WO2017076201A1 - Inhibiteurs du vhc, leur procédé de préparation et leur utilisation - Google Patents

Inhibiteurs du vhc, leur procédé de préparation et leur utilisation Download PDF

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WO2017076201A1
WO2017076201A1 PCT/CN2016/103336 CN2016103336W WO2017076201A1 WO 2017076201 A1 WO2017076201 A1 WO 2017076201A1 CN 2016103336 W CN2016103336 W CN 2016103336W WO 2017076201 A1 WO2017076201 A1 WO 2017076201A1
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group
membered
alkyl
substituted
halogen
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Chinese (zh)
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苏熠东
匡远卓
王宝珠
冯卫东
钟慧娟
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug development, and in particular relates to an HCV inhibitor, a preparation method and application thereof.
  • Hepatitis C virus HCV belongs to the family Flaviviridae, and the Flaviviridae family includes at least three genera: pestiviruses, which cause diseases mainly in cattle and pigs; flaviviruses, which are diseases such as dengue fever and yellow fever. The main reason; and hepaciviruses, HCV is the only member of this group. More than 68 members of the genus Flavivirus are classified into different groups based on serological kinship; clinical symptoms are diverse, including fever, encephalitis, and hemorrhagic fever. Flaviviruses associated with human diseases of global concern include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome virus, and Japanese encephalitis virus.
  • DHF dengue hemorrhagic fever virus
  • shock syndrome virus and Japanese encephalitis virus.
  • Hepatitis C virus is a positive-strand RNA virus that is surrounded by a lipid-containing capsule in the nucleocapsid and has a spike on the capsule.
  • HCV has three in vitro cell culture systems: Huh7, Huh7.5, and Huh7.5.1.
  • Hepatitis C virus was first discovered in 1974. In 1989, American scientist Michael Houghton and his colleagues used molecular biology methods to find the genetic sequence of the virus and cloned the hepatitis C virus.
  • the disease and its virus are hepatitis C (Hepatitis C) and hepatitis C virus (HCV).
  • HCV virions are enveloped positive-strand RNA viruses
  • HCV-RNA consists of approximately 9500-100 bp
  • 5' and 3' non-coding regions (NCR) are 319-341 bp
  • 27-55 bp respectively, containing several forward and
  • the inverted repeat sequence may be related to gene duplication.
  • the genome sequence is 5'-C-E1-E2-p7-NS2-NS3-NS4A/4B-NS5A-NS5B-3', which encodes a length of approximately 3014 amino acids.
  • Non-structural protein fractions include NS2, NS3, NS4A, NS4B, NS5A and NS5B; non-structural proteins are important for the life cycle of the virus.
  • NS2/3 and NS3/4A have protease activity and are involved in the cleavage of viral polyprotein precursors.
  • the NS3 protein also has helicase activity and is involved in unwinding HCV-RNA molecules to aid RNA replication.
  • NS5B has RNA-dependent RNA polymerase activity and is involved in HCV genome replication; NS5B lacks read-reading function, so the frequency of mutations in HCV viral genome replication is high.
  • the exact mechanism of action of NS5A is not well understood, but NS5A interacts with a variety of host cell proteins and is an indispensable protein in viral genome replication and viral particle packaging. Therefore, NS5A is the development of HCV-specific antiviral therapy. An attractive target.
  • HCV The HCVs that have been found can be divided into six genotypes 1-6, and different genotypes have different responses to different treatments.
  • HCV has significant heterogeneity and high variability.
  • the HCV strains of all known genomic sequences have been found to have large differences in nucleotide and amino acid sequences, and the degree of variation in HCV genomes is not consistent, such as '-NCR is the most conservative, with a homology of 92-100%, while the 3' NCR region is highly variable.
  • the C region is the most conserved, non-structural (NS) region
  • the capsular membrane protein E2/NS1 has the highest variability called the hypervariable region.
  • Different genotypes of HCV are distributed all over the world. Gene types 1, 2 and 3 exist in all parts of the world. Genes 4 and 5 are mainly distributed in the Middle East and Africa. Gene 6 is mainly found in Southeast Asia. The United States is mainly genotype 1, accounting for about 70% of HCV patients (1a is about 36%, 1b is about 24%), and the remaining 30% are mainly gene type 2 and gene type 3. About 66% of Chinese HCV patients are gene type 1b, and 14% are gene type 2a. According to the epidemiological statistics published in the 2014 Chinese Journal of Internal Medicine, there are significant regional differences in China. Gene types 2, 3, and 6 account for a high proportion in western and southern China.
  • HCV Hepatitis C virus
  • the HCV virus is mainly transmitted through body fluids, and so far there is no vaccine against HCV infection.
  • WHO World Health Organization
  • HCV patients are a large group, with an estimated 3% of the global population of about 170 million HCV patients.
  • the standard treatment regimen is peginterferon ( ⁇ -2a or ⁇ -2b) combined with Liba. Welline.
  • peginterferon ( ⁇ -2a or ⁇ -2b) in combination with ribavirin, including long drug use cycles, large side effects, and low patient response. Therefore, there is a need to develop more effective and novel therapies to address the unmet medical needs caused by HCV infection.
  • the direct acting antivirals (DAA) developed in recent years have made great progress in these areas.
  • DAA direct acting antivirals
  • the main DAA drugs are NS5B inhibitors, NS5A inhibitors, and NS3/4A inhibitors.
  • the advantages (or potential advantages) of DAA combination include: high sustained viral response rate SVR (basically curable), shortening treatment cycle, avoiding drug resistance, and pursuing broad spectrum Sex (can be effective against multiple genotypes of HCV).
  • NS3/4A inhibitors including Telaprevir (Vertex/Janssen) and Boceprevir (Merck), all of which were approved by the FDA in 2011.
  • NS5B inhibitors include Aofol's Sofosvubir and Abbott's triplet ABT-333.
  • NS5A is the last successful development of these three types of DAA, including Daclatasvir from BMS, Ledipasvir from Gilead (in combination with Sofosbuvir) and GS-5816, ABT-267 from Abbott's triplet, and ACH-3102 from Achillion. , Merck's MK-8742 and so on.
  • NS5A inhibitors can reduce viral load in patients faster and more.
  • ACH-3102 and GS-5816 are still active on many Daclatasvir and Ledipasvir resistant mutations.
  • HCV inhibitors having the structure of formula (I), their preparation methods and applications during the research.
  • This series of compounds has high inhibitory activity against wild-type HCV, and has high inhibitory activity against Daclatasvir and Ledipasvir-resistant mutations. It can be applied to the development of drugs for the treatment of hepatitis C virus (HCV) infection-related diseases. Application prospects.
  • HCV hepatitis C virus
  • the invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 1 ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, C 1-8 alkyl or C 3-8 cycloalkyl, or R 1 and R 1 ' are directly attached to a carbon atom. Forming a 3-6 membered carbon ring or a 3-6 membered heterocyclic ring,
  • R 2 and R 2 ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy , C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0-8 -NR 6 R 7 , -C 0
  • halogen cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0- 8- NR 6 R 7 , -C 0-8 -C(O)NR 6 R 7
  • R 3 and R 3 ' are each independently selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 Heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , or -C 0- 8 -C(O)NR 6 R 7 ,
  • halogen cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0- 8- NR 6 R 7 , -C 0-8 -C(O)NR 6 R 7
  • R 4 and R 4 ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy , C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0-8 -NR 6 R 7 , -C 0
  • R 4 or R 4 ' together with its attached tetrahydropyrrole ring form a 6-10 membered nitrogen-containing spiro, bridge or fused ring,
  • halogen cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0- 8- NR 6 R 7 , -C 0-8 -C(O)NR 6 R 7
  • R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, C 1-8 alkoxy C 1-8 alkyl, hydroxy C 1-8 Alkyl, -C(O)R 10 or -C(O)OR 9 ,
  • halogen cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0- 8- NR 6 R 7 , -C 0-8 -C(O)NR 6 R 7
  • L is selected from a bond, a C 5-10 aryl group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group , C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl Thiothio group, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O) OR 9 , -C
  • M is selected from a bond, a C 5-10 aryl group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, C 1-8 alkyl, C 1-8 alkoxy Substituted by a substituent of a halogen-substituted C 1-8 alkyl group, a halogen-substituted C 1-8 alkoxy group, or a C 1-8 alkylsulfonyl group;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group. , C 5-10 aryl, 5-10 membered heteroaryl, C 1-8 alkyl acyl or C 1-8 alkyl acylamino,
  • halogen hydroxy, thiol, cyano, nitro, acetylamino, azide, sulfonyl, methylsulfonyl, C1-8 alkyl, halo substituted C1-8 alkane a group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 1-8 alkoxy group, a C 1-8 alkoxycarbonyl group, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryl Alkoxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino,
  • R 8 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, di C 1-8 alkylamino, phenyl or p-methylphenyl;
  • R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;
  • R 10 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;
  • n 1;
  • r 0, 1, or 2.
  • R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl, Halogen substituted C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, hydroxy C 1-4 alkyl, -C(O)R 10 or -C(O)OR 9 , optionally further One or more selected from the group consisting of halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3 -8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 aryl sulfide , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio,
  • R 5 is selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl. , cyclopropyl or cyclohexyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from a bond, a phenyl group or a naphthyl group.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, M is selected from the group consisting of a bond, furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, anthracene Oxazine, hydrazine, quinoline, benzimidazole.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following formula (II) or the compound of the formula (III):
  • each of R 1 and R 1 ' is independently selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, amino, C. a 1-4 alkyl group, a halogen-substituted C 1-4 alkyl group or a C 3-6 cycloalkyl group, or R 1 and R 1 ' form a 3-6 membered carbon ring or a 3-6 membered impurity with a directly attached carbon atom. ring.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein R 1 and R 1 ' are each independently selected from the group consisting of hydrogen, hydrazine and fluorine. Hydroxy, amino, methyl, ethyl, cyclopropyl or trifluoromethyl, or R 1 and R 1 ' form a cyclopropyl, cyclobutyl or cyclopentyl group with a directly attached carbon atom.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 4 and R 4 ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano and nitro , azido group, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic ring Alkoxy, 3-6 membered heterocyclylthio, C 5-8 aryl, C 5-8 aryloxy, C 5-8 arylthio, 5-8 membered heteroaryl, 5-8 Nonheteroaryloxy, 5-8 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O) R 10 , -C 0-8 -OR 9 , -
  • R 4 or R 4 ' together with its attached tetrahydropyrrole ring form a 6-10 membered nitrogen-containing spiro, bridge or fused ring,
  • halogen cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0- 8- NR 6 R 7 , -C 0-8 -C(O)NR 6 R 7
  • the compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 4 and R 4 ' are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, and B. Or a isopropyl group, or R 4 or R 4 ' together with its attached tetrahydropyrrole ring form a 6-10 membered nitrogen-containing spiro ring, bridged ring or fused ring, the structure is as follows:
  • halogen cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C(O)R 10 , -C 0-8 -C(O)OR 9 , -C 0-8 -OC(O)R 10 , -C 0- 8- NR 6 R 7 , -C 0-8 -C(O)NR 6 R 7
  • each of R 2 and R 2 ' is independently selected from the group consisting of hydrogen, hydrazine, halogen, methyl, ethyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • the present invention provides a process for the preparation of a compound of the above formula (I), comprising the steps of:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 , R 8 , R 9 , R 10 , L, M, m, m', r are as defined for the compound of formula (I).
  • the acid binding agent is an organic base or an inorganic base, and the organic base is selected from the group consisting of trimethylamine, triethylamine, pyridine, piperidine, morpholine, diisopropylethylamine or a mixture thereof.
  • the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof;
  • the condensing agent is selected from the group consisting of DIC, DCC, HOBT, EDCHCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or mixtures thereof.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the foregoing therapeutically effective doses a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides the use of any of the foregoing compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above, in the manufacture of a medicament for the treatment or prevention of HCV infection.
  • C 1-8 alkyl group means a linear alkyl group having 1 to 8 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group, preferably a C 1-4 alkyl group.
  • C 0-8 means no carbon atom or C 1-8 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, positive Pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl 2,2-Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2 , 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent
  • C 3-8 cycloalkyl refers to a cycloalkyl group of 3 to 8 carbon atoms, preferably 3 to 6 carbons.
  • Atom cycloalkyl for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • the "5-10 membered heterocyclic group” means a ring group containing 5 to 10 ring atoms
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms, preferably 3 to 6 ring atoms. Ring base.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon.
  • r is an integer of 0, 1, 2
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups.
  • Non-limiting examples of bridged cycloalkyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, nitro, azide, C. 1-8 alkyl, halo substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 a monoheterocyclyloxy group, a 3-8 membered heterocyclylthio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O)R 10 ,
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom)
  • the group "C 5-10 aryl” means an all-carbon aryl group having 5 to 10 carbons such as a phenyl group and a naphthyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C 1-8.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O) r (where r is an integer 0, 1, 2), 5-
  • a 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms
  • a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C.
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons A base, preferably a linear or branched alkenyl group of 2 to 4 carbons.
  • a base preferably a linear or branched alkenyl group of 2 to 4 carbons.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C 1-8.
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons.
  • a linear or branched alkynyl group of 2 to 4 carbons is preferred. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C 1-8.
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • C 1-8 alkoxy means an alkyloxy group having 1-8 carbons, preferably an alkyloxy group of 1 to 4 carbons, and a non-limiting example comprises a methoxy group, an ethoxy group, a propoxy group, Butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C 1-8 alkyl, halo substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3- 8-membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl , 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 - C(O)R 10 , -C 0-8 -C(O)
  • Cycloalkoxy refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above.
  • C 3-8 cycloalkoxy refers to a cycloalkyloxy group having 3-8 carbons, preferably a cycloalkyloxy group of 3 to 6 carbons, and a non-limiting example comprises a cyclopropoxy group, a cyclobutoxy group. , cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano, nitro, azide, C. 1-8 alkyl, halo substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 a monoheterocyclyloxy group, a 3-8 membered heterocyclylthio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O)
  • Halo-substituted C 1-8 alkyl means a hydrogen on the alkyl group optionally substituted with a fluorine, chlorine, bromine or iodine atom, preferably from 1 to 8 carbon alkyl groups, preferably hydrogen on the alkyl group. 1-4 carbon alkyl groups substituted with fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl Wait.
  • Hydrogen on a "halo-substituted C 1-8 alkoxy"alkyl group optionally 1-8 carbon alkoxy groups substituted by fluorine, chlorine, bromine or iodine atoms, preferably hydrogen on the alkyl group.
  • One to four carbon alkoxy groups substituted by fluorine, chlorine, bromine or iodine atoms For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • C(O)R 10 means a R 10 -substituted carbonyl group, for example, "C 0-8 alkylcarbonyl” means a C 0-8 alkyl-substituted carbonyl group, preferably a C 0-4 alkyl-substituted carbonyl group;
  • C 1-8 alkanoylamino group means a C 1-8 alkanoyl group-substituted amino group, preferably a C 1-4 alkanoyl group-substituted amino group, for example, a C 2 alkanoylamino group means an acetylamino group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • THF tetrahydrofuran
  • DCM dichloromethane
  • DMAP means 4-dimethylaminopyridine.
  • DME dimethyl ether
  • DMF N,N-dimethylformamide
  • MTBE means methyl tert-butyl ether
  • EA means ethyl acetate
  • DIPEA diisopropylethylamine
  • NBS N-bromosuccinimide
  • NFSI N-fluorobisbenzenesulfonamide
  • NMM refers to N-methylmorpholine.
  • KHMDS means potassium hexamethyldisilazide
  • condensing agent means an agent capable of causing a condensation reaction. Condensation reaction refers to two or more organic components Sub-interactions combine to form a macromolecule by covalent bonding, while losing the reaction of water or other relatively simple inorganic or organic small molecules.
  • the small molecular substance is usually water, hydrogen chloride, methanol or acetic acid.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was determined to be dimethyl sulfoxide (DMSO) and deuterated chloroform (CDCl 3 ) internally labeled as tetramethylsilane (TMS).
  • DMSO dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • An argon atmosphere or a hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 1 L.
  • the solution in the examples means an aqueous solution unless otherwise specified.
  • the temperature of the reaction is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • Column chromatography eluent system includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C dichloromethane and ethyl acetate system
  • D ethyl acetate and methanol
  • solvent The volume ratio is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water and acetic acid.
  • Second step tert-butyl (2S, 3aS, 7aS)-2-((2-amino-4-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate and tert- Butyl (2S,3aS,7aS)-2-((2-amino-5-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate
  • 2-bromo-9,9-dimethyl-9H-indole 7 g was added to a 250 ml three-necked flask, acetic acid (84 ml) was added, and the mixture was cooled to 0 ° C, and fuming nitric acid (20 ml) was added dropwise. The temperature was raised to 25 ° C and stirred for 20 hours.
  • reaction solution was poured into an ice-water mixture (600 g), stirred for 30 minutes, filtered, and the filter cake was taken, acetonitrile (400 ml), refluxed for 2 hours, filtered, and the filter cake was dried in vacuo to give 2-bromo-9,9-dimethyl -7-Nitro-9H-indole (5.6 g).
  • Step 8 tert-Butyl (2S,3aS,7aS)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H-indole ⁇ -1-carboxylate
  • the ninth step tert-butyl (2S, 3aS, 7aS)-2-((7-(2-((2S,3aS,7aS)-1-(tert-butoxycarbonyl) octahydro-1H-indole) Ind-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)octahydro-1H-indole-1 -carboxylate
  • tert-butyl (2S, 3aS, 7aS)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H- ⁇ -1-carboxylate (1.0 g, 1.85 mmol)
  • tert-butyl (2S, 3aS, 7aS)-2-(6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate (0.91 g, 1.94 mmol)
  • tetratriphenyl Palladium phosphine (0.64g, 0.56mmol)
  • sodium bicarbonate 0.52g, 6.1 Methyl
  • reaction mixture was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) was added and the mixture was separated, and the aqueous phase was extracted twice with ethyl acetate (20 mL).
  • Step 10 (2S, 3aS, 7aS)-N-(9,9-Dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)- 1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide
  • EtOAc EtOAc m. 7aS)-N-(9,9-Dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H-benzo[d]imidazole- 5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide (760 mg) was used directly in the next step.
  • the eleventh step methyl ((2S,3R)-3-methoxy-1-((2S,3aS,7aS)-2-(5-(7-((2S,3aS,7aS)-1-) (N-(methoxycarbonyl)-O-methyl-L-threonyl) octahydro-1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indole-2 -yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutan-2-yl)carbamate
  • tert-Butyl (2S,3aS,7aS)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1 - Carboxylic acid ester as raw material refer to step 9 of Example 1, and tert-butyl (S)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Coupling of pentocyclo-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate gives tert-butyl(2S,3aS,7aS)-2-((7- (2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H- Ind-2-yl)carbam
  • Step 5 (2S, 3aS, 7aS)-N-(9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole- 5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide
  • Step 6 Methyl ((S)-1-((S)-2-(5-(7-((2S,3aS,7aS)-1-((methoxycarbonyl)-L-prolyl) Octahydro-1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine- 1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate
  • step 8 of Example 1 Using 7-bromo-9,9-dimethyl-9H-indol-2-amine as the starting material, referring to step 8 of Example 1, to obtain tert-butyl (1R, 3S, 4S)-3-((7-bromo) -9,9-Dimethyl-9H-indol-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate.
  • Second step tert-butyl (2S, 3aS, 7aS)-2-(6-(7-((1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo) [2.2.1] Heptane-3-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro- 1H-indene-1-carboxylate
  • tert-Butyl (1R,3S,4S)-3-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-2-azabicyclo[2.2 .1] heptane-2-carboxylate as a starting material, referring to step 9 of Example 1, to obtain tert-butyl (2S,3aS,7aS)-2-(6-(7-((1R,3S,4S)) -2-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl -1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate.
  • the fourth step methyl ((2S, 3R)-3-methoxy-1-((2S,3aS,7aS)-2-(5-(7-((1R,3S,4S)-2-) N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-azabicyclo[2.2.1]heptane-3-carbamoylamino)-9,9-dimethyl -9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutan-2-yl)carbamate Acid ester
  • tert-butyl(S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 10 g
  • double (frequency) Alcohol) diborane 13.0 g
  • tetrakistriphenylphosphine palladium 1.5 g
  • potassium carbonate 10.5 g
  • DME 100 mL
  • water 100 mL
  • ethyl acetate 100 mL
  • Step 5 tert-Butyl (S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole -5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate
  • tert-butyl(S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate refer to the implementation Step 9 of Example 1, to give tert-butyl(S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H) -Imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate.
  • Step 6 (S)-N-(9,9-Dimethyl-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl) )-9H-indol-2-yl)pyrrolidine-2-carboxamide
  • Step 7 Methyl ((S)-1-((S)-2-(5-(4-(7-((S)-1-((methyl)))) Alkanol-2-carbooxalylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl Alkyl-1-carbonylbutan-2-yl)carbamate
  • Step 9 of Example 1 Starting from tert-butyl(S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate, refer to the implementation Step 9 of Example 1 gave tert-butyl(S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzene) [d] Imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate.
  • the third step methyl ((S)-1-((S)-2-(5-(7-((S)-1-((methoxycarbonyl)-L-prolyl)pyrrolidine-2 -carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl -1-carbonylbutan-2-yl)carbamate
  • step 8 of Example 1 Using 7-bromo-9,9-dimethyl-9H-indol-2-amine as the starting material, referring to step 8 of Example 1, to obtain tert-butyl(2S,4S)-2-((7-bromo-9) , 9-Dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.
  • the fourth step methyl ((S)-1-((S)-2-(5-(4-(7S)4S)-4-fluoro-1-((carbomethoxy)-L) -prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1- Benzyl-3-methyl-1-carbonylbutan-2-yl)carbamate
  • the third step methyl ((S)-1-((S)-2-(5-(7-((2S,4S)-4-fluoro-1-((methyl ester))))) Acyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate
  • the DME was concentrated to remove ethyl acetate (60 ml) and water (20 ml), and the organic layer was concentrated, and the residue was purified by column chromatography to give tert-butyl(2S,4S)-4-fluoro-2-(5- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate Acid ester (1.4 g).
  • the fourth step tert-butyl (2S, 4S)-2-((7-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine- 2-yl)-1H-imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl-4-fluoropyrrolidine-1-carboxylate
  • the sixth step methyl ((S)-1-((2S,4S)-4-fluoro-2-(5-(4-(7-((2S,4S)-4-fluoro-1-(( Methyl ester)-L-prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl Pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate
  • 2-iodo-7-nitro-9H-indole (10.1 g, 30 mmol) and NFSI (30 g) were placed in a 100 ml three-necked flask. Under nitrogen, THF (210 mL) was added and cooled to -30 ° C. KHMDS solution (1.0 M, 100 ml) was added, and the reaction was maintained at -20 ° C to 0 ° C for 2 hours. The reaction was completely completed by TLC, and the reaction was quenched by pouring a saturated ammonium chloride solution (150 mL) at a temperature below 10 ° C.
  • the fifth step tert-butyl (2S, 3aS, 7aS)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H- Benzo[d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate
  • Step 6 (2S, 3aS, 7aS)-N-(9,9-Difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5 -yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide
  • Step 7 Methyl ((S)-1-((S)-2-(5-(9,9-difluoro-7-((2S,3aS,7aS)-1-((carbomethoxy)) -L-prolyl) octahydro-1H-indole-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1 -yl)-3-methyl-1-carbonylbutan-2-yl)carbamate
  • Second step (2S, 3aS, 7aS)-N-(9,9-difluoro-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H) -benzo[d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide
  • the third step methyl ((S)-1-((2S,3aS,7aS)-2-((9,9-difluoro-7-(2-((2S,3aS,7aS)-1-) (methyl ester group)-L-prolyl) octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)carbamoyl ) octahydro-1H-indol-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate
  • Step 11 of Example 1 was obtained to give methyl ((S)-1- ((2S,3aS,7aS)-2-((9,9-Difluoro-7-(2-((2S,3aS,7aS)-1-((carbomethoxy)-L-prolyl)) Hydrogen-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)carbamoyl)octahydro-1H-indol-1-yl) -3-Methyl-1-carbonylbutan-2-yl)carbamate.
  • Step 11 of Example 1 gave methyl ((2S,3R)- 1-((2S,3aS,7aS)-2-(5-(9,9-difluoro-7-((2S,3aS,7aS)-1-(N-(carbomethoxy)-O-methyl) -L-threonyl) octahydro-1H-indole-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H -Indol-1-yl)-3-methoxy-1-carbonylbutan-2-yl)carbamate.
  • Second step tert-butyl(S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole -5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate
  • tert-butyl(S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate refer to the examples. 1 step 9, to give tert-butyl (S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-) Imidazol-5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate.
  • the fourth step methyl ((S)-1-((S)-2-(5-(4-(9,9-difluoro-7-((S)-1-((methoxycarbonyl))-) L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl -1-carbonylbutan-2-yl)carbamate
  • tert-butyl(S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate refer to the examples. 1 step 9, to give tert-butyl (2S,4S)-2-(5-(4-(7-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbamoyl) Amino)-9,9-difluoro-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate.
  • the third step methyl ((S)-1-((2S,4S)-2-(5-(4-(9,9-difluoro-7-((S)-1-) (carbomethoxy) )-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate
  • tert-butyl(S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate refer to the examples.
  • 1-Step 9 gives tert-butyl(S)-2-((7-(2-((R)-1-(tert-butoxycarbonyl))pyrrolidin-2-yl)-1H-benzo[ d] Imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate.
  • the third step methyl ((S)-1-((S)-2-((9,9-difluoro-7-(2-((S))-1-((methyl))-L- Prolyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-indol-2-yl)carbamoylpyrrolidin-1-yl)-3-methyl -1-carbonylbutan-2-yl)carbamate
  • Step 8 of Example 1 Using 9,9-difluoro-7-iodo-9H-indol-2-amine as a starting material, referring to Step 8 of Example 1, to obtain tert-butyl(2S,4S)-2-((9,9-difluoro) -7-iodo-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.
  • the fourth step methyl ((S)-1-((S)-2-(5-(4-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-() (methyl ester group)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate
  • Step 11 of Example 1 methyl ((S)-1-((S)-2-(5-( 4-(9,9-Difluoro-7-((2S,4S)-4-fluoro-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbamoylamino)- 9H-Indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.
  • the third step methyl ((S)-1-((2S,4S)-2-(5-(4-(9,9-difluoro-7-((2S,4S)-4-fluoro-1) -((methyl ester)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoro Pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate
  • the third step methyl ((S)-1-((S)-2-(5-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-((methyl ester) -L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl) -3-methyl-1-carbonylbutan-2-yl)carbamate
  • Second step tert-butyl(S)-2-((7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate
  • the third step tert-butyl (S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole -5-yl)phenyl)-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate
  • tert-butyl(S)-2-((7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate referring to step 9 of Example 1, to obtain a tert- Butyl(S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)benzene Base)-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate.
  • Step 5 Methyl ((S)-1-((S)-2-(5-(4-(7-((S)-1-((methyl)))) Alkan-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutane- 2-base) ammonia Carbamate
  • the inhibitory activity of the compounds of the present invention against HCV replication was determined by the HCV Replicon Reporter Luciferase Assay.
  • Huh-7 cell line stably transfected with the HCV replicon luciferase reporter gene.
  • test compound storage solution was prepared as 10 mM with dimethyl sulfoxide, diluted to the highest concentration in the experiment with DMSO, and then serially diluted 3 times with medium, generally diluted to 8 to 10 concentration points, each concentration point was set. Double double holes. The final concentration of dimethyl sulfoxide was 0.5%.
  • Each experiment contained an internal reference compound, one for the reference compound (Ledipasvir or dacalatasvir) and the other for Cyclosporine.
  • the inhibitory activity of the compounds of the present invention against HCV replication of the NS5A mutation was determined using the HCV Replicon Reporter Luciferase Assay.
  • HCV replicon luciferase reporter gene transiently transfected Huh-7 cell line HCV replicon RNA was prepared by in vitro transcription method, and RNA was transfected into Huh-7 cells by electroporation.
  • test compound storage solution was prepared as 10 mM with dimethyl sulfoxide, diluted to the highest concentration in the experiment with DMSO, and then serially diluted 3 times with medium, generally diluted to 8 to 10 concentration points, each concentration point was set. Double double holes. The final concentration of DMSO was 0.5%. Each experiment contained 1-2 internal reference compounds.
  • the transfected cells were grown on a 96-well culture plate, and after 24 hours, different concentrations of the test compound and the internal reference compound were added to the cultured cells.
  • Example Compound of the present invention and with reference to the active compound (daclatasvir) was measured by the above tests, HCV NS5A mutant replicon inhibitory activity IC 50 values in Table 2:
  • the pharmacokinetic test of the test compound was carried out using SD rats (Shanghai Shrek).
  • ⁇ Mode of administration single oral administration.
  • Formulation formulation 45% 1,2-propanediol and 15% polyethylene glycol 15 hydroxystearate.
  • ⁇ Sampling point 2, 4, and 6 hours before and after administration.
  • Mass Spectrometry Mass Spectrometer Setup Conditions: Cationic Electrospray Ionization (ESI) mode.
  • the concentration of the drug that absorbed the test compound into the liver was performed using SD rats (Shanghai Shrek).
  • ⁇ Mode of administration single oral administration.
  • Formulation formulation 45% 1,2-propanediol and 15% polyethylene glycol 15 hydroxystearate.
  • Mass Spectrometry Mass Spectrometer Setup Conditions: Cationic Electrospray Ionization (ESI) mode.

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Abstract

L'invention concerne des inhibiteurs du VHC présentant une structure telle que dans la formule I, leur procédé de préparation et leur utilisation, chaque substituant dans la formule étant tel que défini dans la description. Cette série de composés inhibe l'activité dU VHC et peut être utilisée dans la mise au point de médicaments pour traiter une infection par le virus de l'hépatite C (VHC), lui conférant de larges perspectives d'application.
PCT/CN2016/103336 2015-11-06 2016-10-26 Inhibiteurs du vhc, leur procédé de préparation et leur utilisation Ceased WO2017076201A1 (fr)

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CN103249731A (zh) * 2010-08-12 2013-08-14 百时美施贵宝公司 丙型肝炎病毒抑制剂
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WO2019059687A1 (fr) * 2017-09-22 2019-03-28 서울대학교 산학협력단 Dérivé de fluorène ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation, et composition pharmaceutique comprenant ledit composé en tant que principe actif pour la prévention ou le traitement d'une maladie liée au vhc
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KR102168124B1 (ko) * 2017-09-22 2020-10-21 서울대학교산학협력단 플루오렌 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 hcv 관련 질환의 예방 또는 치료용 약학적 조성물
US11261175B2 (en) 2017-09-22 2022-03-01 Seoul National University R&Db Foundation Fluorene derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition comprising same as effective ingredient for preventing or treating HCV-related disease

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