CN108349907B

CN108349907B - 1,4(1,4) -diphenylheterocycle hexa-tomato-12,43-diyl derivatives, process for their preparation and their use

Info

Publication number: CN108349907B
Application number: CN201680064922.6A
Authority: CN
Inventors: 苏熠东; 冯卫东; 王宝珠
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2015-11-06
Filing date: 2016-10-25
Publication date: 2021-08-31
Anticipated expiration: 2036-10-25
Also published as: CN108349907A; WO2017076187A1

Abstract

Provides a 1,4(1,4) -diphenyl heterocycle hexa-tomato-12, 43-diyl derivative, a preparation method and application thereof. The series of compounds can inhibit the activity of HCV, can be applied to the development of medicaments for treating diseases related to Hepatitis C Virus (HCV) infection, and have wide application prospects. See formula (I).

Description

1,4(1,4) -diphenylheterocycle hexa-tomato-12，43-diyl derivatives, process for their preparation and their use

Technical Field

The invention belongs to the field of drug development, and particularly relates to 1,4(1,4) -diphenyl heterocycle hexa-tomato-1²，4³-diyl derivatives, processes for their preparation and their use.

Background

Hepatitis c virus HCV belongs to the family flaviviridae, which includes at least three genera: pestiviruses (pestiviruses), which cause disease mainly in cattle and pigs; flaviviruses (flaviviruses), the major cause of dengue and yellow fever; and the hepatitis c virus (hepaciviruses), HCV being the only member of this genus. Flavivirus members, greater than 68, can be divided into different groups based on serological relatedness; clinical symptoms present with diversity, including fever, encephalitis, and hemorrhagic fever. Flaviviruses associated with human diseases of global interest include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome virus and japanese encephalitis virus. Since the HCV genome is similar in structural and phenotypic characteristics to human flaviviruses and pestiviruses, it is classified as a flaviviridae HCV. Hepatitis c virus is a positive-stranded RNA virus that surrounds a lipid-containing envelope, with spikes, outside the nucleocapsid. HCV has three in vitro cell culture systems of Huh7, Huh7.5 and Huh 7.5.1. The Hepatitis C virus was first discovered in 1974, and in 1989, the gene sequence of the virus was found by the scientists Michael Houghton (Michael Houghton) and colleagues in the United states by using a molecular biology method, and the Hepatitis C virus was cloned and named Hepatitis C (Hepatitis C) and Hepatitis C Virus (HCV).

HCV virions are enveloped positive strand RNA viruses, HCV-RNA consisting of approximately 9500-10000bp, 319-341bp in the 5 'and 3' noncoding regions (NCR) and 27-55bp, respectively, containing several forward and reverse repeats, possibly associated with gene replication, the genomic order being 5 '-C-E1-E2-p 7-NS2-NS3-NS4A/4B-NS5A-NS 5B-3', encoding a polyprotein precursor of approximately 3014 amino acids in length, which can be cleaved by the action of host cells and viral self-proteases into 10 viral proteins, including three structural proteins, namely the nucleocapsid protein (or Core protein, Core) of molecular weight 19KD and two glycoproteins (E1 protein of molecular weight 33KD, E2 protein of molecular weight 72 KD), p7 encoding an integral membrane protein, its function may be an ion channel. The non-structural protein part comprises NS2, NS3, NS4A, NS4B, NS5A and NS 5B; nonstructural proteins are important to the life cycle of the virus. NS2/3 and NS3/4A have protease activity and are involved in the cleavage of viral polyprotein precursors. In addition, the NS3 protein also has helicase activity and is involved in unwinding HCV-RNA molecules to facilitate RNA replication. NS5B has RNA-dependent RNA polymerase activity and is involved in HCV genome replication; NS5B lacks proofreading function, and therefore mutations occur at a high frequency when the HCV viral genome replicates. The exact mechanism of action of NS5A is not well understood, but NS5A interacts with a variety of host cell proteins, and is an essential protein in viral genome replication and virion packaging, and therefore NS5A is an attractive target for the development of HCV-specific antiviral therapies.

HCV has been found to be divided into six genotypes 1-6, with the different genotypes responding differently to different treatments. HCV has remarkable heterogeneity and high variability, and the analysis and comparison of HCV strains with known whole genome sequences show that the nucleotide and amino acid sequences of the HCV strains have large differences, and the variation degrees of various parts of the HCV genome are inconsistent, such as the most conservative 5 '-NCR, the homology is 92-100%, and the variation degree of the 3' NCR region is high. The most conserved, non-structural (NS) region of the C region is the second of the HCV-encoding genes, and the most variable region encodes the envelope protein E2/NS 1. Researchers have classified HCV viruses into different genotypes based on sequence similarity of HCV genomes, each genotype may be further classified into different subtypes, and at least 24 subtypes of 6 genotypes have been found so far. HCV has different genotypes distributed around the world, genotype 1, genotype 2 and genotype 3 all occur around the world, genotype 4 and genotype 5 are mainly distributed in the middle east and africa, and genotype 6 is mainly found in southeast asia. The major genotype 1 in the united states accounts for about 70% of HCV patients (of which 1a is about 36% and 1b is about 24%), with the remaining 30% being predominantly genotype 2 and genotype 3. About 66% of HCV patients in China are genotype 1b, and 14% are genotype 2 a. According to epidemiological statistics published in 2014 in the journal of Chinese internal medicine, China has obvious regional differences, and the types 2, 3 and 6 account for a high proportion in the west and south of China.

Hepatitis C Virus (HCV) has severely compromised human health, causing chronic liver diseases such as cirrhosis and hepatocellular carcinoma in a large number of infected individuals, estimated to be 2-15% of the world population. HCV viruses are transmitted mainly through body fluids, and there is no vaccine to prevent HCV infection to date. According to the world health organization, there are over 2 million infected individuals worldwide, with at least 3 to 4 million people infected per year. Once infected, approximately 20% of people clear the virus, but the rest become HCV carriers. HCV patients are a large population, with an estimated 3% of the global population being about 1.7 billion HCV patients. HCV patients in the united states account for 1.4% of the population, approximately 3-4 million people. The epidemiological data of HCV patients lack authority in china, the most conservative estimate is 0.42% of the population, and some reports suggest that HCV patients in china are up to 3.8% of the population, and the number estimates that HCV patients in china should be between 6 million and 3 thousand and 8 million. Of HCV patients, 10% to 20% of chronically infected individuals eventually develop liver-destructive cirrhosis or cancer.

For a long time and even now in many developing countries, either acute or chronic hepatitis c, the standard treatment regimen is peginterferon (α -2a or α -2b) in combination with ribavirin. The treatment scheme of the combination of polyethylene glycol interferon (alpha-2 a or alpha-2 b) and ribavirin has a plurality of problems, including long medication period, great toxic and side effects, low response ratio of patients and the like. Therefore, there is a need to develop more effective and novel therapies to address the unmet medical need caused by HCV infection. The development of Drugs (DAAs) against HCV targets in recent years has made tremendous progress in these areas, and the current trend in HCV therapy worldwide is towards DAA combinations that do not require interferon and ribavirin. The main DAA drugs are NS5B inhibitors, NS5A inhibitors, NS3/4A inhibitors. Advantages (or potential advantages) of the DAA combination compared to interferon in combination with ribavirin include: high persistent virus response rate SVR (basically curable), shortened treatment cycle, avoidance of drug resistance, pursuit of broad spectrum (effective against multiple genotypes of HCV).

The first successful DAA drugs were NS3/4A inhibitors, including Telaprevir (Vertex/Janssen), boceprevir (merck), all approved by the FDA in 2011. NS5B inhibitors include ABT-333 in the Gelidide combination of Sofosvubir and Eberavid. NS5A is the last successfully developed drug for these three DAAs, including DAClatatasvir of BMS, Ledipasvir (in combination with Sofosbuvir) and GS-5816 of Gilidide, ABT-267 of triple drug of Alberd, ACH-3102 of Achillion, MK-8742 of Merck, and so on. NS5A inhibitors may cause a faster and greater reduction in viral load in patients than NS3/4A and NS5B inhibitors. In addition, ACH-3102 and GS-5816 are still active on many of the Daclatasvir and Ledipasvir resistance mutations.

Disclosure of Invention

The inventor finds a 1,4(1,4) -diphenyl heterocycle hexa-tomato-1 with a structure of formula (I) in the research process²，4³The compounds have high inhibitory activity to wild type HCV and also have high inhibitory activity to drug resistance mutation of Daclatasvir and Ledipasvir.

In one aspect, the present invention provides a compound having formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R₁、R₁' independently of each other are selected from hydrogen, deuterium, halogen, hydroxy, amino, C_1-8Alkyl radical, C_1-8Alkoxy or C_3-8A cycloalkyl group,

optionally further substituted by one or more groups selected from halogen, hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy radical,Halogen substituted C_1-8Alkoxy, hydroxy substituted C_1-8Alkoxy radical, C_1-8Cycloalkyl or C_1-8Cycloalkoxy is substituted by a substituent;

R₂、R₂’、R₃、R₃’、R₄、R₄’、R₅、R₅' independently of each other are selected from hydrogen, deuterium, halogen, hydroxy, amino, C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_1-8Alkoxy or C_3-8A cycloalkoxy group,

optionally further substituted by one or more groups selected from halogen, hydroxy, amino, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_1-8Alkoxy radical, C_3-8Cycloalkoxy or 3-8 membered heterocyclyloxy;

l, L' are each independently selected from the following structures:

optionally further substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

R₆、R₆' each ofIndependently selected from hydrogen, deuterium, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl, halo C_1-8Alkyl radical, C_1-8Alkoxy C_1-8Alkyl, hydroxy C_1-8Alkyl, -C (O) R₁₄OR-C (O) OR₁₃，

Optionally further substituted by one or more groups selected from halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

R₇、R₇' independently of each other are selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃，

Or, R₇Or R₇To which it is connectedThe tetrahydropyrrole rings together form a 6-10 membered nitrogen-containing spiro, bridged or fused ring,

R₈、R₈' independently of each other are selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃，

Optionally further substituted by one or more groups selected from halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthioBase, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃；

R₉、R₉' independently of each other are selected from hydrogen, deuterium, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-C(O)R₉、-C_0-8-C(O)OR₉or-C_0-8-C(O)NR₆R₇，

R₁₀、R₁₁each independently selected from hydrogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroarylRadical or C_1-8An alkyl acyl group which is a substituent of a heterocyclic group,

optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, acetamido, azido, sulfonyl, methylsulfonyl, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_1-8Alkoxy radical, C_1-8Alkoxycarbonyl, C_1-8Alkylcarbonyl group, C_1-8Alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C_1-8Alkylamino or di-C_1-8Substituted with a substituent of alkylamino;

R₁₂selected from hydrogen, deuterium, C_1-8Alkyl radical, C_3-8Cycloalkyl, halo-substituted C_1-8Alkyl, di-C_1-8Alkylamino, phenyl or p-methylphenyl;

R₁₃selected from hydrogen, deuterium, C_1-8Alkyl radical, C_3-8Cycloalkyl, halo-substituted C_1-8Alkyl or hydroxy substituted C_1-8An alkyl group;

R₁₄selected from hydrogen, deuterium, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, halo-substituted C_1-8Alkyl, halo-substituted C_1-8Alkoxy, hydroxy substituted C_1-8Alkyl or hydroxy substituted C_1-8An alkoxy group;

m and m' are respectively and independently selected from 0-3;

p and p' are respectively and independently selected from 0-7;

r is 0, 1 or 2.

As a preferred embodiment, the compound, its stereoisomer or its pharmaceutically acceptable salt, R₆、R₆' independently of each other are selected from hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy C_1-4Alkyl, hydroxy C_1-4Alkyl, -C (O) R₁₄OR-C (O) OR₁₃，

Optionally further substituted by one or more groups selected from halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s).

As a further preferred embodiment, said compound, its stereoisomer or its pharmaceutically acceptable salt, R₆、R₆' each is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, methoxy, ethoxy or isopropoxy, more preferably hydrogen.

As a further preferred embodiment, said compound, its stereoisomer or its pharmaceutically acceptable salt, R₁、R₁' independently of each other are selected from hydrogen, deuterium, halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, hydroxy, amino, methoxy or cyclopropyl.

As a further preferred embodiment, said compound, its stereoisomer or its pharmaceutically acceptable salt, R₂、R₂’、R₃、R₃’、R₄、R₄’、R₅、R₅' independently of each other are selected from hydrogen, deuterium, halogen, hydroxy, amino, C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Alkoxy or C_3-8CycloalkanesOxy, more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, hydroxy, amino, methoxy or cyclopropyl.

As a further preferred embodiment, the compound, stereoisomer or pharmaceutically acceptable salt thereof, L, L' is each independently selected from the following structures:

optionally further substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, azido, C_1-8Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-4-S(O)_rR₁₂、-C_0-4-O-R₁₃、-C_0-4-C(O)R₁₄、-C_0-4-C(O)OR₁₃、-C_0-4-O-C(O)R₁₄、-C_0-4-NR₁₀R₁₁、-C_0-4-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

more preferably the following structure:

as a further preferred embodiment, the compound, its stereoisomer or its pharmaceutically acceptable salt is characterized in that,

R₇、R₇' independently of each other are selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio,C_5-8Aryl radical, C_5-8Aryloxy radical, C_5-8Arylthio, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, 5-8 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃，

Or, R₇Or R₇' taken together with the tetrahydropyrrole ring to which it is attached form a 6-to 10-membered nitrogen-containing spiro, bridged or fused ring selected from the following structures:

as a still further preferred embodiment, the compound, stereoisomer thereof or pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (II) below:

wherein R is₇、R₇’、R₈、R₈’、R₉、R₉' as defined in claim 1.

As a still further preferred embodiment, said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R₇、R₇' each independently is selected from hydrogen, deuterium, fluoro, methyl, ethyl or isopropyl, or, R₇Or R₇' together with the tetrahydropyrrole ring to which it is attached form the following structure:

as a further preferable modeThe compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R₈、R₈'independently of each other' is selected from hydrogen, deuterium, halogen, methyl, ethyl, isopropyl, cyclopropyl, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃。

As a still further preferred embodiment, said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R₉、R₉' independently of each other are selected from hydrogen, deuterium, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl or phenyl.

As a most preferred embodiment, the compound, stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of:

in another aspect, the present invention provides a method for preparing the aforementioned compound, comprising the steps of:

wherein: pg is an amino protecting group, preferably selected from tert-butyloxycarbonyl, allylcarbonyl, fluorenyl-methoxycarbonyl, ethoxycarbonyl, trimethylsiloxyethoxycarbonyl or benzyloxycarbonyl, more preferably from tert-butyloxycarbonyl; r₁、R₁’、R₂、R₂’、R₃、R₃’、R₄、R₄’、R₅、R₅’、R₆、R₆’、R₇、R₇’、R₈、R₈’、R₉、R₉’、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄L, L ', p ', m ', r are as defined for compounds of formula (I).

As a further preferred embodiment, the acid-binding agent is an organic base or an inorganic base, the organic base is selected from trimethylamine, triethylamine, pyridine, piperidine, morpholine, diisopropylethylamine or a mixture thereof, and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof; the condensing agent is selected from DIC, DCC, HOBT, EDC & HCI, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or their mixture.

In another aspect, the present invention provides 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.

In another aspect, the present invention provides an application of the aforementioned compound, its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing HCV infection diseases.

Detailed Description

Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

“C_1-8Alkyl "refers to straight and branched alkyl groups comprising 1 to 8 carbon atoms, alkyl refers to a saturated aliphatic hydrocarbon group, C_0-8Means containing no carbon atoms or C_1-8Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutylN-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched isomers thereof, and the like.

Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C_3-8Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms," 5-10 membered cycloalkyl "refers to cycloalkyl groups comprising 5 to 10 carbon atoms, for example:

non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups that share a single carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-, di-or multi-spirocycloalkyl groups, non-limiting examples of which include:

"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in 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 has a fully conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, non-limiting examples of fused ring alkyl groups including:

"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:

。

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

Cycloalkyl groups may be optionally substituted or unsubstituted, when takenWhen substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer 0, 1, 2) but does not include the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. "5-10 membered heterocyclyl" refers to a cyclic group containing 5 to 10 ring atoms, and "3-8 membered heterocyclyl" refers to a cyclic group containing 3 to 8 ring atoms.

Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spirocycloalkyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group, or a multiple spiroheterocyclyl group according to the number of spiro atoms shared between rings. Non-limiting examples of spirocycloalkyl groups include:

"fused heterocyclyl" refers to polycyclic heterocyclic groups in which each ring in 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 of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, non-limiting examples of fused heterocyclic groups include:

"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which 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 heterocyclyl, non-limiting examples of which include:

the heterocyclic group may be optionally substituted or unsubstituted, and when substitutedThe substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and a "C" group_5-10Aryl "means an all-carbon aryl group having 5 to 10 carbons, and" 5-to 10-membered aryl "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 attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-to 10-membered heteroAryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, and S (O)_r(wherein r is an integer of 0, 1, 2), 5-7 membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 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, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, C_2-8Alkenyl means a straight or branched chain alkenyl group containing 2 to 8 carbons. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, C_2-8Alkynyl refers to straight or branched chain alkynyl groups containing 2-8 carbons. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like.

Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxyHeterocyclyl thio radical, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. C_1-8Alkoxy means an alkyloxy group having 1 to 8 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.

Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"Cycloalkoxy" refers to and-O- (unsubstituted cycloalkyl), wherein cycloalkyl is as defined above. C_3-8Cycloalkoxy means cycloalkyloxy containing 3-8 carbons, non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclobutyloxyHexyloxy, and the like.

Cycloalkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₁₂、-C_0-8-O-R₁₃、-C_0-8-C(O)R₁₄、-C_0-8-C(O)OR₁₃、-C_0-8-O-C(O)R₁₄、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

"halogen substituted C_1-8Alkyl "refers to a 1-8 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for hydrogen on the alkyl, such as difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen substituted C_1-8Alkoxy "a 1-8 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

"halogen" means fluorine, chlorine, bromine or iodine.

“C(O)R₁₀"means R₁₀A substituted carbonyl group.

"THF" refers to tetrahydrofuran.

The term "condensing agent" refers to an agent capable of causing a condensation reaction. Condensation is the reaction of two or more organic molecules interacting and covalently bonded to form a macromolecule, while losing water or other relatively simple small inorganic or organic molecules. The small molecule substance is usually water, hydrogen chloride, methanol or acetic acid. The abbreviations for the various condensing agents of the present invention correspond to the Chinese names shown in the following table:

for short	Name of Chinese
		DIC	N, N-diisopropylcarbodiimide
DCC	N, N-dicyclohexylcarbodiimide
		HOBT	1-hydroxybenzotriazoles
EDC·HCl	1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
		PyBOP	Benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphates
PyBroP	Tripyrrolidinobosphonium hexafluorophosphates
		HATU	2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
HCTU	6-chlorobenzotriazole-1, 1, 3, 3-tetramethylUrea hexafluorophosphate esters
		DEPBT	3- (diethoxyphosphoryloxy) -1, 2, 3-benzotriazin-4-one
EEDQ	2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline
		CDI	Carbonyl diimidazoles

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer using Dimethylsulfoxide (DMSO) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, and the solvent is a dry solvent, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L. The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The solutions in the examples are aqueous solutions unless otherwise specified. The reaction temperature was room temperature. The room temperature is the most suitable reaction temperature and is 20-30 ℃.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS) using the following developer systems: the volume ratio of dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, acetone and solvent can be regulated according to different polarities of the compounds. The system of eluent for column chromatography comprises: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, the volume ratio of the solvent is adjusted according to the different polarities of the compounds, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.

Preparation of the Compounds of examples

Example 1 dimethyl ((2S, 2 'S) - ((2S, 2' S) - ((((1, 4(1,4) -diphenylheterocyclic hexatomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (pyrrolidin-2, 1-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate

The first step is as follows: preparation of 4, 16-dibromo [2.2] p-cyclofin

Iron powder (1.2g) and bromine (20.7g) were added to dichloromethane (400mL) in this order, stirred for half an hour, a solution of [2.2] p-cyclofen (50g) in dichloromethane (100mL) was added dropwise, the mixture was heated under reflux for 2 hours, then a mixture of bromine (7g) and dichloromethane (100mL) was added dropwise over 3 hours, the reaction was continued under reflux for 3 hours, cooled to room temperature, and stirred overnight. The reaction solution was washed once with 5% sodium sulfite and water, respectively, dried, concentrated, and the residue was slurried with hot toluene, cooled, and filtered to give 4, 16-dibromo [2.2] p-cyclofin (33.7 g).

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)。

The second step is that: di-tert-butyl (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³-diylbis (4)1-phenylene)) dicarbamate

Under the protection of nitrogen, 4, 16-dibromo [2.2] is reacted]p-Cyclophene (4.5g, 12.15mmol), (4- ((tert-butoxycarbonyl) amino) phenyl) boronic acid (7.2g, 30.37mmol), cesium carbonate (10g, 30.38mmol), Pd (PPh)₃)₄(1.4g, 1.22mmol), followed by addition of N, N-dimethylformamide (113mL) and water (9mL) in this order, and reaction at 130 ℃ for 4 hours. Cooling to 25 deg.C, adding water (100mL) and dichloromethane (200mL), separating organic layer, sequentially washing with water and saturated sodium chloride aqueous solution, concentrating, and performing column chromatography to obtain di-tert-butyl (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) dicarbamate (3.2 g).

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)。

The third step: 4, 4' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Preparation of (di) diphenylamines

Under the protection of nitrogen, in the presence of di-tert-butyl (1, 4(1,4) -diphenyl heterocycle hexa-tomato-1²，4³To diylbis (4, 1-phenylene)) dicarbamate (3.2g, 5.42mmol) was added hydrogen chloride in dioxane (30mL) and methanol (10mL), and the reaction was stirred for 6 hours. Adding 10% sodium hydroxide aqueous solution to adjust reaction liquid to be alkaline, separating out a large amount of solid, filtering, and drying filter cake in vacuum to obtain 4, 4' - (1, 4(1,4) -diphenyl heterocycle hexa-tomato-1²，4³-diyl) diphenylamine (2 g).

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)。

The fourth step: tert-butyl (S) -2- ((4- (4)³- (4- ((R) -1- (tert-butoxycarbonyl) pyrrolidine-2-carbapimelamide) phenyl) -1, 4(1,4) -diphenylheterocyclic hexa-tomato-1²Preparation of (phenyl) carbamoyl) pyrrolidine-1-carboxylic acid esters

Under the protection of nitrogen, 4' - (1, 4(1,4) -diphenyl heterocycle hexa-tomato-1²，4³-diyl) diphenylamine (276mg, 0.71mmol), (tert-butoxycarbonyl) -L-proline (335mg, 1.56mmol), 1-hydroxybenzotriazole (210mg, 1.56mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (338mg, 1.77mmol) and N-methylmorpholine (358mg, 3.54mmol) were mixed, added to a mixture of N, N-dimethylformamide (7.5mL) and tetrahydrofuran (5mL), and the mixture was stirred at 25 ℃ for 20 hours. Adding 10% citric acid aqueous solution (20mL) and ethyl acetate (20mL), stirring, separating organic layer, washing with saturated sodium carbonate aqueous solution, concentrating, and performing column chromatography to obtain tert-butyl (S) -2- ((4- (4)³- (4- ((R) -1- (tert-Butoxycarbonyl) pyrrolidine-2-carbapimelamide) phenyl) -1, 4(1,4) -diphenylheterocyclic hexatomato-1²-yl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (348 mg).

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). The fifth step: (2S, 2 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Preparation of (E) -diylbis (4, 1-phenylene)) bis (pyrrolidine-2-carboxamide)

Under the protection of nitrogen, tert-butyl (S) -2- ((4- (4)³- (4- ((R) -1- (tert-Butoxycarbonyl) pyrrolidine-2-carbapimelamide) phenyl) -1, 4(1,4) -diphenylheterocyclic hexatomato-1²-yl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (348mg, 0.49mmol) was added dichloromethane (5mL), trifluoroacetic acid (2mL) and the reaction stirred at 25 ℃ for 20 h. Adding dichloromethane (45mL) for dilution, washing with water, saturated sodium bicarbonate, and common salt solution, drying, and concentrating to obtain (2S, 2 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (pyrrolidine-2-carboxamide) (316 mg).

LC-MS：585.36(M+H)⁺。

And a sixth step: dimethyl ((2S, 2 'S) - ((2S, 2' S) - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Preparation of (di) diylbis (4, 1-phenylene)) bis (azanediyl)) bis (carbonyl)) bis (pyrrolidin-2, 1-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate

Under the protection of nitrogen, (2S, 2 'S) -N, N' - (1, 4(1,4) -diphenyl heterocycle hexa-tomato-1)²，4³-Diylbis (4, 1-phenylene)) bis (pyrrolidine-2-carboxamide) (316mg, 0.54mmol), carboxy-L-valine (200mg, 1.14mmol), 1-hydroxybenzotriazole (161mg, 1.19mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (260mg, 1.36mmol), N-methylmorpholine (274mg, 2.71mmol) were mixed and N, N-dimethylcarbodiimide was addedDimethylformamide (10mL) was added, and the reaction was stirred at 25 ℃ for 16 hours. Ethyl acetate (30mL) was added, and the mixture was washed once with water (30mL) and 10% aqueous citric acid (20mL), concentrated, and the residue was purified by column chromatography to give dimethyl ((2S, 2 'S) - ((2S, 2' S) - ((1, 4(1,4) -diphenylheterocyclic hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (pyrrolidin-2, 1-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate (150 mg).

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)。

Example 2 dimethyl ((2S, 2 'S) - ((2S, 2' S, 3aS, 3a 'S, 7aS, 7 a' S) - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (octahydro-1H-indole-2, 1-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate

The first step is as follows: preparation of (2S, 3aS, 7aS) -1- (tert-butoxycarbonyl) octahydro-1H-indole-2-carboxylic acid

To a mixed solution of (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid (50g, 0.29mol) in THF (400mL) and water (200mL) at 0 ℃ was added dropwise a cooled aqueous 2.5M NaOH solution (200mL), stirred for 15 minutes, dibutyl dicarbonate (85.4g) was added dropwise at 0 ℃ and the reaction was stirred at room temperature for 12 hours. The reaction was stopped, washed 3 times with MTBE followed by acidification of the aqueous phase with 1M aqueous citric acid, extraction 3 times with ethyl acetate, combining the organic phases, drying over sodium sulfate and concentration to dryness to give preparation of (2S, 3aS, 7aS) -1- (tert-butoxycarbonyl) octahydro-1H-indole-2-carboxylic acid (74.9 g).

The second step is that: preparation of di-tert-butyl 2, 2 '- (((1, 4(1,4) -diphenylheterocyclic hexa-tomato-12, 43-diylbis (4, 1-phenylene)) bis (azanediyl)) bis (carbonyl)) (2S, 2' S, 3aS, 3a 'S, 7aS, 7 a' S) -bis (octahydro-1H-indole-1-carboxylic acid ester)

The compound 4, 4' - (1, 4(1,4) -diphenyl heterocycle hexa-tomato-1²，4³-Diyl) diphenylamine was used aS a starting material, and was condensed with the compound (2S, 3aS, 7aS) -1- (tert-butoxycarbonyl) octahydro-1H-indole-2-carboxylic acid at step 4 of reference example 1 to give the compound di-tert-butyl 2, 2' - (((1, 4(1,4) -diphenylheterocyclic hexatomato-1-ol-1-carboxylic acid)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) (2S, 2 ' S, 3aS, 3a ' S, 7aS, 7a ' S) -bis (octahydro-1H-indole-1-carboxylate).

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)。

The third step: (2S, 2 'S, 3aS, 3 a' S, 7aS, 7a 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexatomato-1²，4³Preparation of (di) diylbis (4, 1-phenylene)) bis (octahydro-1H-indole-2-carboxamide)

Under the protection of nitrogen, di-tert-butyl 2, 2' - (((1, 4(1,4) -diphenyl heterocycle hexa-tomato-1)²，4³-diylbis (4, 1-phenylene)) bis (azanediyl)) bis (carbonyl) (2S, 2 ' S, 3aS, 3a ' S, 7aS, 7a ' S) -bis (octahydro-1H-indole-1-carboxylate) (700mg, 0.78mmol) was dissolved in hydrogen chloride in dioxane (5mL) and stirred at 25 ℃ for 20 hours, then 2M aqueous sodium hydroxide was added dropwise to alkalinity, solids precipitated, filtered, and the filter cake was dried under vacuum to give (2S, 2 ' S, 3aS, 3a ' S, 7aS, 7a ' S) -N, N ' - (1, 4(1,4) -diphenylheterocyclic hexatomato-1²，4³Diylbis (4, 1-phenylene)) bis (octahydro-1H-indole-2-carboxamide) (460 mg).

LC-MS：693.45(M+H)⁺。

The fourth step: dimethyl ((2S, 2 'S) - ((2S, 2' S, 3aS, 3a 'S, 7aS, 7 a' S) - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Preparation of (di) diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (octahydro-1H-indole-2, 1-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate

Reference example 1, step 6 gave the compound dimethyl ((2S, 2 'S) - ((2S, 2' S, 3aS, 3a 'S, 7aS, 7 a' S) - ((1, 4(1,4) -diphenylheterocyclic hexatomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (octahydro-1H-indole-2, 1-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate.

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)。

Example 3 methyl ((2S, 2 ' S, 3R, 3 ' R) - ((2S, 2 ' S, 3aS, 3a ' S, 7aS, 7a ' S) - (((1, 4(1,4) -diphenylheterocyclic hexakis-tomato-1-yl)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (octahydro-1H-indole-2, 1-diyl)) bis (3-methoxy-1-carbonylbutane-1, 2-diyl)) dicarbamate

The first step is as follows: preparation of N-methoxycarbonyl-O-methyl-L-threonine

O-methyl-L-threonine (5.0g, 37.6mmol) was dissolved in a mixture of 1, 4-dioxane (20mL) and THF (20mL), cooled to 0 deg.C, and an aqueous NaOH (4.5g NaOH in 56mL water) solution was added dropwise, followed by addition of methyl chloroformate (4.3g), warmed to room temperature and stirred for 7 h. Acidification with 3N hydrochloric acid followed by extraction with ethyl acetate (60mL) three times, combined organic phases, dried over sodium sulfate, filtered, and concentrated to give N-methoxycarbonyl-O-methyl-L-threonine (5.3 g).

LC-MS：192.1(M+H)⁺。

The second step is that: methyl ((2S, 2 ' S, 3R, 3 ' R) - ((2S, 2 ' S, 3aS, 3a ' S, 7aS, 7a ' S) - ((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Preparation of (di) diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (octahydro-1H-indole-2, 1-diyl)) bis (3-methoxy-1-carbonylbutane-1, 2-diyl)) dicarbamate

With di-tert-butyl 2, 2' - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Starting from diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) (2S, 2 'S, 3aS, 3 a' S, 7aS, 7a 'S) -bis (octahydro-1H-indole-1-carboxylate), reference example 1, step 6, gave methyl ((2S, 2' S, 3R, 3 'R) - ((2S, 2' S, 3aS, 3a 'S, 7aS, 7 a' S) - (((1, 4(1,4) -diphenylheterocyclic hexatomato-1-carboxylate)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (octahydro-1H-indole-2, 1-diyl)) bis (3-methoxy-1-carbonylbutane-1, 2-diyl)) dicarbamate.

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)。

Example 4 dimethyl ((2S, 2 'S) - ((6S, 6' S) - (((1, 4(1,4) -diphenylheterocyclic hexatomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (5-azaspiro [ 2.4%]Heptane-6, 5-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate

The first step is as follows: di-tert-butyl 6, 6' - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-)1²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl) bis (carbonyl)) (6S, 6' S) -bis (5-azaspiro [2.4 ]]Heptane-5-carboxylic acid ester) preparation

Reference example 1 step 4, 4, 4' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³-diyl) diphenylamine and (S) -5- (tert-butoxycarbonyl) -5-azaspiro [2.4]Condensation of heptane-6-carboxylic acid to give di-tert-butyl 6, 6' - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl) bis (carbonyl)) (6S, 6' S) -bis (5-azaspiro [2.4 ]]Heptane-5-carboxylic acid ester).

LC-MS：637.30(M-2Boc+H)⁺。

The second step is that: (6S, 6 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (5-azaspiro [ 2.4%]Heptane-6-carboxamide) preparation

Reference example 1, step 5, di-tert-butyl 6, 6' - (((1, 4(1,4) -diphenylheterocycle hexatomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl) bis (carbonyl)) (6S, 6' S) -bis (5-azaspiro [2.4 ]]Heptane-5-carboxylic acid ester) to obtain (6S, 6 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (5-azaspiro [ 2.4%]Heptane-6-carboxamide).

LC-MS：637.30(M+H)⁺。

The third step: dimethyl ((2S, 2 'S) - ((6S, 6' S) - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (5-azaspiro [ 2.4%]Heptane-6, 5-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate preparationPrepare for

Reference example 1 step 6, (6S, 6 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (5-azaspiro [ 2.4%]Heptane-6-carboxamide condensation to give dimethyl ((2S, 2 'S) - ((6S, 6' S) - ((((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (5-azaspiro [ 2.4%]Heptane-6, 5-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate.

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)。

Example 5 dimethyl ((2S, 2 ' S, 3R, 3 ' R) - ((6S, 6 ' S) - ((((1, 4(1,4) -diphenylheterocycle hexatomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (5-azaspiro [ 2.4%]Heptane-6, 5-diyl)) bis (3-methoxy-1-carbonylbutane-1, 2-diyl)) dicarbamate

Reference example 1 step 6, (6S, 6 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (5-azaspiro [ 2.4%]Heptane-6-carboxamide) and N-methoxycarbonyl-O-methyl-L-Condensation of threonine gives dimethyl ((2S, 2 ' S, 3R, 3 ' R) - ((6S, 6 ' S) - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (5-azaspiro [ 2.4%]Heptane-6, 5-diyl)) bis (3-methoxy-1-carbonylbutane-1, 2-diyl)) dicarbamate.

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)。

Example 6 dimethyl ((2S, 2 'S) - ((1R, 1' R, 3S, 3 'S, 4S, 4' S) - (((1, 4(1,4) -diphenylheterocyclohexagon-12, 43-diylbis (4, 1-phenylene)) bis (azanediyl)) bis (carbonyl)) bis (2-azabicyclo [2.2.1] heptane-3, 2-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate

The first step is as follows: di-tert-butyl 3, 3' - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) (1R, 1 ' R, 3S, 3 ' S, 4S, 4 ' S) -bis (2-azabicyclo [2.2.1]Heptane-2-carboxylic acid ester) preparation

Reference example 1 step 4, 4, 4' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Di-yl) diphenylamine and (1R, 3S, 4S) -2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1]Condensation of heptane-3-carboxylic acid to give di-tert-butyl 3, 3' - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) (1R, 1 ' R, 3S, 3 ' S, 4S, 4 ' S) -bis (2-azabicyclo [2.2.1]Heptane-2-carboxylate).

LC-MS：637.30(M-2Boc+H)⁺。

The second step is that: (1R, 1 'R, 3S, 3' S, 4S, 4 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (2-azabicyclo [ 2.2.1)]Heptane-3-carboxamide) preparation

Reference example 1 step 5, di-tert-butyl 3, 3' - (((1, 4(1,4) -diphenylheterocycle hexatomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) (1R, 1 ' R, 3S, 3 ' S, 4S, 4 ' S) -bis (2-azabicyclo [2.2.1]Heptane-2-carboxylate) to give (1R, 1 'R, 3S, 3' S, 4S, 4 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (2-azabicyclo [ 2.2.1)]Heptane-3-carboxamide).

LC-MS：637.30(M+H)⁺。

The third step: dimethyl ((2S, 2 'S) - ((1R, 1' R, 3S, 3 'S, 4S, 4' S) - ((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (2-azabicyclo [2.2.1]Heptane-3, 2-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate preparation

Reference example 1, step 6, (1R, 1 'R, 3S, 3' S, 4S,4 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexa-tomato-1²，4³Diylbis (4, 1-phenylene)) bis (2-azabicyclo [ 2.2.1)]Heptane-3-carboxamide condensation to give dimethyl ((2S, 2 'S) - ((1R, 1' R, 3S, 3 'S, 4S, 4' S) - (((1, 4(1,4) -diphenylheterocycle hexa-tomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (2-azabicyclo [2.2.1]Heptane-3, 2-diyl)) bis (3-methyl-1-carbonylbutane-1, 2-diyl)) dicarbamate.

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)。

Example 7 dimethyl ((2S, 2 ' S, 3R, 3 ' R) - ((1R, 1 ' R, 3S, 3 ' S, 4S, 4 ' S) - (((1, 4(1,4) -diphenylheterocyclic hexatomato-1)²，4³Diylbis (4, 1-phenylene)) bis (azaalkanediyl)) bis (carbonyl)) bis (2-azabicyclo [2.2.1]Heptane-3, 2-diyl)) bis (3-methoxy-1-carbonylbutane-1, 2-diyl)) dicarbamate

Reference example 1, step 6, (1R, 1 'R, 3S, 3' S, 4S, 4 'S) -N, N' - (1, 4(1,4) -diphenylheterocycle hexatomato-1²，4³Diylbis (4, 1-phenylene)) bis (2-azabicyclo [ 2.2.1)]Condensation of heptane-3-carboxamide with N-methoxycarbonyl-O-methyl-L-threonine affords dimethyl ((2S, 2 ' S, 3R, 3 ' R) - ((1R, 1 ' R, 3S, 3 ' S, 4S, 4 ' S) - ((1, 4(1,4) -diphenylheterocyclic hexa-tomato-1-ol)²，4³Diylbis (4, 1-phenylene)) bis (nitrogenAlkanediyl)) bis (carbonyl)) bis (2-azabicyclo [2.2.1]Heptane-3, 2-diyl)) bis (3-methoxy-1-carbonylbutane-1, 2-diyl)) dicarbamate.

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)。

Biological evaluation

(determination of inhibitory Activity of wild type hepatitis C Virus HCV Gene 1 b)

The inhibitory activity of the compound of the present invention against HCV replication was measured by the HCV Replicon Luciferase Reporter Assay (HCV Reporter Luciferase Assay).

1. Cell model for experiments: an HCV replicon luciferase reporter gene-stabilized Huh-7 cell line.

2. The preparation method of the experimental solution comprises the following steps:

a stock solution of a test compound is prepared to be 10mM by using dimethyl sulfoxide, and is diluted to the highest concentration of the test by using DMSO during the test, and then is subjected to 3-fold serial dilution by using a culture medium, and the dilution is generally carried out to be 8 to 10 concentration points, and each concentration point is provided with double wells. The final concentration of dimethyl sulfoxide was 0.5%. Each experiment contained an internal reference compound, 1 was a reference compound (ACH-3102) and the other 1 was Cyclosporine.

3. The experimental determination steps are as follows:

1) cells were grown in 96-well culture plates, and different concentrations of test compound and reference compound were added to the cultured cells 24 hours later.

2) After 48 hours, luciferase activity was detected with a microplate reader.

3) The raw data were analyzed and the percent inhibition of luciferase activity, i.e., HCV replicon, by different concentrations of the test compound was calculated.

4) Nonlinear fitting analysis is carried out on the inhibition percentage data by adopting GraphPad Prism software to obtain the half inhibition concentration IC of the compound₅₀The value is obtained.

Activity of the Compounds of examples of the present invention and the reference Compound (ACH-3102) was determined by the above assay, and the wild-type hepatitis C Virus HCV Gene 1b inhibitory Activity IC₅₀The value results are shown in table 1:

example numbering	IC₅₀(nM)
		Example 1	0.011
Example 2	0.0064
		Example 3	0.0023
Example 4	0.0037
		Example 5	0.002
Example 7	0.050
		Reference Compound ACH-3102	0.0190

Claims

1. A compound having the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

optionally further substituted by one or more groups selected from halogen, hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy, halogen substituted C_1-8Alkoxy, hydroxy substituted C_1-8Alkoxy radical, C_3-8Cycloalkyl or C_3-8Cycloalkoxy is substituted by a substituent;

l, L' are each independently selected from the following structures:

optionally further substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

R₆、R₆' independently of each other are selected from hydrogen, deuterium, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl, halo C_1-8Alkyl radical, C_1-8Alkoxy C_1-8Alkyl, hydroxy C_1-8Alkyl, -C (O) R₁₄OR-C (O) OR₁₃，

Optionally further substituted by one or more groups selected from halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s);

R₇、R₇' independently of each other are selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃，

Or, R₇Or R₇' together with the tetrahydropyrrole ring to which it is attached form a 6-to 10-membered nitrogen-containing spiro, bridged or fused ring,

R₈、R₈' independently of each other are selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃，

Optionally further substituted by one or more groups selected from halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃；

R₉、R₉' independently of each other are selected from hydrogen, deuterium, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl or-C (O) NR₆R₇，

R₁₀、R₁₁each independently selected from hydrogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroaryl or C_1-8An alkyl acyl group which is a substituent of a heterocyclic group,

optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, acetamido, azido, methylsulfonyl, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_1-8Alkoxy radical, C_1-8Alkoxycarbonyl, C_1-8Alkylcarbonyl group, C_1-8Alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C_1-8Alkylamino or di-C_1-8Substituted with a substituent of alkylamino;

m and m' are respectively and independently selected from 0-3;

p and p' are respectively and independently selected from 0-7;

r is 0, 1 or 2.

2. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1Characterized in that R is₆、R₆' independently of each other are selected from hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy C_1-4Alkyl, hydroxy C_1-4Alkyl, -C (O) R₁₄OR-C (O) OR₁₃，

Optionally further substituted by one or more groups selected from halogen, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s).

3. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 2, wherein R is₆、R₆' are each independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, methoxy, ethoxy or isopropoxy.

4. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 2, wherein R is₆、R₆' each is independently selected from hydrogen.

5. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₁、R₁' independently of each other are selected from hydrogen, deuterium, halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6A cycloalkyl group.

6. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₁、R₁' are each independently selected from hydrogen, deuterium, fluoro, hydroxy, amino, methyl, ethyl or cyclopropyl.

7. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₂、R₂’、R₃、R₃’、R₄、R₄’、R₅、R₅' independently of each other are selected from hydrogen, deuterium, halogen, hydroxy, amino, C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Alkoxy or C_3-8A cycloalkoxy group.

8. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₂、R₂’、R₃、R₃’、R₄、R₄’、R₅、R₅' are each independently selected from hydrogen, deuterium, fluoro, chloro, methyl, ethyl, hydroxy, amino, methoxy or cyclopropyl.

9. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein L, L' are each independently selected from the following structures:

optionally further substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-8 membered heterocyclylthioBase, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃Substituted with the substituent(s).

10. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein L, L' are each independently selected from the following structures:

11. the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, according to claim 1,

R₇、R₇' independently of each other are selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C_5-8Aryl radical, C_5-8Aryloxy radical, C_5-8Arylthio, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, 5-8 membered heteroarylthio, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃，

12. the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to claim 1, selected from the compounds of formula (ii) as follows:

R₇、R₇’、R₈、R₈’、R₉、R₉' as defined in claim 1.

13. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₇、R₇' each independently is selected from hydrogen, deuterium, fluoro, methyl, ethyl or isopropyl, or, R₇Or R₇' together with the tetrahydropyrrole ring to which it is attached form the following structure:

14. the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₈、R₈' independently of each other are selected from hydrogen, deuterium, halogen, methyl, ethyl, isopropyl, cyclopropyl, -S (O)_rR₁₂、-O-R₁₃、-C(O)R₁₄、-C(O)OR₁₃、-O-C(O)R₁₄、-NR₁₀R₁₁、-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₁₄or-N (R)₁₀)-C(O)OR₁₃。

15. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₉、R₉' independently of each other are selected from hydrogen, deuterium, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl or phenyl.

16. A compound having formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, which is selected from the following compounds:

17. a process for the preparation of a compound having formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, comprising the steps of:

wherein: pg is an amino protecting group selected from t-butyloxycarbonyl, allylcarbonyl, fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsiloxyethylcarbonyl or benzyloxycarbonyl; r₁、R₁’、R₂、R₂’、R₃、R₃’、R₄、R₄’、R₅、R₅’、R₆、R₆’、R₇、R₇’、R₈、R₈’、R₉、R₉’、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄L, L ', p ', m ', r are as defined in claim 1.

18. A process according to claim 17, wherein Pg is selected from t-butyloxycarbonyl.

19. The preparation method according to claim 17 or 18, wherein the acid-binding agent is an organic base selected from trimethylamine, triethylamine, pyridine, piperidine, morpholine, diisopropylethylamine or a mixture thereof, or an inorganic base selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof; the condensing agent is selected from DIC, DCC, HOBT, EDC & HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or their mixture.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, and a pharmaceutically acceptable carrier.

21. Use of a compound having formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for the treatment or prevention of an HCV infection disease.