自C4-8杂芳基、C4-8杂环烷基和C4-8杂环烯基，其中所述的苯环、杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基和氰基中的一个或多个基团取代。
  4. 根据权利要求1-3之任一项所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Cy1选自苯环，Cy2选自含有1-3个N原子的五元或六元杂芳基、杂环烷基和杂环烯基，其中所述的苯环、五元或六元杂芳基、杂环烷基或杂环烯基任选被选自卤素、羟基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基和氰基中的一个或多个基团取代。
  5. 根据权利要求1或2所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Cy1选自萘环、杂芳基，Cy2选自氢、芳基、杂芳基、C4-8杂环烷基、C4-8杂环烯基，其中所述的萘环、芳基、杂芳基、杂环烷基、杂环烯 基任选被选自卤素、羟基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基和氰基中的一个或多个基团取代。
  6. 根据权利要求1所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中所述化合物是通式Ia所示的化合物：
    Figure PCTCN2015085380-appb-100002
    其中：
    Ra1选自杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、烷基酰基、烷氧基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基中的一个或多个基团取代；
    Ra2选自氢、卤素、羟基、氨基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、烷基酰基、烷氧基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
    Ra1、Ra2与它们连接的碳原子一起构成杂芳基、杂环烷基或杂环烯基；
    Ra3、Ra4、Ra5独立地选自氢、卤素、羟基、氨基、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、烷基酰基、烷氧基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；
    R1选自H、烷基和卤代烷基；
    R2选自H和卤素；
    R3选自H、OH和烷氧基；
    R4选自H和烷基，其中所述烷基任选被选自烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；和
    R5选自H、烷基、环烷基、芳基和杂芳基，其中所述烷基任选被选自烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、硝基、氰基、烷基 酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代。
  7. 根据权利要求6所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自至少含有一个N原子的五元或六元杂芳基、杂环烷基和杂环烯基，其中所述的杂芳基、杂环烷基和杂环烯基任选被选自卤素、羟基、氨基、C1-6烷基、C2-4烯基、C2-4炔基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基中的一个或多个基团取代；和
    Ra2选自氢、卤素、羟基、氨基、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者
    Ra1、Ra2与它们连接的碳原子一起构成至少含有一个N原子的五元或六元杂芳基、杂环烷基或杂环烯基。
  8. 根据权利要求6所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中Ra1选自呋喃环、吡咯环、噻吩环、咪唑环、吡唑环、噻唑环、异噻唑环、噁唑环、异噁唑环、三氮唑环、噻二唑环、噁二唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环、苯并硫氮杂环，其中所述的Ra1任选被选自卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基和氰基中的一个或多个基团取代；Ra2、Ra3、Ra4、Ra5独立地选自氢、卤素、羟基、氨基、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷基氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基；或者，
    Ra1、Ra2与它们连接的碳原子一起构成苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环或苯并硫氮杂环，其中所述的苯并氮杂环、苯并氧杂环、苯并硫杂环、苯并二氮杂环、苯并二氧杂环、苯并二硫杂环、苯并氧氮杂环或苯并硫氮杂环任选被选自卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、硝基和氰基中的一个或多个基团取代；Ra3、Ra4、Ra5独立地选自氢、卤素、羟基、氨基、 C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氨基、C1-6烷基酰基、C1-6烷氧基酰基、氨基酰基、C1-6烷基氨基酰基、磺酰基、亚磺酰基、巯基、硝基和氰基。
  9. 根据权利要求6-8之任一项所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中R1选自H、C1-6烷基和卤代C1-6烷基；R2选自H、氟、氯和溴；R3选自H和OH；R4选自H和C1-6烷基，其中所述烷基任选被选自C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；和R5选自C1-6烷基和C3-8环烷基，其中所述的烷基和环烷基任选被选自C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基和杂芳基中的一个或多个基团取代；优选地，其中R1为甲基，R2为氟，R3为OH，R4为甲基和R5为异丙基。
  10. 根据权利要求1至9之任一项所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶，其中所述化合物为选自以下的化合物：
    Figure PCTCN2015085380-appb-100003
    Figure PCTCN2015085380-appb-100004
    Figure PCTCN2015085380-appb-100005
    Figure PCTCN2015085380-appb-100006
    Figure PCTCN2015085380-appb-100007
    Figure PCTCN2015085380-appb-100008
  11. 一种药物组合物，其包含权利要求1至10之任一项所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶和可药用载体。
  12. 权利要求1-10之任一项所述的化合物或其立体异构体、药学可接受的盐、水合物、溶剂合物或结晶或权利要求11所述的药物组合物在制备用于治疗和/或预防肝炎病毒感染的药物中的应用。
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