WO2017076201A1 - Hcv inhibitors, preparation method and use thereof - Google Patents

Abstract

HCV inhibitors with a structure as in formula I, preparation method and uses thereof, each substituent in the formula as defined in the description. The present series of compounds inhibits HCV activity and can be used in the development of medications to treat hepatitis C virus (HCV) infection, giving it broad application prospects.

Description

HCV inhibitor, preparation method and application thereof Technical field

The invention belongs to the field of drug development, and in particular relates to an HCV inhibitor, 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 Sex (can be effective against 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 HCV inhibitors having the structure of formula (I), their preparation methods and applications during the research. This series of compounds has high inhibitory activity against wild-type HCV, and has high inhibitory activity against Daclatasvir and Ledipasvir-resistant mutations. It can be applied to the development of drugs for the treatment of hepatitis C virus (HCV) infection-related diseases. Application prospects.

In one aspect, the invention provides 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 or C _3-8 cycloalkyl, or R ₁ and R ₁ ' are directly attached to a carbon atom. Forming a 3-6 membered carbon ring or a 3-6 membered heterocyclic ring,

Optionally further selected from 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, C _1-8 cycloalkyl or C _1- Substituted by a substituent of an ₈ -cycloalkoxy group;

R ₂ and R ₂ ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy , C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C( O) OR ₉ ,

Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _{5 10} arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

R ₃ and R ₃ ' are each independently selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 Heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , or -C _{0- 8} -C(O)NR ₆ R ₇ ,

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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

R ₄ and R ₄ ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy , C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C( O) OR ₉ ,

Alternatively, R ₄ or R ₄ ' 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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

R _{5 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl, C _1-8 alkoxy C _1-8 alkyl, hydroxy C _1-8 Alkyl, -C(O)R ₁₀ or -C(O)OR ₉ ,

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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

L is selected from a bond, a C _5-10 aryl group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group , C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl Thiothio group, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O) OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C Substituting (O) a substituent of R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

M is selected from a bond, a C _5-10 aryl group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, C _1-8 alkyl, C _1-8 alkoxy Substituted by a substituent of a halogen-substituted C _1-8 alkyl group, a halogen-substituted C _1-8 alkoxy group, or a C _1-8 alkylsulfonyl group;

R ₆ and R ₇ are each independently selected from the group consisting of hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group. , C _5-10 aryl, 5-10 membered heteroaryl, C _1-8 alkyl acyl or C _1-8 alkyl acylamino,

Optionally further one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, acetylamino, azide, sulfonyl, methylsulfonyl, _C1-8 alkyl, halo substituted _C1-8 alkane a group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _1-8 alkoxy group, a C _1-8 alkoxycarbonyl group, C _1-8 alkylcarbonyl, C _1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryl Alkoxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C _1-8 alkyl Substituted by a substituent of an amino group or a di-C _1-8 alkylamino group;

R _{8 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl, di C _1-8 alkylamino, phenyl or p-methylphenyl;

R _{9 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl or hydroxy substituted C _1-8 alkyl;

R _{10 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, halogen substituted C _1-8 alkyl, halogen Substituting a C _1-8 alkoxy group, a hydroxy-substituted C _1-8 alkyl group or a hydroxy-substituted C _1-8 alkoxy group;

L and M are not keys at the same time;

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

r is 0, 1, or 2.

And a pharmaceutically acceptable salt thereof, wherein R _{5 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-6 cycloalkyl, Halogen substituted C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, -C(O)R ₁₀ or -C(O)OR ₉ , optionally further One or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3 -8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 aryl sulfide , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 - OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ Substituted by a substituent of R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ .

And a pharmaceutically acceptable salt thereof, wherein R _{5 is} selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl. , cyclopropyl or cyclohexyl.

As a preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from a bond, a phenyl group or a naphthyl group.

As a preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, M is selected from the group consisting of a bond, furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, anthracene Oxazine, hydrazine, quinoline, benzimidazole.

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

As a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each of R ₁ and R ₁ ' is independently selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, amino, C. _{a 1-4} alkyl group, a halogen-substituted C _1-4 alkyl group or a C _3-6 cycloalkyl group, or R ₁ and R ₁ ' form a 3-6 membered carbon ring or a 3-6 membered impurity with a directly attached carbon atom. ring.

And a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₁ ' are each independently selected from the group consisting of hydrogen, hydrazine and fluorine. Hydroxy, amino, methyl, ethyl, cyclopropyl or trifluoromethyl, or R ₁ and R ₁ ' form a cyclopropyl, cyclobutyl or cyclopentyl group with a directly attached carbon atom.

As a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R ₄ and R ₄ ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano and nitro , azido group, C _1-4 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-6 cycloalkyl group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic ring Alkoxy, 3-6 membered heterocyclylthio, C _5-8 aryl, C _5-8 aryloxy, C _5-8 arylthio, 5-8 membered heteroaryl, 5-8 Nonheteroaryloxy, 5-8 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O) R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O) NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ,

Alternatively, R ₄ or R ₄ ' 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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent.

As a still further preferred embodiment, the compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, R ₄ and R ₄ ' are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, and B. Or a isopropyl group, or R ₄ or R ₄ ' together with its attached tetrahydropyrrole ring form a 6-10 membered nitrogen-containing spiro ring, bridged ring or fused ring, the structure is as follows:

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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent.

As a further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each of R ₂ and R ₂ ' is independently selected from the group consisting of hydrogen, hydrazine, halogen, methyl, ethyl. , isopropyl, cyclopropyl, -C _0-4 -OR ₉ , -C _0-4 -C(O)R ₁₀ , -C _0-4 -C(O)OR ₉ , -C _0-4 - OC(O)R ₁₀ , -C _0-4 -NR ₆ R ₇ , -C _0-4 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N( R ₆ )-C(O)OR ₉ .

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

In another aspect, the present invention provides a process for the preparation of a compound of the above formula (I), comprising the steps of:

Wherein R ₁ , R ₁ ', R ₂ , R ₂ ', R ₃ , R ₃ ', R ₄ , R ₄ ', R ₅ , R ₅ ', R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , L, M, m, m', r are as defined for the compound of formula (I).

As a 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, EDCHCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or mixtures thereof.

Another aspect of the invention provides a pharmaceutical composition comprising any of the foregoing therapeutically effective doses a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention provides the use of any of the foregoing compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above, in the manufacture of a medicament for the treatment or prevention of HCV infection.

detailed description

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

The "C _1-8 alkyl group" means a linear alkyl group having 1 to 8 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group, preferably a C _1-4 alkyl group. C _0-8 means no carbon atom or C _1-8 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, positive Pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl 2,2-Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2 , 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4 - dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-di Methylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2 -ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or Its various branched isomers and the like.

The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano. , nitro, azide, C _1-8 alkyl, halo substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3- 8-membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 arylthio group 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R _{7, -C 0-8 -C (O)} NR 6 R 7, -N (R 6) -C (O) R 10 or _{-N (R 6) -C (O} ) oR 9 group substituted with a substituent;

"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, preferably 3 to 6 carbons. Atom cycloalkyl, for example:

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

Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated 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, cyano, nitro, azide, C. _1-8 alkyl, halo substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 a monoheterocyclyloxy group, a 3-8 membered heterocyclylthio group, a C _5-10 aryl group, a C _5-10 aryloxy group, a C _5-10 arylthio group, a 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C (O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C Substituting (O) a substituent of NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"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, preferably 3 to 6 ring atoms. Ring base.

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

Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) _r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

"Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none The ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) _r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon. 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 halogen, hydroxy, cyano, nitro, azide, C. _1-8 alkyl, halo substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 a monoheterocyclyloxy group, a 3-8 membered heterocyclylthio group, a C _5-10 aryl group, a C _5-10 aryloxy group, a C _5-10 arylthio group, a 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C (O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C Substituting (O) a substituent of NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"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) The group "C _5-10 aryl" means an all-carbon aryl group having 5 to 10 carbons such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C _1-8. Alkyl, halogen substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O) R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O) Substituted by a substituent of NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"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, cyano, nitro, azide, C. _1-8 alkyl, halo substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 a monoheterocyclyloxy group, a 3-8 membered heterocyclylthio group, a C _5-10 aryl group, a C _5-10 aryloxy group, a C _5-10 arylthio group, a 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C (O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C Substituting (O) a substituent of NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C _2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons A base, preferably a linear or branched alkenyl group of 2 to 4 carbons. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C _1-8. Alkyl, halogen substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O) R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O) Substituted by a substituent of NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"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. A linear or branched alkynyl group of 2 to 4 carbons is preferred. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C _1-8. Alkyl, halogen substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O) R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O) Substituted by a substituent of NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"Alkoxy" means -O-(alkyl) wherein alkyl is as defined above. C _1-8 alkoxy means an alkyloxy group having 1-8 carbons, preferably an alkyloxy group of 1 to 4 carbons, and a non-limiting example comprises a methoxy group, an ethoxy group, a propoxy group, Butoxy and the like.

The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, azide, C _1-8 alkyl, halo substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3- 8-membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl , 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 - C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 - Substituted by a substituent of C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"Cycloalkoxy" refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above. C _3-8 cycloalkoxy refers to a cycloalkyloxy group having 3-8 carbons, preferably a cycloalkyloxy group of 3 to 6 carbons, and a non-limiting example comprises a cyclopropoxy group, a cyclobutoxy group. , cyclopentyloxy, cyclohexyloxy and the like.

The cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano, nitro, azide, C. _1-8 alkyl, halo substituted C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 a monoheterocyclyloxy group, a 3-8 membered heterocyclylthio group, a C _5-10 aryl group, a C _5-10 aryloxy group, a C _5-10 arylthio group, a 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C (O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C Substituting (O) a substituent of NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

"Halo-substituted C _1-8 alkyl" means a hydrogen on the alkyl group optionally substituted with a fluorine, chlorine, bromine or iodine atom, preferably from 1 to 8 carbon alkyl groups, preferably hydrogen on the alkyl group. 1-4 carbon alkyl groups substituted with fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl Wait.

Hydrogen on a "halo-substituted C _1-8 alkoxy"alkyl group optionally 1-8 carbon alkoxy groups substituted by fluorine, chlorine, bromine or iodine atoms, preferably hydrogen on the alkyl group. One to four carbon alkoxy groups substituted by fluorine, chlorine, bromine or iodine atoms. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"C(O)R ₁₀ "" means a R ₁₀ -substituted carbonyl group, for example, "C _0-8 alkylcarbonyl" means a C _0-8 alkyl-substituted carbonyl group, preferably a C _0-4 alkyl-substituted carbonyl group;

The "C _1-8 alkanoylamino group" means a C _1-8 alkanoyl group-substituted amino group, preferably a C _1-4 alkanoyl group-substituted amino group, for example, a C ₂ alkanoylamino group means an acetylamino group.

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

"THF" refers to tetrahydrofuran.

"DCM" means dichloromethane.

"DMAP" means 4-dimethylaminopyridine.

"DME" refers to dimethyl ether.

"DMF" means N,N-dimethylformamide.

"MTBE" means methyl tert-butyl ether.

"EA" means ethyl acetate.

"DIPEA" refers to diisopropylethylamine.

"NBS" means N-bromosuccinimide.

"NFSI" refers to N-fluorobisbenzenesulfonamide.

"NMM" refers to N-methylmorpholine.

"KHMDS" means potassium hexamethyldisilazide.

The term "condensing agent" means an agent capable of causing a condensation reaction. Condensation reaction refers to two or more organic components Sub-interactions combine to form a macromolecule by covalent bonding, while losing the reaction of water or other relatively simple inorganic or organic small molecules. The small molecular substance is usually water, hydrogen chloride, methanol or acetic acid. 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(3-dimethylaminopropyl)carbodiimide hydrochloride
PyBOP	Benzotriazole hexafluoro-1-yl-oxytripyrrolidinyl
PyBroP	Tripyrrolidinyl bromide hexafluorophosphate
HATU	2‐(7-azobenzotriazole)‐N,N,N′,N′‐tetramethylurea hexafluorophosphate
HCTU	6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
DEPBT	3‐(diethoxyphosphoryloxy)‐1,2,3-benzotriazin-4-ketone
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. 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 a nitrogen balloon having a volume of about 1 L. An argon atmosphere or a hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 1 L.

The solution in the examples means an aqueous solution unless otherwise specified. The temperature of the reaction is room temperature. The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

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 Methyl ((2S,3R)-3-methoxy-1-((2S,3aS,7aS)-2-(5-(7-((2S,3aS,7aS)-1-(N) -methoxycarbonyl)-O-methyl-L-threonyl) octahydro-1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl) -1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutan-2-yl)carbamate

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

(2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (50g) was dissolved in a mixed solution of THF (400 mL) and water (200 mL) at 0 ° C, and the temperature was controlled below 10 ° C. 2.5M NaOH aqueous solution (200mL), at After stirring at 0 ° C for 15 minutes, dibutyl dicarbonate (85.4 g) was added dropwise thereto at a temperature controlled temperature of 10 ° C or lower, and the reaction was stirred at room temperature for 16 hours. Water (500 mL) was added to the reaction mixture, and the mixture was washed three times with MTBE (500 mL). The aqueous phase was adjusted to pH 3-4 with 1M aqueous citric acid, and ethyl acetate (500 mL) was applied 3 times. After drying, filtration and concentration of the filtrate to dryness afforded Compound (2S, 3aS, 7aS)-1-(tert-butoxycarbonyl) octahydro-1H-indole-2-carboxylic acid (74.9 g).

LC-MS m / z: 268.10 [MH] -.

Second step: tert-butyl (2S, 3aS, 7aS)-2-((2-amino-4-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate and tert- Butyl (2S,3aS,7aS)-2-((2-amino-5-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate

Compound (2S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid (30g), 4-bromo-1,2-diaminobenzene at 0 °C (22.5 g), EDCI (23.5 g), HOBt (16.6 g) was dissolved in DMF (300 mL), and N-methylmorpholine (36.8 ml) was added dropwise at a temperature below 10 ° C, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed by LC-MS, water (1200 ml), ethyl acetate (300 mL), and the mixture was extracted three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give tert-butyl (2S) , 3aS, 7aS)-2-((2-Amino-4-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate and tert-butyl (2S,3aS,7aS)- 2-((2-Amino-5-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate (55.1 g in total).

LC-MS m/z: </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIgt;

The third step: tert-butyl (2S, 3aS, 7aS)-2-(6-bromo-1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate

tert-Butyl (2S,3aS,7aS)-2-((2-amino-4-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate and tert-butyl ( 2S,3aS,7aS)-2-((2-Amino-5-bromophenyl)carbamoyl) octahydro-1H-indole-1-carboxylate (55 g total) was dissolved in acetic acid (300 mL). The reaction was carried out at 65 ° C, and the reaction was monitored by LC-MS. The reaction solution was cooled to room temperature, and the solvent was evaporated evaporated evaporated. mjjjjjjjjjjjjjjjjjjjjj Drying over anhydrous sodium sulfate, concentrating to dryness, EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj [d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate (28 g).

LC-MS m / z: 420.10 [M + H] +, 422.05 [M + H] +.

The fourth step: tert-butyl (2S, 3aS, 7aS)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate

tert-Butyl (2S,3aS,7aS)-2-(6-bromo-1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate under nitrogen (10 g, 20.0 mmol), bis(pinacolyl)diborane (12.1 g, 40.0 mmol), tetrakistriphenylphosphine palladium (1.4 g, 1.0 mmol), potassium carbonate (9.9 g) dissolved in DME (100 mL) In a water (10 mL), the mixture was heated to 80 ° C and stirred for 12 hours. After the reaction was completed by LC-MS, the mixture was cooled to room temperature, and water (100 mL) and ethyl acetate (100 mL) were added dropwise, and the aqueous phase was extracted twice with ethyl acetate (100 mL). Concentrated to dryness, and the residue was applied to silica gel column chromatography ( petroleum ether / ethyl acetate) to give tert-butyl(2S,3aS,7aS)-2-(6-(4,4,5,5-tetramethyl) -1,3,2-Dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate (9.8 g).

LC-MS m/z: 468.25 [M+H] ⁺ .

Step 5: 2-Bromo-9,9-dimethyl-9H-oxime

Under a nitrogen atmosphere, 2-bromo-9H-indole (30 g, 0.12 mol) was added to a 1 L three-necked flask, tetrahydrofuran (300 ml) was added, and the mixture was cooled to 5 ° C, and potassium t-butoxide (37.3 g, 0.33 mol) was added portionwise. After stirring for 30 minutes, the temperature was lowered to -5 ° C, methyl iodide (52.4 g, 0.36 mol) was added dropwise, and the mixture was heated to 25 ° C and stirred for 3 hours. After adding ethyl acetate (300 ml), the mixture was cooled to 5 ° C, water (300 ml) was added dropwise, and the organic layer was evaporated. Concentration gave 2-bromo-9,9-dimethyl-9H-indole (33.7 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69-7.71 (m, 1H), 7.60-7.57 (m, 2H), 7.42-7.48 (m, 2H), 7.34-7.36 (m, 2H), 1.49 (s) , 6H).

Step 6: 2-Bromo-9,9-dimethyl-7-nitro-9H-oxime

Under a nitrogen atmosphere, 2-bromo-9,9-dimethyl-9H-indole (7 g) was added to a 250 ml three-necked flask, acetic acid (84 ml) was added, and the mixture was cooled to 0 ° C, and fuming nitric acid (20 ml) was added dropwise. The temperature was raised to 25 ° C and stirred for 20 hours. The reaction solution was poured into an ice-water mixture (600 g), stirred for 30 minutes, filtered, and the filter cake was taken, acetonitrile (400 ml), refluxed for 2 hours, filtered, and the filter cake was dried in vacuo to give 2-bromo-9,9-dimethyl -7-Nitro-9H-indole (5.6 g).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.28-8.25 (m, 2H), 7.80-7.78 (m, 1H), 7.67-7.63 (m, 2H), 7.55-7.52 (m, 1H), 1.59 (s , 6H).

Step 7: 7-Bromo-9,9-dimethyl-9H-indol-2-amine

2-Bromo-9,9-dimethyl-7-nitro-9H-indole (5.6 g, 17.6 mmol) was added to a 1 L three-necked flask under nitrogen, and ammonium chloride (1.9 g, 35.2 mmol) was added. Iron powder (2.95 g, 52.8 mmol), ethanol (250 ml), water (70 ml), and refluxed for 4 hours. Saturated sodium carbonate solution (140 ml) was added, stirred for 1 hour, filtered, and the filtrate was evaporated under reduced pressure, filtered, and then filtered and dried in vacuo to give 7-bromo-9,9-dimethyl-9H-indole-2-amine (4.9 g).

LC-MS m/z: 288.10 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.55-7.38 (m, 4H), 6.73 (d, 1H), 6.67-6.55 (m, 1H), 3.73 (brs, 2H), 1.46 (s, 6H).

Step 8: tert-Butyl (2S,3aS,7aS)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H-indole哚-1-carboxylate

7-Bromo-9,9-dimethyl-9H-indol-2-amine (4 g, 13.9 mmol), (2S, 3aS, 7aS)-1-(tert-butoxycarbonyl) VIII at room temperature Hydrogen-1H-indole-2-carboxylic acid (5.6 g, 20.8 mmol), HATU (10.6 g, 27.8 mmol), DMAP (0.34 g) was dissolved in DMF (40 mL), and diisopropyl B was added dropwise with stirring. The amine (5.4 g, 41.7 mmol) was stirred for 12 hours. After the reaction was completed by LC-MS, water (100 mL) was added to the mixture, and the mixture was combined with ethyl acetate (30 mL). Petroleum ether / ethyl acetate) to give tert-butyl (2S,3aS,7aS)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro -1H-indole-1-carboxylate (55.1 g).

LC-MS m / z: 438.10 [M-Boc + H] +, 440.20 [M-Boc + H] +.

The ninth step: tert-butyl (2S, 3aS, 7aS)-2-((7-(2-((2S,3aS,7aS)-1-(tert-butoxycarbonyl) octahydro-1H-indole) Ind-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)octahydro-1H-indole-1 -carboxylate

Under the protection of nitrogen, tert-butyl (2S, 3aS, 7aS)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H-吲哚-1-carboxylate (1.0 g, 1.85 mmol), tert-butyl (2S, 3aS, 7aS)-2-(6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate (0.91 g, 1.94 mmol), tetratriphenyl Palladium phosphine (0.64g, 0.56mmol), sodium bicarbonate (0.52g, 6.1 Methyl) was dissolved in DME (20 mL) and water (2 mL), warmed to 80 ° C and stirred for 12 hours. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) was added and the mixture was separated, and the aqueous phase was extracted twice with ethyl acetate (20 mL). Drying, concentrating to dryness, EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj )-1-(tert-butoxycarbonyl)octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indole 2-yl)carbamoyl)octahydro-1H-indole-1-carboxylate (270 mg).

LC-MS m/z: 800.35 [M+H] ⁺ .

Step 10: (2S, 3aS, 7aS)-N-(9,9-Dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)- 1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide

Tert-Butyl (2S,3aS,7aS)-2-((7-(2-((2S,3aS,7aS)-1-(tert-butoxycarbonyl) octahydro-1H-indole) at room temperature Ind-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)octahydro-1H-indole-1 The -carboxylic acid ester (1.0 g) was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred for 2 hr. After the reaction was completed by LC-MS, EtOAc (EtOAc m. 7aS)-N-(9,9-Dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H-benzo[d]imidazole- 5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide (760 mg) was used directly in the next step.

LC-MS m/z: 600.30 [M+H] ⁺ .

The eleventh step: methyl ((2S,3R)-3-methoxy-1-((2S,3aS,7aS)-2-(5-(7-((2S,3aS,7aS)-1-) (N-(methoxycarbonyl)-O-methyl-L-threonyl) octahydro-1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indole-2 -yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutan-2-yl)carbamate

(2S,3aS,7aS)-N-(9,9-dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)) 1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide (0.15 g, 0.25 mmol), N-(methoxycarbonyl) -O-methyl-L-threonine (0.1 g, 0.52 mmol), EDCI (0.12 g, 0.63 mmol), HOBt (0.07 g, 0.55 mmol) dissolved in DMF (1 mL), dropwise to the reaction mixture NMM (0.73 mL, 1.25 mmol) was added and the mixture was stirred for 12 hr. After the reaction was completed by LC-MS, water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). Concentration to dryness, the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(7-((2S,3aS,7aS)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl) octahydro-1H-indole-2-carbamoylamino -9,9-Dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutane -2-yl) carbamate (40 mg).

LC-MS m/z: 946.30 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO) δ 12.18 (d, J = 9.2 Hz, 1H), 10.05 (s, 1H), 7.92-7.75 (m, 5H), 7.66-7.49 (m, 6H), 5.10 (s) , 1H), 4.48-4.37 (m, 2H), 4.37-4.35 (m, 1H), 4.10 (t, J = 8.0 Hz, 2H), 3.58 (s, 3H), 3.55 (s, 3H), 3.50- 3.46 (m, 1H), 3.40-3.37 (m, 1H), 3.25 (s, 3H), 3.18 (s, 3H), 2.42 (s, 1H), 2.36-2.08 (m, 4H), 2.03-1.91 ( m, 4H), 1.77-1.69 (m, 5H), 1.49 (s, 6H), 1.43-1.29 (m, 4H), 1.19-1.13 (m, 4H), 1.10 (t, J = 6.0 Hz, 3H) , 0.93 (t, J = 6.0 Hz, 3H).

Example 2 Methyl(S)-5-((2S,3aS,7aS)-2-((7-(2-((2S,3aS,7aS)-1-((S)-5-methoxy) 2-((Methoxycarbonyl)amino)-5-carbonylpentanoyl)octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-di Methyl-9H-indol-2-yl)carbamoyl)octahydro-1H-indol-1-yl)-4-((methoxycarbonyl)amino)-5-carbonylvalerate

Referring to step 11 of Example 1, methyl(S)-5-((2S,3aS,7aS)-2-((7-(2-((2S,3aS,7aS)-1-((S)-)) was obtained. 5-methoxy-2-((methoxycarbonyl)amino)-5-carbonylpentanoyl) octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)- 9,9-Dimethyl-9H-indol-2-yl)carbamoyl)octahydro-1H-indol-1-yl)-4-((methoxycarbonyl)amino)-5-carbonylvalerate .

LC-MS m/z: 10021.30 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO) δ 12.17 (d, J = 18.0 Hz, 1H), 10.17 (s, 1H), 7.90-7.74 (m, 5H), 7.66-7.48 (m, 6H), 5.12-5.07 (m, 1H), 4.45 (t, J = 8.0 Hz, 1H), 4.38-4.31 (m, 4H), 3.60 (s, 3H), 3.57-3.54 (m, 9H), 2.41-2.18 (m, 10H) ), 2.14 - 2.08 (m, 1H), 2.05-1.58 (m, 11H), 1.49 (s, 6H), 1.26-1.23 (m, 8H).

Example 3 Methyl ((S)-1-((S)-2-(5-(7-((2S,3aS,7aS)-1-((methoxycarbonyl)-L-prolyl)) Hydrogen-1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1 -yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl(S)-2-((2-amino-4-bromophenyl)carbamoyl)pyrrolidine-1-carboxylate and tert-butyl(S)-2-( (2-amino-5-bromophenyl)carbamoyl pyrrolidine-1-carboxylate

Starting from 4-bromobenzene-1,2-diamine, referring to step 2 of Example 1, a tert-butyl(S)-2-((2-amino-4-bromophenyl)carbamoylpyrrole was obtained. Alkyl-1-carboxylate and tert-butyl(S)-2-((2-amino-5-bromophenyl)carbamoyl)pyrrolidine-1-carboxylate.

LC-MS m/z: </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIgt;

Second step: tert-butyl(S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

Tert-butyl(S)-2-((2-amino-4-bromophenyl)carbamoyl)pyrrolidine-1-carboxylate and tert-butyl(S)-2-((2- Starting from amino-5-bromophenyl)carbamoylpyrrolidine-1-carboxylate, referring to step 3 of Example 1, to give tert-butyl(S)-2-(5-bromo-1H-benzo [d]imidazol-2-yl)pyrrolidine-1-carboxylate.

LC-MS m/z: </RTI>^</RTI></RTI>^<RTIgt;

The third step: tert-butyl (S)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzene And [d]imidazol-2-yl)pyrrolidine-1-carboxylate

Starting from tert-butyl(S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate, referring to step 4 of Example 1, to obtain a tertiary Butyl (S)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole- 2-yl)pyrrolidine-1-carboxylate.

LC-MS m/z: 413.20 [M+H] ⁺ .

The fourth step: tert-butyl (2S, 3aS, 7aS)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H- Benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate

tert-Butyl (2S,3aS,7aS)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1 - Carboxylic acid ester as raw material, refer to step 9 of Example 1, and tert-butyl (S)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Coupling of pentocyclo-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate gives tert-butyl(2S,3aS,7aS)-2-((7- (2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H- Ind-2-yl)carbamoyl)octahydro-1H-indole-1-carboxylate.

LC-MS m/z: 745.30 [M+H] ⁺ .

Step 5: (2S, 3aS, 7aS)-N-(9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole- 5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide

Tert-butyl(2S,3aS,7aS)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[ d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate as a starting material, referring to the procedure of Example 1. 10, (2S, 3aS, 7aS)-N-(9,9-dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5) -yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide.

LC-MS m/z: 546.31 [M+H] ⁺ .

Step 6: Methyl ((S)-1-((S)-2-(5-(7-((2S,3aS,7aS)-1-((methoxycarbonyl)-L-prolyl) Octahydro-1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine- 1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,3aS,7aS)-N-(9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5-yl) -9H-indol-2-yl) octahydro-1H-indole-2-carboxamide as a starting material, referring to step 11 of Example 1, to give methyl ((S)-1-((S)-2-( 5-(7-((2S,3aS,7aS)-1-((methoxycarbonyl)-L-prolyl) octahydro-1H-indole-2-carbamoylamino)-9,9- Dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)amino Formate.

LC-MS m/z: 860.35 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 10.16 (s, 1H), 7.84 - 7.71 (m, 5H), 7.62 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m) , 4H), 7.32 (d, J = 8.4 Hz, 1H), 5.22-5.20 (m, 1H), 4.47 (t, J = 9.2 Hz, 1H), 4.39-4.29 (m, 1H), 4.07 (t, J=8.4 Hz, 1H), 3.87-3.82 (m, 3H), 3.55 (d, J=2.4 Hz, 6H), 2.35-2.17 (m, 4H), 2.13-1.86 (m, 7H), 1.49 (s) , 6H), 1.29-1.16 (m, 4H), 0.91 - 0.83 (m, 14H).

Example 4 Methyl((2S,3R)-3-methoxy-1-((2S)-2-(5-(7-((2S,3aS,7aS)-1-((3R)-3) -Methoxy-2-((methoxycarbonyl)amino)butyryl)octahydro-1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl -1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-1-carbonylbutan-2-yl)carbamate

(2S,3aS,7aS)-N-(9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5-yl) -9H-indol-2-yl) octahydro-1H-indole-2-carboxamide as a starting material, which was obtained in the same manner as in the step 11 of Example 1, to give methyl ((2S,3R)-3-methoxy-1- ((2S)-2-(5-(7-((2S,3aS,7aS)-1-((3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl) octahydro -1H-indole-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- Base)-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 892.35 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 10.15 (s, 1H), 7.86-7.76 (m, 5H), 7.62-7.60 (m, 2H), 7.55-7.48 (m, 3H) , 7.28 (d, J = 8.4 Hz, 1H), 5.25-5.16 (m, 1H), 4.45 (t, J = 9.0 Hz, 1H), 4.41-4.25 (m, 2H), 4.10 (t, J = 8.0 Hz, 1H), 3.87-3.82 (m, 2H), 3.54 (d, J = 2.4 Hz, 6H), 3.52-3.45 (m, 2H), 3.24 (s, 3H), 3.19 (s, 3H), 2.36 -2.17(m,2H),2.13-2.06(m,2H),1.99(s,3H),1.75-1.62(m,4H), 1.49(s,6H),1.17(t,J=7.2Hz,4H ), 1.08 (t, J = 6.0 Hz, 6H).

Example 5 Methyl((2S,3R)-3-methoxy-1-((2S,3aS,7aS)-2-(5-(7-((1R,3S,4S)-2-(N) -(methoxycarbonyl)-O-methyl-L-threonyl)-2-azabicyclo[2.2.1]heptane-3-carbamoylamino)-9,9-dimethyl- 9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl (1R, 3S, 4S)-3-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-2-aza Bicyclo[2.2.1]heptane-2-carboxylate

Using 7-bromo-9,9-dimethyl-9H-indol-2-amine as the starting material, referring to step 8 of Example 1, to obtain tert-butyl (1R, 3S, 4S)-3-((7-bromo) -9,9-Dimethyl-9H-indol-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate.

LC-MS m/z: 411.10 [M-Boc+H] ⁺ , 413.05 [M-Boc+H] ⁺ ;

Second step: tert-butyl (2S, 3aS, 7aS)-2-(6-(7-((1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo) [2.2.1] Heptane-3-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro- 1H-indene-1-carboxylate

tert-Butyl (1R,3S,4S)-3-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-2-azabicyclo[2.2 .1] heptane-2-carboxylate as a starting material, referring to step 9 of Example 1, to obtain tert-butyl (2S,3aS,7aS)-2-(6-(7-((1R,3S,4S)) -2-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl -1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate.

LC-MS m/z: 772.30 [M+H] ⁺ .

The third step: (1R, 3S, 4S)-N-(9,9-dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)- 1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

tert-Butyl (2S,3aS,7aS)-2-(6-(7-((1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2. 1]heptane-3-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indole哚-1-carboxylate as a raw material, referring to step 10 of Example 1, to obtain (1R,3S,4S)-N-(9,9-dimethyl-7-(2-((2S,3aS,7aS))) - octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)-2-azabicyclo[2.2.1]heptane -3-carboxamide.

LC-MS m/z: 572.32 [M+H] ⁺ .

The fourth step: methyl ((2S, 3R)-3-methoxy-1-((2S,3aS,7aS)-2-(5-(7-((1R,3S,4S)-2-) N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-azabicyclo[2.2.1]heptane-3-carbamoylamino)-9,9-dimethyl -9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutan-2-yl)carbamate Acid ester

(1R,3S,4S)-N-(9,9-Dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H-benzene And [d]imidazol-5-yl)-9H-indol-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide as a starting material, referring to step 11 of Example 1, to obtain a (2S,3R)-3-methoxy-1-((2S,3aS,7aS)-2-(5-(7-((1R,3S,4S)-2-(N-(methoxy) Carbonyl)-O-methyl-L-threonyl)-2-azabicyclo[2.2.1]heptane-3-carbamoylamino)-9,9-dimethyl-9H-indole- 2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 918.25 [M+H] ⁺ ;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.15 (s, 1H), 7.72-7.70 (m, 2H), 7.68 (s, 1H), 7.63-7.51 (m, 5H), 7.39 (d, J = 8.0 Hz, 1H), 5.46 (t, J = 8.8 Hz, 1H), 4.70 - 4.73 (m, 2H), 4.53 (s, 1H), 4.49 (t, J = 6.4 Hz, 1H), 4.34 (s, 1H) ), 4.25-4.21 (m, 1H), 3.81-3.79 (m, 1H), 3.71 (s, 6H), 3.65-3.60 (m, 1H), 3.42 (s, 3H), 3.29 (s, 3H), 2.54-2.50 (m, 1H), 2.41-2.34 (m, 1H), 2.06-2.04 (m, 1H), 1.96-1.68 (m, 8H), 1.61-1.56 (m, 8H), 1.45-1.41 (s , 1H), 1.25 (d, J = 6.0 Hz, 6H), 1.10 (d, J = 6.4 Hz, 3H).

Example 6 Methyl ((S)-1-((1R,3S,4S)-3-((7-(2-((2S,3aS,7aS)-1-((methoxycarbonyl)-L-) Prolyl) octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl -2-Azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

(1R,3S,4S)-N-(9,9-Dimethyl-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H-benzene And [d] imidazolium-6-yl)-9H-indol-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide as a starting material, referring to step 11 of Example 1, to obtain a (S)-1-((1R,3S,4S)-3-((7-(2-((2S,3aS,7aS)-1-((methoxycarbonyl)-L-prolyl) Octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-2- Azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 886.30 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.72 (s, 1H), 7.82 - 7.46 (m, 8H), 7.30 (d, J = 8.4 Hz, 1H), 5.47 (d, J = 8.8 Hz, 1H) , 4.47-4.43 (m, 1H), 4.32-4.27 (m, 1H), 4.22 (t, J = 8.4 Hz, 1H), 3.70 (s, 6H), 3.38 (d, J = 10.4 Hz, 1H), 3.15(s,1H), 2.52-2.47(m,1H), 2.38-2.30(m,1H),1.74-1.68(m,6H),1.47-1.49(m,8H),1.44(s,2H), 1.26 (s, 6H), 1.07 (d, J = 6.8 Hz, 4H), 0.94 - 0.95 (m, 7H), 0.79 (d, J = 6.4 Hz, 3H).

Example 7 Methyl ((S)-1-((S)-2-(5-(4-(7-((S))-1-((carbomethoxy))-L-prolyl)pyrrolidine -2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl -1-carbonylbutan-2-yl)carbamate

First step: 2-(2-(4-bromophenyl)-2-carbonylethyl)1-(tert-butyl)(S)-pyrrolidine-1,2-dicarboxylate

a mixed solution of 2-bromo-1-(4-bromophenyl)ethane-1-one (20 g, 72 mmol) and L-Boc valine (18.7 g, 87 mmol) in acetonitrile (160 mL) at 0 °C Triethylamine (15 mL) was added dropwise dropwise and stirred at room temperature for 2 hr. After the reaction was completed, the reaction mixture was evaporated, evaporated, mjjjjjjjjjjjjjjj (2-(4-Bromophenyl)-2-carbonylethyl) 1-(tert-butyl)(S)-pyrrolidine-1,2-dicarboxylate (27 g).

Second step: tert-butyl(S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

2-(2-(4-Bromophenyl)-2-carbonylethyl) 1-(tert-butyl)(S)-pyrrolidine-1,2-dicarboxylate (27 g) and ammonium acetate ( 50.6 g) was dissolved in xylene (2700 mL) and stirred at 140 ° C until the starting material was completely reacted. After cooling to room temperature, the solvent was evaporated,jjjjjjjjjjjjjjjjjjjjjjjj (S)-2-(5-(4-Bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (15.7 g).

LC-MS m/z: </RTI>^</RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIgt;

The third step: tert-butyl (S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene -1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Under the protection of nitrogen, tert-butyl(S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (10 g), double (frequency) Alcohol) diborane (13.0 g), tetrakistriphenylphosphine palladium (1.5 g), potassium carbonate (10.5 g) was dissolved in DME (100 mL) and water (10 mL), and the mixture was stirred at 80 ° C for 12 hours. After the reaction was cooled to room temperature, water (100 mL) and ethyl acetate (100 mL) was evaporated, evaporated, evaporated, evaporated. Separation of ether/ethyl acetate) gave tert-butyl(S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)- 2-Based)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (6.3 g).

LC-MS m/z: 440.20 [M+H] ⁺ .

Fourth step: tert-butyl(S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate

Using 7-bromo-9,9-dimethyl-9H-indol-2-amine as the starting material, referring to step 8 of Example 1, to obtain tert-butyl(S)-2-((7-bromo-9,9) -Dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.69 (br, 1H), 7.79 (s, 1H), 7.57 (d, 1H), 7.51-7.41 (m, 3H), 7.32 (d, 1H), 4.51- 4.48 (m, 1H), 3.52-3.25 (m, 2H), 2.60-2.53 (m, 1H), 2.04-1.94 (m, 3H), 1.5-1.45 (m, 15H).

Step 5: tert-Butyl (S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole -5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate

Starting from tert-butyl(S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate, refer to the implementation Step 9 of Example 1, to give tert-butyl(S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H) -Imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate.

LC-MS m/z: 718.30 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.21-11.84 (m, 1H), 10.09 (d, 1H), 7.87-7.52 (m, 10H), 4.86 - 4.79 (m, 1H), 4.31-4.22 (m, 1H), 3.58-3.51 (m, 1H), 3.47-3.34 (m, 3H), 2.28-2.15 (m, 2H), 1.93-1.79 (m, 6H), 1.48-1.30 (m, 18H) , 1.19-1.16 (m, 6H).

Step 6: (S)-N-(9,9-Dimethyl-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl) )-9H-indol-2-yl)pyrrolidine-2-carboxamide

tert-Butyl(S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-5-) Base) Phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate is used as a starting material. Referring to step 10 of Example 1, (S)-N-( 9,9-Dimethyl-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H-indol-2-yl)pyrrole Alkano-2-carboxamide.

LC-MS m/z: 518.30 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ10.73 (s, 1H), 9.82 (br, 1H), 9.55-9.52 (m, 1H), 9.20 (br, 1H), 8.73-8.70 (m, 1H ), 7.92-7.81 (m, 8H), 7.72-7.69 (m, 1H), 7.61-7.57 (m, 1H), 4.89-4.83 (m, 1H), 4.39-4.36 (m, 1H), 3.38-3.26 (m, 4H), 2.46-2.38 (m, 2H), 2.32 - 2.23 (m, 1H), 2.21-2.11 (m, 1H), 2.09-1.94 (m, 4H), 1.50 (s, 6H).

Step 7: Methyl ((S)-1-((S)-2-(5-(4-(7-((S)-1-((methyl))))) Alkanol-2-carbooxalylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl Alkyl-1-carbonylbutan-2-yl)carbamate

(S)-N-(9,9-Dimethyl-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H -Indol-2-yl)pyrrolidine-2-carboxamide as a starting material, referring to Step 11 of Example 1, to give methyl ((S)-1-((S)-2-(5-(4-(7-) ((S)-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl -1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 832.50 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ10.13 (br, 1H), 7.85-7.53 (m, 12H), 7.35-7.27 (m, 2H), 5.10-5.08 (m, 1H), 4.51-4.48 (m, 1H), 4.10-4.02 (m, 2H), 3.89-3.79 (m, 3H), 3.69-3.66 (m, 1H), 3.54 (d, J = 2 Hz, 6H), 2.20- 1.90 (m, 10H), 1.48 (s, 6H), 0.98-0.86 (m, 12H).

Example 8 Methyl ((S)-1-((S)-2-(5-(7-((S)-1-((methoxycarbonyl)-L-prolyl)pyrrolidine-2- Carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl- 1-carbonylbutan-2-yl)carbamate

First step: tert-butyl(S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl))pyrrolidin-2-yl)-1H-benzo[d Imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate

Starting from tert-butyl(S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate, refer to the implementation Step 9 of Example 1 gave tert-butyl(S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzene) [d] Imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate.

LC-MS m/z: 692.35 [M+H] ⁺ .

Second step: (S)-N-(9,9-dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl) -9H-indol-2-yl)pyrrolidine-2-carboxamide

Tert-butyl(S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazole- 5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate as a starting material, referring to step 10 of Example 1, to obtain (S)-N- (9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)pyrrole Alkano-2-carboxamide.

LC-MS m/z: 492.30 [M+H] ⁺ .

The third step: methyl ((S)-1-((S)-2-(5-(7-((S)-1-((methoxycarbonyl)-L-prolyl)pyrrolidine-2 -carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl -1-carbonylbutan-2-yl)carbamate

(S)-N-(9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9H- Using indole-2-yl)pyrrolidine-2-carboxamide as a starting material, referring to Step 11 of Example 1, to give methyl ((S)-1-((S)-2-(5-(7-((S))) 1-(((methoxycarbonyl)-L-prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 806.35 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ12.19 (s, 1H), 10.13 (s, 1H), 7.88-7.74 (m, 4H), 7.66-7.51 (m, 6H), 7.34 (t, J = 8.0 Hz, 1H), 5.22 (s, 1H), 4.51-4.48 (m, 1H), 4.15-3.98 (m, 2H), 3.88-3.81 (m, 2H), 3.68-3.61 (m, 2H), 3.55-3.52 (m, 6H), 2.29-2.15 (m, 3H), 2.07-1.90 (m, 5H), 1.48 (s, 6H), 0.97 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.88 - 0.83 (m, 8H).

Example 9 Methyl ((S)-1-((S)-2-(5-(4-(7-(2S,4S)-4-fluoro-1-((methyl))-L- Prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl (2S,4S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1 -carboxylate

Using 7-bromo-9,9-dimethyl-9H-indol-2-amine as the starting material, referring to step 8 of Example 1, to obtain tert-butyl(2S,4S)-2-((7-bromo-9) , 9-Dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 7.84-7.70 (m, 4H), 7.58-7.49 (m, 2H), 5.36-5.22 (m, 1H), 4.44-4.36 (m, 1H), 3.69-3.62 (m, 2H), 2.64-2.53 (m, 1H), 2.32-2.23 (m, 1H), 1.43-1.33 (m, 15H).

Second step: tert-butyl(2S,4S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H) -imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

Tert-butyl(2S,4S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylic acid The ester was used as a starting material. Referring to Step 9 of Example 1, t-butyl(2S,4S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrole) was obtained. Alkan-2-yl)-1H-imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylic acid ester.

LC-MS m/z: 736.30 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.22-11.84 (m, 1H), 9.95 (s, 1H), 7.85-7.52 (m, 11H), 5.36-5.23 (m, 1H), 4.87-4.78 (m, 1H), 4.45-4.37 (m, 1H), 3.70-3.54 (m, 3H), 3.40-3.33 (m, 1H), 2.68-2.56 (m, 2H), 2.33-2.18 (m, 2H) , 1.96-1.83 (m, 2H), 1.49-1.34 (m, 18H), 1.19-1.16 (m, 6H).

The third step: (2S, 4S)-N-(9,9-dimethyl-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)) Phenyl)-9H- 芴-2-yl)-4-fluoropyrrolidine-2-carboxamide

tert-Butyl (2S,4S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl))pyrrolidin-2-yl)-1H-imidazole- 5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate as a starting material, refer to step 10 of Example 1, (2S,4S)-N-(9,9-Dimethyl-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl) -9H-indol-2-yl)-4-fluoropyrrolidine-2-carboxamide.

LC-MS m/z: 536.31 [M+H] ⁺ .

The fourth step: methyl ((S)-1-((S)-2-(5-(4-(7S)4S)-4-fluoro-1-((carbomethoxy)-L) -prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1- Benzyl-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,4S)-N-(9,9-Dimethyl-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl) -9H-Indol-2-yl)-4-fluoropyrrolidine-2-carboxamide was used as a starting material. Referring to Step 11 of Example 1, methyl ((S)-1-((S)-2-(5-) was obtained. (4-(7-(2S,4S)-4-fluoro-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl Benyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 851.3 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO)} δ12.25-11.79 (m, 1H), 10.02 (s, 1H), 7.97-7.19 (m, 13H), 5.48-5.34 (m, 1H), 5.09-5.06 (m, 1H), 4.70-4.67 (m, 1H), 4.20-3.92 (m, 4H), 3.84-3.78 (m, 2H), 3.54 (s, 6H), 2.60-2.55 (m, 1H), 2.37-2.28 ( m, 1H), 2.18-2.13 (m, 2H), 2.02-1.97 (m, 4H), 1.49 (s, 6H), 1.04-0.88 (m, 12H).

Example 10 Methyl ((S)-1-((S)-2-(5-(7-((2S,4S)-4-fluoro-1-((carbomethoxy))-L-prolyl) Pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl) -3-methyl-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl (2S,4S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo) [d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl-4-fluoropyrrolidine-1-carboxylate

Tert-butyl(2S,4S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylic acid The ester was used as a starting material. Referring to Step 9 of Example 1, tert-butyl(2S,4S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2) was obtained. -yl)-1H-benzo[d]imidazol-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl-4-fluoropyrrolidine-1-carboxylate .

LC-MS m/z: 710.35 [M+H] ⁺ .

The second step: (2S, 4S)-N-(9,9-dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5- Base)-9H-indol-2-yl)-4-fluoropyrrolidine-2-carboxamide

tert-Butyl (2S,4S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d] Imidazole-5-yl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate is used as a starting material, and is obtained by referring to step 10 of Example 1. (2S,4S)-N-(9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9H -Indol-2-yl)-4-fluoropyrrolidine-2-carboxamide.

LC-MS m/z: 510.30 [M+H] ⁺ .

The third step: methyl ((S)-1-((S)-2-(5-(7-((2S,4S)-4-fluoro-1-((methyl ester)))) Acyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,4S)-N-(9,9-Dimethyl-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)- 9H-Indol-2-yl)-4-fluoropyrrolidine-2-carboxamide was used as a starting material. Referring to Step 11 of Example 1, methyl ((S)-1-((S)-2-(5-( 7-((2S,4S)-4-fluoro-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H- Ind-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 824.35 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO) δ 12.21. (s, 1H), 9.97 (s, 1H), 7.86-7.72 (m, 5H), 7.67-7.45 (m, 5H), 7.34 (d, J = 8.4 Hz) , 1H), 5.22 (s, 1H), 4.69 (d, J = 10.0 Hz, 1H), 4.21-3.81 (m, 6H), 3.54 (d, J = 2.8 Hz, 6H), 2.38-2.20 (m, 3H), 2.13 - 1.89 (m, 4H), 1.48 (s, 6H), 1.04 (d, J = 8.0 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.88-0.83 (m, 8H) ).

Example 11 Methyl ((S)-1-((2S,4S)-4-fluoro-2-(5-(4-(7-((2S,4S)-4-fluoro-1-((A) Ester)-L-prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl) Pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

First step: 2-(2-(4-bromophenyl)-2-carbonylethyl) 1-(tert-butyl)(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid ester

2-Bromo-1-(4-bromophenyl)ethane-1-one (10.0 g, 36.0 mmol) was dissolved in acetonitrile (100 ml), triethylamine (5.5 g, 54.0 mmol), 20-30 (2S,4S)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (10.1 g, 43.2 mmol) was added portionwise, and the mixture was stirred at room temperature for 16 hr. The acetonitrile was removed by rotary evaporation. EtOAc (EtOAc m. -carbonylethyl) 1-(tert-butyl)(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (10.5 g).

LC-MS m/z: 330.1 (M-Boc+H) ⁺ .

Second step: tert-butyl(2S,4S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate

2-(2-(4-Bromophenyl)-2-carbonylethyl) 1-(tert-butyl)(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (10.5 g, 24.4 mmol) was dissolved in xylene (100 ml), and ammonium acetate (18.8 g, 243.9 mmol) was added, and the mixture was refluxed for 16 hours. Dimethylbenzene was concentrated to remove the residue. EtOAc (EtOAc) (EtOAcjjjjjjjjj -1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate (3.8 g).

LC-MS m/z: 410.0 [M+H] ⁺ .

The third step: tert-butyl (2S, 4S)-4-fluoro-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) -2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

tert-Butyl (2S,4S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate, bis-pinacol Diboron (4.7 g, 18.5 mmol), Pd(PPh ₃ ) ₄ (0.54 g, 0.46 mmol) and K ₂ CO ₃ (3.8 g, 27.8 mmol) were added to a mixed solvent of DME (40 ml) and water (4 ml). The gas was purged three times with nitrogen, and the reaction was stirred under reflux for 16 hours. The DME was concentrated to remove ethyl acetate (60 ml) and water (20 ml), and the organic layer was concentrated, and the residue was purified by column chromatography to give tert-butyl(2S,4S)-4-fluoro-2-(5- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate Acid ester (1.4 g).

LC-MS m/z: 458.2 (M+H) ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84-7.29 (m, 5H), 5.49-5.25 (m, 2H), 4.07-3.42 (m, 2H), 2.91-2.47 (m, 2H), 1.50-1.31 (m, 21H).

The fourth step: tert-butyl (2S, 4S)-2-((7-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine- 2-yl)-1H-imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl-4-fluoropyrrolidine-1-carboxylate

Tert-butyl(2S,4S)-2-((7-bromo-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylic acid The ester was used as a starting material. Referring to Step 9 of Example 1, t-butyl(2S,4S)-2-((7-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl) group) was obtained. )-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrole Alken-1-carboxylate.

LC-MS m/z: 754.30 [M+H] ⁺ .

Step 5: (2S,4S)-4-fluoro-N-(7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl) Phenyl)-9,9-dimethyl-9H-indol-2-yl)pyrrolidine-2-carboxamide

tert-Butyl (2S,4S)-2-((7-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl) )-1H-imidazol-5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate as a raw material, reference Step 11 of Example 1 gave (2S,4S)-4-fluoro-N-(7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazole- 5-yl)phenyl)-9,9-dimethyl-9H-indol-2-yl)pyrrolidine-2-carboxamide.

LC-MS m/z: 554.30 [M+H] ⁺ .

The sixth step: methyl ((S)-1-((2S,4S)-4-fluoro-2-(5-(4-(7-((2S,4S)-4-fluoro-1-(( Methyl ester)-L-prolyl)pyrrolidine-2-carbamoylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl Pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,4S)-4-fluoro-N-(7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl -9,9-Dimethyl-9H-indol-2-yl)pyrrolidine-2-carboxamide as a starting material, referring to Step 11 of Example 1, to obtain methyl ((S)-1-((2S, 4S) )-4-fluoro-2-(5-(4-(7-((2S,4S)-4-fluoro-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbon Oxalylamino)-9,9-dimethyl-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonyl Alk-2-yl)carbamate.

LC-MS m/z: 868.45 [M+H] ⁺ ;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.20 (s, 1H), 7.85-7.74 (m, 2H), 7.65-7.55 (m, 7H), 7.48 (d, J = 6.4Hz, 1H), 5.01 ( d, J=9.2 Hz, 1H), 4.36-4.07 (m, 4H), 4.02-3.94 (m, 3H), 3.70 (s, 6H), 2.39-1.91 (m, 6H), 1.48 (s, 6H) , 1.26 (s, 6H), 1.08-1.02 (m, 8H).

Example 12 Methyl ((S)-1-((S)-2-(5-(9,9-difluoro-7-((2S,3aS,7aS)-1-((methyl ester))- L-prolyl) octahydro-1H-indole-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- Benzyl-3-methyl-1-carbonylbutan-2-yl)carbamate

First step: 2-iodo-7-nitro-9H-oxime

2-Nitro-9H-indole (18.6 g, 88.1 mmol) and elemental iodine (11.1 g, 44.0 mmol) were added to acetic acid (560 ml), and concentrated sulfuric acid (56 ml) and NaNO ₂ (6.1 g, 88.1) were added with stirring. Methyl), the reaction was stirred under reflux for 2 hours. After cooling to room temperature, the reaction solution was poured into 500 g of ice water, filtered, and the filter cake was added to 150 ml of ethyl acetate, and stirred under reflux for 1 hour, cooled to room temperature and stirred for 16 hours, and filtered to give 2-iodo-7-nitro -9H-芴 (24.0g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J = 1.2 Hz, 1H), 8.23 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H) ), 7.78 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H).

The second step: 9,9-difluoro-2-iodo-7-nitro-9H-oxime

2-iodo-7-nitro-9H-indole (10.1 g, 30 mmol) and NFSI (30 g) were placed in a 100 ml three-necked flask. Under nitrogen, THF (210 mL) was added and cooled to -30 ° C. KHMDS solution (1.0 M, 100 ml) was added, and the reaction was maintained at -20 ° C to 0 ° C for 2 hours. The reaction was completely completed by TLC, and the reaction was quenched by pouring a saturated ammonium chloride solution (150 mL) at a temperature below 10 ° C. The organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phase is combined, dried over anhydrous sodium sulfate and evaporated to dryness, and the residue is purified by silica gel column chromatography to give 9,9-difluoro-2-iodo-7-nitro -9H-芴 (11.2g).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.46 (d, J = 1.6Hz, 1H), 8.39 (dd, J = 8.4Hz, J = 1.6Hz, 1H), 7.85 (d, J = 1.2Hz, 1H ), 7.70 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H).

The third step: 9,9-difluoro-7-iodo-9H-indol-2-amine

9,9-Difluoro-2-iodo-7-nitro-9H-indole (10.6 g, 30 mmol) was dissolved in ethyl acetate (100 ml), and stannous chloride dihydrate (20.3 g, 90 mmol) was added and heated. The reaction was carried out at 75 ° C for 2.5 hours. The mixture was cooled to room temperature, and the mixture was poured into EtOAc EtOAc (EtOAc) Concentrated to dryness and the residue was purified eluted eluted eluting eluting

LC-MS m/z: 344. s[M+H] ⁺ .

The fourth step: tert-butyl (2S, 3aS, 7aS)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl) octahydro-1H-indole 1-carboxylic acid ester

Using 9,9-difluoro-7-iodo-9H-indol-2-amine as the starting material, referring to step 8 of Example 1, to obtain tert-butyl (2S, 3aS, 7aS)-2-((9,9-) Difluoro-7-iodo-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate.

LC-MS m/z: 495.10 [M-Boc+H] ⁺ .

The fifth step: tert-butyl (2S, 3aS, 7aS)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H- Benzo[d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate

tert-Butyl (2S,3aS,7aS)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1- The carboxylic acid ester was used as a raw material, and referring to Step 9 of Example 1, a tert-butyl (2S, 3aS, 7aS)-2-((7-(2-((S))) was obtained. 1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamate Acyl) octahydro-1H-indole-1-carboxylate.

LC-MS m/z: 754.30 [M+H] ⁺ .

Step 6: (2S, 3aS, 7aS)-N-(9,9-Difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5 -yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide

Tert-butyl(2S,3aS,7aS)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[ d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate as a starting material, refer to step 10 of Example 1. , (2S, 3aS, 7aS)-N-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5-yl) )-9H-indol-2-yl) octahydro-1H-indole-2-carboxamide.

LC-MS m/z: 552.20 [M+H] ⁺ .

Step 7: Methyl ((S)-1-((S)-2-(5-(9,9-difluoro-7-((2S,3aS,7aS)-1-((carbomethoxy)) -L-prolyl) octahydro-1H-indole-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1 -yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,3aS,7aS)-N-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5-yl) -9H-Indol-2-yl) octahydro-1H-indole-2-carboxamide was used as a starting material. Referring to Step 11 of Example 1, methyl ((S)-1-((S)-2-(5) was obtained. -(9,9-difluoro-7-((2S,3aS,7aS)-1-((carbomethoxy)-L-prolyl) octahydro-1H-indole-2-carbamoylamino )-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamic acid ester.

LC-MS m/z: 868.30 [M+H] ⁺

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.28 (d, J = 12 Hz, 1H), 10.42 (s, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.89-7.76 (m) , 4H), 7.65-7.52 (m, 4H), 7.32 (d, J = 8.4 Hz, 1H), 5.21 (s, 1H), 4.44 (t, J = 8.8 Hz, 1H), 4.37-4.31 (m, 1H), 4.09 (t, J = 8.4 Hz, 1H), 3.87-3.82 (m, 3H), 3.54 (d, J = 2.4 Hz, 6H), 2.34-1.91 (m, 10H), 1.75-1.60 (m , 3H), 1.45-1.16 (m, 4H), 0.92-0.83 (m, 12H).

Example 13 Methyl ((2S,3R)-1-((2S)-2-(5-(9,9-difluoro-7-((2S,3aS,7aS)-1-((3R)-) 3-methoxy-2-((carbomethoxy)amino)butyryl)octahydro-1H-indole-2-carbamoylamino)-9H-indole-2- -1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-carbonylbutan-2-yl)carbamate

(2S,3aS,7aS)-N-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5-yl) -9H-Indol-2-yl) octahydro-1H-indole-2-carboxamide was used as a starting material. Refer to Step 11 of Example 1 to obtain methyl ((2S,3R)-1-((2S)-2-) (5-(9,9-Difluoro-7-((2S,3aS,7aS)-1-((3R)-3-methoxy-2-((methyl)))))) -1H-indole-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy 1-carbonylcarbonylbutan-2-yl)carbamate.

LC-MS m/z: 900.30 [M+H] ⁺ ;

_{^{1 H NMR (DMSO-d 6}} , 400MHz) δ12.28 (s, 1H), 10.41 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.89-7.80 (m, 4H), 7.65-7.53 (m, 4H), 7.27 (d, J = 7.6 Hz, 1H), 5.21-5.19 (m, 1H), 4.43 (t, J = 9.2 Hz, 1H), 4.37-4.29 (m, 2H) , 4.10 (t, J = 8.0 Hz, 1H), 3.90-3.88 (m, 2H), 3.55 (d, J = 2.0 Hz, 6H), 3.50-3.46 (m, 2H), 3.24 (s, 3H), 3.19 (s, 3H), 2.35-1.91 (m, 8H), 1.76-1.64 (m, 3H), 1.46-1.16 (m, 4H), 1.10-1.07 (t, J = 5.6 Hz, 6H).

Example 14 Methyl ((S)-1-((2S,3aS,7aS)-2-((9,9-difluoro-7-(2-((2S,3aS,7aS)-1-(( Methoxycarbonyl)-L-prolyl) octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)carbamoyl) Octahydro-1H-indol-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl (2S, 3aS, 7aS)-2-((7-(2-((2S,3aS,7aS)-1-(tert-butoxycarbonyl) octahydro-1H-indole) Ind-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)octahydro-1H-indole-1- Carboxylic ester

tert-Butyl (2S,3aS,7aS)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1- The carboxylic acid ester was used as a raw material, and referring to Step 9 of Example 1, a tert-butyl (2S, 3aS, 7aS)-2-((7-(2-(2)) was obtained. S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9,9-difluoro -9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate.

LC-MS m/z: 808.30 [M+H] ⁺ .

Second step: (2S, 3aS, 7aS)-N-(9,9-difluoro-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H) -benzo[d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide

(2S,3aS,7aS)-2-((7-(2-((2S,3aS,7aS)-1-(tert-butoxycarbonyl) octahydro-1H-indol-2-yl)-) 1H-benzo[d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl) octahydro-1H-indole-1-carboxylate as a raw material, reference Step 11 of Example 1 gave (2S,3aS,7aS)-N-(9,9-difluoro-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl) -1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide.

LC-MS m/z: 608.30 [M+H] ⁺ .

The third step: methyl ((S)-1-((2S,3aS,7aS)-2-((9,9-difluoro-7-(2-((2S,3aS,7aS)-1-) (methyl ester group)-L-prolyl) octahydro-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)carbamoyl ) octahydro-1H-indol-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,3aS,7aS)-N-(9,9-Difluoro-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H-benzo [d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide was used as a starting material. Step 11 of Example 1 was obtained to give methyl ((S)-1- ((2S,3aS,7aS)-2-((9,9-Difluoro-7-(2-((2S,3aS,7aS)-1-((carbomethoxy)-L-prolyl)) Hydrogen-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)carbamoyl)octahydro-1H-indol-1-yl) -3-Methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 922.30 [M+H] ⁺ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.26 (s, 1H), 10.42 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.90-7.80 (m, 4H), 7.65-7.50 (m, 5H), 5.12-5.09 (m, 1H), 4.45 (t, J = 8.8 Hz, 2H), 4.37-4.33 (m, 1H), 3.85 (t, J = 8.4 Hz, 2H) , 3.55 (d, J = 4.4 Hz, 6H), 2.45 - 2.31 (m, 3H), 2.23 - 2.05 (m, 2H), 2.03-1.69 (m, 11H), 1.51-1.15 (m, 8H), 0.92 -0.69 (m, 12H).

Example 15 Methyl ((2S,3R)-1-((2S,3aS,7aS)-2-(5-(9,9-difluoro-7-((2S,3aS,7aS)-1-) N-(methyl ester)-O-methyl-L-threonyl) octahydro-1H-indole-2-carbamoylamino)-9H-indole-2- -1H-benzo[d]imidazol-2-yl)octahydro-1H-indol-1-yl)-3-methoxy-1-carbonylbutan-2-yl)carbamate

(2S,3aS,7aS)-N-(9,9-Difluoro-7-(2-((2S,3aS,7aS)-octahydro-1H-indol-2-yl)-1H-benzo [d]imidazol-5-yl)-9H-indol-2-yl)octahydro-1H-indole-2-carboxamide was used as a starting material. Step 11 of Example 1 gave methyl ((2S,3R)- 1-((2S,3aS,7aS)-2-(5-(9,9-difluoro-7-((2S,3aS,7aS)-1-(N-(carbomethoxy)-O-methyl) -L-threonyl) octahydro-1H-indole-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)octahydro-1H -Indol-1-yl)-3-methoxy-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 954.40 [M+H] ⁺

_{^{1 H NMR (DMSO-d 6}} , 400MHz) δ12.37 (s, 1H), 10.42 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.90-7.80 (m, 4H), 7.65-7.53 (m, 5H), 5.13-5.08 (m, 1H), 4.46-4.41 (m, 2H), 4.39-4.33 (m, 1H), 4.10 (t, J = 6.8 Hz, 2H), 3.55 ( d, J=4.0 Hz, 6H), 3.50-3.38 (m, 2H), 3.24 (s, 3H), 3.17 (s, 3H), 2.41-2.30 (m, 3H), 2.25-2.09 (m, 2H) , 2.02-1.91 (m, 3H), 1.76-1.63 (m, 6H), 1.51-1.21 (m, 8H), 1.10 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H ).

Example 16 Methyl ((S)-1-((S)-2-(5-(4-(9,9-difluoro-7-((S))-1-((methoxycarbonyl)-L) -prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl- 1-carbonylbutan-2-yl)carbamate

First step: tert-butyl(S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate

Using 9,9-difluoro-7-iodo-9H-indol-2-amine as the starting material, referring to step 8 of Example 1, to obtain tert-butyl(S)-2-((9,9-difluoro-7) - Iodo-9H-indol-2-yl)carbamoyl pyrrolidine-1-carboxylate.

LC-MS m/z: 441.0 [M - 100+H] ⁺ .

Second step: tert-butyl(S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole -5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate

Starting from tert-butyl(S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate, refer to the examples. 1 step 9, to give tert-butyl (S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-) Imidazol-5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate.

LC-MS m/z: 726.36 [M+H] ⁺ .

The third step: (S)-N-(9,9-difluoro-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl) -9H-indol-2-yl)pyrrolidine-2-carboxamide

tert-Butyl(S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-5-) (phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate as a starting material, referring to step 10 of Example 1, to obtain (S)-N- (9,9-Difluoro-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H-indol-2-yl)pyrrole Alkano-2-carboxamide.

LC-MS m/z: 526.30 [M+H] ⁺ .

The fourth step: methyl ((S)-1-((S)-2-(5-(4-(9,9-difluoro-7-((S)-1-((methoxycarbonyl))-) L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl -1-carbonylbutan-2-yl)carbamate

(S)-N-(9,9-Difluoro-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H-芴-2-yl)pyrrolidine-2-carboxamide was used as a starting material. Referring to Step 11 of Example 1, methyl ((S)-1-((S)-2-(5-(4-(9)9) was obtained. -difluoro-7-((S)-1-((methoxycarbonyl)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)- 1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 858.40 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO)} δ12.0-11.65 (m, 1H), 10.41 (s, 1H), 8.11-7.57 (m, 10H), 7.43-7.32 (m, 2H), 7.07-6.98 (m, 1H), 5.53-5.29 (m, 2H), 4.48-4.45 (m, 1H), 4.13-3.63 (m, 6H), 3.55-3.53 (m, 6H), 2.67-2.41 (m, 1H), 2.23 2.18 (m, 2H), 2.09-1.91 (m, 6H), 1.06-0.82 (m, 12H).

Example 17 Methyl ((S)-1-((2S,4S)-2-(5-(4-(9,9-difluoro-7-((S)-1-((methyl))) -L-prolyl)pyridin Prolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidin-1-yl)-3-methyl-1 -carbonylbutane-2-yl)carbamate

First step: tert-butyl(2S,4S)-2-(5-(4-(7-((S))-1-(tert-butoxycarbonyl)pyrrolidine-2-carbamoylamino )-9,9-difluoro-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate

Starting from tert-butyl(S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate, refer to the examples. 1 step 9, to give tert-butyl (2S,4S)-2-(5-(4-(7-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbamoyl) Amino)-9,9-difluoro-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate.

LC-MS m/z: 744.30 [M+H] ⁺ .

The second step: (S)-N-(9,9-difluoro-7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazole-5- Phenyl)-9H-indol-2-yl)pyrrolidine-2-carboxamide

tert-Butyl (2S,4S)-2-(5-(4-(7-((S))-1-(tert-butoxycarbonyl)pyrrolidine-2-carbamoylamino)-9 , 9-difluoro-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate as a starting material, referring to step 10 of Example 1, to obtain S)-N-(9,9-difluoro-7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl) -9H-indol-2-yl)pyrrolidine-2-carboxamide.

LC-MS m/z: 544.30 [M+H] ⁺ .

The third step: methyl ((S)-1-((2S,4S)-2-(5-(4-(9,9-difluoro-7-((S)-1-) (carbomethoxy) )-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate

(S)-N-(9,9-Difluoro-7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)benzene The base (-9H-indol-2-yl)pyrrolidine-2-carboxamide was used as a starting material. Referring to Step 11 of Example 1, methyl ((S)-1-((2S,4S)-2-(5- (4-(9,9-Difluoro-7-((S)-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indole-2 -yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 858.40 [M+H] ⁺ ;

_{^{1 H NMR (DMSO-d 6}} , 400MHz) δ11.73 (br, 1H), 10.41 (s, 1H), 8.11-7.57 (m, 10H), 7.43 (m, 2H), 7.01-6.98 (m, 1H ), 5.53-5.40 (m, 1H), 5.34-5.29 (m, 1H), 4.48-4.45 (m, 1H), 4.11-3.66 (m, 6H), 3.55-3.53 (m, 6H), 2.52-2.48 (m, 1H), 2.23-2.16 (m, 1H), 2.10 to 1.91 (m, 6H), 1.02-0.82 (m, 12H).

Example 18 Methyl ((S)-1-((S)-2-((9,9-difluoro-7-(2-((S))-1-((carbomethoxy)-L-oxime) Aminoacyl pyrrolidine-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-indol-2-yl)carbamoylpyrrolidin-1-yl)-3-methyl- 1-carbonylbutan-2-yl)carbamate

First step: tert-butyl(S)-2-((7-(2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d] Imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate

Starting from tert-butyl(S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate, refer to the examples. 1-Step 9 gives tert-butyl(S)-2-((7-(2-((R)-1-(tert-butoxycarbonyl))pyrrolidin-2-yl)-1H-benzo[ d] Imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate.

LC-MS m/z: 700.30 [M+H] ⁺ .

Second step: (S)-N-(9,9-difluoro-7-(2-((R)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)- 9H-indol-2-yl)pyrrolidine-2-carboxamide

Tert-butyl(S)-2-((7-(2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazole -5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate as a starting material, referring to step 10 of Example 1, to obtain (S)-N- (9,9-Difluoro-7-(2-((R)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indol-2-yl)pyrrolidine -2-carboxamide.

LC-MS m/z: 500.27 [M+H] ⁺ .

The third step: methyl ((S)-1-((S)-2-((9,9-difluoro-7-(2-((S))-1-((methyl))-L- Prolyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-indol-2-yl)carbamoylpyrrolidin-1-yl)-3-methyl -1-carbonylbutan-2-yl)carbamate

(S)-N-(9,9-Difluoro-7-(2-((R)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indole -2-yl)pyrrolidine-2-carboxamide was used as the starting material, and the methyl group ((S)-1-((S)-2-((9,9-difluoro-7-) was obtained according to the step 11 of Example 1. (2-((S)-1-((carbomethoxy)-L-prolyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-indole-2 -yl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 814.40 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.28 (d, 1H), 10.39 (s, 1H), 8.11-7.32 (m, 11H), 5.21-5.19 (m, 1H), 4.48-4.44 (m, 1H) , 4.11-4.00 (m, 2H), 3.86-3.82 (m, 3H), 3.69-3.66 (m, 1H), 3.54 (d, 6H), 2.24-1.91 (m, 10H), 0.98-0.83 (m, 12H).

Example 19 Methyl ((S)-1-((S)-2-(5-(4-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-(( Methyl ester)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl) -3-methyl-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl (2S,4S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1- Carboxylic ester

Using 9,9-difluoro-7-iodo-9H-indol-2-amine as a starting material, referring to Step 8 of Example 1, to obtain tert-butyl(2S,4S)-2-((9,9-difluoro) -7-iodo-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

LC-MS m / z: 459.00 [M + H-Boc] +.

Second step: tert-butyl(2S,4S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H) -imidazol-5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

Tert-butyl(2S,4S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate As a raw material, referring to Step 9 of Example 1, a tert-butyl(2S,4S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidine) was obtained. 2-yl)-1H-imidazol-5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

LC-MS m/z: 744.36 [M+H] ⁺ .

The third step: (2S, 4S)-N-(9,9-difluoro-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)benzene Base)-9H-indol-2-yl)-4-fluoropyrrolidine-2-carboxamide

tert-Butyl (2S,4S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl))pyrrolidin-2-yl)-1H-imidazole- 5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate as a starting material, obtained in the same manner as in the first step of Example 1, (2S,4S)-N-(9,9-Difluoro-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H -Indol-2-yl)-4-fluoropyrrolidine-2-carboxamide.

LC-MS m/z: 544.32 [M+H] ⁺ .

The fourth step: methyl ((S)-1-((S)-2-(5-(4-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-() (methyl ester group)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,4S)-N-(9,9-Difluoro-7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)- 9H-Indol-2-yl)-4-fluoropyrrolidine-2-carboxamide was used as a starting material. Referring to Step 11 of Example 1, methyl ((S)-1-((S)-2-(5-( 4-(9,9-Difluoro-7-((2S,4S)-4-fluoro-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbamoylamino)- 9H-Indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 858.40 [M+H] ⁺ ;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.36 (s, 1H), 7.89-7.49 (m, 10H), 5.01 (d, J = 8.8Hz, 1H), 4.44-4.16 (m, 4H), 4.04- 3.87 (m, 3H), 3.71 (s, 6H), 2.24 - 2.02 (m, 7H), 1.26 (s, 6H), 1.10-1.04 (m, 8H).

Example 20 Methyl ((S)-1-((2S,4S)-2-(5-(4-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-) ((methyl ester)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrole Alkyl-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl (2S,4S)-2-((7-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine- 2-yl)-1H-imidazol-5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

Tert-butyl(2S,4S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate As a raw material, referring to Step 9 of Example 1, a tert-butyl(2S,4S)-2-((7-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)) group) was obtained. 4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine- 1-carboxylate.

LC-MS m/z: 662.38 &lt;EMI&^gt;

The second step: (2S, 4S)-N-(9,9-difluoro-7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazole- 5-yl)phenyl)-9H-indol-2-yl)-4-fluoropyrrolidine-2-carboxamide

tert-Butyl (2S,4S)-2-((7-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl) )-1H-imidazol-5-yl)phenyl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate as a raw material, with reference to implementation In step 10 of Example 1, (2S,4S)-N-(9,9-difluoro-7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-) Imidazol-5-yl)phenyl)-9H-indol-2-yl)-4-fluoropyrrolidine-2-carboxamide.

LC-MS m/z: 562.28 [M+H] ⁺ .

The third step: methyl ((S)-1-((2S,4S)-2-(5-(4-(9,9-difluoro-7-((2S,4S)-4-fluoro-1) -((methyl ester)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoro Pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,4S)-N-(9,9-Difluoro-7-(4-(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl) Phenyl)-9H-indol-2-yl)-4-fluoropyrrolidine-2-carboxamide as a starting material, referring to step 11 of Example 1, to give methyl ((S)-1-((2S,4S)) -2-(5-(4-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-((carbomethoxy))-L-prolyl)pyrrolidine-2- Carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidin-1-yl)-3-methyl-1-carbonylbutane- 2-based) carbamate.

LC-MS m/z: 876.40 [M+H] ⁺ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.64 (s, 1H), 10.30 (s, 1H), 8.09-7.28 (m, 13H), 5.53-5.27 (m, 3H), 4.69-4.67 (m) , 1H), 4.25-3.90 (m, 6H), 3.55-3.53 (m, 6H), 2.67-2.29 (m, 3H), 2.10 - 1.91 (m, 3H), 1.05 - 0.85 (m, 12H).

Example 21 Methyl ((S)-1-((S)-2-(5-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-((carboyl)) )-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)- 3-methyl-1-carbonylbutan-2-yl)carbamate

First step: tert-butyl (2S,4S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo) [d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

Tert-butyl(2S,4S)-2-((9,9-difluoro-7-iodo-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate As a starting material, referring to Step 9 of Example 1, t-butyl(2S,4S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-) -1H-benzo[d]imidazol-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

LC-MS m/z: 718.40 [M+H] ⁺ .

The second step: (2S, 4S)-N-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole-5-yl) )-9H-indol-2-yl)-4-fluoropyrrolidine-2-carboxamide

tert-Butyl (2S,4S)-2-((7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d] Imidazole-5-yl)-9,9-difluoro-9H-indol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate is used as a starting material, and is obtained by referring to step 10 of Example 1. 2S,4S)-N-(9,9-Difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9H-indole 2-yl)-4-fluoropyrrolidine-2-carboxamide.

LC-MS m/z: 518.31 [M+H] ⁺ .

The third step: methyl ((S)-1-((S)-2-(5-(9,9-difluoro-7-((2S,4S)-4-fluoro-1-((methyl ester) -L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl) -3-methyl-1-carbonylbutan-2-yl)carbamate

(2S,4S)-N-(9,9-Difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-9H -Indol-2-yl)-4-fluoropyrrolidine-2-carboxamide as a starting material, referring to Step 11 of Example 1, to give methyl ((S)-1-((S)-2-(5-(9) ,9-Difluoro-7-((2S,4S)-4-fluoro-1-((carbomethoxy)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indole- 2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 832.30 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO) δ 12.27 (d, J = 12.1 Hz, 1H), 10.29 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.87-7.81 (m, 4H) ), 7.66-7.44 (m, 4H), 7.32 (d, J = 8.4 Hz, 1H), 5.22 (s, 1H), 4.68 (d, J = 10.4 Hz, 1H), 4.13 - 3.80 (m, 6H) , 3.54 (d, J = 2.8 Hz, 6H), 2.23 - 3.21 (m, 3H), 1.99-1.99 (m, 4H), 1.04 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.5) Hz, 3H), 0.90-0.81 (m, 8H).

Example 22 Methyl ((S)-1-((S)-2-(5-(4-(7-((S)-1-((carbomethoxy))-L-prolyl)pyrrolidine -2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutane-2 -based) carbamate

First step: 7-iodo-9H-indol-2-amine

2-Iodo-7-nitro-9H-indole (3.0 g, 8.9 mmol), iron powder (1.5 g, 26.7 mmol), ammonium chloride (0.95 g, 17.8 mmol) were added to ethanol (135 ml) and water ( In a mixed solvent of 8 ml), the reaction was stirred under reflux for 16 hours. After cooling to room temperature, a 10% sodium carbonate solution (75 ml) was added and stirred for 0.5 hour, filtered, and the filter cake was added to DCM (100 ml), filtered, and the filtrate was concentrated, and the solid was precipitated, filtered, washed with water, and dried to give 7-iodine- 9H-indol-2-amine (2.4 g).

Second step: tert-butyl(S)-2-((7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate

Starting from 7-iodo-9H-indol-2-amine, referring to step 8 of Example 1, a tert-butyl(S)-2-((7-iodo-9H-indol-2-yl)carbamoyl group was obtained. Pyrrolidine-1-carboxylate.

LC-MS m/z: 405.10 (M-Boc+H) ⁺ .

The third step: tert-butyl (S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole -5-yl)phenyl)-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate

Starting from tert-butyl(S)-2-((7-iodo-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate, referring to step 9 of Example 1, to obtain a tert- Butyl(S)-2-((7-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)benzene Base)-9H-indol-2-yl)carbamoyl)pyrrolidine-1-carboxylate.

LC-MS m/z: 690.30 (M+H) ⁺ .

The fourth step: (S)-N-(7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H-indole-2- Pyrrolidine-2-carboxamide

tert-Butyl(S)-2-((7-(4-(2-((S))-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-5-) Starting from phenyl)-9H-indol-2-yl)carbamoylpyrrolidine-1-carboxylate, referring to step 10 of Example 1, to obtain (S)-N-(7-(4-( 2-((S)-Pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H-indol-2-yl)pyrrolidine-2-carboxamide.

LC-MS m/z: 490.29 [M+H] ⁺ .

Step 5: Methyl ((S)-1-((S)-2-(5-(4-(7-((S)-1-((methyl))))) Alkan-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-carbonylbutane- 2-base) ammonia Carbamate

(S)-N-(7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9H-indol-2-yl)pyrrole Starting from alkane-2-carboxamide, referring to Step 11 of Example 1, methyl ((S)-1-((S)-2-(5-(4-(7-((S)-1-)) (methyl ester group)-L-prolyl)pyrrolidine-2-carbamoylamino)-9H-indol-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl )-3-methyl-1-carbonylbutan-2-yl)carbamate.

LC-MS m/z: 804.40 [M+H] ⁺ ;

_{^{1 H NMR (DMSO-d 6}} , 400MHz) δ11.78 (s, 1H), 10.13 (s, 1H), 7.97 (s, 1H), 7.88-7.80 (m, 5H), 7.70-7.68 (m, 3H ), 7.52-7.50 (m, 2H), 7.36-7.29 (m, 2H), 5.10-5.08 (m, 1H), 4.51-4.48 (m, 1H), 4.09-4.02 (m, 2H), 3.97 (s) , 2H), 3.83-3.81 (m, 3H), 3.69-3.63 (m, 1H), 3.54 (d, J = 2.4 Hz, 6H), 2.19-1.91 (m, 10H), 0.98-0.85 (m, 12H) ).

Biological evaluation

I. Determination of the inhibitory activity of wild-type hepatitis C virus HCV gene 1b

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 (Ledipasvir or Dacalatasvir) 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.

4. Experimental results:

The activity of the compound of the present invention and the reference compound (Ledipasvir, Daclatasvir) was determined by the above test, and the IC ₅₀ value of the wild type hepatitis C virus HCV gene 1b inhibitory activity is shown in Table 1:

2. Determination of HCV inhibitory activity of hepatitis C virus with NS5A mutation

The inhibitory activity of the compounds of the present invention against HCV replication of the NS5A mutation was determined using the HCV Replicon Reporter Luciferase Assay.

1. Experimental cell model: HCV replicon luciferase reporter gene transiently transfected Huh-7 cell line, HCV replicon RNA was prepared by in vitro transcription method, and RNA was transfected into Huh-7 cells by electroporation.

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 DMSO was 0.5%. Each experiment contained 1-2 internal reference compounds.

3. Experimental measurement steps:

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

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,

4. Experimental results:

Example Compound of the present invention and with reference to the active compound (daclatasvir) was measured by the above tests, HCV NS5A mutant replicon inhibitory activity IC ₅₀ values in Table 2:

Third, rat plasma PK analysis

The pharmacokinetic test of the test compound was carried out using SD rats (Shanghai Shrek).

■ Mode of administration: single oral administration.

■ Dosage: 5 mg/10 mL/kg.

■ Formulation formulation: 45% 1,2-propanediol and 15% polyethylene glycol 15 hydroxystearate.

■Sampling point: 2, 4, and 6 hours before and after administration.

■ Plasma sampling and sample processing:

1) 0.2 ml of jugular vein blood was collected, placed in an EDTA-2K test tube, centrifuged at 4 ° C for 6000 minutes for 5 minutes to separate plasma, and stored at -80 ° C.

2) Add 160 μL of acetonitrile to 40 μL of plasma sample, standard, and internal reference, vortex for 3 minutes, centrifuge for 4000 minutes for 10 minutes, take 100 μL of supernatant, then add 100 μL of ion-free water to mix, and take 10 μL for LC/MS. /MS analysis, the instrument used for plasma LC/MS/MS analysis was AB Sciex API 4000.

■ Liquid phase analysis:

●Liquid conditions: Shimadzu LC-20AD pump

●Column: phenomenex Gemiu 5um C18 50X 4.6mm

● Mobile phase: A solution is 0.1% formic acid aqueous solution, and B solution is acetonitrile.

●Flow rate: 0.8mL/min

● Elution time: 0-3.01 minutes, the eluent is as follows:

Time/minute

Liquid A

B liquid

0.01	70%	30%
1	10%	90%
2	10%	90%
2.01	70%	30%
3	70%	30%

■ Mass Spectrometry: Mass Spectrometer Setup Conditions: Cationic Electrospray Ionization (ESI) mode.

■ Test results: The main parameters of pharmacokinetics were calculated using WinNonlin 6.1. The experimental results are shown in Table 3:

Fourth, rat liver drug analysis

The concentration of the drug that absorbed the test compound into the liver was performed using SD rats (Shanghai Shrek).

■ Mode of administration: single oral administration.

■ Dosage: 5 mg/10 mL/kg.

■ Formulation formulation: 45% 1,2-propanediol and 15% polyethylene glycol 15 hydroxystearate.

■Sampling point: Rats were administrated overnight after fasting, and liver samples were taken before administration and at 2, 4, and 6 hours after administration. ■ Liver sampling and sample processing:

1) The small leaflets of the liver were sampled, frozen on dry ice, and stored at -80 °C.

2) Add PBS buffer to the liver sample (W/V = 1:5) for homogenization, add 320 μL of acetonitrile to 40 μL of liver sample, standard, and internal reference, vortex for 3 minutes, centrifuge for 4000 minutes for 10 minutes, 100 μL of the supernatant was mixed with 50 μL of ion-free water, and 10 μL was taken for LC/MS/MS analysis. The instrument used for LC/MS/MS analysis was AB Sciex API 4000.

■ Liquid phase analysis:

●Liquid conditions: Shimadzu LC-20AD pump

●Column: phenomenex Gemiu 5um C18 50X 4.6mm

● Mobile phase: A solution is 0.1% formic acid aqueous solution, and B solution is acetonitrile.

●Flow rate: 0.8mL/min

● Elution time: 0-3.01 minutes, the eluent is as follows:

Time/minute

Liquid A

B liquid

0.01	70%	30%
1	10%	90%
2	10%	90%
2.01	70%	30%
3	70%	30%

■ Mass Spectrometry: Mass Spectrometer Setup Conditions: Cationic Electrospray Ionization (ESI) mode.

■ Test results: The main parameters of pharmacokinetics were calculated using WinNonlin 6.1. The experimental results are shown in Table 4:

Claims (16)

1. 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 or C _3-8 cycloalkyl, or R ₁ and R ₁ ' are directly attached to a carbon atom. Forming a 3-6 membered carbon ring or a 3-6 membered heterocyclic ring,

   Optionally further selected from 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, C _1-8 cycloalkyl or C _1- Substituted by a substituent of an ₈ -cycloalkoxy group;

   R ₂ and R ₂ ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy , C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C( O) OR ₉ ,

   Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _{5 10} arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

   R ₃ and R ₃ ' are each independently selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 Heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , or -C _{0- 8} -C(O)NR ₆ R ₇ ,

   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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

   R ₄ and R ₄ ' are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy , C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C( O) OR ₉ ,

   Alternatively, R ₄ or R ₄ ' 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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

   R _{5 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl, C _1-8 alkoxy C _1-8 alkyl, hydroxy C _1-8 Alkyl, -C(O)R ₁₀ or -C(O)OR ₉ ,

   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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent;

   L is selected from a bond, a C _5-10 aryl group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group , C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl Thiothio group, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O) OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C Substituting (O) a substituent of R ₁₀ or -N(R ₆ )-C(O)OR ₉ ;

   M is selected from a bond, a C _5-10 aryl group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, C _1-8 alkyl, C _1-8 alkoxy Substituted by a substituent of a halogen-substituted C _1-8 alkyl group, a halogen-substituted C _1-8 alkoxy group, or a C _1-8 alkylsulfonyl group;

   R ₆ and R ₇ are each independently selected from the group consisting of hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group. , C _5-10 aryl, 5-10 membered heteroaryl, C _1-8 alkyl acyl or C _1-8 alkyl acylamino,

   Optionally further one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, acetylamino, azide, sulfonyl, methylsulfonyl, _C1-8 alkyl, halo substituted _C1-8 alkane a group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _1-8 alkoxy group, a C _1-8 alkoxycarbonyl group, C _1-8 alkylcarbonyl, C _1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryl Alkoxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C _1-8 alkyl Substituted by a substituent of an amino group or a di-C _1-8 alkylamino group;

   R _{8 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl, di C _1-8 alkylamino, phenyl or p-methylphenyl;

   R _{9 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl or hydroxy substituted C _1-8 alkyl;

   R _{10 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, halogen substituted C _1-8 alkyl, halogen Substituting a C _1-8 alkoxy group, a hydroxy-substituted C _1-8 alkyl group or a hydroxy-substituted C _1-8 alkoxy group;

   L and M are not keys at the same time;

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

   r is 0, 1, or 2.
2. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R _{5 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-6 a cycloalkyl group, a halogen-substituted C _1-4 alkyl group, a C _1-4 alkoxy C _1-4 alkyl group, a hydroxy C _1-4 alkyl group, -C(O)R ₁₀ or -C(O)OR ₉ , Optionally further one or more selected from the group consisting of halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _{5 10} arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent.
3. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 2, wherein R _{5 is} selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, and tri Fluoromethyl, cyclopropyl or cyclohexyl.
4. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein L is selected from the group consisting of a bond, a phenyl group or a naphthyl group.
5. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein M is selected from the group consisting of a bond, furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine , pyrimidine, pyridazine, hydrazine, quinoline or benzimidazole.
6. 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 formula (II) or the compound of the formula (III):

   
7. 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, An amino group, a C _1-4 alkyl group, a halogen-substituted C _1-4 alkyl group or a C _3-6 cycloalkyl group, or R ₁ and R ₁ ' form a 3-6 membered carbocyclic ring or a 3- directly bonded carbon atom. 6 yuan heterocyclic ring.
8. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R ₁ and R ₁ ' are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, hydroxyl group, Amino, methyl, ethyl, cyclopropyl or trifluoromethyl, or R ₁ and R ₁ ' form a cyclopropyl, cyclobutyl or cyclopentyl group with a directly attached carbon atom.
9. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₄ and R ₄ ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, and cyano. , nitro, azido, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 a monoheterocyclyloxy group, a 3-6 membered heterocyclylthio group, a C _5-8 aryl group, a C _5-8 aryloxy group, a C _5-8 arylthio group, a 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy, 5-8 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₉ , -C _0-8 -C (O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _0-8 -NR ₆ R ₇ , -C _0-8 -C (O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ ,

   Alternatively, R ₄ or R ₄ ' 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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent.
10. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 9, wherein R ₄ and R ₄ ' are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, and methyl group. , Ethyl or isopropyl, or R ₄ , R ₄ ' together with the tetrahydropyrrole ring to which it is attached form a 6-10 membered nitrogen-containing spiro ring, bridged ring or fused ring, the structure is as follows:

    

    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 ₈ , -C _0-8 -OR ₉ , -C _0-8 -C(O)R ₁₀ , -C _0-8 -C(O)OR ₉ , -C _0-8 -OC(O)R ₁₀ , -C _{0- 8-} NR ₆ R ₇ , -C _0-8 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ Substituted by a substituent.
11. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₂ and R ₂ ' are each independently selected from the group consisting of hydrogen, hydrazine, halogen, and methyl. , ethyl, isopropyl, cyclopropyl, -C _0-4 -OR ₉ , -C _0-4 -C(O)R ₁₀ , -C _0-4 -C(O)OR ₉ , -C _{0 -4} -OC(O)R ₁₀ , -C _0-4 -NR ₆ R ₇ , -C _0-4 -C(O)NR ₆ R ₇ , -N(R ₆ )-C(O)R ₁₀ or -N(R ₆ )-C(O)OR ₉ .
12. 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:

    

    
13. The method for preparing a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which comprises the following steps:

    

    Wherein R ₁ , R ₁ ', R ₂ , R ₂ ', R ₃ , R ₃ ', R ₄ , R ₄ ', R ₅ , R ₅ ', R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , L, M, m, m', r are as defined in claim 1.
14. 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.
15. 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.
16. The pharmaceutical composition of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 according to any one of claims 1 to 12, in the preparation of a medicament for the treatment or prevention of HCV infection Applications.