CN105384792A

CN105384792A - Compound as hepatitis c inhibitor and application thereof in medicine

Info

Publication number: CN105384792A
Application number: CN201510518407.8A
Authority: CN
Inventors: 张英俊; 罗慧超; 任青云; 熊志敏; 刘洋; 雷义波; 谢洪明; 张健存; 杨凤智
Original assignee: Guangdong HEC Pharmaceutical Co Ltd
Current assignee: Guangdong HEC Pharmaceutical Co Ltd
Priority date: 2014-08-23
Filing date: 2015-08-21
Publication date: 2016-03-09
Anticipated expiration: 2035-08-21
Also published as: CN105384792B

Abstract

The invention provides a compound as shown in formula (I) or a stereisomer, a stereomer, a tautomer, an enantiomer, an oxynitride, an aquo-complex, a solvate, a metabolite and a pharmaceutically acceptable salt or prodrdug of the compound shown in formula (I), which are used for treating hepatitis c virus (HCV) infection or hepatitis c diseases. The invention further discloses a medicine composition containing the compound and a method for treating HCV infection or hepatitis c diseases by using the compound or the medicine composition thereof .

Description

Compound as hepatitis C inhibitor and application thereof in medicine

Technical Field

The present invention is in the field of medicine, and in particular relates to compounds useful for treating Hepatitis C Virus (HCV) infection, compositions of the compounds, and uses and methods of use thereof. In particular, the compounds of the present invention are useful for inhibiting the NS3/4A protease. More particularly, the present invention relates to compounds that can inhibit the function of the NS3/4A protein encoded by the hepatitis c virus, pharmaceutical compositions of said compounds and methods for inhibiting the function of the NS3/4A protein.

Background

HCV is the major human pathogen, estimated to infect approximately 1.7 million people worldwide, 5 times as many as people infected with human immunodeficiency virus type 1. Most of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Thus, chronic HCV infection will be a leading cause of premature death of patients from liver disease worldwide.

Currently, the most effective HCV therapy is the use of a combination of interferon-alpha and ribavirin, which produces sustained efficacy in 40% of patients. Recent clinical results indicate that pegylated interferon-alfa is superior to unmodified interferon-alfa as a monotherapy. However, even with experimental treatment regimens involving combinations of pegylated interferon-alfa and ribavirin, most patients are unable to continue to reduce viral load, and many patients are often associated with side effects that do not allow for long-term treatment. Thus, new effective methods for treating HCV infection are currently urgently needed.

HCV is a positive-stranded RNA virus. Based on a comparison of the broad similarity of the deduced amino acid sequence and the 5' untranslated region, HCV was classified into a single genus of the flaviviridaeffamine family. All members of the flaviviridae family are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins via translation of a single uninterrupted Open Reading Frame (ORF).

Considerable heterogeneity exists within the nucleotide and encoded amino acid sequences of the entire HCV genome. At least 7 major genotypes have been identified and over 50 subtypes have been disclosed. In HCV-infected cells, viral RNA is translated into polyproteins and split into 10 individual proteins. At the amino terminus is the structural protein, immediately following E1 and E2. In addition, there are 6 nonstructural proteins, namely NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a very important role in the HCV life cycle (see, e.g., Lindenbach, b.d. and c.m. rice, nature.436,933-938,2005).

The major genotypes of HCV vary in their distribution throughout the world, and despite the large number of genotypes studied for pathogenesis and therapeutic role, the clinical importance of the genetic heterogeneity of HCV remains unclear.

The single-stranded hcv rna genome is approximately 9500 nucleotides in length, has a single open reading frame, and encodes a single large polyprotein of about 3000 amino acids. In infected cells, the polyprotein is cleaved at multiple sites by cellular and viral proteases, producing structural and non-structural (NS) proteins. In the case of HCV, the formation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is achieved by two viral proteases. The first is generally considered to be a metalloprotease, which cleaves at the NS2-NS3 junction; the second is a serine protease contained in the N-terminal region of NS3 (also referred to herein as NS3 protease) which mediates all subsequent cleavage downstream of NS3 in cis at the NS3-NS4A cleavage site and in trans at the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NA5B sites. The NS4A protein appears to have multiple functions, acting as a cofactor for NS3 protease and possibly assisting in membrane localization of NS3 and other viral replicase components. The formation of the complex of NS3 protein with NS4A appears to be a processing event necessary to increase proteolytic efficiency at all sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV replication.

The compounds of the present invention are useful for treating HCV infection in a patient, and selectively inhibit the replication of the HCV virus. In particular, the compounds of the present invention are effective compounds for inhibiting the function of the NS3/4A protein.

Summary of the invention

The present invention relates to a macrocyclic compound and a method of combating HCV infection. The compound or the pharmaceutical composition has good inhibition effect on HCV infection, in particular on HCV NS3/4A protein.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound of formula (I):

wherein: ring a and ring B are each independently a cycloalkyl, heterocyclyl, aryl or heteroaryl group;

each R¹And R²Independently H, deuterium, hydroxyl, F, Cl, Br, I, N₃、-SR⁵、-S(＝O)R⁵、-S(＝O)₂R⁵、-C(＝O)OR⁵、-C(＝O)R⁵、-N(R⁷)S(＝O)₂R⁵、-N(R⁷)S(＝O)₂NR⁷R¹¹、-S(＝O)₂NR⁷R¹¹、-C(＝O)NR⁷R¹¹、-N(R⁷)C(＝O)R⁵Cyano, nitro, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, alkylthio, cycloalkyl-O-, heterocyclyl, aryl or heteroaryl;

R³and R⁴Each independently is H, deuterium, hydroxyl, amino, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, or heteroaryl;

L is-C (O) -, -OC (O) -, -C (S) -, -OC (S) -, -N (R) -)⁷) C (═ S) -or-N (R)⁷)C(＝O)-；

represents-X or ═ X; when in useWhen it is-X, X is CR⁵R⁶、NR⁷O or S; when in useWhen X is equal to X, X is CR⁵Or N;

y is-CR⁵R⁶-、-NR⁷-, -O-, -S-or-S (═ O)_t-；

T is-CR⁵R⁶-、-O-、-S-、-NR⁷-、-CH₂O-、-OS(＝O)_t-、-OC(＝O)-、-OC(＝O)N(R⁷) -or-N (R)⁷)C(＝O)-；

W is CR⁵Or N;

q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

Z is a bond, -CR⁵R⁶-、-NR⁷-、-O-、-S-、-S(＝O)_t-、-C(＝O)-、-OC(＝O)-、-OC(＝O)N(R⁷)-、-N(R⁷)C(＝O)-、-C(＝O)N(R⁷) -, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene-O, arylene-S, arylene-N, or heteroarylene;

each R⁵、R⁶、R⁸And R⁹Independently is H, deuterium, hydroxy, amino, F, Cl, Br, I, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl;

each R⁷And R¹¹Independently is H, deuterium, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

m and n are each independently 0, 1, 2, 3 or 4;

each t is independently 1 or 2;

p and q are each independently 0, 1, 2, 3, 4 or 5;

to representOr

Alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyl-O-, haloalkyl, haloalkoxy, heterocyclyl, aryl, heteroaryl, alkenylene, cycloalkylene, heterocyclylene, arylene, heteroarylene-O, arylene-S, arylene-N, and heteroarylene as described above are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, wherein ring a and ring B are each independently C_3-10Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

each R¹And R²Independently H, deuterium, hydroxyl, F, Cl, Br, I, N₃Amino, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-O-, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

when X is equal to X, X is CR⁵Or N;

y is-CR⁵R⁶-、-NR⁷-, -O-, -S-or-S (═ O)_t-；

Each R⁵And R⁶Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl or C_2-6An alkynyl group;

each R⁷Independently of one another H, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

m and n are each independently 0, 1, 2, 3 or 4;

c as described above_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-10Heterocyclic group, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C _1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_6-10Aryl radical, C_1-9Heteroaryl or C_2-10A substituent of the heterocyclic group.

In still other embodiments, wherein ring a and ring B are each independently a phenyl, pyridyl, thiazolyl, oxazolyl, imidazolyl, furyl, thienyl, pyrazolyl, isoxazolyl, pyrrolyl, quinolinyl, indolyl, or naphthyl group.

In some embodiments, wherein L is-C (═ O) -, -OC (═ O) -, or-NHC (═ O) -;

R⁴is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

In some embodiments, wherein Q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

Z is a bond, -CR⁵R⁶-、-NR⁷-、-O-、-S-、-S(＝O)₂-、C_2-6Alkenylene radical, C_2-6Alkynylene, C_3-10Cycloalkylene radical, C_2-10Heterocyclylene radical, C _6-10Arylene radical, C_6-10arylene-O, C_6-10arylene-S, C_6-10arylene-N or C_1-9A heteroarylene group;

each R⁵、R⁶、R⁸And R⁹Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl or C_1-9A heteroaryl group;

p and q are each independently 0, 1, 2, 3, 4 or 5.

In some embodiments, wherein R³Is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocycloalkyl radical, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

In some embodiments, whereinIs composed of

Each A is¹And A²Independently is CR¹⁰Or N;

A³is CR ⁵R⁶、NR⁷O or S;

each R¹And R²Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, N₃Cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-O-, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

each R⁵And R⁶Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl or C_1-9A heteroaryl group;

each R¹⁰Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl or C_2-6An alkynyl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-10Cycloalkyl radical, C_3-10Cycloalkane-O, C_2-10Heterocyclic group, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C _1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

In other embodiments, whereinIs composed of

In some embodiments, it has a structure as shown in formula (I'),

or stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compounds of formula (I');

wherein,is composed of

Each A is¹And A²Independently is CR¹⁰Or N;

A³is CR⁵R⁶、NR⁷O or S;

each R¹And R²Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, N₃Cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-O, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

each R⁵And R⁶Independently H, deuterium, hydroxyl, F, Cl, Br, IAmino group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl or C_1-9A heteroaryl group;

each R¹⁰Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl or C_2-6An alkynyl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_3-8Cycloalkane-O, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl or C_2-6A substituent of the heterocyclic group.

In still other embodiments, wherein each A is¹And A²Independently is CR¹⁰Or N;

A³is NH, O or S;

each R¹⁰Independently H, deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, ethynyl, trifluoromethyl or trifluoromethoxy;

each R¹And R²Independently H, deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyclopropyloxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, pyrazolyl, isoxazolyl, indolyl, naphthyl, ethynyl, vinyl, propynyl, or propenyl;

Methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, cyclopropyloxy, trifluoromethyl, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, pyrazolyl, isoxazolyl, indolyl, naphthyl, ethynyl, ethenyl, propynyl and propenyl as described above are independently optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, methyl, ethyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, ethenyl, propenyl, ethynyl, propynyl, trifluoromethyl or trifluoromethoxy.

In still other embodiments, wherein,is composed of

In still other embodiments, wherein R is³And R⁴Each independently is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C _1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

In still other embodiments, wherein R is³And R⁴Each independently of the others is H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenylMorpholinyl, piperazinyl, pyrazinyl, piperidinyl, phenyl, propenyl, propynyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, furanyl, thienyl or pyridinyl;

wherein said methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, morpholinyl, piperazinyl, pyrazinyl, piperidinyl, phenyl, propenyl, propynyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, furanyl, thienyl, and pyridyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, trifluoromethyl, or trifluoromethoxy.

In still other embodiments, where T is-O-, -S-, or-NR⁷-；

R⁷Is H, deuterium, F, Cl, Br, I, methyl, ethyl, isopropyl or trifluoromethyl.

In still other embodiments, wherein W is CH or N.

In still other embodiments, wherein Q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

Z is a bond, -CR⁵R⁶-、-NR⁷-、-O-、-S-、-S(＝O)₂-、C_2-6Alkenylene radical, C_2-6Alkynylene, C_3-8Cycloalkylene radical, C_2-10Heterocyclylene radical, C_6-10Arylene radical, C_6-10arylene-O or C_1-9A heteroarylene group;

each R⁵、R⁶、R⁸And R⁹Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

R⁷is H, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_2-10Heterocyclyl or C_6-10An aryl group;

p and q are each independently 0, 1, 2, 3, 4 or 5;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl radical, C_2-6Alkenylene radical, C_2-6Alkynylene, C_3-8Cycloalkylene radical, C_2-10Heterocyclylene radical, C_6-10Arylene radical, C_6-10arylene-O and C_1-9Heteroarylene is independently optionally substituted with 1, 2, 3 or 4 substituents selected from H, deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl or C_2-6A substituent of the heterocyclic group.

In other embodiments, Z is a bond, -CH₂-、-NR⁷-、-O-、-S-、-S(＝O)₂-, ethenylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene-O, phenylene-S, thiazolylene, imidazolyl or phenylene;

each R⁵、R⁶、R⁸And R⁹Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl or ethynyl;

R⁷is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

wherein said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene-S, thiazolylene, imidazolylene, phenylene-O and phenylene may be independently optionally substituted with 1, 2, 3 or 4 substituents selected from H, deuterium, F, Cl, Br, I, amino, methyl, methoxy, hydroxy, nitro, cyano.

In still other embodiments, wherein,is composed of

Each R¹And R²Independently H, deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, methyl, ethyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, indolyl, naphthyl, ethynyl, ethenyl, propynyl, or propenyl;

n is 0, 1, 2, 3 or 4;

methyl, ethyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, indolyl, naphthyl, ethynyl, ethenyl, propynyl, and propenyl as described above, are independently optionally substituted with 1, 2, 3, or 4 substituents selected from H, deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, methoxy, ethenyl, ethynyl, trifluoromethyl, or trifluoromethoxy.

In another aspect, the present invention provides a pharmaceutical composition comprising any one of the compounds described above; or further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

In some embodiments, it further comprises other anti-HCV agents; wherein the anti-HCV agent is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiqimod, an inosine 5' -monophospate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, baviximab, Civacir ^TMWherein the interferon is selected from the group consisting of boceprevir (boceprevir), telaprevir (telaprevir), sofosbuvir (sofosbuvir), lediprevir (ledipasvir), daclatavir (daclatasvir), danoprevir (danoprevir), cidaprevir (cilaprevir), nalaprevir (narraprevir), deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), bitasvir (ABT-267), neceprevir (ACH-2684), tegobrevir (9190), gradoprevir (MK-5172), sovaprevir (ACH-1625), sasamvirvir (SAx-668), saraprevir (ACH-668), sareprevir (GCT-7137-719-221), PHARX-103, PHARA-103, GCT-102-123, GCT-123, GCT-70-103, GCT-969, GCT-9611, GCT-969, GCT-9, CGI-969, CGI, GCT-969, CGI-9, GCT-9, CPT-9, GCH-969, GCT-9, GCH- Interferon α -2a, consensus α -interferon, interferon gamma, or a combination thereof.

In some embodiments, it further comprises at least one HCV inhibitor for at least one of inhibiting HCV replication processes and inhibiting HCV viral protein function; the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV. The HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A and NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

In another aspect, the compounds or pharmaceutical compositions described herein are useful for at least one of inhibiting the HCV replication process and inhibiting HCV viral protein function; the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV. The HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A and NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament for the prevention, treatment or amelioration of a hepatitis C disease in a patient, comprising administering to the patient an effective amount of a compound according to the invention or a pharmaceutical composition according to the invention.

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I) or (I').

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of organic chemistry can be referred to as described in "organic chemistry", ThomasSorrell, university science Books, Sausaltito: 1999, and "March's sAdvanceorganics" by Michael B.Smith JerreryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-HillDictionaryof chemical terms (1984) McGraw-HillBook company, New York; andEliel, E.andWilen, S., "Stereochemistry of organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers may be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (wiley inter science, new york, 1981); PrinciplesofAsymmetric Synthesis (2)^ndEd.RobertE.Gawley,JeffreyAubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.StereochemistryofCarbonCompounds(McGraw-Hill,NY,1962)；Wilen,S.H.TablesofResolvingAgentsandOpticalResolutionsp.268(E.L.Eliel,Ed.,Univ.ofNotreDamePress,NotreDame,IN1972)；ChiralSeparationTechniques:APracticalApproach(Subramanian,G.Ed.,Wiley-VCHVerlagGmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valentetatomers) include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. When substituents are described as "independently selected" groups, each substituent is selected independently of the other, and thus each substituent may be the same or different from the other.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) T-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH) ₂-, ethylene (-CH)₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like.

The term "heteroalkyl" means that one or more heteroatoms may be inserted in the alkyl chain, wherein the alkyl group and the heteroatoms have the meaning as described herein. Unless otherwise specified, heteroalkyl groups contain from 2 to 10 carbon atoms, othersWhere the heteroalkyl group contains from 2 to 8 carbon atoms, in other embodiments from 2 to 6 carbon atoms, in other embodiments from 2 to 4 carbon atoms, and in yet other embodiments from 2 to 3 carbon atoms. Examples include, but are not limited to, CH₃OCH₂-，CH₃CH₂OCH₂-，CH₃SCH₂-，(CH₃)₂NCH₂-，(CH₃)₂CH₂OCH₂-，CH₃OCH₂CH₂-，CH₃CH₂OCH₂CH₂-and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH) ₂) Allyl (-CH)₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, but wherein at least one ring does not belong to the aromatic group. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH ₂The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is C_2-10Heterocyclyl, meaning that heterocyclyl contains 2 to 10 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heterocyclyl is C_2-9Heterocyclyl, meaning that heterocyclyl contains 2 to 9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heterocyclyl is C_2-7Heterocyclyl, meaning that heterocyclyl contains 2 to 7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heterocyclyl is C_2-5Heterocyclyl, meaning that heterocyclyl contains 2 to 5 carbon atoms and at least one heteroatom selected from O, S and N. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, oxacycloheptyl, oxazetanyl, oxazetan, Thiacycloheptyl, oxazepineRadical diazaRadical, sulfur nitrogen heteroRadicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl groups; the term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy groups in which an oxygen atom is attached to the remainder of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the remainder of the molecule. Wherein heterocyclyl, alkyl, alkoxy and alkylamino have the meanings as described herein, and such examples include, but are not limited to, pyrrol-2-ylmethyl, morpholin-4-ylethyl, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino and the like.

The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, while 1,2,3, 4-tetrahydronaphthalene is a cycloalkyl group of 10 atoms.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, heteroaryl is C_1-9Heteroaryl, meaning that heteroaryl contains 1 to 9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C_1-7Heteroaryl, meaning that heteroaryl contains 1 to 7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C_1-6Heteroaryl, meaning that heteroaryl contains 1 to 6 carbon atomsAnd at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C_1-5Heteroaryl, meaning that heteroaryl contains 1 to 5 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C _1-4Heteroaryl, meaning that heteroaryl contains 1 to 4 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C_1-3Heteroaryl, meaning that heteroaryl contains 1 to 3 carbon atoms and at least one heteroatom selected from O, S and N. .

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO₂H; the term "carbonyl", whether used alone or in combination with other terms, e.g."aminocarbonyl" or "acyloxy" represents- (C ═ O).

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C_1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C_1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "arylamino" denotes an amino group substituted with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

The term "aminoalkyl" includes C substituted with one or more amino groups _1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups_1-6Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. And the alkylene group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, or aryloxy. Examples include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂-CH₂-) isopropylidene (-CH₂-CH(CH₃) -), ethane-1, 1-diyl, 2-methoxypropane-1, 1-diyl, 2-hydroxypropane-1, 1-diyl, 2-methylThe radical-2-hydroxypropane-1, 1-diyl, and the like.

The term "alkenylene" denotes an alkenyl group derived from a straight or branched chain alkene by the removal of two hydrogen atoms. And the alkenylene group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, or aryloxy. Examples include, but are not limited to, ethenylene (-CH-), Cl-substituted ethenylene (-ClC-) and isopropenyl (-C (CH-)) ₃) CH-) and the like.

The term "alkynylene" denotes an alkynyl group derived from a straight or branched chain alkyne by the removal of two hydrogen atoms. And said alkynylene group may be substituted or unsubstituted, wherein alkynyl has the meaning of the present invention. Examples of such include, but are not limited to, ethynylene (-C.ident.C-), propargylene (-CH)₂C.ident.C-) and the like.

The term "cycloalkylene" denotes a saturated divalent hydrocarbon ring obtained by removing two hydrogen atoms from a monocyclic ring having 3 to 12 carbon atoms or a bicyclic ring having 7 to 12 carbon atoms, wherein the carbocyclic group or cycloalkyl group has the meaning as described in the present invention, and examples thereof include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1-enylene, 1-cyclopent-2-enylene and the like.

The term "heterocyclylene" denotes a monocyclic, bicyclic or tricyclic ring system wherein one or more atoms in the ring are independently selected from heteroatoms and may be fully saturated or contain one or more unsaturations, but not belonging to the aromatic class, having two points of attachment to the rest of the molecule, wherein the heterocyclyl group has the meaning as described herein. Examples include, but are not limited to, piperidine-1, 4-diyl, piperazine-1, 4-diyl, tetrahydrofuran-2, 4-diyl, tetrahydrofuran-3, 4-diyl, azetidine-1, 3-diyl, pyrrolidine-1, 3-diyl, and the like.

The term "arylene" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms forming a ring and two attachment points are attached to the rest of the molecule. The term "arylene" may be used interchangeably with the term "arylene ring". Wherein the aryl group has the meaning as described in the present invention. Examples of the arylene group may include phenylene, naphthylene and anthracenylene. The arylene group can be independently optionally substituted with one or more substituents described herein.

The term "heteroarylene" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, wherein each ring system contains a ring of 5 to 7 atoms with two attachment points to the rest of the molecule. Wherein the heteroaryl group has the meaning as described herein. The heteroarylene group is optionally substituted with one or more substituents described herein.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy)、-OCH₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH) ₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "alkylthio" denotes a group resulting from replacement of an oxygen atom in an alkoxy group by a sulfur atom.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.

The term "hydroxyalkyl" or "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, and the like.

The term "amino" (alone or in combination with other terms) means-NH₂；

The term "imino" (alone or in combination with other terms) means NH;

the term "aminoimino" (alone or in combination with other terms) means ═ NNH₂；

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH ₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, protective Groups organic Synthesis, John Wiley&Sons,NewYork,1991；andP.J.Kocienski,ProtectingGroups,Thieme,Stuttgart,2005.

As described herein, -OC (═ O) -, -C (═ S) -, -OC (═ S) -, -N (R) -⁷)C(＝S)-、-N(R⁷)C(＝O)-、CH₂O、-OS(＝O)_t-、-OC(＝O)N(R⁷) -or-C (═ O) N (R)⁷) Two of the attachment points are attached to other groups, as shown in formula (a), the E-terminus and the E '-terminus of-OC (═ O) -can be attached to other groups, and in the present invention, the groups attached to both ends E and E' are interchangeable.

E-C(＝O)O-E′(a)。

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention canAs the ester, in the conventional invention, there are the phenyl ester and the aliphatic (C) as the prodrug of the ester_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs NovelDelivery systems, Vol.14soft HeA.C.S.Symphosis series, Edward dB.Roche, ed., BioredeployCrierserriendDrugDesign, American pharmaceutical Association PergammonPress, 1987, J.Rautooral, Prodrug: DesignationClinical applications, NatureRevietDrugDiscovery, 2008,7, 255-.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: bergeet al, descriptive minor and minor letters of the invention, pharmaceutical sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, bisulfates, salts of sodium, potassium, sodium, potassium, sodium, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In e.g. "Remington's pharmaceutical sciences", 20 th edition, MackPublishing company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (handbook of pharmaceutical salts: Properties, Selection, and use) ", StahlandWermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H、¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the isotopically enriched compounds can be used for metabolic studies (use) ¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For exampleIncreased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

In another aspect, the invention relates to intermediates for the preparation of compounds encompassed by formula (I).

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

"combination" means a fixed combination or a kit of parts for combined administration in the form of a single dosage unit, wherein a compound disclosed herein and a combination partner may be administered separately at the same time or may be administered separately within certain time intervals, in particular such that the combination partners exhibit a cooperative, e.g. synergistic, effect. The terms "co-administration" or "co-administration" and the like as used herein are intended to encompass the administration of the selected combination partners to a single individual in need thereof (e.g., a patient), and are intended to encompass treatment regimens in which the substances are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination product" as used herein denotes a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the disclosed compounds and combination partners, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the disclosed compounds and combination partners, are both administered to a patient as separate entities simultaneously, jointly or sequentially with no specific time limits, wherein the administration provides therapeutically effective levels of both compounds in the patient. The latter is also applicable to cocktail therapy, e.g. administering 3 or more active ingredients.

It should be noted that the term "inhibiting HCV viral proteins" in the present invention is to be understood in a broad sense, and includes both the level of inhibiting expression of HCV viral proteins and the level of inhibiting activity, assembly and release of HCV viral proteins. Among them, HCV protein expression levels include, but are not limited to: the level of translation of viral protein genes, the level of post-translational modification of proteins, the level of replication of progeny genetic material, and the like.

Description of the Compounds of the invention

The invention relates to a macrocyclic compound and a pharmaceutical preparation thereof, which can effectively inhibit HCV infection, in particular can inhibit the activity of HCV NS3/4A protein.

y is-CR⁵R⁶-、-NR⁷-, -O-, -S-or-S (═ O)_t-；

W is CR⁵Or N;

q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

Z is a bond, -CR⁵R⁶-、-NR⁷-、-O-、-S-、-S(＝O)_t-、-C(＝O)-、-OC(＝O)-、-OC(＝O)N(R⁷)-、-N(R⁷)C(＝O)-、-C(＝O)N(R⁷) -, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heterocyclylene-O, arylene-S, arylene-N, or heteroarylene;

m and n are each independently 0, 1, 2, 3 or 4;

each t is independently 1 or 2;

p and q are each independently 0, 1, 2, 3, 4 or 5;

to representOr

The above-described alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyl-O-, haloalkyl, haloalkoxy, heterocyclyl, aryl, heteroaryl, alkenylene, cycloalkylene, heterocyclylene, heterocyclylalkyl, arylene, heterocyclylene-O, heteroarylene-O, arylene-S, arylene-N, and heteroarylene are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

when X is equal to X, X is CR⁵Or N;

y is-CR⁵R⁶-、-NR⁷-, -O-, -S-or-S (═ O)_t-；

m and n are each independently 0, 1, 2, 3 or 4;

In some embodiments, wherein L is-C (═ O) -, -OC (═ O) -, or-NHC (═ O) -;

In some embodiments, wherein Q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

p and q are each independently 0, 1, 2, 3, 4 or 5.

In some embodiments, whereinIs composed of

Each A is¹And A²Independently is CR¹⁰Or N;

A³is CR ⁵R⁶、NR⁷O or S;

In other embodiments, whereinIs composed of

In some embodiments, it has a structure as shown in formula (I'),

wherein,is composed of

Each A is¹And A²Independently is CR¹⁰Or N;

A³is CR⁵R⁶、NR⁷O or S;

each R⁵And R⁶Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl or C_1-9A heteroaryl group;

A³is NH, O or S;

each R¹⁰Independently H, deuterium, hydroxyl, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, ethynyl, trifluoromethyl or trifluoromethoxyA group;

In still other embodiments, wherein,is composed of

In still other embodiments, wherein R is³And R⁴Each independently is H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutylA phenyl group, a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, a cyclohexenyl group, a morpholinyl group, a piperazinyl group, a pyrazinyl group, a piperidinyl group, a phenyl group, a propenyl group, a propynyl group, an oxazolyl group, an isoxazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a triazolyl group, a furyl group, a thienyl group, or a pyridyl group;

In still other embodiments, where T is-O-, -S-, or-NR⁷-；

R⁷Is H, deuterium, F, Cl, Br, I, methyl, ethyl, isopropyl or trifluoromethyl.

In still other embodiments, wherein W is CH or N.

In still other embodiments, wherein Q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

each R⁵、R⁶、R⁸And R⁹Independently is H, deuterium, hydroxy,F. Cl, Br, I, amino, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

p and q are each independently 0, 1, 2, 3, 4 or 5;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl radical, C_2-6Alkenylene radical, C_2-6Alkynylene, C_3-8Cycloalkylene radical, C_2-10Heterocyclylene radical, C_6-10Arylene radical, C_6-10arylene-O and C_1-9Heteroarylene is independently optionally substituted with 1, 2, 3 or 4 substituents selected from H, deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl or C _2-6A substituent of the heterocyclic group.

wherein said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene-S, thiazolylene, imidazolylene, phenylene-O or phenylene may be independently optionally substituted with 1, 2, 3 or 4 substituents selected from H, deuterium, F, Cl, Br, I, amino, methyl, methoxy, hydroxy, nitro, cyano.

In still other embodiments, wherein,is composed of

n is 0, 1, 2, 3 or 4;

In some embodiments, it has the structure of one of:

or stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof.

The compounds of the present invention (in the present context, the expression "compounds of formula (I) or stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of compounds of formula (I)) may be used for the manufacture of a pharmaceutical product for the treatment of acute and chronic HCV infections, including those described herein. Further, the compounds of the present invention may be used in the manufacture of anti-HCV preparations. Thus, the compounds of the present invention may be used in the manufacture of a medicament for alleviating, preventing, controlling or treating HCV mediated disorders, in particular HCV NS3/4A protein mediated diseases. Thus, the compounds of the present invention may be used as active ingredients of pharmaceutical compositions which may comprise a compound represented by formula (I), and which may further comprise at least one pharmaceutically acceptable carrier, adjuvant or diluent.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" means that the substance or composition employed must be compatible chemically or toxicologically with the other ingredients comprising the formulation and the mammal being treated. The "pharmaceutically acceptable" substance or composition may be specifically selected by those skilled in the art depending on the other components employed and the subject, e.g., human, being treated.

Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or isolated enantiomers of the compounds of formula (I).

If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic or organic acids. Among them, examples of the inorganic acid include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include, but are not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compositions, formulations and administration of the Compounds of the invention

The pharmaceutical composition comprises any one of the compounds of the present invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. The pharmaceutical composition can be used for treating Hepatitis C Virus (HCV) infection or hepatitis C disease, and particularly has a good inhibition effect on HCV NS3/4A protein.

The pharmaceutical composition further comprises an anti-HCV agent. The anti-HCV agent can be any other known anti-HCV agent other than the compounds of the present invention. For example, it may be interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiqimod, inosine 5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, baviximab, Civacir ^TMExamples of the "basic" component include but are not limited to, boceprevir (boceprevir), telaprevir (telaprevir), sofosbuvir (sofosbuvir), lediprevir (ledipasvir), daclatavir (daclatasvir), danoprevir (danoprevir), cidaprevir (cilaprevir), naraprevir (narraprevir), deleobrevir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbassvir (MK-8742), bitomasvir (ABT-267), neceprevir (ACH-2684), tegobrevir (9190), gradzoprevir (MK-5172), sovaprevir (ACH-1625), IDsamatvir (X-2684), setrobervivir (GS-719), tmervivir (TMC-450), TMCvic (TMCt-450), TMCvic (TMCb-874), and the like435) The HCV-protein kinase inhibitor is selected from one of the following anti-viral agents consisting of ASunapprevir (BMS-650032), vaniprevir (MK-7009), faldaprevir (BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530, ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANGB-975, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-monophospho, EP-0120, VBY-376, TMC-649128, R-7128, INPSI-7977, INPSI-79184, IPX-2054, IDX-136, IDX-monophosphate, IDX-102, IDX-599, IMX-102, IMX-599, IMX-59728, IMC-102, IMC-103, IMC-III-.

When useful in therapy, a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I) and pharmaceutically acceptable salts thereof, may be administered as the raw chemical or as the active ingredient of a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show meaningful patient benefit (e.g., reduction in viral load). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that, when combined, administered sequentially or simultaneously, result in a therapeutic effect. The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of the present invention, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

The pharmaceutical preparations may be in unit dosage form, each unit dosage containing a predetermined amount of the active ingredient. Dosage levels of the compounds of the present disclosure are between about 0.01 and about 250 mg/kg body weight/day, preferably between about 0.05 and about 100mg/kg body weight/day, often as monotherapy for the prevention or treatment of HCV-mediated diseases. The pharmaceutical compositions of the present disclosure may generally be administered from about 1 to about 5 times per day or as a continuous infusion. Such administration may be used as a long term or short term therapy. The amount of active ingredient mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, body weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose or suitable fraction thereof of the active ingredient described herein above. Treatment can be initiated with small doses, which are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at concentration levels that generally provide effective results in terms of antiviral efficacy without causing any harmful or toxic side effects.

When the compositions of the present disclosure comprise a combination of a compound of the present disclosure and one or more other therapeutic or prophylactic agents, the dosage level of the compound and the additional agent(s) will generally be from about 10% to about 150% of the normally administered dose, more preferably from about 10% to about 80% of the normally administered dose, in a monotherapy regimen. The pharmaceutical formulations are adapted for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.

Pharmaceutical formulations adapted for oral administration are provided in discrete units, such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foam or foam formulations (whip); or an oil-in-water emulsion or a water-in-oil emulsion.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be mixed with a pharmaceutically acceptable oral, non-toxic inert carrier (e.g., ethanol, glycerol, water, etc.). Powders are prepared by pulverizing the compound to a suitable fine size and mixing with a pharmaceutically acceptable carrier (e.g., an edible sugar such as starch or mannitol) which is also pulverized. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules are prepared by preparing a powdered mixture as described above and filling into shaped gelatin shells. Glidants and lubricants (e.g., colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) may be added to the powder mixture prior to the filling operation. Disintegrating or solubilizing agents (e.g., agar-agar, calcium carbonate or sodium carbonate) that will improve the availability of the drug when the capsule is taken can also be added.

In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For example, tablets are prepared by making a powder mixture, granulating or slugging, adding a lubricant and a disintegrant, and compressing into tablets. The powdered mixture is prepared by mixing the appropriately comminuted compound with a diluent or base as described above, optionally with a binder (for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (for example paraffin), an absorption accelerator (quaternary salt) and/or an absorbent (for example bentonite, kaolin or dicalcium phosphate). The powdered mixture may be granulated by wetting with a binder such as syrup, starch slurry, acacia slurry (acadia mucilage) or a solution of cellulosic or polymeric material and pressure sieving. An alternative to granulation is to pass the powder mixture through a tablet press, with the result that poorly formed agglomerates are broken up into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the dies of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure may also be combined with a free-flowing inert carrier and compressed into tablets without going through a granulation or pre-compression step. A transparent or opaque protective coating material may be provided which consists of a shellac seal coat, a sugar or polymeric material coat and a waxy polishing coat (polishcoating offwax). Dyes may be added to these coatings to distinguish different unit doses.

Oral liquid preparations such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs can be prepared through the use of non-toxic vehicles. Solubilizing agents and emulsifiers (e.g., ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers), preservatives, flavoring additives (e.g., peppermint oil or natural sweeteners or saccharin or other artificial sweeteners), and the like may also be added.

Dosage unit formulations for oral administration may be microencapsulated, if appropriate. The formulations may also be formulated for extended or sustained release, for example by coating or embedding in a particulate material such as a polymer, wax or the like.

The compounds of the invention, particularly the compounds of formula (I) and pharmaceutically acceptable salts thereof, may also be administered in liposomal delivery systems, such as small unilamellar liposomes, large unilamellar liposomes, and multilamellar liposomes. Liposomes can be composed of a variety of phospholipids (e.g., cholesterol, octadecylamine, or phosphatidylcholine).

The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, may also be delivered by using the monoclonal antibody as a separate carrier to which the compound molecule is coupled. The compounds may also be conjugated to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamide phenol, or polyethyleneoxide polylysine substituted with palmitoyl residues. In addition, the compounds may be coupled to a class of biodegradable polymers for achieving controlled release of a drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches (discretepatches) to remain in intimate contact with the epidermis of the recipient for an extended period of time. For example, the active ingredient may be delivered by iontophoretic patches, as generally described in pharmaceutical research1986,3(6), 318.

Pharmaceutical preparations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations suitable for nasal administration, wherein the carrier is a solid, include coarse powders having a particle size in the range of, for example, 20 to 500 microns, which are administered by nasal inhalation, i.e. by rapid inhalation through the nasal passage from a coarse powder container adjacent the nose. Suitable formulations in which the carrier is a liquid, suitable for administration as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient.

Pharmaceutical formulations suitable for administration by inhalation include finely divided particulate powders (dust) or mists (mist), which may be prepared in different types of metered dose compressed aerosols, nebulised inhalers, insufflators or other devices adapted to deliver aerosol sprays.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed amkside and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. The injection solution and suspension can be prepared into sterile powder for injection, granule and tablet.

It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example, such formulations which are suitable for oral administration may include flavouring agents.

Use of the Compounds and pharmaceutical compositions of the invention

The present invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament useful for at least one of inhibiting the HCV replication process and inhibiting HCV viral protein function. The HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV. The HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A and NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. Any compound or pharmaceutical composition of the invention can be used for treating Hepatitis C Virus (HCV) infection or hepatitis C disease, and particularly has good inhibition effect on HCV NS3/4A protein.

A method of treatment comprising administering a compound or pharmaceutical composition of the invention further comprising administering to a patient an additional HCV agent, whereby a compound of the invention may be administered in combination therapy with the additional HCV agent, wherein the anti-HCV agent is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiqimod, an inosine 5' -monophospate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, baviximab (Bavituximab), Civacir^TMExamples of the "basic" component include but are not limited to, boceprevir (boceprevir), telaprevir (telaprevir), sofosbuvir (sofosbuvir), lediprevir (ledipasvir), daclatavir (daclatasvir), danoprevir (danoprevir), cidaprevir (cilaprevir), naraprevir (narraprevir), deleobrevir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbassvir (MK-8742), bitomasvir (ABT-267), neceprevir (ACH-2684), tegobrevir (9190), gradoprevir (MK-5172), sovaprevir (ACH-1625), IDsamavavir (X-650032), setoprevir (GS-919450), and tmeprevir (TMCmax-70052), tmeprevir (TMCt-70052), tmoprevir (TMCt-70052), and so-52. the like ) FALDaprevir (BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530, ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-189, INX-189, IDX-102, R184, R-639, HCV-14789, HCV-6130 PSI-6130, PSI-876, TMC-649128, R-7128, PSI-7978, PSI-189, IVT-0819, SAC-32938, SAC-3246, SAC-102, SALT-LSA-102, SALT-IVA-102, SALT-IVI, SALT-IVB, SALT-IVA-IVB, SAC-IVI, SAC-35, SA.

And a method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering an additional anti-HCV agent, wherein the additional anti-HCV agent may be administered in combination with a compound or pharmaceutical composition of the invention as a single dosage form, or as separate compounds or pharmaceutical compositions as part of a multiple dosage form. Other anti-HCV agents may be administered with or without the compounds of the present invention. In the latter case, administration may be carried out by, for example, shifting between 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.

General synthetic procedure

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich chemical company, Inc., Arco chemical company and Alfa chemical company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were used by being dried beforehand over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC1 ₃、DMSO-d₆、CD₃OD or acetone-d₆As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets), d (doublets), t (triplets), q (quatets), m (multiplets), br (broadpeds), dd (doublets), dt (doublets). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were determined by Agilent6320 series LC-MS spectrometer equipped with a G1312A binary pump and an aG1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315BDAD detector were used for analysis, and an ESI source was used for LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were determined by Agilent6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315DDAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent ZorbaxSB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

TABLE 1

Time (min)	A (CH₃CN，0.1％ HCOOH)	B (H₂O，0.1％ HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purification was assessed by Agilent1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

The following acronyms are used throughout the invention:

AcOH acetic acid

BBr₃Boron tribromide

BSA bovine serum albumin

Br₂Bromine compound

Bn benzyl group

BOC, Boc tert-butoxycarbonyl

BAST bis (2-methoxyethyl) aminosulfur trifluoride

Cs₂CO₃Cesium carbonate

CHCl₃Chloroform

CDC1₃Deuterated chloroform

CD₃OD deuterated methanol

Cu copper

CuI cuprous iodide

CH₂Cl₂DCM dichloromethane

CDIN, N' -carbonyldiimidazole

CBZ, Cbz benzyloxycarbonyl

DBU1, 8-diazabicyclo [5.4.0] -undec-7-ene

DBAD azodicarboxylic acid di-tert-butyl ester

DCE1, 2-dichloroethane

DMFN, N-dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide

Dippa Azoic Diphenyl phosphate

DIPEA diisopropylethylamine

DME ethylene glycol dimethyl ether

DAST diethylaminosulfur trifluoride

DPPPy diphenyl-2-pyridylphosphine

Dess-Martin (Dess-Martin oxidant) (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -one

EDC, EDCI1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc ethyl acetate

EA Ethyl acetate

Et₂O Ether

Et₂NSF₃Diethylamine sulfur trifluoride

Et₃N, TEA Triethylamine

Fe iron

Fmoc 9-fluorenylmethyleneoxycarbonyl

HCl. EA hydrochloric acid ethyl acetate

HATU2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HBr hydrobromic acid

HCl hydrochloric acid

HOAt, HOAT 1-hydroxy-7-azabenzotriazole

HOBT 1-hydroxybenzotriazole

H₂Hydrogen gas

H₂O₂Hydrogen peroxide

H₂O water

HOAc acetic acid

I₂Iodine

IPA isopropyl alcohol

IMPDH inosine monophosphate dehydrogenase

IRES internal ribosome entry Point

K₂CO₃Potassium carbonate

KOH potassium hydroxide

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide

LiN(SiMe₃)₂Lithium bis (trimethylsilyl) amide

Lawesson' sRegent (Rous reagent) 2, 4-bis (4-methoxyphenyl) -1, 3-dithio-2, 4-phospholane-2, 4-disulfide

MTBE methyl tert-butyl ether

MCPBA m-chloroperoxybenzoic acid

MgSO₄Magnesium sulfate

MeOH,CH₃OH methanol

MeI methyl iodide

MeCN,CH₃CN acetonitrile

mL of

NH₃Ammonia

NH₄C1 Ammonia chloride

NMPN-methyl pyrrolidone

NISN-iodosuccinimide

N₂Nitrogen gas

NaHCO₃Sodium bicarbonate

NaBH₄Sodium borohydride

NaBH₃CN Cyanoborohydride sodium salt

NaOtBu tert-butyl sodium alcoholate

NaOH sodium hydroxide

NaClO₂Sodium chlorite

NaCl sodium chloride

NaH₂PO₄Sodium dihydrogen phosphate

NaH sodium hydride

NaI sodium iodide

Na₂SO₄Sodium sulfate

NBSN-Bromosuccinimide

PPh₃MeBr Bromomethyltriphenylphosphine

P(t-bu)₃Tri (tert-butyl) phosphine

Pd/C Palladium/carbon

PE Petroleum ether (60-90 deg.C)

PBS phosphate buffered saline

POC1₃Phosphorus oxychloride

PPA polyphosphoric acid

Pd(PPh₃)₄Tetratriphenylphosphine palladium

Pd(dppf)Cl₂1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

PhNTf₂N-phenyl bis (trifluoromethanesulfonyl) imide

P-TSA/PTSA P-toluenesulfonic acid

PMB p-methoxybenzyl

RTrt Room temperature

rf reflow

Rt Retention time

SEMCl2- (trimethylsilyl) ethoxymethyl chloride

SbCl₃Antimony trichloride

SmCl₃Samarium chloride

TBME methyl tert-butyl ether

TBTUO-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

TFA trifluoroacetic acid

TBAI tetrabutylammonium iodide

TBS tert-butyl dimethylsilyl group

TBDPS tert-butyl diphenyl silicon base

TEAF Triethylamine Carboxylic acid

Tf₂O-Trifluoromethanesulfonic anhydride

TFAA trifluoroacetic anhydride

TsOH p-toluenesulfonic acid

TMSA trimethylsilyl acetylene

TMSCl trimethylchlorosilane

TBDMSOTf tert-butyl dimethyl p-toluene sulfonic silane

TCCA trichloroisocyanuric acid

t-BuOK Potassium tert-butoxide

TEMPO2,2,6, 6-tetramethylpiperidine-N-oxide

TEBAC benzyl triethyl ammonium chloride

Meldrum's acid 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone

Synthesis method

Synthesis method 1

Compound 5 can be prepared by synthetic method 1, wherein R¹、R²、A¹、A²M, n have the meanings given in the description of the invention3, synthesizing the compound 1 and the compound 2 under the action of alkali, wherein the alkali is sodium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. The compound 3 is synthesized in an acetic acid system under the action of reduced iron powder to obtain a compound 4, and the compound 4 is further synthesized in POCl ₃And a catalyst N, N-dimethylaniline to form a compound 5.

Synthesis method 2

Compound 9 can be prepared by synthetic method 2, wherein R³The compound 6 and the compound 7 have the meaning of the invention, firstly, the compound 8 is obtained under the action of CDI and DBU, and then the compound 8 is further deprotected and salified to obtain the compound 9.

Synthesis method 3

Compound 18 can be prepared by synthetic method 3, wherein X¹OH, Cl, etc.; r¹、R²、R³、A¹、A²、Q、R⁴L, m, n have the meanings given in the description; the protecting group Pg is Boc, Fmoc, Cbz, Bn, PMB, etc., and the base used is sodium hydride, sodium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. The compound 5 and the compound 10 form a compound 11 under the alkaline condition, and the compound 11 and the compound 9 further form a compound 12 under the action of a condensing agent. Deprotection of compound 12 forms compound 13 and compound 14 are again reacted with a condensing agent to form compound 15. Compound 15 is reacted with a catalyst (e.g., Grubbs second generation catalyst, Janz 1B catalyst, Janz 1C catalyst, etc.) to form compound 16, and finally compound 16 is deprotected further to form compound 17, and compound 17 is reacted with Reaction of compound 17' affords compound 18.

Synthesis method 4

Compound 18 can be prepared by synthetic method 4, wherein X¹OH, Cl, etc.; r¹、R²、R³、A¹、A²、Q、R⁴L, m, n have the meanings given in the description; the protecting group Pg is Boc, Fmoc, Cbz, Bn, PMB, etc., and the base used is sodium hydride, sodium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Wherein compound 20 can be synthesized by reacting compound 10 with compound 19, then removing the amino protecting group to obtain compound 21, and then reacting compound 21 with compound 14 to obtain compound 22. Compound 22 under the action of a catalyst gives compound 23, compound 23 reacts with compound 5 under basic conditions to give compound 24, and compound 24 is hydrolyzed to give compound 25. And the compound 26 can be synthesized by the compound 25 and the compound 7 under the action of CDI, the compound 27 is obtained after the protective group of the compound 26 is removed, and the compound 18 is obtained by the reaction of the compound 27 and the compound 17'.

Synthesis method 5

Compound 18 can be prepared by synthetic method 5, wherein X¹Is OH,Cl, etc.; r¹、R²、R³、A¹、A²、Q、R⁴L, m, n have the meanings given in the description; the protecting group Pg is Boc, Fmoc, Cbz, Bn, PMB, etc., the protecting group Pg2 is TBS, TES, TBDPS, PMB, etc., and the base used is sodium hydride, sodium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Compound 10 is reacted with compound 9 to provide compound 28, followed by removal of the amino protecting group to provide compound 29, and then compound 29 is reacted with compound 14 to provide compound 30. The hydroxyl group in the compound 30 is protected to obtain a compound 31, then the compound 31 is acted by a catalyst (Grubbs second generation catalyst, Janz 1B catalyst, Janz 1C catalyst and the like) to obtain a compound 32, the hydroxyl protecting group of the compound 32 is removed to obtain a compound 33, and then the compound and the compound 5 are reacted under alkaline conditions to obtain a compound 26. Compound 26 is further deprotected to give compound 27, and compound 27 and compound 17' are reacted to give compound 18.

Examples

Example 1

Synthetic route

Step 1: synthesis of Compounds 1-3

Benzaldehyde (95.6mL,943mmol), glycine ethyl ester hydrochloride (131g,943mmol) and Na₂SO₄(80g,565mmol) was added to 900 mL of TBME, then cooled to 0 deg.C and triethylamine (197mL,1414mmol) was added slowly, after which the reaction mixture was warmed to 25 deg.C andstirred at this temperature for 24 hours. The mixture was filtered with celite to remove solids, the filtrate was concentrated under reduced pressure, and the resulting crude product was dried under vacuum to give the compounds 1-3(180g, yield: 100%) as pale yellow oil, which was directly used for the next reaction without further purification.

¹HNMR(600MHz,CDCl₃)：8.28(s,1H),7.86–7.71(m,2H),7.50–7.32(m,3H),4.47–4.32(m,2H),4.29–4.18(m,2H),1.32–1.22(m,3H)ppm。

Step 2: synthesis of Compounds 1-4

Lithium tert-butoxide (17.60g,220mmol) was added to 250 ml of toluene, and then a toluene solution (50 ml) of the compound 1-3(22.00g,117mmol) and a toluene solution (50 ml) of trans-1, 4-dibromo-2-butene (20.00g,94mmol) were simultaneously added dropwise at 0 ℃ while keeping the dropping rates of the two solutions the same, and the addition was completed over about 1 hour. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for two hours, quenched with 200 ml of water, back-extracted twice with 200 ml of TBME and the organic phases combined. Then 200 ml of 1N hydrochloric acid solution were added to the above combined organic phases, stirred for two hours, separated, the resulting organic phase was extracted once with 150 ml of water, then sodium chloride (131.00g,2241mmol) and 200 ml of TBME were added to the combined aqueous phase and the mixture was adjusted to a pH between 12 and 13 with 10N NaOH aqueous solution. The organic phase was separated, the aqueous phase was extracted with 100 ml TBME, the organic phases were combined and Boc was added to the combined organic phase ₂O (21mL,98mmol), the resulting reaction mixture was stirred at room temperature overnight, then warmed to 60 ℃ and stirred for two hours. After that, the mixture was cooled to room temperature, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give 1-4(12g, yield 50%) as a yellow oil.

¹HNMR(400MHz,CDCl₃):5.17–5.80(m,1H),5.29(s,1H),5.06–5.09(m,1H),4.12–4.19(m,2H),2.17–2.14(m,1H),1.77(s,1H),1.43(s,1H),1.41(s,9H),1.24(t,J＝7.2Hz,3H)ppm。

And step 3: synthesis of Compounds 1-5

Alcalase2.4l (52mL) proteolytic enzyme was added to sodium phosphate buffer solution (0.1N,550mL, pH 8), then warmed to 39 ℃, and the pH of the solution was adjusted to 8.0 by the addition of 50% aqueous sodium hydroxide. At this temperature, a further DMSO solution (100mL) of compounds 1-4(10.58g, 42.5mmol) was added slowly over a period of 20 minutes. Then, the reaction mixture was heated to 40 ℃ and stirred for 24 hours, and a 50% aqueous solution of sodium hydroxide was continuously added during the reaction to ensure that the pH of the reaction system was about 8.0. Thereafter, the reaction was cooled to 30 ℃ and stirred for 48 hours, then 50% aqueous sodium hydroxide was added to adjust the pH to 8.5, and extracted twice with 150 ml TBME, and the organic phases were combined and treated with 5% NaHCO₃The aqueous solution was washed (50mL × 3), followed by water (50mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was removed under reduced pressure to give Compound 1-5 as a yellow solid (5.01g, yield: 47%).

MS(ESI,pos.ion)m/z:256.1[M+H]⁺。

And 4, step 4: synthesis of Compounds 1-6

Compound 1-5(14.57g,57mmol) was dissolved in a mixed solvent of 100 mL THF and 50mL methanol, cooled to 0 deg.C, then an aqueous solution (25 mL) of lithium hydroxide (4.79g,114mmol) was added, and after the addition was complete, the reaction mixture was warmed to 30 deg.C and stirred overnight. The organic solvent was removed under reduced pressure to give a crude solid, and the solid was dissolved in 50ml of ethyl acetate and 50ml of water. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 12g of crude product 1-6, which was subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:228.1[M+H]⁺。

And 5: synthesis of Compounds 1-8

Compounds 1-6(1.00g,4.4mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, and CDI (0.93g,5.7mmol) was added thereto. The reaction mixture was warmed to reflux and stirred for two hours, after completion of the reaction, cooled to room temperature, and then added with compounds 1-7(0.80g,6.6mmol) and DBU (1mL,6.6mmol), followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with a 1N aqueous hydrochloric acid solution and then with a saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude products 1 to 8(0.94g, yield: 65%).

MS(ESI,pos.ion)m/z:331.1[M+H]⁺。

Step 6: synthesis of Compounds 1-9

Compound 1-8(2.10g,6.3mmol) was dissolved in 40 ml of isopropanol, p-toluenesulfonic acid (1.8g,9.4mmol) was added thereto, the temperature was raised to 65 ℃, stirred for 4 hours, cooled to room temperature, the organic solvent was removed under reduced pressure to give a white solid, the solid was washed with ethyl acetate, filtered to give compound 1-9(1.49g, yield: 80%)

¹HNMR(400MHz,CD₃OD):7.73(d,J＝8.0Hz,2H),7.26(d,J＝7.9Hz,2H),5.81–5.65(m,1H),5.44(d,J＝17.0Hz,1H),5.36(d,J＝10.3Hz,1H),3.13–2.96(m,1H),2.47–2.32(m,4H),2.20(t,J＝7.9Hz,1H),1.72(t,J＝9.0Hz,1H),1.39–1.20(m,2H),1.20–1.02(m,2H)ppm。

Example 2

The synthetic route is as follows:

step 1: synthesis of Compound 2-1

Compound 2-0(10.0g,72.4mmol) was dissolved in 100ml of methanol, concentrated sulfuric acid (7 ml) was added thereto, and then heated to reflux, reacted for 18 hours, cooled to room temperature, and concentrated under reduced pressure, and the resulting residue was dissolved in 100ml of dichloromethane, and then 1N naHCO was used₃The aqueous solution was washed (100mL × 2), the separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give Compound 2-1(9.8g, yield: 89%).

Step 2: synthesis of Compounds 2-3

Compound 2-1(3g,19.7mmol) and compound 2-2(2.63g,17.9mmol) were dissolved in 50mL DMF, and K was added thereto₂CO₃(2.96g,21.5mmol) and after the addition was complete, the reaction mixture was warmed to reflux and reacted overnight. After the reaction was complete, the reaction was cooled to room temperature, diluted with 100mL of LEtOAc and the resulting mixture was diluted with H ₂O wash (100mL × 2), followed by 50mL saturated brine, and the organic phase over anhydrous Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 2-3(4g, yield: 78%) as a yellow solid.

MS(ESI,pos.ion)m/z:274.1[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.05–7.99(m,1H),7.99–7.93(m,1H),7.61–7.53(m,1H),7.50–7.42(m,1H),7.33(q,J＝7.2Hz,1H),7.16(dt,J＝11.8,6.0Hz,1H),7.13(d,J＝8.2Hz,1H),6.84–6.76(m,1H),3.76(s,3H)ppm。

And step 3: synthesis of Compounds 2-4

Compound 2-3(4.10g,15mmol) was dissolved in 100mL of glacial acetic acid, then reduced iron powder (3.36g,60mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100ml of 1n hcl solution, a large amount of white solid was precipitated, and the obtained white solid was dried under vacuum to obtain compound 2-4(2.8g, yield: 88%) which was directly subjected to the next reaction without further purification.

¹HNMR(400MHz,CDCl₃):8.15(s,1H),7.97(dd,J＝8.2,1.7Hz,1H),7.55(td,J＝8.1,1.7Hz,1H),7.34–7.21(m,2H),7.21–7.10(m,2H),7.06(dt,J＝4.0,3.1Hz,1H)。

And 4, step 4: synthesis of Compounds 2-6

Compound 2-4(2.71g,12.8mmol) was added to 50mL of toluene, phosphorus oxychloride (1.3mL,14.0mmol) was added under nitrogen, and then N, N-dimethylaniline (0.65mL,5.1mmol) was added slowly. The reaction mixture was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, it was cooled to 0 ℃ and quenched with 5mL of water, then washed with 20mL of water (20 mL. times.2), and the organic phase was washed with 20mL of saturated brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 2-6, which was directly subjected to the next reaction without purification.

And 5: synthesis of Compounds 2 to 8

Sodium hydride (0.37g,9.2mmol) was added to 20ml of anhydrous tetrahydrofuran, cooled to 0 ℃ under nitrogen, and then added to an anhydrous tetrahydrofuran solution (5 ml) containing compound 2-7(2.12g,9.2mmol), after which the temperature was raised to 30 ℃ and stirred for two hours.

An anhydrous tetrahydrofuran solution (5 ml) containing compound 2-6(1.07g,4.6mmol) was added to the above reaction solution, followed by reaction overnight. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 20mL of water, washed once with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, then extracted with 20mL of ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compounds 2 to 8 as a white solid (1.27g, yield: 65%).

MS(ESI,pos.ion)m/z:425.2[M+H]⁺。

Step 6: synthesis of Compounds 2-9

Compounds 2-8(0.85g,2.0mmol), compounds 1-9(0.74g,1.8mmol), EDCI (0.37g,1.9mmol) and HOAT (0.27g,2.0mmol) were charged into a round bottom flask, 15 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.8mL,4.6mmol) was added, warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, 10 mL of water was added to quench the reaction, the resulting mixture was extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 2-9(0.89g, yield 70%) as a white solid.

MS(ESI,pos.ion)m/z:637.2[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.13(s,1H),7.49(dd,J＝22.8,15.4Hz,2H),7.35(s,1H),7.21(t,J＝6.9Hz,3H),7.18–7.09(m,3H),5.89–5.75(m,2H),5.29(t,J＝17.8Hz,1H),5.16(d,J＝10.4Hz,1H),3.74–3.48(m,2H),2.96–2.81(m,1H),2.54–2.50(m,2H),2.42–2.25(m,1H),2.14-2.10(m,2H),2.03–1.95(m,1H),1.46(s,9H),1.45–1.36(m,2H),1.08(dd,J＝18.4,7.5Hz,2H)ppm。

And 7: synthesis of Compounds 2-10

Compound 2-9(0.75g,1.1mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 30% strength ethyl acetate hydrochloride solution (10 ml) was added and the reaction was stirred at room temperature for 2 hours. After the reaction, filtration was carried out, and the filter cake was washed with 20 ml of ethyl acetate to obtain 2-10 as a white solid, which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:537.2[M+H]⁺；

¹HNMR(600MHz,CD₃OD)：7.84–7.74(m,1H),7.59(t,J＝7.4Hz,1H),7.32–7.12(m,6H),5.92(s,1H),5.73–5.56(m,1H),5.37(d,J＝17.1Hz,1H),5.17(d,J＝10.3Hz,1H),4.73(dd,J＝23.9,14.3Hz,1H),3.93–3.81(m,2H),2.99–2.96(m,2H),2.50–2.36(m,2H),1.98-1.95(m,2H),1.45–1.38(m,1H),1.33–1.24(m,3H),1.24–1.16(m,1H),1.16–1.03(m,2H)ppm。

And 8: synthesis of Compounds 2-12

Compounds 2-10(0.57g,0.99mmol), compounds 2-11(0.54g,1.2mmol), EDCI (0.23g,1.2mmol) and HOAT (0.16g,1.2mmol) were charged to a round bottom flask, 8 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.52mL,3.0mmol) was added. The temperature was raised to 30 ℃ and stirred for 6 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with 10mL of ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 2-12(0.47g, yield 60%) as a white solid.

MS(ESI,pos.ion)m/z:790.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.40–10.15(m,1H),7.53(t,J＝8.0Hz,1H),7.46(t,J＝7.5Hz,1H),7.22–7.08(m,6H),5.88(s,1H),5.77(ddt,J＝13.4,10.1,8.1Hz,2H),5.27(d,J＝17.2Hz,1H),5.12(d,J＝10.6Hz,1H),4.96(t,J＝14.9Hz,1H),4.91(d,J＝10.0Hz,1H),4.54–4.46(m,1H),4.46–4.37(m,1H),4.24(d,J＝11.7Hz,1H),4.02(dd,J＝11.5,3.5Hz,1H),2.98–2.87(m,1H),2.57(dt,J＝24.3,12.3Hz,1H),2.47–2.37(m,1H),2.23–2.12(m,1H),2.03–1.90(m,4H),1.77–1.66(m,1H),1.57(dt,J＝25.4,12.5Hz,1H),1.45–1.40(m,2H),1.40–1.27(m,15H),1.22–1.08(m,2H),1.08–0.93(m,2H)ppm。

Step 10: synthesis of Compounds 2-13

Compound 2-12(0.16g,0.21mmol) was dissolved in 150 ml of 1, 2-dichloroethane, 0.01 g of Grubbs second generation catalyst was added under nitrogen, and then the temperature was raised to 65 ℃ and stirred at this temperature for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compounds 2 to 13 as white solids (0.08g, yield: 50%).

MS(ESI,pos.ion)m/z:762.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.51(d,J＝56.6Hz,1H),7.52-7.50(m,1H),7.48–7.36(m,1H),7.25(d,J＝6.5Hz,1H),7.20–6.95(m,5H),6.00–5.85(m,1H),5.81–5.61(m,1H),5.05–4.94(m,1H),4.65(d,J＝7.4Hz,1H),4.38(d,J＝7.8Hz,1H),4.11–3.94(m,1H),2.90(s,1H),2.61-2.60(m,3H),2.35(q,J＝8.5Hz,1H),1.99–1.73(m,3H),1.54(dd,J＝12.3,8.9Hz,1H),1.51–1.38(m,6H),1.37(s,9H),1.17–1.00(m,2H),0.99–0.80(m,2H)ppm；

HPLC:95.25％。

Example 3

Synthetic route

Step 1: synthesis of Compound 3-3

Compound 3-1(4g,21.9mmol) and compoundSubstance 2-2(3.38g,24.0mmol) was dissolved in 100mL of DMF and K was added₂CO₃(3.31g,24.0mmol), then warmed to reflux and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 200mL of ethyl acetate was added, and the reaction mixture was washed with H₂O wash (100mL × 2) followed by 50mL brine and the organic phase over anhydrous Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to give 3-3(6.0g, yield 90%) as a yellow solid.

¹HNMR(600MHz,CDCl₃):7.98(dd,J＝8.2,1.5Hz,1H),7.56(dd,J＝7.9,1.4Hz,1H),7.43–7.36(m,1H),7.33(t,J＝8.1Hz,1H),7.21(dd,J＝8.2,1.2Hz,1H),7.14–7.03(m,1H),6.67(dd,J＝8.4,0.8Hz,1H),3.80(s,3H),3.76(s,3H)ppm。

Step 2: synthesis of Compounds 3-4

Compound 3-3(3.0g,9.9mmol) was dissolved in 80mL of glacial acetic acid, and then iron powder (2.2g,39mmol) was added thereto, and the mixture was stirred at 115 ℃ for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100ml of 1n hcl solution to precipitate a large amount of white solid, filtered, and the obtained white solid was dried under vacuum to obtain compound 3-4(2.1g, yield 88%) which was directly subjected to the next reaction without purification.

MS(ESI,pos.ion)m/z:242.1[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.96(s,1H),7.48(d,J＝7.1Hz,1H),7.39(dd,J＝5.9,3.2Hz,1H),7.28(s,1H),7.22–7.17(m,1H),7.15(dd,J＝8.7,5.8Hz,2H),7.11-7.07(m,1H),3.97(s,3H)ppm。

And step 3: synthesis of Compounds 3-5

Compound 3-4(0.5g,2.1mmol) was added to 10mL of toluene, phosphorus oxychloride (0.38mL,4.2mmol) was added under nitrogen, then N, N-dimethylaniline (0.1mL,0.83mmol) was added slowly, the temperature was raised to 110 ℃ and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was cooled to 0 ℃, 2mL of water was added to quench the reaction, then washed with water (10mL × 2), and the organic phase was washed once with 10mL of saturated brine, then dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain crude product 3-5, which was directly subjected to the next reaction without further purification.

And 4, step 4: synthesis of Compounds 3-7

Sodium hydride (0.08g,2.1mmol) was added to 10ml of anhydrous tetrahydrofuran, cooled to 0 ℃ under nitrogen, and then a solution (2 ml) of anhydrous tetrahydrofuran containing compound 2-7(0.24g,1.0mmol) was added, after which the temperature was raised to 30 ℃ and stirred for two hours. An anhydrous tetrahydrofuran solution (2 ml) containing the compound 3-5(0.27g,1.0mmol) was added to the above reaction solution, followed by reaction overnight. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 10mL of water, washed once with 10mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 3-7(0.28g, yield 60%) as a white solid.

MS(ESI,neg.ion)m/z:453.2[M-H]^-；

¹HNMR(600MHz,CDCl₃):7.29(s,1H),7.26–7.22(m,1H),7.19–7.12(m,3H),7.09(dd,J＝18.8,7.4Hz,2H),5.81(d,J＝28.1Hz,1H),4.02–3.87(m,5H),3.83(dd,J＝12.2,4.2Hz,1H),2.83–2.59(m,2H),1.49(d,J＝12.9Hz,9H)ppm。

And 5: synthesis of Compounds 3-9

Compounds 3-7(0.2g,0.44mmol), compounds 1-9(0.19g,0.48mmol), EDCI (0.09g,0.48mmol) and HOAT (0.07g,0.53mmol) were charged to a round bottom flask, protected with nitrogen, 4 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.23mL,1.3mmol) was added. The reaction was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, 5mL of water was added to quench the reaction, extraction was performed with ethyl acetate (15mL × 3), the organic phases were combined, the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 3-9(0.11g, yield 38%) as a white solid.

MS(ESI,pos.ion)m/z:667.2[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.13(s,1H),7.33–7.19(m,2H),7.12–7.05(m,5H),5.82(dd,J＝18.2,9.0Hz,2H),5.32(d,J＝17.1Hz,1H),5.19(t,J＝11.6Hz,1H),4.41–4.30(m,1H),3.95(s,3H),3.93–3.80(m,2H),2.97(s,1H),2.62–2.48(m,2H),2.19–2.17(m,1H),2.02–1.97(m,1H),1.48(s,9H),1.42–1.31(m,2H),1.06(d,J＝7.4Hz,2H)ppm。

Step 6: synthesis of Compounds 3-10

Compound 3-9(1.06g,1.5mmol) was dissolved in 5ml of ethyl acetate, cooled to 0 ℃ and then 30% strength ethyl acetate hydrochloride solution (20 ml) was added, and the reaction was stirred at room temperature for 2 hours. Filtration and washing of the filter cake with 10ml of ethyl acetate gave 3-10 as a white solid which was carried on to the next reaction without further purification.

MS(ESI,pos.ion)m/z:567.2[M+H]⁺。

And 7: synthesis of Compounds 3-12

Compounds 3-10(0.80g,1.32mmol), compounds 2-11(0.77g,1.71mmol), EDCI (0.33g,1.77mmol) and HOAT (0.23g,1.71mmol) were added to a round bottom flask, protected with nitrogen, dichloromethane (13 mL) was added, then cooled to 0 ℃ and DIPEA (0.22mL,1.28mmol) was added. The reaction was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 3-12(0.50g, yield 46%) as a white solid.

MS(ESI,pos.ion)m/z:820.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):9.74(s,1H),7.65(s,1H),7.33–7.26(m,1H),7.21–7.04(m,5H),5.84–5.76(m,2H),5.71–5.59(m,1H),5.37(d,J＝4.7Hz,1H),5.07–4.82(m,5H),4.65(dd,J＝9.1,3.1Hz,1H),4.52(d,J＝11.7Hz,1H),4.19(d,J＝4.2Hz,1H),3.98–3.94(m,2H),3.93(s,3H),2.93–2.91(m,1H),2.65–2.62(m,1H),2.16–1.92(m,3H),1.83–1.81(m,1H),1.77–1.58(m,2H),1.42–1.30(m,7H),1.35(s,9H),1.31–1.19(m,5H),1.07–1.01(m,2H)ppm。

And 8: synthesis of Compounds 3-13

The compound 3-12(0.50g,0.61mmol) was dissolved in 120 ml of 1, 2-dichloroethane, 0.05 g of Grubbs second generation catalyst was added under nitrogen, and then the temperature was raised to 65 ℃ and stirred at this temperature for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compounds 3 to 13(0.2g, yield: 41%) as white solids.

MS(ESI,pos.ion)m/z:792.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.31(s,1H),7.30–7.28(m,2H),7.18–7.08(m,3H),7.08–7.05(m,3H),5.98(s,1H),5.73(dd,J＝18.0,8.7Hz,1H),5.25(s,1H),5.08–4.96(m,1H),4.61(s,1H),4.54(d,J＝11.2Hz,1H),4.38(s,1H),4.11–4.00(m,1H),3.93(s,1H),2.97–2.87(m,1H),2.64(d,J＝11.0Hz,2H),2.59(s,1H),2.33(t,J＝8.7Hz,1H),1.91(s,6H),1.62–1.60(m,1H),1.54–1.39(m,6H),1.33(s,9H),1.21–1.12(m,3H),0.97–0.88(m,1H)ppm；

HPLC purity: 94.99 percent.

Example 4

The synthetic route is as follows:

step 1: synthesis of Compound 4-2

Substrate 2-chloronicotinic acid (3.15g,21.1mmol) is dissolved in 100mL of dichloromethane, cooled to 0 ℃, thionyl chloride (7.5g,63.3mmol) is added under nitrogen protection, then 2 drops of DMF are added dropwise, stirred for a while, warmed to reflux, and reacted overnight. And (3) after the reaction is complete, concentrating the reaction solution under reduced pressure to obtain a crude product 4-2, and directly carrying out the next reaction on the obtained product without purification.

Step 2: synthesis of Compound 4-4

2-Chloronicotinyl chloride (3.1g, 21.1mmol) was dissolved in 10mL of ethyl acetate and the solution was added to a solution of ortho-aminophenol (2.5g,23.2mmol) and DIPEA (6.3mL,35.8mmol) in ethyl acetate (100mL) under nitrogen and stirred at 0 ℃ for about 1 hour. After completion of the reaction, 2mL of water was added to quench the reaction, and the organic phase was washed with 10mL of saturated brine and the organic solvent was spin-dried under reduced pressure. The residue was dissolved in a mixed solvent of tetrahydrofuran and ethanol at a ratio of 1:1(10 mL: 10mL), 10mL of 15% aqueous sodium hydroxide solution was added, the reaction mixture was heated at 50 ℃ for 1 hour, cooled to room temperature, and about 2/3 of the solvent was removed by evaporation. The pH was then adjusted to 2 with 3N HCl aqueous solution, filtered, and the filter cake was dried under vacuum to give compound 4-4(4.4g, yield: 81%) as a brown solid.

MS(ESI,pos.ion)m/z:249.0[M+H]⁺；

¹HNMR(600MHz,DMSO-d₆):9.92-9.82(m,1H),9.79(d,J＝16.8Hz,1H),8.54-8.45(m,1H),8.04(dd,J＝7.5,1.8Hz,1H),7.85(d,J＝7.9Hz,1H),7.56–7.44(m,1H),7.06–6.99(m,1H),6.90(t,J＝11.7Hz,1H),6.88-6.78(m,1H)ppm。

And step 3: synthesis of Compounds 4-5

Compound 4-4(4.4g, 17.9mmol) was dissolved in 100mL of DMF, sodium hydroxide (0.86g,21.5mmol) was added and the reaction was allowed to warm to 130 ℃ and stirred overnight. After the reaction was completed, 200mL of ice water was added to quench the reaction, and a large amount of white solid was precipitated. Filtration and washing of the filter cake with 100mL of water followed by 100mL of ethanol gave compound 4-5 as a white solid (2.3g, yield: 61.8%).

MS(ESI,pos.ion)m/z:213.1[M+H]⁺。

And 4, step 4: synthesis of Compounds 4-6

Compound 4-5(0.64g,3.0mmol) was added to 15mL of toluene, phosphorus oxychloride (0.55mL,6.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.15mL,1.2mmol) was added slowly and the reaction was warmed to 110 ℃ for 6 hours. After the reaction was complete, it was cooled to 0 ℃ and quenched by the addition of 2mL of water and washed twice with 20 mL of water. The separated organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give crude product 4-6, which was directly subjected to the next reaction without further purification.

And 5: synthesis of Compounds 4-8

Sodium hydride (0.24g,6.0mmol) was added to 10 ml of anhydrous tetrahydrofuran, cooled to 0 ℃ under nitrogen, and then a solution of 2ml of anhydrous tetrahydrofuran containing compound 2-7(0.69g,3.0mmol) was added, after which the temperature was raised to 30 ℃ and stirred for two hours.

2ml of an anhydrous tetrahydrofuran solution containing the compound 4-6(0.69g,3.0mmol) was added to the above reaction solution, followed by reaction overnight. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 10mL of water, washed once with 10mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compounds 4 to 8(0.74g, yield 56%) as a white solid.

MS(ESI,neg,ion)m/z:424.2[M-H]^-。

Step 6: synthesis of Compounds 4-10

Compounds 4-8(0.71g,1.67mmol), compounds 1-9(0.80g,2.0mmol), EDCI (0.38g,2.0mmol) and HOAT (0.27g,2.0mmol) were charged to a round bottom flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (1.2mL,6.68mmol) was added. The reaction was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, followed by extraction with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 4-10(0.76g, yield 71%) as a white solid.

MS(ESI,pos.ion)m/z:638.2[M+H]⁺。

And 7: synthesis of Compounds 4-11

Compound 4-10(0.75g,1.2mmol) was dissolved in 5 ml of ethyl acetate, cooled to 0 ℃ and then 15 ml of a 30% strength ethyl acetate hydrochloride solution was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered and the filter cake was washed with 10ml of ethyl acetate to give compound 4-11 as a white solid which was carried on to the next reaction without further purification.

And 8: synthesis of Compounds 4-12

Compounds 2-11(0.53g,1.18mmol), compounds 4-11(0.32g,1.18mmol), EDCI (0.23g,1.18mmol) and HOAT (0.16g,1.18mmol) were charged to a round bottom flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.83mL,4.72mmol) was added. The reaction was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined. The organic phase was washed once with 10ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compounds 4 to 12(0.40g, yield 43%) as pale yellow solids.

MS(ESI,pos.ion)m/z:791.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):8.54(d,J＝7.6Hz,1H),8.46–8.35(m,1H),7.84(d,J＝5.8Hz,1H),7.67(d,J＝7.9Hz,1H),7.43(dd,J＝14.5,7.2Hz,2H),7.19(dd,J＝7.5,5.0Hz,1H),6.04(s,1H),5.83–5.79(m,2H),5.38(d,J＝8.9Hz,1H),5.29(d,J＝17.3Hz,1H),5.16(d,J＝10.4Hz,1H),5.03(d,J＝1.8Hz,1H),4.96(dd,J＝15.0,6.0Hz,2H),4.78(s,1H),4.40(s,1H),4.19(d,J＝12.1Hz,1H),4.08–3.97(m,1H),2.96–2.94(m,1H),2.76(s,1H),2.52(s,1H),2.31–2.15(m,1H),2.09–1.96(m,2H),1.72(s,1H),1.63–1.60(m,1H),1.52–1.43(m,2H),1.43–1.34(m,6H),1.29(d,J＝10.3Hz,12H),1.07(d,J＝7.4Hz,2H)ppm。

And step 9: synthesis of Compounds 4-13

The compound 4-12(0.07g,0.088mmol) was dissolved in 30 ml of 1, 2-dichloroethane, 0.007 g of Grubbs second generation catalyst was added under nitrogen, the reaction was warmed to 75 ℃ and stirred at this temperature for 24 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compounds 4 to 13 as a white solid (0.065g, yield: 97%).

MS(ESI,pos.ion)m/z:763.3181[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.46(d,J＝7.0Hz,1H),8.28(d,J＝3.4Hz,1H),7.76(d,J＝5.0Hz,1H),7.63(dd,J＝16.9,7.6Hz,1H),7.41–7.30(m,2H),7.08(s,1H),5.88(s,1H),5.52(d,J＝7.4Hz,1H),5.45(d,J＝7.7Hz,1H),5.21(s,1H),4.96–4.81(m,1H),4.55(s,1H),4.29(d,J＝6.4Hz,1H),4.16(d,J＝10.5Hz,1H),2.75(d,J＝4.8Hz,2H),2.55(s,1H),2.24–2.06(m,3H),1.90(s,1H),1.77(m,2H),1.31–1.24(m,8H),1.19(s,9H),1.13–1.07(m,2H),0.90–0.85(m,2H),0.83–0.77(m,1H)ppm；

Purity of HPLC 95.64%.

Example 5

The synthetic route is as follows:

step 1: synthesis of Compound 5-2

Compound 5-1(8g,52mmol) and o-fluoronitrobenzene (14.5g,103mmol) were dissolved in DMF (200mL) and K was added₂CO₃(21mg,156mmol), heating the reaction to 120 ℃ for reaction overnight, after the reaction is finished, adding water into the reaction liquid for quenching, extracting with ethyl acetate (50mL × 3), combining organic phases, washing the organic phases with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound 5-2 which is an orange oily liquid, wherein the next reaction is directly carried out without purification.

Step 2: synthesis of Compound 5-3

Compound 5-2(100mg,0.36mmol) was dissolved in DMF (20mL) and NaH (60% dispersed in mineral oil, 72mg,1.8mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 1 hour, then additional methyl iodide (514mg,3.6mmol) was added and the temperature was raised to 80 ℃ and stirring continued for 1 hour. After completion of the reaction, the reaction solution was poured into 50mL of water, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to obtain 5-3(80mg, yield 73%) as a yellow solid.

MS(ESI,pos.ion)m/z:305.1[M+H]⁺。

And step 3: synthesis of Compound 5-4

Compound 5-3(50mg, 0.16mmol) was dissolved in glacial acetic acid (20mL), and iron powder (46mg, 0.82mmol) was added thereto, and the reaction mixture was warmed to 110 ℃ for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was poured into 1N hydrochloric acid (50mL) to precipitate a solid, which was then filtered, and the filter cake was washed with water and then dried to obtain 5-4(38mg, yield 98%) as a yellow solid.

MS(ESI,pos.ion)m/z:243.1[M+H]⁺。

And 4, step 4: synthesis of Compounds 5-5

Compound 5-4(50mg,0.21mmol) was added to toluene (20mL) and POCl was slowly added with stirring₃(100mg,0.63mmol) and N, N-dimethylaniline (14mg,0.11mmol), and after the completion of the addition, the reaction was refluxed at elevated temperature for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 5-5(40mg, yield 73%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:261.1[M+H]⁺。

Step 6: synthesis of Compounds 5-6

The compound N-Boc-4- (R) -hydroxyproline (53mg,0.23mmol) was dissolved in DMF (10mL), NaH (60% dispersed in mineral oil, 23mg,0.6mmol) was added under ice-bath, and after completion of addition, the reaction was warmed to room temperature and stirred for 2 h.

Compound 5-5(50mg,0.19mmol) was dissolved in a small amount of DMF and added to the above reaction and stirring was continued for 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2 to 3 with 1n hcl solution, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 5 to 6(45mg, yield 43%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:456.3[M+H]⁺。

And 7: synthesis of Compounds 5-7

Compounds 5-6(50mg,0.11mmol), compounds 1-9(44mg,0.11mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to CH₂Cl₂To (15mL), DIPEA (48mg,0.37mmol) was added under ice bath, and after the addition, the reaction was warmed to room temperature and stirred for 4 hours, after the reaction was completed, the pH of the reaction solution was adjusted to 2 with 1N aqueous hydrochloric acid, followed by extraction with dichloromethane (10mL × 2), and the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1), to obtain compound 5-7(42mg, yield 63%) as a pale yellow solid.

And 8: synthesis of Compounds 5-9

Compound 5-7(100mg,0.15mmol) was dissolved in 5N HCl in ethyl acetate (30mL), and the reaction was stirred at room temperature for 2 hours. After the reaction is finished, the solvent is evaporated under reduced pressure to obtain a compound 5-8. Compounds 5-8 were then added to 50mLCH₂Cl₂To this mixture were added compounds 2-11(72mg,0.16mmol), EDCI (46mg,0.24mmol) and HOAT (33mg,0.24mmol), and then DIPEA (12mg,0.48mmol) was added under ice-cooling, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (V: V)) 2:1) to give compounds 5-9(95mg, two-step yield 77%) as pale yellow solids.

And step 9: synthesis of Compounds 5-10

The compound 5-9(200mg,0.24mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs second generation catalyst (30mg) was added under nitrogen, and the reaction was warmed to 75 ℃ for 48 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure, and the crude product was purified by preparative HPLC to give 5-10(150mg, yield 78%) as a white solid.

MS(ESI,pos.ion)m/z:793.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.30(s,1H),7.39(s,1H),7.16–7.05(m,3H),6.96(d,J＝7.8Hz,1H),6.68(d,J＝10.0Hz,2H),5.89(d,J＝41.8Hz,1H),5.73(d,J＝8.3Hz,1H),5.36-5.19(m,1H),5.01(d,J＝9.4Hz,1H),4.63(d,J＝55.8Hz,2H),4.42-4.32(m,1H),4.10-4.03(m,1H),3.22(s,3H),2.91(d,J＝16.2Hz,1H),2.61(s,3H),2.35(s,1H),1.88(d,J＝52.8Hz,4H),1.62(s,1H),1.36(m,17H),1.13(d,J＝32.7Hz,2H),0.94(s,2H)ppm；

HPLC:96.72％。

Example 6

The synthetic route is as follows:

step 1: synthesis of Compound 6-2

The compound 4-bromo-2-fluorobenzaldehyde (15.0g,74mmol) was dissolved in acetonitrile (30mL) and NaH was added slowly in sequence under ice bath₂PO₄Solution (1.78g,15mmol in 10mL water), H₂O₂(11.8mL,104mmol) and NaClO₂(9.37g,104mol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was poured into 500mL of water, and a large amount of solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain Compound 6-2(15.2g, yield 93%) as a white solid.

Step 2: synthesis of Compound 6-3

Compound 6-2(6.6g,30mmol) was dissolved in thionyl chloride (15mL) and the reaction was refluxed under nitrogen for 2 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure. The resulting residue was dissolved in 30mL of toluene, and toluene was removed under reduced pressure, and the reaction was repeated twice to obtain compound 6-3 as a yellow oily liquid, which was directly subjected to the next reaction without purification.

And step 3: synthesis of Compounds 6-5

2-Aminothiophenol (5.6g,45mmol) was dissolved in 40mL THF, triethylamine (6.0g,60mmol) and a solution of compound 6-3(7.1g,30mmol) in THF (20mL) were added slowly over an ice bath, and after addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. After the reaction is finished, pouring the reaction liquid into 100mL of water, adjusting the pH value of the reaction liquid to be about 4-5 by using 1N HCl, precipitating yellow solid, filtering, washing a filter cake by using 1N HCl aqueous solution and water in sequence, and drying the obtained solid in vacuum to obtain light yellow solid compound 6-5(7.3g, the yield of the two steps of the step 1 and the step 2 is 75%).

And 4, step 4: synthesis of Compound 6-6

Compound 6-5(5.2g,16mmol) was dissolved in DMF (200mL) and K was added thereto₂CO₃(11g,80mmol) and the reaction mixture refluxed for 5 hours. After the reaction was completed, the reaction mixture was poured into 500mL of water, a yellow solid precipitated, filtered, the filter cake was washed with 50 mL of 1N NaOH aqueous solution and 50 mL of water in this order, and the resulting solid was dried under vacuum to obtainCompound 6-6(3.6g, 74% yield) was a pale yellow solid.

MS(ESI,pos.ion)m/z:305.9[M+H]⁺。

And 5: synthesis of Compounds 6-7

Compound 6-6(2.5g,8mmol) was suspended in toluene (30mL) and POCl was added slowly with stirring₃(2.5g,16mmol) and N, N-dimethylaniline (0.4g,3mmol) were added and the reaction mixture was refluxed at elevated temperature for 3 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether) to obtain compound 6-7(1.5g, yield 57%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:325.9[M+H]⁺。

Step 6: synthesis of Compounds 6-8

The compound N-Boc-4- (R) -hydroxyproline methyl ester (1.3g,5.3mmol) was dissolved in DMF (50mL) and NaH (60% dispersed in mineral oil, 0.37g,9.2mmol) was added portionwise in ice bath and after addition the reaction mixture warmed to room temperature and stirred for 30 min.

Compound 6-7(1.56g,4.8mmol) was dissolved in a small amount of DMF, the resulting solution was added to the above solution, the reaction mixture was stirred for 2 hours, after the reaction was completed, the reaction solution was poured into 300mL of water, pH was adjusted to 2-3 with 1NHCl aqueous solution, and then extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain light yellow solid compound 6-8(1.0g, yield 42%). MS (ESI, neg.ion) M/z:516.9[ M-h.ion) M/z:516.9[ M-h.]^-。

And 7: synthesis of Compounds 6-9

Compounds 6-8(1.0g,1.9mmol), compounds 1-9(0.8g,1.9mmol), EDCI (0.5g,2.5mmol) and HOAT (0.3g,2.1mmol) were added to CH₂Cl₂(30mL), DIPEA (0.9mL,5.0mmol) was added under ice-cooling, and after the addition, the reaction was raised to room temperature After completion of the reaction, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 6-9(1.1g, yield 78%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:731.0[M+H]⁺。

And 8: synthesis of Compounds 6-11

Compound 6-9(850mg,1.16mmol) was added to a solution of 5N HCl in EtOAc (30mL) and the reaction stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain 6-10 as a white solid compound. Compounds 6-10 were then added to 30mLCH₂Cl₂To this mixture were added compounds 2-11(578mg,1.28mmol), EDCI (290mg,1.51mmol) and HOAT (170mg,1.28mmol), followed by DIPEA (0.6mL,3.48mmol) under ice-cooling, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to give compound 6-11(220mg, yield 22%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:629.1[M-H]^-。

And step 9: synthesis of Compounds 6-12

Compound 6-11(220mg,0.25mmol) was dissolved in 1, 2-dichloroethane (200mL), Grubbs second generation catalyst (20mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 6-12(40mg, yield: 19%) as a white solid.

MS(ESI,pos.ion)m/z:856.8[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.31(s,1H),7.65(s,1H),7.48–7.36(m,3H),7.31(d,J＝7.3Hz,1H),7.21(d,J＝7.6Hz,1H),7.15–7.02(m,1H),5.93(s,1H),5.80–5.58(m,1H),5.21(d,J＝7.0Hz,1H),5.00(t,J＝9.2Hz,1H),4.62(t,J＝7.5Hz,2H),4.37(t,J＝7.5Hz,1H),4.05(d,J＝8.0Hz,1H),2.92(s,1H),2.72–2.52(m,3H),2.35–2.28(m,1H),1.95–1.82(m,6H),1.65–1.22(m,15H),1.17–1.08(m,2H),0.97–0.85(m,2H)ppm。

Example 7

Synthetic route

Step 1: synthesis of Compound 7-3

The compounds 4-bromo-2-fluoronitrobenzene (3.30g,15mmol), 4-methoxyphenylboronic acid (2.74g,18mmol) and Pd (PPh)₃)₄(0.5g,0.45mmol) and K₂CO₃(10.35g,75mmol) was dissolved in a mixed solvent of THF (80mL) and water (20mL) and the reaction mixture was stirred overnight at room temperature under nitrogen after the reaction was complete, saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give compound 7-3 as a yellow solid (3.2g, 87% yield).

MS(ESI,pos.ion)m/z:248.2[M+H]⁺。

Step 2: synthesis of Compound 7-5

Compound 7-3(2.8g,11.3mmol), compound 7-5(1.9g,12.5mmol) were dissolved in DMF (50mL) and addedK₂CO₃(3.1g,22.6mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding 100 mL of water to quench the reaction after the reaction is finished, adjusting the pH value to 2-3 by using 1N HCl aqueous solution, extracting by using ethyl acetate (50mL × 3), washing combined organic phases by using saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, and evaporating the organic solvent under reduced pressure to obtain an orange oily liquid compound 7-5, wherein the next reaction is directly carried out without further purification.

MS(ESI,pos.ion)m/z:382.1[M+H]⁺。

And step 3: synthesis of Compound 7-6

Compound 7-5 was dissolved in glacial acetic acid (300mL) and iron powder (2.8g, 56.5mmol) was added and the reaction mixture was warmed to 110 ℃ for 8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, then filtered, the filtrate was concentrated and poured into 300mL of water, and a solid precipitated, filtered, and the filter cake was washed with water and then dried to obtain compound 7-6(3.6g, yield 95% in step 2 and step 3) as a yellow solid.

MS(ESI,pos.ion)m/z:334.1[M+H]⁺。

And 4, step 4: synthesis of Compounds 7-7

Compound 7-6((3.5g,10.5mmol) was dissolved in toluene (30mL) and POCl was added slowly with stirring₃(3.2g,21mmol) and N, N-dimethylaniline (0.51g,4.2mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 7-7(1.2g, yield 33%) as a pale yellow solid.

And 5: synthesis of Compounds 7-8

The compound N-Boc-4- (R) -hydroxyproline (0.87g,3.75mmol) was dissolved in DMF (20mL), NaH (60% dispersed in mineral oil, 0.30g,7.5mmol) was added portionwise in ice bath and after addition the reaction mixture warmed to room temperature and stirred for 30 min. Compound 7-7(1.2g,3.42mmol) was dissolved in a small amount of DMF and the resulting solution was added to the above reaction solution and stirring was continued for 2 hours. After the reaction, the reaction solution was poured into 300mL of water, the pH was adjusted to 2-3 with 1N HCl aqueous solution, followed by extraction with ethyl acetate (50 mL. times.3), the organic phases were combined,

The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compounds 7 to 8(1.7g, yield 83%) as pale yellow solids.

MS(ESI,neg.ion)m/z:547.2[M+H]^-。

Step 6: synthesis of Compounds 7-9

Compound 7-8(1.2g,2.2mmol), compound 1-9(0.97g,2.4mmol), EDCI (546mg,2.9mmol) and HOAT (324mg,2.4mmol) were suspended in CH₂Cl₂To (30mL), DIPEA (1.0mL,5.7mmol) was added under ice bath, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 4 hours, after the completion of the reaction, 5mL of 1N aqueous hydrochloric acid solution was added to quench the reaction, followed by extraction with ethyl acetate (10mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 7-9(1.2g, yield 72%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:759.2[M+H]⁺。

And 7: synthesis of Compounds 7-11

Compounds 7-9(600mg,0.8mmol) were dissolved in 5N HCl in EtOAc (15mL) and the reaction was stirred at room temperature for 3 h.

After the reaction, the solvent was distilled off under reduced pressure to obtain 7-10 as a white solid compound.

Adding Compounds 7-10 to CH₂Cl₂(20mL), then compound 2-11(434mg,0.96mmol), EDCI (200mg,1.04mmol) and HOAT (120mg,0.88 mmol) were added, DIPEA (0.22mL,1.28mmol) was added under ice bath, and the reaction mixture was raised to litersStir at room temperature for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to give light yellow solid compounds 7 to 11(410mg, yield 57%).

MS(ESI,pos.ion)m/z:912.2[M+H]⁺。

And 8: synthesis of Compounds 7-12

Compound 7-11(400mg,0.44mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs second generation catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to give compound 7-12(110mg, yield 28%) as a white solid.

MS(ESI,pos.ion)m/z:884.2[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.32(s,1H),7.66(d,J＝2.0Hz,1H),7.54–7.44(m,5H),7.43–7.34(m,J＝10.7,4.4Hz,1H),7.31–7.25(m,2H),6.97(d,J＝8.8Hz,2H),5.98(s,1H),5.74(dd,J＝18.0,8.7Hz,1H),5.26(s,1H),5.01(t,1H),4.82–4.52(m,2H),4.41(t,J＝7.5Hz,1H),4.14–4.03(m,1H),3.86(s,3H),2.98–2.88(m,1H),2.73–2.51(m,3H),2.42–2.26(m,1H),1.98–1.75(m,6H),1.61–1.31(m,15H),1.18–1.08(m,2H),1.00–0.85(m,2H)ppm。

Example 8

The synthetic route is as follows:

step 1: synthesis of Compound 8-2

Compound 8-1(2.3g,7.2mmol) was added to 50mL of toluene, phosphorus oxychloride (1.32mL,14.4mmol) was added under nitrogen, then N, N-dimethylaniline (0.36mL,2.88mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 ℃, quenched with 10mL water, the resulting mixture washed with water (30mL × 2), the separated organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to give compound 8-2, which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 8-3

Sodium hydride (0.58g,14.4mmol) was added to 40 ml of anhydrous tetrahydrofuran, cooled to 0 ℃ under nitrogen, then 10ml of anhydrous tetrahydrofuran solution containing compound 2-7(0.24g,1.0mmol) was added, and after the addition, the reaction mixture was warmed to 30 ℃ and stirred for two hours.

A10 ml anhydrous tetrahydrofuran solution containing compound 8-2(2.4g,7.2mmol) was added to the above reaction solution, followed by reaction overnight. After completion of the reaction, the reaction was quenched with 30 ml of water at 0 ℃ and washed with 20ml of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 8-4(1.2g, yield 31%) as a white solid.

¹HNMR(600MHz,CDCl₃):7.57(dd,J＝16.5,8.5Hz,3H),7.47–37(m,2H),7.26–7.05(m,4H),6.95(m,2H),5.81(s,1H),4.07–3.94(m,2H),3.95(s,3H),2.68–2.72(m,2H),1.61–1.36(m,9H)ppm。

And step 3: synthesis of Compound 8-4

Compound 8-3(0.94g,1.8mmol), compound 1-9(0.78g,1.95mmol), EDCI (0.44g,2.3mmol) and HOAT (0.26g,1.95mmol) were charged into a round bottom flask, 15 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (1.08mL,6.2mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, followed by extraction with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 8-4(0.85g, yield 65%) as a yellow solid.

¹HNMR(600MHz,CDCl₃):10.24–10.01(m,1H),7.56(d,J＝8.5Hz,3H),7.50–7.34(m,2H),7.30–7.12(m,4H),7.01(d,J＝8.6Hz,2H),5.96–5.75(m,2H),5.35(t,J＝19.5Hz,1H),5.26–5.04(m,1H),4.37(s,1H),3.98–3.81(m,4H),2.98(s,1H),2.57(d,J＝17.4Hz,2H),2.28–2.13(m,1H),1.99(d,J＝37.9Hz,1H),1.47(d,J＝29.9Hz,9H),1.42–1.31(m,2H),1.12–0.96(m,2H)ppm。

And 4, step 4: synthesis of Compounds 8-5

Compound 8-4(1.06g,1.5mmol) was dissolved in 5mL of ethyl acetate, cooled to 0 deg.C, and then a 30% strength solution of hydrochloric acid in ethyl acetate (20 mL) was added and stirred at room temperature until no gas was evolved. The reaction mixture was filtered and the filter cake was washed with 10ml of ethyl acetate to give compound 8-5 as a white solid which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:643.2[M+H]⁺；

¹HNMR(400MHz,CD₃OD):7.75(dd,J＝8.0,5.8Hz,1H),7.65(d,J＝8.8Hz,2H),7.58–7.47(m,2H),7.30–7.15(m,4H),7.05(d,J＝8.8Hz,2H),5.94(s,1H),5.77–5.63(m,1H),5.36(d,J＝17.0Hz,1H),5.19(d,J＝10.4Hz,1H),4.66(d,J＝7.5Hz,1H),3.87(s,4H),3.05–2.92(m,2H),2.48–2.28(m,2H),2.06–1.95(m,2H),1.42(dd,J＝9.6,5.6Hz,1H),1.35–1.26(m,2H),1.26–1.03(m,3H)ppm。

And 5: synthesis of Compounds 8-6

Compounds 8-5(0.48g,0.72mmol), compounds 2-11(0.42g,0.93mmol), EDCI (0.18g,0.93mmol) and HOAT (0.13g,0.93mmol) were charged to a round bottom flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.5mL,2.86mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 6 hours. The reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with 10mL of saturated brine, then dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 8-6(0.35g, yield 54%) as a white solid.

Step 6: synthesis of Compounds 8-7

The compound 8-6(0.31g, 0.35mmol) was dissolved in 100ml of 1, 2-dichloroethane, 0.03 g of Grubbs second generation catalyst was added under nitrogen, and then the temperature was raised to 65 ℃ and stirred at this temperature for 48 hours. Cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compounds 8 to 7(0.1g, yield: 33%) as white solids.

MS(ESI,pos.ion)m/z:868.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.33(s,1H),7.55–7.48(m,3H),7.39–7.28(m,3H),7.23–7.06(m,3H),7.00(d,J＝8.2Hz,2H),5.99(s,1H),5.73(dd,J＝18.1,8.7Hz,1H),5.24(d,J＝7.2Hz,1H),5.05–4.96(m,1H),4.61–4.562(m,2H),4.38–4.10(t,J＝7.7Hz,1H),4.10(dd,J＝20.4,8.5Hz,1H),3.86(d,J＝11.2Hz,3H),3.00–2.86(m,1H),2.66(s,2H),2.57(s,1H),2.34(m,2H),2.04–1.84(m,6H),1.74-1.51(m,1H),1.41–1.28(m,12H),1.20–1.04(m,3H),0.94(pd,J＝13.6,8.4Hz,2H)ppm。

Example 9

The synthetic route is as follows:

step 1: synthesis of Compound 9-3

Compound 9-1(50mg,0.29mmol), compound 2-2(50mg,0.35mmol) were dissolved in DMF (20mL), and K was added thereto₂CO₃(60mg,0.44mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding 20mL of water to quench the reaction after the reaction is finished, extracting with ethyl acetate (20mL × 3), combining organic phases, washing the organic phases with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain an orange oily liquid compound 9-3, wherein the next reaction is directly carried out without purification.

MS(ESI,pos.ion)m/z:292.1[M+H]⁺。

Step 2: synthesis of Compound 9-4

Compound 9-3(1g, 3.4mmol) was dissolved in glacial acetic acid (50mL), and iron powder (0.96g, 17.2mmol) was added thereto, and the temperature was raised to 110 ℃ for reaction for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the obtained filtrate was poured into 100mL of 1N aqueous hydrochloric acid solution, and a solid precipitated, filtered, and the filter cake was washed with water and then dried to obtain compound 9-4(0.6g, 77% yield in steps 1 and 2) as a yellow solid.

And step 3: synthesis of Compounds 9-5

Compound 9-4(50mg,0.22mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring₃(100mg,0.66mmol) and N, N-dimethylaniline (13mg,0.11mmol),after the addition, the reaction was heated and refluxed for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 9-5(42mg, yield 77%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:248.1[M+H]⁺。

And 4, step 4: synthesis of Compounds 9-6

The compound N-Boc-4- (R) -hydroxyproline (60mg,0.24mmol) was dissolved in DMF (10mL), NaH (60%, 25mg,0.6mmol) was added under ice bath, and after completion of addition, the reaction was warmed to room temperature and stirred for 2 hours. Compound 2-7(60mg,0.24mmol) was dissolved in a small amount of DMF and added to the above reaction solution and stirring was continued for 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2-3 with 1n hcl aqueous solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 9-6(93mg, yield 87%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:342.2[M-99]⁺。

And 5: synthesis of Compounds 9-7

Compound 9-6(50mg,0.11mmol), compound 1-9(45mg,0.11mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were suspended in CH₂Cl₂To (15mL) was added DIPEA (48mg,0.37mmol) under ice bath, and after completion of the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, after completion of the reaction, the pH of the reaction mixture was adjusted to 2 with 1N hydrochloric acid aqueous solution, extracted with dichloromethane (10mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried by rotary evaporation under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compounds 9 to 7(588mg, yield 82%) as pale yellow solids.

MS(ESI,pos.ion)m/z:655.2[M+H]⁺。

Step 6: synthesis of Compounds 9-9

Compounds 9-7(1.15g,1.8mmol) were dissolved in 5N HCl in EtOAc (30mL) and stirred at room temperature for 2 h. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is taken up in CH₂Cl₂After dilution (50mL), compounds 2-11(814mg,1.8mmol), EDCI (546mg,2.85mmol) and HOAT (388mg,2.85mmol) were added, DIPEA (924mg,7.15mmol) was added under ice bath, and the reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compounds 9 to 9(726mg, yield in two steps of step 5 and step 6) as pale yellow solids.

MS(ESI,pos.ion)m/z:808.3[M+H]⁺。

And 7: synthesis of Compounds 9-10

Compound 9-9(230mg,0.28mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs's second generation catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 75 ℃ for 48 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give compound 9-10(160mg, yield 73%) as a white solid.

MS(ESI,pos.ion)m/z:780.3079[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.36(s,1H),7.56(d,J＝6.6Hz,1H),7.26–7.10(m,4H),6.88(dd,J＝33.8,7.3Hz,2H),5.92(s,1H),5.72(dd,J＝17.5,8.6Hz,1H),5.32–5.24(m,1H),5.00(t,J＝9.3Hz,1H),4.77–4.46(m,2H),4.35(t,J＝7.7Hz,1H),4.07(dd,J＝48.2,10.0Hz,1H),2.92(s,1H),2.73–2.49(m,3H),2.34(d,J＝8.1Hz,1H),1.98–1.75(m,4H),1.58(s,1H),1.51–1.27(m,18H),1.19–1.05(m,2H),0.98–0.89(m,1H)ppm；

HPLC:97.52％。

Example 10

The synthetic route is as follows:

step 1: synthesis of Compound 10-3

The compounds penta-4-bromo-2-fluoronitrobenzene (1.10g,5mmol), 4-fluorobenzeneboronic acid (0.84g,6mmol) and Pd (PPh)₃)₄(0.58g,0.5mmol) and K₂CO₃(3.45g,25mmol) was added to a mixed solvent of THF (30mL) and water (5mL), and the reaction mixture was refluxed overnight under nitrogen protection after the reaction was completed, a saturated sodium chloride solution (100mL) was added to quench the reaction, extraction was performed with ethyl acetate (3 × 50mL), the organic phases were combined, and then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was evaporated under reduced pressure to give compound 10-3(1.0g, yield 85%) as a yellow solid.

Step 2: synthesis of Compound 10-5

Compound 10-3(1.0g,4.3mmol), 10-4(0.65g,4.3mmol) was dissolved in DMF (20mL), and K was added thereto ₂CO₃(1.19g,8.6mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding 20mL of water to quench the reaction after the reaction is finished, extracting with ethyl acetate (50mL × 3), combining organic phases, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain an orange oily liquid compound 10-5 which is directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:368.1[M+H]⁺。

And step 3: synthesis of Compound 10-6

Compound 10-5 was dissolved in glacial acetic acid (50mL), iron powder (1.12g, 20mmol) was added, and the reaction was allowed to warm to 110 ℃ for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was poured into water (150mL) to precipitate a solid, filtered, and the cake was washed with water and dried to obtain compound 10-6(1.1g, yield in step 2 and step 3 was 84%) as a yellow solid.

MS(ESI,pos.ion)m/z:306.1[M+H]⁺。

And 4, step 4: synthesis of Compound 10-7

Compound 10-6(1.0g,3.3mmol) was dissolved in toluene (20mL) and POCl was slowly added with stirring₃(1.0g,6.6mmol) and N, N-dimethylaniline (0.16g,1.3mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 10-7(0.68g, yield 64%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:324.1[M+H]⁺。

And 5: synthesis of Compound 10-8

The compound N-Boc-4- (R) -hydroxyproline (0.58g,2.5mmol) was dissolved in DMF (15mL) and NaH (60% dispersed in mineral oil, 0.25g,6.3mmol) was added in portions under ice-bath and after the addition was complete the reaction warmed to room temperature and stirred for 30 min. Compound 10-7(0.68g,2.1mmol) was dissolved in a small amount of DMF and added to the above reaction solution, and the reaction was stirred for an additional 12 hours. After completion of the reaction, the reaction solution was poured into 100mL of water, the pH was adjusted to 2-3 with 1n hcl aqueous solution, followed by extraction with ethyl acetate (50mL × 3), organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 10-8(0.90g, yield 83%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:519.1[M+H]⁺。

Step 6: synthesis of Compound 10-9

Compound 10-8(900mg,1.74mmol, compound 1-9(768mg,1.91mmol), EDCI (432mg,2.26mmol) and HOAT (258mg,1.91mmol) were added to CH₂Cl₂DIPEA (0.8mL,4.52mmol) was added to (20mL) under ice-cooling, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was dried under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 10-9(1.0g, yield 79%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:731.2[M+H]⁺。

And 7: synthesis of Compounds 10-11

Compound 10-9(1.0g,1.37mmol) was dissolved in 5N HCl in ethyl acetate (20mL), and the reaction was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain a white solid compound 10-10. The obtained solid compound 10-10 is treated with CH₂Cl₂After dilution (20mL), compounds 2-11(610mg,1.35mmol), EDCI (278mg,1.46mmol) and HOAT (182mg,1.35 mmol) were added, DIPEA (0.6mL,3.36mmol) was added under ice bath, and after addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 10-11(660mg, yield 54%) as a pale yellow solid.

And 8: synthesis of Compounds 10-12

Compound 10-11(600mg,0.68mmol) was dissolved in 1, 2-dichloroethane (500mL), Grubbs' second generation catalyst (80mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure, and the crude product was purified by preparative HPLC to give compound 10-12 as a white solid (400mg, yield 68%).

HRMS(ESI,pos.ion)m/z:856.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.36(s,1H),7.66–7.40(m,4H),7.39–7.26(m,3H),7.24–7.18(m,1H),7.14(d,J＝9.0Hz,3H),5.95(s,1H),5.73(d,J＝8.4Hz,1H),5.30(d,J＝6.3Hz,1H),5.01(t,J＝9.1Hz,1H),4.78–4.47(m,2H),4.38(s,1H),4.13–3.98(m,1H),2.93(s,1H),2.77–2.49(m,3H),2.42–2.29(m,1H),2.04–1.75(m,4H),1.60(s,1H),1.51–1.26(m,16H),1.22–1.06(m,2H),1.06–0.72(m,2H)ppm。

Example 11

The synthetic route is as follows:

step 1: synthesis of Compound 11-3

The compounds 4-bromo-2-fluoronitrobenzene (3.30g,15mmol), 4-methoxyphenylboronic acid (2.74g,18mmol) and Pd (PPh) ₃)₄(0.5g,0.45mmol) and K₂CO₃(10.35g,75mmol) was dissolved in a mixed solvent of THF (80mL) and water (20mL) and the reaction mixture was stirred at room temperature overnight under nitrogen, after completion of the reaction, a saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give compound 11-3 as a yellow solid (3.2g, yield 87%).

MS(ESI,pos.ion)m/z:248.2[M+H]⁺。

Step 2: synthesis of Compound 11-5

Compound 11-3(1.83g,7.4mmol), compound 11-4(1.13g,7.4mmol) were dissolved in DMF (20mL), and K was added thereto₂CO₃(1.12g,8.1mmol), heating the reaction mixture to 110 deg.C for reactionAnd after the reaction is finished, adding 20mL of water to quench the reaction, adjusting the pH value to 2-3 by using 1N HCl aqueous solution, extracting by using ethyl acetate (50mL × 3), combining organic phases, washing the combined organic phases by using saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, and evaporating the organic solvent under reduced pressure to obtain an orange oily liquid compound 11-5, wherein the next reaction is directly carried out without purification.

MS(ESI,pos.ion)m/z:380.1[M+H]⁺。

And step 3: synthesis of Compounds 11-6:

the crude product of compound 11-5 was dissolved in glacial acetic acid (100mL), and then iron powder (2.1g, 37mmol) was added, and the reaction was warmed to 110 ℃ for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was poured into water (200mL) to precipitate a solid, the filtrate was filtered, and the cake was washed with water and then dried to obtain compound 11-6(1.57g, yield 67% in step 2 and step 3) as a yellow solid

MS(ESI,pos.ion)m/z:318.1[M+H]⁺。

And 4, step 4: synthesis of Compounds 11-7

Compound 11-6(1.4g,4.4mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring₃(1.3g,8.8mmol) and N, N-dimethylaniline (0.21g,1.8mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 11-7(1.04g, yield 66%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:336.0[M+H]⁺。

And 5: synthesis of Compounds 11-8

The compound N-Boc-4- (R) -hydroxyproline (0.76g,3.29mmol) was dissolved in DMF (20mL) and NaH (60% dispersed in mineral oil, 0.35g,8.94mmol) was added portionwise in ice bath and after addition the reaction mixture warmed to room temperature and stirred for 30 min. Compound 11-7(1.0g,2.98mmol) was dissolved in a small amount of DMF and added to the above reaction, followed by stirring for an additional 2 hours. After completion of the reaction, the reaction solution was poured into 30mL of water, the pH was adjusted to 2 to 3 with 1n aqueous hcl, extraction was performed with ethyl acetate (50mL × 3), organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 11 to 8(1.5g, yield 95%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:531.1[M+H]⁺。

Step 6: synthesis of Compounds 11-9

Compound 11-8(530mg,1.0mmol), compound 1-9(442mg,1.1mmol), EDCI (248mg,1.3mmol) and HOAT (150mg,1.1mmol) were suspended in CH₂Cl₂DIPEA (0.6mL,2.6mmol) was added to (15mL) under ice-cooling, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 11-9(670mg, yield 90%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:743.2[M+H]⁺。

And 7: synthesis of Compounds 11-11

Compound 11-9(670mg,0.90mmol) was dissolved in 5N HCl in ethyl acetate (15mL), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue is taken up in that CH₂Cl₂(15mL) was diluted and then compound 2-11(488mg,1.08mmol), EDCI (223mg,1.17mmol) and HOAT (146mg,1.08 mmol) were added, DIPEA (0.47mL,2.70mmol) was added under ice bath, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain compound 11-11(320mg, yield 40%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:896.3[M+H]⁺。

And 8: synthesis of Compounds 11-12

Compound 11-11(300mg,0.34mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs second generation catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 11-12(100mg, yield 34%) as a white solid.

MS(ESI,pos.ion)m/z:868.4[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.34(s,1H),7.61–7.53(m,2H),7.51–7.41(m,1H),7.40–7.32(m,2H),7.30–7.28(m,1H),7.21(d,J＝7.9Hz,1H),7.19–7.06(m,2H),6.98(d,J＝8.7Hz,2H),5.97(s,1H),5.74(dd,J＝18.1,8.7Hz,1H),5.35–5.14(m,1H),5.10–4.95(m,1H),4.87–4.45(m,2H),4.38(t,J＝7.7Hz,1H),4.06(d,J＝11.6Hz,1H),3.87(s,3H),3.01–2.80(m,1H),2.76–2.45(m,3H),2.35(q,J＝8.6Hz,1H),2.02–1.76(m,6H),1.72–1.23(m,15H),1.18–1.06(m,2H),0.98–0.86(m,2H)ppm；

HPLC purity: 95.35 percent.

Example 12

The synthetic route is as follows:

step 1: synthesis of Compound 12-3

The compounds 5-bromo-2-fluoronitrobenzene (1.0g,4.5mmol), 4-methoxyphenylboronic acid (0.75g,5.4mmol) and Pd (PPh)₃)₄(0.52g,0.45mmol) and K₂CO₃(1.24g,9mmol) in THF (24mL) and water (6mL)After the reaction was completed, a saturated sodium chloride solution (20mL) was added to quench the reaction, and extraction was performed with ethyl acetate (3 × 10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to obtain compound 12-3(0.8g, yield 72%) as a yellow solid.

¹HNMR(600MHz,CDCl₃):8.24(dd,J＝6.9,2.0Hz,1H),7.88–7.77(m,1H),7.63–7.51(m,2H),7.45–7.32(m,1H),7.25–7.16(m,2H),3.83(s,3H)ppm。

Step 2: synthesis of Compounds 12-5

Compound 12-3(1.16g,7.6mmol) and compound 12-4(2.0g,8.0mmol) were dissolved in DMF (30mL) and K was added ₂CO₃(1.58g,11.43mmol), heating to 140 ℃ for overnight reaction, after the reaction is finished, adding 30mL of water for quenching, extracting with ethyl acetate (10mL × 3), combining organic phases, washing the combined organic phases with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying the obtained residue by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to obtain 12-5(2.37g, yield 81.3%). MS (ESI, pos.ion) M/z 380.1[ M + H.ion ] M/z]⁺；

¹HNMR(600MHz,CDCl₃):8.17(t,J＝19.4Hz,1H),8.03(dd,J＝7.8,1.3Hz,1H),7.63(dd,J＝8.7,2.3Hz,1H),7.58(td,J＝8.2,1.6Hz,1H),7.53–7.48(m,2H),7.33(t,J＝7.6Hz,1H),7.16(d,J＝8.2Hz,1H),7.00(d,J＝8.7Hz,2H),6.88(d,J＝8.7Hz,1H),3.87(d,J＝6.6Hz,3H),3.80(s,3H)ppm。

And step 3: synthesis of Compounds 12-6

Compound 12-5(2.5g,8.9mmol) was dissolved in glacial acetic acid (60mL) and iron powder (2.0g, 35.6mmol) was added to it and the reaction mixture was warmed to 110 ℃ for 8 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was poured into water (200mL) to precipitate a solid, filtered, and the cake was washed with water and dried to obtain 12-6(1.77g, yield: 62%) as a white solid.

MS(ESI,pos.ion)m/z:318.1[M+H]⁺；

¹HNMR(600MHz,DMSO-d₆):10.57(s,1H),7.79(dd,J＝7.7,1.6Hz,1H),7.63(td,J＝8.1,1.7Hz,1H),7.52(dd,J＝14.9,8.0Hz,2H),7.38(dd,J＝8.4,6.0Hz,4H),7.35-7.31(m,1H),7.01(t,J＝11.1Hz,2H),3.82-3.77(m,3H)ppm。

And 4, step 4: synthesis of Compounds 12-7

Compound 12-6(1.77g,5.5mmol) was added to 30mL of toluene, phosphorus oxychloride (1mL,11mmol) was added under nitrogen, then N, N-dimethylaniline (0.28mL,2.2mmol) was slowly added, the reaction was warmed to 110 ℃ and reacted for 6 hours. And (3) detecting the reaction by TLC, cooling to 0 ℃ after the reaction is completed, adding 10mL of water to quench the reaction, washing twice with 20 mL of water, washing the organic phase with 20 mL of saturated saline solution, drying with anhydrous sodium sulfate, and removing the organic solvent under reduced pressure to obtain a crude product, wherein the crude product is directly subjected to the next reaction without further purification.

Sodium hydride (60% in mineral oil, 0.44g,11mmol) was added to 30 ml of anhydrous DMF and cooled to 0 ℃ under nitrogen, then 5 ml of anhydrous DMF solution of compounds 2-7(1.27g,5.5mmol) was added and after addition the reaction mixture was warmed to 30 ℃ and stirred for two hours. The crude product obtained above was dissolved in 5 ml of anhydrous DMF, and then added to the above reaction solution, after which the reaction was continued to stir overnight. The reaction was quenched with 10ml of water at 0 ℃ and washed with 10ml of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 12-7 as a yellow solid (1.48g, yield 47%).

MS(ESI,pos.ion)m/z:531.2[M+H]⁺。

And 5: synthesis of Compounds 12-8

Compounds 12-7(0.7g,1.32mmol), compounds 1-9(0.58g,1.45mmol), EDCI (0.28g,1.45mmol) and HOAT (0.26g,1.45mmol) were charged into a round bottom flask, nitrogen blanketed, 10mL of dichloromethane added, then cooled to 0 deg.C and DIPEA (0.92mL,5.28mmol) added. The reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 12-8(0.9g, yield 92%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:743.2[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.11(s,1H),7.55-7.49(m,4H),7.41(s,1H),7.32(dd,J＝8.3,2.1Hz,1H),7.27–7.19(m,3H),7.14(s,1H),6.97(d,J＝8.7Hz,2H),5.90–5.75(m,2H),5.32(d,J＝17.0Hz,1H),5.18(d,J＝10.5Hz,1H),4.35(s,1H),3.87(d,J＝6.3Hz,4H),2.97(s,1H),2.55(d,J＝7.4Hz,2H),2.16–2.14(m,1H),2.04–1.98(m,1H),1.50(s,9H),1.41–1.31(m,2H),1.07(d,J＝7.8Hz,2H)ppm。

Step 6: synthesis of Compounds 12-9

Compound 12-8(0.8g,1.1mmol) was dissolved in 5 ml of ethyl acetate, cooled to 0 ℃ and then a 30% strength solution of hydrochloric acid in ethyl acetate (15 ml) was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. The resulting white solid was filtered and washed with 10ml ethyl acetate to give compound 12-9, which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:643.3[M+H]⁺。

And 7: synthesis of Compounds 12-10

Compounds 12-9(0.72g,1.05mmol), compounds 2-11(0.52g,1.16mmol), EDCI (0.22g,1.16mmol) and HOAT (0.21g,1.16mmol) were charged to a round bottom flask, 8 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.73mL,4.2mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 6 hours. The reaction was quenched with 5 mL of water, followed by extraction with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 12-10(0.37g, yield 40%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:896.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.26(s,1H),7.51(d,J＝7.3Hz,4H),7.40(s,1H),7.32(d,J＝7.9Hz,1H),7.22(t,J＝8.0Hz,3H),6.98(d,J＝7.5Hz,2H),5.98(s,1H),5.80(td,J＝16.4,6.2Hz,2H),5.34(d,J＝18.0Hz,2H),5.17(d,J＝8.4Hz,1H),4.97(dd,J＝23.8,13.6Hz,2H),4.46(s,1H),4.36–4.22(m,1H),4.01(d,J＝26.2Hz,1H),3.85(d,J＝10.4Hz,3H),2.96(s,1H),2.55(s,2H),2.12(d,J＝20.2Hz,2H),2.06(d,J＝5.8Hz,4H),1.74(d,J＝11.7Hz,1H),1.65(s,1H),1.37(d,J＝20.8Hz,15H),1.07(s,2H)ppm。

And 8: synthesis of Compounds 12-11

Compound 12-10(0.37g,0.41mmol) was dissolved in 100 ml of 1, 2-dichloroethane, 0.03 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 75 ℃ and stirred for 24 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compounds 12 to 11(0.2g, yield: 56%) as white solids.

MS(ESI,pos.ion)m/z:868.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.27(s,1H),7.57(d,J＝7.4Hz,1H),7.52(d,J＝8.6Hz,2H),7.48(t,J＝7.8Hz,1H),7.42(d,J＝1.6Hz,1H),7.20(t,J＝7.6Hz2H),7.15(t, J ═ 7.4Hz,1H),6.98(d, J ═ 8.6Hz,2H),6.94(s,1H),5.96(s,1H),5.74(d, J ═ 8.9Hz,1H),5.14(d, J ═ 7.3Hz,1H),5.02(t, J ═ 9.4Hz,1H), 4.67-4.53 (m,2H),4.37(s,1H),4.05(d, J ═ 8.4Hz,1H),3.86(s,3H), 2.99-2.88 (m,1H),2.68(t, J ═ 10.4Hz,2H),2.58(s,1H),2.34(d, J ═ 8.6, 1H), 1H (1H), 1.94 (t, 1H), 1.14H, 1H), 1H, 14.14 (d, 1H), 1H, 7.9, 14(d, 14H), 1H), 1H, 14H, 1H, 14(d, 14H), 3H), 7.9, 14 (m, 14H, 0.99-0.90 (m,1H) ppm; HPLC purity 95.36%.

Example 13

The synthetic route is as follows:

step 1: synthesis of Compound 13-3

Compound 13-1(10g,50mmol), compound 13-2(7.6g,55mmol) were dissolved in DMF (200mL) and K was added thereto ₂CO₃(10.4g,75mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding 200 mL of water to quench the reaction after the reaction is finished, extracting with ethyl acetate (100mL × 3), combining organic phases, washing the combined organic phases with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain an orange oily liquid 13-3, wherein the next reaction is directly carried out without purification.

MS(ESI,pos.ion)m/z:324.1[M+H]⁺。

Step 2: synthesis of Compound 13-4

Compound 13-3(1g, 3.4mmol) was dissolved in glacial acetic acid (50mL) and iron powder (0.96g, 17.2mmol) was added to it and the reaction mixture was warmed to 110 ℃ for 8 h. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was poured into 100mL of 1N aqueous hydrochloric acid to precipitate a solid, which was then filtered, and the filter cake was washed with water and dried to obtain compound 13-4 as a yellow solid (600mg, 67% yield in step 1 and step 2).

And step 3: synthesis of Compound 13-5

Compound 13-4(50mg,0.19mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring₃(88mg,0.57mmol) and N, N-dimethylaniline (12mg,0.09mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 13-5(42mg, yield 79%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:280.0[M+H]⁺。

And 4, step 4: synthesis of Compound 13-6

The compound N-Boc-4- (R) -hydroxyproline (56mg,0.24mmol) was dissolved in DMF (10mL) and NaH (60%, 25mg,0.6mmol) was added under ice bath and after addition the reaction mixture was warmed to room temperature and stirred for 2 h.

Compound 13-5(67mg,0.24mmol) was dissolved in a small amount of DMF and the resulting solution was added to the above solution and the reaction was stirred for an additional 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2-3 with 1N HCl aqueous solution, followed by extraction with ethyl acetate (20 mL. times.3), and the organic phases were combined. The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 13-6(100mg, yield 87%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:475.2[M+H]⁺。

And 5: synthesis of Compound 13-7

Suspending Compound 13-6(50mg,0.11mmol), Compound 1-9(43mg,0.11mmol), EDCI (22mg,0.12mmol) and HOAT (16mg,0.12mmol) in CH₂Cl₂To (15mL), DIPEA (47mg,0.36mmol) was added under ice bath, and after the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, after the reaction was completed, the pH was adjusted to 2 with 1N hydrochloric acid aqueous solution, followed by extraction with dichloromethane (10mL × 3), the organic phases were combined, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 13-7 as a pale yellow solid (68mg, yield 91%).

MS(ESI,pos.ion)m/z:687.2[M+H]⁺。

Step 6: synthesis of Compound 13-9

Compound 13-7(1.18g,1.7mmol) was dissolved in 5N HCl in EtOAc (30mL) and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is diluted in CH₂Cl₂To (50mL) were then added compounds 2-11(768mg,1.7mmol), EDCI (546mg,2.85mmol) and HOAT (388mg,2.85mmol), and under ice-bath, DIPEA (924mg,7.15mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 4 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 13-9(1.09g, two-step yield 76%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:840.3[M+H]⁺。

And 7: synthesis of Compounds 13-10

Compound 13-9(260mg,0.31mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs second generation catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 75 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 13-10(180mg, yield 72%) as a white solid.

HRMS(ESI,pos.ion)m/z:812.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.61-10.40(m,1H),8.07–7.98(m,1H),7.86–7.76(m,2H),7.60–7.35(m,3H),7.25–7.15(m,4H),5.97(s,1H),5.73(d,J＝7.7Hz,1H),5.36–5.32(m,1H),5.00(s,1H),4.75–4.69(m,1H),4.55–4.42(m,2H),4.18–4.12(m,1H),2.94(s,1H),2.70–2.56(m,3H),2.37(s,1H),1.94–1.85(m,3H),1.61(s,1H),1.46–1.10(m,21H),0.94(s,1H)ppm；

HPLC purity: 95.99 percent.

Example 14

The synthetic route is as follows:

step 1: synthesis of Compound 14-2

Compound 14-1(5.0g,22mmol) was added to 100mL of toluene, phosphorus oxychloride (4mL,44mmol) was added under nitrogen, then N, N-dimethylaniline (1.1mL,8.8mmol) was slowly added, the reaction was warmed to 110 ℃ and reacted for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 ℃, quenched with 50mL water, then washed with water (50mL × 2), the separated organic phase was washed with 50mL of saturated brine, then dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to give compound 14-2, which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 14-3

Sodium hydride (60% in mineral oil, 1.8g,45.1mmol) was added to 100 ml of anhydrous tetrahydrofuran, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(5.08g,22mmol) in 20 ml of anhydrous tetrahydrofuran was added, and after addition, the reaction mixture was warmed to 30 ℃ and stirred for two hours. A solution of compound 14-2(5.4g,22mmol) in 20 mL of anhydrous tetrahydrofuran was added to the reaction and stirring was continued overnight. After completion of the reaction, the reaction was quenched with 50ml of water at 0 ℃ and washed with 50ml of ethyl acetate. The separated aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 14-3(8g, yield 82%) as a white solid.

And step 3: synthesis of Compound 14-4

Dissolving compound 14-3(1.2g,2.7mmol) in a mixed solvent of 10 ml of 1, 2-dichloroethane, 10 ml of water and 10 ml of acetonitrile, and adding NaIO under the protection of nitrogen₄(1.73g,8.1mmol) and RuCl ₃(0.035g,0.03mmol), the reaction mixture was reacted at 30 ℃ overnight, after completion of the reaction, the reaction was quenched with 10mL of water, followed by extraction with ethyl acetate (10mL × 3), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to give compound 14-4(0.92g, yield 72%) as a white solid.

MS(ESI,neg,ion)m/z:471.0[M-H]^-；

¹HNMR(400MHz,CDCl₃):8.08(dd,J＝19.9,7.1Hz,2H),7.88–7.68(m,3H),7.58(t,J＝7.4Hz,1H),7.33(t,J＝7.0Hz,2H),5.81(s,1H),3.98–3.96(m,2H),3.72(d,J＝12.3Hz,1H),2.75–2.65(m,2H),1.51–1.47(m,9H)ppm。

And 4, step 4: synthesis of Compound 14-5

Compound 14-4(0.92g,1.9mmol), compound 1-9(0.86g,2.14mmol), EDCI (0.45g,2.3mmol) and HOAT (0.29g,2.14mmol) were charged to a round bottom flask, protected with nitrogen, 15 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (1.36mL,7.8mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), and the organic phases were combined. The combined organic phases were washed with 10ml of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 14-5(1.26g, yield 95%) as a yellow solid.

MS(ESI,neg,ion)m/z:683.2[M-H]^-；

And 5: synthesis of Compound 14-6

Compound 14-5(1.2g,1.7mmol) was dissolved in 5 ml of ethyl acetate, cooled to 0 ℃ and then a 30% strength solution of hydrochloric acid in ethyl acetate (16 ml) was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. The resulting white solid was filtered and washed with 10ml ethyl acetate to give 14-6 as a white compound which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:585.1[M+H]⁺。

Step 6: synthesis of Compounds 14-7

Compounds 14-6(0.73g,1.17mmol), compounds 2-11(0.64g,1.41mmol), EDCI (0.27g,1.41mmol) and HOAT (0.19g,1.41mmol) were charged to a round bottom flask, protected with nitrogen, 10mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.82mL,4.68mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed with 10ml of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 14-7(0.83g, yield 86%) as a white solid.

And 7: synthesis of Compounds 14-8

Compound 14-7(0.4g, 0.48mmol) was dissolved in 100ml of 1, 2-dichloroethane, 0.04 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain 14 to 8(0.16g, yield: 41%) as a white solid.

MS(ESI,pos.ion)m/z:810.2[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.35(s,1H),8.03(d,J＝7.3Hz,2H),7.68(dd,J＝13.8,4.3Hz,2H),7.60–7.49(m,1H),7.39(d,J＝7.3Hz,1H),7.31(dd,J＝14.8,7.3Hz,2H),6.09–5.91(m,1H),5.83–5.64(m,1H),5.28(s,1H),4.96(m,1H),4.76(d,J＝11.0Hz,1H),4.59(s,1H),4.35(d,J＝46.0Hz,1H),4.08(d,J＝9.5Hz,1H),3.00–2.81(m,1H),2.67(m,1H),2.20(s,2H),1.82(m,3H),1.61(m,1H),1.55–1.37(m,9H),1.37–1.20(m,10H),1.01–0.80(m,4H)ppm；

HPLC purity: 95.41 percent.

Example 15

The synthetic route is as follows:

step 1: synthesis of Compound 15-1

Mixing compound 6-10(1.2g,2.31mmol), 4-methoxyphenylboronic acid (0.35g,2.31mmol), Pd (PPh)₃)₄(223mg,0.19mmol) and K₂CO₃(1.33g,9.56mmol) was dissolved in a mixed solvent of THF (30mL) and water (5mL), the reaction solution was refluxed overnight under nitrogen protection, after the reaction was completed, a saturated sodium chloride solution (100mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), the organic phases were combined, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1), compound 15-1(1.15g, yield 91%) as a yellow solid.

MS(ESI,pos.ion)m/z:547.2[M+H]⁺。

Step 2: synthesis of Compound 15-2

Compound 15-1(1.15g,2.1mmol), compound 1-9(0.93g,2.3mmol), EDCI (0.52g,2.7mmol) and HOAT (0.31g,2.3mmol) were suspended in CH₂Cl₂DIPEA (0.95mL,5.5mmol) was added to (20mL) under ice-cooling, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 15-2(1.3g, yield 81%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:759.1[M+H]⁺。

And step 3: synthesis of Compound 15-3

Compound 15-2(600mg,0.79mmol) was dissolved in 5N HCl in ethyl acetate (15mL), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the organic solvent was distilled off under reduced pressure. The residue obtained is substituted by CH₂Cl₂(15mL) diluted and then addedCompounds 2-11(429mg,0.95mmol), EDCI (197mg,1.03mmol) and HOAT (128mg,0.95mmol) were added, DIPEA (0.36mL,2.05mmol) was added under ice-bath, and the resulting reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain 15-3(220mg, yield 30%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:912.2[M+H]⁺。

And 4, step 4: synthesis of Compound 15-4

Compound 15-3(200mg,0.22mmol) was dissolved in 1, 2-dichloroethane (200mL), Grubbs second generation catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 15-4(70mg, yield 36%) as a white solid.

HRMS(ESI,pos.ion)m/z:884.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.69–7.62(m,1H),7.57–7.52(m,1H),7.50–7.44(m,3H),7.32–7.28(m,1H),7.26–7.15(m,2H),7.11–7.05(m,1H),7.02–6.95(m,2H),5.96(d,J＝2.5Hz,1H),5.71(dd,J＝17.6,8.5Hz,1H),5.31(s,1H),5.10–4.97(m,1H),4.77–4.62(m,1H),4.53(s,1H),4.48–4.38(m,1H),4.11–4.03(m,1H),3.86(s,3H),2.92(s,1H),2.71–2.62(m,2H),2.54(s,1H),2.37–2.28(m,1H),1.99–1.81(m,4H),1.64(s,2H),1.42–1.23(m,15H),1.17–1.07(m,2H),0.96-0.88(m,2H)ppm；

HPLC purity: 91.6 percent.

Example 16

The synthetic route is as follows:

step 1: synthesis of Compound 16-1

The compounds 4-bromo-2-fluoronitrobenzene (3.30g,15mmol), 4-fluorobenzeneboronic acid (2.74g,18mmol) and Pd (PPh)₃)₄(0.5g,0.45mmol) and K₂CO₃(10.35g,75mmol) was dissolved in a mixed solvent of THF (80mL) and water (20mL), the reaction was refluxed overnight under nitrogen, after the reaction was completed, a saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), the organic phases were combined, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give compound 16-1 as a yellow solid (2.8g, yield 87%).

Step 2: synthesis of Compound 16-3

Compound 16-1(1.74g,7.4mmol) and compound 16-2(1.14g,7.4mmol) were dissolved in DMF (20mL) and K was added thereto ₂CO₃(1.12g,8.1mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding 20mL of water to quench the reaction after the reaction is finished, then adjusting the pH value to 2-3 by using 1N HCl aqueous solution, extracting by using ethyl acetate (50mL × 3), combining organic phases, washing the combined organic phases by using saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, and evaporating the organic solvent under reduced pressure to obtain an orange oily liquid compound 16-3, wherein the next reaction is directly carried out without purification.

And step 3: synthesis of Compound 16-4

Compound 16-3 was dissolved in glacial acetic acid (100mL) and iron powder (2.1g, 37mmol) was added to the solution and the reaction mixture was warmed to 110 ℃ for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the obtained filtrate was poured into water (200mL) to precipitate a solid,

filtration, washing of the filter cake with water and drying gave compound 16-4 as a yellow solid (1.5g, 64% yield over two steps).

And 4, step 4: synthesis of Compound 16-5

Compound 16-4(1.4g,4.4mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring₃(1.3g,8.8mmol) and N, N-dimethylaniline (0.21g,1.8mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 16-5(1.0g, yield 67%) as a pale yellow solid.

And 5: synthesis of Compound 16-6

The compound N-Boc-4- (R) -hydroxyproline (0.76g,3.29mmol) was dissolved in DMF (20mL) and NaH (60% dispersed in mineral oil, 0.35g,8.94mmol) was added portionwise in ice bath and after addition the reaction mixture warmed to room temperature and stirred for 30 min. Compound 16-5(1.0g,2.94mmol) was dissolved in a small amount of DMF and added to the above reaction, followed by stirring for an additional 12 hours. After completion of the reaction, the reaction solution was poured into 300mL of water, the pH was adjusted to 2-3 with 1N HCl aqueous solution, followed by extraction with ethyl acetate (50 mL. times.3), and the organic phases were combined. The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 16-6(1.4g, yield 90%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:535.2[M+H]⁺。

Step 6: synthesis of Compounds 16-7

Compound 16-6(530mg,1.0mmol), compound 1-9(442mg,1.1mmol), EDCI (248mg,1.3mmol) and HOAT (150mg,1.1mmol) were suspended in CH₂Cl₂DIPEA (0.6mL,2.6mmol) was added to (15mL) under ice-cooling, and after the addition was completed, the reaction was warmed to room temperature and stirred for 4 hours. After the reaction is finished, removing the reaction product under reduced pressureThe organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 16-7(670mg, yield 90%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:747.2[M+H]⁺。

And 7: synthesis of Compounds 16-8:

compound 16-7(670mg,0.90mmol) was dissolved in 5N HCl in EtOAc (15mL) and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is taken up in CH₂Cl₂After dilution (15mL), compound 2-11(488mg,1.08mmol), EDCI (223mg,1.17mmol) and HOAT (146mg,1.08 mmol) were added, and DIPEA (0.47mL,2.70mmol) was added under ice bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain compound 16-8(320mg, yield 40%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:900.3[M+H]⁺。

And 8: synthesis of Compounds 16-9

Compound 16-8(120mg,0.13mmol) was dissolved in 1, 2-dichloroethane (150mL), Grubbs second generation catalyst (15mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 16-9(50mg, yield 44%) as a white solid.

HRMS(ESI,pos.ion)m/z:872.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.31(s,1H),7.65(s,1H),7.54–7.44(m,4H),7.40(t,1H),7.31–7.27(m,2H),7.12(t,2H),7.02(s,1H),5.98(s,1H),5.74(dd,J＝17.4,8.5Hz,1H),5.23(d,J＝7.3Hz,1H),5.01(t,J＝9.2Hz,1H),4.81–4.49(m,2H),4.41(t,J＝7.5Hz,1H),4.16–4.01(m,1H),2.93(s,1H),2.74–2.49(m,3H),2.39–2.29(m,1H),1.99–1.77(m,4H),1.69–1.57(m,2H),1.47–1.28(m,15H),1.17–1.07(m,2H), 0.95-0.89 (m,2H) ppm; HPLC purity: 94.00 percent.

Example 17

The synthetic route is as follows:

step 1: synthesis of Compound 17-3

The compounds 5-bromo-2-fluoronitrobenzene (1.0g,4.5mmol), 4-fluorobenzeneboronic acid (0.75g,5.4mmol) and Pd (PPh)₃)₄(0.52g,0.45mmol) and K₂CO₃(1.24g,9mmol) was dissolved in a mixed solvent of THF (24mL) and water (6mL), and the reaction mixture was stirred at room temperature overnight under nitrogen protection after the reaction was completed, a saturated sodium chloride solution (20mL) was added to quench, ethyl acetate was extracted (3 × 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to give compound 17-3 as a yellow solid (0.8g, 76% yield).

¹HNMR(600MHz,CDCl₃):8.24(dd,J＝6.9,2.0Hz,1H),7.81(ddd,J＝15.9,9.7,6.1Hz,1H),7.56(dd,J＝8.3,5.3Hz,2H),7.44–7.35(m,1H),7.24–7.17(m,2H)ppm。

Step 2: synthesis of Compound 17-5

Compound 17-3(1.5g,6.3mmol), compound 17-4(1.1g,6.6mmol) were dissolved in DMF (30mL) and K was added₂CO₃(1.04g,7.56mmol), heating to 140 ℃ for reaction overnight, adding 40 mL of water to quench the reaction after the reaction is finished, extracting three times with ethyl acetate (10mL × 3), combining organic phases, washing extract with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain the yellow solid compound 17-5(1.9g, 79.3% yield).

¹HNMR(400MHz,CDCl₃):8.33(d,J＝12.2Hz,1H),7.97(dd,J＝6.8,1.1Hz,1H),7.65–7.45(m,6H),7.17(t,J＝8.5Hz,2H),7.11(d,J＝8.4Hz,1H),3.85(d,J＝5.9Hz,3H)ppm。

And step 3: synthesis of Compound 17-6

Compound 17-5(1.9g,4.9mmol) was dissolved in glacial acetic acid (50mL), iron powder (1.1g, 19.6mmol) was added and the reaction mixture was warmed to 110 ℃ for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was poured into water (200mL) to precipitate a solid, filtered, and the filter cake was washed with water and dried to obtain a white solid compound 17-6.

And 4, step 4: synthesis of Compound 17-7

Compound 17-6(0.9g,2.8mmol) was added to 15mL of toluene, phosphorus oxychloride (0.5mL,5.6mmol) was added under nitrogen, then N, N-dimethylaniline (0.14mL,1.12mmol) was slowly added, the reaction was warmed to 110 ℃ and reacted for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 ℃, and quenched with 10mL of water, then washed with water (20mL × 2), the organic phase was washed with 20mL of saturated brine, then dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to give 600mg of an intermediate product.

Sodium hydride (0.17g,4.4mmol, 60% dispersed in mineral oil) was added to 10ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(0.5g,2.2mmol) in 2 ml of anhydrous DMF was added, after which the temperature was raised to 30 ℃ and stirred for two hours. The intermediate obtained above was dissolved in 2 ml of anhydrous DMF, added to the reaction solution, and then reacted overnight. The reaction was quenched with 10mL of water at 0 ℃, washed with 10mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 17-7(0.4g, yield 23%) as a yellow oil.

MS(ESI,pos.ion)m/z:535.1[M+H]⁺。

And 5: synthesis of Compounds 17-8

Compounds 17-7(0.35g,0.65mmol), compounds 1-9(0.29g,0.72mmol), EDCI (0.14g,0.72mmol) and HOAT (0.13g,0.72mmol) were charged to a round bottom flask, protected with nitrogen, 5mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.45mL,2.8mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 6 hours. The reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 17-8(0.34g, yield 70%) as a white solid.

MS(ESI,pos.ion)m/z:747.2[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.06(d,J＝29.7Hz,1H),7.53(dd,J＝6.6,4.7Hz,4H),7.46(d,J＝7.3Hz,1H),7.42–7.35(m,2H),7.28(s,2H),7.12(t,J＝8.6Hz,2H),5.88(s,1H),5.86-5.73(m,1H),5.33(d,J＝16.9Hz,1H),5.18(d,J＝10.5Hz,1H),4.37(s,1H),3.95(t,J＝10.6Hz,2H),2.97(s,1H),2.58(d,J＝22.2Hz,2H),2.22–2.11(m,1H),2.01(dd,J＝14.3,7.0Hz,1H),1.54–1.41(m,9H),1.40–1.31(m,3H),1.03(d,J＝24.4Hz,2H)ppm。

Step 6: synthesis of Compounds 17-9

Compound 17-8(0.63g,0.84mmol) was dissolved in 5ml of ethyl acetate, cooled to 0 ℃ and then 15 ml of a 30% strength ethyl acetate solution of hydrochloric acid was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. The white solid obtained was filtered and washed with 10ml of ethyl acetate and the solid obtained was taken to the next reaction without further purification.

And 7: synthesis of Compounds 17-10

Compounds 17-9(0.57g,0.84mmol), compounds 2-11(0.42g,0.92mmol), EDCI (0.18g,0.92mmol) and HOAT (0.16g,0.92mmol) were charged to a round bottom flask, protected with nitrogen, 10mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.58mL,3.34mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 5 mL of water and 4 mL of 1N aqueous hydrochloric acid, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 10mL of saturated saline, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 17-10(0.37g, yield 49%) as a white solid.

¹HNMR(400MHz,CDCl₃):10.24(s,1H),7.51–7.56(m,4H),7.44(t,J＝7.3Hz,1H),7.38–7.30(m,2H),7.30–7.22(m,2H),7.12(t,J＝8.6Hz,2H),5.97(s,1H),5.90–5.72(m,2H),5.37(d,J＝8.5Hz,1H),5.30(d,J＝17.2Hz,1H),5.17(d,J＝10.9Hz,1H),4.97(dd,J＝21.8,13.6Hz,2H),4.49(d,J＝8.2Hz,2H),4.35–4.22(m,1H),4.04(d,J＝8.1Hz,1H),2.91–3.01(m,1H),2.61(d,J＝6.7Hz,1H),2.54(s,1H),2.15(dd,J＝17.4,8.5Hz,1H),2.04(d,J＝6.7Hz,4H),1.73(d,J＝8.4Hz,2H),1.69–1.57(m,2H),1.39(s,15H),1.07(d,J＝7.8Hz,2H)。

And 8: synthesis of Compounds 17-11

Compound 17-10(0.37g,0.41mmol) was dissolved in 100 ml of 1, 2-dichloroethane, 0.03 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 75 ℃ and stirred for 24 hours. Cooled to room temperature, the organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 17-11(0.25g, yield: 70%) as a white solid.

MS(ESI,pos.ion)m/z:872.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.28(s,1H),7.63(s,1H),7.53–7.42(m,4H),7.41(t,1H),7.32–7.25(m,2H),7.10(t,2H),7.08(s,1H),5.98(s,1H),5.75(m,1H),5.23(d,J＝7.3Hz,1H),5.01(t,J＝9.2Hz,1H),4.81–4.49(m,2H),4.43(t,J＝7.5Hz,1H),4.16–4.01(m,1H),2.93(s,1H),2.74-2.49(m,3H),2.41–2.31(m,1H),1.97–1.73(m,4H),1.71–1.57(m,2H),1.47–1.28(m,15H),1.16–1.04(m,2H),0.92–0.86(m,2H)ppm；

Purity of HPLC 90.36%.

Example 18

Synthetic route

Step 1: synthesis of Compound 18-2

Compound 11-4(1.23g,5mmol), compound 18-1(0.85g,5mmol) were dissolved in DMF (20mL) and K was added₂CO₃(0.83g,6mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding water into the reaction solution for quenching after the reaction is finished, adjusting the pH value to 2-3 by using 1N HCl aqueous solution, extracting by using ethyl acetate (50mL × 3), combining organic phases, washing the organic phases by using saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain an orange oily liquid 18-2, and directly carrying out next step without purificationAnd (5) carrying out reaction.

MS(ESI,pos.ion)m/z:398.1[M+H]⁺。

Step 2: synthesis of Compound 18-3

The crude compound 18-2 was dissolved in glacial acetic acid (100mL), iron powder (1.4g,25mmol) was added and the reaction mixture was warmed to 110 ℃ for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was poured into water (200mL) to precipitate a solid, which was then filtered, and the filter cake was washed with water and dried to obtain compound 18-3(1.5g, yield in two steps 94%) as a yellow solid.

MS(ESI,pos.ion)m/z:336.1[M+H]⁺。

And step 3: synthesis of Compound 18-4

Compound 18-3(1.5g,4.47mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring ₃(1.37g,8.94mmol) and N, N-dimethylaniline (0.22g,1.79mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 18-4(1.5g, yield 95%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 18-5

The compound N-Boc-4- (R) -hydroxyproline (1.18g,5.1mmol) was dissolved in DMF (20mL) and NaH (60% dispersed in mineral oil, 0.4g,10.2mmol) was added portionwise in ice bath and after addition the reaction mixture warmed to room temperature and stirred for 30 min.

Compound 18-4(1.5g,4.2mmol) was dissolved in a small amount of DMF and then added to the reaction and stirring was continued for 12 hours. After the reaction was completed, the reaction solution was poured into 300mL of water, the pH was adjusted to 2 to 3 with 1n hcl aqueous solution, followed by extraction with ethyl acetate (50mL × 3), organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 18 to 5(900mg, yield 39%) as a pale yellow solid compound.

MS(ESI,neg.ion)m/z:547.1[M-H]^-。

And 5: synthesis of Compound 18-6

Compound 18-5(900mg,1.64mmol), compound 1-9(791mg,1.97mmol), EDCI (407mg,2.13mmol) and HOAT (266mg,1.97mmol) were suspended in CH ₂Cl₂(30mL), DIPEA (0.85mL,4.92mmol) was added under ice-cooling, and after the addition was complete, the reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was removed by evaporation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 18-6(1.1g, yield 88%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:761.0[M+H]⁺。

Step 6: synthesis of Compounds 18-7

Compound 18-6(1.1g,1.45mmol) was dissolved in 5N HCl in ethyl acetate (20mL), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is substituted by CH₂Cl₂After dilution (40mL), compounds 2-11(716g,1.58mmol), EDCI (328mg,1.72mmol) and HOAT (214mg,1.58mmol) were added, DIPEA (0.7mL,3.96mmol) was added under ice bath, and after the addition, the reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain compound 18-7(500mg, yield 38%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:912.2[M-H]^-。

And 7: synthesis of Compounds 18-8

Compound 18-7(480mg,0.52mmol) was dissolved in 1, 2-dichloroethane (500mL), Grubbs second generation catalyst (50mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by preparative HPLC to give compound 18-8 as a white solid (200mg, yield 43%).

HRMS(ESI,pos.ion)m/z:886.4[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.31(s,1H),7.60–7.49(m,3H),7.41–7.33(m,2H),7.28–7.22(m,1H),7.02–6.95(m,3H),6.86(s,1H),5.94(s,1H),5.74(d,J＝8.3Hz,1H),5.17(s,1H),5.02(t,J＝9.1Hz,1H),4.78–4.47(m,2H),4.35(t,J＝7.2Hz,1H),4.04(d,J＝8.5Hz,1H),3.87(s,3H),2.98–2.86(m,1H),2.76–2.52(m,3H),2.43–2.28(m,1H),1.99–1.71(m,5H),1.68–1.56(m,1H),1.44–1.28(m,15H),1.17–1.07(m,2H),0.98–0.88(m,2H)ppm；

HPLC purity 94.64%.

Example 19

The synthetic route is as follows:

step 1: synthesis of Compound 19-3

Compound 19-1(5g,33mmol) and compound 19-2(5.5g,35mmol) were dissolved in DMF (100mL) and K was added₂CO₃(6.8g,50mmol), heating the reaction mixture to 60 ℃ for reaction for 3 hours, adding 100mL of water to quench the reaction after the reaction is finished, extracting with ethyl acetate (30mL × 3), combining organic phases, washing the organic phases with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain an orange oily liquid compound 19-3, wherein the next reaction is directly carried out without purification.

MS(ESI,pos.ion)m/z:292.1[M+H]⁺。

Step 2: synthesis of Compound 19-4

The crude product 19-3(50mg, 0.17mmol) was dissolved in glacial acetic acid (10mL), iron powder (48mg, 0.86mmol) was added and the reaction mixture was warmed to 110 ℃ for 3 h. After the reaction, the reaction mixture was cooled to room temperature, filtered, and then the filtrate was poured into 1N aqueous hydrochloric acid (30mL) to precipitate a solid, the filtrate was filtered, and the cake was washed with water and dried to obtain 19-4(27mg, yield in step 1 and step 2 was 70%)

And step 3: synthesis of Compound 19-5

Compound 19-4(500mg,0.22mmol) was suspended in toluene (50mL) and POCl was added slowly with stirring ₃(1g,6.5mmol) and N, N-dimethylaniline (133mg,1.1mmol) were added, and then the reaction mixture was heated under reflux for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 19-5(44mg, yield 82%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:248.1[M+H]⁺。

And 4, step 4: synthesis of Compound 19-6

The compound N-Boc-4- (R) -hydroxyproline (224mg,0.97mmol) was dissolved in DMF (50mL), NaH (60% dispersed in mineral oil, 78mg,3.2mmol) was added under ice bath, and after addition, the reaction mixture was warmed to room temperature and stirred for 2 h.

Intermediate 19-5(200mg,0.81mmol) was dissolved in a small amount of DMF and added to the above solution and stirring was continued for 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2-3 with 1n hcl aqueous solution, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 19-6(397mg, yield 93%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:441.2[M-H]^-。

And 5: synthesis of Compound 19-7

Compound 19-6(350mg,0.79mmol), compound 1-9(318mg,0.79mmol), EDCI (227mg,1.19mmol) and HOAT (161mg,1.19mmol) were suspended in CH ₂Cl₂(50mL), DIPEA (306mg,2.37mmol) was added under ice bath, after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours, after the reaction was completed, the pH was adjusted to about 2 with 1N hydrochloric acid aqueous solution, followed by extraction with dichloromethane (20mL × 3), organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain pale yellow solid compound 19-7(457mg, yield 87%). MS (ESI, pos.ion) M/z:655.2[ M + H.2 ]/]⁺。

Step 6: synthesis of Compound 19-8

Compound 19-7(480mg,0.73mmol) was dissolved in 5N HCl ethyl acetate solution (30mL) and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is substituted by CH₂Cl₂After dilution (50mL), compound 2-11(322mg,0.71mmol), EDCI (204mg,1.07mmol) and HOAT (146mg,1.07mmol) were added, DIPEA (275mg,2.13mmol) was added under ice bath, and after completion of the addition, the reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compounds 19 to 8(484mg, two-step yield 82%) as pale yellow solids.

And 7: synthesis of Compound 19-9

Compound 19-8(200mg,0.25mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs second generation catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 75 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to give compound 19-9(150mg, yield 78%) as a white solid.

HRMS(ESI,pos.ion)m/z:780.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.33(s,1H),7.51(d,J＝48.0Hz,2H),7.14(d,J＝33.4Hz,3H),6.89(s,2H),5.89(s,1H),5.72(s,1H),5.27(s,1H),5.00(s,1H),4.62(t,J＝38.8Hz,2H),4.36(s,1H),4.03(s,1H),2.92(s,1H),2.62(d,J＝26.2Hz,3H),2.35(s,1H),1.87(m,2H),1.59(s,1H),1.38(d,J＝82.9Hz,18H),1.12(d,J＝30.7Hz,2H),0.93(s,2H)ppm；

HPLC purity 98.29%.

Example 20

The synthetic route is as follows:

step 1: synthesis of Compound 20-1

Mixing compound 6-10(520mg,1.0mmol), 4-fluorobenzeneboronic acid (140mg,1.0mmol), Pd (PPh)₃)₄(35mg,0.03mmol) and K₂CO₃(690mg,5mmol) was dissolved in a mixed solvent of THF (30mL) and water (5mL), the reaction mixture was refluxed overnight under nitrogen protection, after the reaction was completed, a saturated sodium chloride solution (100mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 20-1 as a yellow solid (500mg, yield 93%).

MS(ESI,pos.ion)m/z:535.1[M+H]⁺。

Step 2: synthesis of Compound 20-2

Compound 20-1(500mg,0.94mmol), compound 1-9(415mg,1.03mmol), EDCI (233mg,1.22mmol) and HOAT (140mg,1.03mmol) were suspended in CH ₂Cl₂After the reaction was completed, 5mL of a 1N aqueous hydrochloric acid solution was added thereto to quench the reaction, the reaction mixture was extracted with ethyl acetate (3 × 20mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain a pale yellow solid compound 20-2(520mg, yield 74%).

MS(ESI,pos.ion)m/z:747.2[M+H]⁺。

And step 3: synthesis of Compound 20-3

Compound 20-2(520mg,0.69mmol) was dissolved in 5N HCl in EtOAc (15mL) and stirred at room temperature for 3 h. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is substituted by CH₂Cl₂After dilution (15mL), compounds 2 to 11(375mg,0.83mmol), EDCI (171mg,0.9mmol) and HOAT (102mg,0.76mmol) were added, DIPEA (0.36mL,2.0mmol) was added under ice bath, and after completion of the addition, the reaction solution was warmed to room temperature and stirred for 4 hours.

MS(ESI,pos.ion)m/z:900.0[M+H]⁺。

And 4, step 4: synthesis of Compound 20-4

Compound 20-3(300mg,0.33mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs second generation catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 20-4(100mg, yield 35%) as a white solid.

HRMS(ESI,pos.ion)m/z:872.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.34(s,1H),7.65(s,1H),7.58(d,J＝7.7Hz,1H),7.53–7.42(m,4H),7.33–7.29(m,1H),7.23(d,J＝7.5Hz,1H),7.16–7.08(m,3H),5.97(s,1H),5.73(dd,J＝17.7,8.6Hz,1H),5.30(d,J＝7.2Hz,1H),5.00(t,J＝9.3Hz,1H),4.86–4.48(m,2H),4.41(s,1H),4.14-4.03(m,1H),2.93(s,1H),2.74–2.49(m,3H),2.40–2.28(m,1H),2.00–1.79(m,4H),1.77–1.55(m,2H),1.40–1.21(m,15H),1.18–1.08(m,2H),0.98–0.88(m,2H)ppm。

Example 21

The synthetic route is as follows:

step 1: synthesis of Compound 21-2

Compound 4-bromo-2-fluorobenzaldehyde (6.0g,10.5mmol) was added to 50mL CH under ice-bath₃CN, then adding NaH in turn₂PO₄(690mg,5.7mmol) aqueous solution (10mL), H₂O₂(4.71g,42mmol) and NaClO₂(3.78g,42mmol) and the reaction mixture was stirred at room temperature overnight. Water was added to quench the reaction, a solid was precipitated, filtered to give a white solid, and washed with water to give compound 21-2 as a white solid (6.8g, yield: 54%)。

MS(ESI,neg.ion)m/z:217.0[M-H]^-。

Step 2: synthesis of Compound 21-3

Adding 5ml of OCOCL into a round-bottom flask₂Then, compound 21-2(2.5g,11.5mmol) was added, and the reaction solution was stirred at 75 ℃ under reflux for about 2 hours. After the starting material had reacted, the solvent was evaporated to dryness under reduced pressure, the resulting yellow liquid residue was dissolved in 20mL of dry THF and added to 2-amino-4-fluorophenol (1.46g,11.5mmol) and Et under ice-bath ₃After completion of the reaction, 100mL of water was added to quench the reaction, the pH was adjusted to 7 with 1N aqueous hydrochloric acid, dichloromethane (100mL × 3) was used for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried by spin-drying to obtain 21-3, which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:328.9[M+H]⁺。

And step 3: synthesis of Compound 21-4

Compound 21-3(8.5g,25.8mmol), NaOH (1.03g,25.8mmol) and 60mL DMF were added sequentially to a 100mL round bottom flask and the reaction mixture was stirred at reflux overnight. After the reaction, the reaction mixture was cooled to room temperature, poured into 100mL of ice water, precipitated, filtered, and washed with 20mL of 1N NaOH aqueous solution and 20mL of water in this order. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 21-4(4.1g, yield: 51%) as a white solid.

MS(ESI,pos.ion)m/z:307.9[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.71(s,1H),7.71(dd,J＝5.1,3.2Hz,2H),7.56(dd,J＝8.4,1.8Hz,1H),7.43(dd,J＝8.9,5.4Hz,1H),7.06–6.93(m,2H)ppm。

And 4, step 4: synthesis of Compounds 21-5

In a 100mL round-bottom flask30mL of toluene was added, and under nitrogen protection, the compound 21-4(532mg,1.73mmol) and POCl were added in this order₃(180uL,1.90mmol) and N, N-dimethylaniline (85uL,0.692mmol) were refluxed and stirred overnight, cooled to room temperature, quenched with 10 mL of water, extracted with dichloromethane (50mL × 3), the organic phase was dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spun dry under reduced pressure to give crude 21-5, which was directly subjected to the next reaction without further purification.

And 5: synthesis of Compounds 21-6

NaH (60% dispersed in mineral oil, 0.53g,13mmol) was charged into a 100mL round bottom flask, 50mL of anhydrous DMF was added under nitrogen, cooled in an ice bath, and a solution of (2S,4S) -1- (tert-butoxycarbonyl) -4-hydroxypyrrolidine-2-carboxylic acid (1.5g,6.5mmol,1.0eq) in tetrahydrofuran (20mL) was added. The reaction mixture was allowed to warm to room temperature and stirred until no bubbles were formed, then a solution containing 21-5(2.2g,6.5mmol) of 20mL of THF was added and stirring was continued at room temperature overnight. After completion of the reaction, 10mL of water was added to quench the reaction, the pH was adjusted to 7 with 1N aqueous hydrochloric acid, followed by extraction with dichloromethane (50mL × 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 21-6(2.4g, yield: 71%) as a white solid.

MS(ESI,neg.ion)m/z:519.0[M-H]^-

Step 6: synthesis of Compounds 21-7

Compounds 21-6(802mg,1.54mmol), 1-9(620mg,1.54mmol), EDCI (310mg,1.62mmol) and HOAT (240mg,1.69mmol) were added sequentially to a 100mL round-bottomed flask, 10mL of dichloromethane was added under nitrogen protection, the mixture was cooled in an ice bath, the compound DIPEA (0.660mL,3.85mmol) was added at 0 ℃, and the reaction was stirred overnight at room temperature. After completion of the reaction, the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (50mL × 3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered, the organic solvent was dried by spinning, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 21-7(607mg, yield: 51%) as a white solid.

MS(ESI,pos.ion)m/z:733.1[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.07(s,1H),7.57–7.49(m,1H),7.39(d,J＝15.7Hz,2H),7.23(dd,J＝15.0,7.7Hz,1H),7.17–7.08(m,2H),6.91(m,1H),6.87–6.79(m,1H),5.86–5.78(m,1H),5.74(s,1H),5.37–5.27(m,1H),5.19(d,J＝10.4Hz,1H),4.39–4.27(m,1H),3.94–3.71(m,2H),2.97(s,1H),2.54(s,2H),1.49(s,9H),1.42–1.32(m,2H),1.28(t,J＝7.1Hz,2H),1.07(d,J＝7.5Hz,2H)ppm。

And 7: synthesis of Compounds 21-8

Compound 21-7(719mg,0.98mmol), 50mL of a 5N solution of ethyl acetate in ethyl acetate was placed in a 100mL round-bottomed flask, and the reaction mixture was stirred at room temperature for 2 hours. A white solid precipitated, which was filtered, and the obtained solid was washed with ethyl acetate and then dried in vacuo to obtain compound 21-8(591mg, yield: 90%) as a white solid.

And 8: synthesis of Compounds 21-9

Compounds 21-8(502mg,0.75mmol), compounds 2-11(406mg,0.90mmol), EDCI (190mg,1.0mmol), HOAT (115mg,0.85mmol) were charged into a 25mL round-bottomed flask, 10mL of CCM was added under nitrogen, cooled in an ice bath, and the compound DIPEA (350ul,2.0mmol) was added at 0 ℃. The reaction was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched by addition of 1N aqueous hydrochloric acid solution, extracted with dichloromethane (20mL × 3), the organic phases were combined, followed by washing with saturated brine, drying over anhydrous magnesium sulfate, filtration, spin-drying of the organic solvent, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compounds 21 to 9(253mg, yield: 38%) as a white solid.

¹HNMR(600MHz,CDCl₃):10.20(s,1H),7.40(d,J＝8.5Hz,1H),7.37–7.31(m,1H),7.11(dd,J＝8.5,5.3Hz,1H),7.01(s,1H),6.91(dd,J＝9.2,2.8Hz,1H),6.85(dd,J＝11.9,4.3Hz,1H),5.89(s,1H),5.87–5.76(m,2H),5.31(t,J＝12.8Hz,1H),5.18(d,J＝10.4Hz,1H),4.98(dd,J＝35.4,13.6Hz,2H),4.50–4.36(m,2H),4.27(d,J＝11.8Hz,1H),4.00(dd,J＝11.3,3.9Hz,1H),3.00–2.89(m,1H),2.64–2.49(m,2H),2.17–2.09(m,1H),2.06(d,J＝5.9Hz,2H),1.73(s,1H),1.51(d,J＝9.4Hz,1H),1.49–1.44(m,3H),1.44–1.36(m,9H),1.29(d,J＝18.0Hz,4H),1.13(s,1H),1.08(d,J＝7.0Hz,2H),0.93–0.83(m,2H)ppm。

And step 9: synthesis of Compounds 21-10

Compound 21-9(200mg,0.022mmol), Grubbs second generation catalyst (50mg, 0.08mmol) was added to a 250mL round bottom flask, then 250mL1, 2-dichloroethane was added to dissolve, and the reaction was stirred for 48 hours with warming to 65 ℃ under nitrogen. After completion of the reaction, it was cooled to room temperature, the organic solvent was spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 21 to 10(130mg, yield: 65%) as a white solid.

MS(ESI,pos.ion)m/z:858.2[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.31(s,1H),7.43(d,J＝8.3Hz,1H),7.37(s,1H),7.09(dd,J＝8.7,5.2Hz,1H),7.02(s,1H),6.94(d,J＝6.8Hz,1H),6.83(dd,J＝10.5,5.1Hz,1H),5.89(s,1H),5.73(dd,J＝17.4,8.7Hz,1H),5.16(d,J＝7.4Hz,1H),5.07–4.96(m,1H),4.66–4.60(m,1H),4.38–4.26(m,1H),4.06–3.94(m,1H),2.92(s,1H),2.62(s,1H),2.32(dd,J＝16.7,8.2Hz,1H),2.00–1.87(m,2H),1.87–1.78(m,1H),1.73(s,2H),1.59(dd,J＝32.6,19.3Hz,2H),1.54–1.46(m,4H),1.36–1.28(m,9H),1.19–1.07(m,2H),1.05–0.82(m,4H)ppm；

HPLC purity: 98.98 percent.

Example 22

The synthetic route is as follows:

step 1: synthesis of Compound 22-2

A round-bottomed flask was charged with compound 21-4(3.0g,9.75mmol), 4-fluorophenylboronic acid 22-1(1.4g,9.75mmol), Pd (PPh)₃)₄(1.0g,0.975mmol) and K₂CO₃(6.7g,48.75mmol) followed by 90mL THF and 30mLH₂Under the protection of nitrogen, the reaction mixture is heated to reflux, the reaction is carried out for 14 hours, after the reaction is completed, the reaction is cooled to room temperature, 100mL of water is used for quenching, ethyl acetate (50mL × 3) is used for extraction, organic phases are combined, saturated sodium chloride is used for washing, anhydrous magnesium sulfate is used for drying, filtration and organic solvent is dried in a rotary manner under reduced pressure, and a crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to obtain a white solid compound 22-2(1.5g, yield: 48%).

MS(ESI,pos.ion)m/z:324.0[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.63(s,1H),7.91–7.77(m,3H),7.70(s,1H),7.64(d,J＝7.8Hz,1H),7.47–7.40(m,1H),7.35(t,J＝8.5Hz,2H),6.99(d,J＝9.4Hz,2H)ppm。

Step 2: synthesis of Compound 22-3

In a 100mL round-bottom flask, Compound 22-2(558mg,1.73mmol), POCl₃(180uL,1.90mmol) and N, N-dimethylaniline (85uL,0.692mmol) are dissolved in 30mL of toluene, the reaction solution is refluxed and stirred overnight, after the reaction is finished, the reaction solution is cooled to room temperature, 10mL of water is added for quenching reaction, dichloromethane (50mL × 3) is used for extraction, organic phases are combined, saturated sodium chloride is used for washing, anhydrous magnesium sulfate is used for drying, filtration and organic solvent spin drying are carried out, crude products 22-3 are obtained, and the next reaction is directly carried out without further purification.

And step 3: synthesis of Compound 22-4

NaH (0.52g,13mmol, 60% in mineral oil) was added to a 100mL round bottom flask, 50mL THF was added under nitrogen, cooled in an ice bath, then compound 2-7(2.2g,6.5mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred until no air bubbles were formed, a THF solution (20mL) containing compound 22-3(2.2g,6.5mmol) was added and stirring continued at room temperature overnight. After the reaction was completed, the reaction was quenched with water, adjusted to pH <7 with dilute hydrochloric acid solution, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, the organic solvent was dried by spinning, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 22-4(1.4g, yield: 62%) as a white solid.

MS(ESI,pos.ion)m/z:537.2[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.63–7.55(m,3H),7.40(dd,J＝11.6,3.5Hz,2H),7.21–7.11(m,3H),6.92(dd,J＝8.3,6.4Hz,1H),6.87–6.79(m,1H),5.76(d,J＝3.3Hz,1H),4.65(t,J＝7.7Hz,1H),4.53(t,J＝7.8Hz,1H),3.97(dt,J＝12.2,8.2Hz,1H),3.88(s,1H),2.86–2.74(m,1H),2.55–2.41(m,1H),1.50(d,J＝17.9Hz,9H)ppm。

And 4, step 4: synthesis of Compound 22-5

Compound 22-4(827mg,1.54mmol), compound 1-9(620mg,1.54mmol), EDCI (310mg,1.62mmol) and HOAT (240mg,1.69mmol) were charged into a 100mL round-bottomed flask, 10mL of dichloromethane were added under nitrogen protection, the flask was cooled on an ice bath, compound DIPEA (660uL,3.85mmol) was added at 0 ℃ and the reaction was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, the organic solvent was spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 22-5(607mg, yield: 51%) as a white solid.

MS(ESI,pos.ion)m/z:749.2[M+H]⁺；

And 5: synthesis of Compound 22-6

Compound 22-5(734mg,0.98mmol) and 30mL of a 5N HCl ethyl acetate solution were added to a 100mL round-bottomed flask, and the reaction solution was stirred at room temperature for 2 hours. A white solid was produced during the reaction, which was filtered, washed with ethyl acetate, and dried to obtain 22-6(604mg, yield: 90%) as a white solid.

Step 6: synthesis of Compound 22-7

Compound 22-6(514mg,0.75mmol), compound 2-11(406mg,0.90mmol), EDCI (190mg,1.0mmol), HOAT (115mg,0.85mmol) were charged into a 100mL round-bottomed flask, 10 mL DCM was added under nitrogen protection, the mixture was cooled in an ice bath, compound DIPEA (350uL,2.0mmol) was added at 0 deg.C, and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of saturated sodium bicarbonate solution, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, the organic solvent was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 22-7(358mg, yield: 53%) as a white solid.

Step 10: synthesis of Compound 22-8

Compound 22-7(406mg,0.45mmol), Grubbs' second generation catalyst (50mg, 0.08mmol) and 1, 2-dichloroethane (150mL) were charged to a 250mL round bottom flask and the reaction mixture was stirred under nitrogen at 65 ℃ for 48 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was spin-dried, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 22-8(270mg, yield: 31%) as a white solid.

MS(ESI,pos.ion)m/z:874.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.34(s,1H),7.61(d,J＝8.0Hz,1H),7.58–7.46(m,3H),7.34(s,1H),7.32(d,J＝1.6Hz,1H),7.30(d,J＝1.6Hz,1H),7.16(t,J＝8.5Hz,3H),7.13–7.09(m,1H),6.99–6.92(m,1H),6.82(dd,J＝10.7,5.4Hz,1H),5.92(s,1H),5.73(dd,J＝18.0,8.5Hz,1H),5.24(d,J＝7.5Hz,1H),5.07–4.94(m,1H),4.74–4.51(m,2H),4.44–4.31(m,2H),4.21–3.98(m,1H),2.92(d,J＝4.7Hz,1H),2.74–2.33(m,4H),1.87-1.60(m,6H),1.60-1.28(m,12H),1.20–1.05(m,2H),1.04–0.89(m,2H)ppm；

HPLC purity: 94.74 percent.

Example 23

The synthetic route is as follows:

step 1: synthesis of Compound 23-2

Compound 4-bromo-2-fluorobenzaldehyde (6.0g,10.5mmol) was added to 50mL CH under ice-bath₃CN, then sequentially adding 10mLNaH₂PO₄(690mg,5.7mmol) aqueous solution, H₂O₂(4.71g,42mmol) and NaClO₂(3.78g,42mmol) and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, water was added to quench the reaction, and a solid precipitated, which was filtered to give a white solid, and the filter cake was washed with water to give compound 23-2(6.8g, yield: 54%) as a white solid.

MS(ESI,pos.ion)m/z:219.0[M+H]⁺。

Step 2: synthesis of Compound 23-3

A round-bottom flask was charged with compound 23-2(2.5g,11.5mmol) and 5mL of OCL₂Mixing by reactionThe mixture was heated to 75 ℃ and stirred under reflux for 2 hours. After the reaction of the raw materials, the solvent was evaporated to dryness, the resulting pale yellow liquid residue was dissolved in 20mL of anhydrous THF, and added to a solution containing 2-aminophenol (1.46g,11.5mmol) and Et under ice-bath₃N (3.25mL,23.0mmol) in 25mL THF, the reaction mixture was allowed to warm to room temperature and allowed to react overnight. After completion of the reaction, 100mL of water was added to quench the reaction, the pH was adjusted to 7 with dilute hydrochloric acid solution, and the mixture was extracted with ethyl acetate

(20 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to give the crude product which was used in the next reaction without further purification.

And step 3: synthesis of Compound 23-4

Compound 23-3(8g,25.8mmol), NaOH (1.03g,25.8mmol) were dissolved in this order in a 100mL round-bottomed flask and stirred at reflux overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into 100mL of ice water, precipitated, filtered, washed with 20mL of water, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:2) to give compound 23-4(4.0g, yield: 54%) as a white solid.

MS(ESI,pos.ion)m/z:290.0[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.62(s,1H),7.69(dd,J＝14.2,4.4Hz,2H),7.57–7.51(m,1H),7.37(d,J＝7.9Hz,1H),7.18(tt,J＝14.9,7.3Hz,3H)ppm。

And 4, step 4: synthesis of Compound 23-5

In a 100mL round-bottom flask, compound 23-4(500mg,1.73mmol), POCl were placed in order₃(180uL,1.90mmol), N, N-dimethylaniline (85uL,0.692mmol) were added to 30mL of toluene, the reaction mixture was refluxed and stirred overnight, after completion of the reaction, the mixture was cooled to room temperature, 10mL of water was added to quench the reaction, methylene chloride was used for extraction (10mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain crude product 23-5 without further purificationThe reaction is directly carried out to the next reaction.

And 5: synthesis of Compound 23-6

NaH (60% dispersed in mineral oil, 53mg,1.3mmol) was added to a 100mL round bottom flask, 20mL anhydrous DMF was added under nitrogen, cooled in an ice bath, and compound 2-7(250mg,0.65mmol) was added. The reaction mixture was warmed to room temperature and stirred, and when no air bubbles were generated in the reaction, 20mL of a THF solution containing compound 23-5(150mg,0.65mmol) was added and stirred at room temperature overnight. After completion of the reaction, 1mL of water was added to quench the reaction, the pH was adjusted to 7 with a dilute hydrochloric acid solution, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:2) to give compound 23-6(50mg, yield: 16%) as a white solid.

MS(ESI,pos.ion)m/z:503.1[M+H]⁺。

Step 6: synthesis of Compounds 23-7

Compound 23-6(775mg,1.54mmol), compound 1-9(620mg,1.54mmol), EDCI (310mg,1.62mmol), HOAT (240mg,1.69mmol) were charged into a 100mL round-bottomed flask, 10mL dichloromethane was added under nitrogen protection, the mixture was cooled in an ice bath, compound DIPEA (660uL,3.85mmol) was added at 0 ℃ and the reaction was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched by addition of 5mL of a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:2) to obtain compounds 23 to 7(560mg, yield: 51%) as a white solid.

MS(ESI,pos.ion)m/z:715.0[M+H]⁺；

And 7: synthesis of Compounds 23-8

Compound 23-7(700mg,0.98mmol) was added to a 100mL round-bottom flask, followed by the slow addition of 20mL of a 5N HCl ethyl acetate solution, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, a white solid precipitated, which was filtered, and the obtained solid was washed with 20mL of ethyl acetate and dried to obtain compound 23-8(630mg, yield: 90%) as a white solid.

And 8: synthesis of Compounds 23-9

Compound 23-8(500mg,0.75mmol), compound 2-11(406mg,0.90mmol), EDCI (190mg,1.0mmol) and HOAT (115mg,0.85mmol) were charged into a 100mL round-bottomed flask, 8mL dichloromethane was added under nitrogen, compound DIPEA (350uL,2.0mmol) was added at 0 deg.C, and the reaction was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched by addition of 5mL of a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:2) to obtain compounds 23 to 9(300mg, yield: 46%) as a white solid.

MS(ESI,neg.ion)m/z:866.1[M-H]^-。

And step 9: synthesis of Compounds 23-10

Compound 23-9(300mg,0.35mmol), Grubbs second generation catalyst (30mg, 0.08mmol) was added to 100mL1, 2-dichloroethane and stirred at 65 ℃ for 48 hours under nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, the organic solvent was spin-dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:2) to obtain 23 to 10(130mg, yield: 45%) as a white solid compound.

MS(ESI,pos.ion)m/z:840.2[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.32(s,1H),7.48–7.35(m,3H),7.27–7.21(m,2H),7.17(m,4H),7.06(s,1H),5.92(s,1H),5.73(m,1H),5.21(d,J＝7.3Hz,1H),5.06–4.94(m,1H),4.62(t,J＝7.7Hz,1H),4.55(d,J＝11.4Hz,1H),4.34(t,J＝7.6Hz,2H),4.02(d,J＝8.0Hz,1H),2.92(s,1H),2.62(m3H),2.33(m,1H),1.91–1.76(m,6H),1.76–1.28(m,15H),1.21–1.03(m,2H),1.03–0.78(m,2H)ppm；

HPLC purity: 98.25 percent.

Example 24

Synthetic route

Step 1: synthesis of Compound 24-1

To a 100mL round-bottomed flask was added compound 23-4(3.0g,10.3mmol), p-fluorophenylboronic acid (1.5g,10.3mmol), Pd (PPh) in that order₃)₄(300mg,0.26mmol) and K₂CO₃(7.2g,52mmol) followed by 90mL THF and 30mLH₂After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with 30mL of water, extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:2) to give compound 24-1(2.2g, yield: 69%) as a white solid.

MS(ESI,pos.ion)m/z:306.1[M+H]⁺。

Step 2: synthesis of Compound 24-2

Compound 24-1(2.0g,6.6mmol) was dissolved in 60mL of toluene and POCl was added under nitrogen₃(0.62mL,7.3mmol) and N, N-dimethylaniline (0.34mL,2.7mmol), and the reaction mixture was heated to reflux and reacted overnight. After the reaction was completed, it was cooled to room temperature, and 20mL of water was added to quench the reaction, and the reaction was washed once with 20mL of water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the crude product 24-2 was reacted in the next step without further purification.

And step 3: synthesis of Compound 24-3

NaH (0.52g,13mmol, 60% dispersion in mineral oil) was charged to a 100mL round bottom flask, 30mL anhydrous THF was added under nitrogen, cooled in an ice bath, and compound 2-7(1.5g,6.5mmol) was added. The reaction mixture was warmed to room temperature and stirred until no bubbles were generated, and a solution of 20mL of THF containing compound 24-2(2.1g,6.5mmol) was added and stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with water, the pH was adjusted to less than 7 with a dilute hydrochloric acid solution, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, the organic solvent was spin-dried, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 24-3(2.6g, yield: 77%) as a white solid.

MS(ESI,pos.ion)m/z:519.2[M+H]⁺。

And 4, step 4: synthesis of Compound 24-4

Compound 24-3(2.0g,3.86mmol), compound 1-9(1.56g,3.86mmol), EDCI (780mg,4.02mmol) and HOAT (580mg,4.24mmol) were charged to a 100mL round bottom flask, 25mL dichloromethane was added under nitrogen, cooled in an ice bath, compound DIPEA (1.86mL,10.6mmol) was added at 0 deg.C, and the reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched by addition of 10mL of 1N aqueous hydrochloric acid solution, extracted with dichloromethane (10mL × 3), the organic phases were combined and then washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was dried by spinning, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 24-4(1.7g, yield: 60%) as a white solid.

MS(ESI,pos.ion)m/z:731.2[M+H]⁺。

And 5: synthesis of Compound 24-5

Compound 24-4(200mg,0.28mmol) was added to a 100mL round-bottom flask, followed by the slow addition of 20mL of a 5N HCl ethyl acetate solution and the reaction stirred at room temperature for 2 hours. After completion of the reaction, a white solid precipitated, which was filtered, and the obtained solid was washed with 20mL of ethyl acetate and dried to obtain Compound 24-5(160mg, yield: 87%) as a white solid.

Step 6: synthesis of Compound 24-6

Compound 24-5(150mg,0.23mmol), compound 2-11(122mg,0.27mmol), EDCI (56mg,0.29mmol) and HOAT (35mg,0.25mmol) were charged to a 10mL round bottom flask, 5mL dichloromethane were added under nitrogen, and compound DIPEA (75ul,0.59mmol) was added at 0 ℃. The reaction was then warmed to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched by addition of 5mL of 1N aqueous hydrochloric acid solution, extracted with dichloromethane (5mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 24-6(80mg, yield: 40%) as a white solid.

MS(ESI,pos.ion)m/z:884.3[M+H]⁺。

And 7: synthesis of Compounds 24-7

Compound 24-6(400mg,0.45mmol) and Grubbs second generation catalyst (40mg,0.08mmol) were added to 100mL1, 2-dichloroethane, stirred at 65 ℃ for 48 hours under nitrogen. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 24-7(110mg, yield: 29%) as a white solid. MS (ESI, pos. ion) M/z 856.3[ M + H ]]⁺；

¹HNMR(600MHz,CDCl₃):10.32(s,1H),7.61(d,J＝6.9Hz,1H),7.53(m,2H),7.36(s,1H),7.30(d,J＝8.8Hz,1H),7.25(d,J＝5.7Hz,1H),7.21–7.09(m,4H),7.07(s,1H),5.96(s,1H),5.73(d,J＝7.9Hz,1H),5.23(s,1H),5.07–4.91(m,1H),4.67–4.49(m,1H),4.38(s,1H),4.08(dd,J＝15.9,9.1Hz,1H),2.93(s,1H),2.62(d,J＝54.7Hz,3H),2.34(s,1H),2.06(s,1H),1.99–1.69(m,5H),1.61(s,2H),1.41–1.23(m,12H),1.20–1.05(m,2H),0.95(d,J＝7.1Hz,2H)ppm；

HPLC purity: 98.06 percent.

Example 25

Synthetic route

Step 1 Synthesis of Compound 25-1

Compound 25-0(2.0g, 12.7mmol), isopropanol (0.786g, 13.1mmol), diphenyl-2-pyridylphosphine (DPPPy,5.0g,19.0mmol) and di-tert-butyl azodicarboxylate (DBAD,4.4g,19.0mmol) were dissolved in 100mL of THF under nitrogen, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, the organic solvent was removed under reduced pressure, and the residue was dissolved in 30mL of ethyl acetate, washed with 20mL of 1N HCl solution, and washed with anhydrous Na₂SO₄Drying and removing the organic solvent under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give 25-1(2.46g, yield: 97%) as a pale yellow oily product.

MS(ESI,pos.ion)m/z:200.2[M+H]⁺。

Step 2: synthesis of Compound 25-3

Compound 25-1(4.0g,12mmol) and compound 25-2(2.31g,13.6mmol) were dissolved in 15ml of DMF, and the mixture was added theretoAdding K₂CO₃(3.41g,24.7mmol) and after the addition was complete, the reaction mixture was warmed to reflux and reacted overnight. After the reaction was complete, it was cooled to room temperature, diluted with 100mL of LEtOAc, and then diluted with H₂O wash (100mL × 2) followed by 50mL saturated brine, anhydrous Na₂SO₄Drying and removal of the organic solvent under reduced pressure gave 25-3(4.0g, yield: 95%) as a yellow solid, which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:350.0[M+H]⁺。

And step 3: synthesis of Compound 25-4

Compound 25-3(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction is completed, cooling to room temperature, filtering out solids, dropwise adding the 1N HCl solution into the filtrate to separate out a large amount of white solids, filtering, and drying the obtained white solids under a vacuum condition to obtain 25-4(3.0g, yield: 91%) of a target compound; the reaction was carried out without further purification.

MS(ESI,pos.ion)m/z:288.2[M+H]⁺。

And 4, step 4: synthesis of Compounds 25-5

Compound 25-4(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was slowly added, the reaction solution was warmed to 110 ℃ and reacted for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give 25-5(1.1g, 100%) as a pale yellow solid product.

MS(ESI,pos.ion)m/z:306.2[M+H]⁺。

And 5: synthesis of Compound 25-6

Sodium hydride (60% in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then compound 2-7(1.0g,4.3mmol) was added in 10 ml of anhydrous DMF and after addition the reaction was warmed to 30 ℃ and stirred for two hours. A solution of compound 25-5(1.1g,3.6mmol) in 5ml of anhydrous tetrahydrofuran was added to the above reaction solution, followed by reaction overnight. The reaction was quenched with 20mL of water at 0 ℃, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 25-6(1.0g, yield: 56%) as a white solid.

MS(ESI,pos.ion)m/z:501.3[M+H]⁺。

Step 6: synthesis of Compounds 25-7

Compound 25-6(1.0g,2.0mmol), compound 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged to a round bottom flask, protected with nitrogen, 30 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (1.05mL,6.02mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, followed by extraction with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated saline, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 25-7(0.86g, yield 60%) as a purified white solid.

MS(ESI,pos.ion)m/z:713.4[M+H]⁺。

And 7: synthesis of Compounds 25-9

Compound 25-7(0.86g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the resulting white solid with 20 ml of ethyl acetate.

The solid obtained above, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask, under nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 25-9(0.92g, yield 98%) as a white solid.

MS(ESI,pos.ion)m/z:866.2[M+H]⁺。

And 8: synthesis of Compounds 25-10

Compound 25-9(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 25 to 10(0.25g, yield: 48%) as a white solid compound.

HPLC purity: 96.62 percent;

MS(ESI,pos.ion)m/z:838.4[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.35(s,1H),7.63–7.40(m,1H),7.15–7.04(m,1H),6.90–6.81(m,2H),6.77–6.62(m,2H),5.87(s,1H),5.72(d,J＝8.9Hz,1H),5.29(s,1H),4.99(t,J＝9.4Hz,1H),4.71–4.58(m,1H),4.56–4.46(m,2H),4.40–4.26(m,1H),4.11–3.96(m,1H),2.92(s,1H),2.70–2.49(m,3H),2.33(d,J＝8.3Hz,1H),1.97–1.83(m,,4H),1.48–1.30(m,23H),1.17–1.08(m,2H),0.94–0.88(m,2H)ppm。

example 26:

the synthetic route is as follows:

step 1: synthesis of Compound 26-1

Compound 26-0(1.0g, 5.6mmol) was slowly added dropwise to concentrated sulfuric acid (1.5mL,27mmol) in an ice bath, followed by addition of nitric acid (0.5mL,7mmol), and then reacted for 4 hours in an ice bath. After completion of the reaction, the reaction mixture was slowly warmed to room temperature, poured into 20mL of ice water, extracted with ethyl acetate (15mLx3), and the extract was washed with 20mL of 1N sodium hydroxide solution and saturated sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The organic solvent was removed under reduced pressure to give 26-1(1.1g, yield: 88%) as a pale yellow oily product.

Step 2: synthesis of Compound 26-3

Compound 26-1(1.0g,4.4mmol) and compound 26-2(0.83g,4.9mmol) were dissolved in 20mL DMF, and K was added thereto₂CO₃(1.2g,8.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. Cooled to room temperature, diluted with 100ml of LEtOAc and diluted with H₂O wash (100mL × 2), followed by 50mL saturated brine, and the organic phase over anhydrous Na₂SO₄Drying and removal of the organic solvent under reduced pressure gave 26-3(1.6g, yield: 96%) as a yellow solid which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:376.2[M+H]⁺。

And step 3: synthesis of Compound 26-4

Compound 26-3(1.0g,2.7mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (0.2g,4mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction is completed, cooling to room temperature, filtering out solids, dropwise adding 100mL of 1N HCl solution into the filtrate to separate out a large amount of white solids, filtering, and drying the obtained white solids under a vacuum condition to obtain the target compound 26-4(0.6g, yield: 70%); the reaction was carried out without further purification.

MS(ESI,pos.ion)m/z:314.0[M+H]⁺。

And 4, step 4: synthesis of Compound 26-5

Compound 26-4(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was slowly added, the reaction solution was warmed to 110 ℃ and reacted for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 ℃, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give 26-5(0.5g, 45%) as a pale yellow solid product.

MS(ESI,pos.ion)m/z:332.1[M+H]⁺。

And 5: synthesis of Compounds 26-7

Sodium hydride (60% dispersed in mineral oil, 0.13g,3.25mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(0.4g,1.73mmol) in 10 ml of anhydrous DMF was added, after which the reaction was warmed to 30 ℃ and stirred for two hours. A solution of compound 26-5(0.5g,1.51mmol) in 5mL of anhydrous tetrahydrofuran was added to the reaction mixture, after which the reaction was continued overnight. After completion of the reaction, the reaction was quenched with 20mL of water at 0 ℃ and washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, followed by extraction with ethyl acetate (20 mL. times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V): 2:1) to give 26-7(0.54g, yield: 68%) as a white solid compound

MS(ESI,pos.ion)m/z:527.2[M+H]⁺。

Step 6: synthesis of Compounds 26-8

Compound 26-7(0.54g,1.0mmol), Compound 1-9(0.45g,1.1mmol), EDCI (0.26g,1.5mmol) and HOAT (0.16g,1.2mmol) were charged into a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.5mL,3.0mmol) was added and the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain purified compounds 26 to 8 as a white solid (0.66g, yield 87%).

MS(ESI,pos.ion)m/z:739.3[M+H]⁺。

And 7: synthesis of Compounds 26-10

Compound 26-8(0.65g,0.88mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the resulting white solid with 20ml of ethyl acetate.

The solid obtained above, compound 2-11(0.45g,1mmol), EDCI (0.2g,1mmol) and HOAT (0.13,1mmol) were charged into a round bottom flask, under nitrogen, 20mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.45mL,2.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10 ml of water, extracted twice with 10 ml of ethyl acetate, the organic phases were combined, washed with 20ml of saturated brine and dried over anhydrous sodium sulfate The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give purified compound 26-10(0.66g, yield 51%) as a white solid. MS (ESI, neg. ion) M/z 890.4[ M-H [ ]]^-。

And 8: synthesis of Compounds 26-11

Compound 26-10(0.34g,0.38mmol) was dissolved in 200 ml of 1, 2-dichloroethane, 0.05 g of Grubbs's second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain purified compound 26-11(0.2g, yield: 61%) as a white solid.

MS(ESI,pos.ion)m/z:863.9[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.42(s,1H),7.65–7.49(m,1H),7.24(d,J＝8.5Hz,1H),7.09–7.04(m,2H),6.96–6.85(m,2H),5.88(s,1H),5.73(dd,J＝17.8,8.8Hz,1H),5.18(d,J＝7.6Hz,1H),5.06–4.95(m,1H),4.73–4.53(m,2H),4.33(t,J＝7.7Hz,1H),4.15–3.94(m,1H),2.97–2.86(m,1H),2.71–2.51(m,3H),2.38–2.27(m,1H),1.91–1.73(m,4H),1.48–1.29(m,17H),1.15–1.06(m,2H),0.97–0.87(m,2H)ppm；

HPLC purity: 95.08 percent.

Example 27:

the synthetic route is as follows:

step 1 Synthesis of Compound 27-1

Compound 27-0(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was slowly added, the reaction solution was warmed to 110 ℃ and reacted for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 deg.C, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether) to give the product 27-1(0.7g, 70%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:266[M+H]⁺。

Step 2 Synthesis of Compound 27-2

Sodium hydride (60% dispersed in mineral oil, 0.15g,3.8mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(0.42g,1.8mmol) in 10 ml of anhydrous DMF was added, after which the temperature was raised to 30 ℃ and stirred for two hours.

A solution of compound 27-1(0.43g,1.6mmol) in 5 ml of anhydrous tetrahydrofuran was added to the above reaction solution, followed by reaction overnight. The reaction was quenched with 20mL of water at 0 ℃ and washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL. times.3) and the organic phases combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 27-2(0.4g, yield: 54%) as a white solid compound

MS(ESI,pos.ion)m/z:673.2[M+H]⁺。

Step 3 Synthesis of Compound 27-3

Compound 27-2(0.7g,2mmol), compound 1-9(0.68g,1.7mmol), EDCI (0.4g,2mmol) and HOAT (0.3g,2mmol) were charged into a round bottom flask, protected with nitrogen, 30 mL of dichloromethane were added, then cooled to 0 deg.C, DIPEA (0.8mL,5mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 27-3(0.95g, yield 50%) as a white solid.

MS(ESI,pos.ion)m/z:673[M+H]⁺。

Step 4 Synthesis of Compounds 27-5

Compound 27-3(0.78g,1.28mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature until the reaction was complete when no gas was evolved. Filtration and washing of the resulting white solid with 20 ml of ethyl acetate.

The solid obtained above, compound 2-11(0.7g,1.55mmol), EDCI (0.32g,1.7mmol) and HOAT (0.21,1.5mmol) were charged into a round bottom flask, under nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.7mL,4mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 27-5(0.55g, yield 52%) as a white solid.

MS(ESI,neg.ion)m/z:824[M-H]^-。

Step 5 Synthesis of target 27-6

Compound 27-5(0.5g,0.6mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.05 g of Grubbs's second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After the reaction, the reaction mixture was cooled to room temperature, the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain a white solid Compound 27-6(0.37g, yield: 80%). MS (ESI, pos. ion) M/z 798.2[ M + H ]]⁺；

¹HNMR(600MHz,CDCl₃):10.34(s,1H),7.64–7.50(m,1H),7.21–7.02(m,2H),6.95–6.82(m,3H),5.89(s,1H),5.73(dd,J＝17.4,8.6Hz,1H),5.20(d,J＝7.2Hz,1H),5.00(t,J＝9.3Hz,1H),4.76–4.46(m,2H),4.32(d,J＝7.6Hz,1H),4.13–3.97(m,1H),2.92(s,1H),2.62(t,J＝18.0Hz,3H),2.37–2.27(m,1H),1.95–1.77(m,4H),1.48–1.28(m,17H),1.16–1.09(m,2H),0.91–0.88(m,2H)ppm；

HPLC purity 97.74%.

Example 28:

the synthetic route is as follows:

step 1 Synthesis of Compound 28-1

Compound 28-0(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. TLC detection reaction, after the reaction was completed, cooled to 0 deg.C, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether) to give light yellow solid product 28-1(0.7g, 70%).

MS(ESI,pos.ion)m/z:266[M+H]⁺。

Step 2 Synthesis of Compound 28-2

Sodium hydride (60% dispersed in mineral oil, 0.15g,3.8mmol) was added20mL of anhydrous DMF, cooling to 0 ℃ under nitrogen protection, adding 10 mL of anhydrous DMF solution of compound 2-7(0.42g,1.8mmol), heating to 30 ℃, stirring for two hours, adding 5mL of anhydrous tetrahydrofuran solution of compound 28-1(0.43g,1.6mmol) to the reaction solution, reacting overnight, quenching the reaction solution with 20mL of water at 0 ℃, washing with 20mL of ethyl acetate, adjusting the pH of the aqueous phase to 2-3 with 1N hydrochloric acid solution, extracting with ethyl acetate (20mL × 3), combining the organic phases, washing the organic phases with saturated saline, drying with anhydrous sodium sulfate, removing the organic solvent under reduced pressure, and purifying the obtained crude product by silica gel column chromatography (petroleum ether: ethyl acetate (V: 2:1) to obtain 28-2(0.4g, 54%) MS (ESI, neg.459) M/z: M: 54%) MS (ESI, yield: M-459H: 1) ]^-。

Step 3 Synthesis of Compound 28-3

Compound 28-2(0.7g,2mmol), compound 1-9(0.68g,1.7mmol), EDCI (0.4g,2mmol) and HOAT (0.3g,2mmol) were charged into a round-bottomed flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.8mL,5mmol) was added, the reaction was warmed to 30 deg.C and stirred for 4 hours. The reaction was quenched with 10mL of water, extracted with 20mL of ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by a silica gel column (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 28-3(0.95g, yield 50%) as a white solid.

MS(ESI,pos.ion)m/z:673[M+H]⁺。

Step 4 Synthesis of Compound 28-5

Compound 28-3(0.78g,1.28mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the resulting white solid with 20ml of ethyl acetate.

The solid obtained above, compound 2-11(0.7g,1.55mmol), EDCI (0.32g,1.7mmol) and HOAT (0.21,1.5mmol) were charged into a round bottom flask, under nitrogen, 20mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.7mL,4mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 28-5(0.55g, yield 52%) as a white solid.

MS(ESI,neg.ion)m/z:824[M-H]^-。

Step 5 Synthesis of target 28-6

Compound 28-5(0.5g,0.6mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.05 g of Grubbs's second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 28-6(0.26g, yield: 54%) as a white solid.

MS(ESI,pos.ion)m/z:798[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.49(s,1H),7.78–7.42(m,2H),7.14–6.99(m,1H),6.97–6.88(m,3H),5.96–5.84(m,1H),5.75–5.62(m,1H),5.45(d,J＝5.7Hz,1H),5.05–4.89(m,1H),4.81–4.48(m,2H),4.33(s,1H),4.21–4.01(m,1H),2.90(s,1H),2.70–2.52(m,3H),2.39–2.19(m,2H),1.95–1.77(m,3H),1.52–1.28(m,17H),1.14–1.05(m,2H),0.91–0.86(m,2H)ppm；

HPLC purity 98.85%.

Example 29:

the synthetic route is as follows:

step 1 Synthesis of Compound 29-2

Compound 29-1(3.0g,12.2mmol) was added to toluene (100mL) and POCl was slowly added with stirring₃(3.7g,24.4mmol) and N, N-dimethylaniline (157mg,1.22mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 29-2(1.1g, yield: 33%) as a pale yellow solid.

¹HNMR(600MHz,CDCl₃):7.77(dd,J＝7.8,1.2Hz,1H),7.52–7.43(m,3H),7.41(td,J＝7.6,1.5Hz,1H),7.34(dd,J＝7.3,1.3Hz,1H),7.31(dd,J＝7.9,1.4Hz,1H),7.20(td,J＝7.7,1.5Hz,1H)ppm。

Step 2 Synthesis of Compound 29-3

The compound N-Boc-4- (R) -hydroxyproline methyl ester (2-7,1.5g,6.1mmol) was dissolved in THF (100mL), NaH (60% dispersed in mineral oil, 500mg,6.1mmol) was added portionwise under ice bath, and after addition, the reaction mixture was warmed to room temperature and stirred for 30 min. Compound 29-2(1.5g,6.1mmol) was then dissolved in a small amount of THF, added to the above solution and stirred for an additional 12 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2-3 with 1n cl, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 29-3(1.1g, yield: 36.6%) as a white solid.

MS(ESI,pos.ion)m/z:441.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.58–7.39(m,4H),7.35(t,J＝7.2Hz,1H),7.28(m,1H),7.17(d,J＝7.6Hz,1H),7.08(s,1H),5.77(d,J＝13.9Hz,1H),4.57(m,1H),4.16–3.82(m,2H),2.64(m,2H),1.49(s,9H)ppm。.

Step 3 Synthesis of Compound 29-4

Compound 29-3(200mg,0.45mmol), 1-9(182mg,0.45mmol), EDCI (112mg,0.59mmol) and HOAT (67.5mg,0.49mmol) were added to 5mL CH₂Cl₂In the reaction solution, DIPEA (0.2mL,1.18mmol) was added under nitrogen protection and ice bath, and after completion of the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, after completion of the reaction, the reaction was quenched with 5mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 29-4(150mg, yield: 57.6%) as a white solid.

¹HNMR(600MHz,CDCl₃):10.07(s,1H),7.47(dt,J＝19.1,7.6Hz,4H),7.37(d,J＝7.0Hz,1H),7.23–7.06(m,3H),5.80(br,2H),5.33(d,J＝17.2Hz,1H),5.19(d,J＝10.4Hz,1H),4.42–4.33(m,1H),3.99–3.80(m,2H),3.02–2.92(m,1H),2.57(s,1H),2.22–2.07(m,1H),2.01(s,1H),1.50(s,10H),1.36(s,2H),1.06(d,J＝5.4Hz,2H)ppm。

Step 4 Synthesis of Compound 29-5

Compound 29-4(150mg,0.27mmol) was dissolved in 20mL of 5N HCl EA solution, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is dissolved in 10mLCH₂Cl₂Compound 2-11(41mg,0.27mmol), EDCI (67.4mg,1.35mmol) and HOAT (40mg,0.29mmol) were added simultaneously, under nitrogen protection, DIPEA (1.2mL,0.70mmol) was added in ice bath, and then the reaction solution was warmed to room temperature and stirred for 4 hours, after completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with 20mL of saturated saline, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 29-5(150mg, yield: 68.5%) as a white solid.

Step 5 Synthesis of Compound 29-6

Compound 29-5(150mg,0.18mmol) was dissolved in 1, 2-dichloroethane (100mL), Grubbs second generation catalyst (15mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give compound 29-6(60mg, yield: 40%) as a white solid.

MS(ESI,pos.ion)m/z:779.1[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.26(br,1H),7.47(t,J＝6.9Hz,3H),7.39(m,1H),7.29(m,3H),7.22(s,1H),7.08(s,1H),6.81(br,1H),5.96(s,1H),5.84–5.71(m,1H),5.21–5.12(m,1H),5.10–5.00(m,1H),4.67–4.58(m,2H),4.47–4.36(m,1H),4.11–4.04(m,1H),3.00–2.89(m,1H),2.67(m,1H),2.40–2.27(m,1H),2.02–1.77(m,3H),1.25-150(m,18H),1.22–1.08(m,2H),1.06–0.83(m,2H)ppm；

HPLC purity 97.84%.

Example 30:

the synthetic route is as follows:

step 1 Synthesis of Compound 30-3

Compound 30-1(5.0g,31.4mmol) and compound 30-2(5.3g,34.5mmol) were dissolved in DMF (200mL) and K was added₂CO₃(8.7g,62.8mmol) and the reaction mixture was stirred at 65 ℃ for about 4 hours. After the reaction was completed, the reaction solution was poured into 500mL of water, a yellow solid precipitated, and the filtrate was filtered, and the filter cake was washed with 50mL of 1N NaOH aqueous solution and 50mL of water in this order, and the resulting solid was dried under vacuum to obtain 30-3(3.6g, yield: 74%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:292.0[M-H]^-。

¹HNMR(600MHz,CDCl₃):8.22–8.26(m1H),8.09–8.11(m,1H),7.60–7.61(m,3H),6.91–6.95(m,1H),5.52–6.55(m,1H)ppm。

Step 2 Synthesis of Compound 30-4

In a round-bottomed flask were added compound 30-3(3g,10.5mmol), iron powder (1.72g,17.8mmol) and glacial acetic acid (120mL) in that order, and the reaction mixture was stirred at 110 ℃ for about 12 hours. After the reaction is completed, the solvent is evaporated to dryness to about 30mL, then 100mL of water is added, a solid is separated out, the mixture is filtered, a filter cake is washed with 20mL of water for three times, and the obtained solid is dried in vacuum and is directly used for the next reaction without further purification. MS (ESI, pos. ion) M/z 246.0[ M + H ] ]⁺；

¹HNMR(600MHz,CDCl₃):10.66(br,1H),7.68–7.70(m,1H),7.44–7.52(m,4H),7.24–7.26(m,2H)。

Step 3 Synthesis of Compound 30-5

Compound 30-4(3.0g,12.2mmol) was added to 100mL of toluene and POCl was slowly added with stirring₃(3.7g,24.4mmol) and N, N-dimethylaniline (157mg,1.22mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 30-5(1.1g, yield: 33%) as a pale yellow solid.

¹HNMR(600MHz,CDCl₃):7.81–7.83(m,1H),7.62–7.64(m,1H),7.56–7.58(m,2H),7.43–7.45(m,1H),7.31–7.34(m,2H)ppm。

Step 4 Synthesis of Compounds 30-6

Compounds 2-7(1.11g,4.56mmol) were dissolved in 20mL THF, NaH (60%, 365mg,9.12mmol) was added portionwise on ice, and after addition, the mixture was warmed to room temperature and stirred for 30 minutes. Compound No. 30-5 was dissolved in 5mL of THF, and the mixture was added to the reaction solution, followed by stirring for 12 hours. After completion of the reaction, the reaction solution was poured into 300mL of water, the pH was adjusted to 2-3 with 1N Cl, extraction was performed with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 30-6(1.1g, yield: 47.6%) as a white solid.

MS(ESI,pos.ion)m/z:459.1[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.38–7.39(m,2H),7.33–7.35(m,1H),7.26–7.29(m,1H),7.09–7.10(m,1H),6.99–7.02(m,1H),6.88–6.90(m,1H),5.55(brs,1H),4.31–-4.34(m,1H),3.73–3.86(m,2H),1.99–2.01(m,2H),1.5(s,9H)ppm。

Step 5) Synthesis of Compounds 30-7

Compound 30-6(526mg,2.0mmol), Compound 1-9(804mg,2.0mmol), EDCI (496mg,2.6mmol) and HOAT (297mg,2.2mmol) were added to 15mL CH ₂Cl₂Under nitrogen protection, DIPEA (0.95mL,5.2mmol) was added under ice bath, the reaction mixture was stirred at room temperature for 4 hours, after completion of the reaction, the reaction was quenched with 5mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain 30 to 7(586mg, yield: 44%) as a pale yellow solid compound.

Step 6 Synthesis of Compounds 30-8

Compound 30-7(607mg,0.96mmol) was dissolved in 20mL of 5N HCl in EtOAc and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained was treated with 10mL of CH₂Cl₂After dilution, compound 2-11(452mg,1.0mmol), EDCI (206mg,1.08mmol) and HOAT (123mg,0.91mmol) were added thereto, followed by addition of DIPEA (0.38mL,2.1mmol) under nitrogen protection and ice bath, followed by warming to room temperature and stirring for 4 hours, after completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with 20mL of saturated saline, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 30-8 as a white solid (406mg, yield: 47.2%).

Step 7 Synthesis of Compounds 30-9

Intermediate 30-8(406mg,0.49mmol) was dissolved in 1, 2-dichloroethane (200mL), Grubbs second generation catalyst (50mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give 30-9(140mg, yield: 35%) as a white solid.

¹HNMR(600MHz,CDCl₃)10.24(br,1H),7.39–7.52(m,3H),7.31–7.32(m,1H),7.15–7.21(m,2H),6.97–7.02(m,1H),6.86(br,1H),5.14–5.25(m,1H),4.99–5.02(m,1H),4.60–4.63(m,1H),4.35–4.40(m,1H),3.04–4.07(m,1H),2.89–2.99(m,1H),2.53–2.66(m,3H),2.28–2.36(m,1H),1.72–1.96(m,6H),1.27–2.50(m,15H),0.96–1.18(m,6H)ppm；

HPLC purity 97.13%.

Example 31:

the synthetic route is as follows:

step 1 Synthesis of Compound 31-3

Compound 31-1(5.0g,31.4mmol) and compound 31-2(5.3g,34.5mmol) were dissolved in DMF (200mL) and K was added₂CO₃(8.7g,62.8mmol) and the reaction mixture was stirred at 65 ℃ for about 4 hours. After the reaction was completed, the reaction mixture was poured into 500mL of water, a yellow solid precipitated, which was filtered, and the filter cake was washed with 50mL of 1N NaOH aqueous solution and 50mL of water in this order, and the resulting solid was dried under vacuum to obtain Compound 31-3 as a pale yellow solid (3.6g, yield: 74%).

MS(ESI,neg.ion)m/z:292.1[M-H]^-。

Step 2: synthesis of Compound 31-4

To a round-bottomed flask were added compound 31-3(1.0g,3.4mmol), iron powder (1.0g,17.8mmol), glacial acetic acid (80mL) in this order, and the reaction mixture was stirred at 110 ℃ for about 12 hours. After the reaction is completed, the solvent is evaporated to about 20mL, then 100mL of water is added, solid is separated out, the filtration is carried out, the filter cake is washed with 20mL of water for three times, and the obtained product 31-4 is dried in vacuum and is directly used for the next reaction without further purification.

Step 3 Synthesis of Compound 31-5

Compound 31-4(1.5g,6.1mmol) was added to 70mL of toluene, and POCl was slowly added thereto with stirring₃(2.8g,18.0mmol) and N, N-dimethylaniline (78.9mg,0.61mmol) were added, and the reaction mixture was refluxed at elevated temperature for 3 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 31-5(770mg, yield: 47%) as a pale yellow solid.

Step 4 Synthesis of Compound 31-6

Compound 2-7(664mg,2.9mmol) was dissolved in 20mL THF, NaH (60% dispersed in mineral oil, 351mg,8.78mmol) was added portionwise on ice, and after addition, the reaction mixture was warmed to room temperature and stirred for 30 min.

Intermediate compound 31-5 was dissolved in 5ml of THF, added to the above solution and stirred for an additional 12 hours. After completion of the reaction, the reaction solution was poured into 300mL of water, the pH was adjusted to 2-3 with 1n cl, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 31-6(1.12g, yield: 89.4%) as a white solid.

Step 5 Synthesis of Compounds 31-7

Compound 31-6(500mg,1.09mmol), compound 1-9(438mg,1.09mmol), EDCI (271mg,1.41mmol) and HOAT (147mg,1.09mmol) were added to 15mL CH₂Cl₂Under nitrogen, DIPEA (422mg,3.27mmol) was added under ice bath, and after completion of the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, after completion of the reaction, the reaction was quenched with 5mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated saline, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compounds 31 to 7(580mg, yield: 43.7%) as pale yellow solids.

Step 6 Synthesis of Compounds 31-8

Compound 31-7(580mg,0.84mmol) was dissolved in 20mL of 5N HCl in ethyl acetate and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained was treated with 10mL of CH₂Cl₂Diluting, adding compound 2-11(876mg,1.94mmol), EDCI (160mg,0.86mmol) and HOAT (87mg,0.64mmol), adding DIPEA (0.40mL,1.93mmol) under nitrogen protection in ice bath, after the addition, heating the reaction mixture to room temperature and stirring for 4 hours, quenching the reaction with 10mL of water after the reaction is finished, extracting with ethyl acetate (10mL × 2), combining organic phases, and adding 20mL of organic phase The extract was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 31-8 as a white solid (300mg, yield: 43.4%).

Step 7 Synthesis of Compounds 31-9

The intermediate 31-8(300mg,0.36mmol) was dissolved in 1, 2-dichloroethane (200mL), Grubbs second generation catalyst (30mg) was added under nitrogen, the reaction mixture was warmed to 65 ℃ and reacted for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to give compound 31-9(140mg, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:780.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.35(s,1H),7.58–7.35(m,4H),7.29(s,1H),6.94(d,J＝9.0Hz,1H),6.79(d,J＝6.1Hz,1H),5.91(s,1H),5.73(dd,J＝17.7,8.7Hz,1H),5.35–5.26(m,1H),5.00(t,J＝9.3Hz,1H),4.64(s,1H),4.39(t,J＝7.6Hz,1H),4.06(d,J＝7.8Hz,1H),2.92(s,1H),2.63(d,J＝35.1Hz,3H),2.44–2.27(m,1H),1.98–1.79(m,3H),1.44(m,20H),1.12(m2H),0.91(m,1H)ppm。

Example 32:

the synthetic route is as follows:

step 1: synthesis of Compound 32-3

The compound 4-bromo-2-fluoronitrobenzene (32-1,3.30g,15mmol), 4-methoxyphenylboronic acid (32-2,2.74g,18mmol), Pd (PPh)₃)₄(0.5g,0.45mmol) and K₂CO₃(10.35g,75mmol) was dissolved in THF (80mL) and water (20mL), the reaction mixture was stirred at room temperature overnight under nitrogen, after completion of the reaction, saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give compound 32-3 as a yellow solid (3.2g, 87% yield).

MS(ESI,pos.ion)m/z:248.2[M+H]⁺。

Step 2 Synthesis of Compound 32-5

Compound 32-3(1.83g,7.4mmol) and compound 32-4(1.35g,7.4mmol) were dissolved in DMF (20mL) and K was added₂CO₃(1.12g,8.1mmol), heating the reaction mixture to 110 ℃ for reaction overnight, after the reaction is finished, adding water into the reaction liquid for quenching, adjusting the pH value to 2-3 by using 1N Cl, extracting by using ethyl acetate (50mL × 3), washing the extract by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, removing the organic solvent under reduced pressure to obtain an orange oily liquid 32-5 crude product, and directly carrying out the next reaction.

MS(ESI,pos.ion)m/z:410[M+H]⁺。

Step 3 Synthesis of Compound 32-6

The crude compound 32-5 was dissolved in glacial acetic acid (100mL), iron powder (2.1g, 37mmol) was added and the reaction mixture was warmed to 110 ℃ for 8 h. After the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated and poured into water (200mL) to precipitate a solid, the filtrate was filtered, and the cake was washed with water and dried to obtain a yellow solid compound 32-6(1.5g, yield in two steps: 64%).

MS(ESI,pos.ion)m/z:348[M+H]⁺。

Step 4 Synthesis of Compounds 32-7

Compound 32-6(1.5g,4.3mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring₃(1.3g,8.6mmol) and N, N-dimethylaniline (0.21g,1.8mmol) were added, and then the reaction mixture was refluxed at elevated temperature for 3 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give a pale yellow solid compound 32-7(1.0g, yield 65%).

MS(ESI,pos.ion)m/z:366[M+H]⁺。

Step 5 Synthesis of Compounds 32-8

N-Boc-4- (R) -hydroxyproline (2-7,1.0g,2.8mmol) was dissolved in DMF (20mL) and NaH (60% dispersed in mineral oil, 0.34g,8.4mmol) was added in portions under ice-bath and after addition the reaction mixture warmed to room temperature and stirred for 30 min. Compound 32-7(0.78g,3.3mmol) was dissolved in a small amount of DMF and added to the above solution and stirring was continued for 12 hours. After completion of the reaction, the reaction solution was poured into 30mL of water, the pH was adjusted to 2-3 with 1n cl, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 32-8(1.3g, yield 83%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:561[M+H]⁺。

Step 6 Synthesis of Compounds 32-9

Compounds 32-8(1.3g,2.3mmol), compounds 1-9(1.13g,2.8mmol), EDCI (570mg,3.0mmol) and HOAT (380mg,2.8mmol) were suspended in CH₂Cl₂(30mL), DIPEA (1.2mL,6.9mmol) was added under ice bath, after the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, after the reaction was completed, 10 mL of 1N aqueous hydrochloric acid solution was added to quench the reaction, followed by extraction with ethyl acetate (50mL × 3), organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate) Purification (V: V) ═ 2:1) afforded compound 32-9(1.6g, yield 89%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:723[M+H]⁺。

Step 7 Synthesis of Compounds 32-11

Compound 32-9(1.6g,2.07mmol) was dissolved in 5N HCl in ethyl acetate (20mL) and stirred at room temperature for 3 hours. After the reaction was completed, the organic solvent was removed under reduced pressure to obtain a solid compound 32-10.

Adding the solid compound 32-10 obtained above to CH₂Cl₂To (40mL) were then added compound 2-11(1.1g,2.37mmol), EDCI (490mg,2.56mmol) and HOAT (320mg,2.37 mmol), DIPEA (1.03mL,5.91mmol) was further added under ice bath, then the reaction liquid was warmed to room temperature and stirred for 4 hours after the reaction was completed, the reaction was quenched with 10 mL of 1N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1), to obtain light yellow solid compound 32-11(1.4g, yield 73%).

MS(ESI,pos.ion)m/z:926[M+H]⁺。

Step 8 Synthesis of Compounds 32-12

Compound 32-11(500mg,0.54mmol) was dissolved in 1, 2-dichloroethane (500mL), Grubbs second generation catalyst (50mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative HPLC to give the objective 32-12(330mg, yield 68%) as a white solid.

MS(ESI,pos.ion)m/z:898[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.29(s,1H),7.54(d,J＝8.5Hz,2H),7.48(d,J＝1.4Hz,1H),7.39–7.34(m,1H),7.14–7.03(m,3H),7.02–6.92(m,3H),5.99(s,1H),5.74(dd,J＝17.4,8.6Hz,1H),5.17(d,J＝6.1Hz,1H),5.02(t,J＝9.3Hz,1H),4.81–4.47(m,2H),4.38(s,1H),4.07(d,J＝9.0Hz,1H),3.93(s,3H),3.87(s,3H),2.93(s,1H),2.74–2.49(m,3H),2.34(dd,J＝16.6,8.2Hz,1H),2.02–1.80(m,5H),1.62(s,1H),1.39–1.28(m,15H),1.16–1.08(m,2H),0.94–0.86(m,2H)ppm；

HPLC purity: 95.68 percent.

Example 33:

the synthetic route is as follows:

step 1: synthesis of Compound 33-3

The compounds 4-bromo-2-fluoronitrobenzene (33-1,4.4g,20mmol), 4-methoxyphenylboronic acid (33-2, 3.73g,22mmol) and Pd (PPh)₃)₄(0.7g,0.6mmol) and K₂CO₃(13.8g,100mmol) was dissolved in acetonitrile and mixed in THF (80mL) and water (20mL) and stirred at room temperature overnight after the reaction was complete, saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), the extracts were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give compound 33-3 as a yellow solid (4.8g, yield 90%).

Step 2: synthesis of Compound 33-5

Compound 33-3(1.1g,6mmol), compound 33-4(1.6g,6mmol) were dissolved in DMF (20mL) and K was added₂CO₃(1.66g,12mmol) and the reaction mixtureThe mixture is heated to 110 ℃ for reaction overnight, after the reaction is finished, 20mL of water is added for quenching reaction, then 1N Cl is used for adjusting the pH value to 2-3, ethyl acetate is used for extraction (50mL × 3), organic phases are combined, extract liquor is washed by saturated sodium chloride solution, anhydrous sodium sulfate is used for drying, filtration is carried out, organic solvent is removed under reduced pressure, and an orange oily liquid 33-5 crude product is obtained and directly subjected to the next reaction.

MS(ESI,pos.ion)m/z:428[M+H]⁺。

And step 3: synthesis of Compound 33-6

The crude compound 33-5 was dissolved in glacial acetic acid (100mL), iron powder (1.68g,30mmol) was added and the reaction mixture was warmed to 110 ℃ for 8 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was poured into water (200mL) to precipitate a solid, which was then filtered, and the filter cake was washed with water and dried to obtain compound 33-6(2.1g, yield in two steps: 100%) as a yellow solid.

MS(ESI,pos.ion)m/z:366[M+H]⁺。

And 4, step 4: synthesis of Compound 33-7

Compound 33-6(1.0g,2.74mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring₃(0.84g,5.48mmol) and N, N-dimethylaniline (0.13g,1.09mmol), and after the completion of the addition, the reaction was refluxed at elevated temperature for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether) to give compound 33-7(700mg, yield 67%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:384[M+H]⁺。

And 5: synthesis of Compound 33-8

The compound N-Boc-4- (R) -hydroxyproline (2-7,795mg,3.4mmol) was dissolved in DMF (20mL) and NaH (60% dispersed in mineral oil, 348mg,8.7mmol) was added portionwise in ice bath and after addition the reaction mixture warmed to room temperature and stirred for 30 min. Compound 33-7(1.1g,2.9mmol) was dissolved in a small amount of DMF and added to the reaction and stirring was continued for 2 hours. After completion of the reaction, the reaction solution was poured into 30mL of water, the pH was adjusted to 2 to 3 with 1n hcl aqueous solution, extraction was performed with ethyl acetate (50mL × 3), organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 33 to 8(1.5g, yield 89%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:579[M+H]⁺。

Step 6: synthesis of Compound 33-9

Compounds 33-8(800mg,1.38mmol), compounds 1-9(668mg,1.66mmol), EDCI (344mg,1.8mmol) and HOAT (224mg,1.66mmol) were suspended in CH₂Cl₂(25mL), DIPEA (0.72mL,4.14mmol) was added under ice bath, and after completion of the addition, the reaction solution was warmed to room temperature and stirred for 4 hours, after completion of the reaction, the reaction was quenched with 1N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give a pale yellow solid compound 33-9(1.0g, yield 91%). MS (ESI, pos.ion) M/z:791[ M + H ]: 791]⁺。

And 7: synthesis of Compound 33-11

Compound 33-9(1.0g,1.26mmol) was dissolved in 5N HCl in ethyl acetate (20mL) and stirred at room temperature for 3 hours. After the reaction was completed, the organic solvent was removed under reduced pressure. The residue obtained is substituted by CH₂Cl₂(20mL) was diluted, followed by addition of compounds 2-11(634mg,1.4mmol), EDCI (290mg,1.52mmol) and HOAT (190mg,1.4mol), DIPEA (0.6mL,3.51mmol) was added in ice bath, and after completion of the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours after completion of the reaction, the reaction was quenched with 10 mL of 1N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate (50mL × 3), the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (V) V) ═ 2:1) to give the compound 33-11(1.0g, yield 84%) as a pale yellow solid. MS (ESI, pos.ion) M/z 944[ M + H ]]⁺。

And 8: synthesis of Compounds 33-12

Compound 33-11(500mg,0.53mmol) was dissolved in 1, 2-dichloroethane (300mL), Grubbs's second generation catalyst (50mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative HPLC to give compound 33-12(300mg, yield 62%) as a white solid.

MS(ESI,pos.ion)m/z:916[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.33(s,1H),7.49(d,J＝8.4Hz,1H),7.36–7.30(m,4H),7.28–7.23(m,1H),7.04–7.00(m,1H),6.78–6.62(m,2H),5.93(s,1H),5.74(dd,J＝17.0,8.4Hz,1H),5.24(s,1H),5.01(t,J＝9.3Hz,1H),4.79–4.43(m,2H),4.42–4.30(m,1H),4.04(d,J＝8.8Hz,1H),3.95(s,3H),3.84(s,3H),2.93(s,1H),2.74–2.49(m,3H),2.35(d,J＝8.3Hz,1H),1.99–1.72(m,5H),1.61(s,1H),1.45–1.31(m,15H),1.18–1.07(m,2H),0.98–0.89(m,2H)ppm；

HPLC purity: 94.25 percent.

Example 34:

the synthetic route is as follows:

step 1: synthesis of Compound 34-3

The compound 4-bromo-2-fluoronitrobenzene (34-1,4.4g,20mmol) and 4-methoxyPhenylboronic acid (34-2, 3.73g,22mmol), Pd (PPh)₃)₄(0.7g,0.6mmol) and K₂CO₃(13.8g,100mmol) was dissolved in acetonitrile and mixed in THF (80mL) and water (20mL) and the reaction mixture was stirred at room temperature overnight after the reaction was complete, saturated sodium chloride solution (200mL) was added and quenched, ethyl acetate was extracted (3 × 50mL), the organic phases were combined, the extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the organic solvent was removed under reduced pressure to give compound 34-3 as a yellow solid (4.8g, 90% yield).

Step 2: synthesis of Compound 34-5

Compound 34-3(1.0g,6mmol), compound 34-4(1.6g,6mmol) were dissolved in DMF (20mL) and K was added₂CO₃(1.66g,12mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding 30 mL of water to quench the reaction after the reaction is finished, adjusting the pH to 2-3 by using 1N Cl, extracting by using ethyl acetate (50mL × 3), washing an extract by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, removing an organic solvent under reduced pressure to obtain a crude product of an orange oily liquid 34-5, and directly carrying out the next reaction.

MS(ESI,pos.ion)m/z:416[M+H]⁺。

And step 3: synthesis of Compound 34-6

The crude compound 34-5 was dissolved in glacial acetic acid (100mL), iron powder (1.68g,30mmol) was added, and the reaction was allowed to warm to 110 ℃ for 8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filtrate was poured into water (200mL) to precipitate a solid, which was then filtered, and the filter cake was washed with water and dried to obtain compound 34-6(1.9g, 89% yield in two steps) as a yellow solid.

MS(ESI,pos.ion)m/z:354[M+H]⁺。

And 4, step 4: synthesis of intermediate 34-7

Compound 34-6(1.0g,2.74mmol) was suspended in toluene (20mL) and POCl was added slowly with stirring₃(0.84g,5.48mmol) and N, N-dimethylaniline (0.14g,1.13mmol) were added and the reaction mixture was heated to reflux Should be 3 hours. After the completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether) to give pale yellow solid compound 34-7(870mg, yield 85%).

MS(ESI,pos.ion)m/z:372[M+H]⁺。

And 5: synthesis of Compound 34-8

The compound N-Boc-4- (R) -hydroxyproline (2-7,688mg,2.81mmol) was dissolved in DMF (20mL), NaH (60% dispersed in mineral oil, 280mg,7.02mmol) was added portionwise in ice bath, and after the addition was complete, the reaction was warmed to room temperature and stirred for 30 min. Compound 34-7(870mg,2.34mmol) was dissolved in a small amount of DMF and added to the above reaction solution, followed by stirring for 2 hours. After the reaction was completed, the reaction solution was poured into 300mL of water, the pH was adjusted to 2-3 with 1n hcl, followed by extraction with ethyl acetate (50mL × 3), organic phases were combined, the extracted phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain a pale yellow solid compound 34-8(800mg, yield 60%).

Step 6: synthesis of Compound 34-9

Compounds 34-8(800mg,1.41mmol), compounds 1-9(680mg,1.69mmol), EDCI (350mg,1.83mmol) and HOAT (228mg,1.69mmol) were suspended in CH₂Cl₂To (25mL), DIPEA (0.7mL,4.23mmol) was added under ice bath, and after completion of the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, after completion of the reaction, the reaction was quenched with 1N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 34-9(650mg, yield 59%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:779[M+H]⁺。

And 7: synthesis of Compound 34-11

Compound 34-9(650mg,0.83mmol) was dissolved in 5N HCl in EtOAc (20mL) and stirred at room temperature for 3 h. After the reaction was completed, the organic solvent was removed under reduced pressure to obtain compound 34-10 as a white solid. Adding the obtained white solid compound 34-10 to CH₂Cl₂To (20mL) were then added compound 2-11(380mg,0.84mmol), EDCI (174mg,0.91mmol) and HOAT (113mg,0.84mol), DIPEA (0.37mL,2.1mmol) was added under ice bath, the reaction mixture was warmed to room temperature and stirred for 4 hours, after the reaction was completed, the reaction was quenched with 1N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 34-11 as a pale yellow solid (650mg, yield 83%).

MS(ESI,neg.ion)m/z:930[M-H]^-。

And 8: synthesis of Compounds 34-12

Compound 34-11(650mg,0.70mmol) was dissolved in 1, 2-dichloroethane (300mL), GrubbsI second generation catalyst (70mg) was added under nitrogen, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative HPLC to give the target 34-12(300mg, yield 48%) as a white solid.

MS(ESI,pos.ion)m/z:904[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.36(s,1H),7.61–7.51(m,1H),7.37–7.29(m,4H),7.14(s,1H),7.03(t,J＝8.4Hz,1H),6.98–6.83(m,2H),5.93(s,1H),5.73(dd,J＝17.8,8.7Hz,1H),5.26(d,J＝7.5Hz,1H),5.00(t,J＝9.4Hz,1H),4.74–4.48(m,2H),4.35(dd,J＝13.0,5.3Hz,1H),4.10–3.98(m,1H),3.95(s,3H),2.93(s,1H),2.70–2.51(m,3H),2.35(dd,J＝16.7,8.2Hz,1H),2.00–1.78(m,4H),1.73–1.51(m,2H),1.41–1.27(m,14H),1.16–1.07(m,2H),0.96–0.87(m,2H)ppm；

HPLC purity: 96.01 percent.

Example 35:

the synthetic route is as follows:

step 1: synthesis of Compound 35-2

Dissolving compound 35-0(3g,13.63mmol) and compound 35-1(2.63g,18.65mmol) in 50mL DMF, adding K₂CO₃(2.96g,21.5mmol) and after the addition the reaction mixture was warmed to 110 ℃ under reflux and reacted overnight. Cooled to room temperature, 100mLEtOAc was added, and the mixture was washed with H₂O rinse (100mL × 2), 50mL saturated brine wash, anhydrous Na₂SO₄Drying and removing the organic solvent under reduced pressure. 35-2 was obtained as a yellow solid (4g, yield: 86.95%).

Step 2: synthesis of Compound 35-3

Compound 35-2(4.0g,11.72mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100ml of 1N HCl aqueous solution to precipitate a large amount of white solid, filtered, the filter cake was washed with water, and the obtained white solid was dried under vacuum to obtain 35-3(3.0g, yield: 91.74%) which was directly subjected to the next reaction without further purification.

And step 3: synthesis of Compound 35-4

Compound 35-3(1.0g,3.58mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly, the temperature was raised to 110 ℃ and the reaction was carried out for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 35-4(1.0g, 94.34%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 35-5

Sodium hydride (60% in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF and cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added and after addition the reaction mixture was warmed to 30 ℃ and stirred for two hours. A solution of compound 35-4(1.1g,3.7mmol) in 5ml of anhydrous tetrahydrofuran was added to the above reaction solution, after which the reaction was continued overnight. After completion of the reaction, the reaction was quenched with 20mL of water at 0 ℃, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 35-5(1.0g, yield: 56%) as a white solid.

And 5: synthesis of Compound 35-6

Compound 35-5(1.0g,2.0mmol), compound 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged into a round-bottomed flask, under nitrogen, 30 mL of dichloromethane were added, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction was warmed to 30 deg.C and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 35-6(0.86g, yield 60%) as a white solid.

Step 6: synthesis of Compound 35-8

Compound 35-6(0.86g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the resulting white solid with 20 ml of ethyl acetate.

The solid from the above filtration, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 4 hours. The reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 35-8(0.92g, yield: 98%) as a white solid.

MS(ESI,pos.ion)m/z:858.5[M+H]⁺。

And 7: synthesis of Compound 35-9

Compound 35-8(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. Cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 35-9(0.25g, yield: 48%) as a white solid. MS (ESI, pos.ion) M/z 830.9[ M + H ] ]⁺；

¹HNMR(400MHz,DMSO-d₆):11.19(s,1H),9.08(s,1H),7.76(d,J＝6.3Hz,2H),7.60(d,J＝8.3Hz,1H),7.39–7.30(m,1H),7.30–7.25(m,1H),7.18(dd,J＝26.9,23.4Hz,2H),5.85(d,J＝29.2Hz,1H),5.60(s,1H),5.08(s,1H),4.55(dd,J＝30.9,22.6Hz,2H),4.00(d,J＝38.9Hz,2H),2.89(s,1H),2.05–1.86(m,1H),1.69(d,J＝42.1Hz,2H),1.59(s,2H),1.49–0.69(m,22H)ppm；

HPLC purity: 90.49 percent.

Example 36:

the synthetic route is as follows:

step 1: synthesis of Compound 36-2

Dissolving compound 36-0(4.0g,12mmol) and compound 36-1(2.31g,13.6mmol) in 15mL DMF, adding K₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction solution was cooled to room temperature, and then 100ml of LEtOAc was added thereto with H₂O wash (100mL × 2), 50mL saturated brine wash, and dry Na over the organic phase₂SO₄Drying and removal of the organic solvent under reduced pressure gave 36-2(4.0g, yield: 95%) as a yellow solid which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 36-3

Compound 36-2(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction is completed, cooling to room temperature, filtering out solids, pouring the filtrate into 200 ml of 1N HCl solution, precipitating a large amount of white solids, filtering, and drying the obtained white solids under vacuum condition to obtain the target compound 36-3(3.0g, yield: 91%); the reaction was carried out without further purification.

And step 3: synthesis of Compound 36-4

Compound 36-3(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. The reaction was checked by TLC, after completion of the reaction, cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 36-4(1.1g, yield 100%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 36-5

Sodium hydride (60% in mineral oil 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added, after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. 5ml of an anhydrous tetrahydrofuran solution containing compound 36-4(1.1g,3.6mmol) was added to the above reaction solution, after which the reaction was continued overnight. The reaction was quenched with 20mL of water at 0 ℃, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 36-5 as a white solid (1.0g, yield: 56%).

And 5: synthesis of Compound 36-6

Compound 36-5(1.0g,2.0mmol), Compound 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged into a round-bottomed flask, 30 mL of dichloromethane was added under nitrogen protection, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, and the reaction was warmed to 30 deg.C and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 36-6(0.86g, yield 60%) as a white solid.

Step 6: synthesis of Compounds 36-8

Compound 36-6(0.82g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the resulting white solid with 20ml of ethyl acetate.

The solid obtained above, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask, under nitrogen, 20mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 4 hours. The reaction was quenched with 10 ml of water, extracted twice with 10 ml of ethyl acetate, the organic phases were combined, the organic phase was washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 36-8 as a white solid (0.92g, yield 98%).

MS(ESI,pos.ion)m/z:836.5[M+H]⁺。

And 7: synthesis of Compounds 36-9

Compound 36-8(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, the temperature was then raised to 65 ℃ and the reaction mixture was stirred at this temperature for 48 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 36-9(0.25g, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:810.4[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆):11.13(s,1H),7.61(dd,J＝8.4,6.9Hz,1H),7.26(dd,J＝9.3,2.1Hz,1H),7.13(dd,J＝18.9,5.3Hz,2H),6.74(dt,J＝8.7,2.9Hz,2H),5.89–5.76(m,1H),5.61(d,J＝7.4Hz,1H),5.22–4.93(m,1H),4.69–4.39(m,2H),4.06(s,1H),3.97–3.84(m,1H),3.73(s,3H),2.90(s,1H),2.72–2.53(m,2H),2.45–2.25(m,2H),1.72(t,J＝22.6Hz,2H),1.65–1.50(m,2H),1.53–0.67(m,22H)ppm；

HPLC purity: 97.43 percent.

Example 37:

the synthetic route is as follows:

step 1: synthesis of Compound 37-2

Dissolving compound 37-0(4.0g,12mmol) and compound 37-1(2.31g,13.6mmol) in 15mL DMF, adding K₂CO₃(3.41g,24.7mmol), after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 100ml of LEtOAc was added, and the reaction mixture was washed with H₂O wash (100mL × 2), 50mL saturated brine wash, and dry Na over the organic phase₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 37-2(4.0g, yield: 95%) as a yellow solid which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 37-3

Compound 37-2(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100 ml of 1N HCl aqueous solution to precipitate a large amount of white solid, and the obtained white solid was filtered and dried under vacuum to obtain compound 37-3(3.0g, yield: 91%).

And step 3: synthesis of Compound 37-4

The compound 37-3(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was slowly added, the reaction solution was heated to 110 ℃ and reacted for 6 hours. After completion of the reaction, it was cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 37-4(1.1g, 100%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 37-5

Sodium hydride (60% dispersed in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added, after which the reaction mixture was warmed to 30 ℃ and stirred for two hours.

A solution of compound 37-4(1.1g,3.6mmol) in 5ml of anhydrous tetrahydrofuran was added to the above reaction solution, followed by reaction overnight. After completion of the reaction, the reaction was quenched with 20mL of water at 0 ℃, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 37-5(1.0g, yield: 56%) as a white solid compound

And 5: synthesis of Compound 37-6

Compounds 37-5(1.0g,2.0mmol), compounds 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were added to a round bottom flask, protected with nitrogen, 30 mL of dichloromethane were added, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, warmed to 30 deg.C and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 37-6(0.86g, yield 60%) as a white solid.

Step 6: synthesis of Compounds 37-8

Compound 37-6(0.83g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained above, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask, under nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 37-8(0.92g, yield 98%) as a white solid.

And 7: synthesis of Compounds 37-9

The compound 37-8(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred at this temperature for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 37-9(0.25g, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:814.3[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆):11.12(s,1H),8.99(s,1H),7.69–7.61(m,1H),7.34(dd,J＝5.8,3.6Hz,1H),7.26(d,J＝8.9Hz,1H),7.20(m,1H),7.12(s,1H),5.79(s,1H),5.62(d,J＝7.9Hz,1H),5.07(s,1H),4.68(d,J＝11.0Hz,1H),4.54–4.47(m,1H),4.03(dd,J＝14.2,7.1Hz,2H),3.88(d,J＝10.1Hz,1H),2.90(s,1H),1.99(s,1H),1.91(s,1H),1.74(d,J＝10.3Hz,2H),1.62–1.50(m,2H),1.35(s,5H),1.27–0.91(m,18H)ppm；

HPLC purity: 94.18 percent.

Example 38:

the synthetic route is as follows:

step 1: synthesis of Compound 38-2

Dissolving compound 38-0(4.0g,12mmol) and compound 38-1(2.31g,13.6mmol) in 15mL DMF, adding K₂CO₃(3.41g,24.7mmol) and then the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 100ml of LEtOAc was added, and the reaction mixture was washed with H₂O washing (100mL × 2), 50mL saturated brine washingOnce washed, the organic phase is treated with anhydrous Na₂SO₄Drying and removal of the organic solvent under reduced pressure gave 38-2(4.0g, yield: 95%) as a yellow solid which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 38-3

Compound 38-2(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100ml of 1N HCl aqueous solution to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain compound 38-3(3.0g, yield: 91%).

And step 3: synthesis of Compound 38-4

Compound 38-3(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was slowly added, the reaction solution was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, the reaction mixture was cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give 38-4(1.1g, 100%) as a pale yellow solid product.

And 4, step 4: synthesis of Compound 38-5

Sodium hydride (60% dispersed in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added, after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. A solution of compound 38-4(1.1g,3.6mmol) in 5ml of anhydrous tetrahydrofuran was added to the above reaction solution, followed by reaction overnight. The reaction was quenched with 20mL of water at 0 ℃, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 38-5 as a white solid (1.0g, yield: 56%).

And 5: synthesis of Compound 38-6

Compound 38-5(1.0g,2.0mmol), compound 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were added to a round bottom flask, under nitrogen, 30 mL of dichloromethane were added, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 38-6(0.86g, yield 60%) as a white solid.

Step 6: synthesis of Compound 38-8

Compound 38-6(0.83g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added until the reaction was complete when no gas was evolved. Filtration and washing of the filter cake with 20 ml of ethyl acetate. The resulting solid, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged to a round bottom flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The temperature was raised to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 38-8(0.92g, yield 98%) as a white solid.

And 7: synthesis of Compound 38-9

Compound 38-8(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred at this temperature for 48 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 38-9(0.25g, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:814.3[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆):11.12(s,1H),8.98(s,1H),7.61(dd,J＝8.6,6.6Hz,1H),7.41(d,J＝1.8Hz,1H),7.37–7.31(m,1H),7.27(dt,J＝13.7,5.3Hz,2H),7.13(s,1H),5.78(s,1H),5.69–5.56(m,1H),5.07(t,J＝9.3Hz,1H),4.67(d,J＝11.8Hz,1H),4.50(dd,J＝9.5,7.2Hz,1H),4.03(s,1H),3.88(d,J＝10.0Hz,1H),3.17(d,J＝5.2Hz,1H),2.90(d,J＝5.5Hz,1H),2.59(dd,J＝13.8,6.2Hz,2H),2.42–2.27(m,2H),1.74(d,J＝10.9Hz,2H),1.63–1.52(m,2H),1.37–0.95(m,20H)ppm；

HPLC purity: 96.03 percent.

Example 39:

the synthetic route is as follows:

step 1: synthesis of Compound 39-2

Dissolving compound 39-0(4.0g,12mmol) and compound 39-1(2.31g,13.6mmol) in 15mL DMF, adding K₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 100ml of LEtOAc was added, and the reaction mixture was washed with H₂O wash (100mL × 2), 50mL saturated brine wash, and dry Na over the organic phase₂SO₄Drying and removal of the organic solvent under reduced pressure gave 39-2(4.0g, yield: 95%) as a yellow solid which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 39-3

Compound 39-2(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, then reduced iron powder (3.2g,57.25mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100ml of 1N HCl aqueous solution to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain compound 39-3(3.0g, yield: 91%).

And step 3: synthesis of Compound 39-4

Compound 39-3(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was slowly added, the reaction solution was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, the reaction solution was cooled to 0 ℃ and 5mL of water was added to quench the reaction, which was then washed with water (10mL × 2), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give a pale yellow solid product 39-4(1.1g, 100%) which was directly subjected to the next reaction without further purification.

And 4, step 4: synthesis of Compound 39-5

Sodium hydride (60% dispersed in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added, after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing compound 39-4(1.1g,3.6mmol) was further added to the above reaction solution, and then the reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was cooled to 0 ℃, quenched with 20mL of water, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V): 2:1) to give 39-5(1.0g, yield: 56%) as a white solid compound

And 5: synthesis of Compound 39-6

Compounds 39-5(1.0g,2.0mmol), compounds 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were added to a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, 10 mL of water was added to quench the reaction, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 39-6(0.86g, yield 60%) as a white solid.

Step 6: synthesis of Compounds 39-8

Compound 39-6(0.91g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained above, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask, under nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 39-8(0.92g, yield 98%) as a white solid.

And 7: synthesis of Compounds 39-9

The compound 39-8(0.53g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred at this temperature for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain purified compound 39-9(0.25g, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:886.0[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆):11.13(s,1H),9.01(s,1H),7.66–7.57(m,1H),7.26(d,J＝8.5Hz,1H),7.20–7.04(m,3H),6.80–6.69(m,2H),5.81(s,1H),5.61(d,J＝7.1Hz,1H),5.07(s,1H),4.58(t,J＝15.6Hz,1H),4.54–4.46(m,1H),4.06(s,1H),3.90(d,J＝8.8Hz,1H),3.73(s,3H),2.90(s,1H),2.70–2.53(m,2H),2.35(d,J＝9.0Hz,2H),1.75(d,J＝9.0Hz,2H),1.59(dd,J＝16.8,9.0Hz,2H),1.31(d,J＝40.2Hz,6H),1.28–0.41(m,18H)ppm；

HPLC purity: 95.43 percent.

Example 40:

the synthetic route is as follows:

step 1: synthesis of Compound 40-2

Dissolving compound 40-0(4.0g,12mmol) and compound 40-1(2.31g,13.6mmol) in 15ml DMF, adding K₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After the reaction was complete, the reaction was cooled to room temperature, 100ml of LEtOAc was added, and the organic phase was washed with H₂O wash (100mL × 2), 50mL saturated brine rinse once, anhydrous Na₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 40-2(4.0g, yield: 95%) as a yellow solid which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 40-3

Compound 40-2(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100ml of 1N HCl aqueous solution to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain Compound 40-3(3.0g, yield: 91%).

And step 3: synthesis of Compound 40-4

Compound 40-3(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was slowly added, the reaction solution was warmed to 110 ℃ and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to 0 ℃, 5mL of water was added to quench the reaction, the organic phase was washed with water (10mL × 2), once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give a pale yellow solid product 40-4(1.1g, 100%) which was directly subjected to the next reaction without further purification.

And 4, step 4: synthesis of Compound 40-5

Sodium hydride (60% dispersed in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10ml of anhydrous DMF was added, after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing compound 40-4(1.1g,3.6mmol) was further added to the above reaction solution, followed by stirring overnight. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 20mL of water, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 40 to 5(1.0g, yield: 56%) as a white solid compound.

And 5: synthesis of Compound 40-6

Compound 40-5(1.0g,2.0mmol), compound 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were added to a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 40-6(0.86g, yield 60%) as a white solid.

Step 6: synthesis of Compounds 40-8

Compound 40-6(0.82g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20ml of ethyl acetate and then dried in vacuo.

The solid from the above reaction, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask, 20mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 40-8(0.92g, yield 98%) as a white solid.

And 7: synthesis of Compound targets 40-9

Compound 40-8(0.48g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 40-9(0.25g, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:810.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.50(d,J＝91.5Hz,1H),7.20–7.15(m,1H),7.11–7.01(m,3H),7.00(dd,J＝8.6,2.4Hz,1H),6.86(t,J＝6.9Hz,1H),5.89(s,1H),5.70(dd,J＝17.9,8.6Hz,1H),5.40(t,J＝20.8Hz,1H),4.97(t,J＝9.0Hz,1H),4.66(d,J＝38.8Hz,1H),4.46(dd,J＝54.5,22.1Hz,1H),4.36(d,J＝6.9Hz,1H),4.15–4.08(m,1H),4.03(d,J＝9.2Hz,1H),3.90(s,3H),2.89(s,1H),2.59(d,J＝44.2Hz,3H),2.34(dt,J＝14.9,7.4Hz,1H),2.04(s,1H),1.88(d,J＝37.4Hz,3H),1.52–1.20(m,20H)ppm；

HPLC purity: 93.36 percent.

Example 41:

the synthetic route is as follows:

step 1: synthesis of Compound 41-2

Dissolving compound 41-0(4.0g,12mmol) and compound 41-1(2.31g,13.6mmol) in 15mL DMF, adding K₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction solution was cooled to room temperature, 100ml of LEtOAc was added, and the mixture was reacted with H₂O wash (100mL × 2) and the organic phase washed once with 50mL saturated brine, anhydrous Na₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 41-2 as a yellow solid (4.0g, yield: 95%).

Step 2: synthesis of Compound 41-3

Compound 41-2(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the solid was filtered off, the filtrate was poured into 100ml of 1N HCl solution, a large amount of white solid was precipitated, and the obtained white solid was filtered off and dried under vacuum to obtain compound 41-3(3.0g, yield: 91%).

And step 3: synthesis of Compound 41-4

Compound 41-3(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. After completion of the reaction, the reaction solution was cooled to 0 ℃ and 5mL of water was added to quench the reaction, the organic phase was washed with water (10 mL. times.2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain compound 41-4(0.97g, yield: 100%) as a pale yellow solid, which was then subjected to the next reaction without further purification.

And 4, step 4: synthesis of Compound 41-5

Sodium hydride (60% in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10ml of anhydrous DMF was added, after which the temperature was raised to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing compound 41-4(1.1g,3.6mmol) was added to the above reaction solution, followed by stirring overnight. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 20mL of water, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 41-5(1.0g, yield: 56%) as a white solid.

And 5: synthesis of Compound 41-6

Compounds 41-5(1.0g,2.0mmol), compounds 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were added to a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with 20mL of ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 41-6(0.86g, yield 60%) as a white solid.

Step 6: synthesis of Compounds 41-8

Compound 41-6(0.86g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas was evolved. Filtration and washing of the resulting white solid with 20ml of ethyl acetate.

The solid from the above reaction, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask, protected with nitrogen, 20mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 41-8(0.92g, yield 98%) as a white solid.

And 7: synthesis of target 41-9

The compound 41-8(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 41-9(0.25g, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:810.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.58–10.23(m,1H),7.47(d,J＝9.0Hz,1H),7.16(dd,J＝9.6,5.9Hz,1H),6.91–6.82(m,2H),6.68(d,J＝7.1Hz,2H),5.87(s,1H),5.73(dd,J＝17.9,8.7Hz,1H),5.39–5.08(m,1H),4.98(dd,J＝22.7,13.0Hz,1H),4.61(t,J＝7.2Hz,1H),4.51(d,J＝11.1Hz,1H),4.36(t,J＝7.7Hz,1H),4.03(d,J＝9.8Hz,1H),3.84(s,3H),2.92(dd,J＝12.5,7.8Hz,1H),2.69–2.49(m,3H),2.39–2.27(m,1H),2.12–1.79(m,4H),1.77(s,3H),1.31(d,J＝21.9Hz,19H)ppm；

HPLC purity: 92.14 percent.

Example 42:

the synthetic route is as follows:

step 1: synthesis of Compound 42-2

Mixing compound 42-0(2.2g,10mmol), compound 42-1(1.5g,11mmol), Pd (PPh)₃)₄(0.35g,0.3mmol) and K₂CO₃(6.9g,50mmol) was dissolved in a mixture solvent of THF (60mL) and water (5mL), the solution was heated to 80 ℃ under nitrogen protection and stirred overnight, after the reaction was completed, a saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 50mL), the organic phases were combined, the extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 42-2 as a yellow solid (2.4g, yield: 96%))。

Step 2: synthesis of Compound 42-4

Compound 42-2(2.25g,9.57mmol) and compound 42-3(1.79g,13.6mmol) were dissolved in 15mL DMF, and K was added thereto₂CO₃(2.64g,19.1mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with 100ml of LEtOAc, and then diluted with H₂O wash (100mL × 2), 50mL saturated brine wash, and dry Na over the organic phase₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 42-4(3.2g, yield: 87%) as a yellow solid which was carried on to the next reaction without further purification.

MS(ESI,pos.ion)m/z:386[M+H]⁺。

And step 3: synthesis of Compound 42-5

Compound 42-4(3.2g,8.3mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100ml of 1N HCl solution to precipitate a large amount of white solid, and the obtained white solid was filtered and dried under vacuum to obtain compound 42-5(2.6g, yield: 97%).

MS(ESI,pos.ion)m/z:324.1[M+H]⁺。

And 4, step 4: synthesis of Compound 42-6

Compound 42-5(1.0g,3.1mmol) was added to 20mL of toluene, phosphorus oxychloride (0.6mL,6.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.16mL,1.3mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. After completion of the reaction, the reaction mixture was cooled to 0 ℃ and quenched with 5mL of water, and the organic phase was washed with water (10 mL. times.2) and then once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain Compound 42-6(0.75g, yield: 71%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:342[M+H]⁺。

And 5: synthesis of Compound 42-7

Sodium hydride (60% in mineral oil, 0.26g,6.5mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(0.56g,2.4mmol) in 10 ml of anhydrous DMF was added, after which the temperature was raised to 30 ℃ and stirred for two hours. Then, 5 ml of an anhydrous tetrahydrofuran solution containing compound 42-6(0.75g,2.2mmol) was added to the above reaction solution, followed by overnight reaction. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 20mL of water, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 42-7(1.2g, yield: 100%) as a white solid

MS(ESI,neg.ion)m/z:535[M-H]^-。

Step 6: synthesis of Compound 42-8

Compounds 42-7(1.2g,2.2mmol), compounds 1-9(1.1g,2.7mmol), EDCI (0.56g,2.9mmol) and HOAT (0.37g,2.7mmol) were added to a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.2mL,6.9mmol) was added and the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 42-8(1.2g, yield 72%) as a white solid.

And 7: synthesis of Compounds 42-10

Compound 42-8(1.2g,1.6mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas was evolved. The reaction mixture was filtered and the filter cake was rinsed with 20 ml of ethyl acetate.

The solid from the above reaction, compound 2-11(0.7g,2mmol), EDCI (0.33g,1.7mmol) and HOAT (0.22g,1.6mmol) were charged into a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.7mL,4mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 42-10(0.98g, yield 80%) as a white solid.

And 8: synthesis of target 42-11

The compound 42-10(0.4g,0.4mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.05 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred at this temperature for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 42-11(0.24g, yield: 60%) as a white solid.

MS(ESI,pos.ion)m/z:874[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.34(s,1H),7.66–7.51(m,1H),7.49–7.42(m,1H),7.41–7.36(m,2H),7.36–7.29(m,2H),7.22(t,1H),7.20–7.13(m,1H),7.13(s,1H),6.98–6.83(m,2H),5.95(s,1H),5.74(dd,J＝17.7,8.7Hz,1H),5.21(d,J＝7.4Hz,1H),5.01(t,J＝9.4Hz,1H),4.75–4.53(m,2H),4.42–4.31(m,1H),4.13–3.98(m,1H),2.93(s,1H),2.74–2.48(m,3H),2.41–2.30(m,1H),1.99–1.69(m,6H),1.45–1.32(m,11H),1.25–1.04(m,3H),1.00–0.78(m,4H)ppm；

HPLC purity: 96.15 percent.

Example 43:

the synthetic route is as follows:

step 1: synthesis of Compound 43-2

Mixing compound 43-0(1.1g,5mmol), compound 43-1(1.0g,5mmol), Pd (PPh)₃)₄(0.17g,0.15mmol) and K₂CO₃(3.5g,25mmol) was added to a mixed solvent of THF (60mL) and water (15mL), the reaction mixture was heated to reflux under nitrogen, stirred overnight, after completion of the reaction, a saturated sodium chloride solution (100mL) was added to quench, followed by extraction with ethyl acetate (3 × 50mL), the extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give compound 43-2 as a yellow solid (1.3g, yield: 89%).

Step 2: synthesis of Compound 43-4

Compound 43-2(1.32g,4.46mmol) and compound 43-3(0.76g,4.5mmol) were dissolved in 20mL DMF, K was added₂CO₃(1.3g,9.3mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 100ml of LEtOAc was added, and the reaction mixture was washed with H₂O wash (100mL × 2) followed by 50mL brine and the organic phase over anhydrous Na₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 43-4(0.94g, yield: 4) as a yellow solid 7%) was carried out without further purification in the next reaction.

MS(ESI,pos.ion)m/z:446[M+H]⁺。

And step 3: synthesis of Compound 43-5

Compound 43-4(0.94g,2.1mmol) was dissolved in 15mL of glacial acetic acid, and then reduced iron powder (0.6g,10mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 50 ml of 1N HCl solution to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain Compound 43-5(0.8g, yield: 99%). MS (ESI, pos.ion) M/z 384[ M + H ]]⁺。

And 4, step 4: synthesis of Compound 43-6

Compound 43-5(0.94g,2.4mmol) was added to 20mL of toluene, phosphorus oxychloride (0.45mL,4.9mmol) was added under nitrogen, then N, N-dimethylaniline (0.12mL,0.98mmol) was added slowly, the temperature was raised to 110 ℃ and the reaction was carried out for 6 hours. After completion of the reaction, the reaction mixture was cooled to 0 ℃ and 5mL of water was added to quench the reaction, and the organic phase was washed with water (10 mL. times.2), once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain Compound 43-6(0.68g, yield: 69%) as a pale yellow solid.

And 5: synthesis of Compounds 43-7

Sodium hydride (60% dispersed in mineral oil, 0.2g,5mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(0.43g,1.9mmol) in 10ml of anhydrous DMF was added and the reaction mixture was then warmed to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing compound 43-6(0.68g,1.7mmol) was further added to the above reaction solution, followed by reaction overnight. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 20ml of water, and washed with 20ml of ethyl acetate. The aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, followed by extraction with ethyl acetate (20 mL. times.3), the organic phases were combined, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 43-7(1.0g, yield: 99%) as a white solid

MS(ESI,neg.ion)m/z:595[M-H]^-。

Step 6: synthesis of Compound 43-8

Compounds 43-7(1.0g,1.7mmol), compounds 1-9(0.81g,2.0mmol), EDCI (0.43g,2.2mmol) and HOAT (0.27g,2.0mmol) were charged into a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.9mL,5mmol) was added and the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 43-8(0.9g, yield 70%) as a white solid.

MS(ESI,pos.ion)m/z:809[M+H]⁺。

And 7: synthesis of Compounds 43-10

Compound 43-8(0.9g,1mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 20ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. The reaction mixture was filtered, and the resulting white solid was washed with 20ml of ethyl acetate.

The solid from the above reaction, compound 2-11(0.54g,1.2mmol), EDCI (0.25g,1.3mmol) and HOAT (0.17g,1.2mmol) were charged into a round bottom flask, 20mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.52mL,3mmol) was added, after which the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 43-10(0.78g, yield 82%) as a white solid.

And 8: synthesis of Compounds 43-11

The compound 43-10(0.5g,0.5mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.05 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. The reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 43-11(0.17g, yield: 40%) as a white solid.

MS(ESI,pos.ion)m/z:934[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.36(s,1H),7.70(m,1H),7.63–7.50(m,1H),7.40–7.31(m,2H),7.31–7.18(m,5H),6.97–6.84(m,2H),5.94(s,1H),5.73(dd,J＝17.7,8.7Hz,1H),5.25(d,J＝7.3Hz,1H),5.07–4.96(m,1H),4.80–4.49(m,2H),4.40–4.29(m,1H),4.12–4.00(m,1H),2.93(s,1H),2.74–2.50(m,3H),2.40–2.29(m,1H),2.00–1.72(m,6H),1.49–1.33(m,11H),1.22–1.07(m,3H),0.98–0.83(m,4H)ppm；

HPLC purity: 97.29 percent.

Example 44:

the synthetic route is as follows:

step 1: synthesis of Compound 44-3

Compound 9-10(0.11g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. Filtration and washing of the resulting white solid with 20 ml of ethyl acetate, compound 44-1 was dried in vacuo.

The compound 44-1, compound 44-2(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged to a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 44-3(0.70g, yield 59%) as a white solid.

MS(ESI,pos.ion)m/z:789.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.40(s,1H),7.97(d,J＝5.9Hz,1H),7.70(s,1H),7.55–7.44(m,1H),7.30–7.26(m,1H),7.20–7.11(m,3H),6.91(d,J＝7.3Hz,1H),6.78(t,J＝7.3Hz,1H),6.19(s,1H),5.95(s,1H),5.75(d,J＝8.5Hz,1H),5.00(t,J＝8.7Hz,1H),4.83(d,J＝7.4Hz,1H),4.71–4.55(m,2H),4.12(d,J＝7.9Hz,1H),2.92(s,1H),2.66(s,3H),2.41(s,3H),2.35–2.26(m,1H),2.20–2.08(m,1H),2.02–1.60(m,7H),1.46–1.38(m,3H),0.94–0.79(m,4H)ppm；

HPLC purity: 92.01 percent.

Example 45:

the synthetic route is as follows:

step 1: synthesis of Compound 45-3

Compound 9-10(0.12g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 45-1.

Compound 45-1, compound 45-2(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) obtained above were charged into a round-bottomed flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 45-3(0.11g, yield 93%) as a white solid.

MS(ESI,pos.ion)m/z:786[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.32(s,1H),9.21(s,1H),8.73(s,1H),8.54(s,1H),8.22(d,J＝7.1Hz,1H),7.58(dd,J＝8.3,6.6Hz,1H),7.27–7.23(m,1H),7.22–7.12(m,4H),6.95–6.77(m,2H),5.95(s,1H),5.76(dd,J＝17.8,8.6Hz,1H),5.02(t,J＝9.4Hz,1H),4.79(t,J＝7.0Hz,1H),4.61(t,J＝7.7Hz,1H),4.55(d,J＝11.4Hz,1H),4.19–4.10(m,1H),2.97–2.88(m,1H),2.66–2.51(m,3H),2.33(q,J＝8.6Hz,1H),2.11–2.04(m,1H),1.99–1.90(m,2H),1.83–1.62(m,5H),1.41–1.31(m,3H),1.01–0.80(m,4H)ppm；

HPLC purity: 97.15 percent.

Example 46:

the synthetic route is as follows:

step 1: synthesis of Compound 46-2

Compound 25-10(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. Filtration and washing of the filter cake with 20 ml of ethyl acetate followed by drying under vacuum gave compound 46-0.

The compound 46-0, the compound 46-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) obtained above were charged into a round-bottomed flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 ℃ and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 46-2(0.09g, yield 75%) as a white solid.

MS(ESI,pos.ion)m/z:847[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.40(s,1H),8.01(d,J＝7.1Hz,1H),7.74(s,1H),7.46(dd,J＝8.2,6.7Hz,1H),7.15(d,J＝8.7Hz,1H),6.87(dd,J＝8.8,1.7Hz,1H),6.81–6.65(m,3H),6.19(s,1H),5.90(d,J＝2.3Hz,1H),5.75(dd,J＝17.6,8.8Hz,1H),5.00(t,J＝9.3Hz,1H),4.82(t,J＝8.0Hz,1H),4.65(t,J＝7.7Hz,1H),4.60(d,J＝11.4Hz,1H),4.51(dt,J＝12.0,6.0Hz,1H),4.10(dd,J＝11.3,3.8Hz,1H),2.99–2.86(m,1H),2.65(d,J＝4.3Hz,3H),2.42(s,3H),2.31(q,J＝8.4Hz,1H),2.21–2.10(m,1H),1.97–1.61(m,7H),1.37–1.31(m,9H),

0.94–0.80(m,4H)ppm；

HPLC purity: 94.80 percent.

Example 47:

the synthetic route is as follows:

step 1: synthesis of Compound 47-2

Compound 25-10(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas evolution occurred. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 47-0.

Compound 47-0, compound 47-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 47-2(0.075g, yield 63%) as a white solid.

MS(ESI,pos.ion)m/z:844[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.33(s,1H),9.22(s,1H),8.72(s,1H),8.54(s,1H),8.24(d,J＝6.7Hz,1H),7.65–7.52(m,1H),7.28(s,1H),7.14(d,J＝8.5Hz,1H),6.91–6.79(m,2H),6.76–6.65(m,2H),5.90(s,1H),5.75(dd,J＝17.4,8.6Hz,1H),5.01(t,J＝9.2Hz,1H),4.80(s,1H),4.60(t,J＝7.4Hz,1H),4.55–4.43(m,2H),4.13(d,J＝7.8Hz,1H),2.92(s,1H),2.56(s,3H),2.38–2.27(m,1H),2.10–2.03(m,1H),2.01–1.88(m,3H),1.85–1.71(m,4H),1.57–1.40(m,9H),0.96–0.82(m,4H)ppm；

HPLC purity: 95.90 percent.

Example 48:

the synthetic route is as follows:

Step 1: synthesis of Compound 48-3

Compound 11-12(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 48-1 as a white solid.

Compound 48-1, compound 48-2(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) obtained above were charged into a round-bottomed flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 48-3(0.11g, yield 83%) as a white solid.

¹HNMR(400MHz,CDCl₃):10.37(s,1H),7.93(d,J＝7.9Hz,1H),7.59(s,1H),7.53(d,J＝8.7Hz,2H),7.46(dd,J＝7.7,1.3Hz,1H),7.44–7.39(m,1H),7.37(dt,J＝4.4,2.1Hz,2H),7.32–7.29(m,1H),7.20(d,J＝8.0Hz,1H),7.05(t,J＝7.5Hz,1H),6.99(d,J＝8.7Hz,2H),6.17(s,1H),5.97(d,J＝3.2Hz,1H),5.83–5.68(m,1H),5.06–4.96(m,1H),4.92–4.78(m,1H),4.66(dd,J＝13.9,6.0Hz,2H),4.13(dd,J＝11.5,4.1Hz,1H),3.87(s,3H),3.00–2.85(m,1H),2.73–2.59(m,3H),2.40(s,3H),2.34(q,J＝8.8Hz,1H),1.96–1.87(m,2H),1.56–1.50(m,3H),1.33–1.29(m,3H),1.19–1.10(m,3H),0.96–0.89(m,4H)ppm；

HPLC purity: 99.14 percent.

Example 49:

the synthetic route is as follows:

step 1 Synthesis of Compound 49-1

Compound 49-0(2.0g,12.7mmol), isopropanol (0.786g,13.1mmol), diphenyl-2-pyridylphosphine (DPPPy,5.0g,19.0mmol) and di-tert-butyl azodicarboxylate (DBAD,4.4g,19.0mmol) were dissolved in 100mL of THF, and the reaction was stirred at room temperature for 24 hours under nitrogen. After the reaction was completed, the organic solvent was removed under reduced pressure, the obtained residue was dissolved in 30mL of ethyl acetate and then washed with 20mL of 1N HCl solution, and the separated organic phase was washed with anhydrous Na₂SO₄Drying and removing the organic solvent under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give 49-1(2.46g, yield: 97%) as a pale yellow oily product

Step 2: synthesis of Compound 49-3

Compound 49-1(4.0g,12mmol) and compound 49-2(2.31g,13.6mmol) were dissolved in 15mL of DMF and K was added₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 100ml of LEtOAc, and diluted with H₂O wash (100mL × 2), 50mL saturated brine wash, and dry Na over the organic phase₂SO₄Drying, filtering, and removing the organic solvent under reduced pressure to obtain 49-3(4.0g, yield: 95%) as a yellow solid, which was directly subjected to the next reaction without further purification

MS(ESI,pos.ion)m/z:350[M+H]⁺。

And step 3: synthesis of Compound 49-4

Compound 49-3(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100 ml of 1N HCl solution to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain 49-4(3.0g, yield: 91%).

MS(ESI,pos.ion)m/z:288[M+H]⁺。

And 4, step 4: synthesis of Compound 49-5

Compound 49-4(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. After completion of the reaction, it was cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to obtain 49-5(1.1g, 100%) as a pale yellow solid product.

MS(ESI,pos.ion)m/z:306[M+H]⁺。

And 5: synthesis of Compound 49-6

Sodium hydride (60% dispersed in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added, after which the temperature was raised to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing 49-5(1.1g,3.6mmol) was added to the above reaction solution, followed by stirring overnight. After completion of the reaction, the reaction solution was cooled to 0 ℃, and then quenched with 20mL of water, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 49-6(1.0g, yield: 56%) as a white solid.

MS(ESI,pos.ion)m/z:501[M+H]⁺。

Step 6: synthesis of Compound 49-7

Compound 49-6(1.0g,2.0mmol), compound 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged into a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added and the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, 10mL of water was added to quench the reaction, the reaction was extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 49-7(0.86g, yield 60%) as a purified white solid.

MS(ESI,pos.ion)m/z:713[M+H]⁺。

And 7: synthesis of Compound 49-9

Compound 49-7(0.86g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas was evolved. Filtration and washing of the filter cake with 20ml of ethyl acetate gave compound 49-8.

Compound 49-8, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) obtained above were charged in a round-bottom flask, 20mL dichloromethane was added under nitrogen protection, then DIPEA (0.6mL,3.0mmol) was added, the reaction mixture was warmed to 30 ℃ and stirred for 4 hours, after completion of the reaction, 10mL water was added to quench the reaction, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, washed with 20mL saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V): 2: 1%) to obtain compound 49-9(0.92g, yield 98. MS (ESI, pos.ion) M/z:866[ M + H ] (M + H): 866[ M + H ] ]⁺。

And 8: synthesis of Compounds 49-10

Compound 49-9(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 49-10(0.25g, yield: 48%) as a white solid compound.

MS(ESI,pos.ion)m/z:838[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.61–7.49(m,1H),7.14(s,1H),7.02(d,J＝8.8Hz,1H),6.91–6.80(m,2H),6.74(s,1H),6.69–6.62(m,1H),5.91(s,1H),5.72(d,J＝9.2Hz,1H),5.24(d,J＝7.3Hz,1H),5.07–4.96(m,1H),4.73–4.57(m,1H),4.57–4.45(m,2H),4.39–4.31(m,1H),4.11–4.00(m,1H),2.96–2.90(m,1H),2.70–2.51(m,3H),2.39–2.27(m,1H),2.01–1.72(m,5H),1.60(s,2H),1.51–1.42(m,6H),1.32–1.23(m,11H),1.21–1.02(m,3H),1.06–0.77(m,4H)ppm；

HPLC purity: 96.88 percent.

Example 50:

the synthetic route is as follows:

step 1: synthesis of Compound 50-1

Compound 50-0(0.9g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether) to give 50-1(0.7g, 72%) as a pale yellow solid product.

MS(ESI,pos.ion)m/z:278[M+H]⁺。

Step 2: synthesis of Compound 50-2

Sodium hydride (60% dispersed in mineral oil, 0.15g,3.8mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(0.42g,1.8mmol) in 10 ml of anhydrous DMF was added, after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing compound 50-1(0.44g,1.6mmol) was added to the above reaction solution, followed by overnight reaction. After completion of the reaction, the reaction solution was cooled to 0 ℃, quenched with 20mL of water, washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 2 to 3 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 50-2(0.4g, yield: 53%) as a white solid.

And step 3: synthesis of Compound 50-3

Compound 50-2(0.94g,2mmol), compound 1-9(0.68g,1.7mmol), EDCI (0.4g,2mmol) and HOAT (0.3g,2mmol) were added to a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.8mL,5mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 50-3(0.95g, yield 69%) as a white solid.

MS(ESI,pos.ion)m/z:685[M+H]⁺。

And 4, step 4: synthesis of Compound 50-5

Compound 50-3(0.87g,1.28mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas was evolved. Filtration and washing of the filter cake with 20ml of ethyl acetate gave compound 50-4 as a white solid.

The compound 50-4, compound 2-11(0.7g,1.55mmol), EDCI (0.32g,1.7mmol) and HOAT (0.21,1.5mmol) obtained above were charged into a round bottom flask, protected with nitrogen, 20mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.7mL,4mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 50-5(0.75g, yield 70%) as a white solid.

MS(ESI,neg.ion)m/z:838[M-H]^-。

And 5: synthesis of target 50-6

Compound 50-5(0.15g,0.18mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.05 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred at this temperature for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 50-6(80mg, yield: 54%) as a white solid.

MS(ESI,pos.ion)m/z:798[M+H]⁺；

¹HNMR(400MHz,CDCl₃):7.62–7.41(m,1H),7.20–7.01(m,2H),6.92–6.84(m,2H),6.81–6.73(m,2H),5.97(s,1H),5.72(d,J＝9.3Hz,1H),5.23(d,J＝7.1Hz,1H),5.01(t,J＝9.4Hz,1H),4.83–4.42(m,2H),4.42–4.32(m,1H),4.17–4.01(m,1H),3.89(s,3H),2.96–2.90(m,1H),2.69–2.50(m,3H),2.34–2.25(m,1H),2.01–1.72(m,5H),1.67–1.59(m,1H),1.39–1.33(m,11H),1.22–1.03(m,4H),0.91–0.83(m,J＝6.5Hz,4H)ppm；

HPLC purity: 94.12 percent.

Example 51:

the synthetic route is as follows:

step 1: synthesis of Compound 51-2

Compound 49-10(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas was evolved. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 51-0 as a white solid.

Compound 51-0, compound 51-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction solution was heated to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 51-2(0.075g, yield 63%) as a white solid.

MS(ESI,neg.ion)m/z:856[M-H]^-；

¹HNMR(600MHz,CDCl₃):10.36(s,1H),9.08(s,1H),8.42(s,1H),8.16(s,1H),7.61–7.52(m,2H),7.02(d,J＝8.8Hz,1H),6.87–6.73(m,3H),6.65(dd,J＝8.8,2.9Hz,1H),5.93(s,1H),5.75(d,J＝9.3Hz,1H),5.04–4.98(m,1H),4.74(t,J＝6.7Hz,1H),4.59(t,J＝7.6Hz,1H),4.55–4.44(m,2H),4.19–4.11(m,1H),2.96–2.86(m,1H),2.63(s,3H),2.60–2.42(m,3H),2.30(q,J＝8.5Hz,1H),2.09–2.02(m,1H),1.97–1.89(m,3H),1.82–1.74(m,1H),1.68–1.59(m,1H),1.58–1.42(m,6H),1.37–1.34(m,2H),1.20–1.04(m,3H),1.06–0.63(m,4H)ppm；

HPLC purity: 95.29 percent.

Example 52:

the synthetic route is as follows:

step 1: synthesis of Compound 52-2

Compound 49-10(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until no gas was evolved. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 52-0 as a white solid.

Compound 52-0, compound 52-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 52-2(0.09g, yield 75%) as a white solid.

MS(ESI,pos.ion)m/z:847[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.39(s,1H),8.01(s,1H),7.74(s,1H),7.47(dd,J＝8.6,6.4Hz,1H),7.02(d,J＝7.6Hz,1H),6.88(dd,J＝9.0,2.3Hz,1H),6.82–6.72(m,2H),6.66(dd,J＝8.8,2.9Hz,1H),6.21(s,1H),5.93(d,J＝3.1Hz,1H),5.75(dd,J＝17.8,8.9Hz,1H),5.00(t,J＝9.3Hz,1H),4.89–4.77(m,1H),4.71–4.58(m,2H),4.57–4.48(m,1H),4.10(dd,J＝11.5,4.1Hz,1H),2.98–2.85(m,1H),2.77–2.58(m,3H),2.42(s,3H),2.31(q,J＝8.5Hz,1H),2.21–2.12(m,1H),1.92–1.83(m,3H),1.74–1.65(m,1H),1.37–1.30(m,9H),1.22–1.01(m,3H),1.02–0.74(m,4H)ppm；

HPLC purity: 95.17 percent.

Example 53:

The synthetic route is as follows:

step 1: synthesis of Compound 53-2

Compound 26-11(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 53-0 as a white solid.

Compound 53-0, compound 53-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged to a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. The reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 53-2(0.070g, yield 52%) as a white solid.

MS(ESI,neg.ion)m/z:883.8[M-H]^-；

¹HNMR(400MHz,CDCl₃):10.34(s,1H),9.06(s,1H),8.41(s,1H),8.15(d,J＝6.9Hz,1H),7.62(dd,J＝8.5,6.4Hz,1H),7.48(s,1H),7.27–7.22(m,1H),7.10–6.99(m,2H),6.95–6.82(m,2H),5.92(s,1H),5.81–5.70(m,1H),5.07–4.95(m,1H),4.78–4.68(m,1H),4.63–4.47(m,2H),4.20–4.10(m,1H),2.97–2.83(m,1H),2.66–2.50(m,6H),2.37–2.25(m,1H),2.05–1.80(m,5H),1.53–1.48(m,3H),1.17–1.06(m,3H),0.92–0.84(m,4H)ppm；

HPLC purity: 92.49 percent.

Example 54:

the synthetic route is as follows:

step 1: synthesis of Compound 54-3

Compound 11-12(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 54-1 as a white solid.

Compound 54-1, compound 54-2(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The temperature was raised to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 54-3(0.10g, yield 75%) as a white solid.

¹HNMR(400MHz,CDCl₃):10.34(s,1H),9.10(s,1H),8.42(s,1H),8.17(d,J＝6.9Hz,1H),7.64–7.58(m,1H),7.53(d,J＝8.7Hz,2H),7.46(s,1H),7.37(t,J＝9.0Hz,3H),7.30–7.28(m,1H),7.22–7.08(m,2H),6.98(d,J＝8.7Hz,2H),5.97(s,1H),5.76(d,J＝9.5Hz,1H),5.03(t,J＝9.4Hz,1H),4.78(s,1H),4.63–4.49(m,2H),4.22–4.12(m,1H),3.86(s,3H),3.00–2.86(m,1H),2.63(s,3H),2.60–2.51(m,2H),2.37–2.27(m,1H),2.12–2.04(m,1H),1.99–1.91(m,2H),1.85–1.70(m,3H),1.41–1.33(m,3H),1.19–1.08(m,3H),0.98–0.89(m,4H)ppm；

HPLC purity: 98.98 percent.

Example 55:

the synthetic route is as follows:

step 1: synthesis of Compound 55-2

Compound 26-11(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the filter cake with 20 ml of ethyl acetate gave compound 55-0 as a white solid.

Compound 55-0, compound 55-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round-bottom flask, protected with nitrogen, 20 mL of dichloromethane were added, then cooled to 0 ℃, DIPEA (0.1mL,0.6mmol) was added, the reaction mixture was warmed to 30 ℃, stirred for 4 hours, after completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 55-2(0.07g, yield 75. MS%) (ESI, pos.ion) m/z as a white solid compound :873.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.35(s,1H),7.82(d,J＝7.3Hz,1H),7.53(t,J＝7.4Hz,2H),7.30–7.23(m,2H),7.06(d,J＝9.3Hz,2H),6.92(dd,J＝8.8,2.1Hz,1H),6.89–6.76(m,1H),6.21(s,1H),5.93(d,J＝2.6Hz,1H),5.82–5.71(m,1H),5.06–4.95(m,1H),4.79(t,J＝7.6Hz,1H),4.70–4.56(m,2H),4.11(dd,J＝11.4,4.2Hz,1H),2.99–2.85(m,1H),2.74–2.60(m,3H),2.44(s,3H),2.36–2.27(m,1H),2.16–2.06(m,1H),1.94–1.85(m,2H),1.52–1.47(m,4H),1.18–1.08(m,3H),0.97–0.87(m,4H)ppm；

HPLC purity: 98.44 percent.

Example 56

Synthetic route

Step 1 Synthesis of Compound 56-2

Compound 56-1(944mg,3.1mmol) was added to toluene (100mL), and POCl was slowly added with stirring₃(939mg,6.1mmol) and N, N-dimethylaniline (185mg,1.5mmol), and after the addition was complete, the reaction mixture was refluxed for 5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 56-2(0.8g, yield: 80%) as a pale yellow solid.

Step 2: synthesis of Compound 56-3

The compound N-Boc-4- (R) -hydroxyproline (1.5g,6.5mmol) was dissolved in DMF (50mL), NaH (60% dispersed in mineral oil, 520mg,13mmol) was added under ice-bath and after addition the reaction mixture was warmed to room temperature and stirred for 2 h. Compound 56-2(2.1g, 6.5mmol) was dissolved in a small amount of DMF and then added to the above reaction solution and stirred for 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2 to 3 with 1n hcl solution, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain 56-3(3.0g, yield: 90%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:518.9[M-H]^-。

And step 3: synthesis of Compound 56-5

Mixing compound 56-3(100mg,0.19mmol), compound 56-4(31mg,0.2mmol), Pd (PPh)₃)₄(22mg,0.02mmol) and K₂CO₃(180mg,0.58mmol) was dissolved in a mixed solvent of THF (20mL) and water (0.1mL), and the reaction mixture was stirred at room temperature overnight under nitrogen protection, after the completion of the reaction, a saturated sodium chloride solution (20mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 10mL), the organic phases were combined, the extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain 56-5(90mg, yield: 86%) as a yellow solid.

MS(ESI,pos.ion)m/z:549.0[M+H]⁺。

And 4, step 4: synthesis of Compound 56-6

Compound 56-5(55mg,0.1mmol), compound 1-9(42mg,0.1mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to CH₂Cl₂In (15mL), DIPEA (48mg,0.37mmol) was added under nitrogen and ice bath to complete the additionThe reaction mixture was warmed to room temperature and stirred for 4 hours, after completion of the reaction, the pH was adjusted to about 2 with a 1N hydrochloric acid solution, followed by extraction with dichloromethane (10ml × 2), combination of organic phases, followed by washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtration, and spin-drying of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 56-6(50mg, yield: 70%) as a pale yellow solid.

And 5: synthesis of Compound 56-8

Compound 56-6(580mg,0.76mmol) was dissolved in 5N HCl ethyl acetate solution (30mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was distilled off under reduced pressure to obtain 56-7 as a white solid. The resulting white solid compound (314mg,0.45mmol) was added to CH₂Cl₂To (50mL) were then added compounds 2-11(223mg,0.49mmol), EDCI (103mg,0.54mmol) and HOAT (73mg,0.54mmol), DIPEA (177mg,1.3mmol) was added under ice bath, and the reaction mixture was warmed to room temperature and stirred for 4 hours after the reaction was completed, 10mL of water was added to quench the reaction, extraction was performed with dichloromethane (10mL × 2), the organic phases were combined, and then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compounds 56-8 as pale yellow solids (0.34g, yield: 80%).

Step 6: synthesis of Compound 56-9

Compound 56-8(453mg,0.5mmol) was dissolved in 1, 2-dichloroethane (300mL) and then Jansen's 1B catalyst (45mg) was added and the reaction mixture was warmed to 75 ℃ under nitrogen for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the resulting residue was purified by preparative HPLC to give compound 56-9(0.3g, yield: 70%) as a white solid.

And 7: synthesis of Compounds 56-10

Compound 56-9(339mg,0.38mmol) was dissolved in 5N HCl ethyl acetate solution (30mL) and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 56-10(0.29g, yield: 90%) as a white solid compound.

And 8: synthesis of Compounds 56-12

Dissolve compound 56-10(110mg,0.13mmol) in CH₂Cl₂To (50mL) were then added compound 56-11(20mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol), DIPEA (54mg,0.42mmol) was added under ice bath, and the reaction mixture was warmed to room temperature and stirred for 4 hours after the reaction was completed, 10mL of water was added to quench the reaction, extraction was performed with dichloromethane (10mL × 2), the organic phases were combined, followed by washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtration, spin-drying of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 56-12 as a pale yellow solid (0.1g, yield: 80%).

MS(ESI,pos.ion)m/z:895.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.45(s,1H),8.10(d,J＝7.5Hz,1H),7.88(s,1H),7.53(d,J＝8.6Hz,2H),7.49(dd,J＝8.5,6.5Hz,1H),7.45(d,J＝2.1Hz,1H),7.32(dd,J＝8.3,2.1Hz,1H),7.18(d,J＝8.3Hz,1H),6.98(d,J＝8.7Hz,2H),6.92(dd,J＝8.9,2.2Hz,1H),6.78(td,J＝8.5,2.2Hz,1H),6.20(s,1H),5.97(s,1H),5.75(dd,J＝17.8,8.8Hz,1H),5.05–4.95(m,1H),4.91–4.78(m,1H),4.68(dd,J＝14.7,7.1Hz,2H),4.14–4.08(m,1H),3.85(s,3H),2.97–2.88(m,1H),2.67(dd,J＝17.1,9.0Hz,3H),2.40(d,J＝10.8Hz,3H),2.33(q,J＝8.6Hz,1H),2.18(d,J＝11.9Hz,1H),1.91–1.80(m,2H),1.67(dd,J＝16.2,7.6Hz,1H),1.48(ddd,J＝13.1,11.9,8.0Hz,5H),1.35–1.27(m,4H),1.12(ddd,J＝13.1,10.0,6.2Hz,2H),0.93(dd,J＝12.9,7.6Hz,1H)ppm；

HPLC purity 93.00%.

Example 57

Synthetic route

Step 1 Synthesis of Compound 57-1

Compound 27-6(0.20g,2.5mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was warmed to room temperature and stirred until the reaction was complete without gas evolution. Filtration, the filter cake washed with 20 ml of ethyl acetate and the solid dried under vacuum to give the compound as a white solid. The resulting white compound was charged as 2-carboxy-5-methylpyrazine (0.4g,2.8mmol), EDCI (0.4g,2.6mmol) and HOAT (0.35g,2.7mmol) in a round bottom flask, 20 mL of dichloromethane was added under nitrogen, then cooled to 0 deg.C and DIPEA (1.2mL,6.0mmol) was added slowly. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 57-1(0.16g, yield: 78%) as a white solid.

MS(ESI,pos.ion)m/z:818.4[M+H]⁺；

¹HNMR(600MHz,CDCl₃):9.04(s,1H),8.41(s,1H),8.17(d,J＝6.4Hz,1H),7.63(dd,J＝34.3,27.3Hz,2H),7.08(dd,J＝8.1,5.2Hz,1H),6.94(d,J＝7.2Hz,1H),6.90–6.78(m,3H),5.91(s,1H),5.73(dd,J＝17.2,8.4Hz,1H),5.00(t,J＝9.2Hz,1H),4.73(s,1H),4.61(t,J＝7.2Hz,1H),4.51(d,J＝11.1Hz,1H),4.13(dd,J＝23.4,16.0Hz,1H),2.90(s,1H),2.65–2.48(m,6H),2.29(dd,J＝16.5,8.1Hz,1H),2.11–1.99(m,3H),1.91(d,J＝6.0Hz,2H),1.77(s,1H),1.67–1.57(m,1H),1.34(s,3H),1.17–1.04(m,3H),0.97–0.77(m,3H)ppm。

Example 58

Synthetic route

Step 1: synthesis of Compound 58-2

Compound 58-0(4.0g,12mmol) and compound 58-1(2.31g,13.6mmol) were dissolved in 15mL of DMF, and K was added thereto₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 100mL of ethyl acetate, and the resulting organic phase was diluted with H₂O wash (100mL × 2), 50mL saturated brine wash once, anhydrous Na₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave compound 58-2 as a yellow solid (4.0g, yield: 95%).

MS(ESI,pos.ion)m/z:336[M+H]⁺。

Step 2: synthesis of Compound 58-3

Compound 58-2(4.0g,11.45mmol) was dissolved in 50mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered, and the filtrate was poured into 100mL of 1N HCl solution to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain 58-3(3.0g, yield: 91%) as a white solid.

And step 3: synthesis of Compound 58-4

Compound 58-3(1.0g,3.5mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly and the reaction mixture was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, it was cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 58-4(1.1g, yield: 100%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 58-5

Sodium hydride (0.45g,11mmol) was added to 20ml of anhydrous DMF and cooled to 0 ℃ under nitrogen, then a solution of compound 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing compound 58-4(1.1g,3.6mmol) was added to the above reaction solution, followed by overnight reaction. The reaction was quenched with 20ml of water at 0 ℃, then washed with 20ml of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mLx3), the organic phases were combined, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 58-5 as a white solid (1.0g, yield: 56%).

MS(ESI,pos.ion)m/z:487.4[M+H]⁺。

And 5: synthesis of Compound 58-6

Compound 58-5(1.0g,2.0mmol), Compound 1-9(0.9g,2.0mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were added to a round bottom flask, under nitrogen, 30 mL of dichloromethane were added, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 ml of water, extracted with ethyl acetate (20ml x3), the organic phases were combined, the organic phase was washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 58-6(0.86g, yield: 60%) as a white solid.

MS(ESI,pos.ion)m/z:699.3[M+H]⁺。

Step 6: synthesis of Compound 58-8

Compound 58-6(0.86g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution were added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the resulting white solid with 20 ml of ethyl acetate and drying of the resulting solid in vacuo gave compound 58-7 as a white solid.

Compound 58-7, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol) and HOAT (0.2g,1mmol) were charged to a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.6mL,3.0mmol) was added slowly. The reaction mixture was then warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 58-8(0.92g, yield: 98%) as a white solid. MS (ESI, pos. ion) M/z 852.3[ M + H ]]⁺。

And 7: synthesis of Compound 58-9

Compound 58-8(0.5g,0.58mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred at this temperature for 48 hours. Cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 58-9(0.25g, yield: 48%) as a white solid.

MS(ESI,pos.ion)m/z:824.3[M+H]⁺。

And 8: synthesis of Compounds 58-10

Compound 58-9(0.20g,2.5mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution were added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration, the filter cake washed with 20 ml of ethyl acetate and the resulting white solid dried in vacuo.

The white solid obtained above, 2-carboxy-5-methylpyrazine (0.4g,2.8mmol), EDCI (0.4g,2.6mmol) and HOAT (0.35g,2.7mmol) were added to a round-bottom flask, 20 mL dichloromethane were added under nitrogen, cooled to 0 ℃ and DIPEA (1.2mL,6.0mmol) was added slowly, then the reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10ml of water was added to quench the reaction, extraction was performed with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 58 to 10(0.16g, yield: 78%) as a white solid.

MS(ESI,pos.ion)m/z:844.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):9.09(s,1H),8.38(s,1H),7.51(s,1H),7.14(d,J＝8.6Hz,1H),7.03–6.74(m,2H),6.75–6.42(m,2H),5.84(s,1H),5.59(s,1H),5.25(s,1H),4.91(s,1H),4.72(s,4H),4.27(d,J＝44.6Hz,2H),4.00(d,J＝6.8Hz,2H),2.70(d,J＝43.9Hz,5H),2.55–2.00(m,10H),1.90(s,2H),1.27(s,9H)ppm。

Example 59

Synthetic route

Step 1: synthesis of Compound 59-1

Compound 58-9(0.25g,2.5mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration was carried out, the filter cake was washed with 20 ml of ethyl acetate and the solid was dried under vacuum. The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.4g,2.9mmol), EDCI (0.4g,2.6mmol) and HOAT (0.35g,2.7mmol) were then added to a round bottom flask, 20 mL dichloromethane were added under nitrogen protection, then cooled to 0 ℃ and DIPEA (1.2mL,6.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 59-1(0.16g, yield: 78%) as a white solid.

MS(ESI,pos.ion)m/z:819.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):7.87(d,J＝6.6Hz,1H),7.61(s,1H),7.48(dd,J＝8.6,6.5Hz,1H),7.15(d,J＝8.7Hz,1H),6.87(dd,J＝9.0,2.3Hz,1H),6.79(td,J＝8.4,2.3Hz,1H),6.75–6.68(m,2H),6.22(s,1H),5.89(s,1H),5.69(s,1H),5.06(s,1H),4.83(s,1H),4.69(s,1H),4.49(s,1H),4.16–4.08(m,1H),4.02(q,J＝6.9Hz,2H),2.87(s,1H),2.75–2.50(m,3H),2.51–2.35(m,4H),2.26(s,1H),2.19–1.89(m,6H),1.89–1.64(m,3H),1.30(dt,J＝14.1,6.7Hz,5H)ppm。

Example 60

Synthetic route

Step 1: synthesis of Compound 60-1

Compound 2-13(0.30g,0.39mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 5 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with 10ml of ethyl acetate and the resulting solid was dried in vacuo.

The solid obtained above, as well as the compound 1-methylpyrazole-3-carboxylic acid (0.05g,0.39mmol), EDCI (0.1g,0.67mmol) and HOAT (0.1g,0.6mmol) were charged into a round-bottomed flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was slowly added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10ml of water was added to quench the reaction, extraction was performed with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 60-1(0.160g, yield: 53%) ppm as a white solid.

MS(ESI,pos.ion)m/z:770.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.94(s,1H),7.61(dd,J＝7.7,1.4Hz,1H),7.34(d,J＝6.5Hz,1H),7.32–7.29(m,1H),7.24–7.23(m,1H),7.13(dt,J＝13.7,8.0Hz,5H),6.62(d,J＝2.2Hz,1H),5.95(dd,J＝8.0,4.5Hz,1H),5.72(dd,J＝18.2,8.6Hz,1H),5.02–4.97(m,1H),4.68(ddd,J＝9.8,6.5,3.2Hz,1H),4.53(t,J＝7.2Hz,1H),4.36(dd,J＝11.1,2.5Hz,1H),4.18(dd,J＝11.1,5.1Hz,1H),3.87(d,J＝6.5Hz,3H),2.92–2.87(m,1H),2.59–2.52(m,1H),2.44(dd,J＝12.0,5.9Hz,2H),2.27(q,J＝8.6Hz,1H),2.04(s,2H),1.86(dd,J＝8.0,5.9Hz,1H),1.78–1.71(m,1H),1.67(dd,J＝9.3,5.8Hz,1H),1.56–1.42(m,6H),1.34(dd,J＝12.0,6.0Hz,2H),1.14–1.07(m,2H),0.94–0.86(m,2H)ppm。

Example 61

Synthetic route

Step 2: synthesis of Compound 61-1

The solid obtained above, the compound 5-methyl-2-thiophenecarboxylic acid (0.06g,0.39mmol), EDCI (0.1g,0.67mmol) and HOAT (0.1g,0.6mmol) were charged in a round-bottomed flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was added slowly. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 61-1(0.12g, yield: 38%) as a white solid.

MS(ESI,pos.ion)m/z:786.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):7.60(d,J＝6.9Hz,1H),7.44(dd,J＝11.4,3.9Hz,2H),7.30(d,J＝3.6Hz,1H),7.26–7.21(m,1H),7.15(dt,J＝14.8,5.5Hz,5H),6.68(dd,J＝16.2,4.5Hz,2H),5.97(s,1H),5.71(d,J＝8.6Hz,1H),5.04(s,1H),4.81(s,1H),4.65(s,1H),4.47(d,J＝10.1Hz,1H),4.14(dd,J＝13.8,6.5Hz,1H),2.88(s,1H),2.61(s,2H),2.50(d,J＝13.1Hz,4H),2.25(dd,J＝13.7,7.9Hz,1H),1.87(d,J＝6.7Hz,4H),1.48(dd,J＝15.1,6.5Hz,6H),1.12(dd,J＝21.5,16.3Hz,3H),0.98–0.82(m,3H)ppm。

Example 62

Synthetic route

Step 1: synthesis of Compound 62-2

Dissolving compound 62-0(2.0g,14mmol) and compound 62-1(2.7g,14.8mmol) in 40mL DMF, adding K₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 100mL of ethyl acetate, and the mixture was poured into a flaskBy H₂O wash (100mLx2) and one more 50mL saturated saline wash. Anhydrous Na for organic phase₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 62-2(4.0g, yield: 94%) as a yellow solid, which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:304.3[M+H]⁺。

Step 2: synthesis of Compound 62-3

Compound 62-2(4.0g,13.19mmol) was dissolved in 100mL of glacial acetic acid, then reduced iron powder (3.2g,57.25mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100ml of 1N HCl solution to precipitate a large amount of white solid, filtered, the cake was washed with water, and the resulting solid was dried under vacuum to obtain compound 62-3(2.0g, yield: 62.8%) as a white solid.

And step 3: synthesis of Compound 62-4

Compound 62-3(1.0g,4.14mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. After completion of the reaction, it was cooled to 0 ℃ and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 62-4(1.00g, yield: 93%) as a white solid.

And 4, step 4: synthesis of Compound 62-5

Sodium hydride (60% dispersed in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF, cooled to 0 ℃ under nitrogen, then a solution of compounds 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added, after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. Then, 5ml of an anhydrous tetrahydrofuran solution containing compound 62-4(1.0g,3.8mmol) was further added to the above reaction solution, followed by overnight reaction. The reaction is quenched with 20ml of water at 0 ℃, washed with 20ml of ethyl acetate, the aqueous phase is adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mLx3) and the organic phases are combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 62-5(1.0g, yield: 58%) as a white solid.

MS(ESI,pos.ion)m/z:455.2[M+H]⁺。

And 5: synthesis of Compound 62-6

Compounds 62-5(1.0g,2.2mmol), compounds 1-9(0.9g,2.2mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged into a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added and the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 ml of water, extracted with ethyl acetate (20ml x3), the organic phases were combined, the organic phase was washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 62-6(0.86g, yield: 58.6%) as a white solid.

MS(ESI,pos.ion)m/z:667.3[M+H]⁺。

Step 6: synthesis of Compounds 62-8

Compound 62-6(0.80g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After the reaction was completed, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate and dried in vacuo.

The solid obtained by the above reaction, and compounds 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol), and HOAT (0.2g,1mmol) were charged into a round-bottomed flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, and DIPEA (0.6mL,3.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. The reaction was quenched with 10ml of water, extracted with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 62-8(0.92g, yield: 93.87%) as a white solid.

MS(ESI,pos.ion)m/z:820.3[M+H]⁺。

And 7: synthesis of Compounds 62-9

The compound 62-8(0.5g,0.61mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. Cooled to room temperature, the organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 62-9(0.3g, yield: 62.5%) as a white solid.

MS(ESI,pos.ion)m/z:792.3[M+H]⁺。

And 8: synthesis of target 62-10

Compound 62-9(0.3g,0.38mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained from the above reaction, compound 2-carboxy-5-methylpyrazine (0.06g,0.043mmol), EDCI (0.1g,0.65mmol) and HOAT (0.07g,0.54mmol) were charged into a round bottom flask, 20 mL dichloromethane were added under nitrogen protection, then cooled to 0 deg.C and DIPEA (0.2mL,1.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. The reaction was quenched with 10ml of water, extracted with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 62 to 10(0.16g, yield: 53.3%) as a white solid compound.

MS(ESI,pos.ion)m/z:812.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.28(s,1H),9.07(d,J＝23.6Hz,1H),8.40(d,J＝15.0Hz,1H),8.14(d,J＝24.6Hz,1H),7.25–7.20(m,1H),7.19–7.02(m,5H),6.95(dd,J＝8.9,3.0Hz,1H),5.96(s,1H),5.73(s,1H),5.06(s,1H),4.80(s,1H),4.64(s,2H),4.15(d,J＝8.0Hz,1H),3.81–3.63(m,3H),2.90(s,1H),2.74–2.54(m,6H),2.32(s,1H),2.14–1.90(m,2H),1.74(s,8H),1.21–0.73(m,6H)ppm。

Example 63

Synthetic route

Step 1: synthesis of Compound 63-2

Compound 2-10(0.80g,1.5mmol), compound 63-1(0.45g,1.6mmol), EDCI (0.3g,2mmol) and HOAT (0.3g,1.7mmol) were charged to a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (1.2mL,6.0mmol) was added slowly. The reaction mixture was then warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 63-2 as a white solid (0.82g, yield 68.33%).

MS(ESI,pos.ion)m/z:801.3[M+H]⁺。

Step 2: synthesis of Compound 63-3

Compound 63-2(0.5g,0.6mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.06 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, it was cooled to room temperature, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 63-3(0.25g, yield: 51.82%) as a white solid.

MS(ESI,pos.ion)m/z:773.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.63(d,J＝7.3Hz,1H),7.54(s,1H),7.40(t,J＝7.3Hz,1H),7.23(d,J＝7.1Hz,1H),7.13(d,J＝8.9Hz,5H),5.97(s,1H),5.74(d,J＝8.6Hz,1H),5.06–4.96(m,2H),4.61(t,J＝6.9Hz,1H),4.50(d,J＝10.8Hz,2H),4.09(d,J＝7.1Hz,1H),3.30(d,J＝5.1Hz,2H),3.24–3.17(m,2H),2.92(s,1H),2.64–2.54(m,3H),2.26(d,J＝8.3Hz,1H),2.05(d,J＝16.6Hz,1H),1.91(d,J＝6.1Hz,3H),1.84(s,2H),1.65(s,1H),1.59–1.38(m,15H)ppm。

Example 64

Synthetic route

Step 1: synthesis of Compound 64-1

Compound 3-13(0.30g,0.38mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 5 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with 10ml of ethyl acetate and the resulting solid was dried in vacuo.

The solid obtained above, the compound 2-carboxy-5-methylpyrazine (0.06g,0.43mmol), EDCI (0.1g,0.67mmol) and HOAT (0.1g,0.6mmol) were added to a round bottom flask, 10mL dichloromethane were added under nitrogen protection, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was slowly added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 64-1(0.14g, yield: 45%) as a white solid.

MS(ESI,pos.ion)m/z:812.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):9.17(d,J＝59.0Hz,1H),8.42(d,J＝12.2Hz,1H),8.34–8.10(m,1H),7.38(s,1H),7.28–7.21(m,2H),7.13(dt,J＝15.2,6.7Hz,3H),6.99(q,J＝7.9Hz,2H),5.95(s,1H),5.70(d,J＝8.7Hz,1H),5.09(d,J＝9.4Hz,1H),4.85(s,1H),4.67(s,1H),4.44(s,1H),4.19(d,J＝7.3Hz,1H),3.90(s,3H),2.86(s,1H),2.70–2.48(m,6H),2.27(d,J＝8.2Hz,1H),2.04(d,J＝8.2Hz,5H),1.90(dd,J＝25.6,18.9Hz,3H),0.89(dd,J＝15.2,8.2Hz,8H)ppm。

Example 65

Synthetic route

Step 1: synthesis of Compound 65-2

Compound 65-0(2.0g,14mmol) and compound 65-1(2.7g,14.8mmol) were dissolved in 40mL of DMF, and K was added thereto₂CO₃(3.41g,24.7mmol) after which the reaction mixture was warmed to reflux and reacted overnight. After the reaction was complete, it was cooled to room temperature, 100mL of ethyl acetate were added, and the mixture was taken up in H₂O wash (100mLx2) and one more 50mL saturated saline wash. Anhydrous Na for organic phase₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 65-2 as a yellow solid (4.0g, yield: 94%) which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:304.1[M+H]⁺。

Step 2: synthesis of Compound 65-3

Compound 65-2(4.0g,13.19mmol) was dissolved in 100mL of glacial acetic acid, and then reduced iron powder (3.2g,57.25mmol) was added. The reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, and the solid was removed by filtration, 100ml of 1N HCl solution was added dropwise to the filtrate to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain 65-3(2.0g, yield: 62.9%) as a compound.

And step 3: synthesis of Compound 65-4

Compound 65-3(1.0g,4.14mmol) was added to 20mL of toluene, phosphorus oxychloride (0.65mL,7.0mmol) was added under nitrogen, and then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly. The reaction mixture was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, it was cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to obtain compound 65-4(1.00g, yield: 93%) as a white solid.

And 4, step 4: synthesis of Compound 65-5

Sodium hydride (0.45g,11mmol) was added to 20ml of anhydrous DMF and cooled to 0 ℃ under nitrogen, then a solution of compound 2-7(1.0g,4.3mmol) in 10 ml of anhydrous DMF was added after which the reaction mixture was warmed to 30 ℃ and stirred for two hours. A solution of compound 65-4(1.0g,3.8mmol) in 5ml of anhydrous tetrahydrofuran was added to the above reaction solution, followed by reaction overnight. The reaction was quenched with 20ml of water at 0 ℃ and washed once with 20ml of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution and then extracted with ethyl acetate (20mLx3) and the organic phases combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 65-5(1.0g, yield: 58%) as a white solid.

MS(ESI,pos.ion)m/z:455.2[M+H]⁺。

And 5: synthesis of Compound 65-6

Compound 65-5(1.0g,2.2mmol), compound 1-9(0.9g,2.2mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged into a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 ml of water, extracted with ethyl acetate (20ml x3) and the organic phases were combined. The organic phase was washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 65-6(0.86g, yield: 58.6%) as a white solid.

MS(ESI,pos.ion)m/z:667.3[M+H]⁺。

Step 6: synthesis of Compound 65-8

Compound 65-6(0.80g,1.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. Filtration and washing of the resulting white solid with 20 ml of ethyl acetate.

The solid obtained in the above reaction, compound 2-11(0.6g,1.3mmol), EDCI (0.3g,2mmol), and HOAT (0.2g,1mmol) were charged into a round-bottomed flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, and DIPEA (0.6mL,3.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10ml of water was added to quench the reaction, followed by extraction with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 65-8 as a white solid (0.92g, yield: 93.9%).

MS(ESI,pos.ion)m/z:820.3[M+H]⁺。

And 7: synthesis of Compound 65-9

Compound 65-8(0.5g,0.61mmol) was dissolved in 400 ml of 1, 2-dichloroethane, 0.07 g of Grubbs second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred at this temperature for 48 hours. Cooled to room temperature, the organic solvent was removed, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 65-9(0.3g, yield: 62.5%) as a white solid.

And 8: synthesis of Compounds 65-10

Compound 65-9(0.3g,0.38mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 2ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained from the above reaction, compound 2-carboxy-5-methylpyrazine (0.06g,0.043mmol), EDCI (0.1g,0.65mmol) and HOAT (0.07g,0.54mmol) were charged into a round bottom flask, 20 mL dichloromethane were added under nitrogen protection, then cooled to 0 deg.C and DIPEA (0.2mL,1.0mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, 10ml of water was added to quench the reaction, extraction was performed with ethyl acetate (10ml x3), the organic phases were combined, the organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 65-10(0.10g, yield: 32.46%) as a white solid.

MS(ESI,pos.ion)m/z:812.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.38(s,1H),9.06(s,1H),8.40(s,1H),8.19(d,J＝7.2Hz,1H),7.64(s,1H),7.47(d,J＝8.7Hz,1H),7.23(d,J＝7.3Hz,1H),7.12(d,J＝2.3Hz,2H),6.67(d,J＝2.4Hz,1H),6.61(dd,J＝8.7,2.4Hz,1H),5.94(s,1H),5.74(dd,J＝18.2,8.7Hz,1H),5.04–4.98(m,1H),4.83–4.76(m,1H),4.62(t,J＝7.6Hz,1H),4.47(d,J＝11.4Hz,1H),4.15(dd,J＝11.3,4.4Hz,1H),3.77(s,3H),3.69–3.58(m,1H),2.91(ddd,J＝13.0,8.0,4.9Hz,1H),2.64–2.48(m,7H),2.37–2.23(m,2H),1.80–1.74(m,1H),1.63–1.59(m,1H),1.53–1.45(m,5H),1.14–1.10(m,2H),0.96–0.82(m,4H)ppm。

Example 66

Synthetic route

Step 1: synthesis of Compound 66-1

The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.39mmol), EDCI (0.1g,0.67mmol), HOAT (0.1g,0.6mmol) were added to a round bottom flask, 10mL dichloromethane were added under nitrogen protection, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was added slowly. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 66-1(0.12g, yield 39.5%) as a white solid.

MS(ESI,pos.ion)m/z:801.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.35(s,1H),7.87(d,J＝7.7Hz,1H),7.55(s,1H),7.24–7.06(m,3H),7.02–6.95(m,3H),6.13(s,1H),5.96(d,J＝3.1Hz,1H),5.76(dd,J＝17.9,8.7Hz,1H),5.04–4.98(m,1H),4.85(t,J＝7.6Hz,1H),4.69–4.59(m,2H),4.12(dd,J＝11.5,4.0Hz,1H),3.91(s,3H),3.77–3.61(m,2H),3.50(q,J＝7.0Hz,3H),2.95–2.89(m,1H),2.67(dd,J＝7.7,3.2Hz,3H),2.44–2.27(m,3H),1.97–1.83(m,3H),1.52–1.48(m,3H),0.99–0.83(m,6H)ppm。

Example 67

Synthetic route

Step 1: synthesis of Compound 67-1

Compound 65-9(0.3g,0.38mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 5 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with 10ml of ethyl acetate and the resulting solid was dried in vacuo.

The solid obtained above, 5-methylisoxazole-3-carboxylic acid (0.05g,0.39mmol), EDCI (0.1g,0.67mmol), HOAT (0.1g,0.6mmol) were added to a round bottom flask, 10mL dichloromethane were added under nitrogen protection, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was added slowly. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 67-1(0.15g, yield: 49.3%) as a white solid.

MS(ESI,pos.ion)m/z:801.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.44(s,1H),8.07(d,J＝8.0Hz,1H),7.92(s,1H),7.36(d,J＝8.7Hz,1H),7.24(d,J＝7.4Hz,1H),7.14(dt,J＝13.7,4.3Hz,3H),6.68(d,J＝2.4Hz,1H),6.57(dd,J＝8.7,2.4Hz,1H),6.17(s,1H),5.93(d,J＝2.9Hz,1H),5.74(dd,J＝18.0,8.8Hz,1H),5.02–4.96(m,1H),4.84(dd,J＝13.2,5.3Hz,1H),4.67(t,J＝7.8Hz,1H),4.59(d,J＝11.5Hz,1H),4.12(dd,J＝11.4,4.2Hz,1H),3.79(s,3H),2.92(ddd,J＝13.0,8.1,4.9Hz,1H),2.65(d,J＝7.7Hz,3H),2.39(s,3H),2.32(d,J＝8.6Hz,1H),2.11(d,J＝4.8Hz,1H),1.85(ddd,J＝13.9,8.6,5.1Hz,2H),1.54–1.38(m,8H),1.00–0.80(m,4H)ppm。

Example 68

Synthetic route

Step 1: synthesis of Compound 68-1

Compound 62-9(0.3g,0.38mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 5 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with 10ml of ethyl acetate and the resulting solid was dried in vacuo. The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.39mmol), EDCI (0.1g,0.67mmol), HOAT (0.1g,0.6mmol) were added to a round bottom flask, 10mL dichloromethane were added under nitrogen protection, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was added slowly. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 68-1(0.16g, yield: 52.6%) as a white solid.

MS(ESI,pos.ion)m/z:801.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.38(s,1H),7.96(d,J＝7.8Hz,1H),7.69(s,1H),7.19–7.08(m,5H),6.94–6.88(m,2H),6.13(s,1H),5.98–5.69(m,3H),5.46–5.29(m,1H),5.05–4.89(m,2H),4.83(t,J＝8.0Hz,1H),4.68(dd,J＝19.4,10.7Hz,2H),4.11(dd,J＝11.5,4.0Hz,1H),3.78(dd,J＝12.7,7.8Hz,1H),3.50(q,J＝7.0Hz,6H),2.96–2.91(m,1H),2.72–2.63(m,3H),2.49(d,J＝8.3Hz,1H),2.43–2.29(m,5H),2.04(dd,J＝19.0,11.1Hz,3H),0.90(m,3H)ppm。

Example 69

Synthetic route

Step 1: synthesis of Compound 69-1

Compound 2-13(0.30g,0.39mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 5 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with 10ml of ethyl acetate and the resulting solid was dried in vacuo. The solid obtained above, compound 6-methylpyridine-3-carboxylic acid (0.06g,0.43mmol), EDCI (0.1g,0.67mmol), HOAT (0.1g,0.6mmol) were charged into a round bottom flask, 10mL dichloromethane were added under nitrogen protection, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was slowly added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 69-1(0.16g, yield: 53%) as a white solid.

MS(ESI,pos.ion)m/z:781.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.99(d,J＝1.3Hz,1H),8.21(s,1H),8.04(d,J＝6.8Hz,1H),7.92(d,J＝7.4Hz,1H),7.62(dd,J＝7.7,1.2Hz,1H),7.48–7.42(m,1H),7.25(dd,J＝7.5,1.6Hz,1H),7.18(d,J＝7.9Hz,1H),7.17–7.13(m,3H),7.13–7.08(m,2H),5.97(d,J＝34.0Hz,1H),5.67(dd,J＝18.1,8.5Hz,1H),4.94(dd,J＝18.9,10.0Hz,1H),4.79(d,J＝11.5Hz,1H),4.75–4.69(m,1H),4.65(q,J＝7.7Hz,1H),4.16–4.07(m,1H),2.94–2.85(m,1H),2.64(dd,J＝13.9,8.0Hz,1H),2.60–2.47(m,5H),2.17(q,J＝8.5Hz,1H),2.05(s,5H),1.88–1.80(m,1H),1.78(dd,J＝7.9,6.2Hz,1H),1.65–1.59(m,1H),1.52–1.42(m,4H),1.37–1.32(m,2H),1.13-0.88(m,2H)ppm。

Example 70

Synthetic route

Step 1: synthesis of Compound 70-1

Compound 2-13(0.30g,0.39mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 5 ml of 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with 10ml of ethyl acetate and the resulting solid was dried in vacuo. The solid obtained above, the compound 5-methyl-2-carboxylic acid pyridine (0.06g,0.43mmol), EDCI (0.1g,0.67mmol) and HOAT (0.1g,0.6mmol) were charged into a round bottom flask, 10mL dichloromethane were added under nitrogen protection, then cooled to 0 deg.C and DIPEA (0.2mL,1.0mmol) was added slowly. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water, extracted with dichloromethane (10ml x3), the organic phases were combined, the organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the organic solvent under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 70-1(0.13g, yield: 43.6%) as a white solid.

MS(ESI,pos.ion)m/z:781.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.47–8.36(m,2H),7.92–7.78(m,2H),7.57(d,J＝7.5Hz,1H),7.47(d,J＝7.6Hz,1H),7.33(t,J＝7.4Hz,1H),7.23(d,J＝7.0Hz,1H),7.12(ddd,J＝18.3,16.7,8.2Hz,5H),5.91(s,1H),5.71(dd,J＝17.4,8.3Hz,1H),5.04(t,J＝9.3Hz,1H),4.76(s,1H),4.57(t,J＝6.8Hz,1H),4.39(t,J＝15.7Hz,1H),4.18(dd,J＝10.9,4.6Hz,1H),2.89(s,1H),2.54(s,1H),2.43–2.25(m,6H),2.10–1.86(m,4H),1.79(s,1H),1.68–1.63(m,1H),1.45(dd,J＝23.2,9.7Hz,5H),1.07(ddd,J＝40.4,22.2,5.9Hz,3H),0.89(d,J＝6.8Hz,2H)ppm。

Example 71

Synthetic route

Step 1: synthesis of Compound 71-1

Adding compound 71-0(944mg,3.1mmol) into 10mL of toluene, stirring under nitrogen, and slowly adding POCl₃(939mg,6.1mmol) and N, N-dimethylaniline (185mg,1.5 mmol). After the addition, the reaction mixture was heated to 110 ℃ and reacted for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 71-1(0.8g, yield 80%) as a pale yellow solid.

Step 2: synthesis of Compound 71-2

N-Boc-4- (R) -hydroxyproline (1.5g,6.5mmol) was dissolved in 50mL DMF, cooled to 0 ℃ under nitrogen, NaH (30% dispersed in mineral oil, 520mg,13mmol) was added and after addition warmed to room temperature and stirred for 2 h.

Compound 71-1(2.1g,6.5mmol) was dissolved in 10mL of DMF, and the resulting solution was added to the above reaction solution, followed by stirring for 4 hours. After the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to about 2 to 3 with 1n hcl aqueous solution, and then extracted with ethyl acetate (20mL × 3), the organic phases were combined, the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1), to obtain compound 71-2 as a pale yellow solid (3.0g, yield 90%).

MS(ESI,neg.ion)m/z:518.9[M-H]^–。

And step 3: synthesis of Compound 71-3

A round-bottomed flask was charged with compound 71-2(50mg,0.1mmol), compound 1-9(42mg,0.1mmol), EDCI (24mg,0.12mmol), HOAT (17mg,0.12mmol) and 15 mL of dichloromethane in this order, and DIPEA (48mg,0.37mmol) was further charged at 0 ℃. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the pH was adjusted to about 2 with a 1N hydrochloric acid solution, then the aqueous phase was extracted with dichloromethane (10mL × 2), the organic phases were combined, the combined organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered, the resulting filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 71-3(50mg, yield 70%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:734.9[M+H]⁺。

And 4, step 4: synthesis of Compound 71-5

Compound 71-3(600mg,0.8mmol) was dissolved in a 5N HCl solution in ethyl acetate (30mL), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting residue (300mg,0.45mmol) was dissolved in CH₂Cl₂(50mL), to which were added compounds 2-11(223mg,0.49mmol), EDCI (103mg,0.54mmol) and HOAT (73mg,0.54mmol), under nitrogen and at 0 deg.C, additional DIPEA (177mg,1.3mmol) and the resulting reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 71-5(0.34g, two-step yield 64%) as a pale yellow solid.

And 5: synthesis of Compound 71-6

Compound 71-5(230mg,0.28mmol) was dissolved in 300mL1, 2-dichloroethane, 30mg of the Jansen 1B catalyst was added under nitrogen and the reaction mixture was warmed to 75 ℃ for 48 h. After completion of the reaction, it was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 71-6(160mg, yield 73%) as a white solid.

MS(ESI,pos.ion)m/z:859.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.44(d,J＝93.7Hz,1H),7.67–7.45(m,1H),7.35(d,J＝39.0Hz,1H),7.23(d,J＝13.1Hz,2H),7.00(d,J＝8.4Hz,1H),6.94–6.81(m,2H),5.90(d,J＝34.1Hz,1H),5.72(dd,J＝17.6,8.7Hz,1H),5.25(d,J＝7.1Hz,1H),4.99(t,J＝9.3Hz,1H),4.75–4.51(m,2H),4.32(s,1H),4.03(t,J＝24.9Hz,1H),2.92(s,1H),2.75–2.45(m,3H),2.33(d,J＝8.3Hz,1H),1.97–1.79(m,4H),1.45(d,J＝10.8Hz,5H),1.29(m,9H),1.16–0.78(m,6H)ppm。

HPLC purity 97.49%.

Example 72

Synthetic route

Step 1: synthesis of Compound 72-2

Compound 72-1(100mg,0.27mmol) was dissolved in 100mL of glacial acetic acid, and iron powder (74mg, 1.3mmol) was added thereto, and the reaction mixture was warmed to 110 ℃ and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered again, the obtained filtrate was poured into 200mL of water, a solid precipitated, filtered, the cake was washed with water, and the obtained solid was dried in a vacuum oven to obtain 72-2(70mg, yield 84%) as a yellow solid.

Step 2: synthesis of Compound 72-3

Compound 72-2(944mg,3.0mmol) was added to 10mL of toluene, under nitrogen, and POCl was slowly added₃(927mg,6.0mmol) and N, N-dimethylaniline (183mg,1.51mmol) were added, and then the reaction mixture was heated to 110 ℃ for reaction for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 72-3(0.8g, yield 80%) as a pale yellow solid.

And step 3: synthesis of Compound 72-4

N-Boc-4- (R) -hydroxyproline (573mg,2.48mmol) was dissolved in 50mL DMF under nitrogen and 0 deg.C, to which NaH (60% dispersed in mineral oil, 247mg,6.2mmol) was added portionwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes.

Compound 72-3(820mg,2.48mmol) was dissolved in a small amount of DMF and added to the above reaction mixture, and stirring was continued at room temperature for 2 hours. After the reaction, the reaction was quenched with 50mL of water, the aqueous phase was adjusted to pH 2 to 3 with 1n hcl aqueous solution, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the resulting filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 72-4(1g, yield 77%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:526.3[M+H]⁺。

And 4, step 4: synthesis of Compound 72-5

Compound 72-4(720mg,1.4mmol), compound 1-9(661mg,1.6mmol), EDCI (317mg,1.6mmol) and HOAT (225mg,1.6mmol) were added to 100mL CH₂Cl₂Then cooled to 0 ℃ and DIPEA (546mg,4.1mmol) was added and after addition the reaction mixture was warmed to room temperature and stirred for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 72-5(0.8g, yield 80%) as a pale yellow solid.

And 5: synthesis of Compound 72-7

Compound 72-5(810mg,1.1mmol) was dissolved in 5N HCl in 50mL ethyl acetate and stirred at room temperature for 3 hours. After the reaction was completed, the organic solvent was distilled off under reduced pressure. The resulting residue (300mg,0.4mmol) was dissolved in 50mL CH₂Cl₂Then, compound 2-11(221mg,0.5mmol), EDCI (102mg,0.5mmol) and HOAT (72mg,0.5mmol) were added, DIPEA (176mg,1.3mmol) was added under nitrogen protection and ice bath conditions, and then warmed to room temperature and stirred for 4 hours. Inverse directionAfter completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain compound 72-7(0.3g, yield 80%) as a pale yellow solid. MS (ESI, pos.ion) M/z 791[ M + H-100 ]]⁺。

Step 6: synthesis of Compound 72-8

Compound 72-7(130mg,0.18mmol) was dissolved in 300mL1, 2-dichloroethane, the Jansen 1B catalyst (13mg,0.017mmol) was added under nitrogen and the reaction mixture was warmed to 75 deg.C for 36 h. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC to give compound 72-8(155mg, yield 65%) as a white solid.

MS(ESI,neg.ion)m/z:861[M-H]^-；

¹HNMR(600MHz,CDCl₃):10.41(d,J＝116.1Hz,1H),7.88(t,J＝9.6Hz,1H),7.80(s,1H),7.74(d,J＝8.0Hz,1H),7.63–7.53(m,1H),7.35(s,1H),7.29(d,J＝4.2Hz,1H),7.04(d,J＝18.9Hz,1H),6.97(d,J＝8.1Hz,1H),6.87(s,1H),5.93(s,1H),5.74(dd,J＝17.5,8.7Hz,1H),5.16(d,J＝7.3Hz,1H),5.01(t,J＝9.3Hz,1H),4.34(t,J＝7.4Hz,1H),4.06(t,J＝27.1Hz,1H),2.93(s,1H),2.63(d,J＝41.3Hz,3H),2.30(dd,J＝31.5,23.5Hz,1H),1.99–1.78(m,3H),1.73(s,2H),1.57(d,J＝33.1Hz,1H),1.53–1.44(m,4H),1.37–1.26(m,11H),1.13(ddd,J＝20.7,12.6,6.4Hz,2H),0.98–0.80(m,3H)ppm。

Purity of HPLC 94.71%.

Example 73

Synthetic route

Step 1: synthesis of intermediate 73-1

Compound 73-0(1.0g,3.0mmol) was added to 20mL of toluene and POCl was added slowly with stirring under nitrogen₃(927mg,6.0mmol) and N, N-dimethylaniline (183mg,1.51mmol) were added, and then the reaction mixture was heated to 110 ℃ to react for 3 hours. After the completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain a pale yellow solid compound 73-1(0.8g, yield 80%).

Step 2: synthesis of Compound 73-2

The compound N-Boc-4- (R) -hydroxyproline (573mg,2.48mmol) was dissolved in 50mL DMF, cooled to 0 ℃ under nitrogen, NaH (60% dispersed in mineral oil, 247mg,6.2mmol) was added in portions, and after addition, the reaction was warmed to room temperature and stirred for 30 min at room temperature.

Compound 73-1(875mg,2.48mmol) was dissolved in 10mL of anhydrous DMF and added to the reaction mixture and the mixture was stirred for an additional 2 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2-3 with 1n hcl, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 73-2(1g, yield 77%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:549.0[M+H]⁺。

And step 3: synthesis of Compound 73-3

Compound 73-2(767mg,1.4mmol), compound 1-9(661mg,1.6mmol), EDCI (317mg,1.6mmol) and HOAT (225mg,1.6mmol) were added to 100mL CH₂Cl₂DIPEA (546mg,4.1mmol) was added to the mixture in an ice bath, and the mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtainTo Compound 73-3 as a pale yellow solid (0.8g, 80% yield).

And 4, step 4: synthesis of Compounds 73-5

Compound 73-3(891mg,1.1mmol) was dissolved in 5NHCl in 50mL ethyl acetate and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting residue (300mg,0.4mmol) was dissolved in 50mL CH₂Cl₂To this mixture were added compound 2-11(221mg,0.5mmol), EDCI (102mg,0.5mmol) and HOAT (72mg,0.5mmol), and the resulting mixture was added DIPEA (176mg,1.3mmol) under ice bath, then warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain 73-5(0.3g, yield 80%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:914.4[M+H]⁺。

And 5: synthesis of Compounds 73-6

Compound 73-5(165mg,0.18mmol) was dissolved in 1, 2-dichloroethane (300mL), and Jansen's 1B catalyst (13mg,0.017mmol) was added under nitrogen, followed by warming to 75 ℃ and reaction for 36 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC to give compound 73-6(103mg, yield 65%) as a white solid.

MS(ESI,pos.ion)m/z:886[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.48(d,J＝116.1Hz,1H),7.56(d,J＝33.0Hz,1H),7.40–7.30(m,4H),7.26(d,J＝7.5Hz,1H),7.09–6.96(m,2H),6.92(d,J＝8.2Hz,1H),6.86(s,1H),5.95(s,1H),5.74(dd,J＝17.2,8.5Hz,1H),5.34(d,J＝34.4Hz,1H),5.01(t,J＝9.3Hz,1H),4.63(dd,J＝69.3,29.5Hz,2H),4.37(t,J＝7.4Hz,1H),4.09(dd,J＝45.1,13.5Hz,1H),3.84(s,3H),2.93(s,1H),2.63(dd,J＝23.8,17.0Hz,3H),2.30(ddd,J＝26.0,16.4,6.7Hz,2H),1.97–1.82(m,4H),1.60(s,1H),1.46(d,J＝14.7Hz,5H),1.33(d,J＝22.5Hz,9H),1.19–1.09(m,2H),0.98–0.84(m,3H)ppm。

HPLC purification of 92.90%.

Example 74

Synthetic route

Step 1: synthesis of Compound 74-1

Compound 74-0(0.86g,3.0mmol) was added to 20mL of toluene, and POCl was slowly added thereto with stirring₃(927mg,6.0mmol) and N, N-dimethylaniline (183mg,1.51mmol) were added, and then the reaction mixture was heated to 110 ℃ to react for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 74-1(734mg, yield 80%) as a pale yellow solid.

Step 2: synthesis of Compound 74-2

The compound N-Boc-4- (R) -hydroxyproline (759mg,2.48mmol) was dissolved in DMF (50mL) and the reaction was blanketed with nitrogen and cooled to 0 deg.C, then NaH (60% dispersed in mineral oil, 247mg,6.2mmol) was added in portions and after addition the reaction was allowed to warm to room temperature and stirred for 30 min.

Compound 74-1(875mg,2.48mmol) was dissolved in 10mL of anhydrous DMF and then added to the reaction mixture and the mixture was stirred for an additional 2 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2-3 with 1n hcl solution, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 74-2(0.957g, yield 77%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:501.0[M+H]⁺。

And step 3: synthesis of Compound 74-3

Compound 74-2(701mg,1.4mmol), compound 1-9(661mg,1.6mmol), EDCI (317mg,1.6mmol) and HOAT (225mg,1.6mmol) were added to 100mL CH₂Cl₂DIPEA (546mg,4.1mmol) was added to the mixture in an ice bath, and the mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 74-3(0.79g, yield 80%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 74-5

Compound 74-3(2.0g,2.8mmol) was dissolved in 5N HCl in 50mL ethyl acetate, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting crude product (200mg,0.3mmol) was dissolved in 50mL CH₂Cl₂And thereto were added compound 2-11(157mg,0.33mmol), EDCI (70mg,0.37mmol) and HOAT (50mg,0.37mmol), followed by addition of DIPEA (122mg,0.9mmol) under ice bath, and the resulting mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain 74-5(0.2g, yield 74%) as a pale yellow solid compound.

And 5: synthesis of Compound 74-6

Compound 74-5(200mg,0.22mmol) was dissolved in 300mL1, 2-dichloroethane, and Jansen's 1B catalyst (17mg,0.02mmol) was added under nitrogen, and the reaction was warmed to 75 ℃ for 36 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC to give compound 74-6(100mg, yield 50%) as a white solid.

¹HNMR(600MHz,CDCl₃):10.44(s,1H),7.90(s,1H),7.72–7.53(m,1H),7.11(d,J＝8.6Hz,1H),6.84(dd,J＝19.6,8.6Hz,2H),6.72–6.65(m,2H),5.94(s,1H) 5.71(dd, J ═ 17.6,8.5Hz,1H),5.23(d, J ═ 5.5Hz,1H),4.95(t, J ═ 9.3Hz,1H),4.83(d, J ═ 5.3Hz,1H),4.61(t, J ═ 7.5Hz,1H), 4.55-4.46 (m,3H),4.06(dd, J ═ 11.0,3.6Hz,1H),3.85(dd, J ═ 13.0,6.5Hz,1H),2.89(d, J ═ 4.3Hz,1H), 2.61-2.49 (m,3H),2.28(dd, J ═ 16.7,8.2, 1H),1.99(s,2H), 1.92H, 1.8.85 (d, 1H), 1.6.5H, 1H), 1H, 1.6H, 1H, 14.6.5H, 1H, 14.6H, 14.7 (d, 3H), 1.85 (dd, 14.7, 5H, 1H, 5H, 1H, 5H, 1H, 5H, 1H, 5H, 1H, 5H, 1H. HPLC purity 95.75%.

Example 75

Synthetic route

Step 1: synthesis of Compound 75-1

Compound 75-0(0.86g,3.0mmol) was added to 20mL of toluene and POCl was added slowly under nitrogen₃(927mg,6.0mmol) and N, N-dimethylaniline (183mg,1.51mmol), and after the addition, the reaction was refluxed at 110 ℃ for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 75-1(734mg, yield 80%) as a pale yellow solid.

Step 2: synthesis of Compound 75-2

The compound N-Boc-4- (R) -hydroxyproline (759mg,2.48mmol) was dissolved in 50mL of DMF, the resulting mixture was cooled to 0 ℃ under nitrogen, NaH (60% dispersed in mineral oil, 247mg,6.2mmol) was added portionwise and after addition warmed to room temperature and stirred for 30 min.

Compound 75-1(875mg,2.48mmol) was dissolved in 10mL anhydrous DMF and the resulting mixture was added to the above solution, followed by stirring for an additional 2 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the resulting mixture was adjusted to pH 2-3 with 1n hcl solution, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 75-2(0.957g, yield 77%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:501.0[M+H]⁺。

And step 3: synthesis of Compound 75-3

Compound 75-2(701mg,1.4mmol), compound 1-9(661mg,1.6mmol), EDCI (317mg,1.6mmol) and HOAT (225mg,1.6mmol) were added to 100mL CH₂Cl₂Then DIPEA (546mg,4.1mmol) was added while cooling on ice. The reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was removed from the reaction mixture under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 75-3(0.79g, yield 80%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 75-6

Compound 75-3(2.0g,2.8mmol) was dissolved in 5N HCl in 50mL ethyl acetate and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting crude product (200mg,0.3mmol) was dissolved in 50mL CH₂Cl₂To this, 75-5(147mg,0.3mmol), EDCI (70mg,0.37mmol) and HOAT (50mg,0.37mmol) were added, DIPEA (122mg,0.9mmol) was finally added under ice bath, and the reaction solution was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain compound 75-6(0.15g, yield 55%) as a pale yellow solid.

And 5: synthesis of Compounds 75-7

Compound 75-6(200mg,0.22mmol) was dissolved in 300mL1, 2-dichloroethane, Jansene 1B catalyst (17mg,0.02mmol) was added under nitrogen, and the reaction was warmed to 75 deg.C for 36 h. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by preparative HPLC to give compound 75-7(100mg, yield 50%) as a white solid.

MS(ESI,pos.ion)m/z:863.0[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.29(s,1H),7.60(s,1H),7.11(d,J＝7.5Hz,1H),6.87(s,2H),6.69(d,J＝14.9Hz,2H),5.92(s,1H),5.74(s,1H),5.37(s,1H),4.95(d,J＝46.4Hz,2H),4.51(dd,J＝59.7,46.9Hz,4H),4.30–3.92(m,3H),3.48–3.13(m,2H),2.92(s,1H),2.61(s,2H),2.28(s,1H),2.06(d,J＝24.6Hz,1H),1.88(s,4H),1.31(d,J＝38.7Hz,22H),0.92(d,J＝30.1Hz,4H)ppm。

HPLC purity 94.93%.

Example 76

Synthetic route

Step 1: synthesis of Compound 76-2

Dissolve compound 76-0(50mg,0.29mmol), compound 76-1(50mg,0.35mmol) in 20mL DMF, then add K ₂CO₃(60mg,0.44mmol), heating the reaction solution to 110 ℃ for reaction overnight, adding 1 mL of water to quench the reaction after the reaction is finished, extracting with ethyl acetate (20mL × 3), washing an organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and carrying out reduced pressure evaporation and concentration to obtain an orange oily liquid compound 76-2 which can be directly used without further purificationThe next reaction is carried out.

MS(ESI,pos.ion)m/z＝292.1[M+H]⁺。

Step 2: synthesis of Compound 76-3:

the compound 76-2(1g, 3.4mmol) obtained in the above reaction was dissolved in 50mL of glacial acetic acid, and iron powder (0.96g, 17.2mmol) was added thereto, and the temperature was raised to 110 ℃ for reaction for 8 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered, the obtained filtrate was concentrated and poured into 1N 100mL of hydrochloric acid solution, and a solid precipitated, filtered, the filter cake was washed with water, and the obtained solid was dried in a vacuum oven to obtain 76-3(822mg, two-step yield 61%)

And step 3: synthesis of Compound 76-4

Compound 76-3(50mg,0.22mmol) was added to 20mL of toluene under nitrogen, and POCl was slowly added thereto₃(100mg,0.66mmol) and N, N-dimethylaniline (13mg,0.11mmol) were added, and then the reaction mixture was heated to 110 ℃ to react for 5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether) to give 76-4(35mg, yield 64%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:248.1[M+H]⁺。

And 4, step 4: synthesis of Compound 76-5

The compound N-Boc-4- (R) -hydroxyproline (60mg,0.24mmol) was dissolved in 10mL of DMF, the resulting mixture was cooled to 0 ℃ under nitrogen, NaH (60% dispersed in mineral oil, 25mg,0.6mmol) was added thereto, and after the addition, the reaction was warmed to room temperature and stirred for 2 hours.

Compound 76-4(60mg,0.24mmol) was dissolved in 10mL of anhydrous DMF, added to the above reaction solution, and stirred for an additional 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the resulting mixture was adjusted to pH 2 to 3 with 1n hcl solution, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 76-5(85mg, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:443.1[M+H]⁺。

And 5: synthesis of Compound 76-6

Compound 76-5(50mg,0.11mmol), compound 1-9(45mg,0.11mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to 15mL CH₂Cl₂In the reaction, DIPEA (48mg,0.37mmol) was added under ice bath, and after the addition was completed, the mixture was warmed to room temperature and stirred for 4 hours, after the reaction was completed, the pH was adjusted to about 2 with 1N hydrochloric acid, followed by extraction with dichloromethane (10mL × 2), the organic phases were combined, the extract was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 76-6(65mg, yield 90%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:655.2[M+H]⁺。

Step 6: synthesis of Compound 76-8

Compound 76-6(1.15g,1.8mmol) was dissolved in 5N HCl in ethyl acetate (30mL) and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product obtained is dissolved in 50mLCH₂Cl₂Then, to the resulting mixture were added compound 2-11(488mg,1.8mmol), EDCI (546mg,2.85mmol) and HOAT (388mg,2.85mmol), and DIPEA (924mg,7.15mmol) under ice bath, and the reaction solution was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 76 to 8(400mg, two-step yield 40%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:808.3[M+H]⁺。

And 7: synthesis of Compounds 76-9

Compound 76-8(230mg,0.28mmol) was dissolved in 300mL1, 2-dichloroethane, and Jansen 1B catalyst (30mg) was added thereto under nitrogen protection, and the reaction mixture was warmed to 75 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 76-9(160mg, yield 73%) as a white solid.

MS(ESI,pos.ion)m/z:780.2[M+H]⁺。

And 8: synthesis of Compounds 76-10

Compound 76-9(339mg,0.38mmol) was dissolved in 5N HCl EA solution (30mL), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 76-10(0.29g, yield 99%) as a white solid compound.

And step 9: synthesis of Compound 76-11

Dissolve compound 76-10(150mg,0.21mmol) in 50mL CH₂Cl₂To this, compound 5-methylpyrazine-2-carboxylic acid (32mg,0.23mmol), EDCI (48mg,0.25mmol) and HOAT (34mg,0.25mmol) were added, then DIPEA (82mg,0.63mmol) was added under ice bath, and the reaction solution was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 76-11(0.14g, yield 84%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:800.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.37(s,1H),9.05(s,1H),8.41(d,J＝0.7Hz,1H),8.16(d,J＝6.9Hz,1H),7.69–7.51(m,2H),7.24(d,J＝7.2Hz,1H),7.18–7.15(m,1H),7.14–7.12(m,2H),6.88(dd,J＝8.9,2.0Hz,1H),6.83(td,J＝8.4,2.4Hz,1H),5.94(s,1H),5.74(dd,J＝18.1,8.8Hz,1H),5.06–4.90(m,1H),4.79–4.69(m,1H),4.60(t,J＝7.6Hz,1H),4.48(d,J＝11.1Hz,1H),4.16(dd,J＝11.3,4.5Hz,1H),2.94–2.86(m,1H),2.62(d,J＝8.4Hz,3H),2.61–2.51(m,2H),2.48(dd,J＝13.3,5.8Hz,1H),2.30(q,J＝8.6Hz,1H),2.05(dd,J＝7.5,4.5Hz,1H), 1.94-1.91 (m,2H), 1.82-1.72 (m,1H),1.63(dd, J ═ 9.2,5.9Hz,1H), 1.53-1.47 (m,4H), 1.38-1.32 (m,2H), 1.17-1.06 (m,3H),0.92(dd, J ═ 8.3,4.8Hz,1H) ppm. HPLC purity 96.43%.

Example 77

Synthetic route

Step 1: synthesis of Compound 77-2

Compound 77-1(944mg,3.1mmol) was added to 100mL of toluene, and POCl was slowly added thereto with stirring₃(939mg,6.1mmol) and N, N-dimethylaniline (185mg,1.5mmol), and after the addition, the reaction was warmed to 110 ℃ for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to give 77-2(0.8g, yield 80%) as a pale yellow solid compound.

Step 2: synthesis of Compound 77-3

The compound N-Boc-4- (R) -hydroxyproline (1.5g,6.5mmol) was dissolved in 50mL DMF under ice bath and NaH (60%, 520mg,13mmol) was added thereto and after the addition was complete, the reaction was warmed to room temperature and stirred for 2 h.

Compound 77-2(2.1g,6.5mmol) was dissolved in 10mL of anhydrous DMF, the resulting mixture was added to the above solution, and the resulting reaction was stirred for an additional 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2 to 3 with 1n hcl, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, then filtered, and finally concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain 77 to 3(3.0g, yield 90%) as a pale yellow solid compound.

MS(ESI,neg.ion)m/z:518.9[M-1]^-。

And step 3: synthesis of Compound 77-4

Compound 77-3(50mg,0.1mmol), compound 1-9(42mg,0.1mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to 15mL CH₂Cl₂After completion of the reaction, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, the aqueous phase was extracted with dichloromethane (10mL × 2), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 77-4(50mg, yield 70%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:734.9[M+H]⁺。

And 4, step 4: synthesis of Compound 77-6

Compound 77-4(600mg,0.8mmol) was dissolved in 5N HCl in 30mL ethyl acetate, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting residue (300mg,0.45mmol) was dissolved in 50mL CH₂Cl₂To this were added compounds 2-11(223mg,0.49mmol), EDCI (103mg,0.54mmol) and HOAT (73mg,0.54mmol), followed by DIPEA (177mg,1.3mmol) under ice-cooling, and the resulting mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 77-6(0.34g, two-step yield 64%) as a pale yellow solid.

And 5: synthesis of Compound 77-7

Compound 77-6(230mg,0.28mmol) was dissolved in 300mL1, 2-dichloroethane, the Jansene 1B catalyst (30mg) was added under nitrogen, and the reaction mixture was warmed to 75 ℃ for 48 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure, and the resulting crude product was purified by preparative HPLC to give compound 77-7(160mg, yield 73%) as a white solid.

MS(ESI,pos.ion)m/z:859.3[M+H]⁺。

Step 6: synthesis of Compound 77-8

Compound 77-7(237mg,0.3mmol) was dissolved in 5N HCl in 30mL ethyl acetate, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 77-8(0.2g, two-step yield 90%) as a white solid.

And 7: synthesis of Compounds 77-9

Dissolve compound 77-8(110mg,0.14mmol) in 50mL CH₂Cl₂To this, compound 5-methylpyrazine-2-carboxylic acid (21mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol) were added, and DIPEA (54mg,0.42mmol) was further added under ice bath. The reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 77-9(0.1g, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:878.2[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.33(s,1H),9.04(s,1H),8.41(s,1H),8.14(d,J＝6.8Hz,1H),7.60(dt,J＝45.5,22.8Hz,1H),7.47(d,J＝22.4Hz,1H),7.40(d,J＝2.3Hz,1H),7.23(dd,J＝8.6,2.4Hz,1H),7.01(d,J＝8.6Hz,1H),6.91–6.82(m,2H),5.91(s,1H),5.75(dd,J＝18.1,8.7Hz,1H),5.06–4.96(m,1H),4.76–4.67(m,1H),4.60(t,J＝7.7Hz,1H),4.53(d,J＝11.5Hz,1H),4.12(dt,J＝25.5,12.8Hz,1H),2.96–2.87(m,1H),2.64(s,3H),2.54(dd,J＝19.5,11.8Hz,1H),2.52–2.46(m,1H),2.30(q,J＝8.7Hz,1H),2.06(dd,J＝23.8,11.1Hz,1H),1.93(dt,J＝18.1,9.1Hz,2H),1.84–1.76(m,2H),1.62(dd,J＝9.3,5.9Hz,1H),1.54–1.48(m,4H),1.37(dd,J＝14.9,9.3Hz,2H),1.16–1.08(m,2H),0.96–0.85(m,2H)ppm。

Purity of HPLC 95.68%.

Example 78

Synthetic route

Step 1 Synthesis of Compound 78-2

Compound 78-1(944mg,3.1mmol) was added to 100mL of toluene, and POCl was slowly added thereto with stirring₃(939mg,6.1mmol) and N, N-dimethylaniline (185mg,1.5 mmol). After the addition, the reaction mixture was heated to 110 ℃ and reacted for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 78-2(0.8g, yield 80%) as a pale yellow solid.

Step 2: synthesis of Compound 78-3

The compound N-Boc-4- (R) -hydroxyproline (1.5g,6.5mmol) was dissolved in 50mL of DMF solution and added NaH (30% in mineral oil, 520mg,13mmol) under ice-cooling, after which the reaction was allowed to warm to room temperature and stirred for 2 h.

Compound 78-2(2.1g,6.5mmol) was dissolved in 10mL of anhydrous DMF, and then added to the above reaction solution, followed by stirring for another 4 hours. After the reaction was completed, the reaction solution was poured into 50mL of water, the resulting mixture was adjusted to pH 2 to 3 with 1n hcl aqueous solution, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give 78-3(3.0g, yield 90%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:518.9[M+H]⁺。

And step 3: synthesis of Compound 78-4

Compound 78-3(50mg,0.1mmol), compound 2-11(42mg,0.1mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to 15mL CH₂Cl₂In the reaction solution, DIPEA (48mg,0.37mmol) was further added under ice bath, after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours, after the reaction was completed, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, then the aqueous phase was extracted with dichloromethane (10mL × 2), the organic phases were combined, then the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 78-4(50mg, yield 70%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:734.9[M+H]⁺。

And 4, step 4: synthesis of Compound 78-6

Compound 78-4(600mg,0.8mmol) was dissolved in 5N HCl in 30mL ethyl acetate and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting residue (300mg,0.45mmol) was dissolved in 50mL CH₂Cl₂To this solution, compounds 2 to 11(223mg,0.49mmol), EDCI (103mg,0.54mmol) and HOAT (73mg,0.54mmol) were added, and DIPEA (177mg,1.3mmol) was added under ice-cooling, followed by warming to room temperature and stirring for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 78-6(0.34g, two-step yield 64%) as a pale yellow solid.

And 5: synthesis of Compound 78-7

Compound 78-6(230mg,0.28mmol) was dissolved in 300mL1, 2-dichloroethane, and Jansen 1B catalyst (30mg) was added thereto under nitrogen protection, and the reaction mixture was warmed to 75 ℃ for 48 hours. After completion of the reaction, concentration was performed under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 78-7(160mg, yield 73%) as a white solid.

MS(ESI,pos.ion)m/z:859.3[M+H]⁺。

Step 6: synthesis of Compound 78-8

Compound 78-7(237mg,0.3mmol) was dissolved in 5N HCl solution in 30mL ethyl acetate, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 78-8(0.2g, two-step yield 90%) as a white solid.

And 7: synthesis of Compounds 78-9

Dissolve compound 78-8(110mg,0.14mmol) in 50mL CH₂Cl₂To this was added the compounds 5-methylisoxazole-3-carboxylic acid (21mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol), and under ice bath, DIPEA (54mg,0.42mmol) was added. The reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, concentration was performed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain 78-9(0.1g, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:867.2[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.39(s,1H),7.98(s,1H),7.73(s,1H),7.61–7.46(m,1H),7.28(s,1H),7.26–7.18(m,1H),7.01(d,J＝8.5Hz,1H),6.93–6.86(m,1H),6.81(dd,J＝11.3,4.8Hz,1H),6.20(s,1H),5.91(s,1H),5.75(d,J＝8.7Hz,1H),5.00(t,J＝9.2Hz,1H),4.80(t,J＝7.8Hz,1H),4.73–4.58(m,2H),4.10(dd,J＝11.3,3.7Hz,1H),2.92(d,J＝4.2Hz,1H),2.65(d,J＝4.4Hz,3H),2.42(s,3H),2.31(dd,J＝16.8,8.4Hz,1H),2.14(dd,J＝22.1,10.5Hz,1H),1.91–1.84(m,2H),1.69(s,1H),1.50(dd,J＝13.8,7.7Hz,5H),1.31(s,2H),1.20–1.07(m,2H),0.93(dd,J＝18.6,12.8Hz,2H)ppm。

HPLC purity 95.17%.

Example 79

Synthetic route

Step 1: synthesis of Compound 79-2

Compound 79-1(944mg,3.1mmol) was added to 100mL of toluene, and POCl was slowly added thereto with stirring₃(939mg,6.1mmol) and N, N-dimethylaniline (185mg,1.5mmol) were added, and then the reaction mixture was heated to 110 ℃ to react for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 79-2(0.8g, yield 80%) as a pale yellow solid.

Step 2: synthesis of Compound 79-3

The compound N-Boc-4- (R) -hydroxyproline (1.5g,6.5mmol) was dissolved in 50mL DMF and NaH (30% dispersion in mineral oil, 520mg,13mmol) was added thereto under ice bath. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 2 hours.

Compound 79-2(2.1g,6.5mmol) was dissolved in 10ml of anhydrous DMF and then added to the above reaction solution, and the reaction solution was stirred for another 4 hours. After the reaction was completed, the reaction solution was poured into 50mL of water, the resulting mixture was adjusted to pH 2-3 with 1N HCl, followed by extraction with ethyl acetate (20 mL. times.3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered,

the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 79-3(3.0g, yield 90%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:518.9[M+H]⁺。

And step 3: synthesis of Compound 79-4

Mixing 79-3(100mg,0.19mmol), 4-methoxyphenylboronic acid (31mg,0.2mmol), and Pd (PPh)₃)₄(22mg,0.02mmol) and K₂CO₃(180mg,0.58mmol) was dissolved in a mixed solvent of THF (20mL) and water (0.1mL), and the reaction mixture was stirred at room temperature overnight.

After the reaction was completed, the reaction was quenched with a saturated sodium chloride solution (20mL), the resulting mixture was extracted with ethyl acetate (10 mL. times.3), the organic phases were combined,

the organic phase was then washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to give compound 79-4(90mg, yield 86%) as a yellow solid.

MS(ESI,pos.ion)m/z:549.0[M+H]⁺。

And 4, step 4: synthesis of Compound 79-5

Compound 79-4(55mg,0.1mmol), compound 1-9(42mg,0.1mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to 15mL CH₂Cl₂In the reaction solution, DIPEA (48mg,0.37mmol) was added thereto under ice-cooling, and after the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours, after the completion of the reaction, the reaction mixture was adjusted to pH 2 with 1N hydrochloric acid, followed by extraction with dichloromethane (10ml × 2), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then filtered, the resulting filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1), to obtain 79-5(50mg, yield 70%) as a pale yellow solid compound.

And 5: synthesis of Compound 79-7:

compound 79-5(580mg,0.76mmol) was dissolved in 5N HCl in ethyl acetate (30mL), and the reaction was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue (314mg,0.45mmol) was dissolved in 50mL CH₂Cl₂And thereto were added compounds 2-11(223mg,0.49mmol), EDCI (103mg,0.54mmol) and HOAT (73mg,0.54mmol), under ice bath,

DIPEA (177mg,1.3mmol) was added thereto, and then the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction is finished, the solvent is evaporated under reduced pressure,

The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 79-7(0.34g, yield 80%) as a pale yellow solid.

Step 6: synthesis of Compound 79-8

Compound 79-7(453mg,0.5mmol) was dissolved in 300mL1, 2-dichloroethane, and Jansen 1B catalyst (37mg) was added thereto under nitrogen, and the reaction mixture was warmed to 75 ℃ for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 79-8(0.3g, yield 70%) as a white solid.

And 7: synthesis of Compound 79-9

Compound 79-8(339mg,0.38mmol) was dissolved in 5N HCl in ethyl acetate (30mL), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 79-9(0.29g, yield 90%) as a white solid.

And 8: synthesis of Compound 79-10

Compound 79-9(123mg,0.14mmol) was dissolved in 50mLCH₂Cl₂To this, compound 5-methylpyrazine-2-carboxylic acid (21mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol) were added, DIPEA (54mg,0.42mmol) was further added under ice bath, and then the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue Purification by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) gave 79-10(0.1g, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:906.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.39(s,1H),9.07(s,1H),8.42(s,1H),8.16(d,J＝6.6Hz,1H),7.63(dd,J＝15.0,8.2Hz,2H),7.52(d,J＝8.5Hz,2H),7.43(d,J＝1.4Hz,1H),7.30(dd,J＝8.3,1.6Hz,1H),7.17(d,J＝8.3Hz,1H),6.96(d,J＝8.5Hz,2H),6.93–6.87(m,1H),6.85(dd,J＝11.3,4.8Hz,1H),5.96(s,1H),5.74(d,J＝9.1Hz,1H),5.01(t,J＝9.4Hz,1H),4.73(s,1H),4.61(t,J＝7.5Hz,1H),4.50(d,J＝11.2Hz,1H),3.84(s,3H),2.91(d,J＝4.9Hz,1H),2.65–2.53(m,5H),2.49(dd,J＝13.0,6.0Hz,1H),2.31(dd,J＝17.0,8.4Hz,1H),1.98–1.88(m,2H),1.78(s,1H),1.64(dd,J＝8.9,5.9Hz,1H),1.49(d,J＝4.2Hz,5H),1.35(s,3H),1.17–1.05(m,2H),0.90(ddd,J＝22.0,13.1,7.0Hz,2H)ppm。

Purity of HPLC 95.61%.

Example 80

Synthetic route

Step 1: synthesis of Compound 80-2

Mixing compound 80-1(4.4g,20mmol), 4-methoxyphenylboronic acid (3.73g,22mmol), Pd (PPh)₃)₄(0.7g,0.6mmol) and K₂CO₃(13.8g,100mmol) was dissolved in a mixed solvent of THF (80mL) and water (20mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated sodium chloride solution (200mL), thenThe resulting mixture was extracted with ethyl acetate (50mL × 3), the organic phases were combined, and the combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to give compound 80-2 as a yellow solid (4.8g, yield 90%).

Step 2: synthesis of Compound 80-4

Compounds 80-2(1.0g,6mmol), 80-3(1.6g,6mmol) were dissolved in DMF (20mL) and K was added thereto₂CO₃(1.66g,12mmol), heating the reaction solution to 110 ℃ for reaction overnight, adding 5 mL of water to quench the reaction after the reaction is finished, adjusting the pH value of the obtained mixture to about 2-3 by using 1N hydrochloric acid solution, extracting by using ethyl acetate (50mL × 3), washing the combined organic phase by using saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to obtain an orange oily liquid compound 80-4 crude product, and directly carrying out the next reaction.

MS(ESI,pos.ion)m/z:416[M+H]⁺。

And step 3: synthesis of Compound 80-5

The crude compound 80-4 was dissolved in 100mL of glacial acetic acid, reduced iron powder (1.68g,30mmol) was added, and the reaction mixture was heated to 110 ℃ for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered again, the filtrate was concentrated, and the concentrated residue was poured into 200mL of water, and a solid precipitated, and filtered. The filter cake was washed with water and dried to give 80-5(1.8g, 85% yield in two steps) as a yellow solid

MS(ESI,pos.ion)m/z:354[M+H]⁺。

And 4, step 4: synthesis of Compound 80-6

Compound 80-5(1.0g,2.74mmol) was added to 20mL of toluene, followed by slow addition of POCl with stirring₃(0.84g,5.48mmol) and N, N-dimethylaniline (0.14g,1.13mmol) were added, and then the reaction mixture was heated to 110 ℃ to react for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether)To give Compound 80-6(950mg, yield 93%) as a pale yellow solid. MS (ESI, pos. ion) M/z 372[ M + H ]]⁺。

And 5: synthesis of Compound 80-7

Compounds 2-7(750mg,3.07mmol) were dissolved in 20mL DMF and NaH (60% dispersed in mineral oil, 307mg,7.68mmol) was added portionwise thereto under ice bath and after addition, the reaction mixture was warmed to room temperature and stirred for 30 min.

Compound 80-6(950mg,2.56mmol) was dissolved in 2 mL of DMF and then added to the above reaction system and stirring was continued for 2 hours. After completion of the reaction, the reaction solution was poured into 30mL of water, the resulting mixture was adjusted to pH 2 to 3 with 1n aqueous hcl, followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 80 to 7(920mg, yield 62%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:565[M-H]^-。

Step 6: synthesis of Compound 80-8

Compound 80-7(920mg,1.62mmol), compound 1-9(783mg,1.93mmol), EDCI (402mg,2.11mmol) and HOAT (260mg,1.93mmol) were added to CH₂Cl₂In (25mL) under ice-bath, DIPEA (0.85mL,4.86mmol) was added thereto, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 80 to 8(1.2g, yield 95%) as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:779[M+H]⁺。

And 7: synthesis of Compounds 80-10

Compound 80-8(1.2g,1.54mmol) was dissolved in 5N HCl in ethyl acetate (20mL) and reacted The solution was stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. The residue obtained is dissolved in 20mLCH₂Cl₂Then, compound 2-11(683mg,1.52mmol), EDCI (313mg,1.64mmol) and HOAT (205mg,1.52mol) were added, and DIPEA (0.7mL,3.78mmol) was further added under ice bath. The reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 3:1) to obtain 80 to 10(1.0g, yield 70%) as a pale yellow solid compound.

MS(ESI,neg.ion)m/z:930[M-H]^-。

And 8: synthesis of Compounds 80-11

Compound 80-10(500mg,0.54mmol) was dissolved in 100mL1, 2-dichloroethane, GrubbsII catalyst (50mg) was added thereto under nitrogen protection, and the reaction mixture was warmed to 65 ℃ for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give compound 80-11(330mg, yield 68%) as a white solid.

MS(ESI,pos.ion)m/z:904.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.38(s,1H),7.42(s,1H),7.37–7.28(m,5H),7.19(s,1H),7.12–7.00(m,2H),5.94(s,1H),5.73(dd,J＝17.7,8.7Hz,1H),5.27(s,1H),5.00(t,J＝9.4Hz,1H),4.79–4.52(m,2H),4.40–4.32(m,1H),4.09–4.00(m,1H),3.94(s,3H),2.92(s,1H),2.74–2.52(m,3H),2.40–2.28(m,1H),1.99–1.81(m,4H),1.67–1.52(m,2H),1.42–1.26(m,14H),1.18–1.09(m,2H),0.97–0.87(m,2H)ppm。

HPLC purity 97.23%.

Example 81

Synthetic route

Step 1: synthesis of Compound 81-1

Compound 35-9(249mg,0.3mmol) was dissolved in 5N HCl in ethyl acetate (30mL) and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 81-1(0.2g, yield 90%) as a white solid.

Step 2: synthesis of Compound 81-2

Compound 81-1(107mg,0.14mmol) was dissolved in 50mLCH₂Cl₂To this, compound 5-methylpyrazine-2-carboxylic acid (21mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol) were added, and DIPEA (54mg,0.42mmol) was further added under ice bath. The reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 81-2(0.1g, yield 80%) as a pale yellow solid.

¹HNMR(400MHz,CDCl₃)10.31(s,1H),9.04(s,1H),8.38(s,1H),8.15(d,J＝7.1Hz,1H),7.69(d,J＝8.1Hz,1H),7.44(s,1H),7.34(d,J＝8.0Hz,1H),7.21–7.17(m,3H),5.98(s,1H),5.75(dd,J＝18.0,8.7Hz,1H),5.02(t,J＝9.4Hz,1H),4.78(t,J＝7.2Hz,1H),4.69–4.49(m,2H),4.15(dd,J＝11.4,4.2Hz,1H),2.99–2.86(m,1H),2.64(s,3H),2.34(d,J＝8.6Hz,1H),2.07(d,J＝7.5Hz,1H),1.99–1.91(m,2H),1.72(s,4H),1.51(dd,J＝21.4,17.2Hz,5H),1.35(s,4H),1.13(ddd,J＝12.6,8.7,4.5Hz,2H),0.96–0.86(m,2H)ppm。

Example 82

Synthetic route

Step 1: synthesis of Compound 82-1

Compound 35-9(249mg,0.3mmol) was dissolved in 5N HCl in 30mL ethyl acetate. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure to obtain compound 82-1(0.2g, yield 90%) as a white solid.

Step 2: synthesis of Compound 82-2

Compound 82-1(107mg,0.14mmol) was dissolved in 50mLCH₂Cl₂To this, the compound 5-methylisoxazole-3-carboxylic acid (21mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol) were then added in this order, and DIPEA (54mg,0.42mmol) was further added under ice bath, followed by warming to room temperature and stirring for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 82-2(0.1g, yield 80%) as a pale yellow solid.

¹HNMR(600MHz,CDCl₃):10.30(s,1H),7.63(d,J＝8.2Hz,2H),7.46(s,1H),7.35(d,J＝8.1Hz,1H),7.29(s,1H),7.19(td,J＝5.8,2.1Hz,3H),6.17(s,1H),5.97(s,1H),5.76(dd,J＝17.8,9.0Hz,1H),5.06–4.97(m,1H),4.81–4.75(m,1H),4.64(dd,J＝16.9,9.3Hz,2H),4.11(dd,J＝11.5,4.0Hz,1H),2.97–2.91(m,1H),2.69(dd,J＝7.7,4.6Hz,2H),2.62(s,1H),2.43(s,3H),2.31(q,J＝8.6Hz,1H),1.97–1.87(m,2H),1.51(ddd,J＝10.0,8.4,4.4Hz,6H),1.37–1.31(m,4H),1.20–1.08(m,3H),0.96(d,J＝7.7Hz,1H),0.90(d,J＝7.0Hz,1H)ppm。

Example 83

Synthetic route

Step 1: synthesis of Compound 83-2

Compound 83-1(710mg,3.1mmol) was added to 100mL of toluene, and POCl was slowly added thereto with stirring₃(939mg,6.1mmol) and N, N-dimethylaniline (185mg,1.5mmol) were added, and then the reaction mixture was heated to 110 ℃ to react for 5 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 83-2(0.8g, yield 80%) as a pale yellow solid compound.

Step 2: synthesis of Compound 83-3

The compound N-Boc-4- (R) -hydroxyproline (1.6g,6.5mmol) was dissolved in 50mL of DMF solution and NaH (30% dispersed in mineral oil, 520mg,13mmol) was added thereto under ice-bath and after the addition the reaction mixture was warmed to room temperature and stirred for 2 h.

Compound 83-2(2.1g,6.5mmol) was dissolved in 10mL of anhydrous DMF solution and then added to the above reaction mixture and the reaction mixture was stirred for an additional 4 hours. After completion of the reaction, the reaction mixture was poured into 50mL of water, the resulting mixture was adjusted to pH 2-3 with 1n aqueous hcl, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 83-3(3.0g, yield 90%) as a pale yellow solid compound.

And step 3: synthesis of Compound 83-4

Compound 83-3(44mg,0.1mmol), compound 1-9(42mg,0.1mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to 15mL CH₂Cl₂After the reaction was completed, the pH was adjusted to about 2 with a 1N hydrochloric acid solution, and then extracted with dichloromethane (10mL × 2), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then filtered, the resulting filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain 83-4(50mg, yield 70%) as a pale yellow solid compound.

And 4, step 4: synthesis of Compound 83-5

Compound 83-4(524mg,0.8mmol) was dissolved in 5N HCl in ethyl acetate (30mL), and the reaction was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. The residue (263mg,0.45mmol) was dissolved in 50mL CH₂Cl₂To this, compounds 2-11(223mg,0.49mmol), EDCI (103mg,0.54mmol) and HOAT (73mg,0.54mmol) were added, DIPEA (177mg,1.3mmol) was added under ice bath, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 83-6(0.34g, yield 64%) as a pale yellow solid.

And 5: synthesis of Compound 83-7

Compound 83-6(226mg,0.28mmol) was dissolved in 300mL1, 2-dichloroethane solution, and Jansen 1B catalyst (30mg) was added under nitrogen and the temperature was raised to 75 ℃ for reaction for 48 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC to give compound 83-7(160mg, yield 73%) as a white solid.

MS(ESI,pos.ion)m/z:780.9[M+H]⁺。

Step 6: synthesis of Compound 83-8

Compound 83-7(234mg,0.3mmol) was dissolved in 30mL of ethyl ester of 5N HCl, and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 83-8(0.2g, yield 90%) as a white solid.

And 7: synthesis of Compound 83-9

Dissolve 83-8(110mg,0.14mmol) in 50mL CH₂Cl₂To the solution, intermediate 5-methylpyrazine-2-carboxylic acid (21mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol) were added, DIPEA (54mg,0.42mmol) was further added under ice bath, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure from the reaction mixture, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 83-9(0.1g, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:800.3M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.40(s,1H),9.03(s,1H),8.42(s,1H),8.15(d,J＝5.9Hz,1H),7.90(s,1H),7.59(d,J＝7.2Hz,1H),7.35(s,1H),7.11(s,3H),6.93(d,J＝7.9Hz,1H),6.78(s,1H),5.89(s,1H),5.72(d,J＝8.5Hz,1H),4.99(t,J＝9.0Hz,1H),4.71(s,1H),4.57(t,J＝6.7Hz,1H),4.45(d,J＝10.7Hz,1H),4.13(dd,J＝11.3,7.9Hz,1H),2.89(s,1H),2.60(s,3H),2.43(d,J＝31.6Hz,2H),2.27(d,J＝8.2Hz,1H),2.03(s,2H),1.77(s,1H),1.67(s,1H),1.47(s,5H),1.33(d,J＝7.6Hz,3H),1.09(d,J＝4.7Hz,2H),0.87(d,J＝24.4Hz,2H)ppm。

Example 84

Synthetic route

Synthesis of Compound 84-1

Compound 92-9(0.13g,0.16mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of a 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered and the resulting white solid was washed with 20ml of ethyl acetate.

The solid obtained above, compound 5-methylpyrazine-2-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20mL dichloromethane were added under nitrogen protection, then the mixture was cooled to 0 ℃ and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, followed by extraction with ethyl acetate (20mL × 2), the organic phases were combined, the combined organic phases were washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified with a silica gel column (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 84-1(0.076g, yield 58%) as a white solid.

MS(ESI,pos.ion)m/z:800.3M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.31(s,1H),9.05(d,J＝1.3Hz,1H),8.40(d,J＝0.9Hz,1H),8.14(d,J＝6.9Hz,1H),7.49(s,1H),7.34(d,J＝7.9Hz,1H),7.26–7.22(m,2H),7.20–7.11(m,3H),7.05–6.99(m,1H),5.97–5.91(m,1H),5.73(d,J＝10.1Hz,1H),5.04–4.96(m,1H),4.77–4.70(m,1H),4.58(t,J＝7.7Hz,1H),4.50(d,J＝11.5Hz,1H),4.14(dd,J＝11.4,4.5Hz,1H),2.94–2.84(m,1H),2.62(s,3H),2.59–2.46(m,3H),2.33–2.24(m,1H),2.07–2.01(m,1H),1.95–1.90(m,2H),1.62–1.58(m,1H),1.54–1.45(m,5H),1.16–1.05(m,3H),0.91–0.83(m,4H)ppm。

Purity of HPLC 96.91%.

Example 85

Synthetic route

Synthesis of Compound 85-1

Compound 5-9(0.12g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained above, compound 5-methylpyrazine-2-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20 mL dichloromethane were added under nitrogen protection, the mixture was cooled to 0 ℃ and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, followed by extraction with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting crude product was purified by a silica gel column (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 85-1(0.080g, yield 65%) as a white solid.

MS(ESI,pos.ion)m/z:813[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.33(s,1H),9.08(d,J＝43.5Hz,1H),8.42(s,1H),8.21(d,J＝32.1Hz,1H),7.64–7.52(m,1H),7.48–7.34(m,2H),7.18–7.06(m,3H),6.99–6.92(m,1H),6.65(d,J＝10.5Hz,2H),5.96(s,1H),5.75(d,J＝9.5Hz,1H),5.07–4.97(m,1H),4.80(s,1H),4.61(t,J＝7.5Hz,1H),4.27–4.09(m,1H),3.23(s,3H),2.98–2.85(m,1H),2.64(s,3H),2.61–2.40(m,3H),2.37–2.25(m,1H),2.09–1.90(m,4H),1.57–1.48(m,4H),1.20–1.09(m,3H),0.95–0.87(m,4H)ppm。

Purity of HPLC 95.49%.

Example 86

Synthetic route

Step 1: synthesis of Compound 86-2

Compound 86-0(1.0g,7.1mmol) and compound 86-1(1.3g,7.6mmol) were dissolved in 15ml DMF, and K was added thereto₂CO₃(2.0g,14.2mmol) and the reaction mixture was refluxed overnight. After the reaction was complete, the mixture was cooled to room temperature, 100mL of ethyl acetate was added, and the resulting mixture was taken with H₂O wash (100mL × 2), followed by 50mL saturated brine, and the organic phase over anhydrous Na₂SO₄Drying and concentration under reduced pressure gave compound 86-2(2.0g, yield: 97%) as a yellow solid, which was used in the next reaction without further purification.

Step 2: synthesis of Compound 86-3

Compound 86-2(2.0g,6.9mmol) was dissolved in 50mL of glacial acetic acid, and reduced iron powder (1.9g,36mmol) was added thereto,

the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction, cooling to room temperature, filtering to remove the solid, dropwise adding 100ml of 1N HCl solution into the obtained filtrate to separate out a large amount of white solid, filtering, and drying the obtained white solid under a vacuum condition to obtain a white solid compound 86-3(0.87g, yield: 55%); the reaction was carried out without further purification.

And step 3: synthesis of Compound 86-4

Compound 86-3(0.8g,3mmol) was added to 20mL of toluene, phosphorus oxychloride (0.6mL,7mmol) was added thereto under nitrogen, then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly, and the reaction mixture was warmed to 110 ℃ for 6 hours. After completion of the reaction, it was cooled to 0 ℃, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give compound 86-4(0.8g, yield 90%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 86-5

Sodium hydride (60% in mineral oil, 0.45g,11mmol) was added to 20mL of anhydrous DMF under nitrogen at 0 ℃ and then a solution of compounds 2-7(0.86g,4mmol) in anhydrous DMF (10mL) was added and the reaction was warmed to 30 ℃ and stirred for 2 hours. A solution of compound 86-4(0.8g,3mmol) in anhydrous tetrahydrofuran (10mL) was added to the reaction mixture, followed by stirring overnight. After completion of the reaction, the reaction was quenched with 20mL of water at 0 ℃, the resulting mixture was washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, then washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 86-5 as a white solid (1.0g, yield: 70%).

MS(ESI,neg.ion)m/z:441[M-H]^-。

And 5: synthesis of Compound 86-6

Compound 86-5(1.0g,2.3mmol), compound 1-9(1.0g,2.5mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged to a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (1.05mL,6.02mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, followed by extraction with ethyl acetate (20mL × 2), the organic phases were combined, the combined organic phases were washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 86-6(1.0g, yield 66%) as a white solid.

MS(ESI,pro.ion)m/z:655[M+H]⁺。

Step 6: synthesis of Compound 86-8

Compound 86-6(1.0g,1.5mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength ethyl acetate solution of hydrochloric acid was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained above, compounds 2-11(0.74g,1.6mmol), EDCI (0.34g,1.8mmol) and HOAT (0.23g,1.7mmol) were charged into a round-bottomed flask, and 20 mL of dichloromethane were added under nitrogen protection at 0 ℃ followed by DIPEA (0.7mL,4.0 mmol). The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting crude product was purified by a silica gel column (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 86-8(1.0g, yield 90%) as a white solid.

MS(ESI,neg.ion)m/z:806[M-H]^-。

And 7: synthesis of Compound 86-9

Compound 86-8(0.38g,0.47mmol) was dissolved in 300 ml of 1, 2-dichloroethane, 0.05 g of Grubbs's second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After the reaction is finished, the reaction is carried out The mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 86-9(0.22g, yield: 60%) as a white solid. MS (ESI, pos. ion) M/z 780[ M + H ]]⁺。

Step 8 Synthesis of Compound 86-11

Compound 86-9(0.13g,0.16mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The resulting solid, compound 5-methylpyrazine-2-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged to a round bottom flask, 20 mL of dichloromethane were added under nitrogen, 0 deg.C and DIPEA (0.1mL,0.6mmol) was added last. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 86-11 as a white solid (0.082g, yield 64%).

MS(ESI,pos.ion)m/z:800[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.33(s,1H),9.11(d,J＝1.0Hz,1H),8.43(s,1H),8.12(d,J＝6.3Hz,1H),7.63(s,1H),7.45–7.40(m,1H),7.25(d,J＝7.4Hz,1H),7.18–7.12(m,3H),7.10–7.03(m,2H),6.03(s,1H),5.76(d,J＝9.3Hz,1H),5.07–4.99(m,1H),4.69–4.60(m,2H),4.57(d,J＝11.4Hz,1H),4.09(dd,J＝11.4,4.0Hz,1H),2.96–2.86(m,1H),2.69–2.59(m,5H),2.55–2.47(m,1H),2.32–2.25(m,1H),2.10–2.02(m,1H),1.97–1.88(m,2H),1.56–1.48(m,5H),1.18–1.08(m,3H),0.92–0.85(m,4H)ppm。

HPLC purity 96.14%.

Example 87

Synthetic route

Synthesis of Compound 87-1

Compound 5-10(0.12g,0.15mmol) was dissolved in 2 ml of ethyl acetate, 20 ml of a 30% hydrochloric acid/ethyl acetate solution was added thereto at 0 ℃ and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged to a round bottom flask, 20 mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃ and finally DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 87-1(0.07g, yield 58%) as a white solid.

MS(ESI,pos.ion)m/z:802[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.36(s,1H),7.99–7.74(m,1H),7.62–7.53(m,1H),7.45–7.29(m,2H),7.18–7.05(m,3H),6.97(d,J＝7.6Hz,1H),6.68(dd,J＝10.7,2.3Hz,1H),5.93(d,J＝23.5Hz,1H),5.75(dd,J＝18.3,8.6Hz,1H),5.05–4.98(m,1H),4.84(s,1H),4.65(s,2H),4.12(s,1H),3.24(s,3H),2.93(s,1H),2.72–2.57(m,3H),2.48–2.37(m,3H),2.35–2.27(m,1H),2.12–2.00(m,1H),1.94–1.81(m,3H),1.79–1.68(m,2H),1.57–1.44(m,6H),0.94–0.85(m,4H)ppm。

Purity of HPLC 93.39%.

Example 88

Synthetic route

Synthesis of Compound 88-1

Compound 24-7(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained above, compound 5-methylpyrazine-2-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, under nitrogen protection, 20 mL dichloromethane was added, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 88-1(0.07g, yield 54%) as a white solid.

MS(ESI,pos.ion)m/z:876[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.34(s,1H),9.05(s,1H),8.38(s,1H),8.17(d,J＝7.1Hz,1H),7.57(d,J＝8.1Hz,1H),7.49–7.41(m,3H),7.31(d,J＝1.4Hz,1H),7.25(s,1H),7.20(dd,J＝8.1,1.5Hz,1H),7.17–7.07(m,5H),5.97(s,1H),5.73(dd,J＝18.1,8.7Hz,1H),5.00(t,J＝9.4Hz,1H),4.82–4.75(m,1H),4.64(t,J＝7.7Hz,1H),4.54(d,J＝11.4Hz,1H),4.15(dd,J＝11.4,4.4Hz,1H),3.65(d,J＝2.1Hz,1H),2.95–2.84(m,1H),2.64–2.54(m,5H),2.31(dd,J＝17.4,8.7Hz,1H),2.09–2.01(m,1H),1.96–1.90(m,2H),1.62–1.58(m,1H),1.52–1.46(m,4H),1.17–1.05(m,3H),0.94–0.84(m,4H)ppm。

HPLC purity 94.74.

Example 89

Synthetic route

Synthesis of Compound 89-2

The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged to a round bottom flask, 20 mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃ and finally DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. The reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 89-1(0.06g, yield 47%) as a white solid.

MS(ESI,pos.ion)m/z:789[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.41(s,1H),8.13(s,1H),7.86(s,1H),7.27(d,J＝7.5Hz,1H),7.22–7.14(m,4H),7.14–7.11(m,1H),7.10–7.04(m,1H),6.21(s,1H),5.98(s,1H),5.76(dd,J＝17.3,9.4Hz,1H),5.05–4.96(m,1H),4.84–4.74(m,2H),4.66(t,J＝8.1Hz,1H),4.08(dd,J＝11.5,3.8Hz,1H),2.98–2.86(m,1H),2.79–2.62(m,3H),2.38(s,3H),2.35(d,J＝8.3Hz,1H),2.27–2.16(m,1H),1.91–1.82(m,2H),1.57–1.48(m,4H),1.18–1.05(m,3H),0.94–0.85(m,4H)ppm。

HPLC purity 97.78%.

Example 90

Synthetic route

Synthesis of Compound 90-2

Compound 24-7(0.13g,0.15mmol) was dissolved in 2 ml of ethyl acetate, 20 ml of a 30% hydrochloric acid/ethyl acetate solution was added at 0 ℃ and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, protected with nitrogen, 20 mL dichloromethane were added, and DIPEA (0.1mL,0.6mmol) was added at 0 ℃. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 90-1(0.09g, yield 69%) as a white solid.

MS(ESI,pos.ion)m/z:865[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.38(s,1H),7.95(d,J＝7.9Hz,1H),7.67(s,1H),7.52–7.45(m,3H),7.34(d,J＝1.7Hz,1H),7.28–7.26(m,1H),7.21(dd,J＝8.1,1.7Hz,1H),7.19–7.09(m,5H),6.16(s,J＝0.8Hz,1H),5.97(d,J＝3.0Hz,1H),5.78–5.68(m,1H),5.03–4.95(m,1H),4.89–4.81(m,1H),4.67(t,J＝7.8Hz,1H),4.59(d,J＝11.5Hz,1H),4.14(dd,J＝11.5,4.3Hz,1H),2.95–2.88(m,1H),2.70–2.57(m,3H),2.34(s,J＝0.6Hz,3H),2.18–2.09(m,1H),1.93–1.72(m,4H),1.52–1.46(m,4H),1.20–1.03(m,3H),0.93–0.81(m,4H)ppm。

HPLC purity 98.19%.

Example 91

Synthetic route

Synthesis of Compound 91-1

Compound 92-9(0.13g,0.16mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and 20 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20 mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃ and finally DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 91-1(0.06g, yield 47%) as a white solid.

MS(ESI,pos.ion)m/z:789.2M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.38(s,1H),7.98(d,J＝7.7Hz,1H),7.73(s,1H),7.28–7.24(m,2H),7.21–7.13(m,4H),6.98–6.91(m,1H),6.13(d,J＝0.6Hz,1H),5.93(d,J＝3.3Hz,1H),5.77–5.69(m,1H),4.99(dd,J＝10.0,8.7Hz,1H),4.84–4.77(m,1H),4.70–4.60(m,2H),4.10(dd,J＝11.5,4.1Hz,1H),2.95–2.88(m,1H),2.69–2.60(m,3H),2.39(s,3H),2.31(q,J＝8.8Hz,1H),2.16(d,J＝12.5Hz,1H),1.87–1.82(m,2H),1.50–1.45(m,4H),1.18–1.04(m,3H),0.94–0.85(m,4H)ppm。

Purity of HPLC 98.12%.

Example 92

Synthetic route

Step 1: synthesis of Compound 92-2

Compound 92-0(1.0g,7.1mmol) and compound 92-1(1.3g,7.6mmol) were dissolved in 15ml DMF, and K was added thereto₂CO₃(2.0g,14.2mmol) and the reaction mixture was refluxed overnight. After the reaction was complete, the reaction was cooled to room temperature and diluted with 100ml of OAc and then 100mLH₂O twice, the organic phase was washed with 50mL of saturated brine and then with anhydrous Na₂SO₄Drying and then filtration were carried out, and the filtrate was concentrated under reduced pressure to give compound 92-2(2.0g, yield: 97%) as a yellow solid, which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 92-3

Compound 92-2(2.0g,6.9mmol) was dissolved in 50mL of glacial acetic acid, then reduced iron powder (1.9g,36mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction, the reaction system was cooled to room temperature, the solid was removed by filtration, 1n hcl solution was added dropwise to the filtrate to precipitate a large amount of white solid, which was then filtered again, and the obtained solid was dried under vacuum to obtain 92-3(0.87g, yield: 55%) as a white solid, which was directly subjected to the next reaction without further purification.

And step 3: synthesis of Compound 92-4

Compound 92-3(0.8g,3mmol) was added to 20mL of toluene, under nitrogen, phosphorus oxychloride (0.6mL,7mmol) was added, and finally N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly. After the addition was complete, the reaction mixture was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, the reaction liquid was cooled to 0 ℃, and then concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 92-4(0.8g, yield: 90%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 92-5

Sodium hydride (60% in mineral oil, 0.45g,11mmol) was added to 20ml of anhydrous DMF and under nitrogen at 0 ℃ a solution of compounds 2-7(0.92g,4mmol) in 10 ml of anhydrous DMF was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 2 hours.

A solution of compound 92-4(0.8g,3mmol) in dry tetrahydrofuran (5mL) was added to the reaction and the reaction mixture was stirred overnight. After the reaction was complete, the reaction was quenched with 20mL of water at 0 ℃ and washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution and extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 92-5(1.0g, yield: 70%) as a white solid.

MS(ESI,neg.ion)m/z:441[M-H]^-。

And 5: synthesis of Compound 92-6

Compound 92-5(1.0g,2.3mmol), compound 1-9(1.0g,2.5mmol), EDCI (0.5g,3.0mmol) and HOAT (0.33g,2.4mmol) were charged into a round bottom flask, 30 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (1.05mL,6.02mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (20mL × 2), the organic phases were combined, the combined organic phases were washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 92-6(1.0g, yield 66%) as a white solid.

MS(ESI,neg.ion)m/z:653.2[M-H]^-。

Step 6: synthesis of Compound 92-8

Compound 92-6(1.0g,1.5mmol) was dissolved in 2 ml of ethyl acetate, 20ml of a 30% strength hydrochloric acid/ethyl acetate solution was added thereto at 0 ℃ and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered, and the resulting white solid was washed with 20ml of ethyl acetate.

The resulting solid, compounds 2-11(0.74g,1.6mmol), EDCI (0.34g,1.8mmol) and HOAT (0.23g,1.7mmol) were charged to a round bottom flask, 20mL of dichloromethane were added under nitrogen, 0 deg.C, and DIPEA (0.7mL,4.0mmol) was added last. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 92-8(1.0g, yield 90%) as a white solid.

MS(ESI,neg.ion)m/z:806[M-H]^-。

And 7: synthesis of target 92-9

Compound 92-8(0.38g,0.47mmol) was dissolved in 300 ml of 1, 2-dichloroethane, 0.05 g of Grubbs's second generation catalyst was added under nitrogen, and the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, the reaction system was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain a white solid compound 92-9(0.22g, yield: 60%).

MS(ESI,pos.ion)m/z:780[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.35–7.20(m,2H),7.18–7.12(m,3H),7.10–7.02(m,2H),7.02–6.94(m,1H),5.82(s,1H),5.60(s,1H),5.40–5.17(m,1H),5.11–4.88(m,1H),4.66–4.51(m,1H),4.48–4.19(m,2H),4.04–3.92(m,1H),2.78(s,1H),2.55(s,3H),1.88–1.73(m,3H),1.33–1.20(m,16H),1.09–0.91(m,3H),0.87–0.76(m,4H)ppm。

Purity of HPLC 97.40%.

Example 93

Synthetic route

Step 1: synthesis of Compound 93-1

Compound 26-9(0.2g,0.3mmol), compound 93-0(0.1g,0.4mmol), EDCI (0.08g,0.4mmol) and HOAT (0.05,0.4mmol) were charged to a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.15mL,1mmol) was added. After the addition was completed, the reaction solution was heated to 30 ℃ and stirred for 4 hours. After the reaction, the reaction was quenched with 10mL of water and extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 93-1(0.24g, yield 89%) as a white solid.

MS(ESI,neg.ion)m/z:901.3[M-H]^-。

Step 2: synthesis of target 93-2

Compound 93-1(0.2g,0.2mmol) was dissolved in 200 mL of 1, 2-dichloroethane and under nitrogen, 0.02 g of Janz 1B catalyst was added. After the addition was complete, the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 93-2(0.085g, yield: 43%) as a white solid.

MS(ESI,pos.ion)m/z:875[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.41(s,1H),7.75–7.62(m,1H),7.40(s,1H),7.21(d,J＝8.5Hz,1H),7.01(d,J＝10.5Hz,2H),6.86(t,J＝8.5Hz,2H),5.93(s,1H),5.80–5.69(m,1H),4.99(t,J＝9.4Hz,1H),4.91(d,J＝7.0Hz,1H),4.59(t,J＝7.5Hz,1H),4.52(d,J＝11.2Hz,1H),4.40(t,J＝7.1Hz,1H),4.04(dd,J＝11.2,4.4Hz,1H),3.33–3.23(m,2H),3.23–3.12(m,2H),2.95–2.86(m,1H),2.65–2.50(m,3H),2.28–2.18(m,1H),1.95–1.86(m,2H),1.84–1.72(m,3H),1.50–1.41(m,9H),1.18–1.05(m,3H),0.98–0.74(m,4H)ppm。

Purity of HPLC 93.46%.

Example 94

Synthetic route

Synthesis of Compound 94-1

Compound 2-13(0.13g,0.17mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 2ml of a 30% strength hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 4 ml of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.03g,0.23mmol), EDCI (0.12g,0.61mmol) and HOAT (0.1g,0.7mmol) were charged into a round bottom flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 ℃ and DIPEA (0.2mL,1.0mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with dichloromethane (10mL × 2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 94-1(0.110g, yield 77%) as a white solid.

¹HNMR(600MHz,CDCl₃):8.03(d,J＝7.9Hz,1H),7.81(s,1H),7.44(dd,J＝7.8,1.6Hz,1H),7.39(tt,J＝4.3,2.2Hz,1H),7.28–7.26(m,1H),7.18–7.15(m,3H),7.15–7.12(m,1H),6.13(d,J＝0.7Hz,1H),5.95(d,J＝3.3Hz,1H),5.75(dd,J＝18.4,8.5Hz,1H),5.03–4.98(m,1H),4.88–4.82(m,1H),4.70–4.62(m,2H),4.13(dd,J＝11.5,4.2Hz,1H),2.95–2.89(m,1H),2.66(dd,J＝7.9,3.6Hz,3H),2.38(s,3H),2.32(q,J＝8.7Hz,1H),2.17(dd,J＝24.1,11.4Hz,1H),2.08–2.03(m,1H),1.87(ddd,J＝14.0,8.9,5.2Hz,2H),1.69(ddd,J＝17.0,8.1,4.0Hz,1H),1.54–1.46(m,5H),1.13(dtdd,J＝15.5,13.0,7.6,5.3Hz,3H),0.96–0.87(m,3H)ppm。

HPLC purity 97.05%.

Example 95

Synthetic route

Step 1: synthesis of Compound 95-1

Compound 58-7(0.5g,0.83mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and 5 ml of a 30% strength hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate.

The solid from the above reaction, compound 95-0(0.25g,0.9mmol), EDCI (0.1.5g,1mmol) and HOAT (0.2g,1mmol) were charged into a round bottom flask under nitrogen, 10mL of dichloromethane were added, and DIPEA (0.6mL,3.0mmol) was added at 0 deg.C. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, the combined organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the resulting filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 95-1 as a white solid (0.4g, yield 55.86%).

MS(ESI,pos.ion)m/z:864.6[M+H]⁺。

Step 2: synthesis of target Compound 95-2

Compound 95-1(0.4g,0.46mmol) was dissolved in 400 ml of 1, 2-dichloroethane, and 0.05 g of Grubbs's secondary catalyst was added thereto under nitrogen protection. After the addition was complete, the reaction mixture was warmed to 65 ℃ and stirred for 48 hours. After completion of the reaction, the reaction system was cooled to room temperature, and then concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 95-2(0.25g, yield: 65.78%) as a white solid.

MS(ESI,pos.ion)m/z:835.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):7.64(dd,J＝8.2,6.7Hz,1H),7.55(s,1H),7.13(t,J＝11.9Hz,1H),6.88–6.81(m,2H),6.74–6.65(m,2H),5.92(s,1H),5.71(dd,J＝17.5,8.5Hz,1H),5.10–4.99(m,2H),4.62(t,J＝7.3Hz,1H),4.51–4.40(m,2H),4.08(dd,J＝11.1,4.4Hz,1H),4.01(q,J＝6.9Hz,2H),3.34–3.28(m,2H),3.24–3.18(m,2H),2.88(s,1H),2.63–2.51(m,3H),2.23(dd,J＝16.9,8.4Hz,1H),1.96–1.79(m,3H),1.64(d,J＝12.1Hz,1H),1.58–1.53(m,3H),1.50–1.40(m,11H),1.34–1.29(m,3H),1.16–1.11(m,1H),1.07(d,J＝6.3Hz,1H),0.95–0.86(m,2H)ppm。

Purity of HPLC 96.18%.

Example 96

Synthetic route

Step 1: synthesis of Compound 96-2

Mixing compound 96-0(3.3g,15mmol), compound 96-1(2.5g,16mmol), and H₂O (25mL), toluene (25mL), potassium acetate (4.14g,29.7mmol) and tetrakis (triphenylphosphine) palladium (0.5g,0.4mmol) were added to a round bottom flask under nitrogen, the reaction mixture was stirred at 100 ℃ for 2 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, the organic solvent was spun off under reduced pressure, then 50mL of water was added and extracted with ethyl acetate (50mL × 2), the organic phases were combined, the combined organic phases were washed once with 50mL of saturated brine, and anhydrous Na was used again₂SO₄Dried and filtered, and then the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to give the product 96-2(2.7g, yield: 73%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:248.2[M+H]⁺。

Step 2: synthesis of Compound 96-4

Compound 96-2(2.94g,11.89mmol) and compound 96-3(2g,12.0mmol) were dissolved in 60mL DMF, and K was added thereto₂CO₃(6g,42.97 mmol). After the addition was complete, the reaction mixture was warmed to 90 ℃ and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 100ml of LEtOAc and diluted with H₂O wash (100mL × 2), combine the organic phases, wash the combined organic phases with 50mL saturated brine, and dry Na₂SO₄Drying and then filtration were carried out, and the filtrate was concentrated under reduced pressure to give compound 96-4(4.6g, yield: 93%) as a yellow solid.

And step 3: synthesis of Compound 96-5

Compound 96-4(4.5g,12mmol) was dissolved in 90mL of glacial acetic acid, and reduced iron powder (4.5g,81mmol) was added thereto. After the addition was complete, the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, then filtered to remove the solid, and 1N HCl solution (100mL) was added to the obtained filtrate to precipitate a large amount of white solid, which was then filtered, and the obtained solid was dried under heating under vacuum to obtain 96-5(4.0g, yield: 100%) as a white solid, which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:318.9[M+H]⁺。

And 4, step 4: synthesis of Compound 96-6

Compound 96-5(1.0g,3.15mmol) was added to 20mL of toluene, under nitrogen, phosphorus oxychloride (1mL,10.62mmol) was added, and finally N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly. After the addition was complete, the reaction mixture was warmed to 110 ℃ and stirred for 6 hours. After completion of the reaction, the reaction mixture was cooled to 0 ℃, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give 96-6(0.8g, 80.00%) as a pale yellow solid product.

MS(ESI,pos.ion)m/z:337.1[M+H]⁺。

And 5: synthesis of Compound 96-8

Potassium tert-butoxide (0.10g,0.9mmol), compound 96-6(0.2g,0.6mmol) and compound 96-7(0.2g,0.4mmol) were added to 20ml of anhydrous DMF. After the addition was complete, the reaction mixture was warmed to 40 ℃ and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 20mL of water and washed with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 96-8(0.19g, yield: 60%) as a white solid

MS(ESI,pos.ion)m/z:869.0[M+H]⁺。

Step 6: synthesis of Compound 96-9

Compound 96-8(0.19g,0.24mmol) was dissolved in 2mL of ethyl acetate, a 30% hydrochloric acid/ethyl acetate solution (2mL) was added at 0 ℃ and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20ml of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.4mmol), EDCI (0.13g,2.8mmol) and HOAT (0.1g,3.0mmol) were charged into a round bottom flask, under nitrogen protection, 20mL dichloromethane was added, then cooled to 0 ℃, and finally DIPEA (0.5mL,10mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, extracted with dichloromethane (20mL × 2), and the organic phases were combined. The combined organic phases were washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 96-9(0.168g, yield 81%) as a white solid.

MS(ESI,pos.ion)m/z:878.0[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.09(d,J＝7.9Hz,1H),7.93(s,1H),7.54–7.52(m,2H),7.48–7.45(m,2H),7.40(td,J＝8.2,1.6Hz,1H),7.31(dd,J＝8.3,2.3Hz,1H),7.19(dd,J＝14.0,4.5Hz,2H),7.06–7.02(m,1H),6.98–6.96(m,2H),6.16(d,J＝0.6Hz,1H),5.97(s,1H),5.74(dd,J＝18.1,8.6Hz,1H),5.02–4.98(m,1H),4.88–4.83(m,1H),4.71–4.66(m,2H),4.13(dd,J＝11.5,4.1Hz,1H),3.85(s,3H),2.94–2.90(m,1H),2.70–2.63(m,3H),2.37(s,3H),2.32(t,J＝8.5Hz,1H),2.18(dd,J＝23.8,11.3Hz,1H),2.05(d,J＝11.0Hz,1H),1.86(ddd,J＝13.9,8.9,5.3Hz,2H),1.71–1.65(m,1H),1.50–1.44(m,4H),1.19–1.00(m,3H),0.98–0.74(m,3H)ppm。

HPLC purity 91.60%.

Example 97

Synthetic route

Step 1: synthesis of Compound 97-2

Compound 97-0(1g,5.02mmol) and compound 97-1(1g,6.57mmol) were dissolved in 20mL DMF, and K was added thereto₂CO₃(4g,28.64 mmol). The reaction mixture was stirred at 90 ℃ overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with 20ml of OAc, then with H₂O wash (20mL × 2), and wash once with 50mL saturated brine₂SO₄Drying, filtering, and decompressing the filtrateConcentration under reduced pressure gave 97-2(1.4g, yield: 84%) as a yellow solid, which was directly subjected to the next reaction without further purification.

Step 2: synthesis of Compound 97-3

Compound 97-2(1.4g,4.23mmol) was dissolved in 20mL of glacial acetic acid, then reduced iron powder (4.0g,71mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, then filtered to remove the solid, and 1N HCl solution (50mL) was added to the obtained filtrate to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain 97-3(0.8g, yield: 70%) as a white solid, which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:270.2[M+H]⁺。

And step 3: synthesis of Compound 97-4

Compound 97-3(0.8g,2.97mmol) was added to 20mL of toluene, phosphorus oxychloride (1mL,10.62mmol) was added under nitrogen, and then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly. After the addition, the reaction solution was heated to 110 ℃ and stirred for 6 hours. After completion of the reaction, the reaction solution was cooled to 0 ℃ and concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give compound 97-4(0.24g, yield: 30%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:288.1[M+H]⁺。

And 4, step 4: synthesis of Compound 97-6

Potassium tert-butoxide (0.10g,0.9mmol), compound 97-4(0.24g,0.83mmol) and compound 97-5(0.2g,0.4mmol) were added to 20ml of anhydrous DMF and after addition the reaction mixture was warmed to 40 ℃ and stirred for 4 h. After completion of the reaction, the reaction was quenched with 20mL of water, washed once with 20mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20mL × 3), the organic phases were combined, the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered, then the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 97-6(0.24g, yield: 90%) as a white solid.

MS(ESI,pos.ion)m/z:820.3[M+H]⁺。

And 5: synthesis of Compound 97-7

Compound 97-6(0.22g,0.26mmol) was dissolved in 2mL of ethyl acetate, cooled to 0 deg.C, and then 30% hydrochloric acid/ethyl acetate solution (2mL) was added and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20ml of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.4mmol), EDCI (0.13g,2.8mmol) and HOAT (0.1g,3.0mmol) were charged into a round bottom flask, under nitrogen protection, 20mL dichloromethane was added, then cooled to 0 ℃, and finally DIPEA (0.5mL,10mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, then taken with dichloromethane (20mL × 2), the organic phases were combined, the combined organic phases were washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and filtered, then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 97-7(0.196g, yield 81%) as a white solid.

MS(ESI,pos.ion)m/z:829.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.12(d,J＝7.9Hz,1H),7.94(s,1H),7.42(dd,J＝7.7,1.3Hz,1H),7.39–7.34(m,1H),7.12(t,J＝8.3Hz,1H),7.05(t,J＝7.4Hz,1H),7.00(t,J＝7.5Hz,1H),6.79(d,J＝2.9Hz,1H),6.65(dd,J＝8.8,2.9Hz,1H),6.14(s,1H),5.94(s,1H),5.75(dd,J＝17.9,8.8Hz,1H),5.02–4.98(m,1H),4.87–4.82(m,1H),4.66(dd,J＝17.1,9.4Hz,2H),4.55–4.49(m,1H),4.14–4.09(m,1H),2.94–2.89(m,1H),2.70–2.62(m,3H),2.38(d,J＝7.0Hz,3H),2.34–2.30(m,1H),2.19(dd,J＝23.9,11.1Hz,1H),1.85(ddd,J＝13.9,8.9,5.3Hz,2H),1.71–1.65(m,1H),1.55–1.42(m,6H),1.33(d,J＝6.0Hz,6H),1.22–1.07(m,3H),0.96–0.84(m,2H)ppm。

HPLC purity 91.65%.

Example 98

Synthetic route

Step 1: synthesis of Compound 98-1

Compound 98-0(0.5g,1.49mmol) was added to 10mL of toluene, phosphorus oxychloride (0.5mL,5.31mmol) was added under nitrogen, and N, N-dimethylaniline (0.1mL,0.7mmol) was added slowly. After the addition, the reaction solution was heated to 110 ℃ and stirred for 6 hours. After completion of the reaction, the reaction solution was cooled to 0 ℃, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 98-1(0.11g, yield: 20%) as a pale yellow solid.

Step 2: synthesis of Compound 98-3

Potassium tert-butoxide (0.10g,0.9mmol), compound 98-1(0.11g,0.3mmol) and compound 98-2(0.15g,0.26mmol) were added to 15 ml of anhydrous DMF. After the addition was complete, the reaction mixture was warmed to 40 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 20mL of water, the resulting mixture was washed once with 20mL of ethyl acetate, the separated aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 98-3(0.12g, yield: 51%) as a white solid.

MS(ESI,pos.ion)m/z:887.0[M+H]⁺。

And step 3: synthesis of Compound 98-4

Compound 98-3(0.12g,0.13mmol) was dissolved in 2mL of ethyl acetate, cooled to 0 ℃ and then 30% hydrochloric acid/ethyl acetate solution (2mL) was added and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, filtration was performed, and the resulting white solid was washed with 20ml of ethyl acetate.

The white solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.4mmol), EDCI (0.13g,2.8mmol) and HOAT (0.1g,3.0mmol) were charged to a round bottom flask, 20mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃ and finally DIPEA (0.5mL,10mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, taken up with dichloromethane (20 mL. times.2) and the organic phases were combined. The combined organic phases were washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 98-4(0.080g, yield 67%) as a white solid.

MS(ESI,pos.ion)m/z:895.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.38(s,1H),7.92(d,J＝7.8Hz,1H),7.64(s,1H),7.55(dd,J＝8.6,5.4Hz,2H),7.42(dd,J＝10.5,5.5Hz,2H),7.19(d,J＝8.3Hz,1H),7.12(t,J＝8.6Hz,2H),6.72(d,J＝2.4Hz,1H),6.62(dd,J＝8.7,2.4Hz,1H),6.23(s,1H),5.96(d,J＝3.0Hz,1H),5.75(dd,J＝18.0,8.8Hz,1H),5.02–4.98(m,1H),4.88–4.82(m,1H),4.67(t,J＝7.8Hz,1H),4.58(d,J＝11.4Hz,1H),4.13(dd,J＝11.4,4.2Hz,1H),3.82(s,3H),2.97–2.90(m,1H),2.69–2.62(m,3H),2.42(s,3H),2.34–2.30(m,1H),1.91–1.86(m,2H),1.70(d,J＝9.0Hz,1H),1.54–1.45(m,6H),1.19–1.08(m,3H),0.97–0.85(m,4H)ppm。

HPLC purity 96.28%.

Example 99

Synthetic route

Step 1: synthesis of Compound 99-2

Compound 99-0(8.1g,14mmol), CDI (5g,30mmol) and dichloromethane (80mL) were added to a round bottom flask, and the reaction was stirred at room temperature for 3 hours, followed by DBU (5.1g,33mmol) and compound 99-1(4g,29.6mmol), and stirred at room temperature overnight. After the reaction was complete, the reaction was quenched by addition of 80mL of 1M hydrochloric acid, separated by extraction, the aqueous phase was extracted once more with dichloromethane (40mL), and the organic phases were combined. The organic phase is washed once with 50mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the filtrate is dried under reduced pressure. The crude product obtained after the spin-drying was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 99-2(2.3g, yield: 24%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:697.4[M+H]⁺。

Step 2: synthesis of Compound 99-3

Compound 99-2(2g,2.9mmol), TBAF (6mL,5.74mmol) and tetrahydrofuran (20mL) were added to a round-bottom flask and the reaction was stirred at room temperature overnight. After completion of the reaction, the organic solvent was dried under reduced pressure, and the crude product obtained after the drying was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 99-3(1.62g, yield 96.9%) as a white solid.

MS(ESI,pos.ion)m/z:583.2[M+H]⁺。

And step 3: synthesis of Compound 99-5

The compound 99-3(0.25g,0.43mmol), the compound 99-4(0.25g, 0.68mmol), potassium tert-butoxide (0.3g, 3mmol) and DMF (20mL) were added to a reaction flask, and the reaction was warmed to 50 ℃ and stirred overnight. After completion of the reaction, 1mol/L hydrochloric acid (20mL) was added to quench the reaction, ethyl acetate (20mL) was added to dilute the reaction solution, the mixture was extracted and separated, the aqueous phase was extracted once with ethyl acetate (20mL), the organic phases were combined, the resulting organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spun off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 4:1) to give 99-5 as a pale yellow solid compound (0.140g, yield 36%).

MS(ESI,pos.ion)m/z:912.4[M+H]⁺。

And 4, step 4: synthesis of Compounds 99-7

Compound 99-5(0.13g,0.15mmol) was dissolved in 2 ml of isopropanol, cooled to 0 ℃ and then 5 ml of 40% strength isopropanol hydrochloride solution was added and the reaction mixture was stirred at room temperature for two hours. After the reaction was completed, filtration was performed, and the resulting white solid was washed with 5 ml of ethyl acetate, followed by vacuum drying. The solid obtained after drying above, and compound 99-6(0.05g,0.4mmol), EDCI (0.07g,0.4mmol) and HOAT (0.05g,0.4mmol) were charged into a round bottom flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.1mL,0.6mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water, taken out with dichloromethane (10mL × 2), the organic phases were combined, the organic phase was washed once with 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 99-7(0.074g, yield 52%) as a white solid.

MS(ESI,pos.ion)m/z:921.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.31(s,1H),8.05(t,J＝11.7Hz,1H),7.80(s,1H),7.54(d,J＝8.7Hz,2H),7.45(t,J＝4.8Hz,1H),7.39(d,J＝8.7Hz,1H),7.30–7.26(m,2H),7.17(t,J＝12.0Hz,1H),6.98(d,J＝8.7Hz,2H),6.71(d,J＝2.3Hz,1H),6.63–6.57(m,1H),6.21(s,1H),5.96(d,J＝3.0Hz,1H),5.75(dd,J＝18.0,8.7Hz,1H),5.05–4.99(m,1H),4.90–4.82(m,1H),4.70–4.61(m,2H),4.15–4.12(m,1H),3.87–3.81(m,6H),2.73–2.63(m,3H),2.40(s,3H),2.33(q,J＝8.6Hz,1H),2.17(dd,J＝23.0,11.0Hz,1H),2.11–2.01(m,1H),1.95–1.82(m,4H),1.81–1.77(m,1H),1.68(dd,J＝8.3,3.9Hz,1H),1.49–1.43(m,3H),1.28(d,J＝6.2Hz,3H),0.90–0.77(m,3H)ppm。

Example 100

Step 1 Synthesis of Compound 100-1

Compound 100-0(2.2g,10mmol) and compound 1-1(1.66g, 10.9mmol) were added to a mixed solvent of 20mL of toluene, 20mL of anhydrous ethanol and 10mL of water, followed by the addition of the catalyst tetrakis (triphenylphosphine) palladium (0.33 g). The reaction mixture was warmed to 100 ℃ under nitrogen and stirred overnight. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to remove the organic solvent, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give compound 100-1(2.1g, yield: 85%) as a yellow solid.

MS(ESI,pos.ion)m/z:248.1[M+H]⁺。

Step 2 Synthesis of Compound 100-2

Compound 100-1(1.4g,5.9mmol) and compound 1-2(0.95,5.6mmol) were added to a 30ml of a DMF solution, and stirred at room temperature, to which was addedInto K₂CO₃(1.2g,8.4 mmol). The reaction mixture was warmed to 75 ℃ under nitrogen blanket and reacted overnight. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give compound 100-2(1.6g, yield: 70%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:397.8[M+H]⁺。

Step 3 Synthesis of Compound 100-3

Compound 100-2(1.4g,3.5mmol) was added to a 35mL AcOH solution, reduced iron powder (0.79g,14mmol) was added at room temperature, and the reaction mixture was allowed to warm to 105 ℃ under nitrogen for overnight reaction. After completion of the reaction, the reaction mixture was poured into 200mL of water, a large amount of solid was precipitated, filtered, and the obtained solid was washed with water and then left to dry under vacuum to obtain Compound 100-3 as a white solid (1.0g, yield: 85%). MS (ESI, pos.ion) M/z 336.1[ M + H ]]⁺。

And 4, step 4: synthesis of Compound 100-4

Compound 100-3(1g,2.982mmol) was added to 20mL of toluene and phosphorus oxychloride (0.554mL,5.965mmol) and N, N-dimethylaniline (0.15mL,1.193mmol) were slowly injected under nitrogen at room temperature. After the addition was complete, the reaction mixture was warmed to 115 ℃ and stirred overnight. After completion of the reaction, the reaction mixture was cooled to-6 ℃ and stirred for 10 minutes, then quenched with 2 ml of water, followed by addition of 20ml of toluene and washing with saturated brine once. The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 100-4(1.0g, yield: 95%) as a brown solid, which was directly subjected to the next reaction without further purification.

And 5: synthesis of Compound 100-5

Compound 100-4(1.055g,3mmol) and compound 1-3(0.5g,0.9mmol) were added to 15mL of anhydrous DMF, followed by t-BuOK (0.3g,3mmol) and the reaction mixture was cooled to 40 ℃ under nitrogen for 1 hour. After completion of the reaction, the reaction was quenched with 10mL of water, followed by extraction with ethyl acetate (10 mL. times.3), and the organic phases were combined. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give 100-5(0.2g, yield 30%) as a white solid.

Step 6: synthesis of Compound 100-6

Compound 100-5(0.2g,0.2mmol) was dissolved in 10ml of 30% ethyl acetate hydrochloride solution and the reaction mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the obtained solid was washed once with 10ml of ethyl acetate to obtain 100-6(0.19g, yield 100%) as a white solid, which was directly subjected to the next reaction without further purification.

MS(ESI,neg.ion)m/z:784.3[M-H]^-。

And 7: synthesis of Compounds 100-7

Compound 100-6(0.2g,0.2mmol), compound 5-methylisoxazole-3-carboxylic acid (0.03g,0.3mmol), EDCI (0.05g,0.3mmol) and HOAT (0.04g,0.3mmol) were added to a round bottom flask, 10mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃ and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to room temperature and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 5mL of water and extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed once with 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give 100-7(90mg, yield 40%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:893.3[M-H]^-；

¹HNMR(600MHz,CDCl₃):10.38(s,1H),7.91(d,J＝6Hz,1H),7.63(s,1H),7.54–7.53(m,2H),7.46(d,J＝3Hz,1H),7.35–7.33(m,1H),7.30(s,1H),7.25–7.20(m,2H),7.01–6.97(m,1H),6.20(s,1H),5.97–5.96(m,1H),5.78–5.74(m,1H),5.02–4.99(m,1H),4.84–4.81(m,1H),4.70–4.66(m,2H),4.16–4.10(m,1H),3.86(s,3H),2.95–2.91(m,1H),2.70–2.68(m,2H),2.42(s,3H),2.35–2.31(m,1H),2.18–2.11(m,1H),1.92–1.86(m,2H),1.72–1.67(m,4H),1.53–1.41(m,5H),1.37–1.27(m,4H),1.18–0.84(m,3H)ppm。

HPLC purity 97.57%.

Example 101

Synthetic route

Step 1: synthesis of Compound 101-3

Compound 101-1(50mg,0.29mmol), compound 101-2(50mg,0.35mmol) were dissolved in DMF (20mL) and K was added₂CO₃(60mg,0.44mmol), heating the reaction mixture to 110 ℃ for reaction overnight, adding 10 mL of water to quench after the reaction is finished, extracting with ethyl acetate (20mL × 3), combining organic phases, washing the organic phases once with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and removing the organic solvent under reduced pressure to obtain an orange oily liquid compound 101-3, wherein the next reaction is directly carried out without further purification.

MS(ESI,pos.ion)m/z:292.1[M+H]⁺。

Step 2: synthesis of Compound 101-4

The compound 121-3(1g, 3.4mmol) obtained in the above reaction was dissolved in glacial acetic acid (50mL), iron powder (0.96g, 17.2mmol) was added, and the reaction mixture was warmed to 110 ℃ for reaction for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was poured into 1N hydrochloric acid (100mL) to precipitate a white solid, which was then filtered, and the filter cake was washed with water and dried in vacuo to give compound 101-4(475mg, two-step yield 61%) as a yellow solid.

MS(ESI,pos.ion)m/z:230.2[M+H]⁺。

And step 3: synthesis of Compound 101-5

Compound 101-4(50mg,0.22mmol) was added to toluene (20mL) and POCl was slowly added with stirring at room temperature₃(100mg,0.66mmol) and N, N-dimethylaniline (13mg,0.11mmol) were added, and then the reaction mixture was heated under reflux for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether) to obtain compound 101-5(35mg, yield 64%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:248.1[M+H]⁺。

And 4, step 4: synthesis of intermediate 101-6

The compound N-Boc-4- (R) -hydroxyproline (60mg,0.24mmol) was dissolved in DMF (10mL) and NaH (60% dispersed in mineral oil, 25mg,0.6mmol) was added under ice-bath and after addition the reaction mixture was warmed to room temperature and stirred for 2 h. Compound 101-5(60mg,0.24mmol) was dissolved in DMF (1mL) and added to the above reaction solution and stirring was continued for 4 hours. After completion of the reaction, the reaction solution was poured into 50mL of water, the pH was adjusted to 2-3 with 1n cl, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 101-6(85mg, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:443.1[M+H]⁺。

And 5: synthesis of 101-7

Compound 101-6(50mg,0.11mmol), compound 1-9(45mg,0.11mmol), EDCI (24mg,0.12mmol) and HOAT (17mg,0.12mmol) were added to CH₂Cl₂In (15mL), DIPEA (48mg,0.37mmol) was added under nitrogen protection under ice bath, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 4 hours, after the completion of the reaction, the pH was adjusted to about 2 with 1N hydrochloric acid, followed by extraction with dichloromethane (10mL × 3), the organic phases were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was dried under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 101-7 as a pale yellow solid (65mg, yield 90%).

MS(ESI,pos.ion)m/z:655.2[M+H]⁺。

Step 6: synthesis of Compounds 101-10

Compound 101-7(135mg,0.23mmol) was dissolved in 5N HCl ethyl acetate solution (10mL), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, and the obtained solid was washed with 10ml of ethyl acetate and then dried in vacuo.

The compound obtained after the above drying, compound 101-9(116mg,0.25mmol), EDCI (52mg,0.27mmol) and HOAT (37mg,0.27mmol) were added to dichloromethane (10ml), DIPEA (90mg,0.68mmol) was added under ice bath, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 12:1) to obtain 101 to 10(94mg, two-step yield 50%) ppm as a pale yellow solid compound.

MS(ESI,pos.ion)m/z:820.4[M+H]⁺。

Step 6: synthesis of Compounds 101-11

Compound 101-10(100mg,0.12mmol) was dissolved in 1, 2-dichloroethane (300mL), GrubbsII catalyst (20mg) was added under nitrogen, and the reaction mixture was warmed to 75 ℃ and reacted for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative HPLC to give 101-11(69mg, yield 73%) as a white solid.

MS(ESI,pos.ion)m/z:792.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.42(d,J＝113.0Hz,1H),7.57(dd,J＝33.2,26.0Hz,1H),7.23(d,J＝7.5Hz,1H),7.16(dd,J＝15.1,7.4Hz,3H),6.95–6.83(m,2H),5.92(d,J＝20.4Hz,1H),5.73(dd,J＝17.2,8.5Hz,1H),5.35(d,J＝4.5Hz,1H),4.98(dd,J＝31.8,22.1Hz,2H),4.62(t,J＝7.5Hz,1H),4.54–4.32(m,2H),4.05(d,J＝7.9Hz,1H),2.92(s,1H),2.62(dd,J＝34.2,25.7Hz,3H),2.39–2.24(m,1H),2.00–1.73(m,6H),1.72–1.55(m,6H),1.54–1.43(m,6H),1.18–1.08(m,2H),1.00–0.78(m,4H)ppm。

Example 102

Synthetic route

Step 1 Synthesis of Compound 102-2

Mixing compound 102-0(3.3g,15mmol), compound 102-1(2.3g,15mmol), Pd (PPh)₃)₄(0.6g,0.5mmol) and K₂CO₃(10g,75mmol) was dissolved in a mixed solvent of THF (150mL) and water (15mL), and the reaction mixture was stirred at room temperature overnight after the reaction was completed, a saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 100mL), and the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered, and then the organic solvent was distilled off under reduced pressure to give compound 102-2 as a yellow solid (3.1g, yield: 84%).

Step 2 Synthesis of Compound 102-4

Compound 102-2(1.0g,4.0mmol) and compound 102-3(0.9g, 5mmol)l) dissolved in 20ml of DMF and K was added thereto ₂CO₃(1.1g,8mmol) and after the addition was complete, the reaction mixture was refluxed overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 100ml of LEtOAc and then diluted with H₂O rinse (100mL × 2), then 50mL saturated saline rinse once, then anhydrous Na₂SO₄Dried and filtered, and the organic solvent was removed under reduced pressure to give 102-4(1.5g, yield: 91%) as a yellow solid, which was directly subjected to the next reaction without further purification.

Step 3 Synthesis of Compound 102-5

Compound 102-4(1.7g,4.2mmol) was dissolved in 30mL of glacial acetic acid, then reduced iron powder (1.2g,21mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction is completed, cooling the reaction system to room temperature, filtering to remove solids, dropwise adding 50ml of 1N HCl aqueous solution into the filtrate to separate out a large amount of white solids, filtering, and drying the obtained white solids under vacuum conditions to obtain the target compound 102-5(1.2g, yield: 83%); the reaction was carried out without further purification.

MS(ESI,pos.ion)m/z:348[M+H]⁺。

Step 4 Synthesis of Compound 102-6

Compound 102-5(0.5g,1.4mmol) was added to 15mL of toluene, phosphorus oxychloride (0.5g,3mmol) was added under nitrogen, then N, N-dimethylaniline (0.08g,0.6mmol) was added slowly and the reaction mixture was warmed to 110 ℃ for 6 hours. After completion of the reaction, the reaction system was cooled to 0 ℃ and the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 102-6(0.32g, yield: 61%) as a pale yellow solid.

Step 5 Synthesis of Compound 102-7

Compound 102-6(0.26g,0.7mmol) was dissolved in DMF (20mL) and then compound 96-7(0.2g,0.4mmol) and potassium tert-butoxide (0.08g,0.7mmol) were added and the reaction mixture stirred at room temperature for 4 hours. After the reaction was completed, the pH was adjusted to 2-3 with 1N HCl aqueous solution, 50 mL of water was added, and the aqueous phase (20 mL. times.3) was extracted with ethyl acetate, and then the organic phases were combined. The combined organic phases were washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered, and then the organic phase was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 102-7(0.19g, yield 60%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:898[M+H]⁺。

Step 6 Synthesis of Compound 102-10

Compound 102-7(0.13g,0.16mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 deg.C, and then 30% ethyl acetate hydrochloride solution (20mL) was added and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the resulting white solid was washed once with 20ml of ethyl acetate, and then dried in vacuo.

The dried solid obtained above, compound 102-9(0.03g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 102-10(0.13g, yield 85%) as a white solid.

MS(ESI,pos.ion)m/z:907.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.37(s,1H),7.94(d,J＝7.7Hz,1H),7.63(s,1H),7.51(d,J＝8.7Hz,2H),7.41(d,J＝2.2Hz,1H),7.37(d,J＝8.7Hz,1H),7.29–7.26(m,1H),7.15(d,J＝8.3Hz,1H),6.95(d,J＝8.7Hz,2H),6.69(d,J＝2.4Hz,1H),6.58(dd,J＝8.7,2.4Hz,1H),6.20(s,1H),5.94(d,J＝3.5Hz,1H),5.73(dd,J＝18.0,8.8Hz,1H),5.02–4.94(m,1H),4.87–4.79(m,1H),4.64(t,J＝7.9Hz,1H),4.57(d,J＝11.5Hz,1H),4.10(dd,J＝11.5,4.2Hz,1H),3.84(s,3H),3.79(s,3H),2.93–2.88(m,1H),2.67–2.63(m,2H),2.39(s,3H),2.31(q,J＝8.6Hz,1H),2.17–2.07(m,1H),1.89–1.82(m,2H),1.52–1.39(m,6H),1.17–1.04(m,3H),0.89–0.82(m,4H)ppm。

Example 103

Synthetic route

Synthesis of Compound 103-2

Compound 2-13(0.22g,0.29mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 30% strength ethyl acetate hydrochloride solution (20 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate and then dried in vacuo.

The above dried solid, compound 103-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. After the dripping is finished. The reaction mixture was warmed to 30 ℃ and reacted for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 103-2(0.05g, yield 22%) as a white solid.

Example 104

Synthetic route

Step 1: synthesis of Compound 104-2

Compound 104-0(2g,10.04mmol) and compound 104-1(2g,11.75mmol) were dissolved in 40mL of DMF, and K was added thereto₂CO₃(4g,28.64mmol) and after the addition was complete, the reaction mixture was warmed to 90 ℃ for reaction overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 40ml of LEtOAc and the resulting mixture was diluted with H₂O rinse (40mL × 2), organic phase washed once with 50mL saturated brine and then with anhydrous Na₂SO₄Drying, followed by filtration and concentration under reduced pressure gave compound 104-2 as a yellow solid (3.3g, yield: 94%). MS (ESI, pos.ion) M/z 349.9[ M + H ]]⁺。

Step 2: synthesis of Compound 104-3

Compound 104-2(3.3g,9.4mmol) was dissolved in 40mL of glacial acetic acid, then reduced iron powder (4.0g,71mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, the reaction system was cooled to room temperature and then filtered. Dropwise adding 1N HCl solution into the obtained filtrate to separate out a large amount of white solid, filtering, and drying the obtained white solid under vacuum condition to obtain compound 104-3(2.7g, yield: 99%); the reaction was carried out without further purification.

MS(ESI,pos.ion)m/z:288.0[M+H]⁺。

And step 3: synthesis of Compound 104-4

Compound 104-3(1g,3.48mmol) was added to 20mL of toluene, phosphorus oxychloride (1mL,10.62mmol) was added under nitrogen, and then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly. After the addition was complete, the reaction mixture was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, the reaction system was cooled to 0 ℃, and then the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to obtain compound 104-4(0.89g, 83.4%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 104-6

Potassium tert-butoxide (0.10g,0.9mmol), compound 104-4(0.20g,0.65mmol) and compound 104-5(0.2g,0.4mmol) are added to 20ml of anhydrous DMF and the reaction mixture is warmed to 40 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 20ml of water and washed once with 20ml of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, followed by extraction with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was then washed once with 20mL of saturated saline, dried over anhydrous sodium sulfate, then filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 104-6(0.24g, yield: 43.71%) as a white solid.

MS(ESI,pos.ion)m/z:838.3[M+H]⁺。

And 5: synthesis of target Compound 104-7

Compound 104-6(0.15g,0.19mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 30% strength ethyl acetate hydrochloride solution (2 ml) was added and the reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, and the resulting white solid was washed once with 20ml of ethyl acetate and then dried in vacuo.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.4mmol), EDCI (0.13g,2.8mmol) and HOAT (0.1g,3.0mmol) were charged into a round bottom flask, 20mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃, and DIPEA (0.5mL,10mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 mL of water and extracted with dichloromethane (20mL × 2), and then the organic phases were combined. The organic phase was washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, then filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 104-7(0.132g, yield 80%) as a white solid.

MS(ESI,pos.ion)m/z:847.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.45(s,1H),8.23(d,J＝7.3Hz,1H),8.03(s,1H),7.17(dd,J＝8.5,2.9Hz,1H),7.09–7.01(m,3H),6.78(d,J＝2.9Hz,1H),6.66(dd,J＝8.8,2.9Hz,1H),6.35–6.15(m,2H),5.95(s,1H),5.76(dd,J＝17.5,9.2Hz,1H),5.02–4.98(m,1H),4.83–4.77(m,2H),4.65(t,J＝8.1Hz,1H),4.52(dt,J＝12.1,6.0Hz,1H),4.06(dd,J＝11.5,3.7Hz,1H),2.97–2.88(m,1H),2.75–2.63(m,3H),2.24(dd,J＝22.5,11.1Hz,1H),1.84(dd,J＝7.8,6.1Hz,3H),1.69–1.64(m,1H),1.48(dddd,J＝38.1,32.1,15.6,8.3Hz,8H),1.33(dd,J＝5.9,1.1Hz,6H),1.20–1.04(m,3H),0.98–0.86(m,2H)ppm。

HPLC purity 90.46%.

Example 105

Synthetic route

Step 1: synthesis of Compound 105-2

Compound 105-0(2g,10.04mmol) and compound 105-1(2g,10.97mmol) were dissolved in 40mL of DMF, and K was added thereto₂CO₃(4g,28.64 mmol). After the addition was complete, the reaction mixture was warmed to 90 ℃ for reaction overnight. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with 40ml of LEtOAc, and then diluted with 40mLH₂Wash twice with O and once with 50mL of saturated saline. Anhydrous Na for organic phase₂SO₄Drying and then filtration were carried out, and the organic solvent was removed under reduced pressure to obtain compound 105-2(3g, yield: 82.69%) as a yellow solid. MS (ESI, pos. ion) M/z 361.9[ M + H ]]⁺。

Step 2: synthesis of Compound 105-3

Compound 105-2(3g,8.3mmol) was dissolved in 60mL of glacial acetic acid, then reduced iron powder (4.0g,71mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, the solid was removed by filtration, 100 ml of 1N HCl solution was added dropwise to the obtained filtrate to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain compound 105-3(2g, yield: 80.6%); the reaction was carried out without further purification.

MS(ESI,pos.ion)m/z:300.0[M+H]⁺。

And step 3: synthesis of Compound 105-4

Compound 105-3(0.5g,1.67mmol) was added to 20mL of toluene, phosphorus oxychloride (1mL,10.62mmol) was added under nitrogen, and then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly. After the addition was complete, the reaction mixture was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, the reaction system was cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to obtain compound 105-4(0.33g, 60%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 105-6

Potassium tert-butoxide (0.10g,0.9mmol), compound 105-4(0.24g,0.75mmol) and compound 105-5(0.2g,0.4mmol) were added to 20ml of anhydrous DMF. After the addition was complete, the reaction mixture was warmed to 40 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 20ml of water, and the resulting mixture was washed once with 20ml of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, followed by extraction with ethyl acetate (20 mL. times.3), the organic phases were combined, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, then filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 105-6 as a white solid (0.33g, yield: 54.56%)

MS(ESI,pos.ion)m/z:851.0[M+H]⁺。

And 5: synthesis of Compound 105-7

Compound 105-6(0.3g,0.35mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 2 ml of a 30% strength ethyl acetate hydrochloride solution was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the resulting white solid was washed once with 20ml of ethyl acetate, and then dried in vacuo.

The above dried solid, 5-methylisoxazole-3-carboxylic acid (0.05g,0.4mmol), EDCI (0.13g,2.8mmol) and HOAT (0.1g,3.0mmol) were charged to a round bottom flask, 20mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃, and DIPEA (0.5mL,10mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, taken up with 20mL of dichloromethane (20mL × 2) and the organic phases were combined. The organic phase was washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 105-7(0.261g, yield 80%) as a white solid.

¹HNMR(600MHz,CDCl₃):10.34(d,J＝70.3Hz,1H),7.98(d,J＝7.9Hz,1H),7.73(s,1H),7.37(d,J＝8.7Hz,1H),7.02(d,J＝8.8Hz,1H),6.76(d,J＝3.0Hz,1H),6.67–6.63(m,2H),6.58(dd,J＝8.7,2.5Hz,1H),6.22(s,1H),5.93(d,J＝3.4Hz,1H),5.75(dd,J＝18.2,8.7Hz,1H),5.02–4.98(m,1H),4.87–4.82(m,1H),4.65(t,J＝7.9Hz,1H),4.58–4.50(m,2H),4.15–4.10(m,1H),3.80(s,3H),2.96–2.88(m,1H),2.68–2.61(m,3H),2.32(q,J＝8.7Hz,1H),2.17–2.11(m,1H),2.07(d,J＝7.8Hz,1H),1.88(ddd,J＝14.0,12.8,9.5Hz,3H),1.72–1.67(m,1H),1.54–1.43(m,6H),1.33(d,J＝6.1Hz,6H),1.20–1.02(m,3H),0.94–0.84(m,2H)ppm。

Purity of HPLC 92.89%.

Example 106

Synthetic route

Synthesis of Compound 106-1

Compound 96-8(0.21g,0.26mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 2 ml of a 30% strength ethyl acetate hydrochloride solution was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the resulting white solid was washed once with 20 ml of ethyl acetate, and then the resulting solid was dried in vacuo.

The above dried solid, compound 1-methylpyrazole-3-carboxylic acid (0.05g,0.4mmol), EDCI (0.13g,2.8mmol) and HOAT (0.1g,3.0mmol) were charged into a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.5mL,10mmol) was added slowly. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After the reaction was complete, the reaction was quenched with 10 ml of water, taken twice with 20 ml of dichloromethane and the organic phases were combined. The organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the liquid was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 106-1(0.203g, yield 88.6%) as a white solid.

¹HNMR(600MHz,CDCl₃):7.68(s,1H),7.63(d,J＝7.4Hz,1H),7.54(d,J＝8.4Hz,2H),7.44(s,1H),7.36(t,J＝7.3Hz,1H),7.31(s,1H),7.17–7.13(m,2H),6.98(d,J＝8.4Hz,2H),6.64(d,J＝8.5Hz,1H),6.00(s,1H),5.74(dd,J＝17.5,8.6Hz,1H),5.07–4.92(m,2H),4.71(s,1H),4.57(t,J＝7.2Hz,1H),4.44(d,J＝10.8Hz,1H),4.18(dd,J＝11.0,4.7Hz,1H),3.87(d,J＝5.4Hz,6H),3.51(q,J＝7.1Hz,2H),2.94–2.90(m,1H),2.62–2.50(m,3H),2.38(s,2H),2.31(d,J＝8.6Hz,1H),2.08–1.89(m,7H),1.18–1.09(m,4H),0.92(d,J＝4.5Hz,2H)ppm。

HPLC purity 91.73%.

Example 107

Synthetic route

Step 1: synthesis of Compound 107-2

Compound 107-0(0.96g,4.1mmol) and compound 107-1(1g,6.5mmol) were dissolved in 20mL of DMF, and K was added thereto₂CO₃(2g,14.32mmol) and, after the addition, the reaction mixture is warmed to 90 ℃ and reactedAnd (4) at night. After completion of the reaction, the reaction was cooled to room temperature, diluted with 20ml of LEtOAc and then diluted with 20mLH₂Wash twice with 10mL of saturated saline. Anhydrous Na for organic phase₂SO₄Drying and filtration were carried out, and then the filtrate was concentrated under reduced pressure to obtain Compound 107-2(1.5g, yield: 100%) as a yellow solid. Step 2: synthesis of Compound 107-3

Compound 107-2(1.5g,4.1mmol) was dissolved in 30mL of glacial acetic acid, then reduced iron powder (2g,35mmol) was added and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction is completed, cooling the reaction system to room temperature, then filtering to remove solids, dropwise adding 50 ml of 1N HCl solution into the obtained filtrate to separate out a large amount of white solids, filtering again, and drying the obtained white solids under the vacuum condition to obtain the target compound 107-3(1g, yield: 80%); the reaction was carried out without further purification.

MS(ESI,pos.ion)m/z:306.1[M+H]⁺。

And step 3: synthesis of Compound 107-4

Compound 107-3(0.5g,2mmol) was added to 20mL of toluene, phosphorus oxychloride (1mL,10.62mmol) was added under nitrogen, and then N, N-dimethylaniline (0.2mL,1.4mmol) was added slowly. The reaction mixture was warmed to 110 ℃ and stirred for 6 hours. After completion of the reaction, the reaction system was cooled to 0 ℃, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to give compound 107-4(0.29g, 50.00%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:324.1[M+H]⁺。

And 4, step 4: synthesis of Compound 107-6

Potassium tert-butoxide (0.10g,0.9mmol), compound 107-4(0.28g,0.86mmol) and compound 107-5(0.2g,0.4mmol) were added to 20ml of anhydrous DMF at room temperature and the reaction mixture was warmed to 40 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 20ml of water and washed once with 20ml of ethyl acetate. The separated aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 107-6(0.165g, yield: 50%) as a white solid

MS(ESI,pos.ion)m/z:856.3[M+H]⁺。

And 5: synthesis of Compound 107-7

Compound 107-6(0.165g,0.193mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 30% strength ethyl acetate hydrochloride solution (2 ml) was added and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed once with 10 ml of ethyl acetate, and then dried in vacuo.

The above dried solid, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.4mmol), EDCI (0.13g,2.8mmol), HOAT (0.1g,3.0mmol) were charged into a round bottom flask, 20mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃, and DIPEA (0.5mL,10mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, taken up with dichloromethane (20mL × 2), and then the organic phases were combined. The organic phase was washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 107-7(0.1189g, yield 71%) as a white solid.

MS(ESI,pos.ion)m/z:865.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.45(s,1H),8.11(d,J＝7.8Hz,1H),7.91(s,1H),7.57–7.54(m,2H),7.48–7.45(m,2H),7.43–7.40(m,1H),7.31–7.29(m,1H),7.23–7.21(m,1H),7.19(d,J＝8.1Hz,1H),7.12(t,J＝8.7Hz,2H),7.05(t,J＝7.6Hz,1H),6.16(s,1H),5.97(d,J＝3.3Hz,1H),5.75(dd,J＝17.9,8.8Hz,1H),5.02–4.98(m,1H),4.88–4.83(m,1H),4.69(dd,J＝13.9,6.0Hz,2H),4.13(dd,J＝11.5,4.2Hz,1H),2.95–2.90(m,1H),2.70–2.65(m,3H),2.38(s,3H),2.33(dd,J＝17.1,8.6Hz,1H),2.19(dd,J＝23.4,11.1Hz,1H),1.89–1.84(m,2H),1.68(dd,J＝16.1,7.2Hz,1H),1.49(qdd,J＝11.0,8.0,3.3Hz,6H),1.19–1.04(m,3H),0.97–0.85(m,3H)ppm。

HPLC purity 91.55%.

Example 108

Synthetic route

Synthesis of Compound 108-1

Compound 100-6(0.1g,0.1mmol), Compound 1-4(0.02g,0.1mmol), EDCI (0.03g,0.1mmol) and HOAT (0.02g,0.1mmol) were charged into a round-bottomed flask, 10mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.05mL,0.3mmol) were added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 5mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed twice with 10mL of saturated common salt water, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 108-1(40mg, yield 40%) as a purified pale yellow solid.

MS(ESI,neg,ion)m/z:892.2[M-H]^-；

¹HNMR(600MHz,CDCl₃):10.39(s,1H),7.53(d, J ═ 6.0Hz,2H),7.44(s,1H),7.39(d, J ═ 3.0Hz, 1H),7.32(s,3H),7.20 to 7.18(m,1H),7.07(s,1H),6.98(d, J ═ 12.0Hz,2H),6.64(s,1H),6.01(s,1H),5.80 to 5.70(m,1H),5.04 to 5.01(m,1H),4.71(s,1H),4.61 to 4.53(m,1H),4.50(d, J ═ 12.0Hz,1H),4.17 to 4.15(m,1H),3.95(s,1H),3.88(s,3H),3.86(s,3H),2.92(s, 2H), 2.01(m,1H), 1.17 to 4.15(m,1H),3.95(s,1H),3.88(s, 1H), 3.51 (m,2H), 2.51 (m,1H), 2H), 1.16-1.09 (m,2H), 0.93-0.88 (m,3H) ppm. Purity of HPLC 92.40%.

Example 109

Synthetic route

Step 1: synthesis of Compound 109-3

Compound 109-1(0.69g,4.0mmol) and compound 109-2(1g,4.0mmol) were dissolved in 20mL of the DMF solution, and K was added thereto₂CO₃(1.0g,7.3 mmol.) the reaction mixture was warmed to 110 ℃ for reaction overnight, after the reaction was completed, 10 mL of water was added to quench the reaction, then ethyl acetate (20mL × 3) was used for extraction, the organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 109-3 as an orange oily liquid, which was directly subjected to the next reaction without purification.

Step 2: synthesis of Compound 109-4

The crude compound 109-3(1.6g,4mmol) from the previous step was dissolved in 50mL of glacial acetic acid, then iron powder (1.1g,20mmol) was added and the reaction mixture was warmed to 110 ℃ for 8 h. After the reaction was completed, the reaction system was cooled to room temperature and then filtered. The filtrate was concentrated and poured into 1N 100mL hydrochloric acid solution to precipitate a solid, which was then filtered, and the filter cake was washed with water and dried under vacuum to give compound 109-4 as a yellow solid (990mg, 74% yield over two steps).

And step 3: synthesis of Compound 109-5

Compound 109-4(1g,3.1mmol) was dissolved in 100mL of toluene and POCl3(939mg,6.1mmol) and N, N-dimethylaniline (185mg,1.5mmol) were added slowly with stirring at room temperature. After the addition was complete, the reaction mixture was refluxed for 5 hours. After completion of the reaction, the reaction system was cooled to room temperature, then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent petroleum ether) to obtain compound 109-5(0.8g, yield 80%) as a pale yellow solid.

And 4, step 4: synthesis of Compound 109-7

Compound 107-5(150mg,0.26mmol) was dissolved in 50mL of a solution of DMF, and compound 109-5(140mg,0.39mmol) and potassium tert-butoxide (88mg,0.79mmol) were added thereto. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the pH was adjusted to 2-3 with 1N HCl solution, then diluted with 50mL of water, the aqueous phase was extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined. The organic phase was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give 109-7(0.18g, yield 77%) as a pale yellow solid.

And 5: synthesis of Compound 109-8

Compound 109-7(339mg,0.38mmol) was dissolved in 5N HCl in ethyl acetate (30mL), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the organic solvent was distilled off under reduced pressure to obtain compound 109-8(0.29g, yield 90%) as a white solid.

Step 6: synthesis of Compound 109-9

Dissolve compound 109-8(110mg,0.13mmol) in 50mL CH₂Cl₂In (1), adding a compound of 5-methylisoOxazole-3-carboxylic acid (20mg,0.15mmol), EDCI (32mg,0.17mmol) and HOAT (22mg,0.17mmol) was added to the solution in ice with DIPEA (54mg,0.42 mmol). The reaction was then warmed to room temperature and stirred for 4 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 109-9(0.1g, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:895.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.40(s,1H),8.05(d,J＝6.7Hz,1H),7.73(s,1H),7.59–7.50(m,2H),7.39(dd,J＝8.2,2.0Hz,1H),7.36(d,J＝2.0Hz,1H),7.30(d,J＝8.1Hz,1H),7.23(dd,J＝8.6,3.0Hz,1H),7.16(dd,J＝8.9,4.6Hz,1H),7.11–7.07(m,1H),7.02–6.96(m,2H),6.24(d,J＝0.6Hz,1H),5.99(s,1H),5.77(dd,J＝17.2,9.5Hz,1H),5.08–4.97(m,1H),4.79(dd,J＝11.2,7.1Hz,2H),4.66(t,J＝8.1Hz,1H),4.09(dd,J＝11.5,3.9Hz,1H),3.87(s,3H),2.99–2.88(m,1H),2.77–2.64(m,3H),2.39(s,3H),2.36(dd,J＝16.9,8.5Hz,1H),2.28–2.15(m,1H),1.94–1.79(m,2H),1.56(dd,J＝9.5,5.9Hz,1H),1.53–1.48(m,3H),1.34(dd,J＝10.8,6.7Hz,3H),1.28(s,3H),1.20–0.95(m,2H)ppm。

Purity of HPLC 97.04%.

Example 110

Synthetic route

Step 1 Synthesis of Compound 110-2

Mixing compound 110-0(3.3g,15mmol), compound 110-1(2.5g,15mmol), Pd (PPh)₃)₄(0.6g,0.5mmol) and K₂CO₃(10g,72mmol) was added to a mixed solvent of THF (150mL) and water (15mL), and the reaction mixture was stirred at room temperature overnight after the reaction was completed, a saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 100mL), and then the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give compound 110-2 as a yellow solid (3.3g, yield: 83%).

Step 2 Synthesis of Compound 110-4

Compound 110-2(1.0g,3.8mmol) and compound 110-3(0.8g,5mmol) were dissolved in 20mL DMF, and K was added thereto₂CO₃(1.0g,7.2 mmol). After addition was complete, the reaction mixture was refluxed overnight. After the reaction was complete, the reaction was cooled to room temperature, diluted with 100ml of LEtOAc and then diluted with 100mLH₂O rinse twice, followed by 50mL of saturated saline. Anhydrous Na for separated organic phase₂SO₄Drying and then concentration under reduced pressure gave compound 110-4(1.5g, yield: 96%) as a yellow solid, which was directly subjected to the next reaction without further purification.

And step 3: synthesis of Compound 110-5

Compound 110-4(1.5g,3.6mmol) was dissolved in 30mL of glacial acetic acid, and then reduced iron powder (0.7g,10mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, then filtered to remove solids, 1n hcl solution was added dropwise to the obtained filtrate to precipitate a large amount of white solids, and then filtered, and the obtained white solids were dried under vacuum to obtain the target compound 110-5(1.2g, yield: 94%) which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:354.1[M+H]⁺

And 4, step 4: synthesis of Compound 110-6

Compound 110-5(0.5g,1.4mmol) was added to 15mL of toluene, phosphorus oxychloride (0.5g,3mmol) was added under nitrogen, and then N, N-dimethylaniline (0.08g,0.6mmol) was slowly added. The reaction mixture was warmed to 110 ℃ and reacted for 6 hours. The reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was cooled to 0 ℃, then concentrated under reduced pressure, and the resulting mixture was purified by silica gel column (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give compound 110-6(0.4g, yield: 76%) as a pale yellow solid.

And 5: synthesis of Compound 110-7

Compound 110-6(0.2g,0.54mmol) was dissolved in DMF (20mL), and compound 107-5(0.15g,0.26mmol) and potassium tert-butoxide (0.06g,0.53mmol) were added thereto. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was adjusted to pH2-3 with 1N HCl, and then diluted with 50 mL of water, followed by extraction of the aqueous phase (20 mL. times.3) with ethyl acetate and combination of the organic phases. The organic phase was washed with a saturated sodium chloride solution, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 110-7(0.23g, yield 96%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:904.3[M+H]⁺。

Step 6: synthesis of Compounds 110-10

Compound 110-7(0.23g,0.25mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20ml of a 30% hydrochloric acid/ethyl acetate solution was added. The reaction mixture was stirred at room temperature for 2 hours, then filtered, and the resulting white solid was washed with 20ml of ethyl acetate.

The solid from the above reaction, compound 110-9(0.04g,0.31mmol), EDCI (0.07g,0.36mmol) and HOAT (0.05g,0.37mmol) were charged into a round bottom flask, 20mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.15mL,0.86mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 110-10(0.15g, yield 63%) as a white solid.

MS(ESI,pos.ion)m/z:913.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.41(s,1H),8.07(s,1H),7.88(s,1H),7.42(d,J＝2.2Hz,1H),7.33–7.27(m,3H),7.23–7.20(m,1H),7.18(d,J＝8.3Hz,1H),7.15–7.11(m,1H),7.11–7.05(m,1H),7.01(t,J＝8.8Hz,1H),6.22(s,1H),5.97(s,1H),5.74(dd,J＝17.3,9.4Hz,1H),5.03–4.96(m,1H),4.83–4.73(m,2H),4.64(t,J＝8.1Hz,1H),4.07(dd,J＝11.5,3.9Hz,1H),3.92(s,3H),2.94–2.86(m,1H),2.75–2.61(m,3H),2.37(s,3H),2.33(dd,J＝17.2,8.7Hz,1H),2.20(d,J＝8.6Hz,1H),1.87–1.79(m,2H),1.52–1.45(m,3H),1.17–1.05(m,3H),0.96–0.78(m,6H)ppm。

Example 111

Synthetic route

Step 1 Synthesis of Compound 111-2

Mixing compound 111-0(3.3g,15mmol), compound 111-1(2.5g,15mmol), Pd (PPh)₃)₄(0.6g,0.5mmol) and K₂CO₃(10g,72mmol) was suspended in a mixed solvent of THF (150mL) and water (15 mL.) the reaction mixture was stirred at room temperature overnight, after completion of the reaction, a saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 100mL), the organic phases were combined, the organic phase was washed once with 50mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressureTo obtain compound 111-2(3.3g, yield: 83%) as a yellow solid.

Step 2 Synthesis of Compound 111-4

Compound 111-2(1.0g,3.8mmol) and compound 111-3(0.85g,4.7mmol) were dissolved in 20mL DMF, and K was added thereto₂CO₃(1.0g,7.2 mmol). After addition was complete, the reaction mixture was refluxed overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 100ml of LEtOAc, and then 100mLH was added₂O rinse (10mL × 2) followed by 50mL saturated brine and the separated organic phase over anhydrous Na₂SO₄Drying, filtration and removal of the organic solvent under reduced pressure gave 111-4(1.5g, yield: 93%) as a yellow solid, which was directly subjected to the next reaction without further purification.

And step 3: synthesis of Compound 111-5

Compound 111-4(1.5g,3.5mmol) was dissolved in 30mL of glacial acetic acid, and then reduced iron powder (0.7g,10mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered to remove the solid, 50 ml of 1N Cl solution was dropwise added to the obtained filtrate to precipitate a large amount of white solid, and then filtered, and the obtained white solid was dried under vacuum to obtain compound 111-5(1.3g, yield: 100%) which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:366[M+H]⁺

And 4, step 4: synthesis of Compound 111-6

Compound 111-5(0.5g,1.4mmol) was added to 15mL of toluene, phosphorus oxychloride (0.5g,3mmol) was added under nitrogen, then N, N-dimethylaniline (0.08g,0.6mmol) was added slowly and the reaction mixture was warmed to 110 deg.C and reacted for 6 hours. After completion of the reaction, the reaction mixture was cooled to 0 ℃, and then the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give compound 111-6(0.12g, yield: 23%) as a pale yellow solid.

And 5: synthesis of Compound 111-7

Compound 111-6(0.12g,0.31mmol) was dissolved in DMF (20mL), and compound 107-5(0.12g,0.21mmol) and potassium tert-butoxide (0.06g,0.53mmol) were added thereto. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 2 to 3 with 1N HCl aqueous solution, and then diluted with 50 mL of water, followed by extraction with ethyl acetate (20 mL. times.3), and the organic phases were combined. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give the compound 111-7(0.1g, yield 51%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:916[M+H]⁺。

Step 6: synthesis of Compounds 111-10

Compound 111-7(0.1g,0.11mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃, then 30% strength ethyl acetate hydrochloride solution 20 ml was added, the reaction mixture was stirred at room temperature for 2 hours, then filtered, and the resulting white solid was washed with 20 ml of ethyl acetate and dried in vacuo.

The above dried solid, compound 111-9(0.02g,0.16mmol), EDCI (0.03g,0.16mmol) and HOAT (0.02g,0.15mmol) were charged into a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed with 10ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give 111-10(77mg, yield 83%) as a white solid compound.

MS(ESI,pos.ion)m/z:925[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.36(s,1H),7.91(s,1H),7.58(s,1H),7.42–7.36(m,2H),7.34–7.28(m,2H),7.26–7.23(m,1H),7.16(d,J＝8.3Hz,1H),7.00(t,J＝8.8Hz,1H),6.69(d,J＝2.4Hz,1H),6.59(dd,J＝8.7,2.4Hz,1H),6.20(s,1H),5.94(d,J＝3.3Hz,1H),5.74(d,J＝9.4Hz,1H),5.02–4.94(m,1H),4.86–4.79(m,1H),4.64(t,J＝7.8Hz,1H),4.57(d,J＝11.4Hz,1H),4.10(dd,J＝11.4,4.3Hz,1H),3.92(s,3H),3.80(s,3H),2.97–2.85(m,1H),2.70–2.57(m,3H),2.39(s,3H),2.35–2.27(m,1H),2.12(d,J＝11.7Hz,1H),1.93–1.83(m,2H),1.50–1.45(m,3H),1.18–1.04(m,3H),0.95–0.80(m,6H)ppm。

Example 112

Synthetic route

Synthesis of Compound 112-2

Compound 109-7(0.21g,0.24mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃, then 30% strength ethyl acetate hydrochloride solution 20 ml was added, the reaction mixture was stirred at room temperature for 2 hours, then filtered, and the resulting white solid was washed once with 20 ml of ethyl acetate and dried in vacuo.

The above dried solid, compound 112-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined. The organic phase was washed once with 10ml of saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 112-2 as a white solid (0.14g, yield 64%).

MS(ESI,pos.ion)m/z:894[M+H]⁺；

¹HNMR(400MHz,CDCl₃)10.51(s,1H),7.92(s,1H),7.56–7.46(m,3H),7.38(d,J＝2.1Hz,1H),7.29–7.26(m,2H),7.20–7.11(m,2H),7.02–6.93(m,4H),6.63(d,J＝2.1Hz,1H),6.04(s,1H),5.76–5.64(m,1H),5.05–4.94(m,1H),4.60(t,J＝7.7Hz,1H),4.54–4.40(m,2H),4.08(dd,J＝11.2,4.2Hz,1H),3.86(s,3H),3.83(s,3H),2.92–2.82(m,1H),2.70–2.57(m,2H),2.51–2.42(m,1H),2.30–2.21(m,1H),2.06–1.90(m,2H),1.88–1.71(m,4H),1.56–1.47(m,4H),1.12–1.04(m,2H),0.90–0.82(m,3H)ppm。

Example 113

Synthetic route

Step 1: synthesis of Compound 113-2

Mixing compound 113-0(3.3g,15mmol), 113-1(2.3g,15mmol), Pd (PPh)₃)₄(0.6g,0.5mmol) and K₂CO₃(10g,75mmol) was added to a mixture of THF (150mL) and water (15mL) and the reaction mixture was stirred overnight at room temperature under nitrogen after the reaction was complete, saturated sodium chloride solution (200mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 100mL), and the organic phases were combined . The organic phase was washed with 40 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain compound 113-2(3.1g, yield: 84%) as a yellow solid.

Step 2: synthesis of Compound 113-4

Compound 113-2(0.8g,3.2mmol) and compound 113-3(0.75g,4mmol) were dissolved in 20mL of DMF, and K was added thereto₂CO₃(0.9g,7 mmol). After addition was complete, the reaction mixture was refluxed overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with additional 100ml of LEtOAc, and then diluted with H₂O wash (100mL × 2) and a 50mL saturated brine rinse₂SO₄Drying, then filtration, and finally concentration under reduced pressure gave compound 113-4(1.3g, yield: 97%) as a yellow solid, which was directly subjected to the next reaction without further purification.

And step 3: synthesis of Compound 113-5

Compound 113-4(1.3g,3.1mmol) was dissolved in 20mL of glacial acetic acid, and then reduced iron powder (0.8g,5mmol) was added, and the reaction mixture was warmed to 115 ℃ and stirred for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered and the solid was removed, 50ml of 1N Cl solution was added dropwise to the obtained filtrate to precipitate a large amount of white solid, which was then filtered and dried under vacuum to obtain compound 113-5(1.0g, yield: 90%).

MS(ESI,pos.ion)m/z:352[M+H]⁺。

And 4, step 4: synthesis of Compound 113-6

Compound 113-5(0.5g,1.4mmol) was added to 15mL of toluene, phosphorus oxychloride (0.5g,3mmol) was added under nitrogen, and then N, N-dimethylaniline (0.08g,0.6mmol) was added slowly. The reaction mixture was warmed to 110 ℃ and reacted for 6 hours. After completion of the reaction, it was cooled to 0 ℃, the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 113-6(0.35g, yield: 66%) as a pale yellow solid.

And 5: synthesis of Compound 113-7

Compound 113-6(0.2g,0.54mmol) was dissolved in DMF (20mL) and compound 107-5(0.2g,0.35mmol) and potassium tert-butoxide (0.08g,0.7mmol) were added and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 2 to 3 with 1N HCl aqueous solution, and then 50 mL of water was added for dilution, followed by extraction with ethyl acetate (20 mL. times.3), and the organic phases were combined. The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give 113-7(0.25g, yield 78%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:902.3[M+H]⁺。

Step 6: synthesis of Compound 113-10

Compound 113-7(0.2g,0.2mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃, then 30% strength ethyl acetate hydrochloride solution 20 ml was added, the reaction mixture was stirred at room temperature for 2 hours, then filtered, and the resulting white solid was washed with 20 ml of ethyl acetate and dried in vacuo.

The solid obtained after drying, compound 113-9(0.03g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were added to a round bottom flask, 20 mL dichloromethane was added under nitrogen, then cooled to 0 ℃ and DIPEA (0.1mL,0.6mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10ml of water and extracted with ethyl acetate (10 ml. times.3), and the organic phases were combined. The organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 113-10(0.17g, yield 78%) as a white solid.

MS(ESI,pos.ion)m/z:911.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.43(s,1H),8.22(s,1H),7.95(s,1H),7.55–7.48(m,2H),7.45(d,J＝2.3Hz,1H),7.33–7.29(m,2H),7.28–7.26(m,1H),7.17(d,J＝8.3Hz,1H),7.10(d,J＝8.6Hz,1H),7.00–6.89(m,2H),6.07(s,1H),5.90(s,1H),5.80–5.69(m,1H),5.03–4.95(m,1H),4.88–4.76(m,2H),4.68(t,J＝8.1Hz,1H),4.07(dd,J＝11.6,3.8Hz,1H),3.84(s,3H),2.94–2.87(m,1H),2.77–2.58(m,3H),2.39–2.33(m,1H),2.29(s,3H),1.87–1.79(m,2H),1.73–1.61(m,2H),1.49(m,4H),1.20–1.02(m,3H),0.90–0.81(m,4H)ppm。

Example 114

Synthetic route

Synthesis of Compound 114-2

Compound 109-7(0.16g,0.18mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 20 ml of a 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate, and then the resulting solid was left to dry in vacuo. The above dried solid, compound 114-1(0.02g,0.2mmol), EDCI (0.04g,0.2mmol) and HOAT (0.03g,0.2mmol) were charged into a round bottom flask, 20 mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C and DIPEA (0.1mL,0.6mmol) was added. After the addition was complete, the reaction mixture was warmed to 30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10 mL. times.3), and then the organic phases were combined. The organic phase was washed once with 10ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 114-2(0.15g, yield 89%) as a white solid.

MS(ESI,pos.ion)m/z:922[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.41(s,1H),7.52(d,J＝8.7Hz,2H),7.45(dd,J＝8.4,2.5Hz,1H),7.42(d,J＝2.2Hz,1H),7.37–7.34(m,2H),7.32–7.29(m,1H),7.27(d,J＝6.8Hz,1H),7.18(d,J＝8.3Hz,1H),7.13–7.09(m,2H),6.97(d,J＝8.8Hz,2H),6.69(d,J＝2.3Hz,1H),6.02(s,1H),5.78–5.70(m,1H),5.05–4.98(m,1H),4.69–4.60(m,3H),4.49–4.43(m,1H),4.11(dd,J＝11.3,4.3Hz,1H),3.86(s,3H),2.96–2.86(m,1H),2.67–2.61(m,2H),2.60–2.53(m,1H),2.37(q,J＝8.6Hz,1H),2.07–2.03(m,1H),1.94–1.90(m,2H),1.80–1.75(m,1H),1.64–1.61(m,1H),1.53–1.44(m,11H),1.16–1.08(m,2H),0.95–0.85(m,3H)ppm。

Example 115

Synthetic route

Step 1: synthesis of Compound 115-2

Mixing compound 115-0(2.7g,12mmol), compound 115-1(1.5g,11mmol), and H₂O (15mL), toluene (30mL), methanol (30mL), potassium acetate (3g,21.5mmol) and tetrakis (triphenylphosphine) palladium (0.5g,0.4mmol) were added to the round bottom flask. The reaction mixture was warmed to 100 ℃ under nitrogen and stirred for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature,the organic solvent was spin-dried under reduced pressure. Then, 50mL of water and 50mL of ethyl acetate were added to dilute the mixture, the mixture was separated, the aqueous phase was extracted twice with 50mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 50mL of saturated saline and then with anhydrous Na₂SO4 was dried and then filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1), to give compound 115-2(2.0g, yield: 79%) as a pale yellow solid.

Step 2: synthesis of Compound 115-3

Compound 115-2(2g,8.6mmol), di-tert-butyl azodicarboxylate (3g,12.7mmol), diphenyl-2-pyridylphosphine (3.5g,13mmol) and isopropanol (4mL,6.1mmol) were dissolved in 100mL of THF. The reaction mixture was stirred at room temperature for 8 hours, and after completion of the reaction, the organic solvent was removed under reduced pressure. The obtained residue was purified by a silica gel column (petroleum ether: ethyl acetate (V: V) ═ 10:1), to give compound 115-3(2.0g, yield: 79%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:276.0[M+H]⁺。

And step 3: synthesis of Compound 115-5

Compound 115-3(2.3g,8.4mmol) and compound 115-4(1.8g,11.0mmol) were dissolved in 40mL DMF, and K was added thereto₂CO₃(4g,28.6mmol) and after the addition was complete, the reaction mixture was warmed to 90 ℃ for reaction overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with 100ml of LEtOAc, then diluted with H₂O wash (50mL × 2) and a 50mL saturated brine rinse₂SO₄Drying and then filtration, and the obtained filtrate was concentrated under reduced pressure to obtain compound 115-5(3g, yield: 84%) as a yellow solid.

MS(ESI,pos.ion)m/z:426.2[M+H]⁺。

And 4, step 4: synthesis of Compound 115-6

Compound 115-5(3.2g,7.5mmol) was dissolved in 60mL of glacial acetic acid, and then reduced iron powder (2g,45mmol) was added. The reaction mixture was warmed to 115 ℃ and stirred for 3 hours, after the reaction was completed, cooled to room temperature, filtered to remove solids, 100ml of 1n hcl solution was added dropwise to the obtained filtrate to precipitate a large amount of white solids, and then filtered, the filter cake was washed once with 50ml of water, and the obtained white solids were dried under vacuum to obtain the white solid compound 115-6(2.7g, yield: 99%) which was directly subjected to the next reaction without further purification.

MS(ESI,pos.ion)m/z:364.1[M+H]⁺。

And 5: synthesis of Compound 115-7

Compound 115-6(0.5g,1mmol) was added to 10mL of toluene, and under nitrogen, phosphorus oxychloride (0.5mL,5mmol) was added, followed by N, N-dimethylaniline (0.1mL,0.8mmol) slowly. After the addition was completed, the reaction mixture was warmed to 110 ℃ for 6 hours, and after the completion of the reaction, cooled to 0 ℃, and the organic solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 5:1) to give the product 115-7(0.472g, yield 90%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:382.2[M+H]⁺。

Step 6: synthesis of Compound 115-9

Potassium tert-butoxide (0.30g,3mmol), compound 115-7(0.47g,1.2mmol) and compound 115-8(0.5g,0.9mmol) were added to 15 ml of anhydrous DMF, and after the addition was complete, the reaction mixture was warmed to 40 ℃ and stirred for 4 hours, after completion of the reaction, the reaction was quenched with 20 ml of water and then separated. The aqueous phase is washed once with 20 ml of ethyl acetate, the pH is then adjusted to about 4 with 1N hydrochloric acid solution, extracted three times with 20 ml of ethyl acetate and the organic phases are combined. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 115-9(0.37g, yield: 50%) as a white solid.

MS(ESI,pos.ion)m/z:914.4[M+H]⁺。

And 7: synthesis of Compound 115-10

Compound 115-9(0.19g,0.24mmol) was dissolved in 2ml of ethyl acetate, cooled to 0 ℃ and then 2ml of a 30% strength ethyl acetate hydrochloride solution was added and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 5 ml of ethyl acetate, and then dried in vacuo.

The dried solid, compound 5-methylisoxazole-3-carboxylic acid (0.04g,0.3mmol), EDCI (0.13g,0.6mmol) and HOAT (0.09g,0.66mmol) were added to a round bottom flask, then 10mL dichloromethane was added, cooled to 0 ℃, and DIPEA (0.2mL,1mmol) was added. The reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10mL of water and taken up with dichloromethane (10 mL. times.2), and the organic phases were combined. The organic phase was washed once with 10ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 115-10(0.131g, yield 86%) as a white solid.

MS(ESI,pos.ion)m/z:923.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃):10.48(s,1H),8.28(s,1H),8.10(s,1H),7.51(d,J＝8.7Hz,2H),7.47(d,J＝2.1Hz,1H),7.33(dd,J＝8.3,2.3Hz,1H),7.22–7.18(m,2H),7.14(dd,J＝8.9,4.6Hz,1H),7.09–7.05(m,1H),6.96(d,J＝8.7Hz,2H),6.22(s,1H),5.98(s,1H),5.76(dd,J＝17.4,9.2Hz,1H),5.01(dd,J＝11.9,6.6Hz,1H),4.86–4.79(m,2H),4.67(t,J＝8.1Hz,1H),4.59(dq,J＝12.1,6.1Hz,1H),4.08(dd,J＝11.5,3.7Hz,1H),2.96–2.90(m,1H),2.76–2.64(m,3H),2.39–2.34(m,4H),2.28–2.22(m,1H),1.84(dd,J＝14.4,7.0Hz,2H),1.67(t,J＝8.6Hz,1H),1.58–1.55(m,1H),1.53–1.47(m,3H),1.44(d,J＝11.9Hz,2H),1.38(d,J＝4.6Hz,4H),1.21–1.05(m,3H),0.96–0.88(m,3H)ppm。

Example 116

Synthetic route

Step 1: synthesis of Compound 116-2

Compound 116-1(5g,30.101mmol) was charged to a round bottom flask and glacial acetic acid (50mL) and concentrated sulfuric acid (10mL) were added thereto. The reaction solution was heated to 100 ℃ and stirred for 8 hours. After completion of the reaction, 100 mL of water was added for dilution, followed by extraction with ethyl acetate (50 mL. times.3), and then the organic phases were combined. The organic phase was washed once with 50ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, then filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 116-2(3.5g, yield 63%) as a yellow solid.

MS(ESI,pos.ion)m/z:185.1[M+H]⁺。

Step 2: synthesis of Compound 116-3

Compound 116-2(6.08g,33.0mmol) was added to 100 ml of toluene, lawson's reagent (6.88g,16.5mmol) was then added, the reaction was heated to 120 ℃ and refluxed for 2 hours, after completion of the reaction, the reaction was cooled to room temperature, the organic solvent was then spun off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 116-3 as a yellow solid (5g, 76% yield).

And step 3: synthesis of Compound 116-4

Compound 116-3(4.11g,20.5mmol) was added to 100 ml of ethanol, followed by 1-bromo-3-methyl-butan-2-one (6.21g,22.6mmol), the reaction was refluxed for 10 hours, and after completion of the reaction, the reaction was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 10:1) to give compound 116-4 as a yellow solid (3g, 55% yield).

MS(ESI,pos.ion)m/z:267.1[M+H]⁺。

And 4, step 4: synthesis of Compound 116-6

Compound 116-5(2.3g,14mmol), compound 116-4(3.3g,12mmol) were dissolved in DMF (200mL) and K was added thereto₂CO₃(3.1g,22 mmol.) after the addition, the reaction mixture was warmed to 120 ℃ for reaction overnight after the reaction was complete, the reaction mixture was cooled to room temperature, then 200mL of water was added to quench the reaction, which was extracted with ethyl acetate (50mL × 3). the organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give compound 116-6 as an orange oily liquid (4.0g, yield 78%) which was directly subjected to the next reaction.

And 5: synthesis of Compound 116-7

The crude compound 116-6(5g,12.01mmol) obtained in step 4 was dissolved in glacial acetic acid (20mL), and iron powder (3.3g,59mmol) was added thereto. The reaction mixture was warmed to 110 ℃ for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The resulting filtrate was poured into a 1N hydrochloric acid (50mL) solution to precipitate a white solid, which was then filtered, and the filter cake was washed with water, and the resulting solid was dried under vacuum to give compound 116-7 as a yellow solid (3g, yield 71%).

MS(ESI,pos.ion)m/z:354.9[M+H]⁺。

Step 6: synthesis of Compound 116-8

Compound 116-7(3g,8.465mmol) was added to toluene (100mL) and POCl was added slowly with stirring₃(2.6g,17mmol) and N, N-dimethylaniline (512mg,4.22mmol) were added and the reaction mixture was refluxed for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and then reducedConcentration under reduced pressure, and purification of the crude product by silica gel column chromatography (eluent petroleum ether) to give compound 116-8(2.8g, yield 89%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:372.8[M+H]⁺。

And 7: synthesis of Compound 116-9

Compound 107-5(686mg,1.206mmol) was dissolved in DMF (50mL) and compound 116-8(500mg,1.341mmol) and potassium tert-butoxide (451mg,4.0192mmol) were added thereto. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to about 2 to 3 with 1N HCl aqueous solution, and then diluted with 50mL of water, followed by extraction with ethyl acetate (20 mL. times.3), and the organic phases were combined. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 116-9(0.8g, yield 70%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:905.4[M+H]⁺。

And 8: synthesis of Compound 116-10

Compound 116-9(500mg,0.55mmol) was dissolved in 5N HCl ethyl acetate solution (10mL), the reaction mixture was stirred at room temperature for 2 hours, and after completion of the reaction, it was concentrated under reduced pressure to give compound 116-10(0.4g, 90% yield) as a white solid.

And step 9: synthesis of Compound 116-11

Compound 116-10(100mg,0.12mmol) was dissolved in CH₂Cl₂(50mL) and to this were added the compounds 5-methylisoxazole-3-carboxylic acid (16mg,0.13mmol), EDCI (27mg,0.14mmol) and HOAT (19mg,0.14mmol), and under ice bath, DIPEA (47mg,0.36mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to give compound 116-11(0.09g, yield 80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:914.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.44(s,1H),8.19(s,1H),7.96(s,1H),7.82(s,1H),7.75(d,J＝8.1Hz,1H),7.27–7.23(m,1H),7.20(d,J＝8.3Hz,1H),7.13(ddd,J＝15.9,11.1,6.4Hz,2H),6.88(s,1H),6.26(s,1H),6.02(s,1H),5.77(dd,J＝17.2,8.9Hz,1H),5.11–4.97(m,1H),4.88–4.72(m,2H),4.65(t,J＝8.0Hz,1H),4.09(d,J＝8.4Hz,1H),3.17(dt,J＝13.4,6.7Hz,1H),2.93(d,J＝4.3Hz,1H),2.82–2.60(m,3H),2.45–2.29(m,4H),2.27–2.18(m,1H),1.89–1.83(m,2H),1.69(s,1H),1.58(dd,J＝8.7,6.1Hz,1H),1.54–1.43(m,4H),1.37(d,J＝6.8Hz,5H),1.28(s,3H),1.19–1.09(m,2H),0.97–0.86(m,2H)ppm。

Example 117

Synthetic route

Synthesis of Compound 117-1

Compound 109-7(0.34g,0.38mmol) was dissolved in 2 ml of ethyl acetate, cooled to 0 ℃ and then 2 ml of a 30% strength ethyl acetate hydrochloride solution was added, and the reaction solution was reacted at room temperature for two hours. After the reaction was complete, it was filtered, and the resulting white solid was washed with 20 ml of ethyl acetate and then dried in vacuo.

The solid obtained after the above reaction was dried, compound 117-0(0.1g,0.56mmol), EDCI (0.10g,2.5mmol) and HOAT (0.16g,2.5mmol) were added to a round bottom flask, 20mL of dichloromethane were added under nitrogen, then cooled to 0 deg.C, DIPEA (0.5mL,10mmol) was added, the reaction mixture was warmed to 30 deg.C and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 ml of water, extracted with dichloromethane (20ml × 2), the organic phases were combined, the organic phase was washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 2:1) to obtain compound 117-1 as a white solid (0.145g, yield 39%).

MS(ESI,pos.ion)m/z:923.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.46(s,1H),8.00(d,J＝7.0Hz,1H),7.82(s,1H),7.68(s,1H),7.52(d,J＝8.5Hz,2H),7.46(d,J＝1.3Hz,1H),7.32(dd,J＝8.3,1.9Hz,1H),7.20–7.13(m,4H),6.97(d,J＝8.6Hz,2H),5.89(s,1H),5.74(dd,J＝17.7,8.7Hz,1H),5.38(dt,J＝13.0,6.4Hz,1H),5.05–4.98(m,1H),4.73(ddd,J＝27.5,21.8,9.4Hz,3H),4.09(dd,J＝11.4,3.6Hz,1H),3.85(s,3H),2.94(ddd,J＝12.8,8.1,4.9Hz,1H),2.71–2.61(m,3H),2.37(dd,J＝17.0,8.4Hz,1H),2.09(dd,J＝20.0,14.9Hz,2H),1.94–1.89(m,2H),1.72(s,1H),1.51(ddd,J＝41.3,24.0,7.9Hz,8H),1.39–1.35(m,2H),1.18–1.09(m,3H),0.96–0.87(m,3H)ppm。

Example 118

Synthetic route

Step 1: synthesis of Compound 118-1

The compound 99-3(0.4g,0.6mmol), the compound 109-5(4.25g,1.3mmol), potassium tert-butoxide (0.3g,3mmol) and DMF (20mL) were added to a reaction flask, and the reaction was warmed to 50 ℃ and stirred overnight. After completion of the reaction, the reaction was quenched by addition of 1mol/L hydrochloric acid (20mL), followed by extraction with ethyl acetate (20mL), liquid separation, extraction of the aqueous phase with ethyl acetate (20mL) once, combination of the organic phases, washing with saturated brine once, drying over anhydrous sodium sulfate, filtration, and spin-drying under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 4:1) to give compound 118-1 as a pale yellow solid (0.40g, yield 60%).

MS(ESI,pos.ion)m/z:901.3[M+H]⁺

Step 2: synthesis of Compound 118-2

Compound 118-1(0.3g,0.3mmol) was dissolved in 2 mL of isopropanol, cooled to 0 deg.C, then 5mL of 40% strength isopropanol hydrochloride solution was added and stirred at room temperature for two hours. Filtration and washing of the resulting white solid with 5ml of ethyl acetate followed by vacuum drying of the resulting solid.

The solid obtained after the above reaction was dried, compound 5-methylisoxazole-3-carboxylic acid (0.1g,0.7mmol), EDCI (0.2g,1mmol) and HOAT (0.15g,1.1mmol) were added to a round bottom flask, 20mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃, DIPEA (0.5mL,3mmol) was added, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 ml of water, taken out with dichloromethane (20 ml. times.2), the organic phases were combined, washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to obtain compound 118-2 as a white solid (0.081g, yield 20%).

MS(ESI,pos.ion)m/z:909.3[M+H]⁺；

¹HNMR(400MHz,CDCl₃):10.32(s,1H),8.14(d,J＝7.4Hz,1H),7.93(s,1H),7.53(d,J＝8.5Hz,2H),7.46(s,1H),7.32(d,J＝8.3Hz,1H),7.25–7.07(m,4H),6.98(d,J＝8.5Hz,2H),6.24(s,1H),5.99(s,1H),5.76(dd,J＝17.4,8.7Hz,1H),5.03(t,J＝9.3Hz,1H),4.81(d,J＝11.0Hz,2H),4.67(t,J＝8.0Hz,1H),4.10(d,J＝8.0Hz,1H),3.89(d,J＝28.2Hz,3H),2.70(s,3H),2.38(s,3H),2.22(d,J＝10.4Hz,2H),1.88–1.75(m,3H),1.53(d,J＝10.6Hz,6H),1.35(d,J＝5.2Hz,2H),0.99–0.65(m,6H)ppm。

Example 119

Synthetic route

Step 1: synthesis of Compound 119-1

The compound 99-3(0.18g,0.31mmol), the compound 104-4(0.14g,0.46mmol), potassium tert-butoxide (0.15g, 1.3mmol) and DMF (20mL) were added to a reaction flask, and the reaction was warmed to 50 ℃ and stirred overnight. After completion of the reaction, the reaction was quenched by addition of 1mol/L hydrochloric acid (20mL), followed by extraction with ethyl acetate (20mL), liquid separation, extraction of the aqueous phase with ethyl acetate (20mL) once, combination of the organic phases, washing with saturated brine once, drying over anhydrous sodium sulfate, filtration, and spin-drying under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 4:1) to give 119-1(0.10g, yield 40%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:852.9[M+H]⁺。

Step 2: synthesis of Compound 119-2

Compound 119-1(0.1g,0.1mmol) was dissolved in 2 ml of isopropanol, cooled to 0 ℃ and then 5ml of a 40% strength isopropanol hydrochloride solution was added and the reaction was stirred at room temperature for two hours. After the reaction was complete, it was filtered, the filter cake was rinsed with 5ml of ethyl acetate, and the resulting solid was dried in vacuo.

The above dried solid, compound 5-methylisoxazole-3-carboxylic acid (0.05g,0.3mmol), EDCI (0.07g,0.4mmol) and HOAT (0.05g,0.4mmol) were added to a round bottom flask, 20mL dichloromethane was added under nitrogen protection, then cooled to 0 ℃, DIPEA (0.5mL,3mmol) was added, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. The reaction was quenched with 10 ml of water, extracted with dichloromethane (20ml × 2), the organic phases were combined, the organic phase was washed once with 20ml of saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give 119-2(0.057g, yield 50%) as a white solid.

MS(ESI,pos.ion)m/z:861.7[M+H]⁺；

¹HNMR(600MHz,CDCl₃):8.09(s,2H),7.34(d,J＝32.4Hz,1H),7.22(d,J＝6.5Hz,1H),7.15–6.98(m,4H),6.78(d,J＝1.7Hz,1H),6.69–6.63(m,1H),6.26(s,1H),5.95(s,1H),5.74(dd,J＝17.2,8.6Hz,1H),5.04(d,J＝9.5Hz,1H),4.80–4.65(m,3H),4.53(dd,J＝11.7,5.8Hz,1H),4.09(d,J＝9.0Hz,1H),3.76(s,4H),3.67(s,2H),3.61(s,3H),3.05(dd,J＝136.9,60.9Hz,5H),2.75–2.61(m,4H),2.39(s,3H),2.32(d,J＝8.7Hz,1H),2.20(d,J＝11.7Hz,1H),2.03(dd,J＝25.0,18.3Hz,1H),0.89(t,J＝6.6Hz,6H)ppm。

Example 120

Synthetic route

Step 1: synthesis of Compound 120-2

The compound 99-3(0.4g,0.7mmol), the compound 120-1(0.3g,1mmol), potassium tert-butoxide (0.15g,1.3mmol) and DMF (20mL) were added to a reaction flask, and the mixture was heated to 50 ℃ and stirred overnight. After completion of the reaction, 1mol/L hydrochloric acid (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted once with ethyl acetate (20mL), the organic phases were combined, washed once with saturated saline, dried over anhydrous sodium sulfate, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 4:1) to obtain compound 120-2 as a pale yellow solid (0.35g, yield 60%).

MS(ESI,pos.ion)m/z:824.8[M+H]⁺。

Step 2: synthesis of Compound 120-3

Compound 120-2(0.2g,0.3mmol) was dissolved in 2 ml of isopropanol, cooled to 0 ℃ and then 5ml of a 40% strength hydrochloric acid/isopropanol solution was added and the reaction mixture was stirred at room temperature until the reaction was complete without gas evolution. After completion of the reaction, the reaction mixture was filtered, and the resulting white solid was washed with 5ml of ethyl acetate.

The solid obtained above, the compound 5-methylisoxazole-3-carboxylic acid (0.08g,0.6mmol), EDCI (0.14g,0.73mmol) and HOAT (0.1g,0.7mmol) were added to a round bottom flask under nitrogen protection, 20mL dichloromethane was added, then cooled to 0 ℃, DIPEA (0.5mL,3mmol) was added, the reaction mixture was warmed to 30 ℃ and stirred for 6 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, taken out with dichloromethane (20mL × 2), the organic phases were combined, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) ═ 1:1) to give compound 120-3 as a white solid (0.165g, yield 80%).

MS(ESI,pos.ion)m/z:833.7[M+H]⁺；

¹HNMR(600MHz,CDCl₃)10.37(s,1H),8.36(d,J＝7.0Hz,1H),8.17(s,1H),7.16(dd,J＝8.3,2.6Hz,1H),7.10–7.02(m,3H),6.79(d,J＝2.7Hz,1H),6.68(dd,J＝8.8,2.8Hz,1H),6.21(s,1H),5.95(s,1H),5.75(dd,J＝17.4,8.9Hz,1H),5.01(t,J＝9.3Hz,1H),4.82(dd,J＝16.1,10.0Hz,2H),4.65(t,J＝8.1Hz,1H),4.08(dd,J＝11.3,3.3Hz,1H),3.81(s,3H),2.77–2.64(m,3H),2.38–2.32(m,4H),2.29–2.24(m,1H),2.04(d,J＝14.5Hz,1H),1.83–1.76(m,3H),1.65(d,J＝11.0Hz,1H),1.54–1.51(m,3H),1.47–1.37(m,3H),1.31(dd,J＝25.1,13.3Hz,3H),0.94–0.75(m,3H)ppm。

Biological activity

1) HCV NS3/4A protease inhibition assay

High throughput screening of HCV ns3/4A protease inhibitors was performed using the sensorlyte 520HCV protease detection kit (Anaspec) based on Fluorescence Resonance Energy Transfer (FRET) technology. In the 5-FAM/QXL520FRET substrate peptide, the fluorescence of 5-FAM is quenched by QXL 520. 5-FAM/QXL ^TMThe 520FRET substrate peptide contains an HCVNS3/4A protease cleavage site, can be cleaved into two independent fragments by HCVNS3/4A protease, recovers the fluorescence of 5-FAM, and can be detected under the condition that Ex/Em is 490/510 nm.

The inhibitory effect of the compounds on HCV NS3/4A protease was evaluated by detecting the change in the intensity of the fluorescent signal of 5-FAM. The experimental procedure is briefly described as follows, compounds are dissolved in DMSO, and mixed well to prepare 10mM mother liquor, diluted with Assaybuffer containing DTT, 1 μ M as the initial concentration of drug test, 3-fold gradient dilution, 10 dilution points, 3 μ l of the compound diluted in gradient is added into 384-well plates, and the final concentration of DMSO in each well is 1%. Then, 3. mu.l of HCV NS3/4A recombinant protease genotype 1a (Anaspec) or HCV NS3/4A recombinant protease genotype 1b (Anaspec) was added to the 384-well plates at a final enzyme concentration of 0.25 ng/. mu.l for each well. Positive compound control, negative control and substrate control were set. The 384 well plates were incubated at 25 ℃ for 15min for enzymatic reactions while the substrate solutions were incubated at the same temperature. After 15min, adding 50 times diluted FRET substrate peptide into each hole, and mixing by gentle shaking for 1 min. Immediately placing in PHERAStarFS multifunctional microplate reader (BMGLAbtech), detecting fluorescence intensity under Ex/Em ═ 490/520nm condition by kinetic method, recording data every 1min, and continuously detecting for 30 min. Using GraphPadP The results were processed by the rism software to calculate the IC50 value for compound inhibition of hcv ns3/4A enzyme. IC of Compounds on NS3/4A protease genotypes 1a and 1b₅₀The results are shown in Table 2.

TABLE 2

Example numbering	1a(nM)	1b(nM)	Example numbering	1a(nM)	1b(nM)
						Example 2	3.6	N/A	Example 16	38.4	N/A
Example 3	1.7	N/A	Example 17	69.2	35.6
						Example 4	10.8	N/A	Example 18	8.9	N/A
Example 5	7.5	N/A	Example 19	3.7	N/A
						Example 7	66.4	N/A	Example 20	29.2	N/A
Example 8	17.6	16.8	Example 21	6.3	N/A
						Example 9	1.9	N/A	Example 22	6.7	N/A
Example 10	4.4	N/A	Example 23	14.8	N/A
						Example 11	12.5	N/A	Example 24	16	N/A
Example 12	7.3	14.3	Example 29	15.1	8.5
						Example 13	4.8	N/A	Example 30	15.6	N/A
Example 14	6.5	12.3	Example 31	10.6	N/A
						Example 15	60.8	N/A	Example 32	6.9	N/A

N/A: indicating that no relevant monitoring was performed

2) HCV subgenomic replicon assay

Activity assays of compounds were performed using two stable transgenic cell lines with HCV subgenomic replicons: one cell line was derived from HCV genotype 1a and one cell line was derived from HCV genotype 1 b. This replicon construct is reported in Science,1999,285(5424):110-3 and J.VIROL,2003,77(5): 3007-19. The replicon construct is a bicistronic subgenomic replicon, with the first cistron having a luciferase reporter and a neomycin phosphotransferase (neo) selectable marker. The second cistron was the coding region of HCV NS3-NS5B with the addition of an adaptive mutation. The coding region of the HCV genotype 1a replicon NS3-NS5B is derived from the H77 strain of HCV (1a-H77), and adaptive mutations are E1202G, K1691R, K2040R and S2204I. The coding region of the HCV genotype 1b replicon NS3-NS5B is derived from the Con1 strain of HCV (1b-Con1), and adaptive mutations are E1202G, T1280I and S2204I.

The inhibitory effect of the compounds on HCV replication was evaluated by detecting the activity of a luciferase reporter gene. Experimental methods briefly described, stably transfected cells Huh7-H77 and Huh7-Con1b containing HCV genotype 1a (1a-H77) and genotype 1b (1a-Con1) replicons were seeded in 96-well plates at a density of 8000 cells/well in a volume of 125. mu.l. After 16-24h, the compound was diluted to the appropriate concentration using a 3-fold gradient, 11 dilution points dilution method, and POD was used^TM810 microplate pretreatment system diluted compounds were added to 96-well plates at a final DMSO concentration of 0.5% per well. At 37 ℃ 5% CO₂CO of₂After incubation for 72h in the isothermal culture, 40. mu.l of luciferase assay reagent (Promega Bright-Glo) was added to each well, and after 5min, detection was performed using a chemiluminescence detection system (Envision). The results of the experiment were processed using GraphPadPrism software to calculate the EC50 for compound inhibition of HCV replicons. The EC50 results for the HCV genotype 1a and genotype 1b replicons for the compounds are shown in table 3.

TABLE 3

Example numbering	1b(nM)	1a(nM)	Example numbering	1b(nM)	1a(nM)
						Example 2	25.84	45.41	Example 36	14.22	25.89
Example 3	11.13	9.19	Example 37	62.79	54.78
						Example 8	16.07	28.11	Example 44	18.2	60.3
Example 9	9.40	32.83	Example 47	67.4	44.4
						Example 12	30.7	76.77	Example 52	32.1	47.3
Example 19	11.87	33.83	Example 56	40.3	37.8
						Example 21	38.76	89.28	Example 66	26.3	23.5
Example 23	18.63	37.69	Example 67	7.3	13.5

Example 27	28.8	46.4	Example 68	22.2	7.4
						Example 28	20.3	29.0

IC of compound for inhibition of HCVNS3/4A protease₅₀Results and EC for HCV replicon inhibition₅₀The result is combined with the molecular docking simulation result, which shows that the compound can specifically inhibit HCV NS3/4A protease and has good antiviral effect.

3) Rat PK screening assay:

the test method comprises the following steps: dividing 250-300g male SD rats into two groups, wherein each group comprises 3 male SD rats, respectively administering a compound to be detected to the male rats through veins and gavages, collecting blood for 8-9 time points within 24h, establishing a standard curve in a proper range according to the concentration of a sample, determining the concentration of the compound to be detected in a plasma sample in an MRM mode by using ABSCIEAPI 4000 or Agilent6430 type LC-MS/MS, and carrying out quantitative analysis. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using the winnonlin6.3 software non-compartmental model method. The results of the in vivo rat PK assay for the compounds are shown in table 4.

TABLE 4

N/A: indicating that no relevant monitoring was performed

And (4) conclusion: the compound of the invention has more obvious advantages in exposure, half-life and clearance compared with the reported compound (ABT-450).

It will be evident to those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from the essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments without departing from the principle and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound of formula (I):

R³and R⁴Each independently is H, deuterium, hydroxyl, amino, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl;

y is-CR⁵R⁶-、-NR⁷-, -O-, -S-or-S (═ O)_t-；

W is CR⁵Or N;

q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

Z is a bond, -CR ⁵R⁶-、-NR⁷-、-O-、-S-、-S(＝O)_t-、-C(＝O)-、-OC(＝O)-、-OC(＝O)N(R⁷)-、-N(R⁷)C(＝O)-、-C(＝O)N(R⁷) -, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heterocyclylene-O, arylene-S, arylene-N, or heteroarylene;

each R⁷And R¹¹Independently is H, deuterium, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

m and n are each independently 0, 1, 2, 3 or 4;

each t is independently 1 or 2;

p and q are each independently 0, 1, 2, 3, 4 or 5;

to representOr

2. The compound of claim 1, wherein,

ring A and ring B are each independently C_3-10Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

when X is equal to X, X is CR⁵Or N;

y is-CR⁵R⁶-、-NR⁷-, -O-, -S-or-S (═ O)_t-；

m and n are each independently 0, 1, 2, 3 or 4;

c as described above_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-10CycloalkanesBase, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-10Heterocyclic group, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C _1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_6-10Aryl radical, C_1-9Heteroaryl or C_2-10A substituent of the heterocyclic group.

3. The compound of claim 2, wherein,

ring a and ring B are each independently a phenyl, pyridyl, thiazolyl, oxazolyl, imidazolyl, furyl, thienyl, pyrazolyl, isoxazolyl, pyrrolyl, quinolinyl, indolyl, or naphthyl group.

4. The compound of claim 1, wherein,

l is-C (═ O) -, -OC (═ O) -, or-NHC (═ O) -;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

5. The compound of claim 1, wherein,

q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

Z is a bond, -CR ⁵R⁶-、-NR⁷-、-O-、-S-、-S(＝O)₂-、C_2-6Alkenylene radical, C_2-6Alkynylene, C_3-10Cycloalkylene radical, C_2-10Heterocyclylene radical, C_6-10Arylene radical, C_6-10arylene-O, C_6-10arylene-S, C_6-10arylene-N or C_1-9A heteroarylene group;

p and q are each independently 0, 1, 2, 3, 4 or 5.

6. The compound of claim 1, wherein,

R³is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic group, C_6-10Aryl andC_1-9heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

7. The compound of claim 1, wherein Is composed of

Each A is¹And A²Independently is CR¹⁰Or N;

A³is CR⁵R⁶、NR⁷O or S;

each R⁷Independently of one another H, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_2-10Heterocyclic radical、C_6-10Aryl or C_1-9A heteroaryl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-10Cycloalkyl radical, C_3-10Cycloalkane-O, C_2-10Heterocyclic group, C_6-10Aryl and C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C _1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

8. The compound of claim 7, whereinIs composed of

9. The compound of claim 1, having a structure according to formula (I'),

wherein,is composed of

Each A is¹And A²Independently is CR¹⁰Or N;

A³is CR⁵R⁶、NR⁷O or S;

each R⁷Independently of one another H, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_2-10Heterocyclic group, C _6-10Aryl or C_1-9A heteroaryl group;

10. The compound of claim 9, wherein,

each A is¹And A²Independently is CR¹⁰Or N;

A³is NH, O or S;

each R¹And R²Independently H, deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, cyclopropyloxy, trifluoromethoxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, pyrazolyl, isoxazolyl, indolyl, naphthyl, ethynyl, vinyl, propynyl, or propenyl;

11. The compound of claim 9, wherein,is composed of

12. The compound of claim 9, wherein R³And R⁴Each independently is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C _1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-9Heteroaryl group is substituted.

13. The compound of claim 12, wherein R³And R⁴Each independently is H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, morpholinyl, piperazinyl, pyrazinyl, piperidinyl, phenyl, propenyl, propynyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, furyl, thienyl, or pyridyl;

14. The compound of claim 9, wherein T is-O-, -S-, or-NR⁷-；

R⁷Is H, deuterium, F, Cl, Br, I, methyl, ethyl, isopropyl or trifluoromethyl.

15. The compound of claim 9, wherein W is CH or N.

16. The compound of claim 9, wherein Q is- (CR)⁵R⁶)_p-Z-(CR⁸R⁹)_q-；

p and q are each independently 0, 1, 2, 3, 4 or 5;

wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl radical, C_2-6Alkenylene radical, C_2-6Alkynylene, C_3-8Cycloalkylene radical、C_2-10Heterocyclylene radical, C_6-10Arylene radical, C_6-10arylene-O and C_1-9Heteroarylene is independently optionally substituted with 1, 2, 3 or 4 substituents selected from H, deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C _3-6Cycloalkyl or C_2-6A substituent of the heterocyclic group.

17. The compound of claim 16, wherein Z is a bond, -CH₂-、-NR⁷-、-O-、-S-、-S(＝O)₂-, ethenylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene-O, phenylene-S, thiazolylene, imidazolyl or phenylene;

wherein said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, thiazolyl ene, imidazolyl ene, phenylene-O, phenylene-S, and phenylene are independently optionally substituted with 1, 2, 3, or 4 substituents selected from H, deuterium, F, Cl, Br, I, amino, methyl, methoxy, hydroxy, nitro, cyano.

18. The compound of claim 9, wherein, Is composed of

n is 0, 1, 2, 3 or 4;

19. The compound of claim 1, wherein said compound has the structure of one of:

20. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound according to any one of claims 1-19; or further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

21. The pharmaceutical composition of claim 20, further comprising an additional anti-HCV agent; wherein the anti-HCV agent is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiqimod, an inosine 5' -monophospate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, baviximab, Civacir^TMBoceprevir (boceprevir), telaprevir (telaprevir), sofosbuvir (sofosbuvir), lediprevir (ledipasvir), daclatavir (daclatasvir), danoprevir (danoprevir), cidaprevir (cilaprevir), naraprevir (narlaprevir), deleobrevir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), bitomasvir (ABT-267), neceprevir (ACH-2684), tegobrevir (919-0), gradoprevir (MK-51) 72) Wherein the interferon is interferon of interferon-94-31, interferon-1625, sumatasvir (IDX-719), setrobivir, veruprevir (ABT-450), erlotinib (erlotinib), simeprevir (TMC-435), asunaprevir (BMS-650032), vanipredvir (MK-7009), faldaprevir (BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530, ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA 1765, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH-5, VX-985, VX-375, PHPSI-500, PHP-668, PHGS-5816, MK-8325, PHX-8317, PHX-102, PHX-599, IMX-102, VLC-68, VLA-68, VLP-35, VLP-102, VLA-102, VLP-102, VLA-IV-35, VLP-102, VLA-11, VLA-102, VLA-35, VLA-III-9, VLA-35, VLA-9, VLA-35, VLA-9, VLP-9, VLA-9, VLP-III, VLP-9, VLA-9, VLP.

22. The pharmaceutical composition of any one of claims 20-21, further comprising at least one HCV inhibitor; wherein the HCV inhibitor is for at least one of inhibiting the HCV replication process and inhibiting the function of HCV viral proteins; wherein the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV; the HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A or NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

23. Use of a compound according to any one of claims 1-19 or a pharmaceutical composition of any one of claims 20-22 in the manufacture of a medicament for at least one of inhibiting HCV replication and inhibiting HCV viral protein function; wherein the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV; the HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A or NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

24. Use of a compound according to any one of claims 1-19 or a pharmaceutical composition according to any one of claims 20-22 in the manufacture of a medicament for preventing, treating or alleviating HCV infection or hepatitis c disease in a patient.