WO2017076187A1 - 1,4(1,4)-diphenylhexacyclophane-12,43-diyl derivative, and preparation method therefor and application thereof - Google Patents

Abstract

Provided are a 1,4(1,4)-diphenylhexacyclophane-1²,4³-diyl derivative, and a preparation method therefor and application thereof. The series of compounds can inhibit the activity of HCV, can be applied to development of medicines for treating diseases related to hepatitis c virus (HCV) infection, and have a broad application prospect. See formula (I).

Description

1,4(1,4)-diphenylheterocyclohexan-12,43-diyl derivative, preparation method and application thereof Technical field

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.

Background technique

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. Since the HCV genome is similar in structure and phenotype to human flavivirus and prion, it is classified as Flaviviridae HCV. 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, and 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. a precursor of a polyprotein that can be cleaved into 10 viral proteins by host cell and viral autoprotease, including three structural proteins, a nucleocapsid protein (or core protein, Core) with a molecular weight of 19 kD and Two glycoproteins (E1 protein with a molecular weight of 33 kD and E2 protein with a molecular weight of 72 Kd), p7 encodes a membrane-intrinsic protein, which may function as an ion channel. 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. In addition, 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.

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. Among the HCV-encoding genes, the C region is the most conserved, non-structural (NS) region, and the capsular membrane protein E2/NS1 has the highest variability called the hypervariable region. The researchers divided the HCV viruses into different genotypes based on the sequence similarity of the HCV genome. Each genotype can be further divided into different subtypes. So far, at least 24 genotypes of 24 genotypes have been found. 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.

Hepatitis C virus (HCV) has severely jeopardized 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's population). The HCV virus is mainly transmitted through body fluids, and so far there is no vaccine against HCV infection. According to the World Health Organization, there are more than 200 million infected individuals worldwide, and at least 3 to 4 million people are infected each year. Once infected, approximately 20% of people can clear the virus, but the rest become HCV carriers. HCV patients are a large group, with an estimated 3% of the global population of about 170 million HCV patients. HCV patients in the United States account for 1.4% of the population, about 3-4 million people. China lacks authoritative epidemiological data on HCV patients. The most conservative estimate is 0.42% of the population. Some reports suggest that Chinese HCV patients have a population of 3.8%. According to these figures, Chinese HCV patients should be between 6 million and 3 thousand. Between 8 million. In HCV patients, 10% to 20% of chronically infected individuals eventually develop liver-destructive sclerosis or cancer.

For a long time and even in many developing countries, whether it is acute hepatitis C or chronic hepatitis C, the standard treatment regimen is peginterferon (α-2a or α-2b) combined with Liba. Welline. There are many problems with the treatment of peginterferon (α-2a or α-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. Currently, the development trend of HCV treatment in the world is that DAA combination of interferon and ribavirin is not required. Medication. The main DAA drugs are NS5B inhibitors, NS5A inhibitors, and NS3/4A inhibitors. Compared with interferon combined with ribavirin, 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).

The first successful DAA drugs were 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. Compared to NS3/4A and NS5B inhibitors, NS5A inhibitors can reduce viral load in patients faster and more. In addition, ACH-3102 and GS-5816 are still active on many Daclatasvir and Ledipasvir resistant mutations.

Summary of the invention

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.

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

among them:

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,

Optionally further substituted by one or more selected from the group consisting of halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, halo substituted C _1-8 alkoxy, hydroxy substituted C _1-8 alkoxy, C Substituted by a substituent of _1-8 cycloalkyl or C _1-8 cycloalkoxy;

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,

Optionally further one or more selected from the group consisting of 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:

Optionally further one or more selected from the group consisting of halogen, hydroxy, 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 , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR Substituted by a substituent of ₁₃ ;

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 ,

Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent;

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 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C( O) OR ₁₃ ,

Alternatively, R ₇ or R ₇ ' together with its attached tetrahydropyrrole ring form a 6-10 membered nitrogen-containing spiro, bridge or fused ring,

Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent;

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 , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C( O) OR ₁₃ ,

Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ ;

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 ,

Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent;

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,

Optionally further one or more selected from the group consisting of 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;

m, m' are each independently selected from 0 to 3;

p, p' are each independently selected from 0 to 7;

r is 0, 1, or 2.

Preferably, 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, C _1-4 alkyl, and C _1-4 alkane. Oxyl, C _3-6 cycloalkyl, halo C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, -C(O)R ₁₄ or - C(O)OR ₁₃ ,

Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent.

As a further preferred embodiment, 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.

As a further preferred embodiment, the compound, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, 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.

And a pharmaceutically acceptable salt thereof, R ₂ , R ₂ ', R ₃ , R ₃ ', R ₄ , R ₄ ', R ₅ , R ₅ 'Separately selected from hydrogen, hydrazine, halogen, hydroxy, amino, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy or C _3-8 cycloalkoxy, more preferably Hydrogen, hydrazine, fluorine, chlorine, methyl, ethyl, hydroxy, amino, methoxy or cyclopropyl.

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

Optionally further one or more selected from the group consisting of 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)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR Substituted by a substituent of ₁₃ ;

More preferably, the following structure:

A further preferred embodiment, the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that

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 , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C( O) OR ₁₃ ,

Alternatively, 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:

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

Wherein R ₇ , R ₇ ', R ₈ , R ₈ ', R ₉ and R ₉ ' are as defined in claim 1.

As a still further preferred embodiment, 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 base or isopropyl group, or R ₇ or R ₇ ' together with the tetrahydropyrrole ring to which it is attached, forms the following structure:

As a still further preferred embodiment, 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. Base, isopropyl, cyclopropyl, -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 , -N (R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ .

As a still further preferred embodiment, 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.

As a most preferred embodiment, 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:

Wherein: 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.

As a still further preferred embodiment, 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 comprising a therapeutically effective amount of the aforementioned compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

According to another aspect of the present invention, there is provided a use of the aforementioned compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for the preparation of a medicament for treating or preventing a disease of HCV infection.

detailed description

DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"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-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-di Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branches thereof Isomers, etc.

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(O)OR ₁₃ , -C _0-8 -OC(O)R ₁₄ , -C _0-8 -NR ₁₀ R ₁₁ , -C _0-8 Substituted with a substituent of -C(O)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ ;

"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 π-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. , 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 Oxyl, 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 Substituting a substituent of -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ ;

"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, and 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. Depending on the number of constituent rings, 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. , 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 Oxyl, 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 Substituting a substituent of -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ ;

"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 π-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, and "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. When substituted, 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 , -C _0-8 -OC(O)R ₁₄ , -C _0-8 -NR ₁₀ R ₁₁ , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N Substituted by a substituent of (R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-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, and 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. , 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 Oxyl, 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 Substituting a substituent of -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ ;

"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. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

Alkenyl group may be substituted or unsubstituted. When substituted, 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 , -C _0-8 -OC(O)R ₁₄ , -C _0-8 -NR ₁₀ R ₁₁ , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N Substituted by a substituent of (R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-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, and _C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons. . For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

Alkynyl group may be substituted or unsubstituted. When substituted, 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 , -C _0-8 -OC(O)R ₁₄ , -C _0-8 -NR ₁₀ R ₁₁ , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N Substituted by a substituent of (R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-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 , -C _0-8 -OC(O)R ₁₄ , -C _0-8 -NR ₁₀ R ₁₁ , -C _0-8 -C(O)NR ₁₀ R _{11, -N (R 10) -C} (O) R 14 or _{-N (R 10) -C (O} ) oR _13, substituted with a substituent;

"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. , 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 Oxyl, 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 Substituting a substituent of -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ ;

"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. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"Halogen" means fluoro, chloro, bromo or iodo.

"C(O)R ₁₀ "" means an R ₁₀ substituted carbonyl group.

"THF" refers to tetrahydrofuran.

The term "condensing 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. The Chinese names corresponding to the abbreviations of the various condensing agents in the present invention are as follows:

Abbreviation Chinese name DIC N,N-diisopropylcarbodiimide DCC N,N-dicyclohexylcarbodiimide HOBT 1-hydroxybenzotriazole EDC·HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride PyBOP Benzotriazole-1-yl-oxytripyrrolidinyl hexafluorophosphate PyBroP Tripyrrolidinyl bromide hexafluorophosphate HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate DEPBT 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-one EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline CDI Carbonyldiimidazole

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "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 present invention is further described in detail with reference to the accompanying drawings, but by no way of limitation,

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) 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).

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.

Starting materials in the examples of the invention are known and commercially available or can be synthesized or synthesized according to methods known in the art.

Unless otherwise stated, all reactions of the present invention were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, and the solvent was a dry solvent.

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.

Monitoring of the progress of the reaction in the examples using the thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS) reaction using the developer system: dichloromethane and methanol system, n-hexane and ethyl acetate system The volume ratio of the petroleum ether and ethyl acetate systems, acetone, and solvent can be adjusted depending on the polarity of the compound. 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 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.

Preparation of example compounds

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

First step: Preparation of 4,16-dibromo[2.2]-p-cyclophene

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. The 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).

_{^{1 H NMR (400MHz, CDCl 3}} ) 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: di-tert-butyl (1,4(1,4)-diphenyl heterocyclohexan-1 ² ,4 ³ -diylbis(4,1-phenylene))dicarbamic acid ester

4,16-dibromo[2.2]-p-cyclophene (4.5 g, 12.15 mmol), (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (7.2 g, 30.37 mmol) under N2. The mixture was mixed with hydrazine carbonate (10 g, 30.38 mmol) and Pd(PPh ₃ ) ₄ (1.4 g, 1.22 mmol), and then N,N-dimethylformamide (113 mL) and water (9 mL) were added thereto, and the mixture was heated to 130 ° C. 4 hours. The temperature was lowered to 25 ° C, water (100 mL) and dichloromethane (200 mL) were added, and the organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride, concentrated, and the residue was subjected to column chromatography to give di-tert-butyl ( 1,4 (1,4) - diphenyl heterocyclic six Fan ^-12, 4 ³ - diyl (4,1-phenylene)) dicarbamate (3.2g).

^{1 H NMR (400MHz, DMSO-} d 6) δ9.45 (s, 2H), 7.58 (d, J = 8.4Hz, 4H), 7.41 (d, J = 8.4Hz, 4H), 6.72 (d, J = 7.6 Hz, 2H), 6.60 (s, 2H), 6.42 (d, J = 7.6 Hz, 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: preparation of 4,4'-(1,4(1,4)-diphenyl heterocyclohexan-1 ² ,4 ³ -diyl)diphenylamine

Under the protection of nitrogen, 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).

LC-MS: 391.26 (M+H) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.17 (d, J = 8.4 Hz, 4H), 6.68 (d, J = 8.4 Hz, 4H), 6.61 (d, J = 7.6 Hz, 2H), 6.51 (s, 2H), 6.38 (d, J = 7.6 Hz, 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).

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)

4,4'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyl)diphenylamine (276 mg, 0.71 mmol), (t-butoxy) under nitrogen Carbonyl)-L-proline (335 mg, 1.56 mmol), 1-hydroxybenzotriazole (210 mg, 1.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide The hydrochloride salt (338 mg, 1.77 mmol) and N-methylmorpholine (358 mg, 3.54 mmol) were mixed and added to a mixture of N,N-dimethylformamide (7.5 mL) and tetrahydrofuran (5 mL), 25 The reaction was stirred at ° C for 20 hours. A mixture of a 10% aqueous citric acid solution (20 mL) and ethyl acetate (20 mL) was added, and the organic layer was evaporated, evaporated, evaporated, evaporated 2-((4-(4 ⁾ -(4-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-carbamoylamino)phenyl)-1,4(1,4) )-Diphenylheterocyclohexan-1 ² -yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate (348 mg).

LC-MS: 685.3 (M-Boc+H) ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ10.1 (s, 2H), 7.73 (d, J = 7.6Hz, 4H), 7.48 (d, J = 8.0Hz, 4H), 6.75 (d, J = 7.2 Hz, 2H), 6.64 (s, 2H), 6.44 (d, J = 7.6 Hz, 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) ).

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)

tert-Butyl(S)-2-((4-(4 ³ -(4-((R)-1-(tert-butoxycarbonyl))pyrrolidine-2-carbamoyl) amino) phenyl) -1,4 (1,4) - diphenyl heterocyclic six Fan ^-12---yl) phenyl) carbamoyl) pyrrolidine-l-carboxylate (348mg, 0.49mmol) was added Dichloromethane (5 mL) and trifluoroacetic acid (2 mL) were stirred at 25 ° C for 20 hours. Diluted with dichloromethane (45 mL), washed once with water, saturated sodium bicarbonate and brine, dried and concentrated to give (2S,2'S)-N,N'-(1,4(1,4)-diphenyl Heterocyclic Liufan-1 ² ,4 ³ -diylbis(4,1-phenylene))bis(pyrrolidine-2-carboxamide) (316 mg).

LC-MS: 585.36 (M+H) ⁺ .

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

(2S,2'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyldi(4,1-phenylene) under nitrogen protection )) bis(pyrrolidine-2-carboxamide) (316 mg, 0.54 mmol), carboxy-L-valine (200 mg, 1.14 mmol), 1-hydroxybenzotriazole (161 mg, 1.19 mmol), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260 mg, 1.36 mmol), N-methylmorpholine (274 mg, 2.71 mmol), N,N-dimethylmethyl The amide (10 mL) was stirred at 25 ° C for 16 hours. Ethyl acetate (30 mL) was added, and each was washed with water (30 mL) and 10% aqueous citric acid (20 mL), and concentrated and purified by column chromatography to give dimethyl ((2S, 2'S)-((2S, 2'S) )-((1,4(1,4)-diphenylheterocyclohexan-1 ² ,4 ³ -diylbis(4,1-phenylene)) bis(azanediyl))di Carbonyl)) bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-carbonylbutane-1,2-diyl))dicarbamate (150 mg).

LC-MS: 899.40 (M+H) ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) 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 = 8.0 Hz, 2H), 6.62 (s, 2H), 6.50 (d, J = 7.6 Hz, 2H), 4.52-4.48 (m, 2H), 4.06 (t, J = 8.4) Hz, 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, 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

First step: Preparation of (2S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid

Add dropwise 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 °C A 2.5 M aqueous NaOH solution (200 mL) was stirred for 15 minutes, and dibutyl dicarbonate (85.4 g) was added dropwise at 0 ° C, and the reaction was stirred at room temperature for 12 hours. The reaction was stopped, washed three times with MTBE, the aqueous phase was acidified with 1M aqueous citric acid, and extracted with ethyl acetate three times. The organic phase was combined, dried over sodium sulfate, and concentrated to dryness (2S,3aS,7aS)-1-( Preparation of butoxycarbonyl) octahydro-1H-indole-2-carboxylic acid (74.9 g).

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)

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).

LC-MS: 685.3 (M-Boc+H) ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) 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 = 7.6 Hz, 2H), 4.28 (t, J = 8.8 Hz, 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, 3a'S, 7aS, 7a'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyl 2 ( Preparation of 4,1-phenylene))bis(octahydro-1H-indole-2-carboxamide)

Di-tert-butyl 2,2'-((1,4(1,4)-diphenyl heterocyclohexan-1 ² ,4 ³ -diyldi(4,1- sub) under nitrogen protection Phenyl)) bis(azanediyl))bis(carbonyl))(2S,2'S,3aS,3a'S,7aS,7a'S)-bis(octahydro-1H-indole-1-carboxylate) (700 mg, 0.78 mmol) dissolved in hydrogen chloride in dioxane solution (5 mL), stirred at 25 ° C for 20 hours, then added dropwise 2M aqueous sodium hydroxide solution to alkaline, precipitated solid, filtered, and dried under vacuum. 2S,2'S,3aS,3a'S,7aS,7a'S)-N,N'-(1,4(1,4)-diphenylheterocyclohexan-1 ² ,4 ³ -diyldi(4,1-Asia Phenyl)) 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, 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 Preparation of 3-methyl-1-carbonylbutane-1,2-diyl))dicarbamate

Referring to Step 6 of Example 1, the compound dimethyl ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-((1,4(1,4)-diphenyl heterocycle) was obtained. Fan-1 ² ,4 ³ -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))di(octahydro-1H-indole-2,1-diyl) )) bis(3-methyl-1-carbonylbutane-1,2-diyl)) dicarbamate.

LC-MS: 1007.25 (M+H) ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ10.18 (s, 2H), 7.75 (d, J = 7.6Hz, 4H), 7.53 (d, J = 8.0Hz, 2H), 7.48 (d, J = 8.4 Hz, 4H), 6.75 (d, J = 8.0 Hz 2H), 6.63 (s, 2H), 6.46 (d, J = 8.0 Hz 2H), 4.48 (t, J = 9.2 Hz 2H), 4.37 - 4.32 ( m, 2H), 3.85 (t, J = 8.8 Hz, 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)-diphenylheterocyclohexane) Fan-1 ² ,4 ³ -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))di(octahydro-1H-indole-2,1-diyl) )) bis(3-methoxy-1-carbonylbutane-1,2-diyl))dicarbamate

First step: Preparation of N-methoxycarbonyl-O-methyl-L-threonine

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)EtOAcEtOAcEtOAcEtOAc.

LC-MS: 192.1 (M+H) ⁺ .

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 Preparation of bis(3-methoxy-1-carbonylbutane-1,2-diyl))dicarbamate

Di-tert-butyl 2,2'-((1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diylbis(4,1-phenylene)) Bis(azanediyl))bis(carbonyl))(2S,2'S,3aS,3a'S,7aS,7a'S)-bis(octahydro-1H-indole-1-carboxylate) as starting material, reference example 1 Step 6, to give 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 Base)) bis(3-methoxy-1-carbonylbutane-1,2-diyl))dicarbamate.

LC-MS: 1039.40 (M+H) ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ10.18 (s, 2H), 7.75 (d, J = 8.0Hz, 4H), 7.62 (d, J = 7.6Hz, 2H), 7.48 (d, J = 8.4 Hz, 4H), 6.75 (d, J = 8.0 Hz, 2H), 6.63 (s, 2H), 6.46 (d, J = 7.6 Hz, 2H), 4.47 (t, J = 8.8 Hz, 2H), 4.38 -4.35 (m, 2H), 4.11 (t, J = 8.4 Hz, 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)-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

First step: di-tert-butyl 6,6'-((1,4(1,4)-diphenyl heterocyclohexan-1 ² ,4 ³ -diyldi(4,1-phenylene) Preparation of bis(azanediyl))bis(carbonyl))(6S,6'S)-bis(5-azaspiro[2.4]heptane-5-carboxylate)

Reference Example Example 1, Step 4,4,4 '- (1,4 (1,4) - diphenyl heterocyclic six Fan ^-12, 4 ³ - diyl) dianiline and (S) -5- (tert - Condensation of butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid to give di-tert-butyl 6,6'-((1,4(1,4)-diphenyl heterocycle Liufan-1 ² ,4 ³ -diylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))(6S,6'S)-bis(5-azaspiro[2.4 ]heptane-5-carboxylate).

LC-MS: 637.30 (M-2 Bos+H) ⁺ .

The second step: (6S,6'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyldi(4,1-phenylene) Preparation of bis(5-azaspiro[2.4]heptane-6-carboxamide)

Reference Example 1, Step 5, Di-tert-butyl 6,6'-((1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyldi(4,1) -phenylene)) bis(azanediyl))bis(carbonyl))(6S,6'S)-bis(5-azaspiro[2.4]heptane-5-carboxylate) deprotected to give (6S, 6'S)-N,N'-(1,4(1,4)-diphenylheterocyclohexan-1 ² ,4 ³ -diylbis(4,1-phenylene))di(5-aza Spiro [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)-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

Reference Example 1, Step 6, (6S, 6'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyldi(4,1-Asia) Phenyl)) bis(5-azaspiro[2.4]heptane-6-carboxamide) condensation gives dimethyl ((2S,2'S)-((6S,6'S)-((1,4 (1,4,1, 4) - diphenyl heterocyclic six Fan ^-12, 4 ³ - diyl (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.

LC-MS: 951.40 (M+H) ⁺

^{1 H 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 = 7.6 Hz, 2H), 4.64 (t, J = 7.6 Hz, 2H), 3.96 (t, J = 9.6 Hz, 2H), 3.74 (d, J=9.6 Hz, 2H), 3.67 (d, J=9.6 Hz, 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)-((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

Reference Example 1, Step 6, (6S, 6'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyldi(4,1-Asia) Phenyl)) bis(5-azaspiro[2.4]heptane-6-carboxamide) is condensed with N-methoxycarbonyl-O-methyl-L-threonine to give dimethyl ((2S, 2'S, 3R,3'R)-((6S,6'S)-((1,4(1,4)-diphenylheterocyclohexan-1 ² ,4 ³ -diyldi(4,1-phenylene) )) bis(azanediyl))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) ⁺ ;

^{1 H 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 = 8.0 Hz, 2H), 6.64 (s, 2H), 6.46 (d, J = 7.6 Hz, 2H), 4.63 (t, J = 7.2 Hz, 2H), 4.21 (t, J=7.6 Hz, 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)-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

First step: di-tert-butyl 3,3'-((1,4(1,4)-diphenyl heterocyclohexan-1 ² ,4 ³ -diyldi(4,1-phenylene) Base)) bis(azanediyl))bis(carbonyl))(1R,1'R,3S,3'S,4S,4'S)-bis(2-azabicyclo[2.2.1]heptane-2- Preparation of carboxylic acid esters

Reference Example 1 Step 4, 4,4'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyl)diphenylamine and (1R,3S,4S)-2 Condensation of -(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid to give di-tert-butyl 3,3'-((1,4(1) 4) - diphenyl heterocyclic six Fan ^-12, 4 ³ - diyl (4,1-phenylene)) bis (azanediyl)) bis (carbonyl)) (1R, 1'R, Preparation of 3S,3'S,4S,4'S)-bis(2-azabicyclo[2.2.1]heptane-2-carboxylate).

LC-MS: 637.30 (M-2 Bos+H) ⁺ .

Step 2: (1R, 1'R, 3S, 3'S, 4S, 4'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyl Preparation of bis(4,1-phenylene))bis(2-azabicyclo[2.2.1]heptane-3-carboxamide)

Reference Example 1, Step 5, Di-tert-butyl 3,3'-((1,4(1,4)-diphenylcyclohexan-1 ² ,4 ³ -diyldi(4,1) -phenylene))bis(azanediyl))bis(carbonyl))(1R,1'R,3S,3'S,4S,4'S)-bis(2-azabicyclo[2.2.1]heptane Deprotection of 2-carboxyl ester to give (1R,1'R,3S,3'S,4S,4'S)-N,N'-(1,4(1,4)-diphenylcyclohexan- ¹ , 4 ³ -diylbis(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)-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

Reference Example 1, Step 6, (1R, 1'R, 3S, 3'S, 4S, 4'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² , 4 ³ -Diylbis(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)-diphenylheterocyclohexan-1 ² ,4 ³ -diyldi(4,1-phenylene) )) bis(azanediyl))bis(carbonyl))bis(2-azabicyclo[2.2.1]heptane-3,2-diyl))bis(3-methyl-1-carbonylbutene) Alkenyl-1,2-diyl)) dicarbamate.

LC-MS: 951.35 (M+H) ⁺

^{1 H 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 = 7.6 Hz, 2H), 6.62 (s, 2H), 6.45 (d, J = 7.6 Hz, 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)-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

Reference Example 1, Step 6, (1R, 1'R, 3S, 3'S, 4S, 4'S)-N,N'-(1,4(1,4)-diphenylcyclohexan-1 ² , 4 ³ -diylbis(4,1-phenylene))bis(2-azabicyclo[2.2.1]heptane-3-carboxamide) and N-methoxycarbonyl-O-methyl-L-Su Condensation to give dimethyl ((2S,2'S,3R,3'R)-((1R,1'R,3S,3'S,4S,4'S)-((1,4(1,4)- Fan benzene heterocyclic six ^-12, 4 ³ - diyl (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.

LC-MS: 983.35 (M + H) +;

^{1 H 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 = 7.6 Hz, 2H), 6.62 (s, 2H), 6.46 (d, J = 7.6 Hz, 2H), 4.57 (s, 2H), 4.32 (t, J = 7.6 Hz, 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

(Measurement of wild type hepatitis C virus HCV gene 1b inhibitory activity)

The inhibitory activity of the compounds of the present invention against HCV replication was determined by the HCV Replicon Reporter Luciferase Assay.

1. Experimental cell model: Huh-7 cell line stably transfected with the HCV replicon luciferase reporter gene.

2. Preparation method of experimental solution:

The 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.

3. Experimental measurement steps:

1) The cells were grown on a 96-well culture plate, and after 24 hours, different concentrations of the test compound and the internal reference compound were added to the cultured cells.

2) After 48 hours, the luciferase activity was measured using a microplate reader.

3) Analyze the raw data and calculate the inhibition of luciferase activity at different concentration points of the test compound, ie the percentage inhibition of HCV replicon.

4) using GraphPad Prism software fitting the percent inhibition data analysis nonlinear compound obtained half inhibitory concentration ₅₀ value IC.

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):

Example number IC ₅₀ (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 (16)

A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

among them: R ₁ and 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. Optionally further substituted by one or more selected from the group consisting of halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, halo substituted C _1-8 alkoxy, hydroxy substituted C _1-8 alkoxy, C Substituted by a substituent of _1-8 cycloalkyl or C _1-8 cycloalkoxy; 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, Optionally further one or more selected from the group consisting of 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:

Optionally further one or more selected from the group consisting of halogen, hydroxy, 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 , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR Substituted by a substituent of ₁₃ ; 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 , Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent; 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 heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclic thio group, C _5-10 aryl, C _5-10 aryloxy , C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C( O) OR ₁₃ , Alternatively, R ₇ or R ₇ ' together with its attached tetrahydropyrrole ring form a 6-10 membered nitrogen-containing spiro, bridge or fused ring, Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent; 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 , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C( O) OR ₁₃ , Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ ; 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 , Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent; 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, Optionally further one or more selected from the group consisting of 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; m, m' are each independently selected from 0 to 3; p, p' are each independently selected from 0 to 7; r is 0, 1, or 2. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₆ and R ₆ ' are each independently selected from the group consisting of hydrogen, hydrazine, and C _1-4. Alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, halo C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, - C(O)R ₁₄ or -C(O)OR ₁₃ , Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ Substituted by a substituent. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 2, wherein R ₆ and R ₆ ' are each independently selected from the group consisting of hydrogen, hydrazine, methyl group and ethyl group. Base, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, methoxy, ethoxy or isopropoxy, preferably hydrogen. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₁ and R ₁ ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, Amino, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl, preferably hydrogen, hydrazine, fluorine, hydroxy, amino, methyl, ethyl or cyclopropyl. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₂ , R ₂ ', R ₃ , R ₃ ', R ₄ and R ₄ ', R ₅ , R ₅ ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy or C _3-8 Cycloalkoxy, preferably hydrogen, hydrazine, fluorine, chlorine, methyl, ethyl, hydroxy, amino, methoxy or cyclopropyl. The compound of the formula (I), the 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 one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3 - 6} cycloalkyl, 3-6 membered heterocyclic, 3-6 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 _0-4 -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) NR 10 R 11, -N (R 10) -C (O) R 14 or _{-N (R 10) -C (O} ) oR Substituted by a substituent of ₁₃ ; The following structure is preferred:

The compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein 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 , -C _0-8 -C(O)NR ₁₀ R ₁₁ , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C( O) OR ₁₃ , Alternatively, 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 of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the group consisting of the following compounds of the 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 (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₇ and R ₇ ' are each independently selected from the group consisting of hydrogen, hydrazine, fluorine and methyl. Ethyl or isopropyl, or R ₇ or R ₇ ' together with the tetrahydropyrrole ring to which they are attached form the following structure:

The compound of formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₈ and R ₈ ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, and methyl. , ethyl, isopropyl, cyclopropyl, -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 , -N(R ₁₀ )-C(O)R ₁₄ or -N(R ₁₀ )-C(O)OR ₁₃ . The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₉ and R ₉ ' are each independently selected from the group consisting of hydrogen, hydrazine and C _{1- 4-} alkyl, allyl, ethynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic or phenyl. A compound of the 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 group consisting of:

A compound of formula (I), a stereoisomer thereof or a pharmaceutical thereof according to any one of claims 1-12 A method for preparing an acceptable salt, comprising the steps of:

Wherein: 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 Requirement 1 is defined. The preparation method according to claim 13, wherein 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, and diiso). a propylethylamine or a mixture thereof, the inorganic base being 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. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier according to any one of claims 1-12. A pharmaceutical composition of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 according to any one of claims 1 to 12 for the treatment or prevention of HCV infection Application in medicine.