WO2017076187A1 - 1,4(1,4)-二苯杂环六蕃-12,43-二基衍生物及其制备方法与应用 - Google Patents

1,4(1,4)-二苯杂环六蕃-12,43-二基衍生物及其制备方法与应用 Download PDF

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WO2017076187A1
WO2017076187A1 PCT/CN2016/103166 CN2016103166W WO2017076187A1 WO 2017076187 A1 WO2017076187 A1 WO 2017076187A1 CN 2016103166 W CN2016103166 W CN 2016103166W WO 2017076187 A1 WO2017076187 A1 WO 2017076187A1
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membered
group
alkyl
cycloalkyl
halogen
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French (fr)
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苏熠东
冯卫东
王宝珠
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN201680064922.6A priority Critical patent/CN108349907B/zh
Publication of WO2017076187A1 publication Critical patent/WO2017076187A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug development, and particularly relates to a 1,4(1,4)-diphenylheterocyclohexan-1 2 ,4 3 -diyl derivative and 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 (effective for 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.
  • the inventors discovered a class of 1,4(1,4)-diphenylheterocyclohexan-1 2 ,4 3 -diyl derivatives having the structure of formula (I), and preparation methods and applications thereof. These compounds have high inhibitory activity against wild-type HCV and high inhibitory activity against Daclatasvir and Ledipasvir resistant mutations.
  • the invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 1 ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, C 1-8 alkyl, C 1-8 alkoxy or C 3-8 cycloalkyl,
  • R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy or C 3-8 cycloalkoxy,
  • halogen hydroxy, amino, cyano, nitro, azide
  • C 1-8 alkyl C 2-8 alkenyl, C 2-8 alkynyl, C Substituted with a substituent of a 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 1-8 alkoxy group, a C 3-8 cycloalkoxy group or a 3-8 membered heterocyclyloxy group;
  • L and L' are each independently selected from the following structures:
  • R 6 and R 6 ' are each independently selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, halogenated C 1-8 alkyl, C 1- 8 -alkoxy C 1-8 alkyl, hydroxy C 1-8 alkyl, -C(O)R 14 or -C(O)OR 13 ,
  • 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 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0- 8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -C 0-8 -C(O)
  • R 7 and R 7 ' 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 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0-8 -NR 10 R 11 , -C 0-8 -NR 10 R 11 ,
  • R 7 or R 7 ' 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 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0- 8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -C 0-8 -C(O)
  • R 8 and R 8 ' are each independently selected from the group consisting of hydrogen, hydrazine, 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 heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0-8 -NR 10 R 11 , -
  • 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 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0- 8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -C 0-8 -C(O)
  • R 9 and R 9 ' 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 9 , -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 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0- 8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -C 0-8 -C(O)
  • R 10 and R 11 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 or C 1-8 alkyl acyl group,
  • halogen hydroxy, thiol, cyano, nitro, acetylamino, azide, sulfonyl, methylsulfonyl, C1-8 alkyl, C2-8 alkenyl , C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 aryl Thiothio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C 1-8 alkylamino or di C 1-8 alkyl Substituted by a substituent of an amino group;
  • R 12 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 13 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 14 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;
  • p, p' are each independently selected from 0 to 7;
  • r 0, 1, or 2.
  • R 6 and R 6 ' are each independently selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, and C 1-4 alkane.
  • 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 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0- 8 -NR 10 R 11 , -C 0-8 -C(O)NR 10 R 11 , -C 0-8 -C(O)
  • the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 6 and R 6 ' are each independently selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, and tris. Fluoromethyl, cyclopropyl, cyclohexyl, methoxy, ethoxy or isopropoxy, more preferably hydrogen.
  • R 1 and R 1 ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, amino, C 1-4 alkane. group, C 1-4 alkoxy or C 3-6 cycloalkyl, more preferably hydrogen, deuterium, fluoro, chloro, methyl, ethyl, hydroxy, amino, methoxy or cyclopropyl.
  • the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, L and L' are each independently selected from the following structures:
  • halogen hydroxy, cyano, nitro, azide, C 1-8 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 - 6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 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 0-4 -S(O) r R 12 , -C 0-4 -OR 13 , -C 0-4 -C(O)R 14 , -C 0-4 -C(O)OR 13 , -C 0-4 -OC(O)R 14 , -C 0-4 -NR 10 R 11 , -C 0-4 -C(O)
  • R 7 and R 7 ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C 5-8 aryl, C 5-8 aryloxy , C 5-8 arylthio, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, 5-8 membered heteroarylthio, -C 0-8 -S(O) r R 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 , -C 0-8 -OC(O)R 14 , -C 0-8 -NR 10 R 11 , -
  • R 7 or R 7 ' together with the tetrahydropyrrole ring to which it is attached form a 6-10 membered nitrogen-containing spiro ring, bridged ring or fused ring selected from the group consisting of:
  • the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of formula (II):
  • R 7 , R 7 ', R 8 , R 8 ', R 9 and R 9 ' are as defined in claim 1.
  • the compound of the formula (the I), acceptable salt thereof, R 7 a stereoisomer thereof or a pharmaceutically, R 7 ' are each independently selected from hydrogen, deuterium, fluoro, methyl, ethyl
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 8 and R 8 ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, methyl, and ethyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 9 and R 9 ' are each independently selected from the group consisting of hydrogen, hydrazine and C 1-4 alkane. Alkyl, allyl, ethynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or phenyl.
  • the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • Another aspect of the invention provides a method of preparing the aforementioned compound, comprising the steps of:
  • Pg is an amino protecting group, preferably from a preferred t-butoxycarbonyl, allylcarbonyl, fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilyloxycarbonyl or benzyloxycarbonyl, more preferably from uncle Butoxycarbonyl; R 1 , R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 6 ', R 7 , R 7 ', R 8 , R 8 ', R 9 , R 9 ', R 10 , R 11 , R 12 , R 13 , R 14 , L, L', p, p', m, m', r (I) The definition of the compound.
  • 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, EDC ⁇ HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or mixtures thereof.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • C 1-8 alkyl means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, the alkyl group means a saturated aliphatic hydrocarbon group, and C 0-8 means no carbon atom or C.
  • 1-8 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 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-methylhexyl, 5-methylhex
  • 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, thiol, 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 Base, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C 3-8 cycloalkyl” refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.”
  • Alkyl means a cycloalkyl group of 5 to 10 carbon atoms, 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, thiol, cyano, nitro, azide.
  • 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.
  • 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 a single ring, 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 the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide.
  • 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) a group
  • C 5-10 aryl means an all-carbon aryl group having 5 to 10 carbons
  • 5-10 membered aryl group means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl.
  • 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 can be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, 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 a heterocyclic heterothio 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, a 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0- 8 -C(O)OR 13
  • 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, thiol, cyano, nitro, azide.
  • 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 base.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like are examples of the alkenyl group.
  • Alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, 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 a heterocyclic heterothio 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, a 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0- 8 -C(O)OR 13
  • 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.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, 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 a heterocyclic heterothio 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, a 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0- 8 -C(O)OR 13
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • the C 1-8 alkoxy group means an alkyloxy group having 1-8 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group 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, thiol, 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 heteroaryl Alkoxy group, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 12 , -C 0-8 -OR 13 , -C 0-8 -C(O)R 14 , -C 0-8 -C(O)OR 13 ,
  • Cycloalkoxy refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above.
  • the C 3-8 cycloalkoxy group means a cycloalkyloxy group having 3-8 carbons, and the non-limiting examples include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group 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, thiol, cyano, nitro, azide.
  • Halo-substituted C 1-8 alkyl means a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl , dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • a fluorine chlorine, bromine or iodine atom.
  • Halogen means fluoro, chloro, bromo or iodo.
  • C(O)R 10 means an R 10 substituted carbonyl group.
  • THF tetrahydrofuran
  • condensation agent means an agent capable of causing a condensation reaction.
  • a condensation reaction refers to a reaction in which two or more organic molecules interact to form a macromolecule by covalent bonding while losing 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. Body 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 an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • 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.
  • Example 1 Dimethyl((2S,2'S)-((2S,2'S)-((1,4(1,4)-diphenylcyclohexan-1 2 ,4 3 -diyldi(4) , 1-phenylene)) bis(azanediyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-carbonylbutane-1,2 -diyl))dicarbamate
  • Iron powder (1.2 g) and bromine (20.7 g) were successively added to dichloromethane (400 mL), and stirred for half an hour, and a solution of [2.2] p-cyclopropanol (50 g) in dichloromethane (100 mL) was added dropwise and heated to reflux. After 2 hours, a mixture of bromine (7 g) and dichloromethane (100 mL) was added dropwise over 3 hours, and the reaction was refluxed for 3 hours, cooled to room temperature and stirred overnight.
  • reaction solution was washed once with 5% sodium sulfite and water, dried and concentrated, and the residue was purified from hot toluene, cooled, and filtered to give 4,16-dibromo[2.2] p-cyclopropane (33.7 g).
  • the second step di-tert-butyl (1,4(1,4)-diphenyl heterocyclohexan-1 2 ,4 3 -diylbis(4,1-phenylene))dicarbamic acid ester
  • the third step preparation of 4,4'-(1,4(1,4)-diphenyl heterocyclohexan-1 2 ,4 3 -diyl)diphenylamine
  • di-tert-butyl (1,4(1,4)-diphenylcyclohexan-1 2 ,4 3 -diylbis(4,1-phenylene))diaminocarb A hydrogen chloride-containing dioxane solution (30 mL) and methanol (10 mL) were added to the acid ester (3.2 g, 5.42 mmol), and the mixture was stirred for 6 hours. Add 10% aqueous sodium hydroxide solution to adjust the reaction to alkaline, precipitate a large amount of solid, filter, filter cake vacuum drying to obtain 4,4'-(1,4(1,4)-diphenylcyclohexan- 1 , 4 3 -diyl)diphenylamine (2 g).
  • Step 4 tert-Butyl (S)-2-((4-(4 3 -(4-((R))-1-(tert-butoxycarbonyl)pyrrolidine-2-carbamoylamino) Fan diphenyl heterocycle six --12 - - preparation yl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid ester) phenyl) 1,4 (1,4)
  • Step 5 (2S, 2'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 2 ,4 3 -diyldi(4,1-phenylene) Preparation of bis(pyrrolidine-2-carboxamide)
  • the sixth step dimethyl ((2S, 2'S)-((2S, 2'S)-((1,4(1,4)-diphenyl heterocyclohexan-1 2 , 4 3 -diyl 2 ( 4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-carbonylbutane-1, Preparation of 2-diyl)) dicarbamate
  • Example 2 dimethyl ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-((1,4(1,4)-diphenylheterocyclohexan-1 2 , 4 3 -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(octahydro-1H-indole-2,1-diyl))di(3) -methyl-1-carbonylbutane-1,2-diyl))dicarbamate
  • Second step di-tert-butyl 2,2'-((1,4(1,4)-diphenylcyclohexan-12,43-diylbis(4,1-phenylene) Preparation of bis(azanediyl))bis(carbonyl))(2S,2'S,3aS,3a'S,7aS,7a'S)-bis(octahydro-1H-indole-1-carboxylate)
  • Example 4 Taking the compound 4,4'-(1,4(1,4)-diphenylcyclohexan-1 2 ,4 3 -diyl)diphenylamine as a starting material, refer to Example 4, Step 4, and Compound (2S, Condensation of 3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid to give the compound di-tert-butyl 2,2'-((1,4(1) 4) - diphenyl heterocyclic six Fan -12, 4 3 - diyl (4,1-phenylene)) bis (azanediyl)) bis (carbonyl)) (2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-bis(octahydro-1H-indole-1-carboxylate).
  • the fourth step dimethyl ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-((1,4(1,4)-diphenyl heterocyclohexan-1 2 , 4 3 -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(octahydro-1H-indole-2,1-diyl))di
  • O-methyl-L-threonine (5.0 g, 37.6 mmol) was dissolved in a mixture of 1,4-dioxane (20 mL) and THF (20 mL), cooled to 0 ° C, and NaOH was added dropwise. 4.5 g of NaOH was dissolved in 56 mL of water), then methyl chloroformate (4.3 g) was added, then warmed to room temperature and stirred for 7 h. It was acidified with EtOAc (3 mL)EtOAcEtOAcEtOAcEtOAcEtOAc.
  • Step 2 Methyl ((2S, 2'S, 3R, 3'R)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-((1,4(1,4)-diphenylheterocycle Liufan-1 2 ,4 3 -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))di(octahydro-1H-indole-2,1-di
  • Example 4 Dimethyl((2S,2'S)-((6S,6'S)-((1,4(1,4)-diphenylcyclohexan-1 2 ,4 3 -diyldi(4) , 1-phenylene)) bis(azanediyl))bis(carbonyl))bis(5-azaspiro[2.4]heptane-6,5-diyl))bis(3-methyl-1) -carbonylbutane-1,2-diyl))dicarbamate
  • the third step dimethyl ((2S, 2'S)-((6S,6'S)-((1,4(1,4)-diphenyl heterocyclohexan-1 2 ,4 3 -diyl 2 ( 4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(5-azaspiro[2.4]heptane-6,5-diyl))bis(3-methyl- Preparation of 1-carbonylbutane-1,2-diyl))dicarbamate
  • Example 5 Dimethyl ((2S, 2'S, 3R, 3'R)-((6,6'S)-((1,4(1,4)-diphenylheterocyclohexan-1 2 ,4 3 -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(5-azaspiro[2.4]heptane-6,5-diyl))di 3-methoxy-1-carbonylbutane-1,2-diyl))dicarbamate
  • Example 6 Dimethyl((2S,2'S)-((1R,1'R,3S,3'S,4S,4'S)-((1,4(1,4)-diphenylcyclohexan-12) ,43-diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(2-azabicyclo[2.2.1]heptane-3,2-di Base)) bis(3-methyl-1-carbonylbutane-1,2-diyl))dicarbamate
  • Step 2 (1R, 1'R, 3S, 3'S, 4S, 4'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 2 ,4 3 -diyl
  • Step 2 (1R, 1'R, 3S, 3'S, 4S, 4'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 2 ,4 3 -diyl
  • the third step dimethyl ((2S, 2'S)-((1R, 1'R, 3S, 3'S, 4S, 4'S)-((1,4(1,4)-diphenyl heterocyclohexan- 1 2 ,4 3 -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(2-azabicyclo[2.2.1]heptane-3, Preparation of 2-(diyl))bis(3-methyl-1-carbonylbutane-1,2-diyl))dicarbamate
  • Example 7 Dimethyl ((2S, 2'S, 3R, 3'R)-((1R, 1'R, 3S, 3'S, 4S, 4'S)-((1,4(1,4)-diphenyl) Heterocyclic Liufan-1 2 ,4 3 -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(2-azabicyclo[2.2.1] Heptane-3,2-diyl))bis(3-methoxy-1-carbonylbutane-1,2-diyl))dicarbamate
  • 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 (ACH-3102) and the other for Cyclosporine.
  • Example Compound and reference active compound (ACH-3102) was determined by the above testing of the present invention, the wild-type Hepatitis C virus genotype 1b HCV inhibitory activity IC 50 values (Table 1):

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Abstract

提供一种1,4(1,4)-二苯杂环六蕃-12,43-二基衍生物及其制备方法与应用。该系列化合物可以抑制HCV的活性，可应用于治疗丙型肝炎病毒（HCV）感染相关疾病药物的开发，具有广阔的应用前景。见式（I）。

Description

1,4(1,4)-二苯杂环六蕃-12,43-二基衍生物及其制备方法与应用 技术领域
本发明属于药物开发领域，具体涉及1,4(1,4)-二苯杂环六蕃-12,43-二基衍生物及其制备方法与应用。
背景技术
丙肝病毒HCV属于黄病毒科家族，黄病毒科家族包括至少三个属：瘟病毒属(pestiviruses)，主要在牛和猪中引起疾病；黄病毒属(flaviviruses)，为登革热和黄热病等疾病的主要原因；以及丙型肝炎病毒属(hepaciviruses)，HCV为此属唯一成员。黄病毒属成员超过68个，基于血清学亲缘关系可分为不同的组；临床症状呈现多样性，包括发热、脑炎和出血热等。全球所关注的与人类疾病有关的黄病毒属病毒包括登革出血热病毒(DHF)、黄热病病毒、休克综合征病毒和日本脑炎病毒。由于HCV基因组在结构和表型特征上与人黄病毒和瘟病毒相类似，将其归为黄病毒科HCV。丙型肝炎病毒是正链RNA病毒，在核衣壳外包绕含脂质的囊膜，囊膜上有刺突。HCV现有Huh7，Huh7.5，Huh7.5.1三种体外细胞培养***。丙型肝炎病毒于1974年被首次发现，1989年美国科学家迈克尔·侯顿(Michael Houghton)和他的同事们利用分子生物学方法找到了该病毒的基因序列，并克隆出了丙肝病毒，命名本病及其病毒为丙型肝炎(Hepatitis C)和丙型肝炎病毒(HCV)。
HCV病毒体是包膜的正链RNA病毒，HCV-RNA大约有9500-10000bp组成，5′和3′非编码区(NCR)分别有319-341bp，和27-55bp，含有几个顺向和反向重复序列，可能与基因复制有关，基因组排列顺序为5'-C-E1-E2-p7-NS2-NS3-NS4A/4B-NS5A-NS5B-3'，能编码一长度大约为3014个氨基酸的多聚蛋白前体，后者可经宿主细胞和病毒自身蛋白酶作用后，裂解成10种病毒蛋白，包括三种结构蛋白，即分子量19KD的核衣壳蛋白(或称核心蛋白，Core)和两种糖蛋白(分子量为33KD的E1蛋白，分子量72Kd的E2蛋白)，p7编码一种膜内在蛋白，其功能可能是一种离子通道。非结构蛋白部分则包括NS2，NS3，NS4A，NS4B，NS5A和NS5B；非结构蛋白对病毒的生活周期非常重要。NS2/3和NS3/4A具有蛋白酶活性，参与病毒多聚蛋白前体的切割。此外，NS3蛋白还具有螺旋酶活性，参与解旋HCV-RNA分子，以协助RNA复制。NS5B具有RNA依赖的RNA聚合酶活性，参与HCV基因组复制；NS5B缺乏校读功能，所以HCV病毒基因组复制时发生突变的频率很高。NS5A的确切作用机理还不是很清楚，但NS5A可与多种宿主细胞蛋白相互作用，是病毒基因组复制以及病毒颗粒包装过程中不可缺少的一种蛋白，因此NS5A是开发HCV特异性抗病毒疗法 的一个具吸引力的靶点。
已发现的HCV可分为六种基因型1-6,不同基因型对不同治疗的应答有所差别。HCV具有显著异源性和高度可变性，对已知全部基因组序列的HCV株进行分析比较发现其核苷酸和氨基酸序列存在较大差异，并且HCV基因组各部位的变异程度不相一致，如5′-NCR最保守，同源性在92-100％，而3′NCR区变异程度较高。在HCV的编码基因中，C区最保守、非结构(NS)区次之，编码囊膜蛋白E2/NS1可变性最高称为高可变区。研究人员根据HCV基因组的序列相似性将HCV病毒分为不同的基因型，每一基因型还可进一步分为不同的亚型，迄今已发现至少已发现6种基因型24个亚型。HCV不同基因型在世界各地分布不同，基因1型、2型、3型在世界各地均存在，基因4型和5型主要分布在中东和非洲，基因6型主要发现于东南亚。美国主要为基因1型，约占HCV病人的70％(其中1a约为36％，1b约为24％)，其余的30％主要为基因2型和基因3型。中国HCV病人约66％为基因1b型，14％为基因2a型。根据发表于2014年中华内科杂志的流行病学统计，中国各地有明显地域差异，基因2型、3型、6型在中国西部和南部占很高的比例。
丙型肝炎病毒(HCV)已经严重危及人类健康，其在大量的受感染个体(据估计为全世界人口的2-15％)中导致慢性肝脏疾病如肝硬化和肝细胞癌。HCV病毒主要通过体液传播，迄今还没有防止HCV感染的疫苗。根据世界卫生组织，全世界有超过2亿的受感染个体，每年至少有3至4百万人被感染。一旦被感染后，大约20％的人能清除该病毒，但是其余的人则成为HCV携带者。HCV病人是一个很大的群体，估计全球人口的3％约1.7亿为HCV病人。美国的HCV病人占人口的1.4％，约3-4百万人。中国缺乏权威性的HCV病人的流行病学数据，最保守的估计是人口的0.42％，有的报道认为中国HCV病人高达3.8％人口,按照这些数字估计中国HCV病人应在6百万-3千8百万之间。HCV病人中，10％至20％的慢性感染个体最终发展成肝脏破坏性的硬化或癌症。
在很长的一段时间甚至目前在很多发展中国家，无论是急性丙型肝炎，还是慢性丙型肝炎，标准治疗方案都是聚乙二醇干扰素(α-2a或α-2b)联合利巴韦林。聚乙二醇干扰素(α-2a或α-2b)联合利巴韦林的治疗方案存在很多问题，包括用药周期长，毒副作用大，病人应答比例低等。因此，需要发展更为有效和新型的疗法，以解决由HCV感染造成的未被满足的医疗需求。最近几年开发出的针对HCV靶点的药物(DAA,direct acting antivirals)在这几方面取得了巨大的进展，目前世界上HCV治疗的发展趋势是不需要干扰素和利巴韦林的DAA联合用药。主要的DAA药物为NS5B抑制剂，NS5A抑制剂，NS3/4A抑制剂。与干扰素联合利巴韦林相比，DAA联合用药的优势(或潜在优势)包括：高的持续性病毒应答率SVR(基本可以治愈)，缩短治疗周期，避免耐药性的产生，追求 广谱性(可对HCV多种基因型有效)。
最先取得成功的DAA药物是NS3/4A抑制剂，包括Telaprevir(Vertex/Janssen),Boceprevir(Merck)，均在2011年获得FDA批准。NS5B抑制剂包括吉利德的Sofosvubir和艾伯维的三联药中的ABT-333。NS5A是这三类DAA最后开发成功的药物，包括BMS的Daclatasvir，吉利德的Ledipasvir(与Sofosbuvir联用)和GS-5816，艾伯维的三联药中的ABT-267，Achillion公司的ACH-3102，Merck的MK-8742等。与NS3/4A和NS5B抑制剂相比，NS5A抑制剂可使病人体内的病毒载量下降地更快和更多。此外，ACH-3102和GS-5816在很多Daclatasvir和Ledipasvir耐药突变上仍有活性。
发明内容
发明人在研究过程中发现了一类具有式(I)结构的1,4(1,4)-二苯杂环六蕃-12,43-二基衍生物、其制备方法和应用，该类化合物既对野生型HCV具有很高的抑制活性，也对Daclatasvir和Ledipasvir耐药突变具有很高的抑制活性。
本发明一方面提供一种具有式(I)化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2016103166-appb-000001
其中：
R1、：R1’各自独立的选自氢、氘、卤素、羟基、氨基、C1-8烷基、C1-8烷氧基或C3-8环烷基，
任选进一步被一个或多个选自卤素、羟基、C1-8烷基、C1-8烷氧基、卤取代C1-8烷氧基、羟基取代C1-8烷氧基、C1-8环烷基或C1-8环烷氧基的取代基所取代；
R2、R2’、R3、R3’、R4、R4’、R5、R5’各自独立的选自氢、氘、卤素、羟基、氨基、C1-8烷基、C3-8环烷基、C1-8烷氧基或C3-8环烷氧基，
任选进一步被一个或多个选自卤素、羟基、氨基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C3-8环烷氧基或3-8元杂环基氧基的取代基所取代；
L、L’各自独立的选自如下结构：
Figure PCTCN2016103166-appb-000002
任选进一步被一个或多个选自卤素、羟基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
R6、R6’各自独立的选自氢、氘、C1-8烷基、C1-8烷氧基、C3-8环烷基、卤代C1-8烷基、C1-8烷氧C1-8烷基、羟基C1-8烷基、-C(O)R14或-C(O)OR13，
任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
R7、R7’各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、 C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13，
或者，R7或R7’与其相连的四氢吡咯环一起形成6-10元含氮螺环、桥环或稠环，
任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
R8、R8’各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13，
任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13；
R9、R9’各自独立的选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-C(O)R9、-C0-8-C(O)OR9、或-C0-8-C(O)NR6R7，
任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
R10、R11各自独立的选自氢、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环 烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷基酰基，
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰氨基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、单C1-8烷基氨基或二C1-8烷基氨基的取代基所取代；
R12选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、二C1-8烷基氨基、苯基或对甲基苯基；
R13选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基或羟取代C1-8烷基；
R14选自氢、氘、C1-8烷基、C1-8烷氧基、C3-8环烷基、C3-8环烷氧基、卤取代C1-8烷基、卤取代C1-8烷氧基、羟取代C1-8烷基或羟取代C1-8烷氧基；
m、m’各自独立的选自0～3；
p、p’各自独立的选自0～7；
r为0、1或2。
作为优选的方案，所述的化合物、其立体异构体或其药学上可接受盐，R6、R6’各自独立的选自氢、氘、C1-4烷基、C1-4烷氧基、C3-6环烷基、卤代C1-4烷基、C1-4烷氧C1-4烷基、羟基C1-4烷基、-C(O)R14或-C(O)OR13，
任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代。
作为进一步优选的方案，所述的化合物、其立体异构体或其药学上可接受盐，R6、R6’各自独立的选自氢、氘、甲基、乙基、异丙基、三氟甲基、环丙基、环已基、甲氧基、乙氧基或异丙氧基，更优选氢。
作为进一步优选的方案，所述的化合物、其立体异构体或其药学上可接受盐，R1、R1’各自独立的选自氢、氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基或C3-6环烷基，更优选氢、氘、氟、氯、甲基、乙基、羟基、氨基、甲氧基或环丙基。
作为进一步优选的方案，所述的化合物、其立体异构体或其药学上可接受盐，R2、R2’、R3、R3’、R4、R4’、R5、R5’各自独立的选自氢、氘、卤素、羟基、氨基、C1-4烷基、C3-6环烷基、C1-4烷氧基或C3-8环烷氧基，更优选氢、氘、氟、氯、甲基、乙基、羟基、氨基、甲氧基或环丙基。
作为进一步优选的方案，所述的化合物、其立体异构体或其药学上可接受盐， L、L’各自独立的选自如下结构：
Figure PCTCN2016103166-appb-000003
任选进一步被一个或多个选自卤素、羟基、氰基、硝基、叠氮基、C1-8烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-4-S(O)rR12、-C0-4-O-R13、-C0-4-C(O)R14、-C0-4-C(O)OR13、-C0-4-O-C(O)R14、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
更优选如下结构：
Figure PCTCN2016103166-appb-000004
作为进一步优选的方案，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，
R7、R7’各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-6链烯基、C2-6链炔基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13，
或者，R7或R7’与其相连的四氢吡咯环一起形成6-10元含氮螺环、桥环或稠环，选自如下结构：
Figure PCTCN2016103166-appb-000005
作为更进一步优选的方案，所述的化合物、其立体异构体或其药学上可接受盐，选自如下式(Ⅱ)化合物：
Figure PCTCN2016103166-appb-000006
其中，R7、R7’、R8、R8’、R9、R9’如权利要求1所定义。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，R7、R7’各自独立的选自氢、氘、氟、甲基、乙基或异丙基，或者，R7或R7’与其相连的四氢吡咯环一起形成如下结构：
Figure PCTCN2016103166-appb-000007
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学 上可接受盐，R8、R8’各自独立的选自氢、氘、卤素、甲基、乙基、异丙基、环丙基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，R9、R9’各自独立的选自自氢、氘、C1-4烷基、烯丙基、乙炔基、C3-6环烷基、3-6元杂环基或苯基。
作为最优选的方案，所述的化合物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016103166-appb-000008
本发明另一方面提供一种前述化合物的制备方法，包括如下步骤：
Figure PCTCN2016103166-appb-000009
其中：Pg为氨基保护基，优选自优选叔丁氧羰基、烯丙基羰基、笏甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基或苄氧羰基，更优选自叔丁氧羰基；R1、R1’、R2、R2’、R3、R3’、R4、R4’、R5、R5’、R6、R6’、R7、R7’、R8、R8’、R9、R9’、R10、R11、R12、R13、R14、L、L’、p、p’、m、m’、r如式(I)化合物所定义。
作为更进一步优选的方案，所述的缚酸剂为有机碱或无机碱，所述有机碱选自三甲胺、三乙胺、吡啶、哌啶、吗啉、二异丙基乙胺或其混合物，所述无机碱选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠，氢氧化钾，氢氧化锂，醋酸钠或其混合物；所述的缩合剂选自DIC、DCC、HOBT、EDC·HCl、PyBOP、PyBroP、HATU、HCTU、DEPBT、EEDQ、CDI或其混合物。
本发明另一方面提供一种药物组合物，其包括治疗有效剂量的前述的化合物、其立体异构体或其药学上可接受盐及可药用的载体。
本发明另一方面提供一种前述化合物、其立体异构体或其药学上可接受盐、或前述药物组合物在制备治疗或预防HCV感染疾病药物中的应用。
具体实施方式
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
“C1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，烷基指饱和的脂族烃基团，C0-8是指不含碳原子或者C1-8烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基 己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，“C3-8环烷基”指包括3至8个碳原子的环烷基，“5-10元环烷基”指包括5至10个碳原子的环烷基，例如：
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基的非限制性实施例包含：
Figure PCTCN2016103166-appb-000010
“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基的非限制性实施例包含：
Figure PCTCN2016103166-appb-000011
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含：
Figure PCTCN2016103166-appb-000012
。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“5-10元杂环基”指包含5至10个环原子的环基，“3-8元杂环基”指包含3至8个环原子的环基。
单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基。螺环烷基的非限制性实施例包含：
Figure PCTCN2016103166-appb-000013
“稠杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基的非限制性实施例包含：
Figure PCTCN2016103166-appb-000014
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含：
Figure PCTCN2016103166-appb-000015
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，非限制性实施例包含：
Figure PCTCN2016103166-appb-000016
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，“C5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2016103166-appb-000017
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，5-7元杂芳基指含有5-7个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2016103166-appb-000018
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，C2-8链烯基指含有2-8个碳的直链或含支链烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、 C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，C2-8链炔基指含有2-8个碳的直链或含支链炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。C1-8烷氧基指含1-8个碳的烷基氧基，非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“环烷氧基”指和-O-(未取代的环烷基)，其中环烷基的定义如上所述。C3-8环烷氧基指含3-8个碳的环烷基氧基，非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
环烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
“卤取代C1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团，例如二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“卤取代C1-8烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。例如二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
“卤素”指氟、氯、溴或碘。
“C(O)R10”指R10取代的羰基。
“THF”指四氢呋喃。
术语“缩合剂”是指能引起缩合反应的试剂。缩合反应是指两个或多个有机分子相互作用后以共价键结合成一个大分子，同时失去水或其他比较简单的无机或有机小分子的反应。其中的小分子物质通常是水、氯化氢、甲醇或乙酸等。本发明中各种缩合剂的简称对应的中文名称如下表所示：
简称 中文名称
DIC N,N-二异丙基碳二亚胺
DCC N,N-二环己基碳二亚胺
HOBT 1-羟基苯并***
EDC·HCl 1-乙基-3-(3-二甲氨丙基)碳二亚胺盐酸盐
PyBOP 六氟磷酸苯并***-1-基-氧基三吡咯烷基
PyBroP 三吡咯烷基溴化鏻六氟磷酸盐
HATU 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
HCTU 6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯
DEPBT 3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮
EEDQ 2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉
CDI 羰基二咪唑
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载 体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为二甲亚砜(DMSO)和氘代氯仿(CDCl3)内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。
在无特殊说明的情况下，实施例中的溶液是指水溶液。反应的温度为室温。室温为最适宜的反应温度，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)或液质联用色谱(LC-MS)反应所使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，丙酮，溶剂的体积比可根据化合物的极性不同而进行调节。柱层析的洗脱剂的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和乙酸乙酯体系，D：乙酸乙酯和甲醇，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的氨水和醋酸等进行调节。
实施例化合物的制备
实施例1二甲基((2S,2'S)-((2S,2'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(吡咯烷-2,1-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000019
第一步:4,16-二溴[2.2]对环芬的制备
Figure PCTCN2016103166-appb-000020
在二氯甲烷(400mL)中依次加入铁粉(1.2g)、溴素(20.7g)，搅拌半小时，滴加[2.2]对环芬(50g)的二氯甲烷(100mL)溶液，加热回流2小时，然后在3小时内滴加溴素(7g)和二氯甲烷(100mL)混合液，继续回流反应3小时，冷却至室温，搅拌过夜。反应液依次用5％亚硫酸钠、水各洗涤一次，干燥，浓缩，残留物用热甲苯打浆，冷却，抽滤得到4,16-二溴[2.2]对环芬(33.7g)。
1H NMR(400MHz,CDCl3)δ7.17-7.14(m,2H),6.53(d,J＝2.0Hz 2H),6.42(d,J＝8.0Hz,2H),3.57-3.46(m,2H),3.20-3.11(m,2H),2.98-2.71(m,4H)。
第二步:二-叔-丁基(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000021
氮气保护下，将4,16-二溴[2.2]对环芬(4.5g，12.15mmol)、(4-((叔-丁氧基羰基)氨基)苯基)硼酸(7.2g，30.37mmol)、碳酸铯(10g，30.38mmol)、Pd(PPh3)4(1.4g，1.22mmol)混合，依次加入N,N-二甲基甲酰胺(113mL)、水(9mL)，升温至130℃反应4小时。降温至25℃，加入水(100mL)和二氯甲烷(200mL)，分出有机层，依次用水、饱和氯化钠水溶液各洗涤一次，浓缩，残留物柱层析得到二-叔-丁基(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二氨基甲酸酯(3.2g)。
1H NMR(400MHz,DMSO-d6)δ9.45(s,2H),7.58(d,J＝8.4Hz,4H),7.41(d,J＝8.4Hz,4H),6.72(d,J＝7.6Hz,2H),6.60(s,2H),6.42(d,J＝7.6Hz,2H),3.37-3.32(m,2H),2.94-3.01(m,2H),2.79-2.84(m,2H),2.54-2.61(m,2H),1.51(s,18H)。
第三步：4,4'-(1,4(1,4)-二苯杂环六蕃-12,43-二基)二苯胺的制备
Figure PCTCN2016103166-appb-000022
氮气保护下，在二-叔-丁基(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二氨基甲酸酯(3.2g，5.42mmol)中加入氯化氢的二氧六环溶液(30mL)、甲醇(10mL)，搅拌反应6小时。加入10％的氢氧化钠水溶液调反应液至碱性，析出大量固体，过滤，滤饼真空干燥得4,4'-(1,4(1,4)-二苯杂环六蕃-12,43-二基)二苯胺(2g)。
LC-MS：391.26(M+H)+；
1H NMR(400MHz,DMSO-d6)δ7.17(d,J＝8.4Hz,4H),6.68(d,J＝8.4Hz,4H),6.61(d,J＝7.6Hz,2H),6.51(s,2H),6.38(d,J＝7.6Hz,2H),5.15(br s,4H),3.37-3.40(m,2H),2.94-2.88(m,2H),2.79-2.84(m,2H),2.54-2.61(m,2H),1.51(s,18H)。
第四步：叔-丁基(S)-2-((4-(43-(4-((R)-1-(叔-丁氧基羰基)吡咯烷-2-碳杂草酰氨基)苯基)-1,4(1,4)-二苯杂环六蕃--12-基)苯基)氨基甲酰)吡咯烷-1-羧酸酯的制备
Figure PCTCN2016103166-appb-000023
氮气保护下，将4,4'-(1,4(1,4)-二苯杂环六蕃-12,43-二基)二苯胺(276mg,0.71mmol)、(叔-丁氧基羰基)-L-脯氨酸(335mg,1.56mmol)、1-羟基苯并***(210mg，1.56mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(338mg，1.77mmol)、N-甲基吗啉(358mg，3.54mmol)混合，加入到N,N-二甲基甲酰胺(7.5mL)与四氢呋喃(5mL)的混合液中，25℃下搅拌反应20小时。加入10％的柠檬酸水溶液(20mL)与乙酸乙酯(20mL)的混合液，搅拌、分出有机层，饱和碳酸钠水溶液洗涤，浓缩，残留物柱层析得叔-丁基(S)-2-((4-(43-(4-((R)-1-(叔-丁氧基羰基)吡咯烷-2-碳杂草酰氨基)苯基)-1,4(1,4)-二苯杂环六蕃-12-基)苯基)氨基甲酰)吡咯烷-1-羧酸酯(348mg)。
LC-MS：685.3(M-Boc+H)+；
1H NMR(400MHz,DMSO-d6)δ10.1(s,2H),7.73(d,J＝7.6Hz,4H),7.48(d,J＝8.0Hz,4H),6.75(d,J＝7.2Hz,2H),6.64(s,2H),6.44(d,J＝7.6Hz,2H),4.24-4.32(m,2H),3.33-3.45(m,4H),2.98-3.00(m,2H),2.82-2.85(m,2H),2.56-2.59(m,2H),2.18-2.25(m,2H),1.82-1.85(m,8H),1.41(s,9H),1.32(s,9H)。
第五步：(2S,2'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(吡咯烷-2-甲酰胺)的制备
Figure PCTCN2016103166-appb-000024
氮气保护下，将叔-丁基(S)-2-((4-(43-(4-((R)-1-(叔-丁氧基羰基)吡咯烷-2-碳杂草酰氨基)苯基)-1,4(1,4)-二苯杂环六蕃-12-基)苯基)氨基甲酰)吡咯烷-1-羧酸酯(348mg，0.49mmol)中加入二氯甲烷(5mL)、三氟醋酸(2mL)，25℃下搅拌反应20小时。加入二氯甲烷(45mL)稀释，依次用水、饱和碳酸氢钠、食盐水各洗涤一次，干燥，浓缩得(2S,2'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(吡咯烷-2-甲酰胺)(316mg)。
LC-MS：585.36(M+H)+。
第六步：二甲基((2S,2'S)-((2S,2'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(吡咯烷-2,1-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯的制备
Figure PCTCN2016103166-appb-000025
氮气保护下，将(2S,2'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(吡咯烷-2-甲酰胺)(316mg,0.54mmol)、羧基-L-缬氨酸(200mg,1.14mmol)、1-羟基苯并***(161mg,1.19mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(260mg，1.36mmol)、N-甲基吗啉(274mg，2.71mmol)混合，加入N,N-二甲基甲酰胺(10mL)，25℃下搅拌反应16小时。加入乙酸乙酯(30mL)，用水(30mL)与10％的柠檬酸水溶液(20mL)各洗涤一次，浓缩，残留物柱层析纯化得到二甲基((2S,2'S)-((2S,2'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(吡咯烷-2,1-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯(150mg)。
LC-MS：899.40(M+H)+；
1H NMR(400MHz,DMSO-d6)δ10.16(s,2H),7.75-7.72(m,4H),7.48(d,J＝8.4Hz,4H),7.35(d,J＝8.0Hz,2H),6.75(d,J＝8.0Hz,2H),6.62(s,2H),6.50(d,J＝7.6Hz,2H),4.52-4.48(m,2H),4.06(t,J＝8.4Hz,2H),3.88-3.84(m,2H),3.70-3.64(m,2H),3.54(s,6H),3.42-3.35(m,2H),3.02-2.95(m,2H),2.85-2.79(m,2H),2.65-2.55(m,2H),2.24-2.15(m,2H),2.06-1.89(m,8H),0.99-0.90(m,12H)。
实施例2二甲基((2S,2'S)-((2S,2'S,3aS,3a'S,7aS,7a'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(八氢-1H-吲哚 -2,1-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000026
第一步：(2S,3aS,7aS)-1-(叔-丁氧基羰基)八氢-1H-吲哚-2-羧酸的制备
Figure PCTCN2016103166-appb-000027
在0℃下，在(2S,3aS,7aS)-八氢-1H-吲哚-2-羧酸(50g，0.29mol)的THF(400mL)和水(200mL)的混合溶液中逐滴加入冷却的2.5M NaOH水溶液(200mL)，搅拌15分钟，0℃下滴加二碳酸二丁酯(85.4g)，室温下搅拌反应12小时。停止反应，依次用MTBE洗涤3次，1M柠檬酸水溶液酸化水相，乙酸乙酯萃取3次，合并有机相，硫酸钠干燥，浓缩至干得到(2S,3aS,7aS)-1-(叔-丁氧基羰基)八氢-1H-吲哚-2-羧酸的制备(74.9g)。
第二步：二-叔-丁基2,2'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(2S,2'S,3aS,3a'S,7aS,7a'S)-二(八氢-1H-吲哚-1-羧酸酯)的制备
Figure PCTCN2016103166-appb-000028
以化合物4,4'-(1,4(1,4)-二苯杂环六蕃-12,43-二基)二苯胺为原料，参考实施例1步骤4，与化合物(2S,3aS,7aS)-1-(叔-丁氧基羰基)八氢-1H-吲哚-2-羧酸缩合，得到化合物二-叔-丁基2,2'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(2S,2'S,3aS,3a'S,7aS,7a'S)-二(八氢-1H-吲哚-1-羧酸酯)。
LC-MS：685.3(M-Boc+H)+；
1H NMR(400MHz,DMSO-d6)δ10.14(br,2H),7.77(s,4H),7.49(d,J＝8.0Hz,4H),6.76(d,J＝7.2Hz,2H),6.64(s,2H),6.46(d,J＝7.6Hz,2H),4.28(t,J＝8.8Hz,2H),3.73-3.67(m,2H),3.35-3.32(m,2H),3.02-2.97(m,2H),2.86-2.79(m,2H),2.61-2.58(m,2H),2.40-2.30(m,2H),2.12-2.05(m,2H),1.89-1.53(m,10H),1.3.9-1.30(m,18H)。
第三步：(2S,2'S,3aS,3a'S,7aS,7a'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(八氢-1H-吲哚-2-甲酰胺)的制备
Figure PCTCN2016103166-appb-000029
氮气保护下，将二-叔-丁基2,2'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(2S,2'S,3aS,3a'S,7aS,7a'S)-二(八氢-1H-吲哚-1-羧酸酯)(700mg，0.78mmol)溶于氯化氢的二氧六环溶液(5mL)中，在25℃下搅拌20小时，然后逐滴加入2M的氢氧化钠水溶液至碱性，析出固体，过滤，滤饼真空干燥得(2S,2'S,3aS,3a'S,7aS,7a'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(八氢-1H-吲哚-2-甲酰胺)(460mg)。
LC-MS：693.45(M+H)+。
第四步：二甲基((2S,2'S)-((2S,2'S,3aS,3a'S,7aS,7a'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(八氢-1H-吲哚-2,1-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯的制备
Figure PCTCN2016103166-appb-000030
参考实施例1步骤6得到化合物二甲基((2S,2'S)-((2S,2'S,3aS,3a'S,7aS,7a'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(八氢-1H-吲哚-2,1-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯。
LC-MS：1007.25(M+H)+；
1H NMR(400MHz,DMSO-d6)δ10.18(s,2H),7.75(d,J＝7.6Hz,4H),7.53(d,J＝8.0Hz，2H),7.48(d,J＝8.4Hz,4H),6.75(d,J＝8.0Hz 2H),6.63(s,2H),6.46(d,J＝8.0Hz 2H),4.48(t,J＝9.2Hz 2H),4.37-4.32(m,2H),3.85(t,J＝8.8Hz,2H),3.55(s,6H),3.40-3.33(m,2H),3.05-2.96(m,2H),2.85-2.80(m,2H),2.64-2.58(m,2H),2.35-2.25(m,2H),2.14-2.01(m,2H),2.03-1.90(m,6H),1.77-1.52(m,8H),1.49-1.43(m,2H),1.32-1.17(m,4H),0.93-0.84(m,12H)。
实施例3甲基((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,7aS,7a'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(八氢-1H-吲哚-2,1-二基))二(3-甲氧基-1-羰基丁烷-1,2-二基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000031
第一步：N-甲氧羰基-O-甲基-L-苏氨酸的制备
Figure PCTCN2016103166-appb-000032
将O-甲基-L-苏氨酸(5.0g，37.6mmol)溶解在1，4-二氧六环(20mL)和THF(20mL)的混合液中，冷却至0℃，滴加NaOH(4.5g NaOH溶于56mL水)水溶液，再加入氯甲酸甲酯(4.3g)，升至室温并搅拌7h。依次用3N盐酸酸化，乙酸乙酯(60mL)萃取三次，合并有机相，经硫酸钠干燥，过滤，浓缩，得到N-甲氧羰基-O-甲基-L-苏氨酸(5.3g)。
LC-MS：192.1(M+H)+。
第二步：甲基((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,7aS,7a'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(八氢-1H-吲哚-2,1-二基))二(3-甲氧基-1-羰基丁烷-1,2-二基))二氨基甲酸酯的制备
Figure PCTCN2016103166-appb-000033
以二-叔-丁基2,2'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(2S,2'S,3aS,3a'S,7aS,7a'S)-二(八氢-1H-吲哚-1-羧酸酯)为原料，参考实施例1步骤6，得到甲基((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,7aS,7a'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(八氢-1H-吲哚-2,1-二基))二(3-甲氧基-1-羰基丁烷-1,2-二基))二氨基甲酸酯。
LC-MS：1039.40(M+H)+；
1H NMR(400MHz,DMSO-d6)δ10.18(s,2H),7.75(d,J＝8.0Hz，4H),7.62(d,J＝7.6Hz，2H),7.48(d,J＝8.4Hz，4H),6.75(d,J＝8.0Hz，2H),6.63(s,2H),6.46(d,J＝7.6Hz，2H),4.47(t,J＝8.8Hz,2H),4.38-4.35(m,2H),4.11(t,J＝8.4Hz,2H),3.55(s,6H),3.51-3.47(m,2H),3.41-3.27(m,2H),3.25(d,J＝5.2Hz,6H),3.02-2.97(m,2H),2.85-2.80(m,2H),2.61-2.55(m,2H),2.37-2.31(m,2H),2.16-2.10(m,2H),2.02-1.91(m,4H),1.79-1.61(m,8H),1.45-1.41(m,2H),1.32-1.20(m,4H),1.12-1.09(m,6H)。
实施例4二甲基((2S,2'S)-((6S,6'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(5-氮杂螺[2.4]庚烷-6,5-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000034
第一步：二-叔-丁基6,6'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(6S,6'S)-二(5-氮杂螺[2.4]庚烷-5-羧酸酯)的制备
Figure PCTCN2016103166-appb-000035
参考实施例1步骤4，4,4'-(1,4(1,4)-二苯杂环六蕃-12,43-二基)二苯胺与(S)-5-(叔-丁氧基羰基)-5-氮杂螺[2.4]庚烷-6-羧酸缩合得到二-叔-丁基6,6'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(6S,6'S)-二(5-氮杂螺[2.4]庚烷-5-羧酸酯)。
LC-MS：637.30(M-2Boc+H)+。
第二步：(6S,6'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(5-氮杂螺[2.4]庚烷-6-甲酰胺)的制备
Figure PCTCN2016103166-appb-000036
参考实施例1步骤5，二-叔-丁基6,6'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(6S,6'S)-二(5-氮杂螺[2.4]庚烷-5-羧酸酯)去保护得到(6S,6'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(5-氮杂螺[2.4]庚烷-6-甲酰胺)。
LC-MS：637.30(M+H)+。
第三步：二甲基((2S,2'S)-((6S,6'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(5-氮杂螺[2.4]庚烷-6,5-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯的制备
Figure PCTCN2016103166-appb-000037
参考实施例1步骤6，(6S,6'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(5-氮杂螺[2.4]庚烷-6-甲酰胺)缩合得到二甲基((2S,2'S)-((6S,6'S)-(((1,4 (1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(5-氮杂螺[2.4]庚烷-6,5-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯。
LC-MS：951.40(M+H)+；
1H NMR(400MHz,DMSO)δ10.12(s,2H),7.72(d,J＝6.8Hz,4H),7.48(d,J＝8.4Hz,4H),6.75(d,J＝7.6Hz,2H),6.62(s,2H),6.46(d,J＝7.6Hz,2H),4.64(t,J＝7.6Hz,2H),3.96(t,J＝9.6Hz,2H),3.74(d,J＝9.6Hz,2H),3.67(d,J＝9.6Hz,2H),3.54(s,6H),3.02-2.96(m,2H),2.85-2.79(m,2H),2.62-2.59(m,2H),2.15-2.09(m,2H),2.02-1.96(m,4H),1.28-1.23(m,4H),0.99-0.97(m,6H),0.90-0.88(m,6H),0.70-0.68(m,2H),0.64-0.56(m,6H)。
实施例5二甲基((2S,2'S,3R,3'R)-((6S,6'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(5-氮杂螺[2.4]庚烷-6,5-二基))二(3-甲氧基-1-羰基丁烷-1,2-二基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000038
参考实施例1步骤6，(6S,6'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(5-氮杂螺[2.4]庚烷-6-甲酰胺)与N-甲氧羰基-O-甲基-L-苏氨酸缩合得到二甲基((2S,2'S,3R,3'R)-((6S,6'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(5-氮杂螺[2.4]庚烷-6,5-二基))二(3-甲氧基-1-羰基丁烷-1,2-二基))二氨基甲酸酯。
LC-MS：983.50(M+H)+；
1H NMR(400MHz,DMSO)δ10.04(s,2H),7.72(d,J＝7.6Hz,4H),7.48(d,J＝8.4Hz,4H),7.34(d,J＝7.2Hz,2H),6.75(d,J＝8.0Hz,2H),6.64(s,2H),6.46(d,J＝7.6Hz,2H),4.63(t,J＝7.2Hz,2H),4.21(t,J＝7.6Hz,2H),3.77-3.70(m,4H),3.55(s,6H),3.52-3.47(m,2H),3.38-3.35(m,6H),3.28(s,3H),3.27(s,3H),3.02-2.97(m,2H),2.85-2.80(m,2H),2.64-2.61(m,2H),2.16-2.11(m,2H),2.02-1.97(m,2H),1.20-1.18(m,6H),0.72-0.69(m,2H),0.63-0.56(m,4H)。
实施例6二甲基((2S,2'S)-((1R,1'R,3S,3'S,4S,4'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(2-氮杂二环[2.2.1]庚烷-3,2-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000039
第一步：二-叔-丁基3,3'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(1R,1'R,3S,3'S,4S,4'S)-二(2-氮杂二环[2.2.1]庚烷-2-羧酸酯)的制备
Figure PCTCN2016103166-appb-000040
参考实施例1步骤4，4,4'-(1,4(1,4)-二苯杂环六蕃-12,43-二基)二苯胺与(1R,3S,4S)-2-(叔-丁氧基羰基)-2-氮杂二环[2.2.1]庚烷-3-羧酸缩合，得到二-叔-丁基3,3'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(1R,1'R,3S,3'S,4S,4'S)-二(2-氮杂二环[2.2.1]庚烷-2-羧酸酯)的制备。
LC-MS：637.30(M-2Boc+H)+。
第二步：(1R,1'R,3S,3'S,4S,4'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(2-氮杂二环[2.2.1]庚烷-3-甲酰胺)的制备
Figure PCTCN2016103166-appb-000041
参考实施例1步骤5，二-叔-丁基3,3'-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))(1R,1'R,3S,3'S,4S,4'S)-二(2-氮杂二环[2.2.1]庚烷-2-羧酸酯)去保护得到(1R,1'R,3S,3'S,4S,4'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(2-氮杂二环[2.2.1]庚烷-3-甲酰胺)。
LC-MS：637.30(M+H)+。
第三步：二甲基((2S,2'S)-((1R,1'R,3S,3'S,4S,4'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(2-氮杂二环[2.2.1]庚烷-3,2-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯的制备
Figure PCTCN2016103166-appb-000042
参考实施例1步骤6，(1R,1'R,3S,3'S,4S,4'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(2-氮杂二环[2.2.1]庚烷-3-甲酰胺)缩合得到二甲基 ((2S,2'S)-((1R,1'R,3S,3'S,4S,4'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(2-氮杂二环[2.2.1]庚烷-3,2-二基))二(3-甲基-1-羰基丁烷-1,2-二基))二氨基甲酸酯。
LC-MS：951.35(M+H)+；
1H NMR(400MHz,DMSO)δ10.3(s,2H),7.73(d,J＝8.0Hz,4H),7.46(d,J＝8.0Hz,4H),6.74(d,J＝7.6Hz,2H),6.68(d,J＝7.6Hz,2H),6.62(s,2H),6.45(d,J＝7.6Hz,2H),4.51(s,2H),4.13-4.06(m,2H),4.05(s,2H),3.55(s,6H),3.35-3.30(m,2H),3.02-2.96(m,2H),2.85-2.79(m,2H),2.62-2.59(m,2H),2.15-2.09(m,2H),2.12-2.06(m,4H),2.03-1.97(m,6H),1.51-1.41(m,4H),1.02-1.00(m,6H),0.94-0.92(m,6H)。
实施例7二甲基((2S,2'S,3R,3'R)-((1R,1'R,3S,3'S,4S,4'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(2-氮杂二环[2.2.1]庚烷-3,2-二基))二(3-甲氧基-1-羰基丁烷-1,2-二基))二氨基甲酸酯
Figure PCTCN2016103166-appb-000043
参考实施例1步骤6，(1R,1'R,3S,3'S,4S,4'S)-N,N'-(1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(2-氮杂二环[2.2.1]庚烷-3-甲酰胺)与N-甲氧羰基-O-甲基-L-苏氨酸缩合得到二甲基((2S,2'S,3R,3'R)-((1R,1'R,3S,3'S,4S,4'S)-(((1,4(1,4)-二苯杂环六蕃-12,43-二基二(4,1-亚苯基))二(氮烷二基))二(羰基))二(2-氮杂二环[2.2.1]庚烷-3,2-二基))二(3-甲氧基-1-羰基丁烷-1,2-二基))二氨基甲酸酯。
LC-MS：983.35(M+H)+；
1H NMR(400MHz,DMSO)δ10.08(s,2H),7.72(d,J＝8.6Hz,4H),7.48(d,J＝8.4Hz,4H),7.28(d,J＝8.0Hz,2H),6.75(d,J＝7.6Hz,2H),6.62(s,2H),6.46(d,J＝7.6Hz,2H),4.57(s,2H),4.32(t,J＝7.6Hz,2H),4.25-4.23(m,1H),4.02(s,2H),3.55(s,6H),3.52-3.47(m,1H),3.34-3.30(m,4H),3.28(s,3H),3.27(s,3H),2.99-2.96(m,2H),2.79-2.85(m,2H),2.73-2.70(m,2H),2.61-2.59(m,2H),2.10-2.12(m,2H),1.68-1.80(m,4H),1.48-1.42(m,4H),1.24-1.19(m,6H)。
生物学评价
(野生型丙肝病毒HCV基因1b抑制活性测定)
本发明化合物对HCV复制的抑制活性是通过HCV复制子荧光素酶报告基因分析方法(HCV Replicon Reporter Luciferase Assay)测定的。
1、实验用的细胞模型：HCV复制子荧光素酶报告基因稳转的Huh-7细胞系。
2、实验溶液配制方法：
待测化合物贮备溶液用二甲基亚砜配制为10mM，实验时用DMSO稀释至试验最高浓度,然后用培养基进行3倍系列稀释，一般稀释成8到10个浓度点，每个浓度点设双复孔。二甲基亚砜终浓度为0.5％。每次实验均包含内参化合物，1个为参照化合物(ACH-3102)，另1个为Cyclosporine。
3、实验测定步骤：
1)将细胞生长在96孔培养板上，24小时后将不同浓度的待测化合物和内参化合物加到培养的细胞。
2)48小时后，用酶标仪检测荧光素酶活性。
3)分析原始数据，计算受试化合物不同浓度点对荧光素酶活性的抑制即对HCV复制子的抑制百分比。
4)采用GraphPad Prism软件对抑制百分比数据进行非线性拟合分析得到化合物的半数抑制浓度IC50值。
本发明实施例化合物及参照化合物(ACH-3102)的活性通过以上的试验进行测定，野生型丙肝病毒HCV基因1b抑制活性IC50值结果见表1：
实施例编号 IC50(nM)
实施例1 0.011
实施例2 0.0064
实施例3 0.0023
实施例4 0.0037
实施例5 0.002
实施例7 0.050
参照化合物ACH-3102 0.0190

Claims (16)

  1. 一种具有式(I)化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2016103166-appb-100001
    其中：
    R1、R1’各自独立的选自氢、氘、卤素、羟基、氨基、C1-8烷基、C1-8烷氧基或C3-8环烷基，
    任选进一步被一个或多个选自卤素、羟基、C1-8烷基、C1-8烷氧基、卤取代C1-8烷氧基、羟基取代C1-8烷氧基、C1-8环烷基或C1-8环烷氧基的取代基所取代；
    R2、R2’、R3、R3’、R4、R4’、R5、R5’各自独立的选自氢、氘、卤素、羟基、氨基、C1-8烷基、C3-8环烷基、C1-8烷氧基或C3-8环烷氧基，
    任选进一步被一个或多个选自卤素、羟基、氨基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C3-8环烷氧基或3-8元杂环基氧基的取代基所取代；
    L、L’各自独立的选自如下结构：
    Figure PCTCN2016103166-appb-100002
    Figure PCTCN2016103166-appb-100003
    任选进一步被一个或多个选自卤素、羟基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
    R6、R6’各自独立的选自氢、氘、C1-8烷基、C1-8烷氧基、C3-8环烷基、卤代C1-8烷基、C1-8烷氧C1-8烷基、羟基C1-8烷基、-C(O)R14或-C(O)OR13，
    任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
    R7、R7’各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13，
    或者，R7或R7’与其相连的四氢吡咯环一起形成6-10元含氮螺环、桥环或稠环，
    任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、 -C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
    R8、R8’各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13，
    任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13；
    R9、R9’各自独立的选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-C(O)R9、-C0-8-C(O)OR9、或-C0-8-C(O)NR6R7，
    任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
    R10、R11各自独立的选自氢、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷基酰基，
    任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰氨基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、单C1-8烷基氨基或二C1-8烷基氨基的取代基所取代；
    R12选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、二C1-8烷基氨基、苯基或对甲基苯基；
    R13选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基或羟取代C1-8烷基；
    R14选自氢、氘、C1-8烷基、C1-8烷氧基、C3-8环烷基、C3-8环烷氧基、卤取代C1-8烷基、卤取代C1-8烷氧基、羟取代C1-8烷基或羟取代C1-8烷氧基；
    m、m’各自独立的选自0～3；
    p、p’各自独立的选自0～7；
    r为0、1或2。
  2. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R6、R6’各自独立的选自氢、氘、C1-4烷基、C1-4烷氧基、C3-6环烷基、卤代C1-4烷基、C1-4烷氧C1-4烷基、羟基C1-4烷基、-C(O)R14或-C(O)OR13，
    任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代。
  3. 根据权利要求2所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R6、R6’各自独立的选自氢、氘、甲基、乙基、异丙基、三氟甲基、环丙基、环已基、甲氧基、乙氧基或异丙氧基，优选氢。
  4. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R1、R1’各自独立的选自氢、氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基或C3-6环烷基，优选氢、氘、氟、羟基、氨基、甲基、乙基或环丙基。
  5. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R2、R2’、R3、R3’、R4、R4’、R5、R5’各自独立的选自氢、氘、卤素、羟基、氨基、C1-4烷基、C3-6环烷基、C1-4烷氧基或C3-8环烷氧基，优选氢、氘、氟、氯、甲基、乙基、羟基、氨基、甲氧基或环丙基。
  6. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，L、L’各自独立的选自如下结构：
    Figure PCTCN2016103166-appb-100004
    任选进一步被一个或多个选自卤素、羟基、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-4-S(O)rR12、-C0-4-O-R13、-C0-4-C(O)R14、-C0-4-C(O)OR13、-C0-4-O-C(O)R14、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13的取代基所取代；
    优选如下结构：
    Figure PCTCN2016103166-appb-100005
  7. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，
    R7、R7’各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-6链烯基、C2-6链炔基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13，
    或者，R7或R7’与其相连的四氢吡咯环一起形成6-10元含氮螺环、桥环或稠环，选自如下结构：
    Figure PCTCN2016103166-appb-100006
  8. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅱ)化合物：
    Figure PCTCN2016103166-appb-100007
    R7、R7’、R8、R8’、R9、R9’如权利要求1所定义。
  9. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R7、R7’各自独立的选自氢、氘、氟、甲基、乙基或异丙基，或者，R7或R7’与其相连的四氢吡咯环一起形成如下结构：
    Figure PCTCN2016103166-appb-100008
  10. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R8、R8’各自独立的选自氢、氘、卤素、甲基、乙基、异丙基、环丙基、-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14或-N(R10)-C(O)OR13。
  11. 根据权利要求1所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R9、R9’各自独立的选自自氢、氘、C1-4烷基、烯丙基、乙炔基、C3-6环烷基、3-6元杂环基或苯基。
  12. 根据权利要求1-11任一项所述的具有式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016103166-appb-100009
  13. 根据权利要求1-12任一所述的具有式(I)化合物、其立体异构体或其药学 上可接受盐的制备方法，包括如下步骤：
    Figure PCTCN2016103166-appb-100010
    其中：Pg为氨基保护基，优选自优选叔丁氧羰基、烯丙基羰基、笏甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基或苄氧羰基，更优选自叔丁氧羰基；R1、R1’、R2、R2’、R3、R3’、R4、R4’、R5、R5’、R6、R6’、R7、R7’、R8、R8’、R9、R9’、R10、R11、R12、R13、R14、L、L’、p、p’、m、m’、r如权利要求1所定义。
  14. 根据权利要求13所述的制备方法，其特征在于，所述的缚酸剂为有机碱或无机碱，所述有机碱选自三甲胺、三乙胺、吡啶、哌啶、吗啉、二异丙基乙胺或其混合物，所述无机碱选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠，氢氧化钾，氢氧化锂，醋酸钠或其混合物；所述的缩合剂选自DIC、DCC、HOBT、EDC·HCl、PyBOP、PyBroP、HATU、HCTU、DEPBT、EEDQ、CDI或其混合物。
  15. 一种药物组合物，其包括治疗有效剂量的根据权利要求1-12任一所述的具有式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。
  16. 根据权利要求1-12任一所述的具有式(I)化合物、其立体异构体或其药学上可接受盐、或根据权利要求15所述的药物组合物在制备治疗或预防HCV感染疾病药物中的应用。
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