WO2015101215A1 - 9,9,10,10-四氟-9,10二氢菲类丙型肝炎病毒抑制剂及其应用 - Google Patents

9,9,10,10-四氟-9,10二氢菲类丙型肝炎病毒抑制剂及其应用 Download PDF

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WO2015101215A1
WO2015101215A1 PCT/CN2014/095043 CN2014095043W WO2015101215A1 WO 2015101215 A1 WO2015101215 A1 WO 2015101215A1 CN 2014095043 W CN2014095043 W CN 2014095043W WO 2015101215 A1 WO2015101215 A1 WO 2015101215A1
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alkyl
group
acyl
amino
cycloalkyl
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PCT/CN2014/095043
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English (en)
French (fr)
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王勇
赵立文
王德忠
周海平
张先
陈宏雁
张迪
张仓
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南京圣和药业股份有限公司
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Priority to AU2014375584A priority Critical patent/AU2014375584B2/en
Priority to KR1020167011524A priority patent/KR101857689B1/ko
Priority to EP14876481.4A priority patent/EP3091010A4/en
Priority to JP2016531709A priority patent/JP2017536329A/ja
Priority to CA2935089A priority patent/CA2935089C/en
Priority to CN201480071487.0A priority patent/CN105873922B/zh
Priority to US15/030,990 priority patent/US9512108B2/en
Publication of WO2015101215A1 publication Critical patent/WO2015101215A1/zh
Priority to HK16110959.0A priority patent/HK1222845A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/18—Polycyclic aromatic halogenated hydrocarbons
    • C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the invention belongs to the field of chemical medicine, and particularly relates to a compound having a 9,9,10,10-tetrafluoro-9,10 dihydrophenanthrene structure, capable of inhibiting the activity of hepatitis C virus or a pharmaceutically acceptable salt thereof, and isomer , solvates, crystals or prodrugs, as well as pharmaceutical compositions containing these compounds and the use of these compounds or compositions in the preparation of medicaments.
  • Viral hepatitis C is a contagious disease of acute and chronic inflammation of the liver caused by hepatitis C virus (HCV). It can easily evolve into chronic liver disease after HCV infection, such as chronic hepatitis and liver. Hardening and liver cancer, etc., seriously affect people's health.
  • HCV hepatitis C virus
  • HCV belongs to the Flaviviridae family and can be divided into 6 genotypes and different subtypes. According to internationally accepted methods, HCV genotypes are represented by Arabic numerals, and subtypes of genes are represented by lowercase English letters. The distribution, accounting for more than 70% of all HCV infections, the main infection type in the Chinese population is HCV 1b subtype. It has been found that the 5' and 3' ends of HCV positive-stranded RNA contain a non-coding region (UTR), and a large polyprotein open reading frame (ORF) is between UTRs.
  • UTR non-coding region
  • ORF large polyprotein open reading frame
  • the ORF encodes a polyprotein precursor of approximately 3000 amino acids long and is cleaved into a variety of HCV mature proteins by a combination of a host-encoded signal peptidase and a HCV-encoded protease.
  • the HCV mature protein includes 4 structural proteins and 6 non-structural proteins, of which 6 non-structural proteins are named NS2, NS3, NS4A, NS4B, NS5A, NS5B.
  • NS3 which regulates the activity of NS3 serine protease
  • NS5A is a phosphorylated protein containing interferon sensitivity-determining regions, in the efficacy of interferon It has an important role in prediction, viral replication, antiviral resistance, hepatocellular carcinogenesis, etc., and has become the focus of HCV nonstructural protein research.
  • L 1 and L 2 are each independently selected from the group consisting of aryl, heteroaryl, -aryl-aryl-, -aryl-heteroaryl-, -heteroaryl-heteroaryl-, said aryl or A heteroaryl group can be composed of one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, Carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, Bisalkylaminoalkyl, alkylacyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alky
  • p, q are independently selected from 1, 2 and 3;
  • R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetero
  • the aryl group may be one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, single An alkylamino group, a dialkylamino group, an alkyl acyl group, an alkoxy acyl group, an alkyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group, an alkyl acylamino group;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, Carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl a heteroaryl group, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R 5 or R 6 and a C atom to which it is bonded may form a cycloalkyl or heterocycloalkyl group;
  • the hydroxy, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl, heteroaryl groups may be substituted by one or more halogen, hydroxy, amino, carboxy groups.
  • cyano nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, dialkylamino, alkyl acyl, alkoxy acyl Alkyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • a further object of the present invention is to provide a composition comprising a compound of Formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another HCV inhibitor.
  • a further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for the treatment and/or prophylaxis of diseases caused by hepatitis C virus, for example A method of liver disease, and the use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for the manufacture of a medicament for the treatment and/or HCV infection.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • L 1 and L 2 are each independently selected from the group consisting of aryl, heteroaryl, -aryl-aryl-, -aryl-heteroaryl-, -heteroaryl-heteroaryl-, said aryl or A heteroaryl group can be composed of one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, Carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, Bisalkylaminoalkyl, alkylacyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alky
  • p, q are independently selected from 1, 2 and 3;
  • R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetero
  • the aryl group may be one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, single An alkylamino group, a dialkylamino group, an alkyl acyl group, an alkoxy acyl group, an alkyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group, an alkyl acylamino group;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, Carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl a heteroaryl group, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R 5 or R 6 and a C atom to which it is bonded may form a cycloalkyl or heterocycloalkyl group.
  • the hydroxyl group, amino group, carboxyl group, alkyl group, cycloalkyl group, heterocycloalkyl group, alkoxy group, alkoxyalkyl group, aryl group, heteroaryl group may be one or more halogen, hydroxyl group, amino group, Carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl Alkyl acyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • L 1 and L 2 are each independently selected from the group consisting of phenyl, naphthyl, imidazolyl, benzimidazolyl, -phenyl-imidazolyl-, imidazopyridinyl, quinazolinone, pyrrolyl, imidazolidinyl, Furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, phenyl, naphthyl, imidazolyl, benzimidazole , -phenyl-imidazolyl-, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, Isothiazolyl, oxadia
  • L 1 and L 2 are each independently selected from the group consisting of phenyl, naphthyl, imidazolyl, 1H-benzo[d]imidazolyl, 5-phenyl-1H-imidazolyl, 1H-imidazo[4,5 -b]pyridyl, quinazolin-4(3H)keto, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, Oxadiazolyl, triazolyl, phenyl, naphthyl, imidazolyl, 1H-benzo[d]imidazolyl, 5-phenyl-1H-imidazolyl, 1H-imidazo[4,5- b] pyridyl, quinazolin-4(3H)keto, pyrrolyl, imidazolidinyl, furyl,
  • L 1 and L 2 are each independently selected from the group consisting of:
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkane Base, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl , bisalkylamino, bisalkylaminoalkyl, alkyl acyl, alkyl acylalkyl, alkoxy acyl, alkoxyacylalkyl, alkyl acyloxy, alkyl acyloxyalkyl, amino Acyl, aminoacylalkyl, monoalkylaminoacyl, monoalkylaminoacylalkyl, bisalkylaminoacyl, bisal
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl, said C 1-10 Alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, ring Alkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl, alkyl acyloxy, amino acyl, monoalkane Alkylamino, bisalkylaminoacyl, alkylacylamino substituted;
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, aryl or heteroaryl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, aryl or heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 heterocycloalkyl, C 1-6 alkoxy such as methoxy, ethoxy, propoxy, hydroxy-C 1-6 Alkyl, carboxy-C 1-6 alkyl, mono C 1-6 alkylamino, bis C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, C 1- a 6 alkyl acyloxy group, an amino acyl group, a mono C 1-6 alkylamino acyl
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, and ring.
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, said C 1-10 alkyl, C 3-8 A cycloalkyl or C 3-8 heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl , heteroaryl substitution;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, said C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C 1-6 alkyl, C 3-7 cycloalkyl , C 3-7 heterocycloalkyl, C 1-6 alkoxy, aryl, heteroaryl substituted;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, Cyclobutane, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, said Methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, tetra Hydropyrrolidinyl
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, halogen, C 1-6 alkane.
  • the C atom may form a C 3-8 cycloalkyl group or a C 3-8 heterocycloalkyl group; the hydroxy group, the amino group, the C 1-10 alkyl group, the C 3-8 cycloalkyl group, the C 3-8 heterocycloalkane.
  • halogen, C 1-6 alkoxy-C 1-6 alkyl, aryl, heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, naphthenic , heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxyacyl acyloxy, amino acyl, monoalkylamino Acyl, bisalkylaminoacyl, alkylacylamino substituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, halogen, C 1 -6 alkoxy-C 1-6 alkyl, aryl, heteroaryl, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R 5 or R 6
  • the C atom to which it is attached may form a C 3-6 cycloalkyl group or a C 3-6 heterocycloalkyl group; said hydroxy group, amino group, C 1-6 alkyl group, C 3-7 cycloalkyl group, C 3-7 Heterocycloalkyl, halogen, C 1-6 alkoxy-C 1-6 alkyl, aryl, heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl , cycloalkyl,
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.
  • heptyl can be substituted by one or more halogens, Hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, Alkoxyacylalkylacyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.
  • halogens Hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, Alkoxyacylalkylacyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein Each independently selected from substituted or unsubstituted
  • the substituent is selected from the group consisting of halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bis Alkylamino, alkylacyl, alkoxyacyloxycarbonyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.
  • the invention provides a compound of Formula Ia, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof,
  • L 1 and L 2 are each independently selected from the group consisting of aryl, heteroaryl, -aryl-aryl-, -aryl-heteroaryl-, -heteroaryl-heteroaryl-, said aryl or A heteroaryl group can be composed of one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, Carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, Bisalkylaminoalkyl, alkylacyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alky
  • p, q are independently selected from 1, 2 and 3;
  • R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetero
  • the aryl group may be one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, single An alkylamino group, a dialkylamino group, an alkyl acyl group, an alkoxy acyl group, an alkyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group, an alkyl acylamino group;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, Carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl a heteroaryl group, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R 5 or R 6 and a C atom to which it is bonded may form a cycloalkyl or heterocycloalkyl group.
  • the hydroxyl group, amino group, carboxyl group, alkyl group, cycloalkyl group, heterocycloalkyl group, alkoxy group, alkoxyalkyl group, aryl group, heteroaryl group may be one or more halogen, hydroxyl group, amino group, Carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl Alkyl acyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.
  • the compound of the invention is a compound of formula I or formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:
  • p, q are independently selected from 1, 2 and 3;
  • L 1 and L 2 are each independently selected from the group consisting of phenyl, naphthyl, imidazolyl, benzimidazolyl, -phenyl-imidazolyl-, imidazopyridinyl, quinazolinone, pyrrolyl, imidazolidinyl, Furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, phenyl, naphthyl, imidazolyl, benzimidazole , -phenyl-imidazolyl-, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, Isothiazolyl, oxadia
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl, said C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C 1-6 Alkyl, C 1-8 cycloalkyl, C 1-8 heterocycloalkyl, C 1-6 alkoxy, such as methoxy, ethoxy, propoxy, hydroxy-C 1-6 alkyl, Carboxyl-C 1-6 alkyl, mono C 1-6 alkylamino, bis C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, C 1-6 alkyl An acyloxy group, an aminoacyl group, a mono C 1-6 alkylamino acyl group,
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, said C 1-6 alkyl, C 3-8 A cycloalkyl or C 3-8 heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C 1-6 alkyl, C 3-8 cycloalkyl, C 3 - a heterocycloalkyl group, a C 1-6 alkoxy group, an aryl group, a heteroaryl group;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, halogen, C 1-6 alkane.
  • the C atom may form a C 3-8 cycloalkyl group or a C 3-8 heterocycloalkyl group; the hydroxy group, the amino group, the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the C 3-8 heterocycloalkane.
  • halogen, C 1-6 alkoxy-C 1-6 alkyl, aryl, heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C 1-6 alkane , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, mono C 1-6 alkyl Amino group, di-C 1-6 alkylamino group, C 1-6 alkyl acyl group, C 1-6 alkoxy acyl C 1-6 alkyl acyloxy group, amino acyl group, mono C 1-6 alkylamino acyl group, Bis-C 1-6 alkylamino acyl, C 1-6 alkyl acylamino substituted.
  • the compound provided by the present invention is a compound of the formula I or formula Ia or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:
  • L 1 and L 2 are each independently selected from the group consisting of:
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl;
  • p, q are independently selected from 1 and 2;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutane, Cyclopentyl, cyclohexane, phenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, ring Butanyl, cyclopentyl, cyclohexane, phenyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl , C 3-6 heterocycloalkyl, C 1-6 alkoxy, such as methoxy, ethoxy, propoxy, hydroxy-
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl-, C 3-6 heterocycloalkane. , C 3-6 heterocycloalkyl-C 1-6 alkyl-, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkane Base-, C 3-6 heterocycloalkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl- may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C 1 -6 alkyl, C 1-6 alkoxy, aryl, heteroaryl substituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, carboxy, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-6 alkoxyhaloalkyl, cyano C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, nitro C 1-6 alkane a C 3-6 cycloalkyl-C 1-6 alkyl group, a C 3-6 heterocycloalkyl-C 1-6 alkyl group, or when m or n is 2,
  • Each is independently selected from azaspiroalkyl (eg, azaspiro[2.4]heptyl, azaspiro[3.4]octyl, azaspiro[4.4]decyl, azaspiro[2.5]octane Alkyl, azaspiro[3.5]dec
  • the invention provides a compound of Formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein Each independently selected from substituted or unsubstituted
  • the present invention provides the following specific compounds:
  • the invention also provides an intermediate of formula (II) for the preparation of a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof:
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, halogen, triflate, mesylate, p-toluenesulfonate, and Wherein R 31 and R 32 are each independently selected from hydrogen, C 1-6 alkyl or R 31 , R 32 cyclized, together with the atoms to which they are attached constitute 5 to 7 members, optionally by one or more C 1-6 Alkene, halogen, amino, carboxyl, cyano, nitro, C 1-6 alkoxy substituted heterocyclic ring; preferably, R 21 , R 22 are each independently selected from hydrogen, chlorine, bromine, iodine or
  • the invention provides a process for the preparation of a compound of the formula of the invention.
  • the method for preparing a compound of formula I comprises the steps of:
  • an intermediate of the formula (2) is subjected to a coupling reaction to obtain an intermediate of the formula (4) or an intermediate of the formula (3), which is subjected to a coupling reaction to obtain an intermediate of the formula (4');
  • the intermediate of formula (4) or the intermediate of formula (4') is further subjected to a coupling reaction to give an intermediate of formula (5), optionally having a step of removing the protecting group;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 have the meanings in the formula I, and M 1 represents hydrogen, trimethylsilylethoxy, tert-butoxy A carbonyl group, M 2 represents hydrogen, trimethylsilylethoxy, tert-butoxycarbonyl, and Y represents a halogen, preferably chlorine, bromine or iodine.
  • the intermediate of the formula (105) is subjected to a coupling reaction to obtain an intermediate of the formula (107) or an intermediate of the formula (106), which is subjected to a coupling reaction to obtain an intermediate of the formula (107), which may be removed if necessary.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 have the meanings in the formula I, and M 1 represents hydrogen, trimethylsilylethoxy, tert-butoxy Carbonyl group, M 2 represents hydrogen, trimethylsilylethoxy group, tert-butoxycarbonyl group, Y represents halogen, preferably chlorine, bromine, iodine, and the ammonia source refers to ammonia water, ammonia gas or ammonium salt compound, such as Ammonium sulfate, ammonium carbonate, ammonium hydrogencarbonate, ammonium acetate, ammonium chloride, and the like.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a compound comprising the same, or a pharmaceutically acceptable salt, isomer thereof ,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, further comprising one selected from the group consisting of or A variety of: interferon, triazole nucleoside drugs, glycyrrhizin compound preparations, HCV protease inhibitors.
  • the compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation 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, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). 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 of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the present invention, for treating and/or preventing a hepatitis C virus-causing Method for treating liver diseases and use in the preparation of a medicament for preventing and/or treating liver diseases caused by hepatitis C virus, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient suffering from liver disease caused by hepatitis C virus, A composition, solvate, crystal or prodrug or a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for effectively inhibiting HCV and preventing progression of the disease .
  • the invention provides a method for treating and/or preventing an infection caused by a hepatitis C virus, 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 pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof or a pharmaceutical composition of the invention.
  • the compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof or the pharmaceutical composition of the present invention can be administered to a mammal in need thereof to inhibit HCV and prevent progression of the disease.
  • the method or use of treating and/or preventing an infection caused by a hepatitis C virus further comprises administering to the individual a compound of formula I of the invention, or a pharmaceutically acceptable salt thereof, isomerized , solvates, crystals or prodrugs or pharmaceutical compositions containing same and which are administered or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof or a compound thereof
  • the pharmaceutical composition is administered at least one other compound having anti-HCV activity before, after or simultaneously.
  • at least one of the other compounds is 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.
  • alkyl group of the present invention means a linear or branched saturated hydrocarbon group.
  • Suitable alkyl groups are substituted or unsubstituted C 1-10 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl Base, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl and the like.
  • cycloalkyl group of the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • alkoxy group of the present invention means an -O-alkyl group.
  • Suitable alkoxy groups according to the invention are C 1-10 alkoxy groups, such as C 1-8 alkoxy groups, C 1-7 alkoxy groups, C 1-6 alkoxy groups, C 1-5 alkoxy groups.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine.
  • the "monoalkylaminoacyl" of the present invention means -C(O)-NH-alkyl.
  • the "bisalkylamino acyl group" of the present invention means -C(O)-N(alkyl)(alkyl).
  • aryl group of the present invention means an aromatic system which may contain a monocyclic or polycondensed ring such as a bicyclic or tricyclic aromatic ring, wherein at least a part of the fused ring forms a conjugated aromatic system containing 5 to 50 One carbon atom, preferably from about 6 to about 14 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl, biphenylene, and anthracenyl.
  • heteroaryl of the present invention means an aromatic monocyclic or polycondensed ring such as a bicyclic or tricyclic ring having at least one carbon An aromatic group in which a subunit is replaced by a hetero atom, and the hetero atom is O, S, N.
  • Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like.
  • Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.
  • Crystal as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
  • the "isomer” of the present invention refers to a stereoisomer, including enantiomers and diastereomers, which are produced by different arrangement of atoms in a molecule in a space.
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into a compound of the invention by oxidation, reduction, hydrolysis or the like of an enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.
  • the "pharmaceutically acceptable salt” of the present invention means a pharmaceutically acceptable salt of the compound of the present invention and an acid, which includes, but is not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, and Malay. Acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, and the like.
  • a "pharmaceutical composition” is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes a solvent, a diluent or other excipient, a dispersing agent, and a surface active agent. Agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin and the like.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose derivatives. Biological, gelatin, vegetable oil, polyethylene glycol.
  • reaction mixture was poured into 100 g of ice cubes, and then added with 200 mL of saturated aqueous sodium chloride solution and extracted with dichloromethane (3 ⁇ 200 mL). The title compound was obtained and used directly in the next reaction.
  • Step 1 Preparation of (S)-1-tert-butoxycarbonyl-2-(2-(4-bromophenyl)-2-oxoethoxycarbonyl)pyrrolidine
  • Step 1 2,7-Bis(1-ethoxyvinyl-1-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene
  • Step 3 1,1'-(9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2,7-diyl)bis(2-bromoethyl ketone)
  • Step 4 (1R, 1'R, 3S, 3'S, 4S, 4'S)-3,3'-(9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2,7-diyl) Bis((2-oxoethoxy)carbonyl)bis(2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane)
  • Step 5 (1R, 1'R, 3S, 3'S, 4S, 4'S)-3,3'-(5,5'-(9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2 ,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester)
  • Step 6 (1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2 ,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane)
  • Step 2 (2S, 2'S, 3R, 3'R)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9, 9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1] Heptane-3,2-diyl)) bis(3-hydroxy-1-oxobutane-2,1-diyl)dicarbamic acid dimethyl ester
  • Step 1 (2S,2'S)-1,1'-Di-tert-butoxycarbonyl-2,2'-((9,9,10,10-tetrafluoro-9,10-dihydrophenanthene-2,7- Diyl) bis((2-oxoethoxy)carbonyl))bispyrrolidine
  • Example 8 ((2S, 2'S, 3R, 3'R)-((2S, 2'S)-2, 2'-(5,5'-(9,9,10,10-tetrafluoro-9,10- Dihydrophenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-hydroxy-1-oxobutane -2,1-diyl)) dimethyl dicarbamic acid
  • Step 1 2-Acetyl-7-bromo-9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene
  • Step 3 (S)-1-tert-Butoxycarbonyl-2-(((7-bromo-9,9,10,10-tetrafluoro-9,10-dihydrophenan-2-yl)-2-oxo Generation B Oxy)carbonyl)pyrrolidine
  • the 2-bromo-1-(7-bromo-9,9,10,10-tetrafluoro-9,10-dihydrophenanthren-2-yl)ethanone obtained in the step 2 was added to a 50 mL eggplant-shaped bottle. 20 mL of acetonitrile, 0.65 mL of DIEA and 425 mg of N-Boc-L-proline were added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated to give the title compound.
  • Step 4 (S)-1-tert-Butoxycarbonyl-2-(5-(7-bromo-9,9,10,10-tetrafluoro-9,10-dihydrophenan-2-yl)-1H- Imidazol-2-yl)pyrrolidine
  • HATU '-Tetramethylurea hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • the reaction was stopped for 16 h, the reaction was stopped, and the reaction mixture was poured into 200 mL of ice water, and ethyl acetate (2 ⁇ 200 mL) was added, and the organic phase was combined, washed with saturated aqueous sodium chloride (2 ⁇ 200 mL), and dried over anhydrous sodium sulfate. Concentration gave the title compound which was used directly in the next step.
  • Step 8 (S)-1-tert-Butoxycarbonyl-2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzene And [d]imidazol-6-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine
  • Step 10 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenan-2-yl))-1H -Methyl benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate
  • Step 4 (1R,3S,4S)-2-tert-Butoxycarbonyl-3-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)) -1H-imidazole-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2- Azabicyclo[2.2.1]heptane
  • Step 6 N-((2S)-1-((2S)-2-(6-(7-(2-((1R,3S,4S)-2-((S)-2-((methoxycarbonyl)) Amino)-3-methylbutyryl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9,10, 10-tetrafluoro-9,10-dihydrophenanthren-2-yl))-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl Methyl carbamate
  • step 2 Weigh 187 mg of the product obtained in step 2 (S)-8-methoxycarbonyl-1,4-dioxa-7-azaspiro[4.4]nonane, 380 mg HATU, 0.5 mL DIEA and 175 mg MOC-valine The mixture was placed in a reaction flask, and 20 mL of dichloromethane was added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, methylene chloride and water were evaporated.
  • Step 7 (S)-1- Tert-Butoxycarbonyl-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxapentane-2-yl)-1H-benzo[d] Imidazol-2-yl)pyrrolidine and 283 mg of Pd(PPh 3 ) 4 were placed in a reaction flask, and after adding 20 mL of N,N-dimethylacetamide (DME), 4 mL of K 2 CO 3 aqueous solution (2 M) was added. The reaction was refluxed for 4 h under argon. EtOAc (3 ⁇ 20 mL).
  • DME N,N-dimethylacetamide
  • Step 7 (S)-2-(6-(7-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4 -Dioxa-7-azaspiro[4.4]decane-8-yl)-1H-imidazol-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2 Of -1H-benzo[d]imidazol-2-yl)-1-tert-butoxycarbonylpyrrole
  • step 6 Weigh 220 mg of the obtained product of step 6 (S)-2-(6-(7-(2-bromoacetyl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthren-2-yl) -1H-benzo[d]imidazol-2-yl)-1-tert-butoxycarbonylpyrrole and 100 mg of the product of Step 4 (S)-7-((S)-2-(methoxycarbonylamino)-3 -methylbutyryl)-1,4-dioxa-7-azaspiro[4.4]decane-8-carboxylic acid, placed in a reaction flask, dissolved in 5 mL of acetonitrile, added with 77 mg of DIPEA, refluxed for 0.5 h. Concentration, 10 mL of toluene and 254 mg of ammonium acetate were added, and the reaction was carried out at 130 ° C for 2 h.
  • Step 8 N-((S)-3-Methyl-1-oxo-1-((S)-8-(5-(7-(2-((S))-pyrrol-2-yl)-1H) -benzo[d]imidazol-6-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenan-2-yl)-1H-imidazol-2-yl)-1,4- Preparation of Methyl Dioxa-7-azaspiro[4.4]decane-7-yl)butan-2-yl)carbamate
  • Step 9 N-((2S)-1-((S)-2-(5-(7-((S)-2-(7-((S))-2-((methoxycarbonyl)amino)) -3-methylbutyryl)-1,4-dioxa-7-azaspiro[4.4]decane-8-yl)-1H-imidazole-5-yl)-9,9,10,10- Tetrafluoro-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutane-2 Methyl carbamate
  • Step 2 6-(7-(2-((S)-5-Azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9,9,10,10-tetrafluoro Preparation of -9,10-dihydrophenanthren-2-yl)-2-((S)-pyrrol-2-yl)-1H-benzo[d]imidazole
  • the product obtained in step 1 is 5-tert-butoxycarbonyl-(S)-6-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrol-2-yl)-1H- Benzo[d]imidazol-6-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-5-aza snail [2.4] Heptane was used as the starting material.
  • Step 2 ((2S,2'S,3R,3'R)-((2S,2'S)-2,2'-(4,4'-(9,9,10,10-tetrafluoro-9,10-two Hydrogen phenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrole-2,1-diyl))bis(3-methoxy-1-oxobutane Preparation of dimethyl-2,1-diyl))dicarbamic acid
  • Step 1 (S)-2-(2-(7-(((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-) Dioxa-7-azaspiro[4.4]decane-8-yl)carbonyloxy)acetyl)-9,9,10,10-tetrafluoro-9,10-dihydrophenan-2-yl) Preparation of -2-oxoethoxycarbonyl)-1-tert-butoxycarbonylpyrrole
  • Step 2 (S)-2-(5-(7-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4 -Dioxa-7-azaspiro[4.4]decane-8-yl)-1H-imidazol-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2 Of -1)-H-imidazol-2-yl)-1-tert-butoxycarbonylpyrrole
  • Step 3 (S)-2-(5-(7-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4 -Dioxa-7-azaspiro[4.4]decane-8-yl)-1H-imidazol-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2 -yl)-1H-imidazol-2-yl)pyrrole
  • Step 4 N-((2S)-1-((S)-2-(5-(7-((S)-2-(7-((S))-2-((methoxycarbonyl)amino)) -3-methylbutyryl)-1,4-dioxa-7-azaspiro[4.4]decane-8-yl)-1H-imidazole-5-yl)-9,9,10,10- Tetrafluoro-9,10-dihydrogen
  • Step 2 (S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-pyrrole-2 Of -1)-H-imidazole-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrole
  • Step 3 N-((2S)-1-((S)-2-(5-(7-(2-((S))-1-((S)-2-(methoxycarbonylamino)-3) -methylbutyryl)-pyrrol-2-yl)-1H-imidazol-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenan-2-yl)-1H-imidazole
  • Step 2 The product obtained in Step 2 (S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl))- Pyrrol-2-yl)-1H-imidazol-5-yl)-9,9,10,10-tetrafluoro-9,10-dihydrophenanthyl-2-yl)-1H-imidazol-2-yl)pyrrole and Step 1 The obtained (S)-2-(((2-methoxyethoxy)carbonyl)amino)-3-methylbutanoic acid was used as a starting material.
  • Example 16 ((2S,2'S)-((2S,2'S)-2,2'-(6,6'-(9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2, 7-diyl) bis(1H-benzo[d]imidazol-6,2-diyl))bis(pyrrole-2,1-diyl))bis(3-methyl-1-oxobutane- 2,1-diyl))dicarbamic acid dimethyl ester
  • Step 3 N-((S)-3-Methyl-1-oxo-1-((S)-2-(5-(9,9,10,10-tetrafluoro-7-(2-(( S)-1-(3-methyl-2-(methoxycarbonylamino)butyryl)pyrrol-2-yl)-1H-benzene[d]imidazol-5-yl)-9,10-dihydrophenanthrene Methyl-2-yl)-1H-benzene[d]imidazol-2-yl)pyrrol-1-yl)butyl-2-yl)carbamate
  • Example 17 ((2S,2'S)-((2S,2'S)-2,2'-(5,5'-(9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene-2, 7-diyl) bis(1H-imidazole-5,2-diyl))bis(1,4-dioxa-7-azaspiro[4.4]decane-7,8-diyl)) bis ( Dimethyl 3-methyl-1-oxobutane-2,1-diyl))dicarbamate
  • each compound was dissolved in DMSO to 10 mM, diluted to 50 ⁇ M with DMEM complete medium, and then diluted to 20 nM with a complete medium containing 0.5% DMSO, and then diluted three times in total. 10 concentrations.
  • DMEM cell culture medium (DMEM medium), purchased from Invitrogen, USA;
  • Fetal bovine serum purchased from Sigma, USA;
  • L-Glutamine (L(+)-Glutamine), purchased from Invitrogen, USA;
  • Penicillin-streptomycin (Pen-Strep), purchased from Invitrogen, USA;
  • PBS Phosphate buffered saline
  • Trypsin purchased from Invitrogen, USA;
  • DMSO Dimethyl sulfoxide
  • Bright-Glo test reagent purchased from Promega, USA;
  • Cell growth fluorescence assay detection reagent (CellTiter-Fluor), purchased from Promega, USA.
  • Cell viability assay Cell growth fluorescent titration detection reagent was added to each well. After incubating the cells for 1 hour at 37 ° C in a 5% CO 2 incubator, the Fluorescence signal value was detected by a multi-function microplate reader, and the raw data (RFU) was used for the compound. Cytotoxicity calculation;
  • Anti-HCV virus replicon activity assay Luminescence signal value was detected by multi-function microplate reader within 5 minutes with the luciferase luminescent substrate Bright-Glo. The raw data (RLU) was used to calculate the anti-HCV activity of the compound.
  • Inhibition% (RLU ZPE -RLU CPD )/(RLU ZPE -RLU HPE ) ⁇ 100
  • Viability% (RFU CPD -RFU HPE )/(RFU ZPE -RFU HPE ) ⁇ 100
  • CPD fluorescence signal value of the compound pore
  • ZPE Zero percent effect
  • HPE Heundred percent effect
  • the Inhibition% and Viability% were separately introduced into the GraphPad Prism software for data processing, and the half effective concentration EC 50 and the half cytotoxic concentration CC 50 of the compound to the HCV replicon were obtained.
  • the experimental results show that the compounds of the present invention have an EC 50 for the HCV-1b replicon which is much smaller than 0.1 nm, and the CC 50 is much larger than 10 nm.
  • the results of some of the compounds are shown in Table 1.
  • the compound of the present invention has good inhibitory activity against hepatitis C virus, has low toxicity to host cells, is highly effective, and has good safety, and is very promising for treatment and/or prevention and HCV infection. Drugs related to the disease.
  • HCV genotype 1a a Huh7 cell line stably translocated into the HCV genotype 1a replicon (by WuXi PharmaTech (Shanghai) New Drug Development Co., Ltd. provides) experimental cells.
  • the HCV genotype 1a replicon cell system was similarly prepared as described above for the HCV 1b replicon cell system.
  • the activity of the compound of the present invention against HCV-1a was determined by the method of testing the activity of anti-HCV-1b replicon according to Experimental Example 1. The results indicate that the compounds of the present invention have an EC 50 for the HCV-1a replicon of less than 0.2 nm, and the CC 50 is much greater than 10 nm. The results of some of the compounds are shown in Table 2.
  • the compound of the present invention also exhibits good inhibitory activity against the hepatitis C virus 1a subtype, has low toxicity to host cells, is highly effective, and has good safety, and is very promising for treating and/or preventing diseases associated with HCV infection. Drug. 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

本发明属于化学医药领域，具体涉及式I所示的一类具有9,9,10,10-四氟-9,10二氢菲结构、能够抑制丙型肝炎病毒活性的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。本发明的化合物具有良好的HCV抑制效果。

Description

9,9,10,10-四氟-9,10二氢菲类丙型肝炎病毒抑制剂及其应用 技术领域
本发明属于化学医药领域，具体涉及一类具有9,9,10,10-四氟-9,10二氢菲结构、能够抑制丙型肝炎病毒活性的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。
背景技术
丙型病毒性肝炎(Viral hepatitis C)是由丙型肝炎病毒(Hepatitis C virus,HCV)引起的肝脏急、慢性炎症的传染性疾病，HCV感染后极易演变为慢性肝病，如慢性肝炎、肝硬化和肝癌等，严重影响人们身体健康。
HCV属于黄病毒科，目前可分为6个基因型及不同亚型，按照国际通行的方法，以阿拉伯数字表示HCV基因型，以小写的英文字母表示基因亚型，其中基因1型呈现全球性的分布，占所有HCV感染的70％以上，中国人群的主要感染类型是HCV 1b亚型。经研究发现HCV的正链RNA的5’和3’端都含有非编码区(UTR)，UTR之间是一个大的多蛋白开放阅读框架(ORF)。ORF编码一个长约3000个氨基酸的多蛋白前体，经宿主编码的信号肽酶及HCV编码的蛋白酶共同作用，裂解为多种HCV成熟蛋白。HCV成熟蛋白包括4个结构蛋白和6个非结构蛋白，其中6个非结构蛋白分别命名为NS2、NS3、NS4A、NS4B、NS5A、NS5B。研究表明，6个非结构蛋白在HCV的复制中起着非常重要的作用，如NS3，调节NS3丝氨酸蛋白酶的活性，NS5A为一种磷酸化蛋白，含有干扰素敏感性决定区域，在干扰素疗效预测、病毒复制、抗病毒抗性、肝细胞癌变等方面具有重要作用，已经成为HCV非结构蛋白研究的重点。
当前，HCV感染的治疗方式一般为重组干扰素α单独或与核苷类似物利巴韦林联合治疗，但是无论是干扰素还是利巴韦林，都存在着多个禁忌症，具有有限的临床益处。因此，对能够有效治疗HCV感染的药物仍然有着很大的需求。
发明内容
本发明的目的是提供通式I的一类能够抑制HCV，具有9,9,10,10-四氟-9,10二氢菲结构的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014095043-appb-000001
其中：
L1、L2分别独立地选自芳基、杂芳基、-芳基-芳基-、-芳基-杂芳基-、-杂芳基-杂芳基-，所述的芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、单烷基氨基烷基、双烷基氨基、双烷基氨基烷基、烷基酰基、烷基酰基烷基、烷氧基酰基、烷氧基酰基烷基、烷基酰基氧基、烷基酰基氧基烷基、氨基酰基、氨基酰基烷基、单烷基氨基酰基、单烷基氨基酰基烷基、双烷基氨基酰基、双烷基氨基酰基烷基、烷基酰基氨基、烷基酰基氨基烷基取代；
p、q分别独立地选自1、2和3；
R1、R2分别独立地选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基、烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代；
R3、R4分别独立地选自氢、烷基、环烷基、杂环烷基，所述的烷基、环烷基或杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、芳基、杂芳基取代；和
R5、R6分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基，其中m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成环烷基或杂环烷基；所述的羟基、氨基、羧基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、 双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代。
本发明的另一个目的是提供制备本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的方法。
本发明的再一个目的是提供包含本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体的组合物，以及包含本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和另一种或多种HCV抑制剂的组合物。
本发明的还一个目的是提供本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药治疗和/或预防丙型肝炎病毒引起的疾病，例如肝脏疾病的方法，以及本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药在制备用于治疗和/或HCV感染的药物中的应用。
针对上述目的，本发明提供以下技术方案：
第一方面，本发明提供通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014095043-appb-000002
其中：
L1、L2分别独立地选自芳基、杂芳基、-芳基-芳基-、-芳基-杂芳基-、-杂芳基-杂芳基-，所述的芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、单烷基氨基烷基、双烷基氨基、双烷基氨基烷基、烷基酰基、烷基酰基烷基、烷氧基酰基、烷氧基酰基烷基、烷基酰基氧基、烷基酰基氧基烷基、氨基酰基、氨基酰基烷基、单烷基氨基酰基、单烷基氨基酰基烷基、双烷基氨基酰基、双烷基氨基酰基烷基、烷基酰基氨基、烷基酰基氨基烷基取代；
p、q分别独立地选自1、2和3；
R1、R2分别独立地选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基、烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代；
R3、R4分别独立地选自氢、烷基、环烷基、杂环烷基，所述的烷基、环烷基或杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、芳基、杂芳基取代；和
R5、R6分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基，其中，m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成环烷基或杂环烷基；所述的羟基、氨基、羧基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
L1、L2分别独立地选自苯基、萘基、咪唑基、苯并咪唑基、-苯基-咪唑基-、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基，所述的苯基、萘基、咪唑基、苯并咪唑基、-苯基-咪唑基-、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-10烷基、C3-10环烷基、C3-10杂环烷基、C1-10烷氧基、卤代C1-10烷基、羟基-C1-10烷基、氨基-C1-10烷基、羧基-C1-10烷基、氰基-C1-10烷基、硝基C1-10烷基、C3-10环烷基-C1-6烷基、C3-10杂环烷基-C1-6烷基、C1-10烷氧基-C1-6烷基、单C1-10烷基氨基、单C1-10烷基氨基-C1-6烷基、双C1-10烷基氨基、双C1-10烷基氨基-C1-6烷基、C1-10烷基酰基、C1-10烷基酰基-C1-6烷基、C1-10烷氧基酰基、C1-10烷氧基酰基-C1-6 烷基、C1-10烷基酰基氧基、C1-10烷基酰基氧基-C1-6烷基、氨基酰基、氨基酰基-C1-6烷基、单C1-10烷基氨基酰基、单C1-10烷基氨基酰基-C1-6烷基、双C1-10烷基氨基酰基、双C1-10烷基氨基酰基-C1-6烷基、C1-10烷基酰基氨基、C1-10烷基酰基氨基-C1-6烷基取代；
优选地，L1、L2分别独立地选自苯基、萘基、咪唑基、1H-苯并[d]咪唑基、5-苯基-1H-咪唑基、1H-咪唑并[4,5-b]吡啶基、喹唑啉-4(3H)酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基，所述的苯基、萘基、咪唑基、1H-苯并[d]咪唑基、5-苯基-1H-咪唑基、1H-咪唑并[4,5-b]吡啶基、喹唑啉-4(3H)酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、卤代C1-6烷基、羟基-C1-6烷基、氨基-C1-6烷基、羧基-C1-6烷基、氰基-C1-6烷基、硝基C1-6烷基、C3-8环烷基-C1-6烷基、C3-8杂环烷基-C1-6烷基、C1-6烷氧基-C1-6烷基、单C1-6烷基氨基、单C1-6烷基氨基-C1-6烷基、双C1-6烷基氨基、双C1-6烷基氨基-C1-6烷基、C1-6烷基酰基、C1-6烷基酰基-C1-6烷基、C1-6烷氧基酰基、C1-6烷氧基酰基-C1-6烷基、C1-6烷基酰基氧基、C1-6烷基酰基氧基-C1-6烷基、氨基酰基、氨基酰基-C1-6烷基、单C1-6烷基氨基酰基、单C1-6烷基氨基酰基-C1-6烷基、双C1-6烷基氨基酰基、双C1-6烷基氨基酰基-C1-6烷基、C1-6烷基酰基氨基、C1-6烷基酰基氨基-C1-6烷基取代；
进一步优选地，L1、L2分别独立地选自以下基团：
Figure PCTCN2014095043-appb-000003
，其中，R7和R8分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、单烷基氨基烷基、双烷基氨基、双烷基氨基烷基、烷基酰基、烷基酰基烷基、烷氧基酰基、烷氧基酰基烷基、烷基酰基氧基、烷基酰基氧基烷基、氨基酰基、氨基酰基烷基、单烷基氨基酰基、单烷基氨基酰基烷基、双烷基氨基酰基、双烷基 氨基酰基烷基、烷基酰基氨基、烷基酰基氨基烷基；优选地，R7和R8分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、卤代C1-6烷基、羟基-C1-6烷基、氨基-C1-6烷基、羧基-C1-6烷基、氰基-C1-6烷基、硝基C1-6烷基、C3-8环烷基-C1-6烷基、C3-8杂环烷基-C1-6烷基、C1-6烷氧基-C1-6烷基、单C1-6烷基氨基、单C1-6烷基氨基-C1-6烷基、双C1-6烷基氨基、双C1-6烷基氨基-C1-6烷基、C1-6烷基酰基、C1-6烷基酰基-C1-6烷基、C1-6烷氧基酰基、C1-6烷氧基酰基-C1-6烷基、C1-6烷基酰基氧基、C1-6烷基酰基氧基-C1-6烷基、氨基酰基、氨基酰基-C1-6烷基、单C1-6烷基氨基酰基、单C1-6烷基氨基酰基-C1-6烷基、双C1-6烷基氨基酰基、双C1-6烷基氨基酰基-C1-6烷基、C1-6烷基酰基氨基、C1-6烷基酰基氨基-C1-6烷基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
R1、R2分别独立地选自氢、C1-10烷基、C3-8环烷基、C3-8杂环烷基、芳基或杂芳基，所述的C1-10烷基、C3-8环烷基、C3-8杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基、烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代；
优选地，R1、R2分别独立地选自氢、C1-6烷基、C3-6环烷基、C3-6杂环烷基、芳基或杂芳基，所述的C1-6烷基、C3-6环烷基、C3-6杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C1-6环烷基、C1-6杂环烷基、C1-6烷氧基，如甲氧基、乙氧基、丙氧基、羟基-C1-6烷基、羧基-C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基、C1-6烷基酰基、C1-6烷氧基酰基、C1-6烷基酰基氧基、氨基酰基、单C1-6烷基氨基酰基、双C1-6烷基氨基酰基、C1-6烷基酰基氨基取代；
进一步优选地，R1、R2分别独立地选自氢、甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基、N-烷基哌嗪基、苯基、萘基、吡咯基、噻吩基、噻唑基、噁唑基、吡啶基，所述的甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环 丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基、N-烷基哌嗪基、苯基、萘基、吡咯基、噻吩基、噻唑基、噁唑基、吡啶基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C1-6烷氧基，如甲氧基、乙氧基、丙氧基、羟基-C1-6烷基、羧基-C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
R3、R4分别独立地选自氢、C1-10烷基、C3-8环烷基、C3-8杂环烷基，所述的C1-10烷基、C3-8环烷基或C3-8杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、芳基、杂芳基取代；
进一步优选地，R3、R4分别独立地选自氢、C1-6烷基、C3-7环烷基、C3-7杂环烷基，所述的C1-6烷基、C3-7环烷基或C3-7杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-7环烷基、C3-7杂环烷基、C1-6烷氧基、芳基、杂芳基取代；
更进一步优选地，R3、R4分别独立地选自氢、甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基，所述的甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、环丙基、环丁基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基、N-烷基哌嗪基、C1-6烷氧基、苯基、杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
R5、R6分别独立地选自氢、氰基、羟基、氨基、C1-10烷基、C3-8环烷基、C3-8杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基，其中，m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成C3-8环烷基或C3-8杂环烷基；所述的羟基、氨基、C1-10烷基、C3-8环烷基、C3-8杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基可以被一个或多个卤素、 羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代；
优选地，R5、R6分别独立地选自氢、氰基、羟基、氨基、C1-6烷基、C3-7环烷基、C3-7杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基，其中，m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成C3-6环烷基或C3-6杂环烷基；所述的羟基、氨基、C1-6烷基、C3-7环烷基、C3-7杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代；
更进一步优选地，R5、R6分别独立地选自氢、氰基、羟基、氨基、甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、1,3-二氧戊环基、哌啶基、哌嗪基、N-烷基哌嗪基、1,3-二氧己环基、氟、氯、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、苯基、萘基、吡咯基、噻吩基、噻唑基、噁唑基、吡啶基，或者当m或n为2时，
Figure PCTCN2014095043-appb-000004
各自独立地选自氮杂螺烷基(例如氮杂螺[2.4]庚烷基、氮杂螺[3.4]辛烷基、氮杂螺[4.4]壬烷基、氮杂螺[2.5]辛烷基、氮杂螺[3.5]壬烷基、氮杂螺[4.5]葵烷基、氮杂螺[2.6]壬烷基、氮杂螺[3.6]葵烷基)、氧氮杂螺烷基(例如氧杂-氮杂螺[2.4]庚烷基、氧杂-氮杂螺[3.4]辛烷基、氧杂-氮杂螺[4.4]壬烷基、二氧杂-氮杂螺[4.4]壬烷基、氧杂-氮杂螺[4.5]葵烷基、二氧杂-氮杂螺[4.5]葵烷基、三氧杂-氮杂螺[4.5]葵烷基)、氮杂双环烷基(例如氮杂双环[3.1.0]己烷、氮杂双环[3.2.0]庚烷基、八氢环戊并吡咯基、八氢-1H-异吲哚基、八氢-1H-吲哚基、氮杂双环[2.2.1]庚烷基)；所述的羟基、氨基、甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、1,3-二氧戊环基、哌啶基、哌嗪基、N-烷基哌嗪基、1,3-二氧己环基、氟、氯、甲氧基甲基、 甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、苯基、萘基、吡咯基、噻吩基、噻唑基、噁唑基、吡啶基，或者当m或n为2时，所述的氮杂螺烷基(氮杂螺[2.4]庚烷基、氮杂螺[3.4]辛烷基、氮杂螺[4.4]壬烷基、氮杂螺[2.5]辛烷基、氮杂螺[3.5]壬烷基、氮杂螺[4.5]葵烷基、氮杂螺[2.6]壬烷基、氮杂螺[3.6]葵烷基)、氧氮杂螺烷基(例如氧杂-氮杂螺[2.4]庚烷基、氧杂-氮杂螺[3.4]辛烷基、氧杂-氮杂螺[4.4]壬烷基、二氧杂-氮杂螺[4.4]壬烷基、氧杂-氮杂螺[4.5]葵烷基、二氧杂-氮杂螺[4.5]葵烷基、三氧杂-氮杂螺[4.5]葵烷基)、氮杂双环烷基(例如氮杂双环[3.1.0]己烷、氮杂双环[3.2.0]庚烷基、八氢环戊并吡咯基、八氢-1H-异吲哚基、八氢-1H-吲哚基、氮杂双环[2.2.1]庚烷基)可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代。
在一些具体的实施方案中，本发明提供通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中
Figure PCTCN2014095043-appb-000005
各自独立地选自取代或未取代的
Figure PCTCN2014095043-appb-000006
所述取代基选自卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代。
在一些优选的实施方案中，本发明提供通式Ia的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014095043-appb-000007
其中：
C*为S构型；
L1、L2分别独立地选自芳基、杂芳基、-芳基-芳基-、-芳基-杂芳基-、-杂芳基-杂芳基-，所述的芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、单烷基氨基烷基、双烷基氨基、双烷基氨基烷基、烷基酰基、烷基酰基烷基、烷氧基酰基、烷氧基酰基烷基、烷基酰基氧基、烷基酰基氧基烷基、氨基酰基、氨基酰基烷基、单烷基氨基酰基、单烷基氨基酰基烷基、双烷基氨基酰基、双烷基氨基酰基烷基、烷基酰基氨基、烷基酰基氨基烷基取代；
p、q分别独立地选自1、2和3；
R1、R2分别独立地选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基、烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代；
R3、R4分别独立地选自氢、烷基、环烷基、杂环烷基，所述的烷基、环烷基或杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、芳基、杂芳基取代；
R5、R6分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基，其中，m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成环烷基或杂环烷基；所述的羟基、氨基、羧基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代。
根据本发明，在一些优选的实施方案中，本发明的化合物为通式I或通式Ia的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
p、q分别独立地选自1、2和3；
L1、L2分别独立地选自苯基、萘基、咪唑基、苯并咪唑基、-苯基-咪唑基-、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基，所述的苯基、萘基、咪唑基、苯并咪唑基、-苯基-咪唑基-、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、卤代C1-6烷基、羟基-C1-6烷基、氨基-C1-6烷基、羧基-C1-6烷基、氰基-C1-6烷基、硝基C1-6烷基、C3-8环烷基-C1-6烷基、C3-8杂环烷基-C1-6烷基、C1-6烷氧基-C1-6烷基、单C1-6烷基氨基、单C1-6烷基氨基-C1-6烷基、双C1-6烷基氨基、双C1-6烷基氨基-C1-6烷基、C1-6烷基酰基、C1-6烷基酰基-C1-6烷基、C1-6烷氧基酰基、C1-6烷氧基酰基-C1-6烷基、C1-6烷基酰基氧基、C1-6烷基酰基氧基-C1-6烷基、氨基酰基、氨基酰基-C1-6烷基、单C1-6烷基氨基酰基、单C1-6烷基氨基酰基-C1-6烷基、双C1-6烷基氨基酰基、双C1-6烷基氨基酰基-C1-6烷基、C1-6烷基酰基氨基、C1-6烷基酰基氨基-C1-6烷基取代；
R1、R2分别独立地选自氢、C1-6烷基、C3-8环烷基、C3-8杂环烷基、芳基或杂芳基，所述的C1-6烷基、C3-8环烷基、C3-8杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C1-8环烷基、C1-8杂环烷基、C1-6烷氧基，如甲氧基、乙氧基、丙氧基、羟基-C1-6烷基、羧基-C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基、C1-6烷基酰基、C1-6烷氧基酰基、C1-6烷基酰基氧基、氨基酰基、单C1-6烷基氨基酰基、双C1-6烷基氨基酰基、C1-6烷基酰基氨基取代；
R3、R4分别独立地选自氢、C1-6烷基、C3-8环烷基、C3-8杂环烷基，所述的C1-6烷基、C3-8环烷基或C3-8杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、芳基、杂芳基取代；
R5、R6分别独立地选自氢、氰基、羟基、氨基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基，其中，m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成C3-8环烷基或C3-8杂环烷基；所述的羟基、氨基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基可以被一个或多个卤素、羟基、 氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、羟基C1-6烷基、羧基C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基、C1-6烷基酰基、C1-6烷氧基酰基C1-6烷基酰基氧基、氨基酰基、单C1-6烷基氨基酰基、双C1-6烷基氨基酰基、C1-6烷基酰基氨基取代。
进一步优选地，本发明提供的化合物为通式I或通式Ia的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
L1、L2分别独立地选自以下基团：
Figure PCTCN2014095043-appb-000008
，其中，R7和R8分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟基-C1-6烷基、C1-6烷氧基-C1-6烷基；
p、q分别独立地选自1和2；
R1、R2分别独立地选自氢、甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、苯基，所述的甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、苯基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷氧基，如甲氧基、乙氧基、丙氧基、羟基-C1-6烷基、羧基-C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基、C1-6烷基酰基、C1-6烷氧基酰基、C1-6烷基酰基氧基、氨基酰基、单C1-6烷基氨基酰基、双C1-6烷基氨基酰基、C1-6烷基酰基氨基取代；
R3、R4分别独立地选自氢、C1-6烷基、C3-6环烷基、C3-6环烷基-C1-6烷基-、C3-6杂环烷基、C3-6杂环烷基-C1-6烷基-，所述的C1-6烷基、C3-6环烷基、C3-6环烷基-C1-6烷基-、C3-6杂环烷基、C3-6杂环烷基-C1-6烷基-可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C1-6烷氧基、芳基、杂芳基取代；
R5、R6分别独立地选自氢、卤素、氰基、羟基、氨基、羧基、硝基、C1-6烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷氧基卤代烷基、氰基C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、硝基C1-6烷基、C3-6环烷基-C1-6烷基、 C3-6杂环烷基-C1-6烷基，或者当m或n为2时，
Figure PCTCN2014095043-appb-000009
各自独立地选自氮杂螺烷基(例如氮杂螺[2.4]庚烷基、氮杂螺[3.4]辛烷基、氮杂螺[4.4]壬烷基、氮杂螺[2.5]辛烷基、氮杂螺[3.5]壬烷基、氮杂螺[4.5]葵烷基、氮杂螺[2.6]壬烷基、氮杂螺[3.6]葵烷基)、氧氮杂螺烷基(例如氧杂-氮杂螺[2.4]庚烷基、氧杂-氮杂螺[3.4]辛烷基、氧杂-氮杂螺[4.4]壬烷基、二氧杂-氮杂螺[4.4]壬烷基、氧杂-氮杂螺[4.5]葵烷基、二氧杂-氮杂螺[4.5]葵烷基、三氧杂-氮杂螺[4.5]葵烷基)、氮杂双环烷基(例如氮杂双环[3.1.0]己烷、氮杂双环[3.2.0]庚烷基、八氢环戊并吡咯基、八氢-1H-异吲哚基、八氢-1H-吲哚基、氮杂双环[2.2.1]庚烷基)。
在一些具体的实施方案中，本发明提供通式Ia的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中
Figure PCTCN2014095043-appb-000010
各自独立地选自取代或未取代的
Figure PCTCN2014095043-appb-000011
本发明提供了以下具体化合物：
Figure PCTCN2014095043-appb-000012
Figure PCTCN2014095043-appb-000013
Figure PCTCN2014095043-appb-000014
Figure PCTCN2014095043-appb-000015
本发明还提供了式(II)的制备本发明化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的中间体：
Figure PCTCN2014095043-appb-000016
其中，
R21、R22分别独立地选自氢、卤素、三氟甲磺酸酯基、甲磺酸酯基、对甲苯磺酸酯基和
Figure PCTCN2014095043-appb-000017
其中R31、R32分别独立地选自氢、C1-6烷基或R31、R32环合，一起与它们连接的原子构成5至7元任选被一个或多个C1-6烷基、卤素、氨基、羧基、氰基、硝基、C1-6烷氧基取代的杂环；优选地，R21、R22分别独立地选自氢、氯、溴、碘或
Figure PCTCN2014095043-appb-000018
另一方面，本发明提供本发明的通式化合物的制备方法。通式I的化合物的制备方法包括如下步骤：
(1)式(3)的中间体的制备：
Figure PCTCN2014095043-appb-000019
a)式(1)的化合物进行氟化反应得到式(2)的中间体；
b)式(2)的中间体与联硼酸频哪醇酯反应得到式(3)的中间体；
(2)通式(I)的化合物的制备：
Figure PCTCN2014095043-appb-000020
c)式(2)的中间体经过偶联反应得到式(4)的中间体或式(3)的中间体经过偶联反应得到式(4’)的中间体；
d)式(4)的中间体或式(4’)的中间体再经过偶联反应得到式(5)的中间体，必要的时候可以有脱去保护基团的步骤；
e)式(5)的中间体酰胺化得到通式(I)的化合物，必要的时候可以有脱去保护基团的步骤。
其中，R1、R2、R3、R4、R5、R6、L1、L2具有通式I中的含义，M1表示氢、 三甲基硅基乙氧基、叔丁氧羰基，M2表示氢、三甲基硅基乙氧基、叔丁氧羰基，Y表示卤素，优选为氯、溴、碘。
特别地，对于L1或L2中至少有一个选自咪唑基的通式I的化合物的制备，还可以用如下方法，包括：
(1)式(106)的中间体的制备：
Figure PCTCN2014095043-appb-000021
b-1)式(2)的中间体经Stille反应反应、酸催化水解反应得到式(101)的中间体；
b-2)式(101)的中间体经卤代反应得到式(102)的中间体；
b-3)式(102)的中间体与式(103)的中间体反应得到式(104)的中间体；
b-4)式(104)的中间体在氨源的作用下得到式(105)的中间体；
b-5)式(105)的中间体与联硼酸频哪醇酯反应得到式(106)的中间体；
(2)L1或L2中至少有一个选自咪唑基的通式I的化合物的制备：
Figure PCTCN2014095043-appb-000022
b-6)式(105)的中间体经过偶联反应得到式(107)的中间体或式(106)的中间体经过偶联反应得到式(107)的中间体，必要的时候可以有脱去保护基团的步骤；
b-7)式(107)的中间体酰胺化得到通式I的化合物，必要的时候可以有脱去保护基团的步骤。
其中，R1、R2、R3、R4、R5、R6、L1、L2具有通式I中的含义，M1表示氢、三甲基硅基乙氧基、叔丁氧羰基，M2表示氢、三甲基硅基乙氧基、叔丁氧羰基，Y表示卤素，优选为氯、溴、碘，所述的氨源是指氨水、氨气或者铵盐化合物，如硫酸铵、碳酸铵、碳酸氢铵、醋酸铵、氯化铵等。
第三方面，本发明提供药物组合物，其包含本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药。
在一些实施方案中，本发明提供本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药及包含本发明的化合物或其药学可接受的盐、异构体、 溶剂合物、结晶或前药的药物组合物，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，其包含本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，还包含选自下列组成的一种或多种：干扰素、三唑类核苷类药物、甘草甜素复方制剂、HCV蛋白酶抑制剂等。
可以将本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药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化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防由丙型肝炎病毒引起的肝脏疾病的方法和在制备预防和/或治疗丙型肝炎病毒引起的肝脏疾病药物中的应用，包括向丙型肝炎病毒引起的肝脏疾病患者施用本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或者包含本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的药物组合物，以有效抑制HCV，阻止病程进展。在一些实施方案中，本发明提供用于治疗和/或预防由丙型肝炎病毒引起的感染的方法，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药学可接受的盐、异构体、溶剂合物、结晶或前药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药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物以抑制HCV，阻止病程进展。
在另一些实施方案中，所述治疗和/或预防由丙型肝炎病毒引起的感染的方法或用途还包括向所述个体给予本发明的式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或含有它们的药物组合物且在给予本发明的式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药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。
术语说明
本发明的“烷基”是指直链或支链的饱和烃基。合适的烷基为取代或未取代的C1-10烷基，例如甲基、乙基、正丙基、异丙基、环丙基、正丁基、仲丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、环戊基、环己基、正己基等。
本发明的“环烷基”是指环状的饱和烃基。合适的环烷基可以为取代或未取代的具有3-10个碳原子的单环、二环或三环饱和烃基，例如环丙基、环丁基、环戊基、环己基。
本发明的“烷氧基”是指-O-烷基。根据本发明，合适的烷氧基为C1-10烷氧基，如C1-8烷氧基，C1-7烷氧基，C1-6烷氧基，C1-5烷氧基，C1-4烷氧基，C1-3烷氧基，包括甲氧基、乙氧基、丙氧基、异丙氧基、异丁氧基、仲丁氧基等。
本发明的“卤素”是指氟、氯、溴、碘。
本发明的“卤代烷基”是指至少被一个卤素取代的烷基。
本发明的“卤代烷氧基”是指至少被一个卤素取代的烷氧基。
本发明的“氨基酰基”是指-C(O)-NH2。
本发明的“单烷基氨基酰基”是指-C(O)-NH-烷基。
本发明的“双烷基氨基酰基”是指-C(O)-N(烷基)(烷基)。
本发明的“芳基”是指可以包含单环或多稠环例如二环或三环的芳香环的芳香系，其中至少稠合的环的一部分形成共轭的芳香系，其含有5至50个碳原子，优选约6至约14个碳原子。合适的芳基包括但不限于苯基、萘基、联苯基、蒽基、四氢萘基、芴基、茚满基、亚联苯基和苊基。
本发明的“杂芳基”是指芳族单环或多稠环如二环或三环的至少有一个碳原 子被杂原子替代的芳香性基团，所述的杂原子为O、S、N。合适的杂芳基包括但不限于咪唑基、苯并咪唑基、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基等。
本发明的“溶剂合物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂合物通常被称作水合物，例如一水合物、二水合物、三水合物等。
本发明的“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。
本发明的“异构体”是指分子中原子在空间上排列方式不同所产生的立体异构体，包括对映异构体和非对映异构体。
本发明的“前药”是指在生物体的生理条件下，由于与酶、胃酸等反应而转化成本发明的化合物的化合物，即通过酶的氧化、还原、水解等转化成本发明的化合物的化合物和/或通过胃酸等的水解反应等转化成本发明的化合物的化合物。
本发明的“药学可接受的盐”是指本发明的化合物与酸形成的药学上可接受的盐，所述的酸包括但不限于磷酸、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、硝酸等等。
本发明的“药物组合物”是指包含任何一种本文所述的化合物，包括异构体、前药、溶剂合物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。
本发明的“药学上可接受的载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体，包含溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、以及纤维素和乙酸纤维素；麦芽、明胶等。
本发明的“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍 生物、明胶、植物油、聚乙二醇。
具体实施方式
下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。
实施例1 (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(吡咯烷-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000023
步骤1 (S)-1-叔丁氧基羰基-2-甲酰基吡咯烷的制备
Figure PCTCN2014095043-appb-000024
在250mL的茄形瓶中，加入16mL草酰氯和125mL无水二氯甲烷，氮气保护且-78℃下，缓慢加入10mL溶有23mL DMSO的二氯甲烷溶液和10mL溶有10g(s)-1-叔丁氧羰基-2-羟甲基吡咯烷的二氯甲烷溶液，加完后，-78℃下继续搅拌30min，然后慢慢滴加46mL三乙胺(TEA)，滴毕，0-4℃搅拌30min，反应结束后，把反应液慢慢倒入100g冰块中，加入200mL饱和氯化钠水溶液，二氯甲烷萃取(3×200mL)，收集有机相，无水硫酸钠干燥，浓缩，得到标题化合物，直接用于下一步反应。
LC-MSm/z:[M+H]+＝200。
步骤2 (S)-1-叔丁氧基羰基-2-(1H-咪唑-2-基)吡咯烷的制备
Figure PCTCN2014095043-appb-000025
称取12g步骤1制得的化合物(s)-1-叔丁氧基羰基-2-甲酰基吡咯烷于100mL反应瓶中，加入30mL无水甲醇和30mL氨水溶液溶解，0-4℃下，缓慢滴加14mL乙二醛，室温反应16h，反应结束后，反应液经浓缩去除大部分的乙醇，加入二 氯甲烷萃取(3×50mL)，合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，所述粗品在100mL体积比为1：1的石油醚/乙酸乙酯混合溶液中重结晶得到标题化合物。
LC-MSm/z:[M+H]+＝238。
步骤3 (S)-1-叔丁氧基羰基-2-(4,5-二溴-1H-咪唑-2-基)吡咯烷的制备
Figure PCTCN2014095043-appb-000026
称取2.4g步骤2制备的化合物(S)-1-叔丁氧基羰基-2-(1H-咪唑-2-基)吡咯烷于100mL反应瓶中，加入3.6g N-溴代丁二酰亚胺(NBS)和30mL THF，氮气保护条件下室温反应3h，反应结束后，加入20mL水，乙酸乙酯萃取(3×60mL)，合并有机相，干燥，过滤，浓缩，柱层析纯化得到标题化合物。
ESI-MS m/z:[M+H]+＝394.0，计算值为393.9。
步骤4 (S)-1-叔丁氧基羰基-2-(4-溴-1H-咪唑-2-基)吡咯烷的制备
Figure PCTCN2014095043-appb-000027
称取9.58g步骤3制备的化合物(S)-1-叔丁氧基羰基-2-(4,5-二溴-1H-咪唑-2-基)吡咯烷和3.0g亚硫酸钠于100mL反应瓶中，加入50mL体积比为1:1的乙醇/水混合溶液，90℃反应24h，过滤，浓缩，柱层析纯化得到标题化合物。
ESI-MS m/z:[M+H]+＝316.1,318.1，计算值为316.1,318.1。
步骤5 (S)-2-(4-溴-1H-咪唑-2-基)吡咯烷的制备
Figure PCTCN2014095043-appb-000028
称取1g步骤4制备的化合物(S)-1-叔丁氧基羰基-2-(4-溴-1H-咪唑-2-基)吡咯烷于50mL反应瓶中，加入2mL三氟乙酸(TFA)和8mL二氯甲烷，室温反应3h，反应结束后，浓缩，加入30mL二氯甲烷稀释，饱和碳酸氢钠溶液洗涤(1×20mL)，饱和食盐水洗涤(1×20mL)，无水硫酸钠干燥，过滤，浓缩，得到标题化合物。
步骤6 (S)-1-((S)-2-(4-溴-1H-咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000029
称取1.2g步骤5制备的化合物(S)-2-(4-溴-1H-咪唑-2-基)吡咯烷、665mg(S)-2-(甲氧基羰基氨基)-3-甲基丁酸、1.44g 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲 基脲六氟磷酸酯(HATU)和1.23g DIPEA于50mL反应瓶中，加入10mL DMF，室温反应24h，反应结束后，加入20mL水，乙酸乙酯萃取(3×60mL)，合并有机相，干燥，过滤，浓缩，柱层析纯化得到标题化合物。
1HNMR(300MHz,d6-DMSO)δppm:12.0-13.2(brs,1H),7.39(s,1H),7.19(s,1H),4.91-4.93(m,1H),4.51-4.55(m,1H),3.61-3.65(m,1H),3.49-3.52(m,1H),3.47(s,3H),2.66-2.72(m,1H),2.02-2.12(m,2H),1.96-2.02(m,2H),0.79-0.87(m,6H)。
ESI-MSm/z:[M-56+H]+＝317.2，[M+H]+计算值为373.1。
步骤7 2,7-二溴-9,9,10,10-四氟-9,10-二氢菲的制备
Figure PCTCN2014095043-appb-000030
称取1.0g 2,7-二溴菲醌和5.0g双(2-甲氧乙基)氨基三氟化硫(BAST)于50mL四氟闷罐中，80℃反应48h，反应结束后，加入30mL冰水淬灭反应，乙酸乙酯萃取(4×60mL)，合并有机相，饱和食盐水洗涤(3×60mL)，合并有机相，干燥，过滤，浓缩，柱层析纯化得到标题化合物。
1HNMR(300MHz,CDCl3)δppm:7.93(s,2H),7.65-7.75(m,4H)。
步骤8 2,2'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷)的制备
Figure PCTCN2014095043-appb-000031
称取0.8g步骤7制备的化合物2,7-二溴-9,9,10,10-四氟-9,10-二氢菲、1.98g联硼酸频哪醇酯、1.2g醋酸钾和70.2mg 1,1'-二(二苯膦基)二茂铁二氯化钯(Pd(dppf)Cl2)于100mL反应瓶中，加入5mL 1,4-二氧六环，氮气保护条件下100℃反应24h，反应结束后，加入100mL水，乙酸乙酯萃取(3×60mL)，合并有机 相，饱和食盐水洗涤(3×60mL)，合并有机相，干燥，过滤，浓缩，柱层析纯化得到标题化合物。
1HNMR:(300MHz,CDCl3)δppm:8.24(s,2H),8.02(d,2H),7.87(d,2H),1.37(s,24H)。
步骤9 (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(吡咯烷-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000032
称取155mg步骤6制备的化合物(S)-1-((S)-2-(4-溴-1H-咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯、80mg步骤8制备的化合物2,2'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷)、406mg碳酸铯和29.13mg Pd(PPh3)2Cl2于100mL反应瓶中，加入6mL体积比为2:1的DMF/H2O混合溶液，氮气保护条件下100℃反应24h，反应结束后，加入20mL水，乙酸乙酯萃取(3×60mL)，合并有机相，干燥，过滤，浓缩，柱层析纯化得到标题化合物。
1HNMR:(300MHz,MeOD)δppm:8.24-8.30(m,4H),8.06-8.09(m,2H),7.92-7.97(m,2H),5.23-5.28(m,2H),4.23-4.26(m,2H),4.06-4.11(m,2H),3.72-3.86(m,2H),3.68-3.78(m,6H),2.52-2.56(m,2H),2.23-2.27(m,8H),0.86-0.95(m,12H)。
ESI-MSm/z:[M+H]+＝837.2，计算值为837.2。
实施例2 (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(4,4'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(4,1-亚苯基))双(1H-咪唑-5,2-二基))双(吡咯烷-2,1-二基))双(3,3-二甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯的制备
Figure PCTCN2014095043-appb-000033
步骤1：(S)-1-叔丁氧基羰基-2-(2-(4-溴苯基)-2-氧代乙氧基羰基)吡咯烷的制备
Figure PCTCN2014095043-appb-000034
称取5g 2-溴-1-(4-溴苯基)乙基酮于250mL反应瓶中，加入30mL乙腈，0℃条件下，加入4g(S)-1-叔丁氧基羰基脯氨酸，分批加入5.45g三乙胺后，25℃下搅拌2h，反应结束后直接浓缩得到标题化合物，直接用于下一步。
步骤2 (S)-1-叔丁氧基羰基-2-(5-(4-溴苯基)-1H-咪唑-2-基)吡咯烷的制备
称取4g步骤1制备的化合物(S)-1-叔丁氧基羰基-2-(2-(4-溴苯基)-2-氧代乙氧基羰基)吡咯烷和7.5g醋酸铵于250mL反应瓶中，加入50mL二甲苯，120℃下反应4h，反应结束后，旋干，加入60mL乙酸乙酯溶解，饱和碳酸氢钠水溶液洗涤(2×60mL)，饱和食盐水洗涤(1×60mL)，有机相无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到标题化合物。
1HNMR(300MHz,d6-DMSO)δppm:11.92(brs,1H),7.66-7.69(m,2H),7.48-7.51(m,3H),4.75-4.81(m,1H),3.39-3.52(m,1H),3.31-3.37(m,1H),1.85-2.02(m,4H),1.23-1.39(m,9H)。
ESI-MSm/z:[M+H]+＝392.0，计算值为392.0。
步骤3 (S)-1-叔丁氧基羰基-2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)苯基)-1H-咪唑-2-基)吡咯烷的制备
Figure PCTCN2014095043-appb-000036
以步骤2制备的化合物(S)-1-叔丁氧基羰基-2-(5-(4-溴苯基)-1H-咪唑-2-基)吡咯烷和联硼酸频那醇酯为原料，按照实施例1步骤8的方法制得标题化合物。
1HNMR(300MHz,CD3Cl)δppm:7.79-7.81(m,2H),7.62-7.69(m,2H),7.26-7.27(m,1H),4.97-4.99(m,1H),3.39-3.43(m,2H),2.97-3.02(b,1H),2.09-2.16(m,2H),1.96-2.00(m,2H),1.26-1.49(m,21H)。
ESI-MSm/z:[M+H]+＝440.3，计算值为440.2。
步骤4 (S)-2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)苯基)-1H-咪唑-2-基)吡咯烷的制备
Figure PCTCN2014095043-appb-000037
以步骤3制备的化合物(S)-1-叔丁氧基羰基-2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)苯基)-1H-咪唑-2-基)吡咯烷为原料，按照实施例1步骤5的方法制得标题化合物。
步骤5 (S)-2-(甲氧基羰基氨基)-3,3-二甲基丁酸的制备
Figure PCTCN2014095043-appb-000038
称取2g(S)-2-氨基-3,3-二甲基丁酸于100mL茄型瓶中，加入15.27mL NaOH水溶液(1M)和809mg碳酸钠，0-4℃下，缓慢滴加1.3mL氯甲酸甲酯，滴毕，0-4℃下继续反应20min后，室温反应4h，冷却到0℃，加入20mL乙醚稀释后，缓慢滴加3mL浓盐酸，乙酸乙酯萃取(2×50mL)，合并有机相，饱和食盐水洗(1×50mL)，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到标题化合物。
LC-MSm/z:[M+H]＝190。
步骤6 (S)-3,3-二甲基-1-氧代-1-((S)-2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)苯基)-1H-咪唑-2-基)吡咯烷-1-基)丁烷-2-基)氨基甲酸甲酯的制备
Figure PCTCN2014095043-appb-000039
称取0.5g步骤4制备的化合物(S)-2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)苯基)-1H-咪唑-2-基)吡咯烷于100mL反应瓶中，加入5mL二氯甲烷溶解后，加入284mg步骤5制备的化合物(S)-2-(甲氧基羰基氨基)-3,3-二甲基丁酸、621mg HATU和421mg DIPEA，20℃反应2h，反应结束后，加入20mL水，二氯甲烷萃取(3×60mL)，合并有机相，干燥，过滤，浓缩，柱层析纯化得到标题化合物。
步骤7 (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(4,4'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(4,1-亚苯基))双(1H-咪唑-5,2-二基))双(吡咯烷-2,1-二基))双(3,3-二甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯的制备
Figure PCTCN2014095043-appb-000040
以步骤6制备的化合物(S)-3,3-二甲基-1-氧代-1-((S)-2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)苯基)-1H-咪唑-2-基)吡咯烷-1-基)丁烷-2-基)氨基甲酸甲酯和实施例1步骤7制备的化合物2,7-溴-9,9,10,10-四氟-9,10-二氢菲为原料，按照实施例1步骤9的方法制得标题化合物。
1HNMR:(300MHz,MeOD)δppm:7.56-8.20(m,12H),7.30-7.428(m,4H),5.20-5.25(m,2H),4.32-4.36(m,2H),3.92-4.02(m,4H),3.66-3.68(m,6H),2.20-2.28(m,4H),2.00-2.11(m,4H),0.86-0.95(m,18H)。
ESI-MSm/z:[M/2+H]+＝509.2,[M+H]+＝1017.6，计算值为1017.4。
实施例3 (2S,2'S)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-3,2-二基))双(3-甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000041
步骤1 2,7-双(1-乙氧基乙烯-1-基)-9,9,10,10-四氟-9,10-二氢菲
Figure PCTCN2014095043-appb-000042
称取1g实施例1步骤7制备的化合物2,7-二溴-9,9,10,10-四氟-9,10-二氢菲于50mL三颈反应瓶中，加入15mL甲苯、1.95g三丁基(1-乙氧基乙烯)锡和0.1g(PPh3)2PdCl2，Ar气置换3次后，90℃搅拌8h。将反应液冷至室温，加入5mL 溶解有5g氟化钾的水溶液，搅拌3h，加入乙酸乙酯萃取，碳酸氢钠水溶液和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到标题化合物。
步骤2 2,7-二乙酰基-9,9,10,10-四氟-9,10-二氢菲
Figure PCTCN2014095043-appb-000043
将步骤1制备的化合物2,7-双(1-乙氧基乙烯-1-基)-9,9,10,10-四氟-9,10-二氢菲粗品加入反应瓶中，加入20mL THF溶解后，加入10mL 2N盐酸，室温搅拌5h，反应结束后，加入乙酸乙酯萃取(1×30mL)，碳酸氢钠溶液洗涤(2×30mL)，饱和食盐水洗涤(2×50mL)，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到标题化合物。
1HNMR(300MHz,DMSO-d6):8.46(2H,d),8.35((4H,d),2.71(6H,s)。
MS(ESI):[M+1]+＝337.1。
步骤3 1,1'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(2-溴乙酮)
Figure PCTCN2014095043-appb-000044
称取412mg步骤2制备的化合物2,7-二乙酰基-9,9,10,10-四氟-9,10-二氢菲于25mL反应瓶中，加入8mL CHCl3溶解后，加入392mg溴素，室温反应2h，反应结束后，浓缩得到标题化合物。
MS(ESI):[M+1]+＝495.0。
步骤4 (1R,1'R,3S,3'S,4S,4'S)-3,3'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双((2-氧代乙氧基)羰基)双(2-叔丁氧基羰基-2-氮杂双环[2.2.1]庚烷)
Figure PCTCN2014095043-appb-000045
称取580mg步骤3制备的化合物1,1'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(2-溴乙酮)于25mL反应瓶中，加入5mL乙腈、135mg(1R,3S,4S)-2-(叔丁氧基羰基)-2-氮杂双环[2.2.1]庚烷-3-甲酸和137uL N,N-二异丙基乙胺(DIPEA)，室温反 应1h，反应结束后，浓缩反应液得到标题化合物。
MS(ESI):[M+Na]+＝837.3。
步骤5 (1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯)
Figure PCTCN2014095043-appb-000046
以步骤4制备的化合物(1R,1'R,3S,3'S,4S,4'S)-3,3'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双((2-氧代乙氧基)羰基)双(2-叔丁氧基羰基-2-氮杂双环[2.2.1]庚烷)和醋酸铵为原料，按照实施例2步骤2的方法制得标题化合物。
步骤6 (1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷)
Figure PCTCN2014095043-appb-000047
以步骤5制备的化合物(1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯)为原料，按照实施例1步骤5制备的方法制得标题化合物。
MS(ESI):[M+1]+＝575.2。
步骤7 (2S,2'S)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-3,2-二基))双(3-甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000048
称取110mg步骤6制备的化合物(1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷)、67mg MOC-缬氨酸(N-甲氧基羰基-L-缬氨酸)于50mL反应瓶中，加入137uL DIPEA、 145mg HATU、47mg DMAP和3mLDMF，50℃反应12h，反应结束后，加入20mL水，乙酸乙酯萃取(2×20mL)，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化制得标题化合物。
1HNMR(300MHz,DMSO-d6):9.96(2H,s),8.10-8.23(4H,m),7.98-8.10(4H,m),7.44(1H,m),7.25-7.32(1H,m),4.61(2H,s),4.52(2H,s),4.19-4.20(2H,m),3.56(6H,s),2.67-2.69(2H,s),2.06-2.26(4H,m),1.80-1.84(6H,m),1.50-1.54(4H,m),0.98-1.00(6H,m),0.87-0.89(6H,m)。
MS(ESI):[M+1]+＝889.5。
实施例4 (2S,2'S)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-3,2-二基))双(3,3-二甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000049
以实施例3步骤6制备的化合物(1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷)和实施例2步骤5制备的化合物(S)-2-(甲氧羰基氨基)-3,3-二甲基丁酸为原料，按照实施例3步骤7的方法制得标题化合物。
1HNMR(300MHz,DMSO-d6):10.00(2H,s),8.21-8.24(4H,m),8.05-8.08(2H,m),7.96-8.05(2H,m),7.12-7.29(2H,m),4.59-4.63(4H,m),4.27-4.30(2H,m),3.19(1H,s),3.57(6H,s),2.64(1H,s),2.18-2.21(2H,m),1.71-1.79(6H,m),1.44-1.51(4H,m),0.92-1.01(18H,m).
MS(ESI):[M/2+1]+＝459.4。
实施例5 (2S,2'S,3R,3'R)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-3,2-二基))双(3-羟基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000050
步骤1 (2S,3R)-3-羟基-2-(甲氧基羰基氨基)丁酸
Figure PCTCN2014095043-appb-000051
以L-苏氨酸和氯甲酸甲酯为原料，按照实施例2步骤5的方法制得标题化合物。
1HNMR(400MHz,DMSO-d6)δppm:6.86-6.88(d,1H),4.02-4.09(m,1H),3.91-3.94(m,1H),3.55(s,3H),1.08-1.09(d,3H)。
LC-MSm/z:[M+H]+＝178。
步骤2 (2S,2'S,3R,3'R)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-3,2-二基))双(3-羟基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
以实施例3步骤6制备的化合物(1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷)和步骤1制备的化合物(2S,3R)-3-羟基-2-(甲氧基羰基氨基)丁酸为原料，按照实施例3步骤7的方法制得标题化合物。
1HNMR(300MHz,DMSO-d6):9.95(2H,s),8.22-8.25(4H,m),7.95-8.10(4H,m),7.43-7.98(2H,m),7.28-7.41(2H,m),6.95-6.98(2H,m),4.60-4.64(4H,m),4.32-4.34(2H,m),3.95-3.99(2H,m),3.48(6H,s),2.47-2.50(2H,m),2.05-2.09(2H,m),1.75-1.81(4H,m),1.45-1.49(4H,m),1.16-1.23(6H,m)。
MS(ESI):[M+1]+＝893.6。
实施例6 (2S,2'S,3R,3'R)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-3,2-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000052
步骤1 (2S,3R)-3-甲氧基-2-((甲氧羰基)氨基)丁酸
Figure PCTCN2014095043-appb-000053
称取1g O-甲基-L-苏氨酸于50mL单口瓶中，加入10mL四氢呋喃溶解后，0℃下，加入10mL溶解有0.33g氢氧化钠的水溶液，搅拌10min，继续在0℃下滴加5mL溶解有0.64mL氯甲酸甲酯的THF溶液。室温搅拌12h，反应结束后，浓缩，加20mL乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到标题化合物。
MS(ESI):[M+1]+＝192。
步骤2 (2S,2'S,3R,3'R)-1,1'-((1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷-3,2-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
以实施例3步骤6制备的化合物(1R,1'R,3S,3'S,4S,4'S)-3,3'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(2-氮杂双环[2.2.1]庚烷)和步骤1制备的化合物(2S,3R)-3-甲氧基-2-((甲氧羰基)氨基)丁酸为原料，按照实施例3步骤7的方法制得标题化合物。
1HNMR(300MHz,DMSO-d6):8.10-8.26(4H,m),8.01-8.07(4H,m),7.15-7.19(2H,m),4.54-4.61(4H,m),4.32-4.34(2H,m),3.56(6H,s),3.23(6H,s),2.49-2.52(2H,m),1.83-2.15(2H,m),1.72-1.78(6H,m),1.46-1.52(4H,m),1.08-1.16(6H,m)。
MS(ESI):[M+1]+＝921.5。
实施例7 (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(吡咯烷-2,1-二基))双(3,3-二甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000054
步骤1 (2S,2'S)-1,1’-二叔丁氧基羰基-2,2'-((9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双((2-氧代乙氧基)羰基))双吡咯烷
Figure PCTCN2014095043-appb-000055
以实施例3步骤3制备的化合物1,1'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(2-溴乙酮)和(S)-1-叔丁氧基羰基-2-羧基吡咯烷为原料，同实施例3步骤4的方法制得标题化合物。
步骤2 (2S,2'S)-1,1’-二叔丁氧基羰基-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双吡咯烷
Figure PCTCN2014095043-appb-000056
以步骤1制备的化合物(2S,2'S)-1,1’-二叔丁氧基羰基-2,2'-((9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双((2-氧代乙氧基)羰基))双吡咯烷为原料，同实施例2步骤2的方法制得标题化合物。
步骤3 (2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双吡咯烷
Figure PCTCN2014095043-appb-000057
以步骤2制备的(2S,2'S)-1,1’-二叔丁氧基羰基-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双吡咯烷为原料，同实施例1步骤5的方法制得标题化合物。
步骤4 (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(吡咯烷-2,1-二基))双(3,3-二甲基-1-氧代丁烷-2,1-二基)二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000058
以步骤3制备的化合物(2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双吡咯烷和实施例2步骤5制备的化合物(S)-2-(甲氧基羰基氨基)-3,3-二甲基丁酸为原料，同实施例3步骤7的方法制得标题化合物。
1HNMR:(300MHz,MeOD)δppm:8.24-8.30(m,4H),8.05-8.08(m,2H),7.93-7.97(m,2H),5.20-5.25(m,2H),4.32(s,2H),4.06-4.11(m,2H),3.72-3.86(m,2H),3.66(s,6H),2.52-2.56(m,2H),2.23-2.27(m,6H),0.86-0.95(m,18H)。
ESI-MSm/z:[M+H]+＝865.3,432.1，计算值为865.4。
实施例8 ((2S,2'S,3R,3'R)-((2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(吡咯烷-2,1-二基))双(3-羟基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000059
以实施例7步骤3制备的化合物(2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双吡咯烷和实施例5步骤1制备的化合物(2S,3R)-3-羟基-2-(甲氧基羰基氨基)丁酸为原料，同实施例3步骤7的方法制得标题化合物。
1HNMR:(500MHz,MeOD)δppm:8.24-8.30(m,4H),8.06-8.09(m,2H),7.92-9.97(m,2H),5.23-5.28(m,2H),4.51-4.56(m,2H),4.11-4.16(m,2H),3.94-4.02(m,4H),3.68(s,6H),2.52-2.56(m,2H),2.23-2.27(m,6H),1.15-1.20(m,6H)。
ESI-MSm/z:[M+H]+＝841.5，计算值为841.3。
实施例9 N-((2S)-1-((2S)-2-(5-(7-(2-((S)-1-((S)-2-((甲氧羰基)氨基)-3-甲基丁酰基) 吡咯烷-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基))-1H-苯并[d]咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000060
步骤1 2-乙酰基-7-溴-9,9,10,10-四氟-9,10-二氢菲
Figure PCTCN2014095043-appb-000061
称取2.07g实施例1步骤7制备的化合物2,7-二溴-9,9,10,10-四氟-9,10-二氢菲于50mL三颈瓶中，加入2.33g Pd(PPh3)4、1.65g Pd(dppf)Cl2、1.7mL三丁基(1-乙氧基乙烯)锡，加入30mL 1,4-二氧六环，N2保护下80℃反应8h，反应结束后，柱层析纯化得到2-(1-乙氧基乙烯-1-基)-7-溴-9,9,10,10-四氟-9,10-二氢菲。
加入30mL四氢呋喃于柱层析纯化得到的2-(1-乙氧基乙烯-1-基)-7-溴-9,9,10,10-四氟-9,10-二氢菲中，加入3N盐酸，室温搅拌6h，反应结束后，柱层析纯化得到标题化合物。
1H NMR(300MHz,DMSO-d6):8.37(1H,d),8.32(2H,d),8.24(1H,d),8.13(1H,s),8.05(1H,d),2.69(3H,s)。
MS(ESI):[M+1]+＝373.0。
步骤2 2-溴-1-(7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)乙酮
Figure PCTCN2014095043-appb-000062
称取0.74g步骤1制备的化合物2-乙酰基-7-溴-9,9,10,10-四氟-9,10-二氢菲于50mL三颈瓶中，加入20mL无水二氯甲烷、0.35mL三乙胺，N2保护且0℃下，滴加0.43mL三甲硅基三氟甲磺酸脂(TMSOTf)，0℃下继续搅拌30min后，升至室温反应1h，反应结束后，室温下加入0.53g NBS，继续反应1h，反应结束后，浓缩反应液得到标题化合物，直接进行下一步反应。
步骤3 (S)-1-叔丁氧基羰基-2-(((7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)-2-氧代乙 氧基)羰基)吡咯烷
Figure PCTCN2014095043-appb-000063
将步骤2制得的化合物2-溴-1-(7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)乙酮加入50mL茄形瓶中，加入20mL乙腈、0.65mL DIEA和425mg N-Boc-L-脯氨酸，室温反应3h，反应结束后，浓缩反应液得到标题化合物，直接进行下一步反应。
MS(ESI):[M-100+1]+＝486.1,[M+1]+＝586.1(计算值)。
步骤4 (S)-1-叔丁氧基羰基-2-(5-(7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷
Figure PCTCN2014095043-appb-000064
以步骤3制备的化合物(S)-1-叔丁氧基羰基-2-(((7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)-2-氧代乙氧基)羰基)吡咯烷为原料，按照实施例2步骤2的方法，制得标题化合物。
MS(ESI):[M+1]+＝566.1。
步骤5 (S)-1-叔丁氧基羰基-2-(2-氨基-4-溴代苯基氨基酰基)吡咯烷
Figure PCTCN2014095043-appb-000065
称取12.9g Boc-L-脯氨酸于250mL的茄形瓶中，加入150mL DMF溶解后，加入27.4g 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和11.6gN,N-二异丙基乙胺(DIPEA)，室温搅拌30min后，缓慢加入11g 4-溴邻苯二胺，加完后，室温下反应16h，停止反应，将反应液倒入200mL冰水中，加入乙酸乙酯萃取(2×200mL)，合并有机相，饱和氯化钠水溶液洗涤(2×200mL)，无水硫酸钠来干燥，浓缩得到标题化合物，直接用于下一步反应。
LC-MSm/z:[M+H]+＝384。
步骤6 (S)-1-叔丁氧基羰基-2-(6-溴-1H-苯并[d]咪唑-2-基)吡咯烷
Figure PCTCN2014095043-appb-000066
称取22g步骤5制备的化合物(S)-1-叔丁氧基羰基-2-(2-氨基-4-溴代苯基氨基酰基)吡咯烷于反应瓶中，加入150mL醋酸溶解，85℃下反应2h，停止反应，0-4℃搅拌下，慢慢滴加40％氢氧化钠水溶液，调节PH至9左右，乙酸乙酯萃取(2×200mL)，合并有机相，饱和氯化钠水溶液洗涤(2×200mL)，无水硫酸钠干燥，浓缩并经硅胶柱色谱纯化，得到标题化合物。
LC-MSm/z:[M+H]+＝366。
步骤7 (S)-1-叔丁氧基羰基-2-(6-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷
Figure PCTCN2014095043-appb-000067
以步骤6制备的化合物(S)-1-叔丁氧基羰基-2-(6-溴-1H-苯并[d]咪唑-2-基)吡咯烷为原料，按照实施例1步骤8的方法制得标题化合物。
LC-MSm/z:[M+H]+＝414。
步骤8 (S)-1-叔丁氧基羰基-2-(5-(7-(2-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷
Figure PCTCN2014095043-appb-000068
称取150mg步骤7制备的化合物(S)-1-叔丁氧基羰基-2-(6-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷、109mg步骤4制备的化合物(S)-1-叔丁氧基羰基-2-(5-(7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷、31mg四三苯基膦钯(Pd(PPh3)4)和110mg碳酸钾于50mL三颈瓶中，加入8mL乙二醇二甲醚，2mL水，氮气保护下80℃反应2h，反应结束后，冷却至室温，加入10mL水，乙酸乙酯萃取(2×10mL)，饱和食盐水洗涤(1×20mL)，无水硫酸钠干燥，过滤，浓缩得到标题化合物。
LC-MSm/z:[M+H]+＝773.4。
步骤9 (S)-2-(5-(7-(2-((S)-吡咯烷-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷
Figure PCTCN2014095043-appb-000069
以步骤8制备的化合物(S)-1-叔丁氧基羰基-2-(5-(7-(2-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷为原料，按照实施例1步骤5的方法制得标题化合物。
LC-MSm/z:[M+H]+＝573.4。
步骤10 N-((2S)-1-((2S)-2-(5-(7-(2-((S)-1-((S)-2-((甲氧羰基)氨基)-3-甲基丁酰基)吡咯烷-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基))-1H-苯并[d]咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000070
以步骤9制备的化合物(S)-2-(5-(7-(2-((S)-吡咯烷-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷和MOC-缬氨酸为原料，按照实施例1步骤6的方法制得标题化合物。
LC-MSm/z:[M+H]+＝887.5。
1HNMR:(500MHz,DMSO)δppm:8.34～8.36(3H,m),8.17～8.20(4H,m),8.07(1H,s),7.78～7.83(2H,m),5.15～5.18(1H,m),4.80(1H,s),4.60(1H,s),4.24～4.25(1H,m),4.15～4.17(1H,m),3.87～3.91(1H,m),3.60(3H,s),3.59(3H,s),3.20～3.21(1H,m),2.79～2.81(1H,m),2.67～2.69(1H,m),2.39～2.42(1H,m),2.20～2.28(1H,m),2.04～2.07(2H,m),1.81～1.88(2H,m),1.58～1.61(2H,m),1.27～1.33(1H,m),0.84～0.99(12H,m)。
实施例10 N-((2S)-1-((2S)-2-(6-(7-(2-((1R,3S,4S)-2-((S)-2-((甲氧羰基)氨基)-3-甲 基丁酰基)-2-氮杂双环[2.2.1]庚烷-3-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基))-1H-咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000071
步骤1(1R,3S,4S)-2-叔丁氧基羰基-3-(2-氨基-4-溴苯氨基羰基)-2-氮杂双环[2.2.1]庚烷
Figure PCTCN2014095043-appb-000072
以4-溴邻苯二胺和(1R,3S,4S)-2-(叔丁氧基羰基)-2-氮杂双环[2.2.1]庚烷-3-甲酸为原料，按实施例9步骤5的方法制得标题化合物。
LC-MSm/z:[M+H]+＝410，计算值为410.1。
步骤2 (1R,3S,4S)-2-叔丁氧基羰基-3-(6-溴-1H-苯并[d]咪唑-2-基)-2-氮杂双环[2.2.1]庚烷
Figure PCTCN2014095043-appb-000073
以步骤1制得的化合物(1R,3S,4S)-2-叔丁氧基羰基-3-(2-氨基-4-溴苯氨基羰基)-2-氮杂双环[2.2.1]庚烷为原料，按实施例9步骤6的方法制得标题化合物。
LC-MSm/z:[M+H]+＝392.2。
步骤3 (1R,3S,4S)-2-叔丁氧基羰基-3-(6-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[2.2.1]庚烷
Figure PCTCN2014095043-appb-000074
以步骤2制得化合物(1R,3S,4S)-2-叔丁氧基羰基-3-(6-溴-1H-苯并[d]咪唑-2- 基)-2-氮杂双环[2.2.1]庚烷为原料，按照实施例1步骤8的方法制得标题化合物。
1HNMR(300MHz,CDCl3):δ:10.65(1H,br),8.01(1H,m),7.66(2H,d),4.55(1H,s),4.15(1H,m),3.49(1H,m),1.9(2H,m),1.7(4H,m,),1.52(9H,s),1.35(12H,s)。
LC-MSm/z:[M+H]+＝440.3。
步骤4 (1R,3S,4S)-2-叔丁氧基羰基-3-(6-(7-(2-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[2.2.1]庚烷
Figure PCTCN2014095043-appb-000075
以步骤3制得的化合物(1R,3S,4S)-2-叔丁氧基羰基-3-(6-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[2.2.1]庚烷和实施例9步骤4制得的化合物(S)-1-叔丁氧基羰基-2-(5-(7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷为原料，按照实施例9步骤8的方法制得标题化合物。
LC-MSm/z:[M+H]+＝799.4。
步骤5 (1R,3S,4S)-3-(6-(7-(2-((S)-吡咯烷-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[2.2.1]庚烷
Figure PCTCN2014095043-appb-000076
以步骤4制得的化合物(1R,3S,4S)-2-叔丁氧基羰基-3-(6-(7-(2-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[2.2.1]庚烷为原料，按实施例1步骤5的方法制得标题化合物。
LC-MSm/z:[M+H]+＝599.3。
步骤6 N-((2S)-1-((2S)-2-(6-(7-(2-((1R,3S,4S)-2-((S)-2-((甲氧羰基)氨基)-3-甲基丁酰基)-2-氮杂双环[2.2.1]庚烷-3-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基))-1H-咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000077
以步骤5制得的化合物(1R,3S,4S)-3-(6-(7-(2-((S)-吡咯烷-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[2.2.1]庚烷和MOC-缬氨酸为原料，按实施例1步骤6的方法制得标题化合物。
LC-MSm/z:[M+H]+＝913.5。
1HNMR:(500MHz,DMSO)δppm:8.32～8.35(2H,m),8.26～8.28(1H,m),8.16～8.19(4H,m),8.06(1H,s),7.76(2H,s),7.27～7.35(2H,m),5.18～5.20(1H,m),4.79(1H,s),4.61(1H,s),4.15～4.26(3H,m),3.88～3.91(2H,m),3.61(3H,s),3.60(3H,s),2.78(1H,m),2.38～2.39(2H,m),2.13～2.20(1H,m),2.06～2.10(4H,m),1.95～1.97(1H,m),1.81～1.87(2H,m),1.29～1.33(1H,m),0.87～1.02(12H,m)。
实施例11 N-((2S)-1-((S)-2-(6-(7-((S)-2-(7-((S)-2-((甲氧基羰基)氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000078
步骤1 7-苄氧基羰基-(S)-8-甲氧基羰基-1,4-二氧杂-7-氮杂螺[4.4]壬烷的制备
Figure PCTCN2014095043-appb-000079
称取10g(S)-1-苄氧基羰基-2-甲氧基羰基-4-氧代吡咯于反应瓶中，加入100mL甲苯和100mL乙二醇溶解，加入620mg对甲苯磺酸，165℃下Dean-Stark回流带水5h，反应结束后，浓缩除去甲苯，加入乙酸乙酯和水萃取，有机层用 饱和食盐水洗涤、干燥、浓缩得标题化合物。
步骤2 (S)-8-甲氧基羰基-1,4-二氧杂-7-氮杂螺[4.4]壬烷的制备
Figure PCTCN2014095043-appb-000080
称取218mg步骤1所得物7-苄氧基羰基-(S)-8-甲氧基羰基-1,4-二氧杂-7-氮杂螺[4.4]壬烷于反应瓶中，加入5mL甲醇溶解，室温搅拌下加入43mg钯碳，氢气条件下室温反应1小时，过滤，浓缩，得标题化合物，直接用于下一步反应。
步骤3 (S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-8-甲氧基羰基-1,4-二氧杂-7-氮杂螺[4.4]壬烷的制备
Figure PCTCN2014095043-appb-000081
称取187mg步骤2所得物(S)-8-甲氧基羰基-1,4-二氧杂-7-氮杂螺[4.4]壬烷、380mg HATU、0.5mL DIEA和175mg MOC-缬氨酸，置于反应瓶中，加入20mL二氯甲烷，室温反应2h，反应结束后，加入二氯甲烷和水萃取，有机层干燥，过滤，柱层析纯化，得标题化合物。
步骤4 (S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-甲酸的制备
Figure PCTCN2014095043-appb-000082
称取2g步骤3所得物(S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-8-甲氧基羰基-1,4-二氧杂-7-氮杂螺[4.4]壬烷，置于反应瓶中，加入20mL 1,4-二氧六环溶解，加入1N LiOH水溶液15mL，室温反应1h后，调pH至4-5，二氯甲烷萃取，有机相干燥，浓缩，直接用于下一步反应。
步骤5 (S)-2-(6-(7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-1-叔丁氧羰基吡咯的制备
Figure PCTCN2014095043-appb-000083
称取1g实施例1步骤7所得物2,7-二溴-9,9,10,10-四氟-9,10-二氢菲、1.2g实施例9步骤7化合物(S)-1-叔丁氧基羰基-2-(6-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷和283mg Pd(PPh3)4，置于反应瓶中，加入20mL N,N-二甲基乙酰胺(DME)溶解后，加入4mL K2CO3水溶液(2M)，氩气保护下，回流反应4h，反应结束后，乙酸乙酯萃取(3×20mL)，干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-MSm/z:[M+H]+＝616。
步骤6 (S)-2-(6-(7-(2-溴乙酰基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-1-叔丁氧羰基吡咯的制备
Figure PCTCN2014095043-appb-000084
称取930mg步骤5所得物(S)-2-(6-(7-溴-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-1-叔丁氧羰基吡咯、653mg三丁基(1-乙氧基乙烯)锡和106mg Pd(PPh3)2Cl2，置于反应瓶中，加入20mL二氧六环溶解，氩气保护下80℃反应3h，冷却至室温，加入5mL水和270mg NBS，室温反应2h，反应结束后，乙酸乙酯萃取(3×20mL)，干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-MSm/z:[M+H]+＝658。
步骤7 (S)-2-(6-(7-(2-((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-1-叔丁氧羰基吡咯的制备
Figure PCTCN2014095043-appb-000085
称取220mg步骤6所得物(S)-2-(6-(7-(2-溴乙酰基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-1-叔丁氧羰基吡咯和100mg步骤4所得物(S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-甲酸，置于反应瓶中，加入5mL乙腈溶解，加入77mg DIPEA，回流反应0.5h，浓缩，加入10mL甲苯和254mg乙酸铵，130℃反应2h，反应结束后，浓缩，柱层析纯化，得标题化合物。
ESI-MSm/z:[M+H]+＝888。
步骤8 N-((S)-3-甲基-1-氧代-1-((S)-8-(5-(7-(2-((S)-吡咯-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-7-基)丁烷-2-基)氨基甲酸甲酯的制备
Figure PCTCN2014095043-appb-000086
称取130mg步骤7所得物(S)-2-(6-(7-(2-((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-1-叔丁氧羰基吡咯，置于反应瓶中，加入3mL二氯甲烷溶解，加入1mL三氟乙酸，室温反应1h，反应结束后，浓缩干，加水，饱和碳酸氢钠溶液调PH至8，过滤，水洗，干燥得标题化合物。
ESI-MSm/z:[M+H]+＝788。
步骤9 N-((2S)-1-((S)-2-(5-(7-((S)-2-(7-((S)-2-((甲氧基羰基)氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000087
称取115mg步骤8所得物N-((S)-3-甲基-1-氧代-1-((S)-8-(5-(7-(2-((S)-吡咯-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-7-基)丁烷-2-基)氨基甲酸甲酯和31mg MOC-缬氨酸，置于反应瓶中，加入10mL二氯甲烷溶解，加入40mg DIPEA和86mg 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)，室温反应15h，浓缩，柱层析纯化得目标化合物。
1H NMR(500MHz,d6-DMSO)δ12.32(s,1H),12.09(s,1H),8.09-8.20(m,6H),7.91(s,1H),7.74(s,1H),7.63(s,2H),7.27(s,2H),5.21(s,1H),5.10(s,1H),3.68-4.07(m,12H),3.32(s,6H),1.95-2.09(m,6H),0.88(m,12H)。
ESI-MS m/z:[M+H]+＝945。
实施例12 N-((2S)-1-((S)-2-(6-(7-((S)-2-(5-((S)-2-((甲氧基羰基)氨基)-3-甲基丁酰基)-5-氮杂螺[2.4]庚烷-6-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000088
步骤1 5-叔丁氧基羰基-(S)-6-(5-(7-(2-((S)-1-(叔丁氧羰基)吡咯-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-5-氮杂螺[2.4]庚烷的制备
Figure PCTCN2014095043-appb-000089
以实施例11步骤6所得物(S)-2-(6-(7-(2-溴乙酰基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)-1-叔丁氧羰基吡咯和(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-甲酸钾为原料，按照实施例11步骤7的方法制得标题化合物。
ESI-MS m/z:[M+H]+＝799。
步骤2 6-(7-(2-((S)-5-氮杂螺[2.4]庚烷-6-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-2-((S)-吡咯-2-基)-1H-苯并[d]咪唑的制备
Figure PCTCN2014095043-appb-000090
以步骤1所得物5-叔丁氧基羰基-(S)-6-(5-(7-(2-((S)-1-(叔丁氧羰基)吡咯-2-基)-1H-苯并[d]咪唑-6-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-5-氮杂螺[2.4]庚烷为原料，按照实施例11步骤8的方法制得标题化合物。
ESI-MSm/z:[M+H]+＝599。
步骤3 N-((2S)-1-((S)-2-(6-(7-((S)-2-(5-((S)-2-((甲氧基羰基)氨基)-3-甲基丁酰基)-5-氮杂螺[2.4]庚烷-6-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯的制备
Figure PCTCN2014095043-appb-000091
以步骤2所得物6-(7-(2-((S)-5-氮杂螺[2.4]庚烷-6-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-2-((S)-吡咯-2-基)-1H-苯并[d]咪唑和MOC-缬氨酸为原料，按照实施例11步骤9的方法制得标题化合物。
1H NMR(500MHz,d6-DMSO)δ12.32(s,1H),11.97(s,1H),8.08-8.21(m,6H),7.77-7.90(m,2H),7.59(s,2H),7.32(m,2H),5.21(m,2H),3.99-4.07(m,2H),3.64-3.90(m,4H),3.54-3.57(m,6H),1.91-2.24(m,8H),0.60-0.95(m,16H)。
ESI-MS m/z:[M+H]+＝913。
实施例13 ((2S,2'S,3R,3'R)-((2S,2'S)-2,2'-(4,4'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(吡咯-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯的制备
Figure PCTCN2014095043-appb-000092
步骤1 (2S,3R)-3-甲氧基-2-(甲氧基羰基氨基)丁酸的制备
Figure PCTCN2014095043-appb-000093
称取3.0g O-甲基-L-苏氨酸和0.902g氢氧化钠于100mL干燥单口瓶中，加入15mL水，0℃下加入1.74mL氯甲酸甲酯，在冰浴条件下搅拌自然升到室温，反应12h，反应结束后，反应液用1N HCl溶液调节pH到1，加入乙酸乙酯萃取(5×100mL)，有机相干燥，过滤，浓缩得到标题化合物，直接用于下一步反应。MS(ESI):[M+H]+＝192。
步骤2 ((2S,2'S,3R,3'R)-((2S,2'S)-2,2'-(4,4'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(吡咯-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯的制备
Figure PCTCN2014095043-appb-000094
以实施例7步骤3制备的化合物(2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双吡咯烷和步骤1所得物(2S,3R)-3-甲氧基-2-(甲氧基羰基氨基)丁酸为原料，同实施例3步骤7的方法制得标题化合物。
1H NMR:300MHz,DMSO-d6)δ11.96-12.13(m,2H),7.89-8.32(m,6H),7.75-7.83(m,2H),7.22-7.29(m,2H),5.03-5.09(m,2H),4.25-4.33(m,2H),3.60-3.92(m,4H),3.40-3.59(m,8H),3.18(s,6H),1.89-2.32(m,8H),0.96-1.18(m,6H)。
MS(ESI):[M+H]+＝869。
实施例14 N-((2S)-1-((S)-2-(5-(7-((S)-2-(7-((S)-2-((甲氧基羰基)氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000095
步骤1 (S)-2-(2-(7-((((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)羰基氧基)乙酰基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-2-氧代乙氧基羰基)-1-叔丁氧羰基吡咯的制备
Figure PCTCN2014095043-appb-000096
称取1g实施例3步骤3制备的化合物1,1'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(2-溴乙酮)于50mL反应瓶中，加入25mL乙腈、650mg实施例11步骤4所得化合物(S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-甲酸和1mL N,N-二异丙基乙胺(DIPEA)，室温反应0.5h后，加入430mg(叔丁氧基羰基)-L-脯氨酸，室温反应0.5h。反应结束后，浓缩反应液，得到标题化 合物。
MS(ESI):[M+H]＝878.3。
步骤2 (S)-2-(5-(7-(2-((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-1-叔丁氧基羰基吡咯的制备
Figure PCTCN2014095043-appb-000097
以步骤1所得物(S)-2-(2-(7-((((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)羰基氧基)乙酰基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-2-氧代乙氧基羰基)-1-叔丁氧羰基吡咯和醋酸铵为原料，按照实施例2步骤2的方法制得标题化合物。
MS(ESI):[M+H]＝838。
步骤3 (S)-2-(5-(7-(2-((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯
Figure PCTCN2014095043-appb-000098
称取1g步骤2所得物(S)-2-(5-(7-(2-((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-1-叔丁氧基羰基吡咯，置于反应瓶中，加入20mL二氯甲烷溶解，0-4℃下加入5mL三氟醋酸，室温反应2h，除去溶剂，油泵抽干，得标题化合物，直接用于下一步。
MS(ESI):[M+H]＝738。
步骤4 N-((2S)-1-((S)-2-(5-(7-((S)-2-(7-((S)-2-((甲氧基羰基)氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢 菲-2-基)-1H-咪唑-2-基)吡咯烷-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸甲酯的制备
Figure PCTCN2014095043-appb-000099
以步骤3所得物(S)-2-(5-(7-(2-((S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯和MOC-缬氨酸为原料，按照实施例11步骤9的方法制得目标化合物。
1HNMR:(500MHz,DMSO-d6)δ:11.97-12.04(m,2H),8.01-8.15(m,6H),7.75(m,2H),7.25(m,2H),5.08(m,2H),3.75-5.09(m,10H),3.55(m,6H),1.96-2.42(m,8H),0.88-0.96(m,12H)。
ESI-MSm/z:[M+H]＝895。
实施例15 N-((2S)-1-((S)-2-(5-(7-(2-((S)-1-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-吡咯-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-吡咯-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸-2-甲氧基乙酯
Figure PCTCN2014095043-appb-000100
步骤1 (S)-2-(((2-甲氧基乙氧基)羰基)氨基)-3-甲基丁酸的制备
Figure PCTCN2014095043-appb-000101
称取2.52g三光气于反应瓶中，0-4℃下加入50mL二氯甲烷和2.02g吡啶。称取1.6g乙二醇单甲醚，用5mL二氯甲烷稀释后，滴加至反应瓶中。反应1小时后，逐渐升温至室温，将反应液浓缩，加入1,4-二氧六环10mL，溶解后待用。
称取1.17g MOC-缬氨酸于另一反应瓶中，加入10mL 2N氢氧化钠溶液，室温搅拌下，将上述待用的1,4-二氧六环溶液滴加至反应瓶中，室温反应12h，反应结束后，调节pH至4-5，氯仿萃取，有机相浓缩得标题化合物，直接用于下 一步反应。
步骤2 (S)-2-(5-(7-(2-((S)-1-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-吡咯-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯的制备
Figure PCTCN2014095043-appb-000102
以实施例7步骤3所得物(2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双吡咯烷和MOC-缬氨酸为原料，按照实施例11步骤9的方法得标题化合物。
步骤3 N-((2S)-1-((S)-2-(5-(7-(2-((S)-1-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-吡咯-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)-吡咯-1-基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸-2-甲氧基乙酯的制备
Figure PCTCN2014095043-appb-000103
以步骤2所得物(S)-2-(5-(7-(2-((S)-1-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-吡咯-2-基)-1H-咪唑-5-基)-9,9,10,10-四氟-9,10-二氢菲-2-基)-1H-咪唑-2-基)吡咯和步骤1所得物(S)-2-(((2-甲氧基乙氧基)羰基)氨基)-3-甲基丁酸为原料，按照实施例11步骤9的方法制得目标化合物。
1HNMR:(500MHz,DMSO-d6)δ:11.98(m,2H),7.24-8.41(m,10H),5.09(m,2H),3.25-4.06(m,16H),1.98-2.14(m,10H),0.87-0.96(m,12H)。
ESI-MSm/z:[M+H]＝881。
实施例16 ((2S,2'S)-((2S,2'S)-2,2'-(6,6'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-苯并[d]咪唑-6,2-二基))双(吡咯-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000104
步骤1 (2S,2'S)-2,2'-(6,6'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-苯并[d]咪唑-6,2-二基))双(1-叔丁氧基羰基吡咯)的制备
Figure PCTCN2014095043-appb-000105
以实施例9步骤7所得物(S)-1-叔丁氧基羰基-2-(6-(4,4,5,5-四甲基-1,3,2-二氧杂戊环硼烷-2-基)-1H-苯并[d]咪唑-2-基)吡咯烷和实施例1步骤7所得物2,7-二溴-9,9,10,10-四氟-9,10-二氢菲为原料，按照实施例9步骤8的方法制得标题化合物。步骤2(2S,2'S)-2,2'-(6,6'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-苯并[d]咪唑-6,2-二基))双吡咯的制备
Figure PCTCN2014095043-appb-000106
以步骤1所得物(2S,2'S)-2,2'-(6,6'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-苯并[d]咪唑-6,2-二基))双(1-叔丁氧基羰基吡咯)为原料，按照实施例11步骤8的方法制得标题化合物。
步骤3 N-((S)-3-甲基-1-氧代-1-((S)-2-(5-(9,9,10,10-四氟-7-(2-((S)-1-(3-甲基-2-(甲氧基羰基氨基)丁酰基)吡咯-2-基)-1H-苯[d]咪唑-5-基)-9,10-二氢菲-2-基)-1H-苯[d]咪唑-2-基)吡咯-1-基)丁基-2-基)氨基甲酸甲酯
Figure PCTCN2014095043-appb-000107
以步骤2所得物(2S,2'S)-2,2'-(6,6'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-苯并[d]咪唑-6,2-二基))双吡咯和MOC-缬氨酸为原料，按照实施例11步骤 9的方法制得标题化合物。
1HNMR:(500MHz,DMSO-d6)δ:12.29(m,2H),7.28-8.28(m,14H),5.22(m,2H),4.08-4.11(m,2H),3.85-3.87(m,4H),3.30(m,6H),1.93-2.25(m,10H),0.83-0.91(m,12H)。
ESI-MSm/z:[M+H]＝938。
实施例17 ((2S,2'S)-((2S,2'S)-2,2'-(5,5'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(1H-咪唑-5,2-二基))双(1,4-二氧杂-7-氮杂螺[4.4]壬烷-7,8-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯
Figure PCTCN2014095043-appb-000108
以实施例3步骤3所得物1,1'-(9,9,10,10-四氟-9,10-二氢菲-2,7-二基)双(2-溴乙酮)和实施例11步骤4所得物(S)-7-((S)-2-(甲氧基羰基氨基)-3-甲基丁酰基)-1,4-二氧杂-7-氮杂螺[4.4]壬烷-8-甲酸为原料，按照实施例11步骤7的方法制得标题化合物。
1H NMR(300MHz,CDCl3)δ:8.16(d,2H),7.74-7.64(m,3Η),7.33(s,1Η),5.60-5.57(d,2Η),5.38-5.33(t,2H),4.32(m,2H),4.06-4.05(d,6Η),3.96-3.92(m,2Η),3.70(s,6H),3.25(m,2H),2.48(m,2H),1.98-1.96(d,6H),1.26(d,2H),1.08(m,2H),0.92-0.82(dd,8H)。
ESI-MS m/z:[M+H]+＝953。
实验例1 本发明的化合物的抗HCV-1b复制子活性检测
1实验材料
1.1化合物
以上实施例制备的本发明的化合物，每个化合物用DMSO溶解至10mM后，用DMEM完全培养液稀释至50μM，然后用含0.5％DMSO的完全培养液稀释至20nM后，依次3倍稀释，共10个浓度。
1.2细胞HCV 1b复制子细胞，即Huh7细胞系稳定转入HCV基因型1b复制子，由药明康德(上海)新药开发有限公司提供。Huh71b复制子细胞系统的具体制备方法参见Lohmann V,Korner F,Koch J,Herian U,Theilmann L，Bartenschlager R.,Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line,Science 285(5424):110-113(1999).1.3试剂
DMEM细胞培养液(DMEM medium)，购自美国Invitrogen公司；
胎牛血清(Fetal bovine serum,FBS)，购自美国Sigma公司；
L-谷氨酰胺(L(+)-Glutamine)，购自美国Invitrogen公司；
青霉素-链霉素(Pen-Strep)，购自美国Invitrogen公司；
磷酸盐缓冲液(Phosphate buffered saline,PBS)，购自美国Hyclone公司；
胰酶(Trypsin)，购自美国Invitrogen公司；
二甲基亚砜(Dimethyl sulfoxide,DMSO)，购自美国Sigma公司；
Bright-Glo检测试剂，购自美国Promega公司；
细胞生长荧光测定检测试剂(CellTiter-Fluor)，购自美国Promega公司。
1.4仪器
自动聚焦荧光多功能酶标仪(PHERAstar Plus)，购于德国BMG Labtech公司。
2实验方法
1)化合物准备：用POD810系统将75μl上述浓度梯度的本发明的化合物加入96孔板中，每个化合物每个浓度重复2次；
2)细胞准备：收集对数期的HCV 1b复制子细胞，重悬于DMEM完全培养液中，向上述96孔板每孔中加入75μl细胞悬液(8×103个细胞/孔)；同时设立无效作用对照组(Zero percent effect,ZPE)和100％有效作用对照组(Hundred percent effect,HPE)：ZPE组用含0.5％DMSO的完全培养液代替化合物，HPE组孔中只含DMEM培养液；
3)细胞培养：将96孔板置于37℃，5％CO2培养箱中培养3天；
4)细胞活力检测：每孔加入细胞生长荧光滴定检测试剂，37℃，5％CO2培养箱培养细胞1小时后，用多功能酶标仪检测Fluorescence信号值，原始数据(RFU)用于化合物细胞毒性计算；
5)抗HCV病毒复制子活性检测：每孔加荧光素酶发光底物Bright-Glo，5分钟内用多功能酶标仪检测Luminescence信号值，原始数据(RLU)用于化合物抗HCV活性计算；
6)数据处理：使用如下公式将原始数据处理为化合物对HCV复制子的抑制百分比(Inhibition％)和细胞活力百分比(Viability％)：
Inhibition％＝(RLUZPE-RLUCPD)/(RLUZPE-RLUHPE)×100
Viability％＝(RFUCPD-RFUHPE)/(RFUZPE-RFUHPE)×100
其中，CPD：化合物孔的荧光信号值；ZPE(Zero percent effect)：无效作用对照荧光信号值；HPE(Hundred percent effect)：100％有效作用对照荧光信号值。
将Inhibition％、Viability％分别导入GraphPad Prism软件进行数据处理，得出化合物对HCV复制子的半数有效浓度EC50和半数细胞毒性浓度CC50。实验结果显示，本发明的化合物对HCV-1b复制子的EC50均远小于0.1nm，而CC50均远大于10nm。部分化合物的结果见表1。
表1
Figure PCTCN2014095043-appb-000109
从以上实验可以看出，本发明的化合物对丙肝病毒具有较好的抑制活性，同时对宿主细胞具有低的毒性，有效性高，安全性好，非常有希望成为治疗和/或预防与HCV感染相关的疾病的药物。
实验例2 本发明的化合物的抗HCV-1a复制子活性检测
用HCV 1a复制子细胞，即稳定转入HCV基因型1a复制子的Huh7细胞系(由 药明康德(上海)新药开发有限公司提供)为实验细胞。如以上HCV 1b复制子细胞系统所述，类似地制备HCV基因型1a复制子细胞系统。
按照实验例1测试抗HCV-1b复制子活性的方法，测定本发明化合物抗HCV-1a的活性。结果表明，本发明的化合物对HCV-1a复制子的EC50均小于0.2nm，而CC50均远大于10nm。部分化合物的结果见表2。
表2
Figure PCTCN2014095043-appb-000110
本发明的化合物对丙肝病毒1a亚型也表现出良好的抑制活性，同时对宿主细胞具有低的毒性，有效性高，安全性好，非常有希望成为治疗和/或预防与HCV感染相关的疾病的药物。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的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
    Figure PCTCN2014095043-appb-100001
    其中：
    L1、L2分别独立地选自芳基、杂芳基、-芳基-芳基-、-芳基-杂芳基-、-杂芳基-杂芳基-，所述的芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、单烷基氨基烷基、双烷基氨基、双烷基氨基烷基、烷基酰基、烷基酰基烷基、烷氧基酰基、烷氧基酰基烷基、烷基酰基氧基、烷基酰基氧基烷基、氨基酰基、氨基酰基烷基、单烷基氨基酰基、单烷基氨基酰基烷基、双烷基氨基酰基、双烷基氨基酰基烷基、烷基酰基氨基、烷基酰基氨基烷基取代；
    p、q分别独立地选自1、2和3；
    R1、R2分别独立地选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基、烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代；
    R3、R4分别独立地选自氢、烷基、环烷基、杂环烷基，所述的烷基、环烷基或杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、芳基、杂芳基取代；和
    R5、R6分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基，其中，m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成环烷 基或杂环烷基；所述的羟基、氨基、羧基、烷基、环烷基、杂环烷基、烷氧基、烷氧基烷基、芳基、杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、羟基烷基、羧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基烷基酰基氧基、氨基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基取代。
  2. 根据权利要求1所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中，所述化合物为式Ia的化合物，
    Figure PCTCN2014095043-appb-100002
    其中，C*为S构型。
  3. 根据权利要求1或2所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
    L1、L2分别独立地选自苯基、萘基、咪唑基、苯并咪唑基、-苯基-咪唑基-、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基，所述的苯基、萘基、咪唑基、苯并咪唑基、-苯基-咪唑基-、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-10烷基、C3-10环烷基、C3-10杂环烷基、C1-10烷氧基、卤代C1-10烷基、羟基-C1-10烷基、氨基-C1-10烷基、羧基-C1-10烷基、氰基-C1-10烷基、硝基C1-10烷基、C3-10环烷基-C1-6烷基、C3-10杂环烷基-C1-6烷基、C1-10烷氧基-C1-6烷基、单C1-10烷基氨基、单C1-10烷基氨基-C1-6烷基、双C1-10烷基氨基、双C1-10烷基氨基-C1-6烷基、C1-10烷基酰基、C1-10烷基酰基-C1-6烷基、C1-10烷氧基酰基、C1-10烷氧基酰基-C1-6烷基、C1-10烷基酰基氧基、C1-10烷基酰基氧基-C1-6烷基、氨基酰基、氨基酰基-C1-6烷基、单C1-10烷基氨基酰基、单C1-10烷基氨基酰基-C1-6烷基、双C1-10烷基氨基酰基、双C1-10烷基 氨基酰基-C1-6烷基、C1-10烷基酰基氨基、C1-10烷基酰基氨基-C1-6烷基取代；
    R1、R2分别独立地选自氢、C1-6烷基、C3-8环烷基、C3-8杂环烷基、芳基或杂芳基，所述的C1-6烷基、C3-8环烷基、C3-8杂环烷基、芳基或杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、羟基-C1-6烷基、羧基-C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基、C1-6烷基酰基、C1-6烷氧基酰基、C1-6烷基酰基氧基、氨基酰基、单C1-6烷基氨基酰基、双C1-6烷基氨基酰基、C1-6烷基酰基氨基取代
    R3、R4分别独立地选自氢、C1-6烷基、C3-8环烷基、C3-8杂环烷基，所述的C1-6烷基、C3-8环烷基或C3-8杂环烷基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、芳基、杂芳基取代；和
    R5、R6分别独立地选自氢、氰基、羟基、氨基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基，其中，m和n分别独立地选自1、2和3，当m或n为2时，各R5或R6与其连接的C原子可形成C3-8环烷基或C3-8杂环烷基；所述的羟基、氨基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、卤素、C1-6烷氧基-C1-6烷基、芳基、杂芳基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、羟基C1-6烷基、羧基C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基、C1-6烷基酰基、C1-6烷氧基酰基C1-6烷基酰基氧基、氨基酰基、单C1-6烷基氨基酰基、双C1-6烷基氨基酰基、C1-6烷基酰基氨基取代。
  4. 根据权利要求1-3之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
    L1、L2分别独立地选自以下基团：
    Figure PCTCN2014095043-appb-100003
    ，其中，R7和R8分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、烷基、环烷基、杂环烷基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、 单烷基氨基烷基、双烷基氨基、双烷基氨基烷基、烷基酰基、烷基酰基烷基、烷氧基酰基、烷氧基酰基烷基、烷基酰基氧基、烷基酰基氧基烷基、氨基酰基、氨基酰基烷基、单烷基氨基酰基、单烷基氨基酰基烷基、双烷基氨基酰基、双烷基氨基酰基烷基、烷基酰基氨基、烷基酰基氨基烷基；优选地，R7和R8分别独立地选自氢、卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、卤代C1-6烷基、羟基-C1-6烷基、氨基-C1-6烷基、羧基-C1-6烷基、氰基-C1-6烷基、硝基C1-6烷基、C3-8环烷基-C1-6烷基、C3-8杂环烷基-C1-6烷基、C1-6烷氧基-C1-6烷基、单C1-6烷基氨基、单C1-6烷基氨基-C1-6烷基、双C1-6烷基氨基、双C1-6烷基氨基-C1-6烷基、C1-6烷基酰基、C1-6烷基酰基-C1-6烷基、C1-6烷氧基酰基、C1-6烷氧基酰基-C1-6烷基、C1-6烷基酰基氧基、C1-6烷基酰基氧基-C1-6烷基、氨基酰基、氨基酰基-C1-6烷基、单C1-6烷基氨基酰基、单C1-6烷基氨基酰基-C1-6烷基、双C1-6烷基氨基酰基、双C1-6烷基氨基酰基-C1-6烷基、C1-6烷基酰基氨基、C1-6烷基酰基氨基-C1-6烷基。
  5. 根据权利要求1-4之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中，R1、R2分别独立地选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基、N-烷基哌嗪基、苯基、萘基、吡咯基、噻吩基、噻唑基、噁唑基、吡啶基，所述的甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基、N-烷基哌嗪基、苯基、萘基、吡咯基、噻吩基、噻唑基、噁唑基、吡啶基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、羧基-C1-6烷基、单C1-6烷基氨基、双C1-6烷基氨基取代。
  6. 根据权利要求1-5之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中，R3、R4分别独立地选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基，所述的甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙烷基、 环丁烷基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基可以被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、C1-6烷基、环丙基、环丁基、环戊烷基、环己烷基、四氢吡咯烷基、四氢呋喃基、四氢噻吩基、四氢噻唑基、四氢噁唑基、哌啶基、哌嗪基、N-烷基哌嗪基、C1-6烷氧基、苯基、杂芳基取代。
  7. 根据权利要求1-6之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中，R5、R6分别独立地选自氢、卤素、氰基、羟基、氨基、羧基、硝基、C1-6烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷氧基卤代烷基、氰基C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、硝基C1-6烷基、C3-6环烷基-C1-6烷基、C3-6杂环烷基-C1-6烷基，或者当m或n为2时，
    Figure PCTCN2014095043-appb-100004
    各自独立地选自氮杂螺烷基、氧氮杂螺烷基和氮杂双环烷基，优选地，所述氮杂螺烷基为氮杂螺[2.4]庚烷基、氮杂螺[3.4]辛烷基、氮杂螺[4.4]壬烷基、氮杂螺[2.5]辛烷基、氮杂螺[3.5]壬烷基、氮杂螺[4.5]葵烷基、氮杂螺[2.6]壬烷基或氮杂螺[3.6]葵烷基，所述氧氮杂螺烷基为氧杂-氮杂螺[2.4]庚烷基、氧杂-氮杂螺[3.4]辛烷基、氧杂-氮杂螺[4.4]壬烷基、二氧杂-氮杂螺[4.4]壬烷基、氧杂-氮杂螺[4.5]葵烷基、二氧杂-氮杂螺[4.5]葵烷基或三氧杂-氮杂螺[4.5]葵烷基，以及所述氮杂双环烷基为氮杂双环[3.1.0]己烷、氮杂双环[3.2.0]庚烷基、八氢环戊并吡咯基、八氢-1H-异吲哚基、八氢-1H-吲哚基、氮杂双环[2.2.1]庚烷基。
  8. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物选自以下的化合物，
    Figure PCTCN2014095043-appb-100005
    Figure PCTCN2014095043-appb-100006
    Figure PCTCN2014095043-appb-100007
    Figure PCTCN2014095043-appb-100008
  9. 用于制备权利要求1-8之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的中间体II，
    Figure PCTCN2014095043-appb-100009
    其中，R21、R22分别独立地选自氢、卤素、三氟甲磺酸酯基、甲磺酸酯基、对甲苯磺酸酯基和
    Figure PCTCN2014095043-appb-100010
    R31、R32分别独立地选自氢、C1-6烷基或R31、R32环合，一起与它们连接的原子构成5至7元任选被一个或多个C1-6烷基、卤素、氨基、羧基、氰基、硝基、C1-6烷氧基取代的杂环；优选地，R21、R22分别独立地选 自氢、氯、溴、碘或
    Figure PCTCN2014095043-appb-100011
  10. 一种药物组合物，其包含权利要求1至8之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和可药用载体。
  11. 权利要求1-8之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或权利要求10所述的药物组合物在制备用于治疗或预防由丙型肝炎病毒引起的疾病的药物中的应用。
  12. 治疗和/或预防HCV感染的方法，所述方法包括向有此需要的个体给予治疗和/或预防有效量的权利要求1-8之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或权利要求10所述的药物组合物。
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