WO2015096674A1 - Hepatitis c virus inhibitor and uses thereof - Google Patents

Abstract

The present invention belongs to the chemical and pharmaceutical field, in particular relates to a compound as shown in formula I which has a Hepatitis C virus inhibition activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition comprising these compounds and the uses of these compounds or compositions in the preparation of drugs. The compound of the present invention has a good inhibitory effect on HCV.

Description

Hepatitis C virus inhibitor and its application Technical field

The present invention belongs to the field of chemical medicine, and in particular relates to a compound having hepatitis C virus inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition containing the same The use of these compounds or compositions in the preparation of pharmaceuticals.

Background technique

Viral hepatitis C is a contagious disease of acute and chronic inflammation of the liver caused by hepatitis C virus (HCV). It can easily evolve into chronic liver disease after HCV infection, such as chronic hepatitis and liver. Hardening and liver cancer, etc., seriously affect people's health.

HCV belongs to the Flaviviridae family and can be divided into 6 genotypes and different subtypes. According to internationally accepted methods, HCV genotypes are represented by Arabic numerals, and subtypes of genes are represented by lowercase English letters. The distribution, accounting for more than 70% of all HCV infections, the main infection type in the Chinese population is HCV 1b subtype. It has been found that the 5' and 3' ends of HCV positive-stranded RNA contain a non-coding region (UTR), and a large polyprotein open reading frame (ORF) is between UTRs. The ORF encodes a polyprotein precursor of approximately 3000 amino acids long and is cleaved into a variety of HCV mature proteins by a combination of a host-encoded signal peptidase and a HCV-encoded protease. The HCV mature protein includes 4 structural proteins and 6 non-structural proteins, of which 6 non-structural proteins are named NS2, NS3, NS4A, NS4B, NS5A, NS5B. Studies have shown that six non-structural proteins play a very important role in the replication of HCV, such as NS3, which regulates the activity of NS3 serine protease, NS5A is a phosphorylated protein containing interferon sensitivity-determining regions, in the efficacy of interferon It has an important role in prediction, viral replication, antiviral resistance, hepatocellular carcinogenesis, etc., and has become the focus of HCV nonstructural protein research.

Currently, the treatment of HCV infection is generally recombinant interferon alpha alone or in combination with the nucleoside analog ribavirin, but there are multiple contraindications, both interferon and ribavirin, with limited clinical benefit. Therefore, there is still a great demand for drugs that can effectively treat HCV infection.

Summary of the invention

It is an object of the present invention to provide a compound of the formula I having an inhibitory effect on HCV or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

among them:

X _{1 is} selected from the group consisting of O, S, N and CF ₂ ;

L ₁ and L ₂ are each independently selected from the group consisting of aryl, heteroaryl, -aryl-aryl-, -aryl-heteroaryl-, -heteroaryl-heteroaryl-, said aryl or A heteroaryl group can be composed of one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, Carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, Bisalkylaminoalkyl, alkylacyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl a monoalkylaminoacyl group, a monoalkylaminoacylalkyl group, a bisalkylaminoacyl group, a bisalkylaminoacylalkyl group, an alkylacylamino group, an alkylacylaminoalkyl group;

p, q are independently selected from 1, 2 and 3;

R ₁ and R ₂ are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetero The aryl group may be one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, single An alkylamino group, a dialkylamino group, an alkyl acyl group, an alkoxy acyl group, an alkyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group, an alkyl acylamino group;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, Carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl a heteroaryl group, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R ₅ or R ₆ and a C atom to which it is bonded may form a cycloalkyl or heterocycloalkyl group; The hydroxy, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl, heteroaryl groups may be substituted by one or more halogen, hydroxy, amino, carboxy groups. , cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl Alkyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.

Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

A further object of the present invention is to provide a composition comprising a compound of Formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another HCV inhibitor.

A further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for the treatment and/or prophylaxis of diseases caused by hepatitis C virus, for example A method of liver disease, and the use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for the manufacture of a medicament for the treatment and/or HCV infection.

In view of the above purposes, the present invention provides the following technical solutions:

In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

among them:

X _{1 is} selected from the group consisting of O, S, N and CF ₂ ;

L ₁ and L ₂ are each independently selected from the group consisting of aryl, heteroaryl, -aryl-aryl-, -aryl-heteroaryl-, -heteroaryl-heteroaryl-, said aryl or A heteroaryl group can be composed of one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, Carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, Bisalkylaminoalkyl, alkylacyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl a monoalkylaminoacyl group, a monoalkylaminoacylalkyl group, a bisalkylaminoacyl group, a bisalkylaminoacylalkyl group, an alkylacylamino group, an alkylacylaminoalkyl group;

p, q are independently selected from 1, 2 and 3;

R ₁ and R ₂ are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetero The aryl group may be one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, single An alkylamino group, a dialkylamino group, an alkyl acyl group, an alkoxy acyl group, an alkyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group, an alkyl acylamino group;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, Carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl a heteroaryl group, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R ₅ or R ₆ and a C atom to which it is bonded may form a cycloalkyl or heterocycloalkyl group. The hydroxyl group, amino group, carboxyl group, alkyl group, cycloalkyl group, heterocycloalkyl group, alkoxy group, alkoxyalkyl group, aryl group, heteroaryl group may be one or more halogen, hydroxyl group, amino group, Carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl Alkyl acyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.

In some preferred embodiments, the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:

L ₁ and L ₂ are each independently selected from the group consisting of phenyl, naphthyl, imidazolyl, benzimidazolyl, -phenyl-imidazolyl-, imidazopyridinyl, quinazolinone, pyrrolyl, imidazolidinyl, Furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, phenyl, naphthyl, imidazolyl, benzimidazole , -phenyl-imidazolyl-, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, Isothiazolyl, oxadiazolyl, triazolyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-10 alkyl, C _3-10 cycloalkyl, C _{3- 10} heterocycloalkyl, C _1-10 alkoxy, halo C _1-10 alkyl, hydroxy-C _1-10 alkyl, amino-C _1-10 alkyl, carboxy-C _1-10 alkyl, Cyano-C _1-10 alkyl, nitro C _1-10 alkyl, C _3-10 cycloalkyl-C _1-6 alkyl, C _3-10 heterocycloalkyl-C _1-6 alkyl, -C _1-6 alkoxy-C _1-10 alkyl, C _1-10 mono alkylamino, C _1-10 mono alkylamino -C _1-6 alkyl, bis C _1-10 alkyl group, -C _1-6 alkylamino C _1-10 alkyl, C _1-10 alkyl group, C _1-10 alkyl group -C _1-6 alkyl, C _1-10 alkoxy group, C _{1- 10} alkoxyacyl-C _1-6 alkyl, C _1-10 alkyl acyloxy, C _1-10 alkyl acyloxy-C _1-6 alkyl, amino acyl, amino acyl-C _1-6 Alkyl, mono-C _1-10 alkylamino acyl, mono C _1-10 alkylamino acyl-C _1-6 alkyl, bis C _1-10 alkylamino acyl, bis C _1-10 alkylamino acyl - C _1-6 alkyl, C _1-10 alkyl acylamino, C _1-10 alkyl acylamino-C _1-6 alkyl;

Preferably, L ₁ and L ₂ are each independently selected from the group consisting of phenyl, naphthyl, imidazolyl, 1H-benzo[d]imidazolyl, 5-phenyl-1H-imidazolyl, 1H-imidazo[4,5 -b]pyridyl, quinazolin-4(3H)keto, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, Oxadiazolyl, triazolyl, phenyl, naphthyl, imidazolyl, 1H-benzo[d]imidazolyl, 5-phenyl-1H-imidazolyl, 1H-imidazo[4,5- b] pyridyl, quinazolin-4(3H)keto, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, cacao The oxadiazolyl, triazolyl group may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl , C _1-6 alkoxy, halo C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, carboxy-C _1-6 alkyl, cyano-C _{1 -6} alkyl, nitro C _1-6 alkyl, C _3-8 cycloalkyl-C _1-6 alkyl, C _3-8 heterocycloalkyl-C _1-6 alkyl, C _1-6 alkane Oxy-C _1-6 alkyl, mono C _1-6 alkylamino, mono C _1-6 alkyl Amino-C _1-6 alkyl, bis C _1-6 alkylamino, bis C _1-6 alkylamino-C _1-6 alkyl, C _1-6 alkyl acyl, C _1-6 alkyl acyl- C _1-6 alkyl, C _1-6 alkoxy acyl, C _1-6 alkoxy acyl-C _1-6 alkyl, C _1-6 alkyl acyloxy, C _1-6 alkyl acyloxy -C _1-6 alkyl, aminoacyl, aminoacyl-C _1-6 alkyl, mono C _1-6 alkylamino acyl, mono C _1-6 alkylamino acyl-C _1-6 alkyl, double C _1-6 alkylamino acyl, bis C _1-6 alkylamino acyl-C _1-6 alkyl, C _1-6 alkyl acylamino, C _1-6 alkyl acylamino-C _1-6 alkyl Replace

Further preferably, L ₁ and L ₂ are each independently selected from the group consisting of:

Wherein R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl , aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, Dialkylamino, bisalkylaminoalkyl, alkyl acyl, alkyl acylalkyl, alkoxy acyl, alkoxyacylalkyl, alkyl acyloxy, alkyl acyloxyalkyl, amino acyl Aminoacylalkyl, monoalkylaminoacyl, monoalkylaminoacylalkyl, bisalkylaminoacyl, bisalkylaminoacylalkyl, alkylacylamino, alkylacylaminoalkyl; preferably, R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkoxy, halo C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, carboxy-C _1-6 alkyl, cyano-C _1-6 alkyl, nitro C _1-6 alkyl, C _3-8 cycloalkyl -C _1-6 alkyl group, C _3-8 heterocycloalkyl -C _1-6 alkyl, -C _1-6 alkoxy-C _1-6 alkyl, mono-C _1-6 alkylamino, mono C _1-6 alkylamino-C _1-6 alkyl, bis C _1-6 alkylamino, bis C _1-6 alkylamino-C _1-6 alkyl, C _1-6 alkyl acyl, C _{1 -6} alkyl acyl-C _1-6 alkyl, C _1-6 alkoxy acyl, C _1-6 alkoxy acyl-C _1-6 alkyl, C _1-6 alkyl acyloxy, C _{1 -6} -alkylacyloxy-C _1-6 alkyl, aminoacyl, aminoacyl-C _1-6 alkyl, mono C _1-6 alkylamino acyl, mono C _1-6 alkylamino acyl-C _{1 -6} alkyl, bis C _1-6 alkylamino acyl, bis C _1-6 alkylamino acyl-C _1-6 alkyl, C _1-6 alkyl acylamino, C _1-6 alkyl acylamino - C _1-6 alkyl.

In some preferred embodiments, the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:

R ₁ and R ₂ are each independently selected from hydrogen, C _1-10 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl or heteroaryl, said C _1-10 Alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl or heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, ring Alkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl, alkyl acyloxy, amino acyl, monoalkane Alkylamino, bisalkylaminoacyl, alkylacylamino substituted;

Preferably, R ₁ and R ₂ are each independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, aryl or heteroaryl, said C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, aryl or heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hydroxy-C _1-6 Alkyl, carboxy-C _1-6 alkyl, mono C _1-6 alkylamino, bis C _1-6 alkylamino, C _1-6 alkyl acyl, C _1-6 alkoxy acyl, C _{1- a 6} alkyl acyloxy group, an amino acyl group, a mono C _1-6 alkylamino acyl group, a bis C _1-6 alkylamino acyl group, a C _1-6 alkyl acylamino group;

Further preferably, R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, and ring. Butanyl, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, N-alkane Piperazinyl, phenyl, naphthyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, pyridyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl , isobutyl, tert-butyl, cyclopropane, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazole Base, tetrahydrooxazolyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, phenyl, naphthyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, pyridyl can be one or more Halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, such as methoxy, ethoxy, propoxy, hydroxy-C _1-6 alkane Base, carboxy-C _1-6 alkyl, single C _{1 -6} alkylamino, di-C _1-6 alkylamino substituted.

In some preferred embodiments, the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, said C _1-10 alkyl, C _3-8 A cycloalkyl or C _3-8 heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl , heteroaryl substitution;

Further preferably, R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, said C _1-6 alkyl, C _3-7 cycloalkyl or C _3-7 heterocycloalkyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-7 cycloalkyl , C _3-7 heterocycloalkyl, C _1-6 alkoxy, aryl, heteroaryl substituted;

Still more preferably, R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, Cyclobutane, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, said Methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, tetra Hydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro , C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl , piperidinyl, piperazinyl, N-alkylpiperazinyl, C _1-6 alkoxy, phenyl, heteroaryl substituted.

In some preferred embodiments, the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, C _1-10 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, halogen, C _1-6 alkane. Oxy-C _1-6 alkyl, aryl, heteroaryl, wherein m and n are independently selected from 1, 2 and 3, respectively, and when m or n is 2, each R ₅ or R ₆ is attached thereto The C atom may form a C _3-8 cycloalkyl group or a C _3-8 heterocycloalkyl group; the hydroxy group, the amino group, the C _1-10 alkyl group, the C _3-8 cycloalkyl group, the C _3-8 heterocycloalkane. , halogen, C _1-6 alkoxy-C _1-6 alkyl, aryl, heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, naphthenic , heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxyacyl acyloxy, amino acyl, monoalkylamino Acyl, bisalkylaminoacyl, alkylacylamino substituted;

Preferably, R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, halogen, C _{1 -6} alkoxy-C _1-6 alkyl, aryl, heteroaryl, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R ₅ or R ₆ The C atom to which it is attached may form a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group; said hydroxy group, amino group, C _1-6 alkyl group, C _3-7 cycloalkyl group, C _3-7 Heterocycloalkyl, halogen, C _1-6 alkoxy-C _1-6 alkyl, aryl, heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl , cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxyacyl acyloxy, amino acyl, single Alkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted;

Still more preferably, R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert. Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, 1,3- Dioxolane, piperidinyl, piperazinyl, N-alkylpiperazinyl, 1,3-dioxocyclyl, fluoro, chloro, methoxymethyl, methoxyethyl, methoxy Propyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, phenyl, naphthyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, pyridyl, or when m or n is 2 o'clock,

Each is independently selected from azaspiroalkyl (eg, azaspiro[2.4]heptyl, azaspiro[3.4]octyl, azaspiro[4.4]decyl, azaspiro[2.5]octane Alkyl, azaspiro[3.5]decylalkyl, azaspiro[4.5]alkanyl, azaspiro[2.6]decylalkyl, azaspiro[3.6]alkanyl), oxazaspiroalkyl For example, oxa-azaspiro[2.4]heptyl, oxa-azaspiro[3.4]octyl, oxa-azaspiro[4.4]decyl, dioxa-aza snail [4.4]壬alkyl, oxa-azaspiro[4.5]alkanyl, dioxa-azaspiro[4.5]alkanyl, trioxa-azaspiro[4.5]alkanoyl), azabicycloalkane Base (eg, azabicyclo[3.1.0]hexane, azabicyclo[3.2.0]heptanyl, octahydrocyclopenta pyrrolyl, octahydro-1H-isoindolyl, octahydro-1H-indole Mercapto, azabicyclo[2.2.1]heptanyl); hydroxy, amino, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl Base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, 1,3- Oxolyl, piperidine , piperazinyl, N-alkylpiperazinyl, 1,3-dioxocyclo, fluoro, chloro, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl , ethoxyethyl, ethoxypropyl, phenyl, naphthyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, pyridyl, or when m or n is 2, each of said aza Spiroalkyl (azaspiro[2.4]heptyl, azaspiro[3.4]octyl, azaspiro[4.4]decyl, azaspiro[2.5]octyl, azaspiro[3.5] Alkyl, azaspiro[4.5]alkanyl, azaspiro[2.6]decylalkyl, azaspiro[3.6]alkanyl), oxazaspiroalkyl (eg oxa-azaspiro[ 2.4] Heptyl, oxa-azaspiro[3.4]octyl, oxa-azaspiro[4.4]decyl, dioxa-azaspiro[4.4]decyl, oxa-nitrogen Hetero[4.5]alkyl, dioxa-azaspiro[4.5]alkanyl, trioxa-azaspiro[4.5]alkanyl), azabicycloalkyl (eg azabicyclo[3.1] .0]hexane, azabicyclo[3.2.0]heptyl, octahydrocyclopenta pyrrolyl, octahydro-1H-isoindenyl, octahydro-1H-indenyl, azabicyclo[2.2 .1]heptyl) can be halogenated by one or more , hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl An alkoxyacyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group or an alkyl acylamino group.

In some specific embodiments, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein

Each independently selected from substituted or unsubstituted The substituent is selected from the group consisting of halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bis Alkylamino, alkylacyl, alkoxyacyloxycarbonyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.

In some preferred embodiments, the invention provides a compound of Formula Ia, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof,

among them:

C* is the S configuration;

X _{1 is} selected from the group consisting of O, S, N and CF ₂ ;

L ₁ and L ₂ are each independently selected from the group consisting of aryl, heteroaryl, -aryl-aryl-, -aryl-heteroaryl-, -heteroaryl-heteroaryl-, said aryl or A heteroaryl group can be composed of one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, Carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, Bisalkylaminoalkyl, alkylacyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl a monoalkylaminoacyl group, a monoalkylaminoacylalkyl group, a bisalkylaminoacyl group, a bisalkylaminoacylalkyl group, an alkylacylamino group, an alkylacylaminoalkyl group;

p, q are independently selected from 1, 2 and 3;

R ₁ and R ₂ are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetero The aryl group may be one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, single An alkylamino group, a dialkylamino group, an alkyl acyl group, an alkoxy acyl group, an alkyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group, an alkyl acylamino group;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, Carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl a heteroaryl group, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R ₅ or R ₆ and a C atom to which it is bonded may form a cycloalkyl or heterocycloalkyl group. The hydroxyl group, amino group, carboxyl group, alkyl group, cycloalkyl group, heterocycloalkyl group, alkoxy group, alkoxyalkyl group, aryl group, heteroaryl group may be one or more halogen, hydroxyl group, amino group, Carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl Alkyl acyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.

According to the invention, in some preferred embodiments, the compound of the invention is a compound of formula I or formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

X _{1 is} selected from the group consisting of O, S, N and CF ₂ ;

p, q are independently selected from 1, 2 and 3;

L ₁ and L ₂ are each independently selected from the group consisting of phenyl, naphthyl, imidazolyl, benzimidazolyl, -phenyl-imidazolyl-, imidazopyridinyl, quinazolinone, pyrrolyl, imidazolidinyl, Furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, phenyl, naphthyl, imidazolyl, benzimidazole , -phenyl-imidazolyl-, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, Isothiazolyl, oxadiazolyl, triazolyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-8 cycloalkyl, C _{3- 8-} heterocycloalkyl, C _1-6 alkoxy, halo C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, carboxy-C _1-6 alkyl, Cyano-C _1-6 alkyl, nitro C _1-6 alkyl, C _3-8 cycloalkyl-C _1-6 alkyl, C _3-8 heterocycloalkyl-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, mono C _1-6 alkylamino, mono C _1-6 alkylamino-C _1-6 alkyl, di C _1-6 alkylamino, double C _1-6 alkylamino -C _C1-6 alkyl, C _1-6 alkyl group, C _1-6 alkyl group -C _C1-6 alkyl, C _1-6 alkoxy group, C _1-6 alkoxy group -C _1-6 alkyl, C _1-6 alkyl acyloxy, C _1-6 alkyl acyloxy-C _1-6 alkyl, amino acyl, aminoacyl-C _1-6 alkyl, mono C _{1- 6} alkylaminoacyl, mono C _1-6 alkylaminoacyl-C _1-6 alkyl, bis C _1-6 alkylamino acyl, bis C _1-6 alkylamino acyl-C _1-6 alkyl, C _1-6 alkyl acylamino, C _1-6 alkyl acylamino-C _1-6 alkyl substituted;

R ₁ and R ₂ are each independently selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl or heteroaryl, said C _1-6 Alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl or heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 Alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkoxy, such as methoxy, ethoxy, propoxy, hydroxy-C _1-6 alkyl, Carboxyl-C _1-6 alkyl, mono C _1-6 alkylamino, bis C _1-6 alkylamino, C _1-6 alkyl acyl, C _1-6 alkoxy acyl, C _1-6 alkyl Acyloxy, aminoacyl, mono C _1-6 alkylamino acyl, bis C _1-6 alkylamino acyl, C _1-6 alkyl acylamino

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, said C _1-6 alkyl, C _3-8 A cycloalkyl or C _3-8 heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-8 cycloalkyl, C _{3 - a} heterocycloalkyl group, a C _1-6 alkoxy group, an aryl group, a heteroaryl group;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, halogen, C _1-6 alkane. Oxy-C _1-6 alkyl, aryl, heteroaryl, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R ₅ or R ₆ is attached thereto The C atom may form a C _3-8 cycloalkyl group or a C _3-8 heterocycloalkyl group; the hydroxy group, the amino group, the C _1-6 alkyl group, the C _3-8 cycloalkyl group, the C _3-8 heterocycloalkane. Base, halogen, C _1-6 alkoxy-C _1-6 alkyl, aryl, heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, C _1-6 alkane , C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, carboxy C _1-6 alkyl, mono C _1-6 alkyl Amino group, di-C _1-6 alkylamino group, C _1-6 alkyl acyl group, C _1-6 alkoxy acyl C _1-6 alkyl acyloxy group, amino acyl group, mono C _1-6 alkylamino acyl group, Bis-C _1-6 alkylamino acyl, C _1-6 alkyl acylamino substituted.

Further preferably, the compound provided by the present invention is a compound of the formula I or formula Ia or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

X _{1 is} selected from the group consisting of O and CF ₂ ;

L ₁ and L ₂ are each independently selected from the group consisting of:

Wherein R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl;

p, q are independently selected from 1 and 2;

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutane, Cyclopentyl, cyclohexane, phenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, ring Butanyl, cyclopentyl, cyclohexane, phenyl may be one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _1-6 cycloalkyl , C _1-6 heterocycloalkyl, C _1-6 alkoxy, such as methoxy, ethoxy, propoxy, hydroxy-C _1-6 alkyl, carboxy-C _1-6 alkyl, single C _1-6 alkylamino, bis C _1-6 alkylamino, C _1-6 alkyl acyl, C _1-6 alkoxy acyl, C _1-6 alkyl acyloxy, amino acyl, mono C _{1 -6} alkylaminoacyl, bis C _1-6 alkylamino acyl, C _1-6 alkyl acylamino substituted;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl-, C _3-6 heterocycloalkane. , C _3-6 heterocycloalkyl-C _1-6 alkyl-, said C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkane Base-, C _3-6 heterocycloalkyl, C _3-6 heterocycloalkyl-C _1-6 alkyl- may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _{1 -6} alkyl, C _1-6 alkoxy, aryl, heteroaryl substituted;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, carboxy, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _1-6 alkoxyhaloalkyl, cyano C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, carboxy C _1-6 alkyl, nitro C _1-6 alkane a C _3-6 cycloalkyl-C _1-6 alkyl group, a C _3-6 heterocycloalkyl-C _1-6 alkyl group, or when m or n is 2,

Each is independently selected from azaspiroalkyl (eg, azaspiro[2.4]heptyl, azaspiro[3.4]octyl, azaspiro[4.4]decyl, azaspiro[2.5]octane Alkyl, azaspiro[3.5]decylalkyl, azaspiro[4.5]alkanyl, azaspiro[2.6]decylalkyl, azaspiro[3.6]alkanyl), oxazaspiroalkyl For example, oxa-azaspiro[2.4]heptyl, oxa-azaspiro[3.4]octyl, oxa-azaspiro[4.4]decyl, dioxa-aza snail [4.4]壬alkyl, oxa-azaspiro[4.5]alkanyl, dioxa-azaspiro[4.5]alkanyl, trioxa-azaspiro[4.5]alkanoyl), azabicycloalkane Base (eg, azabicyclo[3.1.0]hexane, azabicyclo[3.2.0]heptanyl, octahydrocyclopenta pyrrolyl, octahydro-1H-isoindolyl, octahydro-1H-indole Mercapto, azabicyclo[2.2.1]heptanyl.

In some specific embodiments, the invention provides a compound of Formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein

Each independently selected from substituted or unsubstituted

The present invention provides the following specific compounds:

The invention also provides a compound of formula (II) for the preparation of a compound of the invention, or a pharmaceutically acceptable salt, isomer thereof, Intermediates for solvates, crystals or prodrugs:

among them,

X _{1 is} selected from the group consisting of O, N, S and CF ₂ ;

R ₂₁ and R ₂₂ are each independently selected from the group consisting of hydrogen, halogen, triflate, mesylate, p-toluenesulfonate, and

R ₃₁ and R ₃₂ are each independently selected from hydrogen, C _1-6 alkyl or R ₃₁ , and R ₃₂ together with the respective attached O atom constitutes a ring;

Preferably, X _{1 is} selected from the group consisting of O and CF ₂ ;

R ₂₁ and R ₂₂ are each independently selected from hydrogen, chlorine, bromine, iodine or

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

(1) Preparation of an intermediate of formula (4):

A-1) a compound of formula (1) is subjected to a ring closure reaction to give an intermediate of formula (2);

A-2) an intermediate of formula (2) is subjected to a halogenation reaction to give an intermediate of formula (3);

A-3) an intermediate of formula (3) is reacted with a boronic acid pinacol ester to give an intermediate of formula (4);

(2) Preparation of an intermediate of the formula (9'):

A-4) an intermediate of formula (1') is reacted with TBDPSCl to give an intermediate of formula (2');

A-5) an intermediate of formula (2') is reacted with hydrazine to give an intermediate of formula (4');

A-6) an intermediate of formula (4') is deprotected to give an intermediate of formula (5');

A-7) an intermediate of formula (5') is oxidized to give an intermediate of formula (6');

A-8) an intermediate of formula (6') is fluorinated to give an intermediate of formula (7');

A-9) an intermediate of formula (7') is subjected to a halogenation reaction to give an intermediate of formula (8');

A-10) an intermediate of the formula (8') is reacted with a boronic acid pinacol ester to give an intermediate of the formula (9');

(3) Preparation of a compound of the formula (I) wherein X _{1 is} selected from O:

A-11) The intermediate of formula (3) is subjected to a coupling reaction to obtain an intermediate of formula (5) or an intermediate of formula (4). Coupling reaction to give an intermediate of formula (5-1);

A-12) an intermediate of the formula (5) or an intermediate of the formula (5-1) is further subjected to a coupling reaction to obtain an intermediate of the formula (6), and if necessary, a step of removing the protecting group;

A-13) Amidation of the intermediate of formula (6) gives the compound of formula (I), optionally with the step of deprotecting the group.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , L ₁ , L ₂ have the meanings in the formula I, and M ₁ represents hydrogen, trimethylsilylethoxy, tert-butoxy A carbonyl group, M ₂ represents hydrogen, trimethylsilylethoxy, tert-butoxycarbonyl, and Y represents a halogen, preferably chlorine, bromine or iodine.

Similarly, a compound of the formula I wherein X _{1 is} selected from CF ₂ is obtained by the method of a-11) to a-13) using an intermediate of the formula (8') or an intermediate of the formula (9').

In particular, for the preparation of a compound of the formula I in which at least one of L ₁ or L ₂ is selected from the group consisting of imidazolyl groups, the following methods can also be used, including:

(1) Preparation of an intermediate of formula (106):

B-1) an intermediate of formula (3) is synthesized by Weinrebone to give an intermediate of formula (101);

B-2) an intermediate of formula (101) is halogenated to give an intermediate of formula (102);

B-3) an intermediate of formula (102) is reacted with an intermediate of formula (103) to provide an intermediate of formula (104);

B-4) an intermediate of formula (104) is obtained as an intermediate of formula (105) under the action of an ammonia source;

B-5) an intermediate of formula (105) is reacted with a boronic acid pinacol ester to give an intermediate of formula (106);

(2) Preparation of intermediate of formula (105')

B-6) an intermediate of the formula (8') is subjected to a Weinrebone synthesis reaction to give an intermediate of the formula (101');

B-7) an intermediate of formula (101') is subjected to a halogenation reaction to give an intermediate of formula (102');

B-8) an intermediate of formula (102') is reacted with an intermediate of formula (103) to provide an intermediate of formula (103');

B-9) an intermediate of formula (103') which, under the action of an ammonia source, provides an intermediate of formula (104');

B-10) an intermediate of the formula (104') is reacted with a boronic acid pinacol ester to give an intermediate of the formula (105');

(3) Preparation of a compound of the formula (I) wherein at least one of L ₁ or L ₂ is selected from imidazolyl and X _{1 is} selected from O:

B-11) The intermediate of the formula (105) is subjected to a coupling reaction to obtain an intermediate of the formula (107) or an intermediate of the formula (106), which is subjected to a coupling reaction to obtain an intermediate of the formula (107), which may be removed if necessary. The step of removing the protecting group;

B-12) Amidation of the intermediate of formula (107) gives the compound of formula (I), optionally with the step of deprotecting the group.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , L ₁ , L ₂ have the meanings in the formula I, and M ₁ represents hydrogen, trimethylsilylethoxy, tert-butoxy Carbonyl group, M ₂ represents hydrogen, trimethylsilylethoxy group, tert-butoxycarbonyl group, Y represents halogen, preferably chlorine, bromine, iodine, and the ammonia source refers to ammonia water, ammonia gas or ammonium salt compound, such as Ammonium sulfate, ammonium carbonate, ammonium hydrogencarbonate, ammonium acetate, ammonium chloride, and the like.

Similarly, intermediates of formula (104 ') or intermediates of formula (105') as a starting material, in accordance with step b-11), b-12 ) obtained in Method L ₁ or L ₂ is selected from at least one imidazole The compound of the formula I wherein X _{1 is} selected from CF ₂ may have a step of removing the protecting group if necessary.

In a third aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a compound comprising the same, or a pharmaceutically acceptable salt, isomer thereof A pharmaceutical composition of a solvate, crystallization or prodrug for treating and/or preventing a liver disease caused by a hepatitis C virus.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, further comprising one selected from the group consisting of or A variety of: interferon, triazole nucleoside drugs, glycyrrhizin compound preparations, HCV protease inhibitors.

The compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for Oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.

In a fourth aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the present invention, for treating and/or preventing a hepatitis C virus-causing Method for treating liver diseases and use in the preparation of a medicament for preventing and/or treating liver diseases caused by hepatitis C virus, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient suffering from liver disease caused by hepatitis C virus, A composition, solvate, crystal or prodrug or a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for effectively inhibiting HCV and preventing progression of the disease .

In some embodiments, the invention provides a method for treating and/or preventing an infection caused by a hepatitis C virus, the method comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention Or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof or a pharmaceutical composition of the invention. The compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof or the pharmaceutical composition of the present invention can be administered to a mammal in need thereof to inhibit HCV and prevent progression of the disease.

In other embodiments, the method or use of treating and/or preventing an infection caused by a hepatitis C virus further comprises administering to the individual a compound of formula I of the invention, or a pharmaceutically acceptable salt thereof, isomerized , solvates, crystals or prodrugs or pharmaceutical compositions containing same and are administered to the formula I of the invention The compound, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition containing the same, is administered before, after or simultaneously with at least one other compound having anti-HCV activity. In some embodiments, at least one of the other compounds is an interferon or ribavirin. In some specific embodiments, the interferon is selected from the group consisting of interferon alpha 2B, PEGylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau. In other embodiments, at least one of the other compounds is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, interfering RNA, antisense RNA, imiquimod, ribavirin, 5'-inosine monophosphate dehydrogenase inhibitor, amantadine and rimantadine. In other embodiments, at least one of the other compounds is effective to inhibit the function of a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV NS5B protein, HCV entry, HCV assembly, HCV release, HCV NS3/4A protein and IMPDH.

Terminology

The "alkyl group" of the present invention means a linear or branched saturated hydrocarbon group, and a suitable alkyl group is a substituted or unsubstituted C _1-10 alkyl group such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, Cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl and the like.

The "cycloalkyl group" of the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The "alkoxy group" of the present invention means an -O-alkyl group. Suitable alkoxy groups according to the invention are C _1-10 alkoxy groups, such as C _1-8 alkoxy groups, C _1-7 alkoxy groups, C _1-6 alkoxy groups, C _1-5 alkoxy groups. C _1-4 alkoxy, C _1-3 alkoxy, including methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, sec-butoxy and the like.

The "halogen" of the present invention means fluorine, chlorine, bromine or iodine.

The "haloalkyl group" of the present invention means an alkyl group substituted with at least one halogen.

The "haloalkoxy group" of the present invention means an alkoxy group substituted with at least one halogen.

The "aminoacyl group" of the present invention means -C(O)-NH ₂ .

The "monoalkylaminoacyl" of the present invention means -C(O)-NH-alkyl.

The "bisalkylamino acyl group" of the present invention means -C(O)-N(alkyl)(alkyl).

The "aryl group" of the present invention means an aromatic system which may contain a monocyclic or polycondensed ring such as a bicyclic or tricyclic aromatic ring, wherein at least a part of the fused ring forms a conjugated aromatic system containing 5 to 50 Carbon atoms, It is preferably from about 6 to about 14 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl, biphenylene, and anthracenyl.

The "heteroaryl" of the present invention means an aromatic monocyclic or polycondensed ring such as an aromatic group in which at least one carbon atom of a bicyclic or tricyclic ring is replaced by a hetero atom, and the hetero atom is O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like.

The "solvate" of the present invention means, in a conventional sense, a complex formed by a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water). Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.

"Crystalline" as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.

The "isomer" of the present invention refers to a stereoisomer, including enantiomers and diastereomers, which are produced by different arrangement of atoms in a molecule in a space.

The "prodrug" of the present invention refers to a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into a compound of the invention by oxidation, reduction, hydrolysis or the like of an enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.

The "pharmaceutically acceptable salt" of the present invention means a pharmaceutically acceptable salt of the compound of the present invention and an acid, which includes, but is not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, and Malay. Acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, and the like.

A "pharmaceutical composition" according to the invention is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.

The "pharmaceutically acceptable carrier" of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes a solvent, a diluent or other excipient, a dispersing agent, and a surface active agent. Agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; Malt, gelatin, etc.

"Excipient" as used herein refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

detailed description

The following representative examples are intended to better illustrate the invention and are not intended to limit the scope of the invention.

Example 1 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2, 7-diyl) bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1- Dimethyl dimethyl dicarbamate

Preparation of Step 1 (9H-芴-9,9-diyl) Dimethanol

In a 50 mL round bottom flask, add 7.5 mL of ethanol solution, 450 mg of sodium silk, stir at room temperature until all the sodium silk was dissolved, add 80 mL of DMSO, 6 g of paraformaldehyde and 80 mL of tetrahydrofuran (THF) solution in which 12 g of 9H-indole was dissolved, and continue stirring. After 0.5 h, the reaction was completed, and the reaction mixture was added to EtOAc (1 mL). The organic layer was dried over anhydrous sodium sulfate.

Preparation of step 2 spiro[芴-9,3'-butylene oxide]

Weigh 113 mg of the compound prepared in Step 1 (9H-fluorene-9,9-diyl)dimethanol, 228 mg of bis(dimethylamine) Zinc thioformate) zinc, 197 mg of triphenylphosphine in a reaction flask, dissolved in 1 mL of toluene, sparged with nitrogen for 1 min, and microwaved at 80 ° C for 1 h. After the reaction was completed, the solvent was evaporated to dryness. The title compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.01 (d, 2H), 7.82 - 7.84 (d, 2H), 7.43 - 7.46 (m, 4H), 4.99 (s, 4H).

Step 32, Preparation of 7-dibromospiro[芴-9,3'-butylene oxide]

Weigh 416 mg of the compound Spirulina [芴-9,3'-butylene oxide] prepared in Step 2 in a 50 mL reaction flask, add 15 mL of MeCN to dissolve, and add 890 mg of N-bromosuccinimide (NBS) in portions at room temperature. After the addition, the reaction was carried out at 90 ° C for 12 h. After the reaction was completed, the solvent was evaporated.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.19 - 8.20 (d, 2H), 7.81 - 7.83 (d, 2H), 7.62 - 7.64 (d, 2H), 4.99 (s, 4H).

Step 4 (S)-1-tert-Butoxycarbonyl-2-formylpyrrolidine Preparation

In a 250 mL eggplant-shaped flask, add 16 mL of oxalyl chloride, 125 mL of anhydrous dichloromethane, and protect with nitrogen. At -78 ° C, slowly add 10 mL of dichloromethane solution in 23 mL of DMSO, and 10 mL of 10 g (s)-1. - a solution of tert-butoxy-2-hydroxymethylpyrrolidine in dichloromethane, after the addition is completed, stirring is continued at -78 ° C for 30 min, then 46 mL of triethylamine (TEA) is slowly added dropwise, and the mixture is dropped, 0-4 After stirring at °C for 30 min, the reaction mixture was poured into 100 g of ice cubes, and then added with 200 mL of saturated aqueous sodium chloride solution and extracted with dichloromethane (3×200 mL). The title compound was obtained and used directly in the next reaction.

LC-MS m/z: [M+H] ⁺ = 200.

Preparation of Step 5(S)-1-tert-Butoxycarbonyl-2-(1H-imidazol-2-yl)pyrrolidine

Weigh 12 g of the compound (s)-1-tert-butoxycarbonyl-2-formylpyrrolidine obtained in the step 4 in a 100 mL reaction flask, and dissolve it by adding 30 mL of anhydrous methanol and 30 mL of an aqueous ammonia solution at 0-4 ° C. 14mL of glyoxal was slowly added dropwise, and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated to remove most of the ethanol, and extracted with dichloromethane (3×50 mL). The organic layer was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was recrystallized from 100 mL of a 1:1 mixture of petroleum ether/ethyl acetate to afford the title compound.

LC-MS m/z: [M+H] ⁺ = 238.

Preparation of Step 6(S)-1-tert-Butoxycarbonyl-2-(1-((2-(trimethylsilyl)ethoxy)-1H-imidazolyl)-2-yl)pyrrolidine

1.0 g of the compound (s)-1-tert-butoxycarbonyl-2-(1H-imidazolyl)-2-yl)pyrrolidine prepared in the step 5 was weighed and dissolved in a 100 mL round bottom flask, and dissolved in 5 mL of anhydrous DMF. Slowly add 253 mg of NaH at 0-4 ° C, add and react at room temperature for 0.5 h, cool the reaction solution to 0 ° C, slowly add 1.1 mL of 2-(trimethylsilyl)ethoxymethyl chloride, and react at room temperature for 2 h. After completion, 50 mL of ethyl acetate and 10 mL of 5% LiCl aqueous solution were added to the mixture.

LC-MS m/z: [M+H] ⁺ = 368.

Step 7 (2S, 2'S)-1,1'-di-tert-butoxycarbonyl-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5,2-diyl))bispyrrolidine

Weigh 264 mg of the compound (s)-1-tert-butoxycarbonyl-2-(1-((2-(trimethylsilyl)ethoxy)-1H-imidazole)-2-yl) prepared in Step 6) Pyrrolidine and 109 mg of the compound prepared in Step 3, 2,7-dibromospiro[芴-9,3'-butylene oxide] in a 50 mL eggplant-shaped flask, dissolved in 5 mL of N,N-dimethylacetamide, Then, 124 mg of potassium carbonate, 6.7 mg of palladium acetate, 16.8 mg of tricyclohexylphosphine and 18 mg of pivalic acid were sequentially added, and reacted at 130 ° C for 4 h under nitrogen atmosphere. After the reaction was completed, 20 mL of ethyl acetate was added to dilute, and the organic phase was 10% chlorine. The aqueous lithium solution was washed (3×20 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The title compound was obtained.

LC-MS m/z: [M+H] ⁺ = 939.

Step 8(2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7-diyl)bis(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole-5,2-diyl))bispyrrolidine

Weigh 200 mg of the compound prepared in Step 7 (2S, 2'S)-1,1'-di-tert-butoxycarbonyl-2,2'-(5,5'-(spiro[芴-9,3'-epoxybutyl] Alkyl-2,7-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5,2-diyl))pyrrolidine in 50 mL In the reaction flask, 20 mL of anhydrous toluene and 2.0 g of 200-300 mesh silica gel were added , and after refluxing for 8 hours, the reaction was stopped. The reaction mixture was concentrated and purified to silicagel

LC-MS m/z: [M+H] ⁺ = 739.

Step 9 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5,2-diyl)) bis(pyrrolidine-2,1-diyl) )) dimethyl bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

Weigh 66.6 mg of the compound (2S, 2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7-diyl) double prepared in Step 8. (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5,2-diyl))bispyrrolidine, 46.8 mg (S)-2-(methoxy Carbonylamino)-3-methylbutyric acid (MOC-L-valine) and 36.6 mg of 1-hydroxy-7-azobenzotriazole in a 25 mL round bottom flask were dissolved in 6 mL of anhydrous dichloromethane. Add 42.6 mg of pyridine and 50.4 mg of diisopropylcarbodiimide under nitrogen protection at 0-4 ° C. After the addition, the reaction solution was stirred at room temperature for 30 min. After the reaction was completed, the reaction solution was diluted with dichloromethane and water, and extracted. Drying, spin-drying and purification by column chromatography gave the title compound.

LC-MS m/z: [M+H] ⁺ =1.

Step 10(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-di Dimethyl dicarbamic acid

Weigh 50 mg of the compound prepared in Step 9 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-epoxybutyl] Alkane-2,7-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5,2-diyl))bis(pyrrolidine- 2,1-Diyl)) dimethyl bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate in a 10 mL round bottom flask, dissolved in 4 mL of dichloromethane, 0 2 mL of trifluoroacetic acid (TFA) was slowly added at -4 ° C, and stirred at room temperature for 16 h. After completion of the reaction, trifluoroacetic acid was evaporated under reduced pressure, and 5 mL of saturated aqueous sodium hydrogen carbonate solution and dichloromethane (2×5 mL) The aqueous solution was dried over sodium sulfate, filtered, dried, and then evaporated

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.32-8.30 (d, 2H), 7.78-7.69 (m, 4H), 7.47-7.41 (d, 2H), 5.24-5.13 (m, 6H), 4.28-4.26 (d, 2H), 4.1-4.01 (m, 2H), 3.95-3.89 (m, 2H), 3.67-3.63 (t, 5H), 2.41-2.19 (m, 6H), 2.11-2.03 (m, 5H) , 0.82-0.86 (m, 12H).

LC-MS: m/z: [M+H] ⁺ = 793.

Example 2 (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide] ]-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane- Dimethyl 2,1-diyldicarbamic acid

Step 1 Preparation of (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid

Weigh 2g (2S,3S)-2-amino-3-methylpentanoic acid in a 100mL eggplant bottle, add 15.27mL 1M NaOH aqueous solution, add 809mg sodium carbonate, add 1.3mL chloroformic acid at 0-4 °C The methyl ester was further reacted at 0-4 ° C for 20 min and then reacted at room temperature for 4 h. Cool to 0-4 ° C, add 20 mL of ether and dilute, 2.7 mL of concentrated hydrochloric acid was added dropwise, and ethyl acetate was added (2×50 mL), and the mixture was evaporated. Compound.

LC-MS m/z: [M+H] ⁺ = 190.

Step 2 (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]] -2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-2 ,1-diyl)dicarbamic acid dimethyl ester

The compound (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid obtained in the first step and the compound (2S, 2'S)-2,2'- (Step 8 prepared in Example 1) 5,5'-(spiro[芴-9,3'-butylene oxide]-2,7-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)) -1H-imidazole-5,2-diyl))bispyrrolidine was used as a starting material, and the title compound was obtained according to the procedure of Example 1 Step 9 and Step 10.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.34 (s, 2H), 8.20 (br, 2H), 7.51 (s, 2H), 7.39-7.18 (m, 4H), 5.16-5.24 (m, 6H), 4.28-4.30(d,2H),4.07-4.11(m,2H),3.90-3.97(m,2H),3.67(s,6H),2.22-2.44(m,6H),2.09-2.14(m,2H ), 1.80 - 1.82 (m, 2H), 1.56-1.59 (m, 2H), 1.23-1.26 (m, 2H), 0.91 - 0.97 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ = 411.

Example 3 (1S,1'S)-2,2'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2, 7-diyl) bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(1-cyclohexyl-2-oxoethane-2,1- Dimethyl dimethyl dicarbamate

Step 1 Preparation of (S)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid

Using (S)-2-amino-2-cyclohexyl acetic acid and methyl chloroformate as raw materials, according to the method of step 1 of Example 2. The title compound was obtained by the method.

LC-MS m/z: [M+H] ⁺ = 216.

Step 2 (1S, 1'S)-2,2'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(1-cyclohexyl-2-oxoethane-2,1-di Dimethyl dicarbamic acid

The compound (S)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid obtained in the first step, the compound (2S, 2'S)-2,2'-(5,5' prepared in the first step of Example 1. -(Spiro[芴-9,3'-butylene oxide]-2,7-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole The -5,2-diyl))bispyrrolidin was used as a starting material, and the title compound was obtained according to the procedure of the procedure of Step 1 and Step 10 of Example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.27-8.29 (s, 2H), 4.66-7.69 (m, 4H), 7.39-7.41 (s, 2H), 5.11-5.19 (m, 6H), 4.23-4.25 (d, 2H), 4.03-4.05 (m, 2H), 3.87-3.90 (m, 2H), 3.64 (s, 6H), 2.20-2.38 (m, 6H), 2.04-2.07 (m, 2H), 1.64 -1.74 (m, 12H), 1.13-1.28 (m, 10H).

LC-MS m/z: [M / 2+H] ⁺ =437.

Example 4 (1S,1'S)-2,2'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2, 7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1- Dimethyl dimethyl dicarbamate

Step 1 Preparation of (S)-2-(methoxycarbonylamino)-2-phenylacetic acid

Starting from (S)-2-aminophenylacetic acid and methyl chloroformate, the title compound was obtained in the same manner as in Step 1 of Example 2.

LC-MS: m/z (M+H) = 210.

Step 2 (1S, 1'S)-2,2'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-di Diaminocarbamic acid Preparation of methyl ester

The compound (S)-2-(methoxycarbonylamino)-2-phenylacetic acid obtained in the first step and the compound (2S, 2'S)-2,2'-(5,5) prepared in the first step of Example 1. '-(Spiro[芴-9,3'-butylene oxide]-2,7-diyl)bis(1-((2-(trimethylsilyl))ethoxy)methyl)-1H- The imidazole-5,2-diyl))bispyrrolidin was used as a starting material, and the title compound was obtained according to the step 9 and step 10 of Example 1.

¹ H NMR (400 MHz, d ₆ -DMSO) δ ppm: 11.79 (s, 2H), 8.36 (s, 2H), 7.80-7.56 (m, 7H), 7.42-7.31 (m, 8H), 7.11-6.95 (m, 3H), 5.56-5.41 (d, 2H), 5.07 (s, 6H), 3.90-3.89 (m, 2H), 3.56-3.53 (m, 6H), 3.18-3.09 (m, 2H), 2.03-1.84 ( b, 8H).

LC-MS m/z: [M+H] ⁺ = 861.

Example 5 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2, 7-diyl) bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2 ,1-diyl)dicarbamic acid dimethyl ester

Step 1 Preparation of (S)-2-(methoxycarbonylamino)-3,3-dimethylbutyric acid

Starting from (S)-2-amino-3,3-dimethylbutyric acid and methyl chloroformate, the title compound was obtained in the same manner as in Step 1 of Example 2.

LC-MS m/z: [M+H] ⁺ = 190.

Step 2 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2, Preparation of dimethyl 1-diyl)dicarbamate

The compound (S)-2-(methoxycarbonylamino)-3,3-dimethylbutyric acid obtained in the first step and the compound (2S, 2'S)-2, 2' obtained in the first step of Example 1. -(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7-diyl)bis(1-((2-(trimethylsilyl))ethoxy)) The title compound was obtained according to the procedure of Step 1 and Step 10 of Example 1 as the starting material of the compound-1H-imidazole-5,2-diyl))bispyrrolidine.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.25-8.21 (m, 2H), 8.09 (b, 2H), 7.65-7.58 (t, 4H), 7.39 (s, 2H), 5.13-5.02 (m, 6H) ), 4.28 (s, 2H), 3.95-3.93 (t, 2H), 3.83-3.78 (m, 2H), 3.57 (s, 6H), 2.37-1.91 (m, 8H), 0.82-0.80 (d, 18H) ).

LC-MS m/z: [M+H] ⁺ = 821.

Example 6 (1S,1'S)-2,2'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2, 7-diyl) bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(1-cyclopropyl-2-oxoethane-2,1 -Diyl) Preparation of Dimethyl Dicarbamate

Step 1 Preparation of (S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid

Starting from (S)-2-amino-2-cyclopropaneacetic acid and methyl chloroformate, the title compound was obtained in the same manner as in Step 1 of Example 2.

LC-MS m/z: [M+H] ⁺ = 174.

Step 2 (1S, 1'S)-2,2'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(1-cyclopropyl-2-oxoethane-2,1- Preparation of diyl)dicarbamic acid dimethyl ester

The compound (S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid obtained in the first step and the compound (2S, 2'S)-2, 2'-(5 obtained in the first step of Example 1) , 5'-(spiro[芴-9,3'-butylene oxide]-2,7-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-) 1H-imidazole-5,2-diyl))bispyrrolidine was used as a starting material, and the title compound was obtained according to the step 9 and step 10 of Example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.25-8.20 (m, 2H), 7.66-7.58 (m, 4H), 7.41-7.39 (d, 2H), 5.15-5.12 (t, 2H), 5.09-5.02 (m, 4H), 3.98-3.74 (m, 6H), 3.56 (s, 6H), 2.32-2.25 (d, 2H), 2.20-2.07 (m, 4H), 2.03-1.93 (m, 2H), 1.12 -1.06 (m, 2H), 0.50-0.23 (m, 8H).

LC-MS m/z: [M+H] ⁺ = 789.

Example 7 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2, 7-diyl) double (1H- Benzo[d]imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl) Dimethyl carbamate

Step 1 (S)-1-tert-Butoxycarbonyl-2-(2-amino-4-bromophenylaminoacyl)pyrrolidine

Weigh 12.9 g of Boc-L-valine in a 250 mL eggplant-shaped flask, add 150 mL of DMF, and add 27.4 g of 2-(7-azobenzotriazole)-N,N,N',N. '-Tetramethylurea hexafluorophosphate (HATU) and 11.6 g of N,N-diisopropylethylamine (DIPEA) were stirred at room temperature for 30 min, and then 11 g of 4-bromo-phenylenediamine was slowly added. After the addition was completed, the reaction was allowed to stand at room temperature for 16 h, the reaction was stopped, and the reaction mixture was poured into 200 mL of ice water, and extracted with ethyl acetate (2×200 mL), and the organic phase was combined and washed with saturated aqueous sodium chloride (2×200 mL) Dry over sodium sulfate and concentrate to give the title compound.

LC-MS m/z: [M+H] ⁺ =384.

Step 2(S)-1-tert-Butoxycarbonyl-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine

Weigh 22g of the compound (S)-1-tert-butoxycarbonyl-2-(2-amino-4-bromophenylaminoacyl)pyrrolidine prepared in step 1 in a reaction flask, add 150mL of acetic acid to dissolve, 85 ° C The reaction was stopped for 2 h, and the reaction was stopped. Under stirring at 0-4 ° C, 40% aqueous sodium hydroxide solution was slowly added dropwise, the pH was adjusted to about 9, and ethyl acetate was extracted (2×200 mL), and the organic phase was combined, and saturated aqueous sodium chloride solution was added. This was washed (2×200 mL), dried over anhydrous

LC-MS m/z: [M+H] ⁺ = 366.

Step 3(S)-2-(5-Bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine hydrochloride

Weigh 800 mg of the compound (S)-1-tert-butoxycarbonyl-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine prepared in Step 2 in a 100 mL eggplant bottle, and add After 10 mL of methanol was dissolved, 20 mL of a saturated HCl/MeOH solution was added, and the mixture was reacted at room temperature for 2 hours, and the reaction was completed. The solvent was removed under reduced pressure to give the title compound.

LC-MS m/z: [M+H] ⁺ = 266.

Step 4(S)-1-((S)-2-(5-Bromo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxo Preparation of methyl butane-2-ylcarbamate

Weigh 300 mg of (S)-2-(methoxycarbonylamino)-3-methylbutyric acid, 664 mg of 2-(7-azabenzotriazole)-N,N,N',N'-four Methylurea hexafluorophosphate (HATU), 1.05 mL DIPEA in a 50 mL round bottom flask, after adding 15 mL of DMF to dissolve, add 400 mg of the compound (S)-2-(5-bromo-1H-benzo[ d]imidazol-2-yl)pyrrolidine hydrochloride, reacted at room temperature for 2 h, after completion of the reaction, add 20 mL of water, ethyl acetate (3×15 mL), dried over anhydrous sodium sulfate, filtered, dried, and purified , the title compound was obtained.

LC-MS m/z: [M+H] ⁺ = 423.

Step 52, 7-Bis(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)spiro[芴-9,3'-butylene oxide] preparation

350 mg of the compound prepared in the first step of Example 1, 2,7-dibromospiro[芴-9,3'-butylene oxide], 610 mg of pinacol diborate, 282 mg of potassium acetate (AcOK) and 70 mg [1] were weighed. , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (Pd(dppf)Cl ₂ ) in a 50 mL round bottom flask, adding 10 mL of 1,4-dioxane After dissolving and bubbling with nitrogen for 2 min, the reaction was carried out at 100 ° C for 16 h.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.44 (s, 2H), 7.86-7.88 (d, 2H), 7.71 - 7.72 (d, 2H), 5.15 (s, 4H), 1.39 (s, 24H).

Step 6(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]-2,7 -diyl)bis(1H-benzo[d]imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane- Dimethyl 2,1-diyldicarbamic acid

Weigh 69 mg of the compound prepared in step 5, 7-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)spiro[芴-9,3' -butylene oxide], 190 mg of the compound (S)-1-((S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl prepared in Step 4 ) methyl 3-methyl-1-oxobutane-2-ylcarbamate, 190 mg potassium phosphate (K ₃ PO ₄ ), 24.5 mg Pd(dppf)Cl ₂ in a 50 mL round bottom flask, 3 mL 1 4, Dioxane and 1.2 mL of water were dissolved. After bubbling with nitrogen for 2 min, the reaction was carried out in an oil bath at 100 ° C overnight. After the reaction was completed, 10 mL of water was added, and ethyl acetate was extracted (3×5 mL). Dry, filter, mp dry, mpqqqq

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.17-8.14 (d, 2H), 7.77-7.50 (m, 10H), 5.23-5.19 (m, 2H), 5.10-5.08 (m, 4H), 4.18-4.16 (d, 2H), 3.99-3.82 (m, 4H), 3.56 (s, 6H), 2.37-1.95 (m, 10H) 0.90 - 0.79 (m, 12H).

LC-MS m/z: [M+H] ⁺ = 893.

Example 8 (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide] ]-2,7-diyl)bis(1H-benzo[d]imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1- Dimethyl oxopentan-2,1-diyl)dicarbamic acid

Step 1 (2S,3S)-1-((S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1- Preparation of methyl oxopentan-2-ylcarbamate

Weigh 300.4 mg of the compound (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid prepared in the first step of Example 2 in a 50 ml eggplant-shaped flask, add 15 mL of DMF to dissolve, and then add 664.3 in turn. Mg HATU and 1.05 mL DIPEA, stirred at room temperature for 0.5 h, and then added 400 mg of the compound (S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine salt prepared in Step 3 of Example 7. The acid salt was reacted at room temperature for 2 h. After the reaction was stopped, 20 mL of water was added, ethyl acetate was extracted (3×20 mL), washed with saturated sodium chloride solution (3×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification afforded the title compound.

LC-MS m/z: [M+H] ⁺ =437.

Step 2 (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(spiro[芴-9,3'-butylene oxide]] -2,7-diyl)bis(1H-benzo[d]imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxo Dimethyl pentane-2,1-diyl)dicarbamic acid

The compound (2S,3S)-1-((S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3- Methyl methyl-1-oxopentan-2-ylcarbamate and the compound prepared in Step 5 of Example 7, 2,7-bis(4,4,5,5-tetramethyl-1,3,2 - Dioxaboran-2-yl)spiro[芴-9,3'-butylene oxide] was used as a starting material, and the title compound was obtained according to the procedure of Step 6 of Example 7.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.29 (s, 2H), 8.00 (s, 2H), 7.94 (d, 2H), 7.85 (d, 2H), 7.79 (d, 2H), 7.71 (d, 2H), 5.28 (t, 2H), 5.16 (s, 4H), 4.22 - 4.18 (m, 2H), 4.10 (s, 2H), 3.91 - 3.85 (m, 2H), 3.57 (s, 6H), 2.57 (d, 2H), 2.22 (m, 6H), 1.69 (s, 2H), 1.41 (m, 2H), 1.05 (m, 2H), 0.79 (t, 12H);

LC-MS m/z: [M+H] ⁺ = 921

Example 9 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-difluorospiro[cyclobutane-1,9'-芴]-2,7-diyl) bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane -2,1-diyl)diamino Dimethyl formate

Step 1 1,3-Dibromo-2-tert-butyldiphenylsilyloxy-propane

Weigh 10g of 1,3-dibromopropan-2-ol in a reaction flask, add 150mL of dichloromethane to dissolve, add 3.7g of imidazole and 1.1g of 4-dimethylaminopyridine (DMAP), slowly at 0-4 °C After adding 13.9 g of t-butyldiphenylchlorosilane (TBDPSCl), the reaction was completed at room temperature overnight. After the reaction was completed, the reaction solution was poured into 150 mL of ice water, extracted with dichloromethane (2×100 mL), and the organic phase was combined. The mixture was washed with aq. EtOAc (EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.69-7.67 (d, 4H), 7.48-7.38 (m, 6H), 3.97-3.94 (t, 1H), 4.47-4.46 (t, 4H), 1.09 (s, 9H).

Step 2 Preparation of tert-butyldiphenyl (spiro[cyclobutane-1,9'-fluorenyl]-3-yloxy)silane

Weigh 6g of hydrazine in the reaction flask, add 150mL of THF to dissolve, slowly add 36mL of lithium bis(trimethylsilyl)amide (LiHMDS) at 0-4 ° C under nitrogen protection, and react at 0-4 ° C for 1 h after the addition. , slowly add 50 mL of THF solution in which 16 g of the compound 1,3-dibromo-2-tert-butyldiphenylsilyloxy-propane obtained in the step 1 was dissolved, and the mixture was reacted at room temperature for 1 hour, and the saturated solution of ammonium chloride was added. After quenching, the reaction solution was poured into 150 mL of ice water, extracted with ethyl acetate (3×100 mL), the organic phase was combined, washed with saturated aqueous sodium chloride (2×200 mL), dried over anhydrous sodium sulfate Chromatography to give the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.76-7.64 (m, 7H), 7.45-7.09 (m, 11H), 4.95-4.91 (t, 1H), 2.86-2.81 (m, 2H), 2.66-2.62 (m, 2H), 1.08 (s, 9H).

Step 3 Preparation of spiro [cyclobutane-1,9'-indole]-3-ol

12.0 g of the compound t-butyldiphenyl (spiro[cyclobutane-1,9'-fluorenyl]-3-yloxy)silane prepared in the step 2 was weighed into a 500 mL eggplant type bottle, and 150 mL of THF was added. 13.6 g of tetrabutylammonium fluoride trihydrate (TBAF) was added in portions at 0-4 ° C, and reacted at room temperature for 1 h. After the reaction was completed, 150 mL of water was added, and ethyl acetate was extracted (2×200 mL), and the organic phases were combined and saturated. The mixture was washed with aq. EtOAc (EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.72-7.67 (m, 3H), 7.58-7.56 (m, 1H), 7.41-7.32 (m, 4H), 5.03-4.98 (m, 1H), 2.86-2.70 ( m, 2H), 2.13 - 2.12 (d, 2H).

Step 4 Preparation of spiro [cyclobutane-1,9'-indole]-3-one

Weigh 4g of the compound spiro[cyclobutane-1,9'-indole]-3-ol prepared in step 3 in a 250mL round bottom flask, add 100mL of dichloromethane to dissolve, nitrogen protection at 0-4 ° C, batch After the addition of 11 g of Dess-Martin periodinane, the reaction was carried out for 1 h at room temperature.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.77-7.76 (m, 2H), 7.58-7.56 (m, 2H), 7.43-7.37 (m, 4H), 3.67 (s, 4H).

Step 53, Preparation of 3-difluorospiro[cyclobutane-1,9'-fluorene]

Weigh 10 g of the compound Spirulina [cyclobutane-1,9'-indole]-3-one prepared in Step 4 in a 500 mL round bottom flask, add 300 mL of dichloromethane to dissolve, and protect with nitrogen at 0-4 ° C. Add 15.4 g of diethylamine trifluoride (DAST), 146 mg of ethanol, and react at room temperature overnight. After completion of the reaction, quench with aqueous sodium hydrogensulfite solution, add 100 mL of water, extract with dichloromethane (2×100 mL), and saturate. The mixture was washed with aq. EtOAc (EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.71-7.69 (m, 4H), 7.39-7.37 (m, 4H), 3.23 - 3.17 (m, 4H).

Preparation of Step 62', 7'-Dibromo-3,3-difluorospiro[cyclobutane-1,9'-oxime]

Weigh 1.5 g of the compound prepared in Step 5, 3,3-difluorospiro[cyclobutane-1,9'-indole] in a 100 mL sealed tube, add 50 mL of acetonitrile, and add 2.75 g of N-bromobutane. The imide (NBS) was reacted at 95 ° C for 15 h.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.80 (m, 2H), 7.55-7.52 (m, 4H), 3.22-3.15 (m, 4H).

Step 7 (2S, 2'S)-2,2'-(5,5'-(3,3-Difluorospiro[cyclobutane-1,9'-芴]-2',7'-diyl) double (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))-1, 1'-di-tert-butyl dicarboxylate

The compound obtained in the step 6 was weighed, 400 mg of 2',7'-dibromo-3,3-difluorospiro[cyclobutane-1,9'-oxime] and the compound obtained in the first step of Example 1, 880 mg (S). -1-tert-butoxycarbonyl-2-(1-((2-(trimethylsilyl)ethoxy)-1H-imidazolyl)-2-yl)pyrrolidine in a 50 mL eggplant-shaped flask, After adding 8 mL of N,N-dimethylacetamide to dissolve, 414 mg of potassium carbonate, 22.5 mg of palladium acetate, 56 mg of tricyclohexylphosphine and 61.2 mg of pivalic acid were successively added, and reacted in an oil bath at 130 ° C for 4 h under a nitrogen atmosphere. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc.

LC-MS m/z: [M / 2+H] ⁺ = 487.

Step 8(S)-5,5'-(3,3-Difluorospiro[cyclobutane-1,9'-芴]-2',7'-diyl)bis(2-((S)-) Pyrrolidin-2-yl))-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole)

Weigh 200 mg of the compound prepared in Step 7 (2S, 2'S)-2,2'-(5,5'-(3,3-difluorospiro[cyclobutane-1,9'-芴]-2',7 '-Diyl) bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5,2-diyl)) bis(pyrrolidine-2,1-di) Base))-1,1'-di-tert-butyl dicarboxylate In a 50 mL reaction flask, 20 mL of anhydrous toluene, 2.0 g of 200-300 mesh silica gel were added, and the reaction was refluxed for 15 h to stop the reaction. The reaction mixture was concentrated and purified to silicagel eluting

LC-MS m/z: [M / 2+H] ⁺ = 387.

Step 9(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-Difluorospiro[cyclobutane-1,9'-芴]-2',7'-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5,2-diyl)) bis(pyrrolidine) -2,1-Diyl)) Preparation of dimethyl bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

Weigh 100 mg of the compound (S)-5,5'-(3,3-difluorospiro[cyclobutane-1,9'-芴]-2',7'-diyl) bis (2) prepared in Step 8. -((S)-pyrrolidin-2-yl))-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole), 68 mg (S)-2-(A) Oxycarbonylamino)-3-methylbutyric acid and 53mg 1-hydroxy-7-azobenzotriazole (HOAT) in a 25mL round bottom flask, dissolved in 10mL anhydrous dichloromethane, 0-4 ° C Under nitrogen protection, add 62mg of pyridine, 74mg of diisopropylcarbodiimide (DIC), add, and react at room temperature for 30min. After the reaction is finished, dilute the reaction solution with dichloromethane and water, collect the organic phase, dry and concentrate. Purification by silica gel column chromatography gave the title compound.

LC-MS m/z: [M / 2+H] ⁺ = 544.

Step 10(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-Difluorospiro[cyclobutane-1,9'-芴]-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane- Preparation of dimethyl 2,1-diyldicarbamic acid

Weigh 70 mg of the compound prepared in Step 9 (2S, 2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-difluorospiro[cyclobutane- 1,9'-芴]-2',7'-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5,2-diyl )) bis(pyrrolidine-2,1-diyl)) bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamic acid dimethyl ester in a 25 mL round bottom flask, Dissolve 5 mL of dichloromethane, slowly add 2.5 mL of trifluoroacetic acid (TFA) at 0-4 ° C, and react at room temperature overnight. After the reaction is completed, trifluoroacetic acid is distilled off under reduced pressure, and 5 mL of saturated aqueous sodium hydrogen carbonate solution and dichloromethane are added. The extract was extracted (2×5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.00 (m, 2H), 7.71-7.65 (t, 4H), 7.35-7.34 (d, 2H), 5.20-5.18 (t, 2H), 4.24 - 4.25 (d , 2H), 4.02-4.01 (m, 2H), 3.90-3.88 (m, 2H), 3.65 (s, 6H), 3.30-3.24 (m, 4H), 2.37-2.19 (m, 6H), 2.09-2.04 (m, 4H), 1.00-0.91 (t, 12H).

LC-MS m/z: [M / 2+H] ⁺ = 414.

Example 10 (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-difluorospiro[cyclobutane-1] , 9'-芴]-2',7'-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl- Dimethyl 1-oxopentan-2,1-diyl)dicarbamic acid

Step 1 (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-Difluorospiro[cyclobutane-1, 9'-芴]-2',7'-diyl)bis(1-((2-(trifluoromethyl)ethoxy)methyl)-1H-imidazole-5,2-diyl)) double Preparation of (pyrrolidine-2,1-diyl)) bis(3-methyl-1-oxopentan-2,1-diyl)dicarbamic acid dimethyl ester

Compound (S)-5,5'-(3,3-difluorospiro[cyclobutane-1,9'-indole]-2',7'-diyl) bis (prepared as in Example 9 Step 8) 2-((S)-Pyrrolidin-2-yl))-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole) and the compound prepared in Step 1 of Example 2 (2S,3S)-2-(Methoxycarbonylamino)-3-methylpentanoic acid was used as the starting material.

LC-MSm / z: [M / 2 + H] + = 558.

Step 2 (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-Difluorospiro[cyclobutane-1, 9'-芴]-2',7'-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1) Of dimethyl 2-oxopentane-2,1-diyl)dicarbamate

The compound prepared in the first step (2S, 2'S, 3S, 3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-difluorospiro[ring] Butane-1,9'-芴]-2',7'-diyl)bis(1-((2-(trifluoromethyl)ethoxy)methyl)-1H-imidazole-5,2- Diyl)) bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentan-2,1-diyl)dicarbamic acid dimethyl ester as raw material, according to the examples The method of 9 step 10 produces the target compound.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.07-8.02 (m, 2H), 7.74-7.66 (m, 4H), 7.41-7.37 (m, 2H), 5.23-5.20 (t, 2H), 4.29-4. (d, 2H), 4.14 - 4.06 (m, 2H), 3.94 - 3.88 (m, 2H), 3.67 (s, 6H), 3.29 - 3.22 (m, 4H), 2.40 - 2.22 (m, 6H), 2.12 -2.06 (m, 2H), 1.81-1.79 (m, 2H), 1.61-1.55 (m, 2H), 1.21-1.14 (m, 2H), 1.02-0.88 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ = 428.

Example 11 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-1H-benzo[d] Methyl imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Step 1 Preparation of 1-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)ethanone

366 mg of the compound 2,7-dibromospiro[芴-9,3'-butylene oxide] prepared in the first step of Example 1 was weighed into a reaction flask, dissolved in 5 mL of THF, and 0.6 mL of n-butyl was added dropwise at -78 °C. After the lithium (2.4 M) was further reacted at -78 ° C for 1 h, 515 mg of N-methyl-N-methoxyacetamide was added, and the obtained reaction mixture was allowed to rise to room temperature. After quenching with aq. EtOAc EtOAc (EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.55 (s, 1H), 8.16 (s, 1H), 8.02-8.04 (d, 1H), 7.71-7.73 (d, 1H), 7.58-7.60 (d, 2H) , 5.15-5.16 (d, 2H), 5.07-5.08 (d, 2H), 2.70 (s, 3H).

Step 2 Preparation of 2-bromo-1-(2-bromospiro[芴--9,3'-butylene oxide]-7-yl)ethanone

Weigh 64 mg of the compound 1-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)ethanone prepared in Step 1 in a reaction flask, and add 5 mL of dichloromethane to dissolve, 0- At 4 ° C, 53 mg of trimethylsilyl trifluoromethanesulfonate (TMSOTf) was slowly added under nitrogen. After the addition, the reaction was continued at 0-4 ° C for 1 h, and 53 mg of N-bromosuccinimide (NBS) was added. After the completion of the addition, the reaction was continued at 0-4 ° C for 2 hours. After completion of the reaction, the mixture was evaporated.

Step 3(S)-1,2-Pyrrolidinedicarboxylic acid (2-(2-(2-Bromospiro[芴-9,3'-butylene oxide]-7-yl)-2-oxoethyl) (1-tert-butyl) diester

Weigh 810 mg of the compound 2-bromo-1-(2-bromospiro[芴--9,3'-butylene oxide]-7-yl)ethanone prepared in Step 2 into a 100 mL eggplant bottle and add 20 mL of acetonitrile, 860 mg of (S)-1-tert-butoxycarbonyl-2-carboxy-pyrrolidine and 774 mg of DIPEA were added at 0-4 ° C, and reacted at 70 ° C for 3 h. After the reaction was completed, the solvent was removed under reduced pressure, and silica gel column chromatography Purification afforded the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.51 (s, 1H), 8.16 (s, 1H), 7.94-7.99 (m, 1H), 7.43-7.76 (m, 1H), 7.57-7.3 (m, 2H) , 5.28-5.68 (m, 2H), 5.05-5.14 (m, 4H), 4.43-4.53 (m, 1H), 3.59-3.62 (m, 1H), 3.40-3.58 (m, 1H), 2.36-2.39 ( m, 2H), 1.91-2.11 (m, 2H), 1.47 (s, 9H).

Step 4(S)-1-tert-Butoxycarbonyl-2-(5-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl Pyrrolidine

Weigh 540 mg of the compound (S)-1,2-pyrrolidinedicarboxylic acid prepared in Step 3 (2-(2-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)) 2-Oxoethyl)(1-tert-butyl) diester and 770 mg ammonium acetate in a reaction flask, 10 mL of xylene was added, and microwave reaction was carried out at 140 ° C for 90 min. After the reaction was completed, the solvent was distilled off under reduced pressure, and 50 mL of acetic acid was added. The ethyl ester was washed with water (1×20 mL).

LC-MS m/z: [M+H] ⁺ = 522.

Step 5(S)-1-tert-Butoxycarbonyl-2-(5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl) Snail [芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)pyrrolidine

Weigh 150 mg of the compound (S)-1-tert-butoxycarbonyl-2-(5-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)- 1H-imidazol-2-yl)pyrrolidine and 109 mg of pinacol diborate in a 50 mL eggplant-shaped flask, dissolved in 5 mL of 1,4-dioxane, and sequentially added 21 mg of Pd(dppf)Cl ₂ , 85 mg of AcOK The reaction was carried out in a 100 ° C oil bath for 6 h under nitrogen atmosphere, and the next step was not treated after the reaction was completed.

LC-MSm / z: [M + H] + = 570.

Step 6(S)-1-tert-Butoxycarbonyl-2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d] Imidazol-2-yl)pyrrolidine

1.5 g of the compound (S)-1-tert-butoxycarbonyl 2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine prepared in Step 2 of Example 7 was dissolved in 50 mL of THF. Under nitrogen protection, add 246 mg of NaH in batches at 0-4 ° C, stir at room temperature for 1 h, cool to 0-4 ° C, and slowly add 1.0 g of 2-(trimethylsilyl)ethoxymethyl chloride. Slowly return to room temperature and stir for 2 hours. After the reaction is completed, the reaction solution is poured into 100 mL of ice water, and extracted with ethyl acetate (2×200 mL). The organic phase is combined and washed with saturated aqueous sodium chloride (1×100 mL), organic The title was dried over anhydrous sodium sulfate, filtered, evaporated

LC-MS m/z: [M+H] ⁺ =495.

Step 7(S)-1-tert-Butoxycarbonyl-2-(5-(2-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-() (2-(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl) -1H-imidazol-2-yl)pyrrolidine

196 mg of the compound (S)-1-tert-butoxycarbonyl-2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzene prepared in Step 6 And [d] imidazol-2-yl)pyrrolidine, 21 mg of Pd(dppf)Cl ₂ and 1 mL of 2N K ₃ PO ₄ aqueous solution were added to the reaction liquid of the step 5, and reacted under an atmosphere of nitrogen at 100 ° C in an oil bath overnight. The reaction solution was poured into 25 mL of water, and extracted with ethyl acetate (2×25 mL). The organic phase was combined, washed with saturated aqueous sodium chloride (2×25 mL), dried over anhydrous sodium sulfate The title compound was obtained.

LC-MS m/z: [M / 2+H] ⁺ = 430.

Step 8 2-((S)-Pyrrolidin-2-yl)-5-(2-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) snail [芴- 9,3'-butylene oxide]-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

Compound (S)-1-tert-butoxycarbonyl-2-(5-(2-(2-((S)-1-(tert-butoxycarbonyl)))) Pyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)spiro[芴-9,3' The title compound was obtained according to the procedure of Step 8 of Example 1 using hexanes.

LC-MSm / z: [M / 2 + H] + = 330.

Step 9 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-3) -methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-(N-(2-(3) Methylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl) Methyl carbamate

The compound 2-((S)-pyrrolidin-2-yl)-5-(2-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) Snail [芴-9,3'-butylene oxide]-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole Starting from (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid, the title compound was obtained according

LC-MS m/z: [M / 2+H] ⁺ = 487.

Step 10 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-3) -methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-1H-benzo[d]imidazole Methyl-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxybutane-2-yl)carbamate

The compound N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxy)) Carbonyl)amino)-3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-(N -(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-methoxy The title compound was obtained according to the method of Step 10 of Example 1 using methylene chloride of butane-2-yl)carbamate as a starting material.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.34-8.26 (m, 3H), 7.86-7.63 (m, 6H), 7.45 (s, 1H), 5.23-5.19 (m, 6H), 4.30-3.94 (m) , 6H), 3.68 (s, 6H), 2.37-2.07 (m, 10H), 1.03-0.91 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ =422.

Example 12 N-((2S)-1-((2S)-2-(6-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-1H-imidazo[4, Methyl 5-b]pyridin-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxybutane-2-yl)carbamate

Step 1 (S)-1-tert-Butoxycarbonyl-2-(2-amino-5-bromopyridin-3-aminocarbonyl)pyrrolidine

Starting from (S)-1-tert-butoxycarbonyl-2-carboxy-pyrrolidine and 2,3-diamino-5-bromopyridine, the title compound was obtained in the same manner as in Step 1 of Example 7.

LC-MS m/z: [M+H] ⁺ = 385.

Step 2(S)-1-tert-Butoxycarbonyl-2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine

The compound (S)-1-tert-butoxycarbonyl-2-(2-amino-5-bromopyridin-3-aminocarbonyl)pyrrolidine obtained in the first step was used as the starting material in the same manner as in the step 2 of Example 7. The title compound was obtained.

LC-MS m/z: [M+H] ⁺ = 367.

Step 3(S)-3-tert-Butoxycarbonyl-6-bromo-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3H-imidazo[4,5-b]pyridine

2.7 g of the compound (S)-1-tert-butoxycarbonyl-2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine obtained in the second step was weighed in the reaction. The flask was dissolved in 20 mL of dichloromethane, and 1.9 g of Boc ₂ O, 1.8 g of DIPEA and 85 mg of DMAP was added at 0-4 ° C, and stirred at room temperature for 16 h. After completion of the reaction, the mixture was directly purified by silica gel column chromatography to give the title compound.

LC-MS m/z: [M+H] ⁺ =467.

Step 4 2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-6-(2-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidine) -2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-3H-imidazo[4,5-b]pyridine-3-carboxylic acid Tert-butyl ester

The compound (S)-3-tert-butoxycarbonyl-6-bromo-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3H-imidazo[4,5] prepared in the step 3 -b]pyridine and the compound (S)-2-(5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane) prepared in the step 5 of Example 11 - 2-based) spiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester as a starting material, according to step 11 of Example 11. The title compound was prepared by the method.

LC-MS m/z: [M / 2+H] ⁺ = 416.

Step 5 2-((S)-Pyrrolidin-2-yl)-6-(2-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) snail [芴- 9,3'-butylene oxide]-7-yl)-3H-imidazo[4,5-b]pyridine

The compound of Step 4 is 2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-(2-(2-((S))-1-(tert-butoxycarbonyl) Pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-3H-imidazo[4,5-b]pyridine- The title compound was obtained according to the procedure of Step 8 of Example 1.

LC-MS m/z: [M/2+H] ⁺ =266.

Step 6 N-((2S)-1-((2S)-2-(6-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-3) -methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-1H-imidazo[4,5 -b]pyridin-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamic acid methyl ester

The compound prepared in Step 5 2-((S)-pyrrolidin-2-yl)-6-(2-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) Spiro[芴-9,3'-butylene oxide]-7-yl)-3H-imidazo[4,5-b]pyridine and (S)-2-(methoxycarbonylamino)-3-methyl The title compound was obtained according to the procedure of Step 9 of Example 1 as the starting material.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.72 (s, 1H), 8.36-8.19 (m, 3H), 7.84-7.71 (m, 4H), 7.51 (s, 1H), 5.34-5.17 (m, 6H) ), 4.31-3.94 (m, 6H), 3.68 (s, 6H), 2.42 - 2.15 (m, 10H), 1.01 - 0.93 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ = 423.

Example 13 N-((2S)-1-((2S)-2-(6-(7'-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-芴])-2'-yl Methyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Step 1 1-(2'-Bromo-3,3-difluorospiro[cyclobutane-1,9'-oxime]-7'-yl)ethanone

1.8 g of the compound 2',7'-dibromo-3,3-difluorospiro[cyclobutane-1,9'-oxime] prepared in the step 6 of Example 9 was weighed into a 100 mL three-necked flask, and 30 mL of THF was added. Dissolved, nitrogen protection - slowly add 2.08 mL of n-butyllithium (n-BuLi) at 70 ° C, and react at -70 ° C for 2 h, then add 1.8 g of N-methoxy-N-methylacetamide. After the reaction at room temperature for 1 h, after completion of the reaction, the ammonium chloride saturated solution was quenched, 25 mL of water was added, ethyl acetate was extracted (2×25 mL), and the organic phase was combined and washed with saturated aqueous sodium chloride (2×25 mL) Drying over sodium sulfate, concentration and silica gel column chromatography

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.29 (d, 1H), 8.05-8.03 (m, 1H), 7.90 (d, 1H), 7.77 (d, 1 H), 7.65 (d, 1H), 7.64 7.57 (m, 2H), 3.31-3.19 (m, 4H), 2.71 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 363.

Step 2 2-Bromo-1-(2'-bromo-3,3-difluorospiro[cyclobutane-1,9'-indole]-7'-yl)ethanone

Weigh 500 mg of the compound 1-(2'-bromo-3,3-difluorospiro[cyclobutane-1,9'-indole]-7'-yl)ethanone prepared in Step 1 in a 100 mL three-necked bottle. Adding 15 mL of dichloromethane to dissolve, nitrogen protection at 0-4 ° C, adding 200 mg of triethylamine (TEA) and 500 mg of trimethylsilyl trifluoromethanesulfonate (TMSOTf), reacting at 0-4 ° C for 2 h, then adding 400 mg of N-bromosuccinimide (NBS) was further reacted at room temperature for 1 hour after the addition. After the reaction was completed, the reaction solution was concentrated and used directly for the next reaction.

Step 3(S)-1,2-pyrrolidinedicarboxylic acid (2-(2-(2'-bromo-3,3-difluorospiro[cyclobutane-1,9'-芴]-7'-yl) )-2-oxoethyl))(1-tert-butyl) diester

The compound prepared in the second step is 2-bromo-1-(2'-bromo-3,3-difluorospiro[cyclobutane-1,9'-fluorenyl]-7'-yl)ethanone and (S) 1-((tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid was used as the starting material.

LC-MS m/z: [M+H] ⁺ = 576.

Step 4(S)-1-tert-Butoxycarbonyl-2-(5-(2'-bromo-3,3-difluorospiro[cyclobutane-1,9'-oxime]-7'-yl) -1H-imidazol-2-yl)pyrrolidine

Compound (S)-1,2-pyrrolidinedicarboxylic acid prepared in Step 3 (2-(2-(2'-bromo-3,3-difluorospiro[cyclobutane-1,9'-芴]- The title compound was obtained according to the procedure of Step 4 of Example 11 using the title compound (1).

LC-MSm / z: [M + H] + = 557 +.

Step 5(S)-1-tert-Butoxycarbonyl-2-(5-(3,3-difluoro-2'-(4,4,5,5-tetramethyl-1,3,2-di) Oxoborane-2- Spirulina [cyclobutane-1,9'-芴]-7'-yl)-1H-imidazol-2-yl)pyrrolidine

The compound (S)-1-tert-butoxycarbonyl-2-(5-(2'-bromo-3,3-difluorospiro[cyclobutane-1,9'-芴]-) obtained in the step 4 The title compound was obtained by the same procedure as in the step 5 of Example 7 from the title compound.

LC-MS m/z: [M+H] ⁺ = 604.

Step 6(S)-1-tert-Butoxycarbonyl-2-(5-(2'-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-) ((2-(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-3,3-difluorospiro[cyclobutane-1,9'-芴]-7'-yl)-1H-imidazol-2-yl)pyrrolidine

The compound (S)-1-tert-butoxycarbonyl-2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-) obtained in the step 6 of Example 11 1H-benzo[d]imidazol-2-yl)pyrrolidine and the compound (S)-1-tert-butoxycarbonyl-2-(5-(3,3-difluoro-2'-) obtained in the step 5 (4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)spiro[cyclobutane-1,9'-芴]-7'-yl)-1H The title compound was obtained according to the procedure of Step 6 of Example 7.

LC-MS m/z: [M / 2+H] ⁺ = 447.

Step 7 5-(3,3-Difluoro-2'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[cyclobutane-1,9'-芴]-7'-yl)-2-((S)-pyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[ d]imidazole

Compound (S)-1-tert-butoxycarbonyl-2-(5-(2'-(2-((S)-1-(tert-butoxycarbonyl))pyrrolidine-2-) -1((2-(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-3,3-difluorospiro[cyclobutane- 1,9'-芴]-7'-yl)-1H-imidazol-2-yl)pyrrolidine as a starting material, according to the method of step 8 of Example 1. The title compound was obtained.

LC-MS m/z: [M / 2+H] ⁺ =347.

Step 8 N-((2S)-1-((2S)-2-(5-(7'-(2-((S)-1-((S)-2-((methoxycarbonyl)amino))) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-oxime])-2'-yl) -(N-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1- Methyl oxobutane-2-yl)carbamate

The compound prepared in the step 7 is 5-(3,3-difluoro-2'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[cyclobutane- 1,9'-芴]-7'-yl)-2-((S)-pyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- The title compound was obtained according to the procedure of Step 1 of Example 1 using 1H-benzo[d]imidazole and (S)-2-(methoxycarbonylamino)-3-methylbutyric acid as the starting material.

LC-MS m/z: [M / 2+H] ⁺ = 504.

Step 9 N-((2S)-1-((2S)-2-(5-(7'-(2-((S)-1-((S)-2-((methoxycarbonyl)amino))) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)3,3-difluorospiro[cyclobutane-1,9'-oxime]-2'-yl)-1H -Methyl benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

The compound N-((2S)-1-((2S)-2-(5-(7'-(2-((S))-1-((S)-2-)) Oxycarbonyl)amino)-3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-芴]) -2'-yl)-(N-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3 The title compound was obtained according to the procedure of Step 10 of Example 1 using m.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.09-7.97 (m, 2H), 7.81-7.57 (m, 7H), 7.46-7.40 (m, 1H), 5.33-5.20 (m, 2H), 4.30-4.25 (m, 2H), 4.12-3.90 (m, 4H) 4.12-3.90 (m, 6H), 3.32-3.24 (m, 4H), 2.48-2.07 (m, 10H), 1.06-0.90 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ = 439.

Example 14 N-((2S)-1-((2S)-2-(5-(7'-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)) 3-methylpentanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-oxime])-2'-yl Methyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

Step 1 N-((2S)-1-((2S)-2-(5-(7'-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-) 3-methylpentanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-oxime])-2'-yl) -(N-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1- Methyl oxopentan-2-yl)carbamate

Compound 5-(3,3-difluoro-2'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) snail [Ring] obtained in Step 13 of Example 13 Butane-1,9'-芴]-7'-yl)-2-((S)-pyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy) A -1H-benzo[d]imidazole and the compound (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid prepared in the first step of Example 2 as a starting material, according to Example 9, Step 9. The title compound was prepared by the method.

LC-MS m/z: [M / 2+H] ⁺ = 518.

Step 2 N-((2S)-1-((2S)-2-(5-(7'-(2-((S)-1-((S)-2-((methoxycarbonyl)amino))) 3-methylpentanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-oxime])-2'-yl) Methyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

The compound N-((2S)-1-((2S)-2-(5-(7'-(2-((S))-1-((S)-2-)) Oxycarbonyl)amino)-3-methylpentanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)3,3-difluorospiro[cyclobutane-1,9'-芴]-2 '-yl)-(N-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-A The title compound was obtained according to the method of Step 10 of Example 1 using m-propyl-1-oxopentan-2-yl)carbamate as a starting material.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.09-8.00 (m, 2H), 7.84-7.59 (m, 7H), 7.48-7.43 (m, 1H), 5.33-5.20 (m, 2H), 4.32-4.27 (m, 2H), 4.19-4.10 (m, 2H), 3.98-3.90 (m, 2H), 3.67 (s, 6H), 3.33-3.25 (m, 4H), 2.48-2.06 (m, 8H), 1.83 -1.79 (m, 2H), 1.57-1.51 (m, 2H), 1.18-1.13 (m, 2H), 1.03-0.87 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ = 453.

Example 15 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-4-oxo-3, Methyl 4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)-3-methyl-1-methoxybutan-2-yl)carbamate

Step 12-Amino-4bromo-benzamide

2.15 g of 2-amino-4-bromo-benzoic acid was dissolved in 10 mL of DMF, and 2.8 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 2.0 g of hydroxybenzene was added. Triazolium (HOBT) and 10 mL of NH ₄ OH were reacted under nitrogen for 15 h at room temperature. After the reaction was completed, 100 mL of ethyl acetate was added, and the organic phase was collected, washed successively with 10% LiCl aqueous solution and saturated brine. The title compound was obtained by the title compound.

LC-MS m/z: [M+H] ⁺ = 215.

Step 2(S)-l-Benzyloxycarbonyl-2-(5-bromo-2-carbamoylphenylcarbamoyl)pyrrolidine

1.7 g of (S)-1-benzyloxycarbonyl-2-carboxy-pyrrolidine was dissolved in 100 mL of dichloromethane, and 985 mg of oxalyl chloride (COCl) ₂ and a catalytic amount of DMF (0.1) were slowly added under a nitrogen atmosphere. After the addition, the reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated to give (S)-benzyloxycarbonyl-2-(chlorocarbonyl)pyrrolidine as a crude product.

Weigh 1.0 g of the compound 2-amino-4-bromo-benzamide prepared in Step 1 in another reaction flask, add 9.2 mL of NaOH (1 N) and 30 mL of THF, and slowly add the above-mentioned (S)-benzyloxycarbonyl group. THF solution of crude -2-(chlorocarbonyl)pyrrolidine, after 1 h of reaction, after completion of the reaction, the reaction solution was poured into 25 mL of aqueous solution, extracted with ethyl acetate (2×50 mL), and the organic phase was combined and saturated. The organic layer was dried over anhydrous sodium sulfate, filtered andEtOAc

LC-MS m/z: [M+H] ⁺ = 446.

Step 3(S)-1-Benzyloxycarbonyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine

Weigh 510 mg of the compound (S)-l-benzyloxycarbonyl-2-(5-bromo-2-carbamoylphenylcarbamoyl)pyrrolidine prepared in Step 2 in a reaction flask, and add 10 mL of EtOH to dissolve. 1.9mL of 10% KOH aqueous solution was slowly added, and the reaction was carried out at 80 ° C for 2 h after the completion of the reaction. After the reaction was completed, the pH was adjusted to about 7 with concentrated hydrochloric acid, a white solid was precipitated, filtered, and the filtrate was extracted with ethyl acetate (3×20 mL) and combined. The organic phase was washed with EtOAc EtOAc m.

LC-MS m/z: [M+H] ⁺ = 428.

Step 4(S)-7-Bromo-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one

The compound prepared in the step 3 was weighed 42.7 mg of (S)-1-benzyloxycarbonyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine. In the reaction flask, 1 mL of dichloromethane was added to dissolve. At 0-4 ° C, 0.1 mL of HBr (33%) in AcOH was slowly added. After the addition, the reaction was carried out for 15 h at room temperature. After the reaction was completed, the precipitated solid was filtered and evaporated. Wash and dry to give the title compound.

LC-MS m/z: [M+H] ⁺ = 294.

Step 5(S)-1-tert-Butoxycarbonyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine

1.6 g of the compound (S)-7-bromo-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one prepared in the step 4 was weighed into a reaction flask, and dissolved in 100 mL of dichloromethane, Under nitrogen, 1.7 g of di-tert-butyl dicarbonate (Boc ₂ O) and 2.0 g of DIPEA were added slowly. After the addition, the reaction was carried out for 10 h at room temperature. After the reaction was completed, the reaction mixture was concentrated and purified by silica gel column chromatography .

LC-MS m/z: [M+H] ⁺ = 394.

Step 6(S)-1-tert-Butoxycarbonyl-2-(7-(2-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole) -5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine

The compound (S)-1-tert-butoxycarbonyl-2-(5-(2-(4,4,5,5-tetramethyl-1,3,2-di) obtained in the step 5 of Example 11 Oxoboran-2-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)pyrrolidine and compound (S) obtained in step 5 - Starting from 1-tert-butoxycarbonyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine, the title was obtained according to the method of Step 6 of Example 7. Compound.

LC-MS m/z: [M / 2+H] ⁺ = 379.

Step 72-((S)-Pyrrolidin-2-yl)-7-(2-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) snail [芴-9 , 3'-butylene oxide]-7-yl)quinazoline-4(3H)-one

The compound (S)-1-tert-butoxycarbonyl-2-(7-(2-(2-((S)-1-(tert-butoxycarbonyl))pyrrolidin-2-yl) obtained in the step 6 -1H-imidazole-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) The title compound was obtained according to the procedure of the procedure

LC-MS m/z: [M / 2+H] ⁺ = 279.

Step 8 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino))) -methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-4-oxo-3,4 Methyl-dihydroquinazolin-2-yl)pyrrolidin-1-yl)-3-methyl-1-methoxybutan-2-yl)carbamate

The compound prepared in the step 7 is 2-((S)-pyrrolidin-2-yl)-7-(2-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) Snail [芴-9,3'-butylene oxide]-7-yl)quinazoline-4(3H)-one and (S)-2-(methoxycarbonylamino)-3-methylbutyric acid The title compound was obtained by the method of Step 9 of Example 1 as a material.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.33 - 8.22 (m, 3H), 7.95-7.73 (m, 6H), 7.52-7.48 (m, 1H), 5.23-5.17 (m, 6H), 4.23 - 3.81 (m, 6H), 3.68 (s, 6H), 2.43-2.05 (m, 10H), 1.16-0.90 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ = 436.

Example 16 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)-) 3-methylpentanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-4-oxo-3, Methyl 4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

The compound 2-((S)-pyrrolidin-2-yl)-7-(2-(2-((S)-pyrrolidine-2-) obtained in the step 7 of Example 15 -1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)quinazoline-4(3H)-one and the compound obtained in Step 2 of Example 2 (2S,3S)-2-(Methoxycarbonylamino)-3-methylpentanoic acid was used as a starting material, and the title compound was obtained according to the procedure of Step 9 of Example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.27-8.35 (m, 3H), 7.75-7.92 (m, 6H), 7.45 (s, 1H), 5.16-5.24 (m, 4H), 4.93-4.95 (m) , 2H), 4.28-4.39 (m, 2H), 4.07-4.14 (m, 2H), 3.82-3.94 (m, 2H), 3.71 (m, 6H), 2.24-2.32 (m, 4H), 1.81-2.13 (m, 6H), 1.30-1.50 (m, 4H), 0.95-0.98 (m, 12H).

LC-MS m/z: [M+H] ⁺ = 899.

Example 17 (2S, 2'S, 3R, 3'R)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-difluorospiro[cyclobutane] -1,9'-芴]-2',7'-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-hydroxyl Dimethyl-1-oxobutane-2,1-diyl)dicarbamic acid

Step 1 (2S,3R)-3-hydroxy-2-(methoxycarbonylamino)butyric acid

The title compound was obtained according to the procedure of Step 1 of Example 2 using L-threonine and methyl chloroformate as the starting material.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 6.86-6.88 (d, 1H), 4.02-4.09 (m, 1H), 3.91-3.94 (m, 1H), 3.55 (s, 3H), 1.08-1. d, 3H).

LC-MS m/z: [M+H] ⁺ = 178.

Step 2 (2S, 2'S, 3R, 3'R)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-Difluorospiro[cyclobutane- 1,9'-芴]-2',7'-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5,2-diyl Preparation of bis(pyrrolidine-2,1-diyl))bis(3-hydroxy-1-oxobutane-2,1-diyl)dicarbamic acid dimethyl ester

26 mg of the compound (2S,3R)-3-hydroxy-2-(methoxycarbonylamino)butyric acid prepared in the step 1 and 50 mg of the compound (S)-5,5'-(3) prepared in the step 8 of Example 9 were weighed. ,3-difluorospiro[cyclobutane-1,9'-indole]-2',7'-diyl)bis(2-((S)-pyrrolidin-2-yl)-1-(2 -(Trimethylsilyl)ethoxy)methyl)-1H-imidazole) was dissolved in a 25 mL round bottom flask by adding 1 mL of anhydrous DMF, and 38 mg of DIPEA and 45 mg of HATU were added at 0-4 ° C. After stirring for 1 h, the reaction mixture was diluted with methylene chloride and water.

LC-MS m/z: [M / 2+H] ⁺ = 546.

Step 3 (2S, 2'S, 3R, 3'R)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-Difluorospiro[cyclobutane- 1,9'-芴]-2',7'-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-hydroxy- Dimethyl 1-oxobutane-2,1-diyl)dicarbamic acid

The compound prepared in step 2 (2S, 2'S, 3R, 3'R)-1,1'-((2S,2'S)-2,2'-(5,5'-(3,3-difluorospiro[ Cyclobutane-1,9'-anthracene-2',7'-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5, 2-Diyl)) bis(pyrrolidine-2,1-diyl)) bis(3-hydroxy-1-oxobutane-2,1-diyl)dicarbamic acid dimethyl ester as raw material, according to the implementation The title compound was obtained by the method of Step 10 of Example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.04 (s, 2H), 7.67-7.74 (m, 4H), 7.40 (s, 2H), 5.26-5.29 (m, 2H), 4.54-4.55 (d, 2H) ), 4.14 - 4.17 (m, 2H), 3.97 - 3.98 (m, 4H), 3.69 (s, 6H), 3.24 - 3.29 (m, 4H), 2.40 - 2.41 (m, 2H), 2.10 - 2.22 (m , 6H), 1.20-1.24 (d, 6H).

LC-MS m/z: [M / 2+H] ⁺ = 416.

Example 18 N-((2S)-1-((2S)-2-(5-(7'-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)) -3-methylbutyryl (Pyrrolidin-2-yl)-1H-imidazol-5-yl) (3,3-difluorospiro[cyclobutane-1,9'-indole])-2'-yl)-4-oxo Methyl-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Step 1 (2S)-1-tert-Butoxycarbonyl-2-(7-(2'-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H- Imidazol-5-yl)-3,3-difluorospiro[cyclobutane-1,9'-indole]-7'-yl)-4-oxo-3,4-dihydroquinazolinone-2 -base) pyrrolidine preparation

The compound (S)-1-tert-butoxycarbonyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrole obtained in the same manner as in the step 5 of Example 15 Alkane and compound (S)-tert-butoxycarbonyl--2-(5-(3,3-difluoro-2'-(4,4,5,5-tetramethyl) obtained in Step 5 of Example 11 -1,3,2-dioxoboran-2-yl)spiro[cyclobutane-1,9'-indole]-7'-yl)-1H-imidazol-2-yl)pyrrolidine as a raw material, The title compound was obtained according to the procedure of Step 6 of Example 7.

LC-MS m/z: [M / 2+H] ⁺ = 396.

Step 2 7-(3,3-Difluoro-2'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[cyclobutane-1,9'-芴]-7'-yl)-2-((S)-pyrrolidin-2-yl)quinazolin-4(3H)-one

The compound (2S)-1-tert-butoxycarbonyl-2-(7-(2'-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-) obtained in the step 1 -1H-imidazol-5-yl)-3,3-difluorospiro[cyclobutane-1,9'-indole]-7'-yl)-4-oxo-3,4-dihydroquinoline The title compound was obtained according to the procedure of Step 8 of Example 1 from oxazolone-2-yl)pyrrolidine.

LC-MS m/z: [M/2+H] ⁺ = 296.

Step 3 N-((2S)-1-((2S)-2-(5-(7'-(2-((S)-1-((S)-2-((methoxycarbonyl)amino))) 3-methylbutyryl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-oxime])-2'-yl) -4-oxo-3,4-dihydrogen Preparation of methyl quinazolin-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

The compound 7-(3,3-difluoro-2'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)spiro[cyclobutane] obtained in the step 2 1,9'-芴]-7'-yl)-2-((S)-pyrrolidin-2-yl)quinazolin-4(3H)-one and (S)-2-(methoxycarbonyl) The title compound was obtained according to the procedure of Step 9 of Example 1 using m.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.26-8.21 (m, 1H), 8.06-8.00 (m, 2H), 7.93-7.69 (m, 6H), 7.47-7.43 (m, 1H), 5.31-4.97 (m, 2H), 4.33-3.77 (m, 6H), 3.71-3.67 (m, 6H), 3.28-3.22 (m, 4H), 2.43-2.04 (m, 10H), 1.18-0.83 (m, 12H) .

LC-MS m/z: [M / 2+H] ⁺ = 453.

Example 19 N-((2S)-1-((2S)-2-(5-(7'-(2-((S))-1-((S)-2-((methoxycarbonyl)amino)) 3-methylpentanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)(3,3-difluorospiro[cyclobutane-1,9'-oxime])-2'-yl Methyl 4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

The compound 7-(3,3-difluoro-2'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl) snail [ring] obtained in the step 2 of Example 18 Butane-1,9'-fluorenyl-7'-yl)-2-((S)-pyrrolidin-2-yl)quinazoline-4(3H)-one and obtained in Step 2 of Example 2 The title compound was prepared according to the procedure of Step 1 of Example 1 from Compound (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.26-8.23 (m, 1H), 8.09-8.01 (m, 2H), 7.90-7.74 (m, 6H), 7.47-7.43 (m, 1H), 5.30-5.29 (m, 2H), 4.36-3.95 (m, 6H), 3.68-3.65 (m, 6H), 3.25-3.22 (m, 4H), 2.41-2.03 (m, 8H), 1.87-1.82 (m, 2H) , 1.65-1.59 (m, 2H), 1.28-1.20 (m, 2H), 1.00-0.87 (m, 12H).

LC-MS m/z: [M / 2+H] ⁺ =467.

Example 20 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-5-((S)-2-((methoxycarbonyl)amino)-) 3-methylbutyryl 5-)azaspiro[2.4]heptane-6-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-1H-benzene And [d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamic acid methyl ester

Step 1 (S)-1-Benzyloxycarbonyl-2-methoxycarbonyl-4-oxopyrrolidine

Weigh 25g (2S,4R)-1-benzyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine in a 1L round bottom flask and add 500mL of a 1:1 mixture of toluene/ethyl acetate in a volume ratio of 1:1. Thereafter, 41 mL of an aqueous solution in which 10.6 g of NaBr was dissolved and 139 mg of tetramethylpiperidine (TEMPO) were added, and 150 mL of an aqueous solution of NaClO (1.6 mol/L) in which 22.5 g of NaHCO ₃ was dissolved was slowly added dropwise at 0 to 5 ° C, and the mixture was dropped. After the reaction was completed for 16 h, the reaction was completed, and the reaction was quenched with 1.5 mL of isopropyl alcohol. The organic phase was collected and the aqueous layer was extracted with ethyl acetate (3×100 mL). Title compound.

LC-MS m/z: [M+H] ⁺ = 278.

Step 2(S)-1-Benzyloxycarbonyl-2-methoxycarbonyl-4-methylenepyrrolidine

In a 250 mL round bottom flask, 5.4 g of methyltriphenylphosphonium bromide (PPh3MeBr) was suspended in 50 mL of THF, cooled to 0 ° C, and then 1.7 g of potassium t-butoxide (t-BuOK) was added thereto; Stir at 0 ° C for 30 minutes, room temperature for 30 minutes, then reflux and react for 1 h; cool to 0 ° C, add 5 mL of compound (S) 1-benzyloxycarbonyl-2-methoxycarbonyl-4- dissolved in 2.1 g of Step 1. A solution of oxopyrrolidine in tetrahydrofuran, the reaction mixture was heated to reflux for 6 h. The mixture was purified eluted with EtOAc EtOAc. , the title compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.29-7.37 (m, 5H), 5.01-5.21 (m, 4H), 4.50-4.59 (m, 1H), 3.14 - 3.16 (m, 2H), 3.60-3.74 ( d, 3H), 2.96-2.99 (m, 1H), 2.63-2.67 (m, 1H).

LC-MS m/z: [M+H] ⁺ = 276.

Step 3(S)-5-Benzyloxycarbonyl-6-methoxycarbonyl-5-azaspiro[2.4]heptane

Weigh 137 mg of the compound (S)-1-benzyloxycarbonyl-2-methoxycarbonyl-4-methylenepyrrolidine prepared in Step 2 in a 25 mL three-necked flask, add 5 mL of dichloromethane to dissolve, and protect with nitrogen at -30 ° C. After adding 1.5 mLEt ₂ Zn in hexane solution (1 M), and stirring at -30 ° C for 30 min, 2 mL of a dichloromethane solution in which 531 mg of ClCH ₂ I was dissolved was added, and the reaction was continued at -30 ° C for 10 min, and reacted at room temperature for 16 h. It was quenched with a saturated aqueous solution of ammonium chloride and extracted with dichloromethane. The organic phase was collected, dried, filtered and evaporated to give a crude product.

550 mg of the above crude product was weighed into a 25 mL round bottom flask, and after adding 5 mL of THF/H ₂ O/acetone (volume ratio of 3:1:1), 234 mg of N-methyl-N-oxidized morpholine (NMO) was added. 11 mg of osmium tetroxide (OsO ₄ ), which was stirred at room temperature for 2 h, then extracted with dichloromethane.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.27-7.38 (m, 5H), 4.96-5.13 (m, 2H), 4.39-4.43 (m, 1H), 3.57-3.65 (d, 3H), 3.38- 3.44 (m, 1H), 3.24 - 3.28 (m, 1H), 2.29 - 2.38 (m, 1H), 1.68-1.76 (m, 1H), 0.47 - 0.61 (m, 4H).

LC-MS m/z: [M+H] ⁺ = 290.

Step 4(S)-5-Benzyloxycarbonyl-6-carboxy-5-azaspiro[2.4]heptane

400 mg of the compound (S)-5-benzyloxycarbonyl-6-methoxycarbonyl-5-azaspiro[2.4]heptane prepared in Step 3 was weighed into a 25 mL round bottom flask, and 3.5 mL of MeOH/THF (volume ratio) was added. 1.5:2) The solution was mixed, and 1.38 mL of a lithium hydroxide aqueous solution (1 M) was added, and the mixture was stirred at room temperature for 3 h, then added with EtOAc (1 N), and the solvent was evaporated, ethyl acetate (5 mL) was added and the organic phase was washed with ice water. Dry over anhydrous sodium sulfate, filter, spin dry and directly used for the next reaction.

LC-MS m/z: [M+H] ⁺ = 276.

Step 5(S)-5-Benzyloxycarbonyl-6-(2-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)carbonylethoxycarbonyl)-5-aza Snail [2.4] heptane

900 mg of the compound (S)-5-benzyloxycarbonyl-6-carboxy-5-azaspiro[2.4]heptane prepared in Step 4 and 1.5 g of the compound 2-bromo-1-(Step 2) prepared in Step 2 of Example 11 were weighed. 2-Bromospiro[芴-9,3'-butylene oxide]-7-yl)ethanone was dissolved in a 25 mL round bottom flask, 20 mL of acetonitrile was added, 1.2 g of DIPEA was added, and the reaction was refluxed for 1 h. Purification by silica gel column chromatography gave the title compound.

LC-MS m/z: [M+H] ⁺ = 602.

Step 7(S)-5-Benzyloxycarbonyl-6-(4-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)- 5-azaspiro[2.4]heptane

Weigh 970 mg of the compound (S)-5-benzyloxycarbonyl-6-(2-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)carbonylethoxycarbonyl prepared in Step 5. -5-azaspiro[2.4]heptane and 1.2g of NH ₄ OAc in a reaction flask, dissolved in 10 mL of xylene, microwaved at 140 ° C for 90 min, cooled, added with ethyl acetate, washed with water, dried, filtered Purification by spin column chromatography on silica gel to give the title compound.

LC-MS m/z: [M+H] ⁺ = 582.

Step 8(S)-5-Benzyloxycarbonyl-6-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl) snail [芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane

Compound (S)-5-benzyloxycarbonyl-6-(4-(2-bromospiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazole prepared in the same manner as in Step 7 The title compound was obtained according to the procedure of Step 5 of Example 7 using 2-ethyl)-5-azaspiro[2.4]-heptane and bis-bromo-bronic acid as the starting material.

LC-MS m/z: [M+H] ⁺ = 630.

Step 9(6S)-5-Benzyloxycarbonyl-6-(5-(2-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-((2) -(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-1H -mum Zin-2-yl)-5-aza[2.4]heptane

Compound (S)-5-benzyloxycarbonyl-6-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane)- 2-based) snail [芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane and Example 11 Step 6 The obtained compound (S)-1-tert-butoxycarbonyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole The title compound was obtained according to the method of Step 6 of Example 7 using -2-yl)pyrrolidine as a starting material.

LC-MS m/z: [M / 2+ H] + = 460.

Step 10(6S)-6-(5-(2-(2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-1-((2-(trimethylsilane) Ethyl)methyl)-1H-benzo[d]imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl )-5-aza[2.4]heptane

160 mg of the compound (6S)-5-benzyloxycarbonyl-6-(5-(2-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl))) 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)spiro[芴-9,3'-butylene oxide]- 7-yl)-1H-imidazol-2-yl)-5-aza[2.4]heptane was dissolved in a reaction flask, added with 2 mL of methanol, and then added with 50 mg of Pd(OH) ₂ and hydrogen (50 psi). After the reaction was completed, the title compound was obtained.

LC-MS m/z: [M+H] ⁺ = 785.

Step 11(6S)-6-(5-(2-(2-((S)-1-Pyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)) -1H-benzo[d]imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)-5-aza[ 2.4] heptane

The compound (6S)-6-(5-(2-(2-((S)-1-(tert-butoxycarbonyl))pyrrolidin-2-yl)-1-((2-) Trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazole 2-yl)-5-aza[2.4]heptane as a starting material, according to the method of step 8 of Example 1. The title compound was obtained.

LC-MS m/z: [M+H] ⁺ = 685.

Step 12 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-5-((S)-2-((methoxycarbonyl)amino)-3) -methylbutyryl)-5-azaspiro[2.4]heptane-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5- Snail [芴-9,3'-butylene oxide]-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1- Methyl oxybutane-2-yl)carbamate

Compound (6S)-6-(5-(2-(2-((S)))))(2-(trimethylsilyl)) Ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-7-yl)-1H-imidazol-2-yl)- 5-Aza[2.4]heptane and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid were used as a starting material.

LC-MS m/z: [M+H] ⁺ = 999.

Step 13 N-((2S)-1-((2S)-2-(5-(7-(2-((S))-5-((S)-2-((methoxycarbonyl)amino)-3) -methylbutyryl)-5-azaspiro[2.4]heptane-6-yl)-1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamic acid methyl ester

The compound N-((2S)-1-((2S)-2-(5-(7-(2-((S))))) Carbonyl)amino)-3-methylbutyryl)-5-azaspiro[2.4]heptane-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-5-yl)spiro[芴-9,3'-butylene oxide]-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3 The title compound was obtained according to the procedure of Step 10 of Example 1 using m.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm: 8.25-8.32 (m, 2H), 7.62-7.86 (m, 7H), 7.45-7.47 (m, 1H), 5.30-5.36 (m, 2H), 5.17-5.21 (m, 4H), 3.68-4.30 (m, 6H), 3.68 (s, 6H), 2.05-2.21 (m, 8H), 0.82-1.05 (m, 16H).

LC-MS m/z: [M / 2+H] ⁺ = 435.

Experimental Example 1 Detection of anti-HCV replicon activity of the compound of the present invention

1 experimental material

1.1 compound

The compound of the present invention prepared in the above examples, each compound was dissolved in DMSO to 10 mM, diluted to 50 μM with DMEM complete medium, and then diluted to 20 nM with a complete medium containing 0.5% DMSO, and then diluted three times in total. 10 concentrations.

1.2 cells

The HCV 1b replicon cell, the Huh7 cell line, was stably transferred to the HCV genotype 1b replicon and was provided by WuXi PharmaTech (Shanghai) New Drug Development Co., Ltd. For a specific preparation method of the Huh71b replicon cell system, see Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R., Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line, Science 285 (5424): 110-113 (1999).

1.3 reagent

DMEM cell culture medium (DMEM medium), purchased from Invitrogen, USA;

Fetal bovine serum (FBS), purchased from Sigma, USA;

L-Glutamine (L(+)-Glutamine), purchased from Invitrogen, USA;

Penicillin-streptomycin (Pen-Strep), purchased from Invitrogen, USA;

Phosphate buffered saline (PBS), purchased from Hyclone, USA;

Trypsin, purchased from Invitrogen, USA;

Dimethyl sulfoxide (DMSO), purchased from Sigma, USA;

Bright-Glo test reagent, purchased from Promega, USA;

Cell growth fluorescence assay detection reagent (CellTiter-Fluor), purchased from Promega, USA.

1.4 Instrument

Autofocus fluorescent multi-function microplate reader (PHERAstar Plus), purchased from BMG Labtech, Germany.

2 experimental methods

1) Compound preparation: 75 μl of the above concentration gradient of the compound of the invention was added using a POD810 system In each 96-well plate, each compound was repeated twice per concentration;

2) Cell preparation: Collect log phase HCV 1b replicon cells, resuspend in DMEM complete medium, and add 75 μl of cell suspension (8×10 ³ cells/well) to each well of the above 96-well plate; The Zero percent effect (ZPE) and the 100% effective control group (HPE) were established: the ZPE group replaced the compound with a complete medium containing 0.5% DMSO, and the HPE group contained only DMEM medium. ;

3) Cell culture: 96-well plates were placed in a 37 ° C, 5% CO ₂ incubator for 3 days;

4) Cell viability assay: Cell growth fluorescent titration detection reagent was added to each well. After incubating the cells for 1 hour at 37 ° C in a 5% CO ₂ incubator, the Fluorescence signal value was detected by a multi-function microplate reader, and the raw data (RFU) was used for the compound. Cytotoxicity calculation;

5) Anti-HCV virus replicon activity assay: Luminescence signal value was detected by multi-function microplate reader within 5 minutes with the luciferase luminescent substrate Bright-Glo. The raw data (RLU) was used to calculate the anti-HCV activity of the compound.

6) Data processing: The raw data was processed as the percentage inhibition (Inhibition%) and percentage of cell viability (Viability%) of the compound to the HCV replicon using the following formula:

Inhibition%=(RLU _ZPE -RLU _CPD )/(RLU _ZPE -RLU _HPE )×100

Viability%=(RFU _CPD -RFU _HPE )/(RFU _ZPE -RFU _HPE )×100

Wherein, CPD: fluorescence signal value of the compound pore; ZPE (Zero percent effect): ineffective control control fluorescence signal value; HPE (Hundred percent effect): 100% effective control fluorescence signal value.

The Inhibition% and Viability% were separately introduced into the GraphPad Prism software for data processing, and the half effective concentration EC ₅₀ and the half cytotoxic concentration CC _{50 of the} compound to the HCV replicon were obtained. The results are shown in Table 1.

Table 1

It can be seen from the above experiments that the compound of the present invention has good inhibitory activity against hepatitis C virus, has low toxicity to host cells, is highly effective, and has good safety, and is very promising for treatment and/or prevention and HCV infection. Drugs related to the disease.

While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

Claims (12)

1. a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

   

   among them:

   X _{1 is} selected from the group consisting of O, S, N and CF ₂ ;

   L ₁ and L ₂ are each independently selected from the group consisting of aryl, heteroaryl, -aryl-aryl-, -aryl-heteroaryl-, -heteroaryl-heteroaryl-, said aryl or A heteroaryl group can be composed of one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, Carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, Bisalkylaminoalkyl, alkylacyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl a monoalkylaminoacyl group, a monoalkylaminoacylalkyl group, a bisalkylaminoacyl group, a bisalkylaminoacylalkyl group, an alkylacylamino group, an alkylacylaminoalkyl group;

   p, q are independently selected from 1, 2 and 3;

   R ₁ and R ₂ are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, aryl or hetero The aryl group may be one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, single An alkylamino group, a dialkylamino group, an alkyl acyl group, an alkoxy acyl group, an alkyl acyloxy group, an amino acyl group, a monoalkylamino acyl group, a bisalkylamino acyl group, an alkyl acylamino group;

   R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, Carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;

   R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, aryl a heteroaryl group, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R ₅ or R ₆ and a C atom to which it is bonded may form a cycloalkyl or heterocycloalkyl group. The hydroxyl group, amino group, carboxyl group, alkyl group, cycloalkyl group, heterocycloalkyl group, alkoxy group, alkoxyalkyl group, aryl group, heteroaryl group may be one or more halogen, hydroxyl group, amino group, Carboxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, hydroxyalkyl, carboxyalkyl, monoalkylamino, bisalkylamino, alkyl acyl, alkoxy acyl Alkyl acyloxy, aminoacyl, monoalkylaminoacyl, bisalkylaminoacyl, alkylacylamino substituted.
2. The compound of claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Formula I is Formula Ia,

   

   Among them, C* is the S configuration.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

   L ₁ and L ₂ are each independently selected from the group consisting of phenyl, naphthyl, imidazolyl, benzimidazolyl, -phenyl-imidazolyl-, imidazopyridinyl, quinazolinone, pyrrolyl, imidazolidinyl, Furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, phenyl, naphthyl, imidazolyl, benzimidazole , -phenyl-imidazolyl-, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, Isothiazolyl, oxadiazolyl, triazolyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-10 alkyl, C _3-10 cycloalkyl, C _{3- 10} heterocycloalkyl, C _1-10 alkoxy, halo C _1-10 alkyl, hydroxy-C _1-10 alkyl, amino-C _1-10 alkyl, carboxy-C _1-10 alkyl, Cyano-C _1-10 alkyl, nitro C _1-10 alkyl, C _3-10 cycloalkyl-C _1-6 alkyl, C _3-10 heterocycloalkyl-C _1-6 alkyl, -C _1-6 alkoxy-C _1-10 alkyl, C _1-10 mono alkylamino, C _1-10 mono alkylamino -C _1-6 alkyl, bis C _1-10 alkyl group, -C _1-6 alkylamino C _1-10 alkyl, C _1-10 alkyl group, C _1-10 alkyl group -C _1-6 alkyl, C _1-10 alkoxy group, C _{1- 10} alkoxyacyl-C _1-6 alkyl, C _1-10 alkyl acyloxy, C _1-10 alkyl acyloxy-C _1-6 alkyl, amino acyl, amino acyl-C _1-6 Alkyl, mono-C _1-10 alkylamino acyl, mono C _1-10 alkylamino acyl-C _1-6 alkyl, bis C _1-10 alkylamino acyl, bis C _1-10 alkylamino acyl - C _1-6 alkyl, C _1-10 alkyl acylamino, C _1-10 alkyl acylamino-C _1-6 alkyl;

   R ₁ and R ₂ are each independently selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl or heteroaryl, said C _1-6 Alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl or heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 Alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, carboxy-C _1-6 alkyl, mono C _{1- 6} alkylamino, bis C _1-6 alkylamino, C _1-6 alkyl acyl, C _1-6 alkoxy acyl, C _1-6 alkyl acyloxy, amino acyl, mono C _1-6 alkane Aminoacyl, bis-C _1-6 alkylamino acyl, C _1-6 alkyl acylamino

   R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, said C _1-6 alkyl, C _3-8 A cycloalkyl or C _3-8 heterocycloalkyl group may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-8 cycloalkyl, C _{3 - a} heterocycloalkyl group, a C _1-6 alkoxy group, an aryl group, a heteroaryl group;

   R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, cyano, hydroxy, amino, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, halogen, C _1-6 alkane. Oxy-C _1-6 alkyl, aryl, heteroaryl, wherein m and n are each independently selected from 1, 2 and 3, and when m or n is 2, each R ₅ or R ₆ is attached thereto The C atom may form a C _3-8 cycloalkyl group or a C _3-8 heterocycloalkyl group; the hydroxy group, the amino group, the C _1-6 alkyl group, the C _3-8 cycloalkyl group, the C _3-8 heterocycloalkane. Base, halogen, C _1-6 alkoxy-C _1-6 alkyl, aryl, heteroaryl may be substituted by one or more halogen, hydroxy, amino, carboxyl, cyano, nitro, C _1-6 alkane , C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, carboxy C _1-6 alkyl, mono C _1-6 alkyl Amino group, di-C _1-6 alkylamino group, C _1-6 alkyl acyl group, C _1-6 alkoxy acyl C _1-6 alkyl acyloxy group, amino acyl group, mono C _1-6 alkylamino acyl group, Bis-C _1-6 alkylamino acyl, C _1-6 alkyl acylamino substituted.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

   X _{1 is} selected from the group consisting of O and CF ₂ ;

   L ₁ and L ₂ are each independently selected from the group consisting of:

   

   Wherein R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkane Base, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl , bisalkylamino, bisalkylaminoalkyl, alkyl acyl, alkyl acylalkyl, alkoxy acyl, alkoxyacylalkyl, alkyl acyloxy, alkyl acyloxyalkyl, amino Acyl, aminoacylalkyl, monoalkylaminoacyl, monoalkylaminoacylalkyl, bisalkylaminoacyl, bisalkylaminoacylalkyl, alkylacylamino, alkylacylaminoalkyl; preferably, R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkoxy, halo C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, carboxy-C _1-6 alkyl, cyano-C _{1- 6} alkyl, nitro C _1-6 alkyl, C _3-8 Alkyl -C _1-6 alkyl, C _3-8 heterocycloalkyl -C _1-6 alkyl, -C _1-6 alkoxy-C _1-6 alkyl, mono-C _1-6 alkylamino group, Mono C _1-6 alkylamino-C _1-6 alkyl, bis C _1-6 alkylamino, bis C _1-6 alkylamino-C _1-6 alkyl, C _1-6 alkyl acyl, C _1-6 alkyl acyl-C _1-6 alkyl, C _1-6 alkoxy acyl group, C _1-6 alkoxy acyl-C _1-6 alkyl group, C _1-6 alkyl acyloxy group, C _1-6 alkylacyloxy-C _1-6 alkyl, aminoacyl, aminoacyl-C _1-6 alkyl, mono C _1-6 alkylamino acyl, mono C _1-6 alkylamino acyl-C _1-6 alkyl, bis-C _1-6 alkylamino acyl, bis-C _1-6 alkylamino acyl-C _1-6 alkyl, C _1-6 alkyl acylamino, C _1-6 alkyl acylamino -C _1-6 alkyl.
5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₁ and R ₂ are each independently selected from hydrogen, A Base, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl , tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, phenyl, naphthyl, pyrrolyl, thienyl, thiazolyl, oxazole Base, pyridyl, said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane , cycloheptyl, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, phenyl, Naphthyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, pyridyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkane Oxyl, hydroxy -C _1-6 alkyl, -C _1-6 alkyl carboxy, mono-C _1-6 alkylamino, di-C _1-6 alkylamino substituted.
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₃ and R ₄ are each independently selected from the group consisting of hydrogen and Base, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl , tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl , cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, tetrahydropyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, Piperazinyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, tetrahydrogen Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, _C1-6 alkoxy, phenyl, Heteroaryl .
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₅ and R ₆ are each independently selected from hydrogen and halogen. , cyano, hydroxy, amino, carboxy, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _1-6 alkoxyhaloalkyl, cyano C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, carboxy C _1-6 alkyl, nitro C _1-6 alkyl, C _3-6 cycloalkyl-C _{1- 6} alkyl, C _3-6 heterocycloalkyl-C _1-6 alkyl, or when m or n is 2,

   

   or

   

   Each is independently selected from the group consisting of azaspiroalkyl, oxazaspiroalkyl and azabicycloalkyl. Preferably, the azaspiroalkyl is azaspiro[2.4]heptyl, azaspiro[3.4 ] octyl, azaspiro[4.4]decyl, azaspiro[2.5]octyl, azaspiro[3.5]decyl, azaspiro[4.5]alkanyl, azaspiro[2.6 a nonylalkyl, azaspiro[3.6]alkanyl group, the oxazaspiroalkyl group is oxa-azaspiro[2.4]heptyl, oxa-azaspiro[3.4]octyl, Oxa-azaspiro[4.4]decyl, dioxa-azaspiro[4.4]decyl, oxa-azaspiro[4.5]alkanyl, dioxa-azaspiro[4.5] An alkanoyl or a trioxa-azaspiro[4.5]alkane group, and the azabicycloalkyl group is azabicyclo[3.1.0]hexane, azabicyclo[3.2.0]heptanyl, Arhydrocyclopenta pyrrolyl, octahydro-1H-isodecyl, octahydro-1H-indenyl, azabicyclo[2.2.1]heptyl.
8. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound is selected from the group consisting of

   

   
9. Intermediate II for the preparation of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

   

   Wherein X _{1 is} selected from the group consisting of O, N, S and CF ₂ , and R ₂₁ and R ₂₂ are each independently selected from the group consisting of hydrogen, halogen, triflate, mesylate, p-toluenesulfonate and

   

   R ₃₁ and R ₃₂ are each independently selected from hydrogen, C _1-6 alkyl or R ₃₁ , and R ₃₂ together with the respective attached O atom constitutes a ring;

   Preferably, X _{1 is} selected from O and CF ₂ , and R ₂₁ and R ₂₂ are each independently selected from hydrogen, chlorine, bromine, iodine or

   
10. A pharmaceutical composition comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or the pharmaceutical composition of claim 10, for use in the treatment or prevention Application in medicines for diseases caused by hepatitis C virus.
12. A method of treating and/or preventing an HCV infection, the method comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, Isomer, solvate, crystallization or prodrug or the pharmaceutical composition of claim 10.