Classifications

• • 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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