WO2023185763A1

WO2023185763A1 - Peptidomimetic compound, and preparation method, pharmaceutical composition and use therefor

Info

Publication number: WO2023185763A1
Application number: PCT/CN2023/084172
Authority: WO
Inventors: 柳红; 胡树雷; 李建; 张磊砢; 戴文豪; 谢雄; 蒋华良; 陈凯先; 肖庚富
Original assignee: 中国科学院上海药物研究所; 中国科学院武汉病毒研究所
Priority date: 2022-04-01
Filing date: 2023-03-27
Publication date: 2023-10-05
Also published as: CN114957383A

Abstract

A peptidomimetic compound, and a preparation method, pharmaceutical composition and use therefor. Specifically, disclosed are a peptidomimetic compound represented by general formula (I), or a racemate, a cis-trans isomer, an enantiomer, a diastereomer or a mixture thereof, or a metabolite thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. Also disclosed is a use of the compound in inhibiting coronaviruses comprising SARS-CoV-2, SARS-CoV, MERS-CoV, FIPV, as well as others including RNA viruses such as EV71, EV68 and norovirus.

Description

Peptoid compound and preparation method, pharmaceutical composition and use thereof

Technical field

The present invention relates to the field of medicine. Specifically, the present invention relates to a peptidomimetic compound that blocks the replication of coronaviruses including SARS-CoV-2 and other RNA viruses, as well as its preparation method, pharmaceutical composition and use.

Background technique

RNA viruses are prone to mutation, and some coronaviruses, small RNA viruses, and noroviruses have caused serious disease problems to human society. Coronaviruses belong to the subfamily Coronavirinae of the family Coronaviridae of the order Nidovirales. Based on early serological and subsequent genomic evidence, the subfamily Coronavirus is divided into 4 major genera: α, β, γ and δ, among which the genus βcoronavirus can be further divided into 4 genera: A, B, C and D. pedigree. Among the seven known human coronaviruses (HCoVs), HCoV-229E and HCoV-NL63 belong to the genus Alphacoronavirus. HCoV-OC43 and HCoV-HKU1 belong to lineage A, SARS-CoV belongs to lineage B, and MERS-CoV belongs to lineage C. SARS-CoV-2 belongs to lineage B of the genus Coronavirus in the family Coronaviridae.

The coronavirus genome is an unsegmented, positive-sense single-stranded RNA. After the positive strand enters the host cell, it can directly serve as an mRNA chain to guide protein synthesis; it can also generate a negative strand through the action of RNA-dependent RNA polymerase (RDRP), and then use the negative strand as a template to generate a positive strand under the action of RDRP. chain. This achieves the purpose of replication. At the same time, the generated positive strand can also be used as mRNA to guide protein synthesis. The coronavirus genome is 27-32kb in size, is capped at the 5'-end, polyadenylated at the 3'-end, and contains multiple open reading frames (ORFs). The gene sequence of the coronavirus is consistent, 5'-replicate-S-E-M-N-3', and there are many small ORFs scattered in the genome, encoding some auxiliary proteins. Coronavirus replicase is encoded by two large overlapping ORFs (ORF1a and ORF1b) occupying approximately two-thirds of the genome and is translated directly from genomic RNA. However, structural and auxiliary proteins are translated from subgenomic RNAs (sgRNAs) produced during genome transcription/replication.

SARS-CoV-2 belongs to the genus Coronavirus in the family Coronaviridae. At present, it has affected most countries in the world. home influence. Targeting the replication process of SARS-CoV-2 coronavirus, the main protease (Mpro), also known as 3C-like protease (3CL), is a key target for drug development. Inhibition of 3CL protease can effectively block the cleavage of viral polyprotein precursors, block viral replication, and inhibit the production of progeny viruses. Because it does not have the same enzyme in the human body, it has good safety and is currently recognized as an ideal target for the development of anti-coronavirus drugs.

The acute coronavirus has caused serious social impact, and the virus has produced multiple variants, increasing the social pressure to fight COVID-19. Developing low-toxic, highly effective drugs with independent intellectual property rights to meet the needs of patients is of great social significance.

In summary, there is an urgent need in this field to develop 3CL protease inhibitors against coronaviruses, small RNA viruses, and noroviruses to meet the needs of patients.

Contents of the invention

An object of the present invention is to provide a peptidomimetic compound that blocks the replication of coronaviruses including SARS-CoV-2 and other RNA viruses and its preparation method, pharmaceutical composition and use.

A first aspect of the present invention provides a peptidomimetic compound represented by general formula I, or its racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically active compound Use of metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof for the preparation of (a) SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV and /or 3CL protease inhibitors of norovirus; (b) 3C protease inhibitors of RNA viruses EV71 and/or EV68; and (c) treatment and/or prevention, mitigation of SARS-CoV-2 and/or SARS-CoV and/or drugs for diseases caused by MERS-CoV and/or FIPV, and/or RNA viruses EV71 and/or EV68 and/or norovirus:

in,

*Indicates that the stereochemical isomerism of the carbon atom is independently S and/or R;

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

R ₁ is selected from the following group:

Wherein, R ₅ is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C1～C10 Alkoxy group, substituted or unsubstituted C3-C10 cycloalkyl group, substituted or unsubstituted 3-10 membered heterocyclyl group, substituted or unsubstituted C6～C14 aryl group, substituted or unsubstituted 5～12 membered heterocyclic group Aryl; the substitution refers to being substituted by 1 to 3 substituents selected from the following group: halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C6-10 aryl;

X is O or S;

Y is selected from O, NH, N-Boc, N, or NR _5a ; wherein, when Y is NR _5a , NR _5a and R ₅ together form a 5-7 membered nitrogen-containing heterocycle;

R ₆ is selected from the group consisting of: H, halogen or cyano;

R ₇ is selected from the following group: substituted or unsubstituted 3-10-membered heterocyclyl, substituted or unsubstituted 5-12-membered heteroaryl; the substitution refers to 1 to 3 groups selected from the following group Substitution: halogen, C1-C4 alkyl;

R ₈ is selected from the following group: hydrogen, C1～C6 alkyl or -CO-C1～C6 alkyl;

R ₉ is H, NH4 ⁺ , or a metal ion selected from the following group: Na ⁺ , K ⁺ , Li ⁺ ;

R ₁₀ is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, or substituted or unsubstituted C3-C10 ring Oxygen group; the substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

R ₁₁ and R ₁₂ are each independently selected from the following group: hydrogen, substituted or unsubstituted C1 to C10 alkyl, substituted or unsubstituted C2 to C10 alkenes, substituted or unsubstituted C2 to C10 alkynes; Substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

Among them, R ₁₁ and R ₁₂ are connected to connected oxygen atoms to form a ring, forming a 5-8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen;

R ₁₃ and R ₁₄ are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene Alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3- C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C10 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C10 alkenylene, acyl, sulfonyl ; The said substitutions each independently refer to the substitution of 1, 2, 3 or 4 substituents selected from the following group: halogen, hydroxyl, mercapto, nitro, cyano, amine, imine, tertiary amine, Azide group, C1-C8 alkyl group, halogenated C1-C8 alkyl group, C1-C8 alkoxy group, halogenated C1-C8 alkoxy group, C1-C6 alkylcarbonyl group, C1-C6 alkylthio group, C1- C8 alkoxycarbonyl, trifluoromethyl;

R ₂ ' is selected from the following group: hydrogen, substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C3～ C10 cycloalkyl; the substitution means substitution by 1 to 2 groups selected from the following group: halogen, C1-C4 alkyl;

R ₂ is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C1～C10 alkoxy base, substituted or unsubstituted C3~C10 cycloalkyl group, substituted or unsubstituted 3~10 membered heterocyclyl group, substituted or unsubstituted C6~C14 aryl group, substituted or unsubstituted 5~12 membered heteroaryl group ; The substitution refers to substitution with a group selected from the following group: halogen, C1-C6 alkyl, C6~C10 aryl;

Or when R ₂ and R ₂ ' are connected to form a ring, the α carbon atom, β carbon atom connected to R ₂ , and the α nitrogen atom connected to R ₂ ' form a substituted or unsubstituted 5-10 membered heterocyclic ring, 5 -12-membered heteroaromatic ring; the substitution means substitution by 1-3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;

R ₄ is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C1～C10 alkoxy base, substituted or unsubstituted C3~C10 cycloalkyl, substituted or unsubstituted C6~C14 aryl, substituted or unsubstituted 5~12-membered heteroaryl; the substitution refers to being substituted by 1-3 Substitution with groups independently selected from the following group: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkyl ketone carbonyl, cyano, nitro group, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto, C1~C4 acyl, amide, sulfonyl, aminosulfonyl, C1~C4 alkyl substituted sulfonyl, or two adjacent The substituent together with the carbon atom connected to it forms a 5- to 7-membered ring;

R ₄ ' is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, the substitution refers to being substituted by 1-3 halogens;

Or when R ₄ and R ₄ ' are connected to form a ring, the α carbon atom, β carbon atom connected to R ₄ , and the α nitrogen atom connected to R ₄ ' form a substituted or unsubstituted 5-10 membered heterocyclic ring, 5 -12-membered heteroaromatic ring; the substitution refers to being substituted by 1-3 Substituted with a group from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;

R ₃ is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C3～C10 cycloalkyl , substituted or unsubstituted 3 to 10-membered heterocyclyl, substituted or unsubstituted C6 to C14 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl; the substitution means 1 to 3 members selected from the following group Group substitution: halogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, C6~C10 aryl, halogenated C6~C10 aryl, C1~C6 alkyl Carbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto, C1~C4 acyl, amide, sulfonyl, aminosulfonyl, C1~C4 alkyl substituted Sulfonyl group, or two adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;

Wherein, the heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.

In another preferred embodiment, the virus is infected by SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA virus EV71 and/or EV68 and/or norovirus. The disease caused is selected from the group consisting of: respiratory tract infection, pneumonia and its complications, or a combination thereof.

In another preferred embodiment, when R ₂ and R ₂ ' are connected to form a ring, R ₁ is selected from the following group:

When R ₂ and R ₂ ' are not connected to form a ring, and R ₂ ' is hydrogen, R ₁ is selected from the following group:

When R ₂ and R ₂ ' are not connected to form a ring, and R ₂ ' is not hydrogen, R ₁ is selected from the following group:

Wherein, _R5 is selected from the following group: substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted C1~C6 Alkoxy group, substituted or unsubstituted C3-C7 cycloalkyl group, substituted or unsubstituted 3-7 heterocyclyl group, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted A 5- to 10-membered heteroaryl group; the substitution refers to being substituted by 1 to 3 substituents selected from the following group: halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C6-10 aryl;

X is O or S;

R ₆ is selected from the following group: H, F, Cl or cyano;

R ₇ is selected from the following group: substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

R ₈ is selected from the following group: hydrogen or -CO-C1～C4 alkyl;

R ₉ is Na ⁺ ;

R ₁₀ is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C3-C6 ring Oxygen group; the substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkyne; or R ₁₁ The oxygen atom connected to R ₁₂ constitutes a 5-6 membered heterocyclic group; the substitution refers to being substituted by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

R ₁₃ and R ₁₄ are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C14 aryl C1-C5 alkylene, substituted or unsubstituted C3-C10 heteroaryl C1-C5 Alkylene, substituted or unsubstituted C6-C10 aryl C2-C5 alkenylene, substituted or unsubstituted C3-C10 heteroaryl C2-C5 alkenylene, acyl, sulfonyl; the substitutions are each independently Refers to substitution with 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy , C1-C4 alkylcarbonyl, C1-C4 alkylthio, C1-C6 alkoxycarbonyl, trifluoromethyl;

R ₂ ' is selected from the following group: hydrogen, substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted or unsubstituted C2～C6 alkynyl, substituted or unsubstituted C3～ C6 cycloalkyl; the substitution means substitution by 1 to 2 groups selected from the following group: halogen, C1-C4 alkyl;

R ₂ is selected from the following group: substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted Or unsubstituted C2~C6 alkynyl, substituted or unsubstituted C1~C6 alkoxy, substituted or unsubstituted C3~C6 cycloalkyl, substituted or unsubstituted 3~7 membered heterocyclyl, substituted or unsubstituted Substituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to substitution with a group selected from the following group: halogen, C1-C6 alkyl, C6-C10 aryl ;

Or when R ₂ and R ₂ ' are connected to form a ring, the α carbon atom and β carbon atom connected to R ₂ and the α nitrogen atom connected to R ₂ ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;

R ₄ is selected from the following group: substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted or unsubstituted C2～C6 alkynyl, substituted or unsubstituted C1～C6 alkoxy base, substituted or unsubstituted C3~C7 cycloalkyl, substituted or unsubstituted C6~C10 aryl, substituted or unsubstituted 5~10 membered heteroaryl; the substitution refers to being substituted by 1-3 respective Substitution with groups independently selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or two adjacent substituents together with the Carbon atoms form a 5- to 7-membered ring;

Or when R ₄ and R ₄ ' are connected to form a ring, the α carbon atom, β carbon atom connected to R ₄ , and the α nitrogen atom connected to R ₄ ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 halogens;

R ₃ is selected from the following group: substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted or unsubstituted C2～C6 alkynyl, substituted or unsubstituted C3～C10 cycloalkyl , substituted or unsubstituted 3 to 7-membered heterocyclyl, substituted or unsubstituted C6 to C10 aryl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution means 1 to 3 members selected from the following group Group substitution: halogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, C6~C8 aryl, halogenated C6~C8 aryl, or two phases The adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;

In another preferred embodiment, the ring formed by R ₂ and R ₂ ' and the connected and adjacent atoms has a structure selected from the following group:

In another preferred embodiment, the ring formed by R ₄ and R ₄ ' and the connected and adjacent atoms has a structure selected from the following group:

When R ₂ and R ₂ ' are not connected to form a ring, and R ₂ ' is not hydrogen, R ₁ is

Wherein, R ₅ is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to being substituted by 1 to 3 substituents selected from the following group Substitution: C1-C4 alkyl, C6-10 aryl;

R ₁₀ is selected from the following group: substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, or substituted or unsubstituted C3~C6 epoxy group; the substitution refers to substituted by 1~ 3 groups selected from the following group are substituted: halogen, C1-C4 alkyl;

R ₁₁ and R ₁₂ are each independently selected from the following group: hydrogen, C1-C6 alkyl, or the oxygen atoms to which R ₁₁ and R ₁₂ are connected constitute a 5-6-membered heterocyclic group;

R ₁₃ and R ₁₄ are each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1 -C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aryl C1-C5 alkylene, substituted or unsubstituted C6-C10 Aryl C2-C5 alkenylene; the substitutions each independently refer to substitution with 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylthio, C1-C6 alkoxycarbonyl, trifluoromethyl;

R ₂ ' is selected from hydrogen and C1～C6 alkyl;

R ₂ is selected from the group consisting of substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C1～C6 alkoxy, substituted or unsubstituted C3～C6 cycloalkyl, or substituted or unsubstituted C6～ C8 aryl; the substitution refers to substitution with a group selected from the following group: halogen, C1-C4 alkyl, C6~C8 aryl;

Or when R ₂ and R ₂ ' are connected to form a ring, the α carbon atom and β carbon atom connected to R ₂ and the α nitrogen atom connected to R ₂ ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 halogens;

R ₄ is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to 1-3 groups independently selected from the following group Group substitution: halogen, C1~C6 alkyl;

R ₄ ' is hydrogen;

R ₃ is selected from the following group: substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: Halogen, C1~C4 alkyl, C1~C6 alkoxy, halogenated C6~C8 aryl, or two adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;

In another preferred example, R ₅ is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to being substituted by 1 to 3 selected from The following group of substituents are substituted: C1-C4 alkyl, C6-10 aryl;

In another preferred example, when R ₂ ' is H, R ₁ is selected from the following group:

When R ₂ and R ₂ ' do not form a ring, and R ₂ ' is not H, R ₁ is selected from the following group:

When R ₂ and R ₂ ' form a ring, R ₁ is selected from the following group:

In another preferred embodiment, when R ₂ and R ₂ ' do not form a ring and R ₂ ' is not hydrogen, R ₂ ' is methyl.

In another preferred embodiment, R ₃ is a substituted or unsubstituted benzoheteroaromatic ring; the substitution refers to being substituted by 1-3 groups selected from the following group: halogen, C1-C4 alkyl or C1 -C4 alkoxy.

In another preferred embodiment, R ₃ is selected from the following group: substituted or unsubstituted indole aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted quinoline aromatic heterocycle, substituted or unsubstituted Furan aromatic heterocycle, substituted or unsubstituted thiazole, substituted or unsubstituted quinoxaline, substituted or unsubstituted quinoline aromatic heterocycle, the substitution means that 1, 2 or 3 are selected from the following group Group substitution: halogen, C1~C4 alkyl, C1~C6 alkoxy, halogenated C6~C8 aryl.

In another preferred embodiment, R ₃ is selected from the following group: benzodioxole, indole, isoxazole, 2-hydropyran, pyridine, pyrazole, dihydroimidazopyridine, imidazo Pyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, benzofuran, indazole, benzimidazole or quinoline.

In another preferred embodiment, R ₃ has a structure selected from the following group:

In another preferred embodiment, the compound is selected from the following group:

Table 1

In another preferred example, the compound is compound 5-11, 15-16, 56-62, 65, 67-171 in Table 1.

A second aspect of the present invention provides a method for preparing the peptidomimetic compound described in the first aspect of the present invention, including the steps:

Step (1): react compound Ia and compound Ib in an inert solvent in the presence of a condensing agent to obtain compound Ic;

Step (2): react compound Ic in a mixed solution of an inert solution and an acidic solution to obtain compound Id;

Step (3): react compound Ie and compound Id in an inert solvent in the presence of a condensing agent to obtain compound If;

Step (4): react compound If in a mixed solution of an inert solution and an acidic solution to obtain compound Ig;

Step (5): react compound Ih and compound Ig in an inert solvent in the presence of a condensing agent to obtain compound Ii;

Step (6): In an inert solvent, compound Ii undergoes a reduction reaction with a reducing agent to obtain compound Ij;

Step (7): In an inert solvent, compound Ij undergoes an oxidation reaction with an oxidizing agent to obtain compound Ik;

Step (8): In an inert solvent, compound Ik and compound IL are reacted in the presence of triphenylphosphine to obtain compound Im;

Step (9): In an inert solvent, compound Ik and compound In are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Io;

Step (10): In an inert solvent, compound Ik and compound Ip are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Iq;

Step (11): In an inert solvent, compound Ik and compound Ir are reacted in the presence of a base to obtain compound Is;

Step (12): In a polar solvent, compound Ik reacts with sulfite to obtain compound It; in an inert solvent, compound It reacts with acid anhydride to obtain compound Iu;

Step (13): In a polar solvent, compound Ii is reacted with ammonia water to obtain compound Iv; in an anhydrous inert solvent, compound Iv is reacted with an acid anhydride to obtain compound Iw;

Step (14): In a polar solvent, compound Ii is hydrolyzed under alkaline conditions to obtain compound Ix; in an inert solvent, compound Ix is condensed with N-methyl-N-methoxyamine hydrochloride. React to obtain compound Iy; in an inert solvent, compound Iy reacts with Grignard reagent to obtain compound Iz;

Step (15): In an inert solvent, compound Ix reacts with compound Iα in the presence of a base to obtain compound Iβ; in an inert solvent, compound Iβ reacts in the presence of an oxidizing agent to obtain compound Iγ; in an inert solvent, compound Iγ React with compound I _δ in the presence of a base to obtain compound I _ε ;

Step (16): In an inert solvent, in the presence of a catalytic amount of acid, compound Ik reacts with an alcoholic solvent to obtain compound _Iζ ; compound Ik is stirred in the corresponding alcoholic solvent to obtain compound _In ;

Among them, R ₁ , R ₂ , R ₂ ', R 3 , R ₄ , R ₄ ', R ₅ , R ₆ , R 7 , R ₈ , R ₉ , R ₁₀ , R ₁₁ , _{R 12} _, _{R 13} _, R _14. The definitions of m, n, X and Y are the same as those in the first aspect of the present invention.

In another preferred embodiment, the inert solvent is selected from the following group: C1-C6 alkane solvents, C2-C6 nitrile solvents, C2-C6 ether solvents, or combinations thereof.

In another preferred embodiment, the inert solvent is selected from the following group: dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or a combination thereof.

In another preferred example, the condensation agent is HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate).

In another preferred embodiment, the acidic solution is selected from the following group: 4M hydrochloric acid.1,4-dioxane solution.

In another preferred embodiment, the polar solvent is selected from the following group: water, C1-C6 alcohol solvents, C2-C6 ester solvents, or combinations thereof.

In another preferred embodiment, the polar solvent is selected from the following group: water, ethanol, ethyl acetate, or a combination thereof.

In another preferred embodiment, the reducing agent is borohydride.

In another preferred embodiment, the oxidizing agent is selected from the following group: Dess-Martin oxidizing agent, sulfur trioxide, pyridine oxidizing agent, or a combination thereof.

In another preferred embodiment, the base is selected from the following group: piperidine, NaH, lithium hexamethyldisilazide, or a combination thereof.

In another preferred embodiment, the alcohol solvent is a C1-C6 alcohol solvent selected from the following group: methanol, ethanol, propanol, isopropyl alcohol, n-butanol, ethylene glycol, propylene glycol, or a combination thereof .

In another preferred embodiment, the catalytic amount of acid is p-toluenesulfonic acid.

In another preferred embodiment, the acid anhydride is trifluoroacetic anhydride.

The third aspect of the present invention provides a pharmaceutical composition, including (a) a therapeutically effective amount of a peptidomimetic compound represented by general formula (I), or its racemate, cis-trans isomer, para enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof, and (b) a pharmaceutically acceptable carrier or excipient, Among them, the peptidomimetic compound represented by general formula (I) is as described in the first aspect of the present invention.

The fourth aspect of the present invention provides a use of the pharmaceutical composition according to the third aspect of the present invention for preparing (a) SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/ or 3CL protease inhibitors of FIPV and/or norovirus; (b) 3C protease inhibitors of RNA viruses EV71 and/or EV68; and (c) treatment and/or prevention, mitigation of SARS-CoV-2 and/or Drugs for diseases caused by SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA viruses EV71 and/or EV68 and/or norovirus.

In another preferred embodiment, the virus is infected by SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA virus EV71 and/or EV68 and/or norovirus. The associated disease caused is selected from the group consisting of: respiratory tract infection, pneumonia and its complications, or a combination thereof.

The fifth aspect of the present invention provides a method for treating and/or preventing and alleviating SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA virus EV71 and/or EV68 and/or a method for related diseases caused by norovirus infection, comprising the steps of: administering a safe and effective amount of a peptidomimetic compound represented by general formula I, or its racemate, cis-trans isomer, to a subject in need , enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof, wherein the peptoid represented by the general formula I Compounds are as described above.

A sixth aspect of the present invention provides a method for inhibiting the activity of 3CL protease of SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV and/or norovirus, including the steps: The peptoid compounds of general formula I, or their racemates, cis-trans isomers, enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, and solvates , prodrugs or combinations thereof contact SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or 3CL protease of norovirus, thereby inhibiting SARS-CoV-2 and/or The activity of 3CL protease of SARS-CoV and/or MERS-CoV and/or FIPV, and/or norovirus, wherein the peptidomimetic compound of general formula I is as described above.

The seventh aspect of the present invention provides a method for inhibiting the activity of 3C protease of RNA virus EV71 and/or EV68, including the steps of: adding the peptidomimetic compound represented by general formula I, or its racemate, cis Anti-isomers, enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvation The substance, prodrug, or combination thereof contacts the 3C protease of RNA virus EV71 and/or EV68, thereby inhibiting the activity of the 3C protease of RNA virus EV71 and/or EV68, wherein the peptidomimetic compound of general formula I is as described above narrate.

The eighth aspect of the present invention provides a peptidomimetic compound according to the first aspect of the present invention, or its racemate, cis-trans isomer, enantiomer, diastereomer, A drug's active metabolite, pharmaceutically acceptable salt, solvate, prodrug, or combinations thereof,

in,

R ₁ , R ₂ , R ₂ ', R ₃ , R ₄ , R ₄ ', m, n are as defined in the first aspect of the invention.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.

Detailed ways

After long-term and in-depth research and extensive screening, the inventor unexpectedly discovered and synthesized a series of novel structures that can effectively inhibit SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, etc. The active ingredients of coronavirus, and/or EV71 and/or EV68 and/or norovirus and other RNA virus infections, that is, the compound represented by general formula (I) or its pharmaceutically acceptable salts, enantiomers, Diastereomers or racemates, or combinations thereof. Tests have shown that the active ingredient of the present invention can effectively inhibit the activity of 3CL or 3C protease of coronaviruses such as SARS-CoV-2 and other small RNA viruses, thereby inhibiting coronaviruses such as SARS-CoV-2 and other small RNA viruses. replication and activity. On this basis, the present invention was completed.

the term

As used herein, unless otherwise stated, the term "substituted" means that one or more hydrogen atoms on a group are replaced by Substituted with substituents selected from the following group: C1 to C10 alkyl, C3 to C10 cycloalkyl, C1 to C10 alkoxy, halogen, hydroxyl, carboxyl (-COOH), C1 to C10 aldehyde, C2 to C10 acyl, C2～C10 ester group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group with 1-3 substituents, the substituent group is selected from: halogen, C1～C10 alkyl group, Cyano group, hydroxyl group, nitro group, C3～C10 cycloalkyl group, C1～C10 alkoxy group, amino group.

Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.

The term "C1-C10 alkyl" refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms, preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms; for example, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

The term "C2-C10 alkenyl" refers to a straight-chain or branched alkyl group having 2 to 10 carbon atoms, preferably a straight-chain or branched alkyl group having 2 to 6 carbon atoms; for example, ethylene, propylene, Butene, or similar groups.

The term "C2-C10 alkynyl" refers to a straight-chain or branched alkyl group having 2 to 10 carbon atoms, preferably a straight-chain or branched alkyl group having 2 to 6 carbon atoms; for example, acetylene, propyne , butyne, or similar groups.

The term "heterocyclyl" refers to a saturated or partially saturated cyclic group with heteroatoms selected from N, S and O, which can be a single ring or a bicyclic ring, for example, a bridged ring or a bridged ring. Spiral form. The heterocyclyl group is preferably a 4- to 10-membered heterocyclyl group, more preferably a 5- to 7-membered heterocyclyl group, and even more preferably a 5 to 6-membered heterocyclyl group. Examples of heterocyclyl include, but are not limited to: azetidine, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, and the like. The heterocyclyl group can be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring (such as forming [5+3], [5+5], [5+6], [6+5 ] or [6+6] fused ring system, etc.), in which the ring connected to the parent structure is a heterocyclic group. Five-membered heterocycle is intended to include a five-membered heterocycle and a 3-7-membered ring, a spiro ring formed by a five-membered heterocycle and a 3-7-membered ring, and a bridged ring formed by a five-membered heterocycle and a 4-7-membered ring. Six-membered heterocyclic ring is intended to include a six-membered heterocyclic ring and a 3-7-membered ring, a spiro ring formed by a six-membered heterocyclic ring and a 3-7-membered ring, and a bridged ring formed by a six-membered heterocyclic ring and a 4-7-membered ring.

In the present invention, the term "aryl" refers to an aromatic ring group that does not contain heteroatoms on the ring. The aryl group can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, which is related to the parent structure. The rings joined together are aryl rings. Such as phenyl (ie C6 aryl or six-membered aryl), naphthyl (ie C10 aryl or [6+6] aryl), etc., where the six-membered aryl is also intended to include six-membered aryl and 5-6 One-membered cycloalkyl and six-membered aryl and 5-6-membered heterocyclyl. The term "[5+6]aryl" refers to a fused 6,5 bicyclic ring system. The aryl group is preferably a C6-C14 aryl group, more preferably a C6-C10 aryl group. Examples of aryl groups include phenyl, naphthyl. Aryl groups may be optionally substituted or Not superseded.

The term "heteroaryl" refers to a cyclic aromatic group having 1 to 3 heteroatoms selected from the group consisting of N, S and O, which may be a single ring or a condensed ring. In the present invention, the heteroaryl group is preferably a 5- to 6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring. The term "[5+6]heteroaryl" refers to a fused 6,5 bicyclic ring system, such as benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzene Thiadiazolyl, benzoxazolyl, etc.

The term "5- to 12-membered heteroaryl" refers to a group formed by losing one hydrogen atom from a 5- to 12-membered aryl group having 1 to 3 heteroatoms selected from the following group: N, S, O, where each heteroaryl The cyclic system of the base can be monocyclic or polycyclic: for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolyl or similar groups.

The term "C1-C10 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 10 carbon atoms; preferably, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms; for example, methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or similar groups.

The term "C2-C6 alkenyl" refers to a group formed by losing one or two hydrogen atoms from an alkene with 2 to 6 carbon atoms. The alkene can be a monoolefin, a diene or a triene, such as -CH= CH ₂ , -C ₂ H ₄ =CH ₂ , -CH =C ₂ H ₄ , or similar groups.

The term "halogen" refers to F, Cl, Br and I.

Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, double bond (Z), (E) isomers and (Z), (E) conformational isomers. Therefore, the single stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the present invention.

The term "tautomers" means that structural isomers with different energies can cross a low energy barrier and thus convert into each other. For example, proton tautomers (i.e. proton transfer) include interconversion through proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole , valency tautomers include interconversion through some bonding electron recombination.

As used herein, "C1-C6" is formed to mean that the group may have from 1 to 6 carbon atoms, such as 1, 2, 3, 4 or 5.

active ingredient

In the present invention, an active ingredient that can effectively inhibit the replication of SARS-CoV-2 is provided. The active ingredient is a compound represented by general formula I, which can effectively prevent, treat and/or alleviate COVID-19 related diseases.

It should be understood that the active ingredients of the present invention include peptidomimetic compounds represented by general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, or Its prodrug. It should be understood that the active ingredient of the present invention also includes the crystalline form, amorphous compound, deuterated compound and other forms of the compound of general formula (I).

The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of a compound of general formula (I) with an inorganic acid or organic acid. For example, conventional non-toxic salts can be prepared by reacting compounds of general formula (I) with inorganic acids or organic acids. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid and phosphoric acid, etc. Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, propylene glycol Acid, fumaric acid, succinic acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, parapic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p- Aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, etc.; or compounds of general formula (I) with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid form esters and then form sodium salts, potassium salts, calcium salts, aluminum salts or ammonium salts with inorganic bases; or compounds of general formula (I) and organic bases The formed methylamine salt, ethylamine salt or ethanolamine salt; or the compound of general formula (I) forms ester with lysine, arginine, ornithine and then with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid Or the corresponding inorganic acid salt formed with phosphoric acid or the corresponding organic acid salt formed with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.

Pharmaceutical compositions and applications

The present invention also provides peptidomimetic compounds represented by general formula (I), or their pharmaceutically acceptable salts, enantiomers, diastereomers or racemates and prodrugs. One or more mixtures of active ingredients are prepared to treat and/or prevent and alleviate coronaviruses caused by SARS-CoV-2 and/or SARSCoV and/or MERS-CoV and/or FIPV, and/or EV71 and/or RNA such as EV68 and/or norovirus Used in medicines for respiratory tract infections, pneumonia and other related diseases caused by viral infections.

The pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 0.001 to 99wt%. The preferred ratio is that the compound of general formula (I) as the active ingredient accounts for 0.1wt% to 90wt% of the total weight, and the rest is pharmaceutically acceptable. Acceptable carrier, dilution or solution or saline solution.

When necessary, one or more pharmaceutically acceptable carriers can also be added to the medicine of the present invention. The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents. Neutralize suitable for use in sterile equipment for injection or infusion.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the dosage form formula usually contains 0.05 to 400 mg of the compound of general formula (I). Preferably, the unit dosage of the preparation formula contains 1 mg to 500 mg of the compound of general formula (I).

The compounds and pharmaceutical compositions of the present invention can be used clinically on mammals, including humans and animals, and can be administered through the oral, nasal, skin, lung or gastrointestinal tract. Oral administration is most preferred. The most preferred daily dose is 0.01 to 400 mg/kg body weight, taken at one time, or 0.01 to 200 mg/kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for the individual will depend on the specific treatment. Usually, you start with a small dose and gradually increase the dose until you find the most suitable dose.

The drugs or inhibitors of the present invention can be administered in various ways, for example, through injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method, such as muscle, intradermal, subcutaneous, intravenous introduction into the body. , mucosal tissue; or mixed or wrapped with other substances and introduced into the body.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) retarding solvents, such as paraffin; (f) absorption Accelerators, such as quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate; (6) Adsorbents, such as high Ridge clay; (i) Lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like. Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as other antiviral drugs).

The treatment method of the present invention can be administered alone or in combination with other treatment methods or therapeutic drugs.

Preparation

The compound of formula I of the present invention can be prepared by the following method. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, reaction time required, etc. are not limited to the following solutions: release. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Step (1): In an inert solvent, compound Ia and compound Ib are reacted in the presence of a condensing agent to obtain compound Ic; wherein the condensing agent is preferably HATU (2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate);

Step (2): react compound Ic in a mixed solution of an inert solution and a hydrochloric acid solution to obtain compound Id; wherein the hydrochloric acid solution is preferably 4M hydrochloric acid.1,4-dioxane solution;

Step (3): In an inert solvent, compound Ie and compound Id are reacted in the presence of a condensing agent to obtain compound If; wherein the condensing agent is preferably HATU (2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate);

Step (4): react compound If in a mixed solution of an inert solution and a hydrochloric acid solution to obtain compound Ig; wherein the hydrochloric acid solution is preferably 4M hydrochloric acid.1,4-dioxane solution;

Step (5): In an inert solvent, compound Ih and compound Ig are reacted in the presence of a condensing agent to obtain compound Ii; wherein the condensing agent is preferably HATU (2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate);

Step (6): In an inert solvent, compound Ii is subjected to a reduction reaction under certain conditions to obtain compound Ij; wherein the reducing agent is preferably borohydride;

Step (7): In an inert solvent, compound Ij is subjected to an oxidation reaction under certain conditions to obtain compound Ik; wherein the oxidizing agent is preferably Dess-Martin oxidizing agent or sulfur trioxide-pyridine oxidizing agent;

Step (9): In an inert solvent, compound Ik and compound In are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Io; the base is preferably piperidine;

Step (10): In an inert solvent, compound Ik and compound Ip are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Iq; the base is preferably NaH;

Step (11): In an inert solvent, compound Ik and compound Ir react in the presence of a base to obtain compound Is; the base is preferably lithium hexamethyldisilazide;

Step (12): In a polar solvent, compound Ik reacts with sulfite to obtain compound It; in an inert solvent, the compound reacts with an acid anhydride to obtain compound Iu;

Step (13): In a polar solvent, compound Ii is reacted with ammonia water to obtain compound Iv; in an anhydrous inert solvent, compound Iv is reacted with an acid anhydride to obtain compound Iw; the acid anhydride is preferably trifluoroacetic anhydride;

Step (16): In an inert solvent, in the presence of a catalytic amount of acid, compound Ik is reacted with an alcoholic solvent to obtain compound _Iζ; compound Ik is reacted with a solvent in an alcoholic solvent to obtain compound _In;

Description of drawings

Figure 1: Data on the inhibition of EV71 3C protease activity of compound 72 tested in RD cells.

Figure 2: CC50 data of compound 72 tested in RD cells.

Figure 3: The corresponding blood drug concentration change curves over time after oral administration (10 mg/kg) and intravenous administration (5 mg/kg) of compound 68 in mice.

Figure 4: RI-PCR method detects the inhibitory effect of compound 10, compound 21, and compound 172 on FIPV in CRFK cells.

Figure 5: IFA method to detect the ability of compound 172 to inhibit FIPV replication in CRFK cells.

Figure 6: IFA method to detect the ability of compound 21 to inhibit FIPV replication in CRFK cells.

Figure 7: IFA method to detect the ability of compound 10 to inhibit FIPV replication in CRFK cells.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are for illustration only This invention is not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

Instrument: Nuclear magnetic resonance was measured by GEMINI-300, Brucker AMX-400 and INVOA-600 nuclear magnetic resonance instruments. TMS (tetramethylsilyl) was used as the internal standard, the chemical shift unit was ppm, and the coupling constant unit was Hz; mass spectrometry Measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.

The silica gel used for column chromatography is 200-300 mesh (produced by Qingdao Ocean Chemical); the TLC silica gel plate is a HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Factory; the boiling range of petroleum ether is 60-90°C; a UV lamp is used. Color development in iodine cylinder. Unless otherwise stated, the conventional reagents and drugs used in the following examples were purchased from Sinopharm Group. The reagents and solvents used in the experiment were handled according to the specific conditions of the reaction.

Example 1: Compound 1

synthetic route:

Synthesis of compound 1-2:

Under argon protection, N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester 1-1 (6g, 21.8mmol) was dissolved in 60mL anhydrous tetrahydrofuran, and LiHMDS (1M in THF) in tetrahydrofuran (47 mL, 47 mmol). Keep the temperature stable at -78°C during the dropwise addition, which lasts for 1 hour. After completion of dropping, stir at -78°C for 1 hour. Bromoacetonitrile (2.79g, 23.3mmol) was dissolved in 20 mL of tetrahydrofuran, and then the solution was slowly added dropwise to the reaction system, and the dropping process continued for 1 to 2 hours. Control the temperature to -78°C and continue the reaction for 20 hours. TLC monitoring (iodine cylinder color development) After the reaction is completed, add 3 mL of methanol and 22.7 mL of a mixed solution of glacial acetic acid and tetrahydrofuran (v/v=1/7.5) to the reaction solution to quench the reaction, stir for 10 min and then warm to room temperature. Pour in 40 mL of saturated sodium chloride solution and stir thoroughly. It can be seen that the reaction system is separated into layers. Separate the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases and dry over anhydrous sodium sulfate. Concentrate and separate by column chromatography (PE:EA=4:1) to obtain 3.9g of light yellow oil 1-2, with a yield of 58%.

Synthesis of compounds 1-3:

Compound 1-2 (3g, 9.45mmol) was dissolved in 70mL of anhydrous methanol, stirred to 0°C in an ice bath, and then cobalt dichloride hexahydrate (1.35g, 5.67mmol) was added, and the solution turned purple-red. After 10 minutes, sodium borohydride (2.15g, 56.7mmol) was added in small amounts in batches. It was observed that the color of the solution changed to purple-black. The reaction solution continued to react in an ice bath for 1 hour and then turned to room temperature. After 15h, quench with 5 mL of saturated NH ₄ Cl solution and continue stirring for 10 min. Use diatomaceous earth to filter out the solid, evaporate the filtrate to dryness under reduced pressure, extract with 60 mL of water and 90X3 mL of ethyl acetate, combine the organic phases, and dissolve with anhydrous Na ₂ SO ₄ was dried for 1 hour, concentrated under reduced pressure, and separated by column chromatography (PE:EA=1:2) to obtain 1.38g of white solid 1-3, with a yield of 51%.

Synthesis of compounds 1-4:

Intermediate 1-3 (1g, 3.5mmol) was dissolved in dichloromethane (40mL), 4M HCl dioxane solution (9mL, 35mmol) was added at 0°C, the reaction was continued to stir at room temperature for 12h, and then The solution is evaporated to dryness to obtain intermediate 1-4, which can be directly used for the next reaction without purification.

Synthesis of compounds 1-6:

Dissolve compound 1-5 (1.1g, 3.5mmol) in dichloromethane (40mL), cool the reaction solution to -20°C, then add HATU (1.9g, 4.9mmol) to the reaction solution, and stir for 20 minutes. Intermediate 1-4 obtained in the previous step was added to the reaction solution, stirred again at -20°C for 30 minutes, and then DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution.

After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (40X3mL), saturated sodium bicarbonate solution (40X3mL), and saturated sodium chloride solution (40X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distilled and separated by column chromatography (DCM:MeOH=40:1v/v), 1.3g of white solid 1-6 was obtained with a yield of 83%.

Synthesis of compounds 1-7:

Compound 1-6 (1.5g, 3.5mmol) was dissolved in dichloromethane (40mL), and 4M HCl dioxane solution (9mL, 35mmol) was added at 0°C. The reaction was continued to stir at room temperature for 12h, and then The solution was evaporated to dryness to obtain intermediate 1-7, which was directly carried out to the next reaction without purification.

Synthesis of compounds 1-9:

Compound 1-8 (0.76g, 3.5mmol) was dissolved in dichloromethane (40mL), the reaction solution was cooled to -20°C, then HATU (1.9g, 4.9mmol) was added to the reaction solution, and stirred for 20 minutes. Previous The intermediate 1-7 obtained in step 1-7 was added to the reaction solution, and stirred again at -20°C for 30 minutes. Then DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution.

After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (40X3mL), saturated sodium bicarbonate solution (40X3mL), and saturated sodium chloride solution (40X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distilled and separated by column chromatography (DCM:MeOH=30:1v/v), 1.6g of white solid 1-9 was obtained with a yield of 85%.

Synthesis of compounds 1-10:

Compound 1-9 (1.5g, 3.11mmol) was dissolved in 40mL tetrahydrofuran, sodium borohydride (705mg, 18.55mmol) was slowly added in batches, then 1mL of methanol was added dropwise, and stirred at room temperature for about 4 hours.

After the reaction is completed, add about 40 mL of saturated sodium chloride solution to quench the reaction, and add ethyl acetate for extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=20:1v/v) to obtain 0.98g of white solid 1-10, with a yield of 70%.

Synthesis of compounds 1-11:

Compound 1-10 (0.9g, 1.98mmol) was dissolved in 20 mL of methylene chloride, Dess-Martin oxidant (1.26g, 2.97mmol) was added, and the mixture was stirred at room temperature. After TLC detects that the reaction is complete, the reaction solution is extracted with saturated sodium thiosulfate solution until clear, and the organic phase is dried with anhydrous sodium sulfate and concentrated. After column chromatography separation (DCM:MeOH=20:1, v/v), 0.54g of white solid 1-11 was obtained, with a yield of 60%.

Synthesis of compound 1:

Compound 1-11 (0.1g, 0.22mmol) was dissolved in 10 mL of anhydrous dichloromethane, triphenylphosphine (64mg, 0.24mmol) and compound 1-12 (27mg, 0.24mmol) were added, and the mixture was stirred at room temperature overnight. After TLC detected that the reaction was complete, the reaction solution was concentrated and separated by column chromatography (DCM:MeOH=20:1, v/v) to obtain compound 1 (96 mg) as a white solid with a yield of 80%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.77–11.44(m,1H),8.51–8.33(m,2H),7.72–7.53(m,2H),7.42(dd,J＝8.1,3.2Hz ,1H),7.27(d,J＝2.5Hz,1H),7.21–7.13(m,1H),7.04(td,J＝7.6,2.4Hz,1H),6.51–6.39(m,1H),4.63– 4.45(m,2H),3.47(ddd,J＝21.8,13.8,2.7Hz,2H),3.12(ddt,J＝21.9,15.2,8.5Hz,2H),2.88(d,J＝7.2Hz,3H) ,2.40–1.95(m,4H),1.84–1.43(m,10H),1.14(dd,J＝20.2,10.2Hz,2H),0.89(dt,J＝21.5,9.4Hz,2H).ESI-MS m/z 548.2[M+H] ⁺

Example 2: Compound 2

Compound 2-1 was used to replace maleimide 1-12 in Example 1, and the synthesis method was based on the synthesis of compound 1 to obtain compound 2.

¹ H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.53(d,J＝10.6Hz,1H),7.71–7.63(m,1H),7.46–7.39(m,1H),7.26 –7.18(m,3H),7.16(t,J＝4.6Hz,1H),7.09(d,J＝11.3Hz,1H),6.54(dt,J＝6.2,1.0Hz,1H),4.48–4.34( m,2H),4.08(dq,J＝12.5,8.0Hz,1H),3.96(dq,J＝12.3,7.9Hz,1H),3.26–3.14(m,3H),3.15(t,J＝0.9Hz ,1H),2.54(p,J＝7.1Hz,1H),2.04(dt,J＝12.6,7.0Hz,1H),1.94(dt,J＝12.5,6.9Hz,1H),1.86–1.64(m, 4H),1.61–1.38(m,11H),1.22(t,J＝8.0Hz,3H).ESI-MS m/z 562.3[M+H] ⁺

Example 3: Compound 3

Compound 3-1 was used to replace maleimide 1-12 in Example 1, and the synthesis method was based on the synthesis of compound 1 to obtain compound 3.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 7.69–7.63 (m, 1H), 7.46–7.39 (m, 1H), 7.25 –7.16(m,3H),7.16(t,J＝4.6Hz,1H),7.09(d,J＝11.3Hz,1H),6.54(dt,J＝6.2,1.0Hz,1H),4.61(hept, J＝6.9Hz,1H),4.49–4.34(m,2H),3.26–3.12(m,4H),2.54(p,J＝7.1Hz,1H),2.04(dt,J＝12.6,7.0Hz,1H ),1.94(dt,J＝12.5,6.9Hz,1H),1.86–1.64(m,4H),1.61–1.53(m,1H),1.56–1.48(m,4H),1.49(dd,J＝2.3 ,1.1Hz,1H),1.50–1.43(m,3H),1.43(t,J＝6.6Hz,5H),1.38(d,J＝6.8Hz,3H).ESI-MS m/z 576.3[M+ H] ⁺

Example 4: Compound 4

Compound 4-1 was used to replace maleimide 1-12 in Example 1, and the synthesis method was based on the synthesis of compound 1 to obtain compound 4.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 7.67 (dt, J = 6.9, 1.7Hz, 1H), 7.46–7.39 (m ,1H),7.25–7.16(m,4H),7.09(d,J＝11.4Hz,1H),6.55(dt,J＝6.0,0.9Hz,1H),4.49–4.34(m,2H),3.27– 3.18(m,1H),3.21–3.12(m,3H),2.54(p,J＝7.1Hz,1H),2.04(dt,J＝12.8,7.0Hz,1H),1.94(dt,J＝12.3, 7.0Hz,1H),1.86–1.64(m,4H),1.61–1.38(m,11H),1.47(s,9H).ESI-MS m/z 590.3[M+H] ⁺

Example 5: Compound 5

Dissolve compound 1-11 (100 mg, 0.22 mmol) in 3 mL anhydrous dichloromethane, add compound 5-1 (24 mg, 0.24 mmol) and piperidine (2.2 μL, 22 μmol) dropwise with stirring at room temperature, and react at room temperature for 4 hours. , concentrated under reduced pressure. After column chromatography separation (DCM:MeOH=20:1), white solid compound 5 (70 mg) was obtained with a yield of 60%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62–11.55(m,1H),8.65–8.43(m,2H),7.74–7.40(m,4H),7.27(q,J＝6.1,4.3Hz ,1H),7.19(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),4.83–4.44(m,2H),3.80(d,J＝5.7Hz,2H),3.24 –2.98(m,3H),2.42–2.08(m,3H),1.83–1.52(m,10H),1.43(td,J＝10.5,5.5Hz,1H),1.19–1.11(m,2H),1.01 –0.84(m,2H).ESI-MS m/z 534.2[M+H] ⁺

Example 6: Compound 6

Compound 6-1 was used to replace compound 5-1 in Example 5, and the synthesis method was based on the synthesis of compound 5 to obtain compound 6.

¹ H NMR (600MHz, DMSO-d ₆ ) δ11.58 (dd, J = 9.3, 2.2 Hz, 1H), 8.59 (t, J = 8.0 Hz, 1H), 8.47 (dd, J = 22.9, 8.0 Hz, 1H),7.67(s,1H),7.62(dd,J＝7.9,2.6Hz,1H),7.51(d,J＝8.9Hz,1H),7.43(dt,J＝8.0,2.3Hz,1H), 7.27(dd,J＝5.7,2.2Hz,1H),7.18(ddd,J＝8.2,6.8,1.2Hz,1H),7.04(t,J＝7.5Hz,1H),4.77(tdd,J＝10.5, 8.2,4.2Hz,1H),4.61–4.45(m,1H),4.25(dqd,J＝10.0,7.1,2.4Hz,2H),3.22–3.00(m,2H),2.44–2.33(m,1H) ,2.30–2.01(m,2H),1.82–1.52(m,10H),1.42(ddd,J＝14.2,10.5,4.4Hz,1H),1.26(td,J＝7.1,4.9Hz,3H),1.14 –1.08(m,2H),1.01–0.80(m,2H).ESI-MS m/z 548.2[M+H] ⁺

Example 7: Compound 7

Compound 7-1 was used to replace compound 5-1 in Example 5, and the synthesis method was as described in the synthesis of compound 5, to obtain compound 7.

¹ H NMR (500MHz, DMSO-d ₆ ) δ11.64–11.54(m,1H),8.61(dd,J＝11.3,7.5Hz,1H),8.48(dd,J＝13.6,7.9Hz,1H), 7.72–7.59(m,2H),7.53–7.44(m,2H),7.28(d,J＝2.5Hz,1H),7.22–7.16(m,1H),7.05(t,J＝7.5Hz,1H) ,4.90–4.71(m,1H),4.62–4.45(m,1H),4.17(dtd,J＝9.3,6.6,2.4Hz,2H),3.14(ddd,J＝22.0,9.6,7.2Hz,2H) ,2.44–1.99(m,3H),1.79–1.57(m,12H),1.19–1.08(m, 2H),0.99–0.82(m,5H).ESI-MS m/z 562.3[M+H] ⁺

Example 8: Compound 8

Compound 8-1 was used to replace compound 5-1 in Example 5, and the synthesis method was based on the synthesis of compound 5 to obtain compound 8.

¹ H NMR (600MHz, DMSO-d ₆ ) δ11.61–11.53(m,1H),8.67–8.16(m,2H),7.75–7.58(m,2H),7.52–7.39(m,2H),7.31 –7.23(m,1H),7.18(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),5.13–4.71(m,2H),4.61–4.36(m,1H), 3.21–2.99(m,2H),2.45–1.92(m,3H),1.83–1.55(m,10H),1.44–1.33(m,1H),1.24(dt,J＝21.9,6.1Hz,6H), 1.14–1.06(m,2H),1.02–0.83(m,2H).ESI-MS m/z 562.3[M+H] ⁺

Example 9: Compound 9

Compound 9-1 was used to replace compound 5-1 in Example 5, and the synthesis method was as described in the synthesis of compound 5, to obtain compound 9.

¹ H NMR (500MHz, Chloroform-d) δ9.52 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.67 (ddd, J = 7.0 ,2.5,1.5Hz,1H),7.46–7.40(m,1H),7.33(d,J＝6.0Hz,1H),7.25–7.16(m,4H),4.49–4.38(m,2H),3.34( s,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.02(dt,J＝12.7,7.1Hz,1H),1.93(dt,J ＝12.4,6.9Hz,1H),1.86–1.64(m,4H),1.50(s,9H),1.61–1.39(m,11H).ESI-MS m/z 633.3[M+H] ⁺

Example 10: Compound 10

Compound 10-1 was used to replace compound 5-1 in Example 5, and the synthesis method was as described in the synthesis of compound 5, to obtain compound 10.

¹ H NMR(500MHz,Chloroform-d)δ9.52(s,1H),8.57(d,J＝10.8Hz,1H),8.08(d,J＝10.4Hz,1H),7.70–7.64(m,1H ),7.46–7.40(m,1H),7.33(d,J＝6.0Hz,1H),7.25–7.16(m,4H),4.49–4.36(m,3H),4.26(dq,J＝12.3,7.9 Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.02(dt,J＝12.7,7.1Hz,1H),1.93(dt,J ＝12.4,6.9Hz,1H),1.86–1.64(m,4H),1.61–1.52(m,1H),1.50(s,9H),1.55–1.38(m,9H),1.24(t,J＝8.0 Hz,3H).ESI-MS m/z 647.3[M+H] ⁺

Example 11: Synthesis of Compound 11

Compound 11-1 was used to replace compound 5-1 in Example 5, and the synthesis method was based on the synthesis of compound 5 to obtain compound 11.

¹ H NMR (500MHz, Chloroform-d) δ9.52 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.67 (ddd, J = 6.6 ,2.4,1.4Hz,1H),7.45–7.39(m,1H),7.33(d,J＝6.0Hz,1H),7.25–7.15(m,4H),4.49–4.38(m,2H),3.79( dt,J＝12.3,7.1Hz,1H),3.70(dt,J＝12.3,7.1Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H ),2.02(dt,J＝12.7,7.1Hz,1H),1.93(dt,J＝12.4,6.9Hz,1H),1.86–1.64(m,6H),1.50(s,9H),1.61–1.38( m,10H),0.95(t,J＝8.0Hz,3H).ESI-MS m/z 661.3[M+H] ⁺

Example 12: Synthesis of Compound 12

Compound 9 (80 mg, 126 μmol) was dissolved in 2 mL of methylene chloride, and 4 M HCl dioxane solution (2 mL, 7.8 mmol) was added at 0°C. The reaction was continued to stir at room temperature for 12 h, and then the solution was evaporated to dryness. Thin layer chromatography separated and purified (DCM:MeOH=20:1) to obtain compound 12 (40 mg) as a white solid with a yield of 59%.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.53 (d, J = 10.6Hz, 1H), 8.11 (q, J = 2.7Hz, 1H), 8.08 (d, J = 10.4 Hz,1H),7.67(ddd,J＝4.3,3.4,1.5Hz,1H),7.46–7.39(m,1H),7.25–7.16(m,4H),7.03(d,J＝6.2Hz,1H) ,4.43(dt,J＝10.6,7.0Hz,1H),4.19(dtd,J＝10.4,7.0,6.1Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.87(d,J ＝2.7Hz,3H),2.41(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.1Hz,1H),1.94(dt,J＝12.5,7.0Hz,1H),1.86–1.73 (m,2H),1.70(ddd,J＝14.1,12.6,7.3Hz,2H),1.61–1.38(m,13H).ESI-MS m/z 533.2[M+H] ⁺

Example 13: Synthesis of Compound 13

Compound 10 was used to replace compound 9 in Example 12, and the synthesis method was based on the synthesis of compound 12 to obtain compound 13.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.53 (d, J = 10.6Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.87 (t, J = 5.8 Hz,1H),7.67(dtd,J＝5.6,3.8,1.5Hz,1H),7.47–7.39(m,1H),7.25–7.16(m,4H),7.03(d,J＝6.2Hz,1H) ,4.43(dt,J ＝10.6,7.0Hz,1H),4.19(dtd,J＝10.4,7.0,6.1Hz,1H),3.39–3.18(m,4H),2.41(p,J＝7.0Hz,1H),2.07(dt, J＝12.2,7.1Hz,1H),1.94(dt,J＝12.5,6.9Hz,1H),1.86–1.65(m,4H),1.61–1.38(m,11H),1.16(t,J＝8.0Hz ,3H).ESI-MS m/z547.3[M+H] ⁺

Example 14: Synthesis of Compound 14

Compound 11 was used to replace compound 9 in Example 12, and the synthesis method was based on the synthesis of compound 12 to obtain compound 14.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.53 (d, J = 10.6Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.78 (t, J = 5.7 Hz,1H),7.71–7.64(m,1H),7.46–7.39(m,1H),7.26–7.18(m,3H),7.16(t,J＝4.6Hz,1H),7.03(d,J＝ 6.2Hz,1H),4.43(dt,J＝10.6,7.0Hz,1H),4.19(dtd,J＝10.4,7.0,6.1Hz,1H),3.25–3.20(m,1H),3.23–3.10(m ,3H),2.46(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.1Hz,1H),1.94(dt,J＝12.5,6.9Hz,1H),1.86–1.65(m, 4H),1.61–1.38(m,14H),0.82(t,J＝8.0Hz,3H).ESI-MS m/z 561.3[M+H] ⁺

Example 15: Synthesis of Compound 15

Compound 15-1 was used to replace compound 5-1 in Example 5, and the synthesis method was as described in the synthesis of compound 5, to obtain compound 15.

¹ H NMR(500MHz,Chloroform-d)δ9.49(s,1H),8.57(d,J＝10.8Hz,1H),8.08(d,J＝10.4Hz,1H),7.70–7.64(m,1H ),7.46–7.39(m,1H),7.38–7.26(m, 5H),7.25–7.16(m,5H),5.22(dt,J＝12.4,1.0Hz,1H),5.17(dt,J＝12.4,1.0Hz,1H),4.45(dt,J＝10.8,7.0Hz ,1H),4.19(dtd,J＝10.4,6.9,6.1Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.07–1.91( m,2H),1.86–1.64(m,4H),1.61–1.38(m,12H).ESI-MS m/z 610.3[M+H] ⁺

Example 16: Synthesis of Compound 16

Compound 16-1 was used to replace compound 5-1 in Example 5, and the synthesis method was based on the synthesis of compound 5 to obtain compound 16.

¹ H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.57(d,J＝10.8Hz,1H),8.07(d,J＝10.4Hz,1H),7.69–7.64(m,1H ),7.46–7.39(m,1H),7.25–7.13(m,4H),7.09(d,J＝6.2Hz,1H),4.45(dt,J＝10.8,7.1Hz,1H),4.19(dtd, J＝10.4,6.9,6.1Hz,1H),3.49(td,J＝7.0,5.6Hz,4H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H ),2.06(dt,J＝12.6,7.0Hz,1H),1.97(dt,J＝12.4,6.9Hz,1H),1.86–1.63(m,11H),1.61–1.38(m,12H).ESI- MS m/z 587.3[M+H] ⁺

Example 17: Synthesis of Compound 17

Compound 17-1 was used to replace compound 5-1 in Example 5, and the synthesis method was as described in the synthesis of compound 5 to obtain compound 17.

¹ H NMR (400MHz, Chloroform-d) δ10.24(d,J＝298.3Hz,1H),9.09(dd,J＝42.6,6.7Hz,1H),8.73(dd,J＝13.4,4.9Hz,1H ),8.00–7.47(m,2H),7.43–7.29(m,1H),7.28–6.92(m,5H),6.70–6.38(m,1H),5.50–4.63(m,2H),3.38– 2.81(m,2H),2.67–2.15(m,2H),2.14–1.55(m,11H),1.41(s,1H),1.15(dd,J＝20.9,9.6Hz,2H),1.05–0.83( m,2H).ESI-MS m/z 582.2[M+H] ⁺

Example 18: Synthesis of Compound 18

Synthesis of compound 18-3:

Dissolve diazo compound 18-1 (0.76g, 3.48mmol) in 35 mL of methylene chloride, cool to 0°C, and slowly add tetrafluoroboric acid-diethyl ether complex compound 18-2 (0.62g, 3.83mmol) dropwise. Stir at room temperature for 5 hours, quench the reaction solution with 20 mL of ice water, extract with 30X3 mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (PE:EA=10:1) to obtain Compound 18-3 (0.58g) was a color liquid, yield 80%.

Synthesis of compound 18:

Dissolve compound 1-11 (100mg, 0.22mmol) in 10mL acetonitrile, add compound 18-3 (51mg, 0.24mmol) and cesium carbonate (144mg, 0.44mmol), react for 12 hours, add 8mL water and 8X3mL acetic acid to the reaction solution Extract with ethyl ester, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain compound 18 (71.4 mg) as a white solid with a yield of 60%.

¹ H NMR (400MHz, Chloroform-d) δ10.22(s,1H),8.42(dd,J＝22.4,7.2Hz,1H),7.60(d,J＝8.0Hz,1H),7.52(d,J ＝8.4Hz,1H),7.39(d,J＝8.2Hz,1H),7.24(ddd,J＝8.2,6.9,1.1Hz,1H),7.13–7.05(m,2H),6.84(d,J＝ 13.2Hz,1H),6.09(dd,J＝32.5,8.4Hz,1H),4.94–4.81(m,2H),4.28(qd,J＝7.9,7.1,5.0Hz,2H),3.15(dt,J ＝27.1,8.6Hz,2H),2.48(p,J＝8.3Hz,1H),2.36–2.12(m,2H),1.90–1.51(m,10H),1.33(q,J＝7.1Hz,3H) ,1.24–1.08(m,3H),1.05–0.86(m,2H).ESI-MS m/z 541.2[M+H] ⁺

Example 19: Synthesis of Compound 19

Compound 1-11 (0.15g, 0.33mmol) was dissolved in a mixed solution of ethyl acetate/ethanol/water (7mL, v/v/v, 4/2/1), and compound 19-1 was added at 40°C. After stirring for 2 hours, the solution was cooled and filtered. After the solution was concentrated, it was beaten with dichloromethane and filtered to remove the unreacted raw material aldehyde to obtain compound 19 (130 mg) with a yield of 71%.

1H NMR(600MHz,DMSO-d6)δ11.58(dd,J＝5.5,2.4Hz,1H),8.44(ddd,J＝27.4,20.2,8.1Hz,1H),8.02–7.52(m,2H), 7.51–7.37(m,2H),7.25(dq,J＝6.5,4.2,3.7Hz,1H),7.18(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),5.50 (dd,J＝80.3,5.9Hz,1H),4.62–4.41(m,1H),4.35–4.04(m,1H),4.02–3.77(m,1H),3.07(dddd,J＝40.0,18.7, 14.8,9.9Hz,2H),2.16(dddd,J＝17.1,14.4,7.6,3.5Hz,1H),2.05–1.88(m,1H),1.81–1.51(m,10H),1.36(dddd,J＝ 10.9,6.7,3.3Hz,1H),1.26–1.11(m,2H),1.04–0.79(m,2H).ESI-MS m/z 557.2[M+H]+

Example 20: Synthesis of Compound 20

Compound 19 and acetic anhydride were heated in an oil bath in acetonitrile, and compound 20 was separated by column chromatography.

¹ H NMR (500MHz, Chloroform-d) δ9.49 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 7.80 (d, J = 12.3Hz, 1H), 7.67 (ddd, J = 5.6 ,3.2,1.5Hz,1H),7.47–7.39(m,1H),7.25–7.18(m,3H),7.12(t,J＝4.6Hz,1H),5.40(d,J＝7.0Hz,1H) ,4.55–4.40(m,2H),3.27(dtd,J＝12.4,7.0,4.6Hz,1H),3.19(dtd,J＝12.4,7.1,4.6Hz,1H), 2.48(p,J＝7.0Hz,1H),2.13(s,2H),2.01(dt,J＝12.2,7.0Hz,1H),1.92(dt,J＝12.4,6.9Hz,1H),1.83(dt ,J＝12.3,7.0Hz,1H),1.81–1.70(m,2H),1.72–1.65(m,1H),1.61–1.37(m,12H).ESI-MS m/z 599.2[M+H] ⁺

Example 21: Synthesis of Compound 21

Synthesis of compound 21-1:

Dissolve compound 1-9 (0.15g, 0.31mmol) in 3mL of methanol, add 3mL of ammonia water (w/% 25-28) under stirring at room temperature, and keep at room temperature overnight. After TLC monitors that the reaction is complete, add 6mL of ethyl acetate, and 3mL of ethyl acetate will be saturated. Sodium chloride solution, extract and separate the organic phase, dry with anhydrous sodium sulfate and concentrate under reduced pressure, then separate by column chromatography (DCM:MeOH=20:1) to obtain compound 21-1 (117 mg) as a white solid, with a yield of 81%.

Synthesis of compound 21:

Compound 21-1 (0.1g, 0.214mmol) was dissolved in 5 mL anhydrous acetonitrile, cooled to 0°C, triethylamine (0.052g, 0.428mmol) was added dropwise, and then trifluoroacetic anhydride (0.11g, 0.235 mmol), gradually warmed to room temperature, and continued the reaction for 1 h. Point board monitoring. Add 5 mL of ethyl acetate, wash with 5 mL of saturated ammonium chloride solution, 5 mL of saturated sodium bicarbonate solution, and 5 mL of saturated sodium chloride solution. The organic phase is dried with anhydrous sodium chloride, concentrated under reduced pressure, and separated by column chromatography (DCM :MeOH=20:1), a white solid compound 21 (67 mg) was obtained, with a yield of 69%.

¹ H NMR (400MHz, Chloroform-d) δ9.99 (s, 1H), 8.76 (d, J = 6.9Hz, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.42 (d, J = 8.3 Hz,1H),7.28–7.22(m,2H),7.13(t,J＝7.5Hz,1H),7.03(d,J＝2.1Hz,1H),6.42(s,1H),4.83(dtd,J ＝28.5,9.5,8.7,5.9Hz,2H),3.25(t,J＝9.3Hz,1H),2.35(dddd,J＝32.3,28.4,15.0,8.1Hz,4H),1.83–1.57(m,9H ),1.17(ddt,J＝20.6,15.0,6.1Hz,3H),1.10–0.84(m,3H).ESI-MS m/z 450.2[M+H] ⁺

Example 22: Synthesis of Compound 22

Synthesis of compound 22-1:

Dissolve compound 1-3 (1g, 3.5mmol) in 10mL of methanol, add 5mL of water, add lithium hydroxide monohydrate (290mg, 7.0mmol) while stirring at room temperature, react at room temperature overnight, and monitor the reaction with a spot plate after the reaction is complete. , add 2M hydrochloric acid solution to adjust the reaction system to neutral, add 10mL ethyl acetate and 6mL saturated sodium chloride solution, extract and separate the organic phase, extract the aqueous phase with 10X2mL of ethyl acetate, combine the organic phases, and use saturated sodium chloride for the organic phase 10 mL was washed, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under pressure to obtain compound 22-1 (850 mg, 3.1 mmol). The next reaction was carried out directly without purification, with a yield of 89%.

Synthesis of compound 22-3:

Compound 22-1 (850 mg, 3.1 mmol) was added to dichloromethane (20 mL), N, N-dimethylformamide (3 mL) was used to help dissolve, the reaction solution was cooled to -20°C, and then HATU (1.4 g , 3.7mmol) was added to the reaction solution, and after stirring for 20 minutes, compound 22-2 (304mg, 3.1mmol) was added to the reaction solution, stirred again at -20°C for 30 minutes, and then DIPEA (1.4mL, 9.4mmol) was added dropwise to the reaction. liquid. After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (20X3mL), saturated sodium bicarbonate solution (20X3mL), and saturated sodium chloride solution (20X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distillation and column chromatography separation (DCM:MeOH=50:1v/v) yielded colorless liquid compound 22-3 (0.8g) with a yield of 82%.

Synthesis of compound 22-5:

Dissolve compound 22-3 (0.75g, 2.4mmol) in anhydrous tetrahydrofuran (10mL), slowly add compound 22-4 (9.5mL, 1M in THF) dropwise at 0°C, gradually rise to room temperature and react for 2 hours, add saturated Quench 15 mL of ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (DCM:MeOH=40:1v/v) to obtain a colorless liquid compound 22-5 (0.5g), yield 71%.

Synthesis of compound 22-6:

Compound 22-5 (0.5g, 1.7mmol) was dissolved in dichloromethane (5mL), 4M HCl dioxane solution (5mL) was added at 0°C, the reaction was continued to stir at room temperature for 12h, and then the solution was Evaporate to dryness to obtain intermediate 22-6, which can be directly used in the next reaction without purification.

Synthesis of compound 22-8:

Compound 1-5 (0.6g, 2.2mmol) was dissolved in dichloromethane (15mL), the reaction solution was cooled to -20°C, then HATU (0.97g, 2.6mmol) was added to the reaction solution, and stirred for 20 minutes. Intermediate 22-6 of the previous step was added to the reaction solution, stirred again at -20°C for 30 minutes, and then DIPEA (1 mL, 6.6 mmol) was added dropwise to the reaction solution.

After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (15X3mL), saturated sodium bicarbonate solution (15X3mL), and saturated sodium chloride solution (15X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distillation and column chromatography separation (DCM:MeOH=40:1v/v) gave compound 22-3 (0.6g) as a white solid with a yield of 62%.

Synthesis of compound 22-9:

Compound 22-8 (0.6g, 1.3mmol) was dissolved in dichloromethane (5mL), 4M HCl dioxane solution (5mL) was added at 0°C, the reaction was continued to stir at room temperature for 12h, and then the solution was Evaporate to dryness to obtain intermediate 22-9, which can be directly used in the next reaction without purification.

Synthesis of compound 22:

Compound 1-8 (0.25g, 1.55mmol) was dissolved in dichloromethane (20mL). The reaction solution was cooled to -20°C. Then HATU (0.7g, 1.86mmol) was added to the reaction solution and stirred for 20 minutes. Intermediate 22-9 from the previous step was added to the reaction solution, stirred again at -20°C for 30 minutes, and then DIPEA (0.7 mL, 4.65 mmol) was added dropwise to the reaction solution.

After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (15X3mL), saturated sodium bicarbonate solution (15X3mL), and saturated sodium chloride solution (15X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distillation and column chromatography separation (DCM:MeOH=20:1v/v) gave compound 22 (0.35g) as a white solid with a yield of 46%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.60 (s, 1H), 8.52 (dd, J = 15.8, 8.2Hz, 1H), 8.43 (d, J = 7.9Hz, 1H), 7.64 (t, J＝8.1Hz,2H),7.42(d,J＝8.3Hz,1H),7.27(s,1H),7.18(t,J＝7.7Hz,1H),7.04(t,J＝7.5Hz,1H) ,6.14(d,J＝6.9Hz,1H),5.90(s,1H),5.23–5.00(m,1H),4.59(dq,J＝24.2,8.8Hz,1H),3.10(q,J＝10.9 ,9.2Hz,2H),2.39–2.10(m,2H),2.06–1.89(m,1H),1.80(s,3H),1.77–1.28(m,10H),1.12(q,J＝10.7,10.3 Hz,3H),0.89(dd,J＝21.3,10.2Hz,2H).ESI-MS m/z493.2[M+H] ⁺

Example 23: Synthesis of Compound 23

Compound 23-1 was used to replace compound 22-4 in Example 22, and the synthesis method was based on the synthesis of compound 22 to obtain compound 23.

¹ H NMR (500MHz, Chloroform-d) δ9.56 (s, 1H), 8.51 (d, J = 10.6Hz, 1H), 7.71–7.64 (m, 1H), 7.48–7.39 (m, 2H), 7.27 –7.18(m,3H),7.13(t,J＝4.6Hz,1H),6.22(td,J＝13.3,1.7Hz,1H),6.02(dd,J＝13.4,2.4Hz,1H),5.96( dd,J＝13.3,2.5Hz,1H),4.45(dt,J＝10.6,7.0Hz,1H),4.37(dtd,J＝11.5,7.0,1.8Hz,1H),3.32–3.16(m,2H) ,2.50(p,J＝7.0Hz,1H),1.95–1.65(m,7H),1.61–1.54(m,1H),1.57–1.49(m,3H),1.49(dddd,J＝9.6,6.8, 4.5,3.4Hz,3H),1.48–1.37 (m,5H).ESI-MS m/z 479.2[M+H] ⁺

Example 24: Synthesis of Compound 24

Compound 24-1 was used to replace compound 22-4 in Example 22, and the synthesis method was as described in the synthesis of compound 22, to obtain compound 24.

1H NMR(500MHz,Chloroform-d)δ9.56(s,1H),8.53(d,J＝10.6Hz,1H),7.79(d,J＝10.3Hz,1H),7.67(ddd,J＝6.2, 2.8,1.6Hz,1H),7.46–7.39(m,1H),7.26–7.18(m,3H),7.08(t,J＝4.6Hz,1H),4.48(ddt,J＝30.8,10.6,7.0Hz ,2H),3.20(tt,J＝7.2,4.6Hz,2H),2.50(p,J＝7.0Hz,1H),2.06(dt,J＝12.4,6.9Hz,1H),1.97(dt,J＝ 12.6,7.0Hz,1H),1.92(s,2H),1.83(dq,J＝12.1,7.0Hz,1H),1.80–1.71(m,2H),1.74–1.65(m,1H),1.61–1.53 (m,1H),1.57–1.47(m,4H),1.50–1.37(m,6H).ESI-MS m/z 491.2[M+H]+

Example 25: Synthesis of Compound 25

Compound 25-1 was used to replace compound 22-4 in Example 22, and the synthesis method was as described in the synthesis of compound 22, to obtain compound 25.

¹ H NMR(500MHz,Chloroform-d)δ9.56(s,1H),8.53(d,J＝10.6Hz,1H),7.71–7.63(m,1H),7.55(d,J＝11.3Hz,1H ),7.46–7.39(m,1H),7.26–7.18(m,3H),7.13(t,J＝4.6Hz,1H),6.85(dq,J＝15.2,6.4Hz,1H),6.20(dtd, J＝15.2,2.0,1.1Hz,1H),4.45(dt,J＝10.6,7.0Hz,1H),4.37(dtd,J＝11.4,7.0,1.7Hz,1H),3.32–3.23(m,1H) ,3.19(dtd,J＝12.5,7.1,4.6Hz,1H),2.49(p,J＝7.0Hz, 1H),2.01–1.92(m,4H),1.89–1.65(m,5H),1.61–1.53(m,1H),1.57–1.50(m,2H),1.53–1.47(m,2H),1.50– 1.37(m,6H).ESI-MS m/z 493.2[M+H] ⁺

Example 26: Synthesis of Compound 26

Synthesis of compound 26-2:

Compound 26-1 (1 g) was placed in dichloromethane (10 mL), saturated sodium bicarbonate solution (10 mL) was added, the organic phase was separated, and the solvent was spun to dryness. Dissolve the treated 26-1 in 10 mL of anhydrous benzene, add 1.76 g of triphenylphosphine, reflux for 2 hours under nitrogen protection, spin dry the solvent, add 3 mL of diethyl ether, grind the residue, suction filter, and wash with petroleum ether. , a white solid compound 26-2 (2.1g) was obtained with a yield of 89%.

Synthesis of compound 26:

Compound 26-2 (100 mg, 0.26 mmol) was placed in anhydrous tetrahydrofuran (5 mL), and LHMDS (47 mg, 1 M in THF) was added dropwise at 0°C. After the reaction solution gradually became clear, continue stirring for 30 minutes to remove the compound containing Anhydrous tetrahydrofuran solution (3 mL) of 1-11 (60 mg, 0.18 mmol) was slowly dropped into the reaction solution, and the reaction was carried out for 4 hours. Add 10 mL saturated ammonium chloride solution and 10 mL ethyl acetate, extract and separate the organic phase, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure and then separate by column chromatography (DCM:MeOH=20:1 ), compound 26 (40 mg) was obtained with a yield of 57%.

¹ H NMR(600MHz,Chloroform-d)δ10.03(s,1H),8.51(dd,J＝5.0,1.8Hz,1H),8.01(d,J＝7.8Hz,1H),7.63–7.56(m ,2H),7.41–7.34(m,1H),7.22(tt,J＝7.0,1.4Hz,3H),7.14–7.06(m,2H),7.05–7.02(m,1H),6.65(d,J ＝3.1Hz,2H),6.33(s,1H),4.84(td,J＝8.8,5.4Hz,1H),4.69(ddt,J＝11.5,7.5,3.6Hz,1H), 3.17(dtd,J＝25.6,9.7,7.3Hz,2H),2.54–2.34(m,1H),2.31(dddd,J＝11.9,8.8,6.9,2.2Hz,1H),1.88–1.60(m,9H) ),1.45–1.36(m,1H),1.19–1.04(m,4H),0.96(qd,J＝12.3,3.4Hz,2H).ESI-MS m/z 528.2[M+H] ⁺

Example 27: Synthesis of Compound 27

The synthesis of compound 27 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 27-1.

¹ H NMR (400MHz, Chloroform-d) δ10.26 (d, J = 43.1Hz, 1H), 8.67 (s, 2H), 7.69 (t, J = 10.0Hz, 1H), 7.59 (t, J = 7.3 Hz,1H),7.49(d,J＝6.7Hz,1H),7.41(q,J＝7.9Hz,2H),7.23(d,J＝7.4Hz,1H),7.16–7.00(m,3H), 6.75(d,J＝15.6Hz,1H),6.55(s,1H),5.01–4.63(m,2H),3.17(d,J＝25.3Hz,2H),2.32(m,1H),2.09(d ,J＝39.7Hz,1H),1.94–1.43(m,10H),1.03(ddt,J＝78.2,21.7,10.7Hz,6H).ESI-MS m/z 529.2[M+H] ⁺

Example 28: Synthesis of Compound 28

The synthesis of compound 28 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 28-1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62 (s, 1H), 8.68–8.37 (m, 2H), 8.01 (dd, J = 46.5, 8.1Hz, 2H), 7.78–7.37 (m, 6H) ),7.31(s,1H),7.19(t,J＝7.6Hz,1H),7.04(t,J＝7.7Hz,1H),6.82(s,2H),4.81–4.51(m,2H),3.12 (dt,J＝20.3,9.2Hz,2H),2.45–2.36(m,1H),2.24–1.94(m,2H),1.69(dt,J＝41.1,23.1Hz,10H),1.42(s,1H ),1.23(s,2H),0.95(t,J＝12.1Hz,2H).ESI-MS m/z 584.2[M+H] ⁺

Example 29: Synthesis of Compound 29

The synthesis of compound 29 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 29-1.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 7.69–7.64 (m, 1H), 7.66–7.60 (m, 1H), 7.54 –7.49(m,1H),7.46–7.34(m,3H),7.25–7.18(m,2H),7.21–7.16(m,1H),7.16(t,J＝4.6Hz,1H),6.96(d ,J＝11.2Hz,1H),6.41(dd,J＝15.0,0.9Hz,1H),6.15(dd,J＝15.0,6.2Hz,1H),4.45(dt,J＝10.8,7.1Hz,1H) ,4.09(dtdd,J＝11.2,7.1,6.1,1.0Hz,1H),3.26–3.12(m,2H),2.45(p,J＝7.1Hz,1H),2.02(dt,J＝12.2,7.1Hz ,1H),1.91(dt,J＝12.4,7.0Hz,1H),1.86–1.64(m,4H),1.61–1.38(m,11H).ESI-MS m/z 568.2[M+H] ⁺

Example 30: Synthesis of Compound 30

The synthesis of compound 30 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 30-1.

1H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.53(d,J＝10.6Hz,1H),7.82(d,J＝7.5Hz,1H),7.71–7.64(m,1H) ,7.46–7.37(m,2H),7.26–7.16(m,4H),6.96(d,J＝11.2Hz,1H),6.46–6.39(m,1H),6.05(dd,J＝15.1,6.1Hz ,1H),4.43(dt,J＝10.6,7.0Hz,1H),4.09(dtdd,J＝11.2,7.0,6.1,1.0Hz,1H),3.27–3.12(m,2H),2.40(p,J ＝7.0Hz,1H),2.02(dt,J＝12.2,7.1Hz,1H),1.91(dt,J＝12.4,6.9Hz,1H),1.86–1.66(m,4H),1.62–1.38(m, 12H).ESI-MS m/z 518.2[M+H]+

Example 31: Synthesis of Compound 31

The synthesis of compound 31 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 31-1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.65–11.61(m,1H),8.67–8.60(m,1H),8.57(dd,J＝2.6,1.5Hz,1H),8.53–8.46(m ,2H),8.37(d,J＝8.7Hz,1H),7.66–7.58(m,2H),7.45–7.41(m,1H),7.30(d,J＝2.2Hz,1H),7.19(ddd, J＝8.2,6.9,1.3Hz,1H),7.04(ddd,J＝8.1,6.9,1.1Hz,1H),6.95–6.83(m,1H),6.61(dd,J＝15.8,1.5Hz,1H) ,4.74–4.52(m,2H),3.18–3.01(m,2H),2.38(td,J＝12.1,11.4,6.7Hz,1H),2.18–1.94(m,2H),1.86–1.46(m, 10H),1.20–0.81(m,5H).ESI-MS m/z 529.2[M+H] ⁺

Example 32: Synthesis of Compound 32

The synthesis of compound 32 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 32-1.

δ10.16(d,J＝55.8Hz,1H),9.07(s,1H),8.58(t,J＝4.3Hz,1H),8.24(t,J＝8.5Hz,1H),7.58(t,J ＝7.1Hz,1H),7.38(dd,J＝8.6,3.9Hz,2H),7.21(q,J＝7.2Hz,1H),7.08(q,J＝6.8,5.0Hz,2H),7.04(s ,1H),6.94(dd,J＝15.6,5.8Hz,1H),6.60–6.50(m,2H),4.87(t,J＝7.7Hz,1H),4.69(dd,J＝11.5,5.8Hz, 1H),3.18(dd,J＝24.9,14.2Hz,2H),2.56–2.40(m,1H),2.29(t,J＝9.1Hz,2H),1.88–1.80(m,2H),1.77–1.51 (m,8H),1.45–1.36(m,1H),1.18–1.08(m,2H),1.01–0.87(m,2H).ESI-MS m/z 529.2[M+H] ⁺

Example 33: Synthesis of Compound 33

Compound 22 and m-chloroperoxybenzoic acid were stirred in acetonitrile at room temperature to obtain compound 33.

1H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.55(d,J＝10.6Hz,1H),7.77(d,J＝11.2Hz,1H),7.71–7.65(m,1H) ,7.46–7.39(m,1H),7.26–7.18(m,3H),7.12(t,J＝4.6Hz,1H),4.45(dtd,J＝11.0,7.0,4.9Hz,2H),3.68(d ,J＝12.4Hz,1H),3.58(d,J＝12.4Hz,1H),3.32–3.14(m,2H),2.52(p,J＝7.1Hz,1H),2.04(dt,J＝12.3, 6.9Hz,1H),1.95(dt,J＝12.5,6.9Hz,1H),1.89–1.65(m,5H),1.62–1.38(m,16H).ESI-MS m/z 509.2[M+H] +

Example 34: Synthesis of Compound 34

Dissolve compound 34-1 (29 mg, 0.24 mmol) in anhydrous tetrahydrofuran (5 mL), add NaH (10 mg, 60% dispersion in mineral oil) in batches at 0°C, and after 20 minutes, slowly add dissolved Compound 1-11 (100 mg, 0.22 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), reacted for 2 hours, and monitored by spot plate. Add 5 mL saturated ammonium chloride solution and 5 mL ethyl acetate, separate the organic phase, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure and then separate by column chromatography to obtain white solid compound 34 (60 mg), yield 49%.

1H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.53(d,J＝10.6Hz,1H),7.67(ddt,J＝4.9,3.6,1.5Hz,1H),7.48(d, J＝6.2Hz,1H),7.46–7.39(m,1H),7.35(d,J＝10.3Hz,1H),7.25–7.16(m,4H),4.43(dt,J＝10.6,7.0Hz,1H ),4.19(dtd,J＝10.3,7.0,6.1Hz,1H),3.50(s,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H) ,2.04(dt,J＝12.2,7.0Hz,1H),1.96(dt,J＝12.5,7.2Hz,1H),1.86 –1.65(m,4H),1.61–1.38(m,11H).ESI-MS m/z 554.2[M+H]+

Example 35: Synthesis of Compound 35

The synthesis of compound 35 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 35-1.

¹ H NMR(500MHz,Chloroform-d)δ9.56(s,1H),8.44(d,J＝10.6Hz,1H),7.72–7.65(m,2H),7.43(dd,J＝7.3,1.6Hz ,1H),7.29–7.15(m,9H),7.10(t,J＝4.6Hz,1H),4.74(dt,J＝10.6,7.0Hz,1H),4.52(dt,J＝9.9,7.0Hz, 1H),3.25–3.02(m,4H),2.52(p,J＝7.0Hz,1H),2.10(dt,J＝12.7,7.0Hz,1H),2.01(dt,J＝12.5,7.2Hz,1H ),1.81(ddq,J＝43.2,12.4,7.1Hz,2H).ESI-MS m/z 444.2[M+H] ⁺

Example 36: Synthesis of Compound 36

The synthesis of compound 36 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 35-1.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.51 (d, J = 10.6Hz, 1H), 7.67 (ddd, J = 6.3, 3.4, 1.5Hz, 1H), 7.46–7.39 (m,1H),7.29–7.16(m,11H),6.20(d,J＝6.2Hz,1H),6.10(d,J＝6.2Hz,1H),4.85(dt,J＝10.6,7.0Hz, 1H),4.30–4.14(m,3H),3.21(td,J＝7.1,4.6Hz,2H),3.06(ddt,J＝12.5,7.0,0.9Hz,1H),3.00(ddt,J＝12.4, 7.1,1.0Hz,1H),2.40(p,J＝7.0Hz,1H),2.10(dt,J＝12.3,7.1Hz,1H),1.94(dt,J＝12.2,6.9Hz,1H),1.81( dq,J＝12.2,7.0Hz,1H),1.71(dq,J ＝12.4,7.2Hz,1H),1.27(t,J＝8.0Hz,3H).ESI-MS m/z 535.2[M+H] ⁺

Example 37: Synthesis of Compound 37

The synthesis of compound 37 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediate 1-5 is replaced by 35-1.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.51 (d, J = 10.6Hz, 1H), 8.12 (d, J = 10.4Hz, 1H), 7.67 (ddd, J = 4.3 ,3.4,1.5Hz,1H),7.46–7.39(m,1H),7.30–7.16(m,11H),4.85(dt,J＝10.6,7.0Hz,1H),4.19(dtd,J＝10.4,6.9 ,6.1Hz,1H),3.72(s,2H),3.21(td,J＝7.1,4.6Hz,2H),3.06(ddt,J＝12.4,7.0,0.9Hz,1H),3.00(ddt,J＝ 12.4,7.0,1.0Hz,1H),2.41(p,J＝7.0Hz,1H),2.07(dt,J＝12.1,7.0Hz,1H),1.94(dt,J＝12.5,6.9Hz,1H), 1.81(dq,J＝12.4,7.1Hz,1H),1.72(dq,J＝12.4,7.1Hz,1H).ESI-MS m/z 528.2[M+H] ⁺

Example 38: Synthesis of Compound 38

The synthesis of compound 38 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 35-1 and 38-1.

1H NMR(500MHz,Chloroform-d)δ8.37(d,J＝11.3Hz,1H),7.82(t,J＝4.4Hz,1H),7.69(d,J＝9.9Hz,1H),7.61(t ,J＝4.5Hz,1H),7.30–7.22(m,6H),7.25–7.16(m,2H),7.10(t,J＝4.6Hz,1H),4.79(dt,J＝11.3,7.0Hz, 1H),4.49(dt,J＝9.9,7.0Hz,1H),3.25–3.10(m,2H),3.06(dt,J＝7.0,0.9Hz,2H),2.52(p,J＝7.0Hz,1H ),2.10(dt,J＝12.7,7.0Hz,1H),2.01(dt,J＝12.5,7.2Hz,1H),1.81 (ddq,J＝43.2,12.4,7.1Hz,2H).ESI-MS m/z 445.1[M+H]+

Example 39: Synthesis of Compound 39

The synthesis of compound 39 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 38-1.

1H NMR(500MHz,Chloroform-d)δ8.39(d,J＝11.5Hz,1H),7.82(t,J＝4.4Hz,1H),7.70(d,J＝9.9Hz,1H),7.60(t ,J＝4.5Hz,1H),7.30–7.20(m,2H),7.10(t,J＝4.6Hz,1H),4.57(dt,J＝11.5,7.0Hz,1H),4.49(dt,J＝ 9.9,7.0Hz,1H),3.25–3.10(m,2H),2.52(p,J＝7.0Hz,1H),2.10(dt,J＝12.8,7.0Hz,1H),2.01(dt,J＝12.5 ,7.2Hz,1H),1.90–1.66(m,4H),1.61–1.29(m,12H).ESI-MS m/z 451.2[M+H]+

Example 40: Synthesis of Compound 40

The synthesis of compound 40 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 40-1.

1H NMR(500MHz,Chloroform-d)δ8.44(d,J＝10.6Hz,1H),7.73–7.65(m,2H),7.37(dd,J＝7.2,1.7Hz,1H),7.33–7.23( m,2H),7.23(d,J＝1.5Hz,1H),7.10(t,J＝4.6Hz,1H),4.52(dt,J＝9.8,7.0Hz,1H),4.34(dt,J＝10.6 ,7.0Hz,1H),3.93(s,2H),3.25–3.10(m,2H),2.52(p,J＝7.0Hz,1H),2.10(dt,J＝12.4,6.9Hz,1H),2.01 (dt,J＝12.2,6.9Hz,1H),1.85(dq,J＝12.4,7.0Hz,1H),1.82–1.65(m,3H),1.61–1.54(m,1H),1.56–1.51(m ,1H),1.52(s,1H),1.53– 1.47(m,2H),1.50–1.38(m,6H).ESI-MS m/z 464.2[M+H]+

Example 41: Synthesis of Compound 41

The synthesis of compound 41 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 40-1.

¹ H NMR (500MHz, Chloroform-d) δ8.49 (d, J＝10.6Hz, 1H), 7.68 (dt, J＝7.8, 1.7Hz, 1H), 7.42–7.37 (m, 1H), 7.29 (td ,J＝7.4,1.6Hz,1H),7.26–7.20(m,2H),7.19(t,J＝4.6Hz,1H),7.15(d,J＝11.1Hz,1H),6.20(d,J＝ 6.2Hz,0H),6.10(d,J＝6.2Hz,0H),4.33–4.14(m,4H),3.93(s,2H),3.21(td,J＝7.1,4.6Hz,2H),2.40( p,J＝7.0Hz,1H),2.10(dt,J＝12.2,7.1Hz,1H),1.94(dt,J＝12.2,6.9Hz,1H),1.86–1.65(m,4H),1.61–1.38 (m,11H),1.27(t,J＝8.0Hz,3H).ESI-MS m/z 555.2[M+H] ⁺

Example 42: Synthesis of Compound 42

The synthesis of compound 42 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 42-1.

1H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.53(d,J＝10.6Hz,1H),7.67(dtd,J＝5.6,3.7,1.5Hz,1H),7.46–7.39( m,1H),7.30(td,J＝7.5,5.0Hz,1H),7.25–7.16(m,5H),7.08(dq,J＝7.2,1.4Hz,2H),6.97(tt,J＝7.7, 1.5Hz,1H),6.20(d,J＝6.2Hz,0H),6.10(d,J＝6.2Hz,0H),4.81(dt,J＝10.6,7.0Hz,1H),4.30–4.19(m, 2H),4.23–4.14(m,1H),3.21(td,J＝7.1,4.6Hz,2H),2.96– 2.84(m,2H),2.40(p,J＝7.0Hz,1H),2.10(dt,J＝12.2,7.0Hz,1H),1.94(dt,J＝12.2,6.9Hz,1H),1.81(dq ,J＝12.3,7.1Hz,1H),1.71(dq,J＝12.5,7.0Hz,1H),1.27(t,J＝8.0Hz,3H).ESI-MS m/z 553.2[M+H]+

Example 43: Synthesis of Compound 43

The synthesis of compound 43 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 42-1.

1H NMR(500MHz,Chloroform-d)δ8.44(d,J＝10.3Hz,1H),7.71–7.65(m,2H),7.38(dd,J＝7.4,1.5Hz,1H),7.32–7.20( m,4H),7.16(t,J＝4.6Hz,1H),7.11–7.04(m,2H),6.98(tt,J＝7.6,1.5Hz,1H),4.80(dt,J＝10.4,7.1Hz ,1H),4.52(dt,J＝9.9,7.0Hz,1H),3.93(s,2H),3.25–3.10(m,2H),2.96–2.85(m,2H),2.49(p,J＝7.0 Hz,1H),2.10(dt,J＝12.5,7.0Hz,1H),2.01(dt,J＝12.5,6.9Hz,1H),1.90–1.72(m,2H).ESI-MS m/z 476.2[ M+H]+

Example 44: Synthesis of Compound 44

The synthesis of compound 44 refers to the synthesis of compound 1-8 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 42-1 and 44-1.

¹ H NMR (500MHz, Chloroform-d) δ8.37(d,J＝11.7Hz,1H),7.85(d,J＝1.9Hz,1H),7.69(d,J＝9.9Hz,1H),7.63( dt,J＝7.1,1.7Hz,1H),7.59–7.53(m,1H),7.41–7.30(m,2H),7.28(td,J＝7.5,5.0Hz,1H),7.12–7.04(m, 3H),6.98 (tt,J＝7.7,1.5Hz,1H),4.76(dt,J＝11.7,7.0Hz,1H),4.49(dt,J＝9.9,7.0Hz,1H),3.25–3.10(m,2H), 2.91(ddt,J＝7.0,2.7,1.1Hz,2H),2.52(p,J＝7.0Hz,1H),2.10(dt,J＝12.8,7.0Hz,1H),2.01(dt,J＝12.5, 7.2Hz,1H),1.85(dq,J＝12.2,7.0Hz,1H),1.81–1.71(m,1H).ESI-MS m/z 463.1[M+H] ⁺

Example 45: Synthesis of Compound 45

The synthesis of compound 45 refers to the synthesis of compound 1-8 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 42-1 and 45-1.

1H NMR(500MHz,Chloroform-d)δ9.57(d,J＝1.6Hz,1H),8.70(d,J＝11.5Hz,1H),8.46(s,1H),7.69(d,J＝9.9Hz ,1H),7.49(dd,J＝7.5,1.5Hz,1H),7.42(d,J＝7.4Hz,1H),7.28(td,J＝7.5,5.0Hz,1H),7.16(t,J＝ 4.6Hz,1H),7.11–7.05(m,2H),6.97(tt,J＝7.6,1.5Hz,1H),4.86(dt,J＝11.4,7.0Hz,1H),4.49(dt,J＝9.9 ,7.0Hz,1H),3.24–3.11(m,2H),2.99–2.87(m,2H),2.52(p,J＝7.0Hz,1H),2.10(dt,J＝12.3,7.1Hz,1H) ,2.01(dt,J＝12.2,7.0Hz,1H),1.88–1.72(m,2H).ESI-MS m/z 541.0[M+H]+

Example 46: Synthesis of Compound 46

The synthesis of compound 46 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 46-1.

¹ H NMR (500MHz, Chloroform-d) δ9.71 (s, 1H), 8.53 (d, J = 10.8Hz, 1H), 7.35 (d, J = 7.6Hz, 1H), 7.19–7.12 (m, 3H ),7.09(t,J＝1.6Hz,1H),6.82(dd,J＝ 7.5,1.5Hz,1H),6.20(d,J＝6.2Hz,0H),6.10(d,J＝6.2Hz,0H),4.43(dt,J＝10.6,7.0Hz,1H),4.25(dd, J＝8.0,2.0Hz,1H),4.24–4.19(m,1H),4.22–4.14(m,1H),3.83(s,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46 (p,J＝7.0Hz,1H),2.10(dt,J＝12.2,7.0Hz,1H),1.94(dt,J＝12.2,6.9Hz,1H),1.86–1.65(m,4H),1.61– 1.38(m,11H),1.27(t,J＝8.0Hz,3H).ESI-MS m/z 571.2[M+H] ⁺

Example 47: Synthesis of Compound 47

The synthesis of compound 47 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 47-1.

¹ H NMR(500MHz,Chloroform-d)δ9.59(s,1H),8.53(d,J＝10.8Hz,1H),7.64–7.60(m,1H),7.41(d,J＝7.5Hz,1H ),7.22–7.12(m,4H),6.20(d,J＝6.2Hz,1H),6.10(d,J＝6.2Hz,1H),4.43(dt,J＝10.6,7.0Hz,1H),4.30 –4.14(m,3H),3.21(td,J＝7.1,4.6Hz,2H),2.40(p,J＝7.0Hz,1H),2.10(dt,J＝12.2,7.1Hz,1H),1.94( dt,J＝12.2,6.9Hz,1H),1.86–1.65(m,5H),1.61–1.38(m,13H),1.32–1.25(m,3H).ESI-MS m/z 575.2[M+H ] ⁺

Example 48: Synthesis of Compound 48

The synthesis of compound 48 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 48-1.

¹ H NMR(500MHz,Chloroform-d)δ8.58(d,J＝10.6Hz,1H),7.70(d,J＝9.9Hz,1H),7.64(dt,J＝7.6,1.6Hz,1H), 7.36(td,J＝7.4,5.1Hz,1H),7.25(d,J ＝1.8Hz,1H),7.10(t,J＝4.6Hz,1H),7.03(td,J＝7.6,1.5Hz,1H),4.50(ddt,J＝23.6,10.6,7.0Hz,2H),3.25 –3.10(m,2H),2.49(p,J＝7.0Hz,1H),2.10(dt,J＝12.3,7.0Hz,1H),2.01(dt,J＝12.2,6.9Hz,1H),1.90– 1.65(m,4H),1.61–1.47(m,5H),1.50–1.38(m,7H).ESI-MS m/z 468.2[M+H] ⁺

Example 49: Synthesis of Compound 49

The synthesis of compound 49 refers to the synthesis of compound 1-11 and compound 19, and the corresponding intermediate 1-8 is replaced by 49-1.

¹ H NMR (500MHz, Chloroform-d) δ9.59 (s, 1H), 8.55 (d, J = 10.8Hz, 1H), 7.94 (ddd, J = 7.5, 4.9, 1.5Hz, 1H), 7.78 (d ,J＝12.4Hz,1H),7.28–7.21(m,2H),7.12(t,J＝4.6Hz,1H),7.06(td,J＝7.8,1.5Hz,1H),4.74(dd,J＝ 10.3,7.0Hz,1H),4.43(dt,J＝10.6,7.0Hz,1H),4.15(dq,J＝12.5,7.1Hz,1H),4.04(d,J＝10.1Hz,1H),3.32– 3.14(m,2H),2.45(p,J＝7.0Hz,1H),2.02(dt,J＝12.1,7.1Hz,1H),1.96–1.65(m,6H),1.61–1.38(m,13H) .ESI-MS m/z 575.1[M+H] ⁺

Example 50: Synthesis of Compound 50

The synthesis of compound 50 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediate 1-8 is replaced by 50-1.

¹ H NMR (500MHz, Chloroform-d) δ9.56 (s, 1H), 8.60 (d, J = 10.6Hz, 1H), 8.12 (d, J = 10.4Hz, 1H), 7.79 (d, J = 5.0 Hz,1H),7.43–7.34(m,2H),7.30–7.16(m,7H),7.10(ddd,J＝7.9,6.9,2.1Hz,1H),4.85(dt,J＝10.6,7.1Hz, 1H),4.19 (dtd,J＝10.4,6.9,6.1Hz,1H),3.72(s,2H),3.21(td,J＝7.1,4.6Hz,2H),3.06(ddt,J＝12.5,7.0,0.9Hz,1H ),3.03–2.96(m,1H),2.41(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.0Hz,1H),1.94(dt,J＝12.5,6.9Hz,1H) ,1.81(dq,J＝12.2,7.1Hz,1H),1.72(dq,J＝12.4,7.2Hz,1H).ESI-MS m/z 546.2[M+H] ⁺

Example 51: Synthesis of Compound 51

The synthesis of compound 51 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediate 1-8 is replaced by 51-1.

1H NMR(500MHz,Chloroform-d)δ8.61(d,J＝11.5Hz,1H),8.28–8.21(m,2H),8.19(dd,J＝7.5,1.4Hz,1H),8.08(d, J＝10.4Hz,1H),7.99(dq,J＝7.5,1.1Hz,1H),7.75(td,J＝7.5,1.5Hz,1H),7.55(td,J＝7.5,1.5Hz,1H), 7.22–7.16(m,2H),4.37(dt,J＝11.5,7.0Hz,1H),4.19(dtd,J＝10.4,6.9,6.1Hz,1H),3.72(s,2H),3.21(td, J＝7.1,4.6Hz,2H),2.41(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.0Hz,1H),1.94(dt,J＝12.6,7.0Hz,1H), 1.86–1.65(m,4H),1.61–1.38(m,11H).ESI-MS m/z 546.2[M+H]+

Example 52: Synthesis of Compound 52

Synthesis of compound 52-2:

Compound 52-1 (0.58g, 2.7mmol) was dissolved in dichloromethane (20mL), the reaction solution was cooled to -20°C, then HATU (1.2g, 3.2mmol) was added to the reaction solution, and stirred for 20 minutes. Compound 1-7 (1 g, 2.7 mmol) was added to the reaction solution, and the mixture was stirred again at -20°C for 30 minutes, and then DIPEA (1.2 mL, 8.1 mmol) was added dropwise to the reaction solution. After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (20X3mL), saturated sodium bicarbonate solution (20X3mL), and saturated sodium chloride solution (20X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distillation and column chromatography separation (DCM:MeOH=30:1v/v) yielded white solid 52-2 (1g) with a yield of 71%.

Synthesis of compound 52-3:

Compound 52-2 (1g, 1.9mmol) was dissolved in dichloromethane (10mL), 4M HCl dioxane solution (10mL) was added at 0°C, the reaction was continued to stir at room temperature for 12h, and then the solution was evaporated. After drying, intermediate 52-3 is obtained, which can be directly used in the next reaction without purification.

Synthesis of compound 52-4:

Compound 51-1 (0.3g, 1.7mmol) was dissolved in dichloromethane (20mL), the reaction solution was cooled to -20°C, then HATU (0.76g, 2.0mmol) was added to the reaction solution, and stirred for 20 minutes. Intermediate 52-3 from the previous step was added to the reaction solution, and stirred again at -20°C for 30 minutes. Then DIPEA (0.75 mL, 5.0 mmol) was added dropwise to the reaction solution. After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (20X3mL), saturated sodium bicarbonate solution (20X3mL), and saturated sodium chloride solution (20X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distillation and column chromatography separation (DCM:MeOH=20:1v/v) gave compound 52-4 (0.64g) as a white solid with a yield of 64%.

Synthesis of compound 52-5:

Compound 52-4 (0.6 g, 1.0 mmol) was dissolved in 15 mL of tetrahydrofuran, sodium borohydride (230 mg, 6.1 mmol) was slowly added in batches, and then 1 mL of methanol was added dropwise and stirred at room temperature for about 4 hours. After the reaction is completed, add about 10 mL of saturated sodium chloride solution to quench the reaction, and add ethyl acetate for extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=20:1v/v) to obtain white solid 52-5 (0.4g) with a yield of 70%.

Synthesis of compound 52-6:

Compound 52-5 (0.35g, 0.6mmol) was dissolved in 10 mL of methylene chloride, Dess-Martin oxidant (0.4g, 0.9mmol) was added, and the mixture was stirred at room temperature. After TLC detects that the reaction is complete, the reaction solution is extracted with saturated sodium thiosulfate solution until clear, and the organic phase is dried with anhydrous sodium sulfate and concentrated. After column chromatography separation (DCM:MeOH=20:1, v/v), white solid 52-6 (0.21g) was obtained with a yield of 60%.

Synthesis of compound 52

Compound 52-6 (150 mg, 0.27 mmol) was dissolved in 3 mL of anhydrous dichloromethane, compound 5-1 (29 mg, 0.29 mmol) and piperidine (5.3 μL, 53 μmol) were added dropwise with stirring at room temperature, and the reaction was carried out at room temperature for 4 hours. , concentrated under reduced pressure. After column chromatography separation (DCM:MeOH=20:1), white solid compound 52 (70 mg) was obtained with a yield of 41%.

1H NMR(500MHz,Chloroform-d)δ8.43(d,J＝11.9Hz,1H),8.28–8.21(m,2H),8.19(dd,J＝7.6,1.6Hz,1H),8.08(d, J＝10.4Hz,1H),8.02–7.96(m,1H),7.78–7.71(m,2H),7.54(td,J＝7.5,1.5Hz,1H),7.22–7.16(m,2H),4.51 (dd,J＝11.9,7.0Hz,1H),4.26(dt,J＝11.4,7.0Hz,1H),4.19(dtd,J＝10.4,6.9,6.1Hz,1H),3.74(s,2H), 3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H), 2.21–2.08(m,J＝6.8Hz,1H),2.02(dt,J＝12.3,7.0Hz,1H),1.95(dt,J＝12.2,6.9Hz,1H),1.81(dq,J＝12.4, 7.1Hz,1H),1.77–1.68(m,1H),1.68(t,J＝7.0Hz,2H),1.61–1.37(m,11H),0.94(d,J＝6.8Hz,3H),0.89( d,J＝6.8Hz,3H).ESI-MS m/z 645.3[M+H]+

Example 53: Synthesis of Compound 53

The synthesis of compound 53 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 53-1.

1H NMR(500MHz,Chloroform-d)δ9.60(s,1H),8.42(d,J＝11.0Hz,1H),7.73(d,J＝11.2Hz,1H),7.67(ddd,J＝7.0, 2.5,1.5Hz,1H),7.46–7.40(m,1H),7.25–7.16(m,4H),7.20–7.12(m,1H),6.24(d,J＝6.2Hz,1H),6.14(d ,J＝6.0Hz,0H),4.51(dd,J＝11.0,7.0Hz,1H),4.30–4.14(m,4H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p, J＝7.0Hz,1H),2.18(dp,J＝13.6,6.9Hz,1H),2.04(dt,J＝12.4,7.0Hz,1H),1.95(dt,J＝12.5,6.9Hz,1H), 1.81(dq,J＝12.5,7.1Hz,1H),1.76–1.68(m,1H),1.68(t,J＝7.0Hz,2H),1.61–1.46(m,7H),1.48–1.43(m, 3H),1.46–1.37(m,2H),1.27(t,J＝8.0Hz,3H),0.94(d,J＝6.8Hz,3H),0.89(d,J＝6.8Hz,3H).ESI- MS m/z 640.3[M+H]+

Example 54: Synthesis of Compound 54

The synthesis of compound 54 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 54-1.

1H NMR(500MHz,Chloroform-d)δ9.72(s,1H),8.35(d,J＝11.2Hz,1H),7.74(d,J＝11.2Hz,1H),7.35(d,J＝7.6Hz ,1H),7.19(t,J＝4.6Hz,1H),7.17–7.12(m,2H),7.13(t,J＝1.6Hz,1H),6.81(dd,J＝7.5,1.5Hz,1H) ,6.24(d,J＝6.2Hz,1H),6.14(d,J＝6.0Hz,0H),4.51(dd,J＝11.0,7.0Hz,1H),4.32–4.14(m,4H),3.83( s,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.19(dq,J＝13.7,6.9Hz,1H),2.04(dt,J ＝12.5,6.9Hz,1H),1.95(dt,J＝12.5,6.9Hz,1H),1.81(dq,J＝12.5,7.1Hz,1H),1.76–1.68(m,1H),1.68(t, J＝7.0Hz,2H),1.60–1.37(m,12H),1.27(t,J＝8.0Hz,3H),0.94(d,J＝6.9Hz,3H),0.89(d,J＝6.8Hz, 3H).ESI-MS m/z 670.3[M+H]+

Example 55: Synthesis of Compound 55

The synthesis of compound 55 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 56-1.

1H NMR(500MHz,Chloroform-d)δ7.85(d,J＝11.7Hz,1H),7.76(d,J＝11.3Hz,1H),7.58–7.53(m,2H),7.25(td,J＝ 7.5,1.6Hz,1H),7.19(t,J＝4.6Hz,1H),7.15(d,J＝11.2Hz,1H),7.07(td,J＝7.5,1.5Hz,1H),6.92(dd, J＝7.5,1.5Hz,1H),6.24(d,J＝6.2Hz,1H),6.14(d,J＝6.0Hz,1H),4.99(t,J＝1.2Hz,2H),4.38(dd, J＝11.6,7.1Hz,1H),4.30–4.14(m,4H),3.21(td,J＝7.1,4.5Hz,2H),2.46(p,J＝7.0Hz,1H),2.04(dt,J ＝12.5,7.0Hz,1H),2.00–1.85(m,2H),1.81(dq,J＝12.5,7.1Hz,1H),1.76–1.68(m,1H),1.68(t,J＝7.0Hz, 2H),1.60–1.37(m,12H),1.27(t,J＝8.0Hz,3H),0.90(d,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H).ESI- MS m/z 655.3[M+H]+

Example 56: Synthesis of Compound 56

The synthesis of compound 56 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 56-1.

1H NMR(500MHz,Chloroform-d)δ7.84(dd,J＝11.5,8.0Hz,2H),7.71(d,J＝9.9Hz,1H),7.58–7.53(m,2H),7.25(td, J＝7.5,1.6Hz,1H),7.20(td,J＝7.5,1.7Hz,1H),7.13(t,J＝4.6Hz,1H),6.93(dd,J＝7.4,1.7Hz,1H), 4.99(t,J＝1.1Hz,2H),4.52(dt,J＝9.9,7.1Hz,1H),4.38(dd,J＝11.6,7.1Hz,1H),4.27(dt,J＝11.4,7.0Hz ,1H),3.24–3.10(m,2H),2.55(p,J＝7.0Hz,1H),2.10(dt,J＝12.2,6.9Hz,1H),2.01(dt,J＝12.2,7.0Hz, 1H),1.97–1.80(m,2H),1.80–1.72(m,1H),1.69(td,J＝7.0,1.9Hz,2H),1.61–1.36(m,12H),0.91(d,J＝ 6.8Hz,3H),0.86(d,J＝6.7Hz,3H).ESI-MS m/z 564.3[M+H]+

Example 57: Synthesis of Compound 57

The synthesis of compound 57 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 57-1.

¹ H NMR(500MHz,Chloroform-d)δ9.58(d,J＝1.5Hz,1H),8.78(t,J＝1.7Hz,1H),8.33(dt,J＝7.8,1.6Hz,1H), 8.29(d,J＝11.2Hz,1H),8.03(dd,J＝7.7,1.6Hz,1H),7.80–7.72(m,2H),7.74–7.66(m,2H),7.13(t,J＝ 4.6Hz,1H),4.56–4.43(m,2H),4.27(dt,J＝11.4,7.0Hz,1H),3.24–3.10(m,2H),2.55(p,J＝7.0Hz,1H), 2.21–2.10(m,1H),2.13–2.05(m,1H),2.01(dt,J＝12.2,7.0Hz,1H),1.84(dq,J＝12.1,7.0Hz,1H),1.80–1.72( m,1H),1.69(td,J＝7.0,1.9Hz,2H),1.61–1.36(m,11H),0.95(d,J＝6.7Hz,3H),0.90(d,J＝6.8Hz,3H ).ESI-MS m/z 561.3[M+H] ⁺

Example 58: Synthesis of Compound 58

The synthesis of compound 58 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 58-1.

¹ H NMR (500MHz, Chloroform-d) δ8.36(d,J＝11.9Hz,1H),7.84(d,J＝11.3Hz,1H),7.71(d,J＝9.9Hz,1H),7.16( t,J＝4.6Hz,1H),6.59(s,1H),4.56–4.44(m,2H),4.31(dt,J＝11.4,7.1Hz,1H),3.25–3.10(m,2H),2.52 (s,3H),2.52(p,J＝7.0Hz,1H),2.21–2.06(m,2H),2.01(dt,J＝12.4,7.0Hz,1H),1.90–1.64(m,4H), 1.62–1.37(m,12H),0.94(d,J＝6.8Hz,2H),0.89(d,J＝6.8Hz,3H).

ESI-MS m/z 515.2[M+H] ⁺

Example 59: Synthesis of Compound 59

The synthesis of compound 59 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 59-1.

1H NMR(500MHz,Chloroform-d)δ8.38(d,J＝12.3Hz,1H),7.84(d,J＝10.3Hz,1H),7.71(d,J＝9.9Hz,1H),7.16(t ,J＝4.6Hz,1H),6.57(s,1H),4.52(dt,J＝9.9,7.1Hz,1H),4.42(d,J＝12.3Hz,1H),4.28(dt,J＝10.3, 7.0Hz,1H),3.25–3.10(m,2H),2.56(q,J＝7.0Hz,1H),2.52(s,2H),2.10(dt,J＝12.2,6.9Hz,1H),2.01( dt,J＝12.2,7.0Hz,1H),1.84(dq,J＝12.5,7.0Hz,1H),1.80–1.72(m,1H),1.74–1.64(m,2H),1.61–1.37(m, 11H),0.97(s,6H).ESI-MS m/z 529.3 [M+H]+

Example 60: Synthesis of Compound 60

The synthesis of compound 60 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 60-1.

¹ H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.53(d,J＝9.1Hz,1H),7.89(d,J＝11.3Hz,1H),7.74–7.64(m,2H ),7.46–7.39(m,1H),7.25–7.18(m,3H),7.16(t,J＝4.6Hz,1H),4.52(dt,J＝9.9,7.1Hz,1H),4.34(dd, J＝9.2,7.0Hz,1H),4.27(dt,J＝11.4,7.0Hz,1H),3.25–3.10(m,2H),2.55(p,J＝7.0Hz,1H),2.14–2.05(m ,2H),2.01(dt,J＝12.2,7.0Hz,1H),1.89–1.80(m,1H),1.80–1.72(m,1H),1.69(td,J＝7.0,1.9Hz,2H), 1.61–1.37(m,11H),1.39–1.29(m,2H),1.29–1.17(m,2H).ESI-MS m/z 547.3[M+H] ⁺

Example 61: Synthesis of Compound 61

The synthesis of compound 61 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 61-1.

¹ H NMR(500MHz,Chloroform-d)δ7.76(d,J＝11.3Hz,1H),7.73–7.65(m,2H),7.64(t,J＝1.5Hz,1H),7.59(dtd,J ＝7.3,1.5,0.7Hz,1H),7.52–7.45(m,2H),7.42(t,J＝7.4Hz,1H),7.16(t,J＝4.6Hz,1H),6.49(d,J＝ 15.2Hz,1H),4.52(dt,J＝9.9,7.1Hz,1H),4.36(dd,J＝11.4,7.0Hz,1H),4.27(dt,J＝11.4,7.0Hz,1H),3.24– 3.10(m,2H),2.55(p,J＝7.0Hz,1H),2.10(dt,J＝12.2,6.9Hz, 1H),2.05–1.88(m,2H),1.89–1.80(m,1H),1.80–1.72(m,1H),1.69(td,J＝7.0,1.9Hz,2H),1.61–1.36(m, 11H),0.86(d,J＝6.9Hz,3H),0.81(d,J＝6.8Hz,3H).ESI-MS m/z 570.2[M+H] ⁺

Example 62: Synthesis of Compound 62

The synthesis of compound 62 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 62-2.

¹ H NMR (500MHz, Chloroform-d) δ8.14(d,J＝11.0Hz,1H),7.76(d,J＝11.3Hz,1H),7.67(d,J＝9.9Hz,1H),7.52( dd,J＝7.5,1.6Hz,1H),7.38(d,J＝1.5Hz,1H),7.13(t,J＝4.6Hz,1H),6.91(d,J＝7.5Hz,1H),4.56– 4.43(m,2H),4.33–4.26(m,4H),4.29–4.23(m,1H),3.24–3.10(m,2H),2.55(p,J＝7.0Hz,1H),2.19–2.10( m,1H),2.13–2.05(m,1H),2.01(dt,J＝12.2,7.0Hz,1H),1.84(dq,J＝12.1,7.0Hz,1H),1.80–1.72(m,1H) ,1.69(td,J＝7.0,1.9Hz,2H),1.61–1.36(m,12H),0.95(d,J＝6.8Hz,3H),0.90(d,J＝6.7Hz,3H).ESI- MS m/z568.3[M+H] ⁺

Example 63: Synthesis of Compound 63

The synthesis of compound 63 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 63-1.

1H NMR(500MHz,Chloroform-d)δ9.56(s,1H),8.47(d,J＝10.8Hz,1H),7.73–7.65(m,2H),7.43(dd,J＝7.1,1.8Hz, 1H),7.26–7.15(m,3H),7.10(t,J＝4.6Hz,1H),4.51(ddt,J＝31.9,10.6,7.0Hz,2H),3.25–3.10(m,2H),2.52 (p,J＝ 7.0Hz,1H),2.10(dt,J＝12.8,6.9Hz,1H),2.01(dt,J＝12.5,7.2Hz,1H),1.90–1.65(m,6H),1.68–1.57(m,2H ),1.60–1.52(m,5H),1.55–1.48(m,1H).ESI-MS m/z 436.2[M+H]+

Example 64: Synthesis of Compound 64

The synthesis of compound 64 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 63-1.

1H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.53(d,J＝10.6Hz,1H),7.68(dtt,J＝4.2,3.1,1.5Hz,1H),7.46–7.39( m,1H),7.22(d,J＝3.5Hz,1H),7.24–7.19(m,2H),7.21–7.12(m,2H),6.20(d,J＝6.2Hz,1H),6.10(d ,J＝6.2Hz,1H),4.43(dt,J＝10.6,7.0Hz,1H),4.30–4.14(m,3H),3.21(td,J＝7.1,4.6Hz,2H),2.40(p, J＝7.0Hz,1H),2.09(dt,J＝12.5,6.9Hz,1H),1.94(dt,J＝12.4,7.1Hz,1H),1.86–1.65(m,6H),1.67–1.62(m ,1H),1.65–1.61(m,2H),1.64–1.51(m,4H),1.54–1.46(m,1H),1.27(t,J＝8.0Hz,3H).ESI-MS m/z 527.2 [M+H]+

Example 65: Synthesis of Compound 65

Synthesis of compounds 1-4:

Synthesis of compound 65-2:

Compound 65-1 (0.98g, 3.5mmol) was dissolved in dichloromethane (40mL), the reaction solution was cooled to -20°C, then HATU (1.9g, 4.9mmol) was added to the reaction solution, and stirred for 20 minutes. Intermediate 1-4 obtained in the previous step was added to the reaction solution, stirred again at -20°C for 30 minutes, and then DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution.

After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (40X3mL), saturated sodium bicarbonate solution (40X3mL), and saturated sodium chloride solution (40X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distilled and separated by column chromatography (DCM:MeOH=40:1v/v), 1.3g of white solid 65-2 was obtained with a yield of 82%.

Synthesis of compound 65-3:

Compound 65-2 (1.3g, 2.9mmol) was dissolved in dichloromethane (20mL), 4M HCl dioxane solution (9mL, 35mmol) was added at 0°C, the reaction was continued to stir at room temperature for 12h, and then The solution was evaporated to dryness to obtain intermediate 65-3, which was directly carried out to the next reaction without purification.

Synthesis of compound 65-4:

Dissolve compound 1-8 (0.47g, 2.9mmol) in dichloromethane (40mL), and cool the reaction solution to -20°C, then add HATU (1.3g, 3.5mmol) to the reaction solution, stir for 20 minutes, add the intermediate 1-7 obtained in the previous step to the reaction solution, stir again at -20°C for 30 minutes, and then add DIPEA (1.7mL, 10.5mmol) was added dropwise to the reaction solution.

After the reaction was stirred for 12 hours, the reaction was extracted with saturated ammonium chloride solution (40X3mL), saturated sodium bicarbonate solution (40X3mL), and saturated sodium chloride solution (40X3mL). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and then decompressed. Distilled and separated by column chromatography (DCM:MeOH=30:1v/v), 1.1g of white solid 65-4 was obtained with a yield of 85%.

Synthesis of compound 65-5:

Compound 65-4 (1.0 g, 2.4 mmol) was dissolved in 40 mL of tetrahydrofuran, sodium borohydride (540 mg, 14.3 mmol) was slowly added in batches, and then 1 mL of methanol was added dropwise and stirred at room temperature for about 4 hours. After the reaction is completed, add about 40 mL of saturated sodium chloride solution to quench the reaction, and add ethyl acetate for extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=20:1v/v) to obtain 0.77g of white solid 65-5, with a yield of 70%.

Synthesis of compound 65:

Compound 65-4 (0.7 g, 1.61 mmol) was dissolved in 20 mL of methylene chloride, Dess-Martin oxidant (0.96 g, 2.27 mmol) was added, and the mixture was stirred at room temperature. After TLC detects that the reaction is complete, the reaction solution is extracted with saturated sodium thiosulfate solution until clear, and the organic phase is dried with anhydrous sodium sulfate and concentrated. After column chromatography separation (DCM:MeOH=20:1, v/v), 0.4g of white solid 65 was obtained, with a yield of 60%.

1H NMR(500MHz,Chloroform-d)δ9.54(d,J＝6.2Hz,1H),9.45(s,1H),7.43(dt,J＝7.4,1.6Hz,1H),7.29–7.10(m, 8H),7.07(t,J＝4.6Hz,1H),6.49–6.43(m,2H),4.53(t,J＝7.0Hz,1H),4.35(dtd,J＝11.9,6.9,6.1Hz,1H ),3.32–3.11(m,3H),3.15(s,3H),3.07(ddt,J＝12.3,7.0,0.9Hz,1H),2.49(p,J＝7.0Hz,1H),2.13–1.98( m,2H),1.87–1.68(m,2H).ESI-MS m/z 433.5[M+H]+

Example 66: Synthesis of Compound 66

The synthesis of compound 66 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 66-1.

1H NMR(500MHz,Chloroform-d)δ9.57–9.52(m,2H),8.46(d,J＝11.3Hz,1H),7.71–7.64(m,1H),7.46–7.39(m,1H), 7.37–7.26(m,5H),7.25–7.18(m,3H),7.11(t,J＝4.6Hz,1H),5.97(d,J＝12.4Hz,1H),4.65–4.58(m,2H) ,4.52(d,J＝12.3Hz,1H),4.42–4.29(m,2H),3.32–3.14(m,2H),2.53(p,J＝7.0Hz,1H),2.08(dt,J＝12.2 ,7.1Hz,1H),2.00(dt,J＝12.4,7.2Hz,1H),1.81(dq,J＝12.6,7.0Hz,1H),1.72(dq,J＝12.2,7.0Hz,1H),1.26 (d,J＝6.8Hz,3H).ESI-MS m/z 491.2[M+H]+

Example 67: Synthesis of Compound 67

The synthesis of compound 67 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 67-1.

1H NMR(500MHz,Chloroform-d)δ9.54(d,J＝6.2Hz,1H),9.45(s,1H),7.44(dt,J＝7.4,1.7Hz,1H),7.25(dd,J＝ 7.4,2.0Hz,1H),7.20(td,J＝7.4,1.7Hz,1H),7.15(td,J＝7.4,1.6Hz,1H),7.07(t,J＝4.6Hz,1H),6.41( d,J＝11.9Hz,1H),6.22(d,J＝1.4Hz,1H),4.34(dtd,J＝11.9,6.9,6.1Hz,1H),4.16–4.10(m,1H),3.21(tdd ,J＝7.1,4.6,1.2Hz,2H),3.14(s,2H),2.49(p,J＝7.0Hz,1H),2.09(dt,J＝12.4,6.9Hz,1H),2.00(dt, J＝12.4,7.0Hz,1H),1.87–1.74(m,2H),1.77–1.70(m,1H),1.73–1.65(m,2H),1.68–1.59(m,1H),0.92–0.84( m,3H),0.87–0.79(m,3H).ESI-MS m/z 399.5[M+H]+

Example 68: Synthesis of Compound 68

The synthesis of compound 68 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 68-1.

1H NMR(500MHz,Chloroform-d)δ9.77(s,1H),9.54(d,J＝6.2Hz,1H),7.68(dt,J＝7.3,1.7Hz,1H),7.43(dd,J＝ 7.4,1.6Hz,1H),7.23(td,J＝7.6,1.9Hz,1H),7.22–7.15(m,2H),7.07(t,J＝4.6Hz,1H),6.86(d,J＝11.9 Hz,1H),4.35(dtd,J＝11.9,7.0,6.2Hz,1H),4.26–4.20(m,1H),4.20–4.13(m,1H),3.32–3.16(m,2H),2.48( p,J＝7.0Hz,1H),2.17(hd,J＝7.0,0.7Hz,1H),2.12–1.99(m,2H),2.01–1.94(m,1H),1.87–1.67(m,4H) ,1.55–1.24(m,8H).ESI-MS m/z 451.2[M+H]+

Example 69: Synthesis of Compound 69

The synthesis of compound 69 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 69-1.

1H NMR(500MHz,Chloroform-d)δ9.77(s,1H),9.54(d,J＝6.2Hz,1H),7.68(dt,J＝7.3,1.8Hz,1H),7.43(dd,J＝ 7.3,1.6Hz,1H),7.23(td,J＝7.4,1.7Hz,1H),7.20–7.14(m,2H),7.07(t,J＝4.6Hz,1H),6.65(d,J＝11.9 Hz,1H),4.34(dtd,J＝11.9,6.9,6.2Hz,1H),4.25(t,J＝7.0Hz,1H),3.58(s,2H),3.32–3.16(m,2H),2.49 (p,J＝7.0Hz,1H),2.09(dt,J＝12.6,7.0Hz,1H),2.02(dt,J＝12.5,7.2Hz,1H),1.88(d,J＝6.9Hz,1H) ,1.85–1.68(m,7H).ESI-MS m/z 423.2[M+H]+

Example 70: Synthesis of Compound 70

The synthesis of compound 70 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 70-1.

1H NMR (500MHz, Chloroform-d) δ9.77 (s, 1H), 9.54 (d, J＝6.2Hz, 1H), 7.68 (dt, J＝7.3, 1.6Hz, 1H), 7.43 (dd, J＝ 7.3,1.6Hz,1H),7.23(td,J＝7.4,1.7 Hz,1H),7.20–7.14(m,2H),7.07(t,J＝4.6Hz,1H),6.76(d,J＝12.1Hz,1H),4.69(p,J＝7.0Hz,1H), 4.35(dtd,J＝12.3,6.9,6.1Hz,1H),4.26(d,J＝7.1Hz,1H),3.32–3.16(m,2H),2.49(p,J＝7.0Hz,1H),2.36 (h,J＝7.0Hz,1H),2.13–1.98(m,3H),1.98–1.66(m,9H).ESI-MS m/z 423.2[M+H]+

Example 71: Synthesis of Compound 71

The synthesis of compound 71 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 71-1.

1H NMR(500MHz,Chloroform-d)δ9.81(s,1H),9.54(d,J＝6.2Hz,1H),7.68(dt,J＝7.3,1.6Hz,1H),7.52(dd,J＝ 7.5,1.5Hz,1H),7.43(dd,J＝7.4,1.7Hz,1H),7.33–7.15(m,5H),7.07(t,J＝4.6Hz,1H),7.04–6.92(m,2H ),4.93(t,J＝7.0Hz,1H),4.35(dtd,J＝11.9,6.9,6.1Hz,1H),3.67(ddd,J＝12.4,6.9,1.0Hz,1H),3.44(ddd, J＝12.5,7.0,0.9Hz,1H),3.32–3.16(m,2H),2.49(p,J＝7.0Hz,1H),2.09(dt,J＝12.3,7.0Hz,1H),2.02(dt ,J＝12.4,7.1Hz,1H),1.82(dq,J＝12.1,7.0Hz,1H),1.73(dq,J＝12.5,7.0Hz,1H).ESI-MS m/z 445.2[M+H ]+

Example 72: Synthesis of Compound 72

The synthesis of compound 72 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 72-1.

¹ H NMR (500MHz, Chloroform-d) δ9.68 (s, 1H), 9.54 (d, J = 6.2Hz, 1H), 7.67 (dt, J = 7.3, 1.6Hz, 1H), 7.43 (dd, J ＝7.3,1.7Hz,1H),7.27–7.12(m,6H),7.12–7.04(m,2H),6.83(d,J＝11.9Hz,1H),4.82–4.73(m,2H),4.43( t,J＝7.0Hz,1H),4.35(dtd,J＝11.9,7.0,6.2Hz,1H),3.32–3.16(m,2H),2.98(ddd,J＝12.4,7.0,1.0Hz,1H) ,2.83(ddd,J＝12.4,6.9,1.0Hz,1H),2.49(p,J＝7.0Hz, 1H),2.08(dt,J＝12.4,6.9Hz,1H),2.00(dt,J＝12.5,6.9Hz,1H),1.82(dq,J＝12.1,7.0Hz,1H),1.73(dq,J ＝12.4,7.0Hz,1H).ESI-MS m/z 459.2[M+H] ⁺

Example 73: Synthesis of Compound 73

The synthesis of compound 73 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 68-1.

1H NMR(500MHz,Chloroform-d)δ9.92(s,1H),7.67(ddd,J＝5.4,3.5,1.6Hz,1H),7.58(d,J＝11.0Hz,1H),7.46–7.40( m,1H),7.25–7.16(m,5H),6.20(d,J＝6.2Hz,1H),6.10(d,J＝6.2Hz,1H),4.85–4.79(m,1H),4.27–4.14 (m,5H),3.21(td,J＝7.1,4.6Hz,2H),2.40(p,J＝7.0Hz,1H),2.23–1.89(m,5H),1.86–1.66(m,5H), 1.55–1.45(m,3H),1.48–1.42(m,2H),1.45–1.37(m,1H),1.40–1.32(m,1H),1.35–1.25(m,4H),1.25(s,1H ).ESI-MS m/z 539.2[M+H]+

Example 74: Synthesis of Compound 74

The synthesis of compound 74 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 74-1.

1H NMR (500MHz, Chloroform-d) δ9.65 (s, 1H), 9.54 (d, J＝6.2Hz, 1H), 7.68 (dt, J＝7.3, 1.7Hz, 1H), 7.43 (dd, J＝ 7.1,1.7Hz,1H),7.26–7.13(m,3H),7.07(t,J＝4.6Hz,1H),6.64(d,J＝11.7Hz,1H),4.35(dtd,J＝11.9,6.9 ,6.1Hz,1H),4.24(t,J＝7.0Hz,1H),4.17–3.97(m,2H),3.32–3.16(m,2H),2.53–2.46(m,1H),2.48–2.38( m,1H),2.26(tdd,J＝20.8,12.5,6.8Hz,1H),2.13–1.98(m,2H),1.87–1.68(m,2H).ESI-MS m/z 433.1[M+H ]+

Example 75: Synthesis of Compound 75

The synthesis of compound 75 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 75-1.

1H NMR(500MHz,Chloroform-d)δ9.77(s,2H),9.54(d,J＝6.2Hz,2H),7.68(dt,J＝7.3,1.7Hz,2H),7.43(dd,J＝ 7.1,1.7Hz,2H),7.26–7.15(m,6H),7.07(t,J＝4.6Hz,2H),6.78(d,J＝11.9Hz,2H),5.10(pd,J＝7.0,0.7 Hz,1H),5.01(pd,J＝7.1,0.7Hz,1H),4.39–4.29(m,4H),3.95(dd,J＝12.5,6.9Hz,1H),3.94–3.85(m,2H) ,3.83(dd,J＝12.4,7.0Hz,1H),3.32–3.16(m,4H),2.49(p,J＝7.0Hz,2H),2.29(dddt,J＝49.2,25.1,12.4,6.9Hz ,4H),2.09(dt,J＝12.5,7.0Hz,2H),2.00(dt,J＝12.4,7.0Hz,2H),1.87–1.71(m,5H).ESI-MS m/z 415.1[M +H]+

Example 76: Synthesis of Compound 76

The synthesis of compound 76 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 76-1.

1H NMR (500MHz, Chloroform-d) δ9.77 (s, 2H), 9.54 (d, J＝6.2Hz, 2H), 7.68 (dt, J＝7.3, 1.7Hz, 2H), 7.43 (dd, J＝ 7.2,1.7Hz,2H),7.23(td,J＝7.4,1.6Hz,2H),7.22–7.15(m,4H),7.07(t,J＝4.6Hz,2H),6.78(d,J＝11.9 Hz,2H),5.13(pd,J＝7.1,0.9Hz,1H),5.04(pd,J＝7.0,0.7Hz,1H),4.39–4.29(m,4H),3.79(dddd,J＝36.4, 25.1,12.5,6.9Hz,4H),3.32–3.16(m,4H),2.49(p,J＝7.0Hz,2H),2.36(ddt,J＝25.2,12.4,7.0Hz,2H),2.19(ddt ,J＝25.2,12.6,6.9Hz,2H),2.09(dt,J＝12.5,7.0Hz,2H),2.00(dt,J＝12.4,7.0Hz,2H),1.87–1.71(m,5H). ESI-MS m/z 415.1[M+H]+

Example 77: Synthesis of Compound 77

The synthesis of compound 77 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 77-1.

1H NMR(500MHz,Chloroform-d)δ9.77(s,1H),9.54(d,J＝6.2Hz,1H),7.68(dt,J＝7.3,1.7Hz,1H),7.43(dd,J＝ 7.2,1.6Hz,1H),7.23(td,J＝7.4,1.6Hz,1H),7.22–7.15(m,2H),7.07(t,J＝4.6Hz,1H),6.70(d,J＝11.9 Hz,1H),4.40–4.30(m,2H),3.96(dt,J＝12.4,7.0Hz,1H),3.88(dt,J＝12.5,6.9Hz,1H),3.32–3.16(m,2H) ,2.49(p,J＝7.0Hz,1H),2.09(dt,J＝12.5,7.0Hz,1H),2.00(dt,J＝12.5,6.9Hz,1H),1.92–1.56(m,9H). ESI-MS m/z 411.2[M+H]+

Example 78: Synthesis of Compound 78

The synthesis of compound 78 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by compound 72-1.

1H NMR(500MHz,Chloroform-d)δ9.68(s,1H),7.71–7.64(m,2H),7.43(dd,J＝7.3,1.7Hz,1H),7.27–7.12(m,6H), 7.12–7.07(m,2H),4.82–4.73(m,2H),4.53–4.45(m,2H),3.25–3.10(m,2H),2.94(ddd,J＝12.4,7.0,1.0Hz,1H ),2.86(ddd,J＝12.3,7.0,0.9Hz,1H),2.52(p,J＝7.0Hz,1H),2.10(dt,J＝12.8,7.0Hz,1H),2.01(dt,J＝ 12.4,7.2Hz,1H),1.81(ddq,J＝43.2,12.4,7.1Hz,2H).ESI-MS m/z 456.2[M+H]+

Example 79: Synthesis of Compound 79

The synthesis of compound 79 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 68-1.

1H NMR(500MHz,Chloroform-d)δ9.77(s,1H),7.73–7.65(m,2H),7.43(dd,J＝7.4,1.6Hz,1H),7.26–7.15(m,3H), 7.10(t,J＝4.6Hz,1H),4.49(dt,J＝9.7,7.1Hz,1H),4.26–4.17(m,2H),3.25–3.10(m,2H),2.52(p,J＝ 7.0Hz,1H),2.21(h,J＝7.0Hz,1H),2.10(dt,J＝12.5,7.0Hz,1H),2.06–1.94(m,2H),1.91–1.67(m,4H), 1.55–1.28(m,7H).ESI-MS m/z 448.2[M+H]+

Example 80: Synthesis of Compound 80

The synthesis of compound 80 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 68-1 and 80-1.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 7.96–7.90 (m, 1H), 7.71 (d, J = 9.7Hz, 1H), 7.21–7.16 (m, 1H), 7.16 –7.07(m,3H),4.49(dt,J＝9.7,7.1Hz,1H),4.24(q,J＝6.9Hz,2H),3.25–3.10(m,2H),2.49(p,J＝7.0 Hz,1H),2.21(p,J＝7.0Hz,1H),2.10(dt,J＝12.3,7.0Hz,1H),2.00(ddt,J＝12.4,11.7,6.9Hz,2H),1.91–1.66 (m,5H),1.55–1.44(m,5H),1.47–1.37(m,1H),1.39–1.29(m,1H).ESI-MS m/z 466.2[M+H] ⁺

Example 81: Synthesis of Compound 81

The synthesis of compound 81 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediates 1-5 and 5-1 are replaced by 68-1 and 6-1.

1H NMR(500MHz,Chloroform-d)δ9.92(s,1H),8.49(d,J＝10.2Hz,1H),7.71–7.63(m,1H),7.46–7.39(m,1H),7.25– 7.16(m,5H),4.85–4.79(m,1H),4.30(dq,J＝12.7,8.1Hz,1H),4.26–4.18(m,2H),4.22–4.14(m,1H),3.21( td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.17(hd,J＝7.0,0.7Hz,1H),2.07(dt,J＝12.2,7.1Hz,1H ),1.96(ddt,J＝24.0,12.6,7.0Hz,2H),1.91–1.76(m,2H),1.78–1.67(m,2H),1.54–1.27(m,10H).ESI-MS m/ z 546.2[M+H]+

Example 82: Synthesis of Compound 82

The synthesis of compound 82 was based on the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 was replaced with 70-1.

1H NMR(500MHz,Chloroform-d)δ9.77(s,1H),7.72–7.65(m,2H),7.43(dd,J＝7.2,1.8Hz,1H),7.23(td,J＝7.4,1.6 Hz,1H),7.21–7.14(m,2H),7.10(t,J＝4.6Hz,1H),4.61(p,J＝7.0Hz,1H),4.57–4.48(m,2H),3.25–3.10 (m,2H),2.52(p,J＝7.0Hz,1H),2.36(h,J＝7.0Hz,1H),2.14–1.97(m,3H),1.97–1.74(m,7H),1.69( dq,J＝12.2,6.9Hz,1H).ESI-MS m/z 420.2[M+H]+

Example 83: Synthesis of Compound 83

The synthesis of compound 83 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 70-1 and 80-1.

1H NMR(500MHz,Chloroform-d)δ7.96–7.89(m,1H),7.69(d,J＝10.1Hz,1H),7.18(dd,J＝8.1,1.5Hz,1H),7.15(d, J＝1.4Hz,1H),7.14–7.07(m, 2H),4.64(p,J＝7.0Hz,1H),4.57–4.48(m,2H),3.25–3.10(m,2H),2.52(p,J＝7.0Hz,1H),2.36(h,J ＝7.0Hz,1H),2.14–1.97(m,3H),1.95–1.87(m,1H),1.90–1.83(m,2H),1.86–1.78(m,2H),1.80–1.75(m,1H ),1.78–1.70(m,1H),1.72–1.63(m,1H).ESI-MS m/z 438.1[M+H]+

Example 84: Synthesis of Compound 84

The synthesis of compound 84 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 70-1 and 84-1.

¹ H NMR (500MHz, Chloroform-d) δ8.42 (d, J＝13.4Hz, 1H), 8.28–8.21 (m, 2H), 8.18 (dd, J＝7.6, 1.7Hz, 1H), 8.02–7.96 (m,1H),7.78–7.71(m,2H),7.55(td,J＝7.5,1.5Hz,1H),7.16(t,J＝4.6Hz,1H),4.69–4.61(m,1H), 4.59(d,J＝13.4Hz,1H),4.51(dt,J＝10.1,7.1Hz,1H),4.44(d,J＝7.1Hz,1H),3.25–3.10(m,2H),2.53(p ,J＝7.0Hz,1H),2.42(h,J＝7.0Hz,1H),2.11(dt,J＝12.2,7.0Hz,1H),2.01(dt,J＝12.5,7.0Hz,1H),1.92 (dq,J＝11.7,6.9Hz,1H),1.90–1.83(m,2H),1.87–1.80(m,2H),1.83–1.64(m,4H),1.00(s,7H).ESI-MS m/z 545.2[M+H] ⁺

Example 85: Synthesis of Compound 85

The synthesis of compound 85 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 70-1 and 85-1.

1H NMR(500MHz,Chloroform-d)δ8.33(d,J＝13.2Hz,1H),8.28–8.21(m,2H),8.18(dd,J＝7.7,1.8Hz,1H),7.99(ddt, J＝7.0,1.6,1.0Hz,1H),7.78–7.71(m,2H),7.55(td,J＝7.5,1.5Hz,1H),7.16(t,J＝4.6Hz,1H),4.89(p ,J=6.9 Hz,1H),4.55–4.47(m,2H),4.44(d,J＝7.1Hz,1H),3.25–3.10(m,2H),2.52(p,J＝7.0Hz,1H),2.42(h ,J＝7.0Hz,1H),2.16–1.97(m,3H),1.97–1.88(m,2H),1.91–1.80(m,3H),1.84–1.64(m,4H),0.92(d,J ＝6.8Hz,3H),0.87(d,J＝6.8Hz,3H).ESI-MS m/z 531.2[M+H]+

Example 86: Synthesis of Compound 86

The synthesis of compound 86 refers to the synthesis of compound 65, and the corresponding intermediates 65-1 and 1-8 are replaced by 70-1 and 85-1.

1H NMR(500MHz,Chloroform-d)δ9.54(d,J＝6.2Hz,1H),8.33(d,J＝13.2Hz,1H),8.28–8.21(m,2H),8.18(dd,J＝ 7.7,1.8Hz,1H),7.99(ddt,J＝7.0,1.6,1.0Hz,1H),7.75(td,J＝7.5,1.6Hz,1H),7.55(td,J＝7.5,1.5Hz,1H ),7.12(t,J＝4.6Hz,1H),6.76(d,J＝12.1Hz,1H),4.64(p,J＝7.0Hz,1H),4.51(dd,J＝13.0,7.0Hz,1H ),4.41(d,J＝7.0Hz,1H),4.36(dtd,J＝12.1,7.0,6.1Hz,1H),3.32–3.14(m,2H),2.53(p,J＝7.0Hz,1H) ,2.44(h,J＝7.0Hz,1H),2.13–1.66(m,13H),0.92(d,J＝6.8Hz,3H),0.87(d,J＝6.8Hz,3H).ESI-MS m /z534.2[M+H]+

Example 87: Synthesis of Compound 87

The synthesis of compound 87 refers to the synthesis of compound 65, and the corresponding intermediates 65-1 and 1-8 are replaced by 72-1 and 85-1.

1H NMR(500MHz,Chloroform-d)δ9.54(d,J＝6.2Hz,1H),8.46(d,J＝13.0Hz,1H),8.28–8.21(m,2H),8.17(dd,J＝ 7.5,1.4Hz,1H),7.99(ddt,J＝6.9, 1.6,0.9Hz,1H),7.75(td,J＝7.5,1.5Hz,1H),7.55(td,J＝7.5,1.6Hz,1H),7.27–7.19(m,2H),7.14(td,J ＝7.4,1.6Hz,1H),7.10(t,J＝4.6Hz,1H),7.08–7.03(m,1H),6.82(d,J＝11.7Hz,1H),4.86(dd,J＝12.4, 1.0Hz,1H),4.81(dd,J＝12.4,1.0Hz,1H),4.50(dd,J＝13.1,7.0Hz,1H),4.45(t,J＝7.0Hz,1H),4.34(dtd, J＝11.9,7.0,6.2Hz,1H),3.32–3.22(m,1H),3.19(dtd,J＝12.4,7.1,4.6Hz,1H),3.02(ddd,J＝12.5,7.0,0.9Hz, 1H),2.95(ddd,J＝12.4,7.0,1.1Hz,1H),2.54(p,J＝7.0Hz,1H),2.13–2.01(m,2H),1.98(dt,J＝12.2,6.9Hz ,1H),1.86–1.77(m,1H),1.72(dq,J＝12.4,7.1Hz,1H),0.85(d,J＝6.8Hz,3H),0.80(d,J＝6.9Hz,3H) .ESI-MS m/z 570.2[M+H]+

Example 88: Synthesis of Compound 88

The synthesis of compound 88 refers to the synthesis of compound 65, and the corresponding intermediates 65-1 and 1-8 are replaced by 68-1 and 85-1.

1H NMR(500MHz,Chloroform-d)δ9.54(d,J＝6.2Hz,1H),8.42(d,J＝13.2Hz,1H),8.28–8.21(m,2H),8.17(dd,J＝ 7.5,1.5Hz,1H),7.99(ddt,J＝6.9,1.6,1.0Hz,1H),7.75(td,J＝7.5,1.6Hz,1H),7.55(td,J＝7.5,1.5Hz,1H ),7.10(t,J＝4.6Hz,1H),6.86(d,J＝11.9Hz,1H),4.55(tt,J＝7.1,0.9Hz,1H),4.51(dd,J＝13.1,7.0Hz ,1H),4.34(dtd,J＝11.9,7.0,6.1Hz,1H),3.77(qd,J＝7.0,0.7Hz,1H),3.32–3.14(m,2H),2.54(p,J＝7.0 Hz,1H),2.18(hd,J＝7.0,0.7Hz,1H),2.13–2.00(m,3H),1.96(ddt,J＝24.7,12.3,7.0Hz,2H),1.81(dq,J＝ 12.4,7.0Hz,1H),1.77–1.65(m,2H),1.54–1.39(m,6H),1.41–1.31(m,1H),0.89(d,J＝6.8Hz,3H),0.84(d ,J＝6.8Hz,3H).ESI-MS m/z 562.3[M+H]+

Example 89: Synthesis of Compound 89

Compound 89 was synthesized with reference to compound 65, and the corresponding intermediates 65-1 and 1-8 were replaced by 69-1 and 85-1.

1H NMR(500MHz,Chloroform-d)δ9.54(d,J＝6.2Hz,1H),8.42(d,J＝13.0Hz,1H),8.28–8.21(m,2H),8.18(dd,J＝ 7.7,1.8Hz,1H),7.99(ddt,J＝6.9,1.6,0.9Hz,1H),7.75(td,J＝7.5,1.6Hz,1H),7.55(td,J＝7.5,1.5Hz,1H ),7.12(t,J＝4.6Hz,1H),6.64(d,J＝11.7Hz,1H),4.48(dd,J＝13.1,7.1Hz,1H),4.34(dtd,J＝11.9,7.0, 6.2Hz,1H),4.28(t,J＝7.0Hz,1H),3.34(s,2H),3.32–3.14(m,2H),2.55(p,J＝7.0Hz,1H),2.13–1.89( m,6H),1.88–1.77(m,4H),1.72(dq,J＝12.4,7.1Hz,1H),0.87(d,J＝6.8Hz,3H),0.82(d,J＝6.9Hz,3H ).ESI-MS m/z534.2[M+H]+

Example 90: Synthesis of Compound 90

Compound 90 was synthesized with reference to compound 65, and the corresponding intermediates 65-1 and 1-8 were replaced by 74-1 and 85-1.

¹ H NMR(500MHz,Chloroform-d)δ9.54(d,J＝6.2Hz,1H),8.44(d,J＝13.0Hz,1H),8.28–8.21(m,2H),8.18(dd,J ＝7.6,1.7Hz,1H),7.99(dt,J＝7.2,1.4Hz,1H),7.75(td,J＝7.5,1.5Hz,1H),7.55(td,J＝7.5,1.5Hz,1H) ,7.12(t,J＝4.6Hz,1H),6.64(d,J＝11.7Hz,1H),4.45(dd,J＝13.0,7.0Hz,1H),4.34(dtd,J＝11.9,7.0,6.2 Hz,1H),4.26(t,J＝7.0Hz,1H),3.87(td,J＝20.9,2.4Hz,2H),3.32–3.14(m,2H),2.61–2.53(m,1H),2.57 –2.45(m,1H),2.33(tdd,J＝20.8,12.3,7.0Hz,1H),2.07(ddt,J＝13.7,10.2,6.9Hz,2H),2.04–1.94(m,1H),1.81 (dq,J＝12.4,7.0Hz,1H),1.72(dq,J＝12.4,7.1Hz,1H),0.86(d,J＝6.9Hz,3H),0.81(d,J＝6.8Hz,3H) .ESI-MS m/z 544.2[M+H] ⁺

Example 91: Synthesis of Compound 91

Compound 68 (100 mg, 0.22 mmol) was dissolved in 3 mL of methanol, stirred at room temperature overnight, and spun to dryness to obtain compound 91.

¹ H NMR (500MHz, Chloroform-d) δ9.67 (s, 1H), 7.71–7.63 (m, 1H), 7.54 (d, J = 11.5Hz, 1H), 7.46–7.39 (m, 1H), 7.27 –7.19(m,2H),7.22–7.14(m,1H),7.10(t,J＝4.6Hz,1H),5.37(d,J＝6.2Hz,1H),4.81(tt,J＝7.0,0.7 Hz,1H),4.52(dd,J＝7.0,6.2Hz,1H),4.23–4.15(m,1H),3.79(dq,J＝11.5,7.0Hz,1H),3.32(s,2H),3.32 –3.16(m,2H),2.46(p,J＝7.0Hz,1H),2.22–2.12(m,1H),2.00(dt,J＝12.3,7.0Hz,1H),1.96–1.83(m,2H ),1.86–1.78(m,2H),1.78–1.67(m,2H),1.55–1.47(m,2H),1.48(dd,J＝2.4,1.2Hz,1H),1.49–1.44(m,1H ),1.46–1.36(m,1H),1.39–1.23(m,2H).ESI-MS m/z 483.2[M+H] ⁺

Example 92: Synthesis of Compound 92

Dissolve compound 68 (100 mg, 0.22 mmol) in 10 mL toluene, add p-toluenesulfonic acid (4 mg, 0.022 mmol), drop ethylene glycol (15 mg, 0.24 mmol), and reflux for 4 hours. After the reaction is completed, cool to room temperature. Concentrate under reduced pressure and isolate by column chromatography to obtain compound 92 (70 mg, 64%).

¹ H NMR(500MHz,Chloroform-d)δ9.92(s,1H),7.67(ddt,J＝6.3,5.0,2.5Hz,1H),7.59(d,J＝11.7Hz,1H),7.47–7.39 (m,1H),7.26–7.19(m,2H),7.19(d,J＝1.5Hz,1H),7.13(t,J＝4.6Hz,1H),4.91(d,J＝7.0Hz,1H) ,4.82(tt,J＝6.9,0.8Hz,1H),4.23–4.15(m,1H),3.92(s,4H),3.90(dq,J＝11.9,7.0Hz,1H),3.27(dtd,J ＝12.4,7.1,4.6Hz,1H),3.19(dtd,J＝12.4,7.1,4.6Hz,1H),2.50(p,J ＝7.0Hz,1H),2.17(hd,J＝7.0,0.7Hz,1H),2.00–1.77(m,6H),1.79–1.66(m,2H),1.55–1.44(m,5H),1.47– 1.38(m,1H),1.40–1.30(m,1H).ESI-MS m/z 495.2[M+H] ⁺

Example 93: Synthesis of Compound 93:

Synthesis of compound 93-8:

Among them, the synthesis of intermediate 93-7 refers to 1-8; dissolve compound 93-8 (2.0g, mmol) in 45mL methanol and 15mL water, add lithium hydroxide monohydrate (523mg, 12.46mmol), and react at room temperature for 2h; monitor the raw materials After the reaction is completed, add 1M HCl to adjust the pH to 9.0, add ethyl acetate for extraction (50mL×3), combine the organic phases, wash with saturated sodium chloride (50mL×2), dry over anhydrous sodium sulfate, and rotary evaporate to remove the solvent to obtain a white solid. 93-9, used directly for the next step.

ESI-MS m/z 468.2[M+H] ⁺

Synthesis of compound 93-10:

Compound 93-8 (1.0g, 2.14mmol) was dissolved in 30mL dichloromethane, cooled to -20°C, added HATU (1.22g, 3.21mmol) for activation for 30min, and then added sulfonium salt (779mg, 4.28mmol) and Base (830 mg, 6.42 mmol), keep the reaction at low temperature overnight. After adding an appropriate amount of methylene chloride to the reaction solution, wash with 1M HCl (50mL×3), saturated sodium bicarbonate (50mL×3) and saturated sodium chloride (50mL×1) in sequence, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. Afterwards, 900 mg of white solid 93-10 was obtained by column chromatography, with a yield of 76%. ESI-MS m/z 551.2[M+H] ⁺

Synthesis of compound 93-11:

Dissolve compound 93-10 (800 mg, 1.45 mmol) in 20 mL tetrahydrofuran and 10 mL water, add Oxone (1.0 g, 2.91 mmol), react at room temperature for 30 min, add an appropriate amount of water to dilute, extract with dichloromethane (30 mL × 2), and combine Dichloromethane, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a white solid 93-11, which was directly used in the next step. ESI-MS m/z 496.2[M+H] ⁺

Synthesis of compound 93:

Compound 93-11 (200 mg, 0.40 mmol) was dissolved in 10 mL dichloromethane, cooled to -20°C, added HATU (230 mg, 0.61 mmol) for activation for 30 min, and then added sulfonium salt (86 mg, 0.81 mmol) and base ( 156mg, 1.21mmol), keep the reaction at low temperature overnight. After adding an appropriate amount of methylene chloride to the reaction solution, wash with 1M HCl (20mL×3), saturated sodium bicarbonate (20mL×3) and saturated sodium chloride (20mL×1) in sequence, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. Afterwards, 210 mg of white solid 93-10 was obtained by column chromatography, with a yield of 88%.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,1H),7.84(d,J＝9.7Hz,1H),7.76–7.69(m,1H),7.63(d,J ＝1.8Hz,1H),7.59–7.53(m,1H),7.42–7.35(m,2H),7.35–7.23(m,5H),6.26(t,J＝4.0Hz,1H),4.53–4.34( m,4H),3.72(dd,J＝12.3,3.0Hz,1H),3.63(dd,J＝12.4,1.3Hz,1H),3.26–3.14(m,2H),2.61(tdd,J＝8.9, 6.9,4.3Hz,1H),2.50–2.42(m,2H),2.13(ddd,J＝15.1,8.8,7.3Hz,1H),1.99(ddd,J＝15.0,8.8,7.3Hz,1H),1.80 –1.42(m,10H).ESI-MS m/z 585.2[M+H] ⁺

Example 94: Synthesis of Compound 94

Compound 94 was synthesized with reference to compound 93, and the corresponding intermediate 93-1 was replaced with 94-1.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,1H),7.90(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J ＝1.8Hz,1H),7.60–7.53(m,1H),7.44–7.35(m,2H),7.35–7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.47(dt, J＝5.8,1.1Hz,2H),4.45–4.33(m,2H),3.72(dd,J＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.2Hz,1H),3.34–3.17 (m,2H),2.60(tt,J＝7.0,4.9Hz,1H),2.51–2.40(m,2H),2.12(dt,J＝15.4,7.1Hz,1H),2.02(dt,J＝15.0 ,7.1Hz,1H),1.88(dddd,J＝12.5,4.9,3.8,2.5Hz,1H),1.80(dddd,J＝12.5,4.9,3.8,2.6Hz,1H),1.76–1.42(m,6H ).ESI-MS m/z 571.2[M+H] ⁺

Example 95: Synthesis of Compound 95

Compound 95 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 95-1.

¹ H NMR(500MHz,Chloroform-d)δ7.84(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.48(d,J＝8.2Hz,1H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H) ,4.41–4.35(m,1H),3.75–3.60(m,3H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.50–2.42(m, 2H), 2.13(ddd,J＝15.1,8.8,7.3Hz,1H), 1.99(ddd,J＝15.0,8.8,7.3Hz,1H), 1.81–1.33(m,20H). ESI-MS m/z 577.3[M+H] ⁺

Example 96: Synthesis of Compound 96

Compound 96 was synthesized with reference to compound 93, with the corresponding intermediates 93-1 and 93-12 replaced by 96-1 and 96-2.

¹ H NMR(500MHz,Chloroform-d)δ7.90(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.48(d,J＝8.2Hz,1H),7.43–7.34(m,2H),6.13(t,J＝3.1Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H) ,4.41–4.35(m,1H),3.75–3.68(m,1H),3.68–3.60(m,2H),3.33–3.21(m,2H),2.60(tt,J＝7.0,4.9Hz,1H) ,2.50–2.42(m,2H),2.12(dt,J＝15.4,7.1Hz,1H),2.02(dt,J＝15.0,7.1Hz,1H),1.88(dddd,J＝12.5,4.9,3.8, 2.5Hz,1H),1.80(dddd,J＝12.5,4.9,3.8,2.6Hz,1H),1.76–1.33(m,16H).ESI-MS m/z 563.3[M+H] ⁺

Example 97: Synthesis of Compound 97

Compound 97 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 97-1.

¹ H NMR(500MHz,Chloroform-d)δ7.84(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.62–7.52(m ,2H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H),4.41–4.35(m,1H),3.98( dq,J＝7.6,3.8Hz,1H),3.72(dd,J＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.2Hz,1H),3.27–3.14(m,2H),2.63 (tdd,J＝8.8,7.0,4.2Hz,1H),2.50–2.42(m,2H),2.13(ddd,J＝15.1,8.8,7.3Hz,1H),1.99(ddd,J＝15.0,8.8, 7.3Hz,1H),1.91–1.80(m,2H),1.80–1.42(m,16H).ESI-MS m/z 563.3[M+H] ⁺

Example 98: Synthesis of Compound 98

Compound 98 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 98-1 and 98-2.

¹ H NMR(500MHz,Chloroform-d)δ7.90(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.62–7.52(m ,2H),7.43–7.34(m,2H),6.13(t,J＝3.1Hz, 1H),4.47(dt,J＝9.7,7.3Hz,1H),4.41–4.35(m,1H),3.99(dp,J＝7.6,3.8Hz,1H),3.72(dd,J＝12.4,3.0Hz ,1H),3.63(dd,J＝12.4,1.2Hz,1H),3.33–3.21(m,2H),2.60(tt,J＝7.0,4.9Hz,1H),2.50–2.42(m,2H), 2.12(dt,J＝15.4,7.1Hz,1H),2.02(dt,J＝15.0,7.1Hz,1H),1.92–1.42(m,16H).ESI-MS m/z 563.3[M+H] ⁺

Example 99: Synthesis of Compound 99

Compound 99 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 99-1.

¹ H NMR(500MHz,Chloroform-d)δ7.84(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.59–7.52(m ,2H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.44(dt,J＝9.7,7.3Hz,1H),4.40–4.35(m,1H),3.87– 3.78(m,1H),3.72(dd,J＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.2Hz,1H),3.27–3.14(m,2H),2.63(tdd,J＝ 8.8,7.0,4.2Hz,1H),2.50–2.42(m,2H),2.13(ddd,J＝15.1,8.8,7.3Hz,1H),1.99(ddd,J＝15.0,8.8,7.3Hz,1H) ,1.93–1.42(m,16H).ESI-MS m/z 548.3[M+H] ⁺

Example 100: Synthesis of Compound 100

Compound 100 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 100-1 and 100-2.

¹ H NMR(500MHz,Chloroform-d)δ7.90(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.59–7.52(m ,2H),7.43–7.34(m,2H),6.13(t,J＝3.1Hz,1H),4.45(dt,J＝9.7,7.3Hz,1H),4.41–4.35(m,1H),3.83( dp,J＝7.6,4.3Hz,1H),3.72(dd,J＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.2Hz,1H),3.33–3.26(m,2H),2.60 (tt,J＝6.9,4.9Hz,1H),2.50–2.44(m,2H),2.12(dt,J＝15.2,7.1Hz,1H),2.02(dt,J＝15.0,7.1Hz,1H), 1.96–1.42(m,14H).ESI-MS m/z 535.2[M+H] ⁺

Example 101: Synthesis of Compound 101

Compound 101 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 101-1.

¹ H NMR(500MHz,Chloroform-d)δ7.87–7.81(m,2H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m,1H) ,7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.44(dt,J＝9.7,7.3Hz,1H),4.40–4.35(m,1H),3.72(dd,J ＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.2Hz,1H),3.27–3.14(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.63(tdd, J＝8.8,7.0,4.2Hz,1H),2.50–2.42(m,2H),2.13(ddd,J＝15.1,8.8,7.3Hz,1H),1.99(ddd,J＝15.0,8.8,7.3Hz, 1H),1.81–1.42(m,10H),0.73–0.60(m,4H).ESI-MS m/z 535.2[M+H] ⁺

Example 102: Synthesis of Compound 102

Compound 102 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 102-1 and 102-2.

¹ H NMR(500MHz,Chloroform-d)δ7.90(d,J＝9.7Hz,3H),7.84(d,J＝7.7Hz,3H),7.76–7.68(m,3H),7.63(d,J ＝1.8Hz,3H),7.60–7.52(m,3H),7.43–7.34(m,6H),6.13(t,J＝3.1Hz,3H),4.45(dt,J＝9.7,7.3Hz,3H) ,4.41–4.35(m,3H),3.72(dd,J＝12.4,3.1Hz,3H),3.63(dd,J＝12.4,1.2Hz,3H),3.33–3.26(m,5H),3.26–3.21 (m,1H),2.78(dp,J＝7.7,4.8Hz,3H),2.60(tt,J＝6.9,4.9Hz,3H),2.50–2.44(m,6H),2.12(dt,J＝15.2 ,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(dddd,J＝12.5,5.0,3.8,2.5Hz,3H),1.80(dddd,J＝12.5,4.9,3.8 ,2.6Hz,3H),1.76–1.54(m,10H),1.54–1.42(m,8H),0.73–0.60(m,12H).ESI-MS m/z 521.2[M+H] ⁺

Example 103: Synthesis of Compound 103

Compound 103 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 103-1.

¹ H NMR(500MHz,Chloroform-d)δ7.84(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.43–7.36(m,2H),7.33(t,J＝4.2Hz,1H),6.26(t,J＝4.0Hz,1H),4.45–4.35(m,2H),3.72(dd, J＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.3Hz,1H),3.31(qd,J＝6.4,4.4Hz,2H),3.27–3.14(m,2H),2.61(tdd ,J＝8.9,6.9,4.3Hz,1H),2.46(dddd,J＝9.6,5.3,3.4,1.8Hz,2H),2.13(ddd,J＝15.0,8.9,7.4Hz,1H),1.99(ddd ,J＝15.0,8.8,7.3Hz,1H),1.81–1.42(m,10H),1.24(t,J＝6.4Hz,3H).ESI-MS m/z 523.3[M+H] ⁺

Example 104: Synthesis of Compound 104

Compound 104 was synthesized with reference to compound 103, and the corresponding intermediates 93-1 and 93-12 were replaced by 104-1 and 104-2.

¹ H NMR(500MHz,Chloroform-d)δ7.88(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.43–7.36(m,2H),7.33(t,J＝4.2Hz,1H),6.13(t,J＝3.1Hz,1H),4.45–4.35(m,2H),3.72(dd, J＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.2Hz,1H),3.35–3.21(m,4H),2.60(tt,J＝6.9,4.9Hz,1H),2.50–2.42 (m,2H),2.11(dt,J＝15.2,7.1Hz,1H),2.02(dt,J＝15.2,7.1Hz,1H),1.88(dddd,J＝12.5,4.9,3.8,2.5Hz,1H ),1.80(dddd,J＝12.5,5.0,3.8,2.6Hz,1H),1.76–1.59(m,3H),1.59–1.55(m,1H),1.55–1.42(m,3H),1.24(t ,J＝6.4Hz,3H).ESI-MS m/z 509.2[M+H] ⁺

Example 105: Synthesis of Compound 105

Compound 105 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 105-1.

¹ H NMR(500MHz,Chloroform-d)δ7.85(d,J＝9.9Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.51(t,J＝5.1Hz,1H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H) ,4.41–4.35(m,1H),3.72(dd,J＝12.4,3.1Hz,1H),3.63(dd,J＝12.4,1.3Hz,1H),3.27–3.14(m,2H),2.84(d ,J＝5.3Hz,3H),2.63(tdd,J＝8.8,7.0,4.2Hz,1H),2.50–2.42(m,2H),2.13(ddd,J＝15.0,8.9,7.4Hz,1H), 1.99(ddd,J＝15.0,8.8,7.3Hz,1H),1.81–1.42(m,10H).ESI-MS m/z 509.2[M+H] ⁺

Example 106: Synthesis of Compound 106

Compound 106 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 106-1 and 106-2.

¹ H NMR(500MHz,Chloroform-d)δ7.88(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.52–7.48(m,1H),7.43–7.34(m,2H),6.13(t,J＝3.1Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H),4.41– 4.35(m,1H),3.72(dd,J＝12.4,3.1Hz,1H),3.63(dd,J＝12.4,1.3Hz,1H),3.33–3.26(m,2H),2.84(d,J＝ 5.3Hz,3H),2.60(tt,J＝6.9,5.0Hz,1H),2.50–2.42(m,2H),2.11(dt,J＝15.2,7.1Hz,1H),2.02(dt,J＝15.2 ,7.1Hz,1H),1.88(dddd,J＝12.5,4.9,3.8,2.5Hz,1H),1.80(dddd,J＝12.5,4.9,3.8,2.6Hz,1H),1.76–1.65(m,2H ),1.65–1.54(m,2H),1.50(m,3H).ESI-MS m/z 495.1[M+H] ⁺

Example 107: Synthesis of Compound 107

Compound 107 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 107-1.

¹ H NMR(500MHz,Chloroform-d)δ7.79–7.68(m,2H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m,1H),7.43–7.34(m,2H) ,6.96(d,J＝7.7Hz,1H),6.71(d,J＝7.7Hz,1H),6.26(t,J＝4.0Hz,1H),4.48(dt,J＝10.1,7.7Hz,1H) ,4.41–4.35(m,1H),3.72(dd,J＝12.4,3.0Hz,1H),3.63(dd,J＝12.4,1.3Hz,1H),3.27–3.14(m,2H),2.63(tdd ,J＝8.8,7.0,4.2Hz,1H),2.50–2.44(m,2H),2.12(ddd,J＝15.0,8.8,7.8Hz,1H),1.91(ddd,J＝15.0,8.8,7.7Hz ,1H),1.81–1.42(m,10H).ESI-MS m/z 495.1[M+H] ⁺

Example 108: Synthesis of Compound 108

Compound 108 was synthesized with reference to compound 93, and the corresponding intermediate 93-3 was replaced with 108-1.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,1H),7.88(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J ＝1.8Hz,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),7.34–7.22(m,5H),6.26(t,J＝4.0Hz,1H),4.68(d, J＝7.1Hz,1H),4.47(dt,J＝5.7,1.0Hz,2H),4.41(dt,J＝9.9,7.4Hz,1H),3.61–3.52(m,2H),3.27–3.14(m ,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.2,8.8,7.3Hz,1H),1.99(ddd,J＝15.0,8.8,7.3Hz,1H ),1.81–1.68(m,3H),1.68–1.61(m,1H),1.45(dd,J＝7.1,5.3Hz,1H),1.10–1.02(m,7H).ESI-MS m/z 585.3 [M+H] ⁺

Example 109: Synthesis of Compound 109

The synthesis of compound 109 refers to compound 93, and the corresponding intermediates 93-3 and 93-12 are replaced by 109-1 and 109-2.

¹ H NMR(500MHz,Chloroform-d)δ7.88(d,J＝9.7Hz,1H),7.84(d,J＝7.7Hz,1H),7.76–7.68(m,1H),7.63(d,J ＝1.8Hz,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.68(d,J＝7.1Hz,1H),4.44 (dt,J＝9.7,7.3Hz,1H),3.61–3.52(m,2H),3.27–3.14(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.61(tdd,J ＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.2,8.8,7.3Hz,1H),1.99(ddd,J＝15.0,8.8,7.3Hz,1H),1.81–1.67(m,3H ),1.67–1.61(m,1H),1.45(dd,J＝7.1,5.3Hz,1H),1.10–1.02(m,7H),0.73–0.60(m,4H).ESI-MS m/z 535.3 [M+H] ⁺

Example 110: Synthesis of Compound 110

Compound 110 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 110-1 and 110-2.

¹ H NMR(500MHz,Chloroform-d)δ7.90(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.43–7.34(m,2H),6.13(t,J＝3.1Hz,1H),4.45(dt,J＝9.7,7.3Hz,1H),4.41–4.35(m,1H),3.72( dd,J＝12.3,3.0Hz,1H),3.63(dd,J＝12.3,1.3Hz,1H),3.33–3.21(m,2H),2.60(tt,J＝6.9,4.9Hz,1H),2.50 –2.42(m,2H),2.12(dt,J＝15.2,7.1Hz,1H),2.02(dt,J＝15.0,7.1Hz,1H),1.88(dddd,J＝12.4,4.9,3.8,2.5Hz ,1H),1.84–1.44(m,8H),1.44(s,9H).ESI-MS m/z 537.3[M+H] ⁺

Example 111: Synthesis of Compound 111

Compound 111 was synthesized with reference to compound 93, and the corresponding intermediate 93-12 was replaced with 111-1.

¹ H NMR(500MHz,Chloroform-d)δ7.84(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz, 1H),4.44(dt,J＝9.7,7.3Hz,1H),4.40–4.35(m,1H),3.72(dd,J＝12.3,3.1Hz,1H),3.63(dd,J＝12.3,1.3Hz ,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.50–2.42(m,2H),2.13(ddd,J＝15.2,8.8,7.3Hz ,1H),1.99(ddd,J＝15.0,8.8,7.3Hz,1H),1.81–1.44(m,10H),1.44(s,8H).ESI-MS m/z 551.3[M+H] ⁺

Example 112: Synthesis of Compound 112

Compound 112 was synthesized with reference to compound 93, and the corresponding intermediates 93-3 and 93-12 were replaced by 112-1 and 112-2.

¹ H NMR(500MHz,Chloroform-d)δ7.88(d,J＝9.7Hz,1H),7.76–7.68(m,1H),7.63(d,J＝1.8Hz,1H),7.60–7.52(m ,1H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.68(d,J＝7.1Hz,1H),4.45(dt,J＝9.7,7.3Hz,1H) ,3.61–3.52(m,2H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.2,8.8,7.3Hz,1H) ,1.99(ddd,J＝15.0,8.8,7.3Hz,1H),1.80–1.59(m,4H),1.48–1.43(m,10H),1.10–1.02(m,7H).ESI-MS m/z 551.3[M+H] ⁺

Example 113: Synthesis of Compound 113

Compound 113 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 113-1 and 113-2.

¹ H NMR(500MHz,Chloroform-d)δ9.84(s,3H),8.11(t,J＝5.8Hz,3H),7.84(d,J＝9.9Hz,3H),7.73–7.65(m,3H ),7.47–7.39(m,3H),7.35–7.22(m,14H),7.21–7.13(m,6H),7.08(d,J＝1.8Hz,3H),6.13(t,J＝3.1Hz, 3H),4.58(dd,J＝7.7,1.1Hz,3H),4.47(dt,J＝5.7,1.0Hz,6H),4.41(dt,J＝9.9,7.4Hz,3H),3.81(dd,J ＝12.4,3.1Hz,3H),3.73(dd,J＝12.4,1.3Hz,3H),3.33–3.26(m,5H),3.26–3.21(m,1H),2.60(tt,J＝6.9,4.9 Hz,3H),2.50–2.46(m,1H),2.44(dtd,J＝6.9,3.5,1.8Hz,4H),2.12 (dt,J＝15.2,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(dddd,J＝12.5,5.0,3.8,2.5Hz,3H),1.80(dddd,J ＝12.5,5.0,3.8,2.6Hz,3H),1.76–1.68(m,3H),1.68–1.61(m,3H),1.61–1.55(m,3H),1.55–1.48(m,6H),1.48 –1.42(m,2H).ESI-MS m/z 570.3[M+H] ⁺

Example 114: Synthesis of Compound 114

Compound 114 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 114-1 and 114-2.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,3H),7.84(d,J＝9.9Hz,3H),7.66(ddd,J＝7.2,1.9,0.9Hz,3H ),7.39–7.18(m,21H),7.12(d,J＝1.9Hz,3H),6.13(t,J＝3.1Hz,3H),4.58(dd,J＝7.7,1.1Hz,3H),4.47 (dt,J＝5.8,1.1Hz,6H),4.41(dt,J＝9.9,7.4Hz,3H),3.81(dd,J＝12.4,3.1Hz,3H),3.73(dd,J＝12.4,1.3 Hz,3H),3.33–3.26(m,5H),3.26–3.21(m,1H),2.60(tt,J＝6.9,4.9Hz,3H),2.50–2.41(m,6H),2.12(dt, J＝15.2,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(dddd,J＝12.5,5.0,3.8,2.5Hz,3H),1.80(dddd,J＝12.5, 4.9,3.8,2.6Hz,3H),1.76–1.66(m,4H),1.66–1.54(m,6H),1.54–1.48(m,7H),1.48–1.42(m,2H).ESI-MS m /z 588.3[M+H] ⁺

Example 115: Synthesis of Compound 115

Compound 115 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 115-1 and 115-2.

¹ H NMR(500MHz,Chloroform-d)δ9.81(s,3H),8.11(t,J＝5.8Hz,3H),8.02–7.95(m,3H),7.84(d,J＝9.9Hz,3H ),7.35–7.22(m,15H),7.20(d,J＝2.2Hz,2H),7.16(ddd,J＝16.1,8.2,2.3Hz,4H),7.08(s,3H),6.13(t, J＝3.1Hz,3H),4.58(dd,J＝ 7.7,1.1Hz,3H),4.47(dt,J＝5.6,1.0Hz,6H),4.44–4.39(m,3H),3.81(dd,J＝12.4,3.1Hz,3H),3.73(dd,J ＝12.4,1.3Hz,3H),3.33–3.26(m,5H),3.26–3.21(m,1H),2.60(tt,J＝6.9,4.9Hz,3H),2.50–2.41(m,6H), 2.12(dt,J＝15.2,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(m,3H),1.80(m,3H),1.76–1.68(m,3H) ,1.68–1.55(m,6H),1.55–1.48(m,6H),1.46(m,2H).ESI-MS m/z 588.3[M+H] ⁺

Example 116: Synthesis of Compound 116

Compound 116 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 116-1 and 116-2.

¹ H NMR (500MHz, Chloroform-d) δ9.94 (s, 3H), 8.11 (t, J = 5.8Hz, 3H), 7.84 (d, J = 9.9Hz, 3H), 7.55 (dt, J = 8.1 ,2.1Hz,3H),7.49(dd,J＝7.2,5.0Hz,3H),7.35–7.22(m,15H),7.11–7.04(m,6H),6.13(t,J＝3.1Hz,3H) ,4.58(dd,J＝7.7,1.1Hz,3H),4.50–4.44(m,7H),4.44–4.39(m,2H),3.81(dd,J＝12.4,3.1Hz,3H),3.73(dd ,J＝12.4,1.3Hz,3H),3.33–3.26(m,5H),3.26–3.21(m,1H),2.60(tt,J＝6.9,4.9Hz,3H),2.46(qdd,J＝6.7 ,3.3,1.7Hz,6H),2.12(dt,J＝15.2,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(dddd,J＝12.5,5.0,3.8,2.5 Hz,3H),1.80(dddd,J＝12.5,5.0,3.8,2.6Hz,3H),1.76–1.66(m,4H),1.66–1.54(m,6H),1.54–1.48(m,6H), 1.48–1.42(m,2H).ESI-MS m/z 588.3[M+H] ⁺

Example 117: Synthesis of Compound 117

Compound 117 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 117-1 and 117-2.

¹ H NMR (500MHz, Chloroform-d) δ9.81 (s, 3H), 8.11 (t, J = 5.8Hz, 3H), 7.84 (d, J = 9.9Hz, 3H), 7.51 (d, J = 5.1 Hz,3H),7.40(dd,J＝7.9,1.2Hz,3H),7.38–7.22(m, 18H),7.15(td,J＝8.0,1.5Hz,3H),6.13(t,J＝3.1Hz,3H),4.58(dd,J＝7.6,1.1Hz,3H),4.47(dt,J＝5.7 ,1.0Hz,6H),4.41(dt,J＝9.9,7.4Hz,3H),3.81(dd,J＝12.4,3.1Hz,3H),3.73(dd,J＝12.4,1.3Hz,3H),3.33 –3.26(m,5H),3.26–3.21(m,1H),2.60(tt,J＝6.9,4.9Hz,3H),2.50–2.46(m,1H),2.44(dtd,J＝6.9,3.5, 1.8Hz,5H),2.12(dt,J＝15.2,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(dddd,J＝12.5,5.0,3.8,2.5Hz,3H ),1.80(dddd,J＝12.5,4.9,3.8,2.6Hz,3H),1.76–1.66(m,4H),1.66–1.54(m,6H),1.54–1.48(m,6H),1.46(dddd ,J＝9.3,5.6,2.3,1.3Hz,2H).ESI-MS m/z 588.3[M+H] ⁺

Example 118: Synthesis of Compound 118

Compound 118 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 118-1 and 118-2.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,3H),8.05–7.99(m,3H),7.90–7.81(m,6H),7.77(d,J＝2.2Hz ,3H),7.43(ddd,J＝7.5,6.5,1.2Hz,3H),7.40–7.35(m,3H),7.35–7.33(m,1H),7.32(d,J＝1.3Hz,2H), 7.31–7.22(m,11H),6.13(t,J＝3.1Hz,3H),4.50–4.37(m,12H),3.76–3.64(m,6H),3.33–3.26(m,5H),3.26– 3.21(m,1H),2.60(tt,J＝6.9,4.9Hz,3H),2.50–2.40(m,6H),2.12(dt,J＝15.2,7.1Hz,3H),2.02(dt,J＝ 15.0,7.1Hz,3H),1.88(m,3H),1.80(m,3H),1.76–1.67(m,4H),1.67–1.55(m,6H),1.55–1.48(m,6H),1.46 (m,2H).ESI-MS m/z 587.1[M+H] ⁺

Example 119: Synthesis of Compound 119

Compound 119 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 119-1 and 119-2.

¹ H NMR (500MHz, Chloroform-d) δ9.17 (s, 1H), 8.11 (t, J = 5.8Hz, 1H), 8.02 (dd, J = 8.3, 1.3Hz, 1H), 7.98 (dd, J ＝8.2,1.3Hz,1H),7.84(d,J＝9.9Hz,1H),7.75(td,J＝8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),7.35 –7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.54(dd,J＝7.6,1.0Hz,1H),4.49–4.45(m,2H),4.45–4.39(m,1H ),3.78(dd,J＝12.3,3.0Hz,1H),3.72(dd,J＝12.4,1.4Hz,1H),3.33–3.26(m,2H),2.68(tdd,J＝7.7,5.7,3.9 Hz,1H),2.50–2.41(m,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.85(m,1H),1.82(dtd, J＝12.1,3.7,2.2Hz,1H),1.77–1.66(m,1H),1.66–1.54(m,2H),1.54–1.48(m,2H),1.46(dddd,J＝9.4,3.8,2.5 ,1.1Hz,1H).ESI-MS m/z 583.2[M+H] ⁺

Example 120: Synthesis of Compound 120

Compound 120 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 120-1 and 120-2.

¹ H NMR(500MHz,Chloroform-d)δ8.34(d,J＝8.3Hz,2H),8.11(t,J＝5.8Hz,2H),8.06–7.98(m,4H),7.97–7.91(m ,2H),7.84(d,J＝9.9Hz,2H),7.73(td,J＝7.9,1.1Hz,2H),7.53(td,J＝7.9,1.2Hz,2H),7.35–7.22(m, 10H),6.13(t,J＝3.1Hz,2H),4.54(dd,J＝7.8,1.0Hz,2H),4.49–4.45(m,4H),4.45–4.39(m,2H),3.78(dd ,J＝12.4,3.1Hz,2H),3.72(dd,J＝12.5,1.3Hz,2H),3.33–3.26(m,4H),2.60(tt,J＝6.9,4.9Hz,2H),2.50– 2.46(m,1H),2.44(dddd,J＝6.9,4.7,1.9,1.1Hz,3H),2.12(dt,J＝15.2,7.1Hz,2H),2.02(dt,J＝15.0,7.1Hz, 2H),1.88(dddd,J＝12.5,5.0,3.8,2.5Hz,2H),1.84–1.42(m,14H).ESI-MS m/z 582.2[M+H] ⁺

Example 121: Synthesis of Compound 121

The synthesis of compound 121 refers to compound 93, and the corresponding intermediates 93-1 and 93-6 are replaced by 121-1 and 121-2.

¹ H NMR (500MHz, Chloroform-d) δ9.17 (s, 3H), 8.11 (t, J = 5.8Hz, 3H), 8.00 (ddd, J = 20.4, 8.2, 1.3Hz, 6H), 7.84 (d ,J＝9.9Hz,3H),7.75(td,J＝8.4,1.3Hz,3H),7.60(td,J＝8.4,1.2Hz,3H),7.35–7.22(m,15H),6.13(t, J＝3.1Hz,3H),4.54(dd,J＝7.6,1.0Hz,3H),4.50–4.44(m,7H),4.44–4.39(m,2H),3.78(dd,J＝12.3,3.0Hz ,3H),3.72(dd,J＝12.4,1.4Hz,3H),3.33–3.26(m,5H),3.26–3.21(m,1H),2.60(tt,J＝6.9,4.9Hz,3H), 2.50–2.41(m,6H),2.12(dt,J＝15.2,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(dddd,J＝12.5,5.0,3.8,2.5 Hz,3H),1.80(dddd,J＝12.5,5.0,3.8,2.6Hz,3H),1.76–1.67(m,4H),1.67–1.54(m,6H),1.54–1.48(m,6H), 1.46(dddd,J＝7.7,3.9,2.9,1.9Hz,2H).ESI-MS m/z 583.2[M+H] ⁺

Example 122: Synthesis of Compound 122

Compound 122 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 122-1, 122-2 and 122-3.

¹ H NMR (500MHz, Chloroform-d) δ9.17 (s, 3H), 8.00 (ddd, J＝20.3, 8.3, 1.3Hz, 6H), 7.87–7.81 (m, 6H), 7.75 (td, J＝ 8.4,1.3Hz,3H),7.60(td,J＝8.4,1.2Hz,3H),6.13(t,J＝3.1Hz,3H),4.54(dd,J＝7.6,1.0Hz,3H),4.47( dt,J＝9.7,7.3Hz,3H),3.78(dd,J＝12.3,3.0Hz,3H),3.72(dd,J＝12.4,1.4Hz,3H),3.33–3.26(m,5H),3.26 –3.21(m,1H),2.78(dp,J＝7.7,4.8Hz,3H),2.60(tt,J＝6.9,4.9Hz,3H),2.50–2.41(m,6H),2.12(dt,J ＝15.2,7.1Hz,3H),2.02(dt,J＝15.0,7.1Hz,3H),1.88(dddd,J＝12.5,5.0,3.8,2.5Hz,3H),1.80(dddd,J＝12.5,4.9 ,3.8,2.6Hz,3H),1.76–1.66(m,4H),1.66–1.54(m,6H),1.54–1.48(m,6H),1.48–1.42(m,2H),0.73–0.60(m ,12H).ESI-MS m/z 533.2[M+H] ⁺

Example 123: Synthesis of Compound 123

Compound 123 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 123-1, 123-2 and 123-3.

¹ H NMR(500MHz,Chloroform-d)δ8.34(d,J＝8.3Hz,2H),8.06–7.98(m,4H),7.97–7.91(m,2H),7.87–7.81(m,4H) ,7.73(td,J＝7.9,1.1Hz,2H),7.53(td,J＝7.8,1.1Hz,2H),6.13(t,J＝3.1Hz,2H),4.54(dd,J＝7.7,1.0 Hz,2H),4.47(dt,J＝9.7,7.3Hz,2H),3.78(dd,J＝12.4,3.1Hz,2H),3.72(dd,J＝12.5,1.3Hz,2H),3.29–3.21 (m,4H),2.78(dp,J＝7.7,4.8Hz,2H),2.60(tt,J＝6.9,4.9Hz,2H),2.50–2.46(m,1H),2.44(dddd,J＝6.9 ,4.7,1.9,1.0Hz,3H),2.12(dt,J＝15.2,7.1Hz,2H),2.02(dt,J＝15.0,7.1Hz,2H),1.88(dddd,J＝12.5,5.0,3.8 ,2.5Hz,2H),1.80(dddd,J＝12.5,4.9,3.8,2.6Hz,2H),1.76–1.68(m,2H),1.68–1.42(m,10H),0.73–0.60(m,8H ).ESI-MS m/z 532.2[M+H] ⁺

Example 124: Synthesis of Compound 124

Compound 124 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 124-1, 124-2, 124-3 and 124-4.

¹ H NMR(500MHz,Chloroform-d)δ8.34(d,J＝8.4Hz,1H),8.08–8.00(m,2H),7.97–7.91(m,1H),7.88–7.81(m,2H) ,7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.8,1.1Hz,1H),6.13(t,J＝3.1Hz,1H),4.73(ddd,J＝6.6,4.8 ,1.0Hz,1H),4.43(dt,J＝9.3,7.3Hz,1H),4.14(dddd,J＝5.7,3.9,2.9,0.7Hz,1H),3.29–3.21(m,2H),2.78( dp,J＝7.7,4.8Hz,1H),2.60(tt,J＝6.9,4.9Hz,1H),2.21–2.14(m,1H),2.14–2.07(m,1H),2.07–1.98(m, 2H),1.98–1.88(m,1H),1.88–1.82(m,2H),1.82–1.68(m,2H),1.67–1.52(m,2H),1.52–1.28(m,4H),0.73– 0.60(m,4H).ESI-MS m/z 546.3[M+H] ⁺

Example 125: Synthesis of Compound 125

Compound 125 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 125-1, 125-2, 125-3 and 125-4.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 1H), 8.11 (t, J = 5.8Hz, 1H), 8.02 (dd, J = 8.3, 1.3Hz, 1H), 7.98 (dd, J ＝8.2,1.3Hz,1H),7.85(d,J＝9.3Hz,1H),7.75(td,J＝8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),7.35 –7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.77–4.70(m,1H),4.53(dt,J＝9.5,7.3Hz,1H),4.47(dt,J＝5.7 ,1.0Hz,2H),4.15(dddd,J＝5.8,4.0,3.1,0.8Hz,1H),3.32–3.26(m,2H),2.60(tt,J＝6.9,4.9Hz,1H),2.21– 2.14(m,1H),2.14–2.07(m,1H),2.07–1.68(m,7H),1.67–1.52(m,2H),1.52–1.28(m,4H).ESI-MS m/z 597.3 [M+H] ⁺

Example 126: Synthesis of Compound 126

Compound 126 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 126-1, 126-2, 126-3 and 126-4.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 1H), 8.11 (t, J = 5.8Hz, 1H), 8.00 (ddd, J = 20.4, 8.2, 1.3Hz, 2H), 7.85 (d ,J＝9.3Hz,1H),7.75(td,J＝8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),7.35–7.22(m,5H),6.13(t, J＝3.1Hz,1H),4.78(ddd,J＝6.5,4.8,0.8Hz,1H),4.53(dt,J＝9.5,7.3Hz,1H),4.47(dt,J＝5.8,1.1Hz,2H ),4.15–4.09(m,1H),3.33–3.26(m,2H),2.60(tt,J＝6.9,4.9Hz,1H),2.17–1.98(m,4H), 1.92–1.84(m,1H),1.84–1.73(m,4H),1.65–1.28(m,6H).ESI-MS m/z 597.3[M+H] ⁺

Example 127: Synthesis of Compound 127

Compound 127 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 127-1, 127-2, 127-3 and 127-4.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 1H), 8.00 (ddd, J＝20.4, 8.3, 1.3Hz, 2H), 7.88–7.81 (m, 2H), 7.75 (td, J＝ 8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),6.13(t,J＝3.1Hz,1H),4.78(ddd,J＝6.5,4.8,0.8Hz,1H), 4.43(dt,J＝9.3,7.3Hz,1H),4.15–4.09(m,1H),3.29–3.21(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.60(tt, J＝6.9,4.9Hz,1H),2.17–1.98(m,4H),1.92–1.73(m,5H),1.65–1.28(m,6H),0.73–0.60(m,4H).ESI-MS m /z 547.3[M+H] ⁺

Example 128: Synthesis of Compound 128

Compound 128 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 128-1 and 128-2.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 1H), 8.11 (t, J = 5.8Hz, 1H), 8.00 (ddd, J = 20.4, 8.2, 1.3Hz, 2H), 7.85 (d ,J＝9.3Hz,1H),7.75(td,J＝8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),7.35–7.22(m,5H),6.26(t, J＝4.0Hz,1H),4.74(ddt,J＝6.7,4.8,0.9Hz,1H),4.52(dt,J＝9.3,7.3Hz,1H),4.47(dt,J＝5.7,1.0Hz,2H ),4.15(dddd,J＝5.8,4.0,3.1,0.8Hz,1H),3.29–3.16(m,2H),2.67(tt,J＝7.7,5.9Hz,1H),2.21–2.14(m,1H ),2.14–2.08(m,1H),2.07–2.00(m,2H),2.00–1.88(m,2H),1.88 –1.82(m,1H),1.82–1.52(m,7H),1.52–1.28(m,4H).ESI-MS m/z 611.3[M+H] ⁺

Example 129: Synthesis of Compound 129

Compound 129 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-12 and 93-3 were replaced by 129-1, 129-2 and 129-3.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 1H), 8.00 (ddd, J＝20.2, 8.3, 1.3Hz, 2H), 7.88–7.81 (m, 2H), 7.75 (td, J＝ 8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),6.26(t,J＝4.0Hz,1H),4.74(ddt,J＝6.6,4.8,0.8Hz,1H), 4.42(dt,J＝9.5,7.3Hz,1H),4.15(dddd,J＝5.9,4.0,3.1,0.8Hz,1H),3.29–3.16(m,2H),2.78(dp,J＝7.7,4.8 Hz,1H),2.67(tt,J＝7.7,5.9Hz,1H),2.21–2.14(m,1H),2.11(t,J＝7.5Hz,1H),2.07–1.95(m,2H),1.95 –1.89(m,1H),1.86(ddd,J＝12.3,6.8,4.0Hz,1H),1.83–1.52(m,7H),1.52–1.28(m,4H),0.73–0.60(m,4H) .ESI-MS m/z 561.3[M+H] ⁺

Example 130: Synthesis of Compound 130

Compound 130 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 130-1 and 130-2.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 1H), 8.11 (t, J = 5.8Hz, 1H), 8.00 (ddd, J = 20.4, 8.2, 1.3Hz, 2H), 7.85 (d ,J＝9.3Hz,1H),7.75(td,J＝8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),7.35–7.22(m,5H),6.26(t, J＝4.0Hz,1H),4.78(ddd,J＝6.5,4.8,0.8Hz,1H),4.52(dt,J＝9.3,7.3Hz,1H),4.47(dt,J＝5.7,1.0Hz,2H ),4.15–4.09(m,1H),3.29–3.16(m,2H),2.67(tt,J＝7.7,5.9Hz,1H),2.18–2.08(m,2H),2.06(ddd,J＝12.5 ,4.9,4.0Hz,1H),1.99(dt,J＝15.1,7.5Hz,1H),1.86–1.28(m,13H).ESI-MS m/z 611.3[M+H] ⁺

Example 131: Synthesis of Compound 131

Compound 131 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-12 and 93-3 were replaced by 131-1, 131-2 and 131-3.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 2H), 8.00 (ddd, J＝20.4, 8.2, 1.3Hz, 4H), 7.88–7.81 (m, 4H), 7.75 (td, J＝ 8.4,1.3Hz,2H),7.60(td,J＝8.4,1.2Hz,2H),6.26(t,J＝4.0Hz,2H),4.78(ddd,J＝6.5,4.8,0.8Hz,2H), 4.42(dt,J＝9.5,7.3Hz,2H),4.15–4.09(m,2H),3.29–3.16(m,4H),2.78(dp,J＝7.7,4.8Hz,2H),2.67(tt, J＝7.7,5.9Hz,2H),2.18–2.11(m,3H),2.11–2.08(m,1H),2.06(ddd,J＝12.5,4.9,4.0Hz,2H),1.99(dt,J＝ 15.1,7.5Hz,2H),1.86–1.79(m,3H),1.79–1.72(m,6H),1.72–1.36(m,16H),1.36–1.28(m,2H),0.73–0.60(m, 8H).ESI-MS m/z 561.3[M+H] ⁺

Example 132: Synthesis of Compound 132

Compound 132 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 132-1 and 132-2.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 1H), 8.11 (t, J = 5.8Hz, 1H), 8.00 (ddd, J = 20.4, 8.2, 1.3Hz, 2H), 7.84 (d ,J＝9.9Hz,1H),7.75(td,J＝8.4,1.3Hz,1H),7.60(td,J＝8.4,1.2Hz,1H),7.35–7.22(m,5H),6.26(t, J＝4.0Hz,1H),4.65(d,J＝4.6Hz,1H),4.56(dq,J＝4.4,2.9Hz,1H),4.47(dt,J＝5.7,1.0Hz,2H),4.42( dt,J＝9.7,7.4Hz,1H),3.29–3.16(m,2H),2.67(tt,J＝7.7,5.9Hz,1H),2.45(dtt,J＝4.7,3.6,2.4Hz,1H) ,2.13(dt,J＝15.1,7.5Hz,1H),2.04–1.91(m,2H),1.90(dd,J＝3.1,2.3Hz,1H),1.86–1.60(m,8H).ESI-MS m/z 583.3[M+H] ⁺

Example 133: Synthesis of Compound 133

Compound 133 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 133-1 and 133-2.

¹ H NMR (500MHz, Chloroform-d) δ9.18 (s, 2H), 8.11 (t, J = 5.8Hz, 2H), 8.00 (ddd, J = 20.4, 8.2, 1.3Hz, 4H), 7.84 (d ,J＝9.9Hz,2H),7.75(td,J＝8.4,1.3Hz,2H),7.60(td,J＝8.4,1.2Hz,2H),7.35–7.22(m,10H),6.26(t, J＝4.0Hz,2H),4.74(d,J＝4.6Hz,2H),4.53(dq,J＝4.2,2.9Hz,2H),4.47(dt,J＝5.7,1.0Hz,4H),4.42( dt,J＝9.7,7.4Hz,2H),3.29–3.16(m,4H),2.67(tt,J＝7.7,5.9Hz,2H),2.42(tq,J＝4.8,2.4Hz,2H),2.13 (dt,J＝15.1,7.5Hz,2H),2.04–1.97(m,3H),1.96(t,J＝1.4Hz,1H),1.94–1.87(m,2H),1.86–1.60(m,16H ).ESI-MS m/z 561.3[M+H] ⁺

Example 134: Synthesis of Compound 134

Compound 134 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 134-1 and 134-2.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,1H),7.85(d,J＝9.3Hz,1H),7.35–7.22(m,5H),6.72(d,J ＝8.4Hz,1H),6.26(t,J＝4.0Hz,1H),4.57–4.50(m,2H),4.47(dt,J＝5.7,1.0Hz,2H),3.77–3.71(m,1H) ,3.27–3.14(m,2H),2.63(tdd,J＝8.8,7.0,4.2Hz,1H),2.21–2.13(m,1H),2.13–2.08(m,1H),2.07–2.00(m, 2H),2.00–1.88(m,2H),1.85(ddd,J＝12.3,6.8,4.0Hz,1H),1.81–1.52(m,7H),1.52–1.28(m,4H).ESI-MS m /z 617.3[M+H] ⁺

Example 135: Synthesis of Compound 135

The synthesis of compound 135 refers to compound 93, and the corresponding intermediates 93-6 and 93-3 are replaced by 135-1 and 135-2.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,1H),7.85(d,J＝9.3Hz,1H),7.71(d,J＝9.7Hz,1H),7.35– 7.22(m,6H),6.26(t,J＝4.0Hz,1H),4.63(ddt,J＝6.6,5.0,0.9Hz,1H),4.52(dt,J＝9.3,7.3Hz,1H),4.47 (dt,J＝5.7,1.0Hz,2H),3.78–3.72(m,1H),3.27–3.14(m,2H),2.63(tdd,J＝8.8,7.0,4.2Hz,1H),2.21–2.14 (m,1H),2.14–2.08(m,1H),2.07–1.82(m,4H),1.81–1.52(m,7H),1.52–1.41(m,2H),1.41–1.29(m,2H) .ESI-MS m/z 632.3[M+H] ⁺

Example 136: Synthesis of Compound 136

Compound 136 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 136-1 and 136-2.

¹ H NMR (500MHz, Chloroform-d) δ9.48 (s, 1H), 8.11 (t, J = 5.8Hz, 1H), 7.85 (d, J = 9.3Hz, 1H), 7.50 (d, J = 9.9 Hz,1H),7.35–7.22(m,5H),7.17(d,J＝9.9Hz,1H),6.26(t,J＝4.0Hz,1H),4.78(ddt,J＝6.6,5.0,0.9Hz ,1H),4.57–4.45(m,3H),4.17(dddd,J＝5.7,3.9,3.0,0.8Hz,1H),3.27–3.14(m,2H),2.63(tdd,J＝8.8,7.0, 4.2Hz,1H),2.21–2.14(m,1H),2.14–2.08(m,1H),2.07–1.82(m,4H),1.81–1.52(m,7H),1.52–1.41(m,2H) ,1.41–1.36(m,1H),1.36–1.28(m,1H).ESI-MS m/z 616.3[M+H] ⁺

Example 137: Synthesis of Compound 137

Compound 137 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 137-1 and 137-2.

¹ H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,1H),7.84(d,J＝9.5Hz,1H),7.37–7.22(m,6H),7.18(d,J ＝2.1Hz,1H),6.92(d,J＝8.7Hz,1H),6.26(t,J＝4.0Hz,1H),4.68(ddt,J＝6.6,5.0,0.7Hz,1H),4.57–4.45 (m,3H),4.32–4.24(m, 4H),3.74(dtd,J＝4.8,4.0,0.7Hz,1H),3.27–3.14(m,2H),2.63(tdd,J＝8.8,7.0,4.2Hz,1H),2.18–2.08(m, 2H),2.08–2.02(m,1H),2.02–1.94(m,1H),1.86–1.61(m,7H),1.61–1.55(m,1H),1.55–1.48(m,2H),1.48– 1.43(m,2H),1.43–1.36(m,1H),1.36–1.28(m,1H).ESI-MS m/z 617.3[M+H] ⁺

Example 138: Synthesis of Compound 138

Compound 138 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-3 and 93-12 were replaced by 138-1, 138-2 and 138-3.

¹ H NMR (500MHz, Chloroform-d) δ7.82 (d, J = 9.9 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.7 Hz, 2H), 6.71 ( t,J＝7.9Hz,4H),6.26(t,J＝4.0Hz,2H),4.55–4.49(m,3H),4.49–4.45(m,1H),3.77–3.71(m,2H),3.27 –3.14(m,4H),2.61(tdd,J＝8.9,6.9,4.3Hz,2H),2.21–2.14(m,2H),2.14–2.07(m,2H),2.03(ddd,J＝12.5, 5.9,4.9Hz,2H),1.98–1.86(m,5H),1.86–1.81(m,1H),1.81–1.53(m,14H),1.53–1.28(m,8H).ESI-MS m/z 527.2[M+H] ⁺

Example 139: Synthesis of Compound 139

Compound 139 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-3 and 93-12 were replaced by 139-1, 139-2 and 139-3.

¹ H NMR (500MHz, Chloroform-d) δ7.82(d,J＝9.9Hz,1H),7.14(d,J＝8.4Hz,1H),6.96(d,J＝7.7Hz,1H),6.71( t,J＝7.9Hz,2H),6.26(t,J＝4.0Hz,1H),4.56(ddd,J＝6.7,4.9,0.8Hz,1H),4.49(dt,J＝9.7,7.7Hz,1H ),3.75–3.69(m,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.17–2.11(m,2H),2.11–2.07(m ,1H),2.07–2.02(m,1H),1.91(ddd,J＝15.0,8.8,7.7Hz,1H),1.86–1.37(m,13H),1.37–1.28(m,1H).ESI-MS m/z 527.2[M+H] ⁺

Example 140: Synthesis of Compound 140

Compound 140 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 140-1, 140-2 and 140-3.

¹ H NMR(500MHz,Chloroform-d)δ8.34(d,J＝8.4Hz,2H),8.06–7.98(m,4H),7.97–7.91(m,2H),7.79–7.70(m,4H) ,7.53(td,J＝7.8,1.1Hz,2H),6.96(d,J＝7.7Hz,2H),6.71(d,J＝7.7Hz,2H),6.13(t,J＝3.1Hz,2H) ,4.54(dd,J＝7.7,1.0Hz,2H),4.47(dt,J＝10.1,7.7Hz,2H),3.78(dd,J＝12.4,3.1Hz,2H),3.72(dd,J＝12.5 ,1.3Hz,2H),3.33–3.26(m,4H),2.68(tdd,J＝7.7,5.7,3.8Hz,2H),2.50–2.46(m,1H),2.46–2.41(m,3H), 2.13(dt,J＝15.6,7.9Hz,2H),1.98(dt,J＝15.2,7.7Hz,2H),1.93–1.85(m,2H),1.82(dtd,J＝12.2,3.7,2.3Hz, 2H),1.77–1.42(m,12H).ESI-MS m/z492.2[M+H] ⁺

Example 141: Synthesis of Compound 141

Compound 141 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 141-1, 141-2 and 141-3.

¹ H NMR (500MHz, Chloroform-d) δ9.17 (s, 3H), 8.00 (ddd, J＝20.3, 8.3, 1.3Hz, 6H), 7.79–7.71 (m, 6H), 7.60 (td, J＝ 8.4,1.2Hz,3H),6.96(d,J＝7.7Hz,3H),6.71(d,J＝7.7Hz,3H),6.13(t,J＝3.1Hz,3H),4.54(dd,J＝ 7.6,1.0Hz,3H),4.47(dt,J＝10.1,7.7Hz,3H),3.78(dd,J＝12.4,3.0Hz,3H),3.72(dd,J＝12.5,1.4Hz,3H), 3.33–3.26(m,5H),3.26–3.22(m,1H),2.68(tdd,J＝7.7,5.7,3.8Hz,3H),2.50–2.41(m,6H),2.13(dt,J＝15.6 ,7.9Hz,3H),1.98(dt,J＝15.2,7.7Hz,3H),1.93–1.85(m,3H),1.82(dtd,J＝12.2,3.7,2.3Hz,3H),1.77–1.66( m,4H),1.66–1.54(m,6H),1.54–1.48(m,6H),1.48–1.42(m,2H).ESI-MS m/z 493.2[M+H] ⁺

Example 142: Synthesis of Compound 142

Compound 142 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 142-1, 142-2 and 142-3.

¹ H NMR(500MHz,Chloroform-d)δ7.76(d,J＝10.2Hz,1H),7.22–7.15(m,2H),6.96(d,J＝7.7Hz,1H),6.92(d,J ＝8.6Hz,1H),6.71(d,J＝7.7Hz,1H),6.13(t,J＝3.1Hz,1H),4.52–4.42(m,2H),4.33–4.24(m,4H),3.73 –3.64(m,2H),3.33–3.26(m,2H),2.68(tdd,J＝7.7,5.7,3.8Hz,1H),2.46(dtdd,J＝6.1,3.6,3.0,2.5,1.7Hz, 2H),2.13(dt,J＝15.4,7.8Hz,1H),1.98(dt,J＝15.2,7.7Hz,1H),1.93–1.86(m,1H),1.82(dtd,J＝12.2,3.7, 2.3Hz,1H),1.77–1.66(m,1H),1.66–1.60(m,1H),1.60–1.54(m,1H),1.54–1.48(m,2H),1.48–1.42(m,1H) .ESI-MS m/z 499.2[M+H] ⁺

Example 143: Synthesis of Compound 143

The synthesis of compound 143 was referred to the synthesis of compound 93.

¹ H NMR (500MHz, Chloroform-d) δ8.11(t,J＝5.8Hz,1H),7.96(d,J＝11.2Hz,1H),7.87(d,J＝9.7Hz,1H),7.76( d,J＝2.1Hz,1H),7.74–7.68(m,1H),7.60–7.52(m,1H),7.43–7.36(m,2H),7.36–7.22(m,5H),6.13(t, J＝3.1Hz,1H),4.51–4.37 (m,5H),3.64(dd,J＝12.4,1.5Hz,1H),3.51(dd,J＝12.4,3.4Hz,1H),3.33–3.26(m,2H),2.67(tdd,J＝7.8 ,5.7,3.9Hz,1H),2.45(dddd,J＝7.3,4.4,3.3,2.2Hz,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.02(dt,J＝15.0,7.6 Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.75–1.64(m,1H),1.64–1.40(m,5H),1.00( s,9H).ESI-MS m/z 684.3[M+H] ⁺

Example 144: Synthesis of Compound 144

Compound 144 was synthesized with reference to compound 143, and the corresponding intermediate 143-9 was replaced with 144-1.

¹ H NMR (500MHz, Chloroform-d) δ9.91 (s, 1H), 8.14–8.06 (m, 2H), 7.87 (d, J = 9.7Hz, 1H), 7.73–7.66 (m, 1H), 7.47 –7.39(m,1H),7.35–7.22(m,5H),7.21–7.12(m,2H),7.00(d,J＝1.8Hz,1H),6.13(t,J＝3.1Hz,1H), 4.65(d,J＝9.5Hz,1H),4.49–4.36(m,4H),3.64(dd,J＝12.4,1.5Hz,1H),3.51(dd,J＝12.4,3.4Hz,1H),3.33 –3.22(m,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.45(dddd,J＝7.3,4.4,3.3,2.2Hz,2H),2.12(dt,J＝15.0, 7.5Hz,1H),2.02(dt,J＝15.0,7.6Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.75–1.65(m ,1H),1.65–1.55(m,2H),1.55–1.48(m,2H),1.48–1.40(m,1H),1.00(s,9H).ESI-MS m/z 683.3[M+H] ⁺

Example 145: Synthesis of Compound 145

Compound 145 was synthesized with reference to compound 143, and the corresponding intermediate 143-9 was replaced with 145-1.

¹ H NMR(500MHz,Chloroform-d)δ8.24(d,J＝10.8Hz,1H),8.11(t,J＝5.8Hz,1H),7.87(d,J＝9.7Hz,1H),7.35– 7.22(m,5H),6.50(s,1H),6.13(t,J＝3.1Hz,1H),4.61(d,J＝10.6Hz,1H),4.49–4.36(m,4H),3.64(dd ,J＝12.4,1.5Hz,1H),3.51(dd,J＝12.4,3.4Hz,1H),3.33–3.26(m,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H), 2.52(s, 3H),2.49–2.41(m,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.02(dt,J＝15.0,7.6Hz,1H),1.94–1.85(m,1H),1.82 (dtd,J＝12.2,3.7,2.3Hz,1H),1.75–1.65(m,1H),1.65–1.40(m,5H),1.00(s,9H).ESI-MS m/z 649.3[M+ H] ⁺

Example 146: Synthesis of Compound 146

Compound 146 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 146-1 and 146-2.

¹ H NMR (500MHz, Chloroform-d) δ9.91 (s, 1H), 8.09 (d, J = 9.5Hz, 1H), 7.90–7.85 (m, 1H), 7.83 (s, 1H), 7.73–7.66 (m,1H),7.47–7.39(m,1H),7.21–7.12(m,2H),7.00(d,J＝1.8Hz,1H),6.13(t,J＝3.1Hz,1H),4.64( d,J＝9.7Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H),4.42–4.36(m,1H),3.64(dd,J＝12.4,1.5Hz,1H),3.55–3.47 (m,1H),3.33–3.22(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.49–2.41(m ,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.02(dt,J＝15.0,7.6Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7 ,2.3Hz,1H),1.75–1.65(m,1H),1.65–1.40(m,5H),1.00(s,9H),0.73–0.60(m,4H).ESI-MS m/z 633.3[M +H] ⁺

Example 147: Synthesis of Compound 147

Compound 147 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 147-1 and 147-2.

¹ H NMR (500MHz, Chloroform-d) δ8.24(d,J＝10.8Hz,1H),7.87(d,J＝9.7Hz,1H),7.48(d,J＝8.2Hz,1H),6.50( s,1H),6.13(t,J＝3.1Hz,1H),4.61(d,J＝10.6Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H),4.42–4.36(m,1H ),3.71–3.61(m,2H),3.51(dd,J＝12.4,3.4Hz,1H),3.33–3.22(m,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H), 2.52 (s,3H),2.45(dddd,J＝7.3,4.4,3.3,2.2Hz,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.02(dt,J＝15.0,7.6Hz,1H ),1.94–1.85(m,1H),1.82(dtd,J＝12.2,3.7,2.2Hz,1H),1.75–1.33(m,16H),1.00(s,9H).ESI-MS m/z 641.3 [M+H] ⁺

Example 148: Synthesis of Compound 148

Compound 148 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 148-1 and 148-2.

¹ H NMR(500MHz,Chloroform-d)δ9.91(s,1H),8.09(d,J＝9.5Hz,1H),7.87(d,J＝9.7Hz,1H),7.73–7.66(m,1H ),7.48(d,J＝8.2Hz,1H),7.47–7.39(m,1H),7.21–7.12(m,2H),7.00(d,J＝1.8Hz,1H),6.13(t,J＝ 3.1Hz,1H),4.65(d,J＝9.5Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H),4.42–4.36(m,1H),3.71–3.61(m,2H), 3.51(dd,J＝12.4,3.4Hz,1H),3.33–3.26(m,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.45(dddd,J＝7.3,4.4,3.3 ,2.2Hz,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.02(dt,J＝15.0,7.6Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝ 12.2,3.7,2.3Hz,1H),1.75–1.33(m,16H),1.00(s,9H).ESI-MS m/z 675.3[M+H] ⁺

Example 149: Synthesis of Compound 149

Compound 149 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 149-1 and 149-2.

¹ H NMR(500MHz,Chloroform-d)δ7.96(d,J＝11.2Hz,1H),7.87(d,J＝9.7Hz,1H),7.76(d,J＝2.0Hz,1H),7.74– 7.68(m,1H),7.60–7.52(m,1H),7.48(d,J＝8.2Hz,1H),7.43–7.34(m,2H),6.13(t,J＝3.1Hz,1H),4.52 –4.42(m,2H),4.42–4.36(m,1H),3.71–3.61(m,2H),3.51(dd,J＝12.4,3.4Hz,1H),3.33–3.26(m,2H), 2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.49–2.41(m,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.02(dt,J＝15.0,7.6Hz, 1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.75–1.33(m,16H),1.00(s,9H).ESI-MS m/z 676.3[M+H] ⁺

Example 150: Synthesis of Compound 150

Compound 150 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-6 were replaced by 150-1 and 150-2.

¹ H NMR(500MHz,Chloroform-d)δ8.16(d,J＝10.2Hz,1H),8.11(t,J＝5.8Hz,1H),7.87(d,J＝9.7Hz,1H),7.35– 7.22(m,5H),6.50(s,1H),6.13(t,J＝3.1Hz,1H),4.57(dd,J＝10.3,6.8Hz,1H),4.50–4.45(m,2H),4.45 –4.39(m,1H),3.60(dd,J＝12.4,1.6Hz,1H),3.42(dd,J＝12.4,3.3Hz,1H),3.33–3.26(m,2H),2.68(tdd,J ＝7.7,5.7,3.9Hz,1H),2.52(s,3H),2.45(dddd,J＝7.3,4.4,3.3,2.3Hz,2H),2.12(dt,J＝15.0,7.5Hz,1H), 2.07–2.02(m,1H),2.00(dd,J＝7.2,1.9Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.1,3.7,2.2Hz,1H),1.75– 1.65(m,1H),1.65–1.56(m,2H),1.56–1.51(m,2H),1.48–1.40(m,1H),0.91(dd,J＝6.9,0.9Hz,6H).ESI- MS m/z 634.3[M+H] ⁺

Example 151: Synthesis of Compound 151

Compound 151 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-6 were replaced by 151-1 and 151-2.

¹ H NMR (500MHz, Chloroform-d) δ8.11(t,J＝5.8Hz,1H),7.99(d,J＝10.8Hz,1H),7.87(d,J＝9.7Hz,1H),7.76( d,J＝1.9Hz,1H),7.74–7.68(m,1H),7.60–7.52(m,1H),7.43–7.36(m,2H),7.36–7.22(m,5H),6.13(t, J＝3.1Hz,1H),4.52–4.45 (m,3H),4.45–4.39(m,1H),3.60(dd,J＝12.4,1.6Hz,1H),3.42(dd,J＝12.4,3.3Hz,1H),3.33–3.26(m,2H ),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.45(dddd,J＝7.3,4.4,3.3,2.3Hz,2H),2.17–1.97(m,3H),1.94–1.86(m ,1H),1.82(dtd,J＝12.3,3.8,2.3Hz,1H),1.75–1.64(m,1H),1.64–1.56(m,2H),1.56–1.51(m,2H),1.48–1.40 (m,1H),0.91(dd,J＝7.0,0.9Hz,6H).ESI-MS m/z 670.3[M+H] ⁺

Example 152: Synthesis of Compound 152

Compound 152 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-6 were replaced by 152-1 and 152-2.

¹ H NMR (500MHz, Chloroform-d) δ9.91 (s, 1H), 8.14–8.04 (m, 2H), 7.87 (d, J = 9.7Hz, 1H), 7.73–7.66 (m, 1H), 7.47 –7.39(m,1H),7.35–7.22(m,5H),7.21–7.12(m,2H),7.00(d,J＝1.8Hz,1H),6.13(t,J＝3.1Hz,1H), 4.61(dd,J＝9.1,6.7Hz,1H),4.50–4.45(m,2H),4.45–4.39(m,1H),3.60(dd,J＝12.4,1.6Hz,1H),3.42(dd, J＝12.4,3.3Hz,1H),3.33–3.26(m,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.45(dddd,J＝7.2,4.2,3.2,2.2Hz, 2H),2.12(dt,J＝15.0,7.5Hz,1H),2.07–1.97(m,2H),1.94–1.85(m,1H),1.82(dtd,J＝12.2,3.7,2.2Hz,1H) ,1.75–1.65(m,1H),1.65–1.40(m,5H),0.91(dd,J＝6.9,0.9Hz,6H).ESI-MS m/z 669.3[M+H] ⁺

Example 153: Synthesis of Compound 153

Compound 153 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-6 and 143-15 were replaced by 153-1, 153-2 and 153-3.

¹ H NMR (500MHz, Chloroform-d) δ9.91 (s, 1H), 8.07 (d, J = 9.1Hz, 1H), 7.90–7.81 (m, 2H), 7.73–7.66 (m, 1H), 7.47 –7.39(m,1H),7.21–7.12(m,2H),7.00(d,J＝ 1.8Hz,1H),6.13(t,J＝3.1Hz,1H),4.61(dd,J＝9.2,6.8Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H),4.42–4.36( m,1H),3.60(dd,J＝12.4,1.7Hz,1H),3.42(dd,J＝12.4,3.3Hz,1H),3.33–3.26(m,2H),2.78(dp,J＝7.7, 4.8Hz,1H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.45(dddd,J＝7.3,4.4,3.3,2.3Hz,2H),2.12(dt,J＝15.0,7.5Hz ,1H),2.07–

1.97(m,2H),1.94–1.85(m,1H),1.82(dtd,J＝12.2,3.7,2.2Hz,1H),1.75–1.65(m,1H),1.65–1.40(m,5H), 0.91(dd,J＝6.9,0.9Hz,6H),0.73–0.60(m,4H).ESI-MS m/z 619.3[M+H] ⁺

Example 154: Synthesis of Compound 154

Compound 154 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-6 and 143-15 were replaced by 154-1, 154-2 and 154-3.

¹ H NMR(500MHz,Chloroform-d)δ8.16(d,J＝10.2Hz,1H),7.90–7.81(m,2H),6.50(s,1H),6.13(t,J＝3.1Hz,1H ),4.57(dd,J＝10.3,6.8Hz,1H),4.47(dt,J＝9.7,7.3Hz,1H),4.42–4.36(m,1H),3.60(dd,J＝12.4,1.6Hz, 1H),3.42(dd,J＝12.4,3.3Hz,1H),3.33–3.26(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.67(tdd,J＝7.8,5.7, 3.9Hz,1H),2.52(s,3H),2.45(dddd,J＝7.3,4.3,3.3,2.2Hz,2H),2.12(dt,J＝15.0,7.5Hz,1H),2.07–2.02(m ,1H),2.00(dd,J＝7.3,1.9Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.75–1.65(m,1H ),1.65–1.40(m,5H),0.91(dd,J＝6.9,0.9Hz,6H),0.73–0.60(m,4H).ESI-MS m/z 585.3[M+H] ⁺

Example 155: Synthesis of Compound 155

Compound 155 was synthesized with reference to compound 143, and the corresponding intermediates 143-3 and 143-9 were replaced by 155-1 and 155-2.

¹ H NMR(500MHz,Chloroform-d)δ8.24(d,J＝10.8Hz,1H),8.11(t,J＝5.8Hz,1H),8.04(d,J＝9.7Hz,1H),7.35– 7.22(m,5H),6.50(s,1H),6.13(t,J＝3.1Hz,1H),4.65–4.58(m,2H),4.50–4.45(m,2H),4.45–4.39(m, 1H),3.70(dd,J＝12.4,2.5Hz,1H),3.52(dd,J＝12.4,4.3Hz,1H),3.33–3.26(m,2H),2.67(tdd,J＝7.8,5.7, 3.9Hz,1H),2.52(s,3H),2.12(dt,J＝15.0,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.86(m,1H),1.82(dtd,J ＝12.2,3.7,2.3Hz,1H),1.43(dd,J＝7.7,5.5Hz,1H),1.06(d,J＝21.2Hz,7H),1.00(s,9H).ESI-MS m/z 649.3[M+H] ⁺

Example 156: Synthesis of Compound 156

Compound 156 was synthesized with reference to compound 143, and the corresponding intermediate 143-3 was replaced with 156-1.

¹ H NMR (500MHz, Chloroform-d) δ8.11(t,J＝5.8Hz,1H),8.04(d,J＝9.7Hz,1H),7.96(d,J＝11.2Hz,1H),7.76( d,J＝2.1Hz,1H),7.74–7.68(m,1H),7.60–7.52(m,1H),7.43–7.36(m,2H),7.36–7.22(m,5H),6.13(t, J＝3.1Hz,1H),4.63(d,J＝7.7Hz,1H),4.52–4.45(m,3H),4.45–4.39(m,1H),3.70(dd,J＝12.4,2.5Hz,1H ),3.52(dd,J＝12.4,4.3Hz,1H),3.33–3.26(m,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.12(dt,J＝15.0,7.5 Hz,1H),2.07–1.99(m,1H),1.94–1.85(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.43(dd,J＝7.7,5.5Hz, 1H),1.06(d,J＝21.2Hz,7H),1.00(s,9H).ESI-MS m/z 684.3[M+H] ⁺

Example 157: Synthesis of Compound 157

Compound 157 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-3 were replaced by 157-1 and 157-2.

¹ H NMR(500MHz,Chloroform-d)δ9.91(s,1H),8.14–8.06(m,2H),8.04(d,J ＝9.7Hz,1H),7.73–7.66(m,1H),7.47–7.39(m,1H),7.35–7.22(m,5H),7.21–7.12(m,2H),7.00(d,J＝1.8 Hz,1H),6.13(t,J＝3.1Hz,1H),4.68–4.60(m,2H),4.50–4.45(m,2H),4.45–4.39(m,1H),3.70(dd,J＝ 12.4,2.5Hz,1H),3.52(dd,J＝12.4,4.3Hz,1H),3.33–3.26(m,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.12(dt ,J＝15.0,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.85(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.43(dd,J ＝7.7,5.5Hz,1H),1.06(d,J＝21.2Hz,7H),1.00(s,9H).ESI-MS m/z 683.3[M+H] ⁺

Example 158: Synthesis of Compound 158

Compound 158 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-3 and 143-15 were replaced by 158-1, 158-2 and 158-3.

¹ H NMR (500MHz, Chloroform-d) δ8.24(d,J＝10.8Hz,1H),8.04(d,J＝9.7Hz,1H),7.84(d,J＝7.7Hz,1H),6.50( s,1H),6.13(t,J＝3.1Hz,1H),4.65–4.58(m,2H),4.47(dt,J＝9.7,7.3Hz,1H),3.70(dd,J＝12.4,2.5Hz ,1H),3.52(dd,J＝12.4,4.3Hz,1H),3.33–3.22(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.68(tdd,J＝7.7,5.7 ,3.9Hz,1H),2.52(s,3H),2.12(dt,J＝15.0,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.85(m,1H),1.82(dtd, J＝12.2,3.7,2.3Hz,1H),1.43(dd,J＝7.7,5.5Hz,1H),1.06(d,J＝21.2Hz,7H),1.00(s,9H),0.67(dq,J ＝4.7,1.4Hz,4H).ESI-MS m/z 599.3[M+H] ⁺

Example 159: Synthesis of Compound 159

Compound 159 was synthesized with reference to compound 143, and the corresponding intermediates 143-3 and 143-15 were replaced by 159-1 and 159-2.

¹ H NMR (500MHz, Chloroform-d) δ8.04(d,J＝9.7Hz,1H),7.96(d,J＝11.2Hz,1H),7.84(d,J＝7.7Hz,1H),7.76( d,J＝2.1Hz,1H),7.74–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),6.13(t,J＝3.1Hz,1H),4.63 (d,J＝7.7Hz,1H),4.51–4.42(m,2H),3.70(dd,J＝12.4,2.5Hz,1H),3.52(dd,J＝12.4,4.3Hz,1H),3.33– 3.26(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.12(dt,J＝15.0,7.5Hz,1H) ,2.07–1.99(m,1H),1.94–1.85(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.43(dd,J＝7.7,5.5Hz,1H),1.06 (d,J＝21.2Hz,7H),1.00(s,9H),0.72–0.60(m,4H).ESI-MS m/z 634.3[M+H] ⁺

Example 160: Synthesis of Compound 160

Compound 160 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-3 and 143-15 were replaced by 160-1, 160-2 and 160-3.

¹ H NMR (500MHz, Chloroform-d) δ9.91 (s, 1H), 8.09 (d, J = 9.5Hz, 1H), 8.04 (d, J = 9.7Hz, 1H), 7.84 (d, J = 7.7 Hz,1H),7.73–7.66(m,1H),7.47–7.39(m,1H),7.21–7.12(m,2H),7.00(d,J＝1.8Hz,1H),6.13(t,J＝ 3.1Hz,1H),4.67–4.60(m,2H),4.47(dt,J＝9.7,7.3Hz,1H),3.70(dd,J＝12.4,2.5Hz,1H),3.52(dd,J＝12.4 ,4.3Hz,1H),3.33–3.26(m,2H),2.78(dp,J＝7.7,4.8Hz,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.12(dt, J＝15.0,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.85(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.43(dd,J＝ 7.7,5.5Hz,1H),1.06(d,J＝21.2Hz,7H),1.00(s,9H),0.72–0.61(m,4H).ESI-MS m/z 633.3[M+H] ⁺

Example 161: Synthesis of Compound 161

The synthesis of compound 161 refers to compound 143, and the corresponding intermediates 143-9 and 143-3 are replaced by 161-1 and 161-2.

¹ H NMR(500MHz,Chloroform-d)δ9.16(d,J＝1.5Hz,1H),8.85–8.79(m,2H),8.11(t,J＝5.8Hz,1H),8.04(dd,J ＝10.2,4.5Hz,2H),7.35–7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.65–4.58(m,2H),4.49–4.45(m,2H),4.45– 4.39(m,1H),3.70(dd,J＝12.4,2.5Hz,1H),3.52(dd,J＝12.4,4.3Hz,1H),3.33–3.26(m,2H),2.67(tdd,J＝ 7.8,5.7,3.9Hz,1H),2.12(dt,J＝15.0,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.85(m,1H),1.82(dtd,J＝12.2, 3.7, 2.3Hz, 1H), 1.43 (dd, J＝7.7, 5.5Hz, 1H), 1.06 (d, J＝21.2Hz, 7H), 1.00 (s, 9H). ESI-MS m/z 646.3[M +H] ⁺

Example 162: Synthesis of Compound 162

Compound 162 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-3 were replaced by 162-1 and 162-2.

¹ H NMR (500MHz, Chloroform-d) δ9.25 (s, 1H), 8.20 (d, J = 10.6Hz, 1H), 8.11 (t, J = 5.8Hz, 1H), 8.07–7.98 (m, 3H ),7.76(td,J＝8.5,1.3Hz,1H),7.60(td,J＝8.5,1.1Hz,1H),7.35–7.22(m,5H),6.13(t,J＝3.1Hz,1H) ,4.62(s,2H),4.49–4.45(m,2H),4.45–4.39(m,1H),3.70(dd,J＝12.4,2.5Hz,1H),3.52(dd,J＝12.4,4.3Hz ,1H),3.33–3.26(m,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.12(dt,J＝15.0,7.5Hz,1H),2.07–1.99(m,1H ),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.43(dd,J＝7.7,5.5Hz,1H),1.06(d,J＝21.2Hz, 7H),1.00(s,9H).ESI-MS m/z 696.2[M+H] ⁺

Example 163: Synthesis of Compound 163

The synthesis of compound 163 refers to compound 143, and the corresponding intermediates 143-9 and 143-3 are replaced by 163-1 and 163-2.

¹ H NMR(500MHz,Chloroform-d)δ8.35(d,J＝8.2Hz,1H),8.20(d,J＝8.3Hz,1H),8.11(t,J＝5.8Hz,1H),8.08– 8.01(m,3H),7.94(dt,J＝7.9,0.8Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.8,1.2Hz,1H),7.35 –7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.65–4.57(m,2H),4.50–4.45(m,2H),4.45–4.39(m,1H),3.70(dd ,J＝12.4,2.5Hz,1H),3.52(dd,J＝12.4,4.3Hz,1H),3.33–3.22(m,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H), 2.12(dt,J＝15.0,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.43( dd,J＝7.7,5.5Hz,1H),1.06(d,J＝21.2Hz,7H),1.00(s,9H).ESI-MS m/z 695.2[M+H] ⁺

Example 164: Synthesis of Compound 164

Compound 164 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-3 were replaced by 164-1 and 164-2.

¹ H NMR(500MHz,Chloroform-d)δ8.35(d,J＝8.2Hz,1H),8.20(d,J＝8.3Hz,1H),8.11(t,J＝5.8Hz,1H),8.07– 8.01(m,1H),7.98–7.91(m,2H),7.82(d,J＝10.4Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.8, 1.2Hz,1H),7.35–7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.65–4.56(m,2H),4.47(dt,J＝5.7,1.0Hz,2H), 4.46–4.42(m,1H),3.52–3.45(m,1H),3.33–3.26(m,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.21–2.07(m,2H ),2.02(dt,J＝15.0,7.6Hz,1H),1.94–1.28(m,12H),1.00(s,9H).ESI-MS m/z 709.2[M+H] ⁺

Example 165: Synthesis of Compound 165

The synthesis of compound 165 refers to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 are replaced by 68-1 and 165-1.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 8.49 (d, J = 10.3Hz, 1H), 7.71–7.63 (m, 1H), 7.47–7.39 (m, 1H), 7.25 –7.16(m,5H),4.34–4.23(m,2H),4.19(dtd,J＝10.3,6.9,6.1Hz,1H),3.72(s,2H),3.21(td,J＝7.1,4.6Hz ,2H),2.41(p,J＝7.0Hz,1H),2.22(h,J＝7.0Hz,1H),2.05(ddt,J＝21.0,12.5,7.0Hz,2H),1.94(dt,J＝ 12.6,7.0Hz,1H),1.90–1.77(m,2H),1.77–1.67(m,2H),1.54–1.43(m,5H),1.46–1.39(m,1H),1.41–1.31(m, 1H).ESI-MS m/z 532.2[M+H] ⁺

Example 166: Synthesis of Compound 166

Compound 166 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 166-1.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 8.49 (d, J = 10.2Hz, 1H), 7.70–7.63 (m, 1H), 7.46–7.39 (m, 1H), 7.26 –7.17(m,4H),7.16(t,J＝4.6Hz,1H),4.34–4.23(m,2H),4.19(dtd,J＝10.3,7.0,6.1Hz,1H),4.15–4.02(m ,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.22(h,J＝7.0Hz,1H),2.05(ddt,J＝21.0, 12.4,7.1Hz,2H),1.98–1.60(m,6H),1.60–1.39(m,7H),1.41–1.31(m,1H),0.89(t,J＝8.0Hz,3H).ESI-MS m/z 560.2[M+H] ⁺

Example 167: Synthesis of Compound 167

Compound 167 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 167-1.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 8.49 (d, J = 10.3Hz, 1H), 7.70–7.63 (m, 1H), 7.46–7.39 (m, 1H), 7.26 –7.18(m,4H),7.16(t,J＝4.6Hz, 1H),5.10(hept,J＝6.8Hz,1H),4.31(t,J＝7.0Hz,1H),4.26(q,J＝7.0Hz,1H),4.19(dtd,J＝10.3,6.9,6.1 Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.22(h,J＝7.0Hz,1H),2.05(ddt,J＝21.0 ,12.5,7.0Hz,2H),1.98–1.87(m,1H),1.90–1.76(m,2H),1.78–1.67(m,2H),1.54–1.31(m,7H),1.22(d,J ＝6.8Hz,3H),1.17(d,J＝6.8Hz,3H).ESI-MS m/z 560.2[M+H] ⁺

Example 168: Synthesis of Compound 168

Compound 168 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 168-1.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 8.49 (d, J = 10.3Hz, 1H), 7.69–7.63 (m, 1H), 7.46–7.39 (m, 1H), 7.25 –7.16(m,4H),7.16(t,J＝4.6Hz,1H),4.35(t,J＝7.0Hz,1H),4.26(q,J＝7.0Hz,1H),4.19(dtd,J＝ 10.3,6.9,6.1Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.22(h,J＝7.0Hz,1H),2.05( ddt,J＝21.0,12.4,7.1Hz,2H),1.94(dt,J＝12.6,7.0Hz,1H),1.87(dt,J＝12.5,7.1Hz,1H),1.85–1.76(m,1H) ,1.78–1.67(m,2H),1.49(s,9H),1.54–1.47(m,1H),1.50–1.44(m,3H),1.47–1.40(m,1H),1.43–1.31(m, 1H).ESI-MS m/z 574.2[M+H] ⁺

Example 169: Synthesis of Compound 169

Compound 169 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 169-1.

¹ H NMR (500MHz, Chloroform-d) δ9.88 (s, 1H), 8.48 (d, J = 10.4Hz, 1H), 7.67 (dt, J = 6.9, 1.7Hz, 1H), 7.46–7.39 (m ,1H),7.33(d,J＝6.0Hz,1H),7.25–7.16(m,4H),4.42(dtd,J＝10.2,6.9,6.1Hz,1H),4.35(t,J＝7.0Hz, 1H),3.96(q, J＝7.0Hz,1H),3.34(s,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.20(h,J＝7.0Hz, 1H),2.02(dtd,J＝12.7,7.1,3.7Hz,2H),1.93(dt,J＝12.4,6.9Hz,1H),1.87(dt,J＝12.5,7.1Hz,1H),1.85–1.76 (m,1H),1.78–1.65(m,2H),1.50(s,9H),1.54–1.32(m,6H).ESI-MS m/z 631.3[M+H] ⁺

Example 170: Synthesis of Compound 170

Compound 170 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 170-1.

¹ H NMR(500MHz,Chloroform-d)δ9.88(s,1H),8.50(d,J＝10.3Hz,1H),7.67(dt,J＝7.0,1.6Hz,1H),7.46–7.40(m ,1H),7.33(d,J＝6.0Hz,1H),7.25–7.15(m,4H),4.47–4.37(m,2H),4.35(t,J＝7.0Hz,1H),4.26(dq, J＝12.3,7.9Hz,1H),3.96(q,J＝7.0Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.20( h,J＝7.0Hz,1H),2.02(dtd,J＝12.7,7.1,3.7Hz,2H),1.98–1.76(m,3H),1.78–1.65(m,2H),1.50(s,9H) ,1.54–1.32(m,7H),1.24(t,J＝8.0Hz,3H).ESI-MS m/z 631.3[M+H] ⁺

Example 171: Synthesis of Compound 171

Compound 171 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 171-1.

¹ H NMR (500MHz, Chloroform-d) δ9.88 (s, 1H), 8.50 (d, J = 10.3Hz, 1H), 7.67 (ddd, J = 6.9, 2.6, 1.5Hz, 1H), 7.45–7.39 (m,1H),7.33(d,J＝6.0Hz,1H),7.25–7.15(m,4H),4.42(dtd,J＝10.3,6.9,6.1Hz,1H),4.31(t,J＝7.0 Hz,1H),3.96(q,J＝7.0Hz,1H),3.79(dt,J＝12.3,7.1Hz,1H),3.70(dt,J＝12.3,7.1Hz,1H),3.21(td,J ＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.20(h,J＝7.0Hz,1H), 2.02(dtd,J＝12.7,7.1,3.7Hz,2H),1.98–1.65(m,7H),1.50(s,9H),1.54–1.32(m,7H),0.95(t,J＝8.0Hz, 3H).ESI-MS m/z 659.3[M+H] ⁺

Example 172: Synthesis of Compound 172

The synthesis method refers to the synthesis of compound 5, except that compound 172-1 is used to replace compound 5-1 in Example 5 to obtain compound 172.

1H NMR (600MHz, Chloroform-d) δ10.14 (s, 1H), 8.94 (d, J = 5.8Hz, 1H), 7.59 (d, J = 8.0Hz, 1H), 7.37 (dd, J = 8.6, 2.1Hz,2H),7.22(t,J＝7.6Hz,1H),7.11–7.05(m,2H),7.02(d,J＝2.1Hz,1H),6.83(s,1H),4.86(td, J＝8.7,5.7Hz,1H),4.79(dt,J＝9.4,3.2Hz,1H),3.16(t,J＝9.4Hz,1H),3.02(d,J＝9.2Hz,1H),2.50– 2.45(m,1H),2.23(d,J＝8.1Hz,1H),2.19–2.13(m,1H),1.80–1.58(m,11H),1.51(s,9H),1.19–1.09(m, 2H),0.97–0.88(m,2H).ESI-MS m/z 576.3[M+H] ⁺

Example 173: Synthesis of Compound 173

The synthesis method refers to the synthesis of compound 5, except that compound 173-1 is used to replace compound 5-1 in Example 5 to obtain compound 173.

1H NMR (500MHz, Chloroform-d) δ9.52 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.67 (ddd, J = 6.6, 2.4,1.4Hz,1H),7.43(dd,J＝6.9,2.0Hz,1H),7.33(d,J＝6.2Hz,1H),7.25–7.15(m,4H),4.49–4.38(m,2H ),4.34(p,J＝7.0Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.02(dt,J＝12.7,7.1Hz ,1H),1.93(dt,J＝12.4,6.9Hz,1H),1.86–1.62(m,6H),1.50(s,9H),1.61–1.38(m,10H),1.38–1.26(m,2H ).ESI-MS m/z 659.8[M+H] ⁺

Example 174: Synthesis of Compound 174

The synthesis method refers to the synthesis of compound 12, except that compound 173 is used to replace compound 9 in Example 12 to obtain compound 174.

1H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.53 (d, J = 10.6Hz, 1H), 8.19 (d, J = 9.3Hz, 1H), 8.08 (d, J = 10.4Hz ,1H),7.71–7.63(m,1H),7.46–7.39(m,1H),7.26–7.18(m,3H),7.16(t,J＝4.6Hz,1H),7.03(d,J＝6.2 Hz,1H),4.44(dt,J＝10.8,7.0Hz,1H),4.19(dtd,J＝10.4,7.0,6.1Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.99 (dp,J＝9.3,7.0Hz,1H),2.46(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.1Hz,1H),1.94(dt,J＝12.5,6.9Hz, 1H),1.86–1.65(m,4H),1.61–1.38(m,11H),0.75–0.67(m,1H),0.71–0.63(m,1H),0.58–0.46(m,2H).ESI- MS m/z559.7[M+H] ⁺

Example 175: Synthesis of Compound 175

The synthesis method refers to the synthesis of compound 5, except that compound 175-1 is used to replace compound 5-1 in Example 5 to obtain compound 175.

¹ H NMR (500MHz, Chloroform-d) δ9.58 (s, 1H), 8.57 (d, J = 10.8Hz, 1H), 8.07 (d, J = 10.4Hz, 1H), 7.66 (dt, J = 7.1 ,1.8Hz,1H),7.46–7.39(m,1H),7.25–7.13(m,4H),7.09(d,J＝6.2Hz,1H),4.45(dt,J＝10.8,7.0Hz,1H) ,4.19(dtd,J＝10.4,7.0,6.1Hz,1H),3.58–3.43(m,4H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H ),2.07(dt,J＝12.2,7.1Hz,1H),1.98–1.65(m,11H),1.61–1.38(m,12H).ESI-MS m/z 573.3[M+H] ⁺

Example 176: Synthesis of Compound 176

The synthesis method refers to the synthesis of compound 5, except that compound 176-1 is used to replace compound 5-1 in Example 5 to obtain compound 176.

¹ H NMR(500MHz,Chloroform-d)δ9.58(s,1H),8.53(d,J＝10.6Hz,1H),8.08(d,J＝10.4Hz,1H),7.71–7.63(m,1H ),7.46–7.39(m,1H),7.26–7.18(m,3H),7.16(t,J＝4.6Hz,1H),7.09(d,J＝6.2Hz,1H),4.43(dt,J＝ 10.8,7.0Hz,1H),4.19(dtd,J＝10.4,7.0,6.1Hz,1H),3.60(td,J＝7.1,4.8Hz,4H),3.21(td,J＝7.1,4.6Hz,2H ),2.46(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.1Hz,1H),1.99(q,J＝7.1Hz,2H),1.97–1.89(m,1H),1.86 –1.65(m,4H),1.61–1.38(m,12H).ESI-MS m/z 559.7[M+H] ⁺

Example 177: Synthesis of Compound 177

Compound 177 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 173-1.

¹ H NMR (500MHz, Chloroform-d) δ9.88 (s, 1H), 8.50 (d, J = 10.3Hz, 1H), 7.67 (dt, J = 7.0, 1.6Hz, 1H), 7.43 (dd, J ＝7.0,2.0Hz,1H),7.33(d,J＝6.2Hz,1H),7.25–7.15(m,4H),4.33(dq,J＝13.8,7.0Hz,2H),4.19(dtd,J＝ 10.3,6.9,6.1Hz,1H),3.93(q,J＝7.1Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.20( h,J＝7.0Hz,1H),2.02(dtd,J＝12.7,7.1,3.7Hz,2H),1.93(dt,J＝12.4,6.9Hz,1H),1.87(dt,J＝12.5,7.1Hz ,1H),1.85–1.76(m,1H),1.79–1.62(m,4H),1.50(s,9H),1.54–1.26(m,9H).ESI-MS m/z 657.3[M+H] ⁺

Example 178: Synthesis of Compound 178

The synthesis method refers to the synthesis of compound 12, except that compound 177 is used to replace compound 9 in Example 12 to obtain compound 178.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 8.49 (d, J = 10.4Hz, 1H), 8.19 (d, J = 9.3Hz, 1H), 7.66 (ddd, J = 6.9 ,2.6,1.5Hz,1H),7.46–7.39(m,1H),7.25–7.19(m,1H),7.22–7.16(m,2H),7.16(t,J＝4.6Hz,1H),7.03( d,J＝6.2Hz,1H),4.31(t,J＝7.0Hz,1H),4.26(q,J＝7.0Hz,1H),4.19(dtd,J＝10.3,6.9,6.1Hz,1H), 3.21(td,J＝7.1,4.6Hz,2H),2.99(dp,J＝9.3,7.0Hz,1H),2.46(p,J＝7.0Hz,1H),2.22(h,J＝7.0Hz,1H ),2.05(ddt,J＝21.0,12.5,7.1Hz,2H),1.94(dt,J＝12.6,7.0Hz,1H),1.90–1.74(m,2H),1.77–1.66(m,2H), 1.55–1.43(m,5H),1.47–1.39(m,1H),1.41–1.31(m,1H),0.75–0.67(m,1H),0.71–0.63(m,1H),0.58–0.46(m ,2H).ESI-MS m/z 557.7[M+H] ⁺

Example 179: Synthesis of Compound 179

Compound 179 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 175-1.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 8.48 (d, J = 10.4Hz, 1H), 7.66 (ddd, J = 7.1, 2.6, 1.6Hz, 1H), 7.46–7.39 (m,1H),7.25–7.13(m,4H),7.09(d,J＝6.2Hz,1H),4.35(t,J＝7.0Hz,1H),4.26(q,J＝7.0Hz,1H) ,4.19(dtd,J＝10.3,6.9,6.1Hz,1H),3.58–3.43(m,4H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H ),2.22(h,J＝7.0Hz,1H),2.05(ddt,J＝21.0,12.4,7.1Hz,2H),1.98–1.67(m,10H),1.55–1.43(m,5H),1.47– 1.39(m,1H),1.41–1.31(m,1H).ESI-MS m/z 571.7[M+H] ⁺

Example 180: Synthesis of Compound 180

Compound 180 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 176-1.

¹ H NMR (500MHz, Chloroform-d) δ9.92 (s, 1H), 8.49 (d, J = 10.4Hz, 1H), 7.66 (ddd, J = 7.0, 2.6, 1.4Hz, 1H), 7.46–7.39 (m,1H),7.25–7.16(m,3H),7.16(t,J＝4.6Hz,1H),7.09(d,J＝6.2Hz,1H),4.31(t,J＝7.0Hz,1H) ,4.26(q,J＝7.0Hz,1H),4.19(dtd,J＝10.3,7.0,6.1Hz,1H),3.60(td,J＝7.1,2.1Hz,4H),3.21(td,J＝7.1 ,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.22(h,J＝7.0Hz,1H),2.11–2.04(m,1H),2.06–1.99(m,1H),2.02 –1.95(m,2H),1.97–1.87(m,1H),1.90–1.76(m,2H),1.78–1.67(m,2H),1.54–1.31(m,7H).ESI-MS m/z 557.7[M+H] ⁺

Example 181: Synthesis of Compound 181

The synthesis of compound 181 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 181-2, 181-1 and 181-3.

¹ H NMR (500MHz, Chloroform-d) δ8.43(d,J＝11.7Hz,1H),8.08(d,J＝10.4Hz,1H),7.85(d,J＝1.4Hz,1H),7.61( ddt,J＝6.2,5.0,2.4Hz,1H),7.52–7.46(m,1H),7.38–7.31(m,2H),7.20(d,J＝6.2Hz,1H),7.16(t,J＝ 4.6Hz,1H),4.24–4.14(m,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.0 Hz,1H),1.94(dt,J＝12.6,6.9Hz,1H),1.86–1.45(m,13H),1.49(s,9H).ESI-MS m/z 563.3[M+H] ⁺

Example 182: Synthesis of Compound 182

The synthesis of compound 182 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 182-2, 181-1 and 181-3.

¹ H NMR (500MHz, Chloroform-d) δ8.43(d,J＝11.7Hz,1H),8.08(d,J＝10.4Hz,1H),7.85(d,J＝1.4Hz,1H),7.65– 7.57(m,1H),7.53–7.45(m,1H),7.38–7.29(m,2H),7.23–7.16(m,2H),4.24–4.14(m,2H),3.21(td,J＝7.1 ,4.6Hz,2H),2.41(p,J＝7.0Hz,1H),2.07(dt,J＝12.2,7.0Hz,1H),1.98–1.60(m,6H),1.51–1.41(m,10H) .ESI-MS m/z 535.2[M+H] ⁺

Example 183: Synthesis of Compound 183

The synthesis of compound 183 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 183-2, 183-1 and 183-3.

¹ H NMR (500MHz, Chloroform-d) δ9.56 (s, 1H), 8.64 (d, J = 10.8Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.78 (d, J = 4.8 Hz,1H),7.43–7.30(m,3H),7.19(t,J＝4.6Hz,1H),7.09–7.02(m,1H),4.49–4.36(m,3H),4.26(dq,J＝ 12.3,7.9Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.02(dt,J＝12.7,7.1Hz,1H),1.98– 1.59(m,6H),1.50(s,7H),1.48–1.43(m,1H),1.46–1.39(m,1H),1.42–1.32(m,2H),1.23(t,J＝8.0Hz, 3H).ESI-MS m/z 623.3[M+H] ⁺

Example 184: Synthesis of Compound 184

The synthesis of compound 184 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 184-2, 184-1 and 184-3.

¹ H NMR(500MHz,Chloroform-d)δ8.54(d,J＝10.8Hz,1H),8.08(d,J＝10.4Hz,1H),7.68(dt,J＝7.5,1.5Hz,1H), 7.35–7.27(m,2H),7.22–7.16(m,2H),7.07(d,J＝1.5Hz,1H),4.49–4.36(m,3H),4.26(dq,J＝12.3,7.9Hz, 1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.02(dt,J＝12.7,7.1Hz,1H),1.98–1.89(m,1H ),1.92–1.82(m,1H),1.84–1.74(m,1H),1.77–1.68(m,2H),1.64(dt,J＝12.4,7.0Hz,1H),1.50(s,7H), 1.50–1.43(m,1H),1.46–1.39(m,1H),1.42–1.32(m,2H),1.23(t,J＝8.0Hz,3H).ESI-MS m/z 639.3[M+H ] ⁺

Example 185: Synthesis of Compound 185

The synthesis of compound 185 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-8 and 5-1 are replaced by 185-1 and 184-3.

¹ H NMR (500MHz, Chloroform-d) δ9.61 (s, 1H), 8.52 (d, J = 10.6Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.88 (s, 1H), 7.46(t,J＝1.7Hz,1H),7.39(d,J＝7.5Hz,1H),7.35–7.27(m,2H),7.19(t,J＝4.6Hz,1H),7.15(d,J ＝1.4Hz,1H),4.49–4.36(m,2H),4.32–4.23(m,1H),4.25–4.14(m,1H),3.21(td,J＝7.1,4.6Hz,2H),2.94( s,2H),2.44(p,J＝7.1Hz,1H),2.02(dt,J＝12.7,7.1Hz,1H),1.93(dt,J＝12.4,6.9Hz,1H),1.86–1.64(m ,4H),1.50(s,9H),1.61–1.38(m,10H),1.24(t,J＝8.0Hz,3H).ESI-MS m/z 740.3[M+H] ⁺

Example 186: Synthesis of Compound 186

The synthesis of compound 186 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 184-2, 186-1 and 184-3.

¹ H NMR(500MHz,Chloroform-d)δ8.59(d,J＝11.7Hz,1H),8.48(s,1H),8.31–8.27(m,1H),8.20(dd,J＝7.5,1.4Hz ,1H),8.12(d,J＝7.5Hz,1H),8.08(d,J＝10.4Hz,1H),8.06–8.01(m,1H),7.65(dd,J＝7.5,1.6Hz,1H) ,7.33(d,J＝6.0Hz,1H), 7.19(t,J＝4.6Hz,1H),4.46–4.34(m,2H),4.32–4.14(m,2H),3.21(td,J＝7.1,4.6Hz,2H),2.98(s,2H) ,2.46(p,J＝7.0Hz,1H),2.02(dt,J＝12.7,7.1Hz,1H),1.98–1.60(m,6H),1.50(s,7H),1.48–1.37(m,4H ),1.24(t,J＝8.0Hz,3H).ESI-MS m/z710.2[M+H] ⁺

Example 187: Synthesis of Compound 187

The synthesis of compound 187 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 187-2, 187-1 and 187-3.

¹ H NMR (500MHz, Chloroform-d) δ8.71 (dd, J＝7.5, 1.5Hz, 1H), 8.63 (d, J＝10.8Hz, 1H), 8.41 (dt, J＝7.5, 1.5Hz, 1H ),8.08(d,J＝10.4Hz,1H),7.67(d,J＝1.5Hz,1H),7.36–7.29(m,2H),7.19(t,J＝4.6Hz,1H),4.49–4.38 (m,2H),4.34(p,J＝7.0Hz,1H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0Hz,1H),2.02(dt,J＝ 12.7,7.1Hz,1H),1.93(dt,J＝12.4,6.9Hz,1H),1.86–1.45(m,14H),1.52(s,1H),1.50(s,9H),1.39–1.26(m ,2H).ESI-MS m/z 646.3[M+H] ⁺

Example 188: Synthesis of Compound 188

The synthesis of compound 188 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 187-2, 188-1 and 187-3.

¹ H NMR (500MHz, Chloroform-d) δ9.72 (s, 1H), 8.55 (d, J = 10.8Hz, 1H), 8.08 (d, J = 10.4Hz, 1H), 7.34 (dd, J = 11.5 ,6.8Hz,2H),7.22–7.10(m,3H),6.81(dd,J＝7.4,1.5Hz,1H),4.45(dt,J＝10.8,7.0Hz,1H),4.34(p,J＝ 7.0Hz,1H),4.19(dtd,J＝10.4,6.9,6.1Hz,1H),3.84(s,2H),3.21(td,J＝7.1,4.6Hz,2H),2.46(p,J＝7.0 Hz,1H),2.02(dt,J＝12.7,7.1Hz,1H),1.93(dt,J＝12.4,6.9Hz,1H),1.86–1.46(m,15H),1.50(s,9H),1.39 –1.26(m,2H).ESI-MS m/z 675.3[M+H] ⁺

Pharmacological activity test

1.1 Evaluation of 2019 novel coronavirus 3CL protease inhibitory activity

Recombinant SARS-CoV-2 3CL protease (final concentration 30 nM) was mixed with serial concentrations of compound in 80 μL assay buffer (50 mM Tris–HCl, pH 7.3, 1 mM EDTA) and incubated for 10 min. Start the reaction by adding 40 μL of fluorogenic substrate to a final concentration of 20 μM. Afterwards, a fluorescence signal (emission) was generated at 320nm (excitation)/405nm and measured immediately with a Bio-Tek Synergy4 plate reader every 30 seconds for 10 minutes. Compared with the blank control of adding DMSO, calculate the Vmax of the reaction of adding different concentrations of compounds to obtain the IC50 curve. For some compounds, the anti-SARS-CoV-2 3CL protease IC50 was measured at 9 concentrations and 3 independent experiments. For some compounds, the anti-SARS-CoV-2 3CL protease inhibitory activity is expressed by three concentration gradient inhibition rate levels. All experimental data were analyzed using GraphPad Prism software. The experimental results are shown in Table 2.

Table 2: 2019 novel coronavirus 3CL protease inhibitory activity

Table 3: 2019 novel coronavirus 3CL protease inhibitory activity

Experimental results show that most compounds still have good SARS-CoV-23CL protease inhibitory activity at a concentration level of 1 μM. Some compounds have IC50 values less than 100nM. Among them, the _IC50 values of compound 67 and compound 70 are 73nM and 59nM.

2.1 Evaluation of compound’s inhibitory activity against 2019 novel coronavirus replication

African green monkey kidney Vero E6 cells were obtained from the American Type Culture Collection Center (ATCC) and stored in DMEM medium containing 10% fetal bovine serum (FBS), 1% antibiotic/antifungal (Gibco Invitrogen), at 37 degrees Place in a humidified incubator containing 5% CO2. The strain used for the initial screening test was clinically isolated SARS-CoV-2 (nCoV-2019BetaCoV/Wuhan/WIV04/2019). The EC ₅₀ test strain is the Delta strain. Test experiments were conducted in the P3 laboratory.

Determine the compound's inhibitory activity against the 2019 novel coronavirus (2019-nCov) replication: Add 100 μl/well gradient concentration of compound into 96 wells, then add 50 μl/well virus buffer, and then immediately add 50 μl/well cultured Vero E6 Cells (rhabdomyosarcoma cells) were cultured at 37°C for 3-4 days until maximum cytopathic effects were observed. Aspirate the culture medium, add 75 μl 5% MTS phenol red culture medium, incubate at 37°C, 5% _CO2 for 1.5 hours, measure the fluorescence value of each well at 498nM wavelength, and draw a curve graph of compound concentration and cell response, which is used in Customized software from Accelrys calculates the EC ₅₀ of compounds that inhibit viruses.

Table 4: Anti-SARS-CoV-2 activity data of compound 9

SARS-CoV-2 EC50 of compound 9=1.088 μM.

Anti-SARS-CoV-2 (Vero E6 cells) activity data of some other compounds at 1 μM level

Table 5: Anti-SARS-CoV-2 activity data of some compounds in Vero E6 cells

The test results show that some compounds have the ability to inhibit the activity of SARS-CoV-2. The SARS-CoV-2 EC50 of compound 9 is 1.088 μM. Compound 5, compound 19 and compound 116 have an inhibitory rate of SARS-CoV-2 greater than 98% at a concentration of 10 μM.

3.1 Activity test of compound 72 on EV71 3C protease

The activity of compound 72 in inhibiting EV71 3C protease was tested in RD cell line; compound 72 has EV71 inhibitory activity; IC50=1.97μM (shown in Figure 1); CC50>100μM (shown in Figure 2)

4.1 Pharmacokinetic evaluation of compounds 68 and 69

We further evaluated the pharmacokinetics of compound 68 in mice.

Dosing regimen:

There were 6 male ICR (SD-1) mice, weighing 22-25g. Randomly divide into 2 groups, 3 animals in each group. Administer according to gavage and intravenous regimens respectively.

The subjects were fasted for 12 h before the experiment and had free access to water. Eat at the same time 2 hours after administration.

The experimental grouping, blood collection time points and sample processing are shown in Table 6:

Table 6 Compound 68 dosage regimen

The vehicle solution for intragastric administration was DMSO/0.5% HPMC (5/95, v/v) and was prepared to the final concentration. The intravenous administration vehicle protocol is DMSO/EtOH/PEG300/0.9% NaCl (5/5/40/50, v/v/v/v) to prepare to the final concentration.

The evaluation scheme of compound 69 is consistent with that of compound 68, and the experimental results are shown in Table 7 and Table 8. Among them, the oral exposure of compound 68 is 1288h*ng/mL, the injection exposure is 6178h*ng/mL, and the oral bioavailability is 10.4%. The oral exposure of compound 69 was 615h*ng/mL, the injection exposure was 3484h*ng/mL, and the oral bioavailability was 8.83%.

Table 7 Pharmacokinetic parameters of compound 68 in mice

Table 8 Pharmacokinetic parameters of compound 69 in mice

The pharmacokinetic profile of compound 68 in beagle dogs is as follows:

Fast for 12 hours before the test and drink water freely. Eat at the same time 4 hours after administration. Cleaning period is one week.

Table 9 Pharmacokinetic parameters of compound 68 in beagle dogs

5.1 Evaluation of compounds’ inhibitory activity against feline infectious peritonitis virus (FIPV) replication

The evaluation of the FIPV replication inhibitory activity of the compounds of the present invention is carried out through the CPE method for the first screening, the qPCR method for the second screening, and the IFA method for the third screening. The test cells used for the initial screening of the CPE method are CRFK cells, the virus infection dose is 1000TCID ₅₀ , the drug action dose is 30 μm, and the drug action time is 72 hours. The second screening test conditions of the qPCR method are the same as the CPE method, and the test concentration is 50 μm. The third screening test conditions of the IFA method are the same as the CPE method. The initial test concentration is 30 μm, and the test concentration gradient is 20 μm, 10 μm, 5 μm, 2.5 μm, 1.25 μm, and 0.1625 μm.

After infecting CRFK cells with 1000TCID ₅₀ FIPV 79 1146 for 2 hours, they were incubated with a drug concentration of 50 μM for 72 hours, and RT-PCR detection was performed. The results showed that compound 10, compound 21, and compound 172 had obvious inhibitory effects (shown in Figure 4).

After infecting CRFK cells with FIPV 79 1146 at a dose of 1000TCID ₅₀ for 2 hours, compound 172 was incubated for 72 hours at concentrations of 20 μm, 10 μm, 5 μm, 2.5 μm, 1.25 μm, and 0.61 μm. IFA testing was performed. The results showed that FIPV could still be completely inhibited at 20 μm. The replication of FIPV can still be significantly inhibited at 10 μm (shown in Figure 5).

After infecting CRFK cells with FIPV 79 1146 at a dose of 1000 TCID50 for 2 hours, compound 21 was incubated for 72 hours at concentrations of 20 μm, 10 μm, 5 μm, 2.5 μm, 1.25 μm, and 0.61 μm. IFA testing was performed. The results showed that 20 μm could still completely inhibit FIPV. Replication, 10μm can still significantly inhibit the replication of FIPV (shown in Figure 6).

After infecting CRFK cells with FIPV 79 1146 at a dose of 1000TCID50 for 2 hours, compound 10 was treated with After incubation for 72 hours at concentrations of 20 μm, 10 μm, 5 μm, 2.5 μm, 1.25 μm, and 0.61 μm, IFA testing was performed. The results showed that FIPV replication could still be completely inhibited at 20 μm, and FIPV replication could still be significantly inhibited at 5 μm (shown in Figure 7). .

All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

A peptidomimetic compound represented by general formula I, or its racemate, cis-trans isomers, enantiomers, diastereomers, pharmaceutically active metabolites, and pharmaceutically acceptable salts , the use of solvates, prodrugs or combinations thereof, characterized in that for the preparation of (a) SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV and/or norovirus 3CL protease inhibitor; (b) 3C protease inhibitor of RNA virus EV71 and/or EV68; and (c) treatment and/or prevention, mitigation of SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA viruses EV71 and/or EV68, and/or drugs for diseases caused by norovirus infections:

in,

*Indicates that the stereochemical isomerism of the carbon atom is independently S and/or R;

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

R 1 is selected from the following group:

Wherein, R 5 is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C1～C10 Alkoxy group, substituted or unsubstituted C3-C10 cycloalkyl group, substituted or unsubstituted 3-10 membered heterocyclyl group, substituted or unsubstituted C6～C14 aryl group, substituted or unsubstituted 5～12 membered heterocyclic group Aryl; the substitution refers to being substituted by 1 to 3 substituents selected from the following group: halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C6-10 aryl;

X is O or S;

Y is selected from O, NH, N-Boc, N, or NR 5a ; wherein, when Y is NR 5a , NR 5a and R 5 together Constituting a 5-7 membered nitrogen-containing heterocycle;

R 6 is selected from the group consisting of: H, halogen or cyano;

R 7 is selected from the following group: substituted or unsubstituted 3-10-membered heterocyclyl, substituted or unsubstituted 5-12-membered heteroaryl; the substitution refers to 1 to 3 groups selected from the following group Substitution: halogen, C1-C4 alkyl;

R 8 is selected from the following group: hydrogen, C1～C6 alkyl or -CO-C1～C6 alkyl;

R 9 is H, NH4 + , or a metal ion selected from the following group: Na + , K + , Li + ;

R 10 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, or substituted or unsubstituted C3-C10 ring Oxygen group; the substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

R 11 and R 12 are each independently selected from the following group: hydrogen, substituted or unsubstituted C1 to C10 alkyl, substituted or unsubstituted C2 to C10 alkenes, substituted or unsubstituted C2 to C10 alkynes; Substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

Among them, R 11 and R 12 are connected to connected oxygen atoms to form a ring, forming a 5-8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen;

R 13 and R 14 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 Alkylene, substituted or unsubstituted C6-C20 aryl C2-C10 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C10 alkenylene, acyl, sulfonyl; the substitutions are independent of each other Ground refers to substitution with 1, 2, 3 or 4 substituents selected from the following group: halogen, hydroxyl, mercapto, nitro, cyano, amine, imine, tertiary amine, azide, C1-C8 Alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, tri Fluoromethyl;

R 2 ' is selected from the following group: hydrogen, substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C3～ C10 cycloalkyl; the substitution means substitution by 1 to 2 groups selected from the following group: halogen, C1-C4 alkyl;

R 2 is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C1～C10 alkoxy base, substituted or unsubstituted C3～C10 cycloalkyl, substituted or unsubstituted 3～10 membered heterocyclyl, substituted or unsubstituted C6～C14 aryl, substituted or unsubstituted 5～12 membered heteroaryl; the substitution refers to Substituted with a group selected from the following group: halogen, C1-C6 alkyl, C6~C10 aryl;

Or when R 2 and R 2 ' are connected to form a ring, the α carbon atom, β carbon atom connected to R 2 , and the α nitrogen atom connected to R 2 ' form a substituted or unsubstituted 5-10 membered heterocyclic ring, 5 -12-membered heteroaromatic ring; the substitution means substitution by 1-3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;

R 4 is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C1～C10 alkoxy base, substituted or unsubstituted C3~C10 cycloalkyl, substituted or unsubstituted C6~C14 aryl, substituted or unsubstituted 5~12-membered heteroaryl; the substitution refers to being substituted by 1-3 Substitution with groups independently selected from the following group: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkyl ketone carbonyl, cyano, nitro group, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto, C1~C4 acyl, amide, sulfonyl, aminosulfonyl, C1~C4 alkyl substituted sulfonyl, or two adjacent The substituent together with the carbon atom connected to it forms a 5- to 7-membered ring;

R 4 ' is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, the substitution refers to being substituted by 1-3 halogens;

Or when R 4 and R 4 ' are connected to form a ring, the α carbon atom, β carbon atom connected to R 4 , and the α nitrogen atom connected to R 4 ' form a substituted or unsubstituted 5-10 membered heterocyclic ring, 5 -12-membered heteroaromatic ring; the substitution means substitution by 1-3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;

R 3 is selected from the following group: substituted or unsubstituted C1～C10 alkyl, substituted or unsubstituted C2～C10 alkenyl, substituted or unsubstituted C2～C10 alkynyl, substituted or unsubstituted C3～C10 cycloalkyl , substituted or unsubstituted 3 to 10-membered heterocyclyl, substituted or unsubstituted C6 to C14 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl; the substitution means 1 to 3 members selected from the following group Group substitution: halogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, C6~C10 aryl, halogenated C6~C10 aryl, C1~C6 alkyl Carbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto, C1~C4 acyl, amide, sulfonyl, aminosulfonyl, C1~C4 alkyl substituted Sulfonyl group, or two adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;

Wherein, the heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
The use according to claim 1, characterized in that,

When R 2 and R 2 ' are connected to form a ring, R 1 is selected from the following group:

When R 2 and R 2 ' are not connected to form a ring, and R 2 ' is hydrogen, R 1 is selected from the following group:

When R 2 and R 2 ' are not connected to form a ring, and R 2 ' is not hydrogen, R 1 is selected from the following group:

Wherein, R5 is selected from the following group: substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted C1~C6 Alkoxy group, substituted or unsubstituted C3-C7 cycloalkyl group, substituted or unsubstituted 3-7 heterocyclyl group, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-10 membered heteroaryl group base; the substitution refers to being substituted by 1 to 3 substituents selected from the following group: halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C6-10 aryl;

X is O or S;

Y is selected from O, NH, N-Boc, N, or NR 5a ; wherein, when Y is NR 5a , NR 5a and R 5 together form a 5-7 membered nitrogen-containing heterocycle;

R 6 is selected from the following group: H, F, Cl or cyano;

R 7 is selected from the following group: substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

R 8 is selected from the following group: hydrogen or -CO-C1～C4 alkyl;

R 9 is Na + ;

R 10 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C3-C6 ring Oxygen group; the substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;

R 11 and R 12 are each independently selected from the following group: hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted Substituted C2~C6 alkenes, substituted or unsubstituted C2~C6 alkynes; or the oxygen atoms connected to R 11 and R 12 constitute a 5-6 membered heterocyclic group; the substitution refers to 1 to 3 selected from Substitution of the following groups: halogen, C1-C4 alkyl;

R 13 and R 14 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C14 aryl C1-C5 alkylene, substituted or unsubstituted C3-C10 heteroaryl C1-C5 Alkylene, substituted or unsubstituted C6-C10 aryl C2-C5 alkenylene, substituted or unsubstituted C3-C10 heteroaryl C2-C5 alkenylene, acyl, sulfonyl; the substitutions are each independently Refers to substitution with 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy , C1-C4 alkylcarbonyl, C1-C4 alkylthio, C1-C6 alkoxycarbonyl, trifluoromethyl;

R 2 ' is selected from the following group: hydrogen, substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted or unsubstituted C2～C6 alkynyl, substituted or unsubstituted C3～ C6 cycloalkyl; the substitution means substitution by 1 to 2 groups selected from the following group: halogen, C1-C4 alkyl;

R 2 is selected from the following group: substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted or unsubstituted C2～C6 alkynyl, substituted or unsubstituted C1～C6 alkoxy base, substituted or unsubstituted C3~C6 cycloalkyl group, substituted or unsubstituted 3~7 membered heterocyclyl group, substituted or unsubstituted C6~C10 aryl group, substituted or unsubstituted 5~10 membered heteroaryl group ; The substitution refers to substitution with a group selected from the following group: halogen, C1-C6 alkyl, C6~C10 aryl;

Or when R 2 and R 2 ' are connected to form a ring, the α carbon atom and β carbon atom connected to R 2 and the α nitrogen atom connected to R 2 ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;

R 4 is selected from the following group: substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted or unsubstituted C2～C6 alkynyl, substituted or unsubstituted C1～C6 alkoxy base, substituted or unsubstituted C3~C7 cycloalkyl, substituted or unsubstituted C6~C10 aryl, substituted or unsubstituted 5~10 membered heteroaryl; the substitution refers to being substituted by 1-3 respective Substitution with groups independently selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or two adjacent substituents together with the Carbon atoms form a 5- to 7-membered ring;

R 4 ' is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, the substitution refers to 1-3 halogens replace;

Or when R 4 and R 4 ' are connected to form a ring, the α carbon atom, β carbon atom connected to R 4 , and the α nitrogen atom connected to R 4 ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 halogens;

R 3 is selected from the following group: substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C2～C6 alkenyl, substituted or unsubstituted C2～C6 alkynyl, substituted or unsubstituted C3～C10 cycloalkyl , substituted or unsubstituted 3 to 7-membered heterocyclyl, substituted or unsubstituted C6 to C10 aryl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution means 1 to 3 members selected from the following group Group substitution: halogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, C6~C8 aryl, halogenated C6~C8 aryl, or two phases The adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;

Wherein, the heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
The use according to claim 1, characterized in that,

When R 2 and R 2 ' are connected to form a ring, R 1 is selected from the following group:

When R 2 and R 2 ' are not connected to form a ring, and R 2 ' is hydrogen, R 1 is selected from the following group:

When R 2 and R 2 ' are not connected to form a ring, and R 2 ' is not hydrogen, R 1 is

Wherein, R 5 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to being substituted by 1 to 3 substituents selected from the following group Substitution: C1-C4 alkyl, C6-10 aryl;

R 10 is selected from the following group: substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, or substituted or unsubstituted C3~C6 epoxy group; the substitution refers to substituted by 1~ 3 groups selected from the following group are substituted: halogen, C1-C4 alkyl;

R 11 and R 12 are each independently selected from the following group: hydrogen, C1-C6 alkyl, or the oxygen atoms to which R 11 and R 12 are connected constitute a 5-6-membered heterocyclic group;

R 13 and R 14 are each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1 -C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aryl C1-C5 alkylene, substituted or unsubstituted C6-C10 Aryl C2-C5 alkenylene; the substitutions each independently refer to substitution with 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylthio, C1-C6 alkoxycarbonyl, trifluoromethyl;

R 2 ' is selected from hydrogen and C1～C6 alkyl;

R 2 is selected from the group consisting of substituted or unsubstituted C1～C6 alkyl, substituted or unsubstituted C1～C6 alkoxy, substituted or unsubstituted C3～C6 cycloalkyl, or substituted or unsubstituted C6～ C8 aryl; the substitution refers to substitution with a group selected from the following group: halogen, C1-C4 alkyl, C6~C8 aryl;

Or when R 2 and R 2 ' are connected to form a ring, the α carbon atom and β carbon atom connected to R 2 and the α nitrogen atom connected to R 2 ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 halogens;

R 4 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to 1-3 groups independently selected from the following group Group substitution: halogen, C1~C6 alkyl;

R 4 ' is hydrogen;

R 3 is selected from the following group: substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: Halogen, C1~C4 alkyl, C1~C6 alkoxy, halogenated C6~C8 aryl, or two adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;

Wherein, the heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
The use according to claim 1, characterized in that,

R 5 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to being substituted by 1 to 3 substituents selected from the following group: C1-C4 alkyl, C6-10 aryl;

R 3 is selected from the following group: substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: Halogen, C1~C4 alkyl, C1~C6 alkoxy, halogenated C6~C8 aryl, or two adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;

Wherein, the heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
The use according to claim 1, characterized in that,

When R 2 ' is H, R 1 is selected from the following group:

When R 2 and R 2 ' do not form a ring, and R 2 ' is not H, R 1 is selected from the following group:

When R 2 and R 2 ' form a ring, R 1 is selected from the following group:
The use according to claim 1, characterized in that the ring formed by R 2 and R 2 ' and the connected and adjacent atoms has a structure selected from the following group:
The use according to claim 1, characterized in that the compound is selected from the following group:

Table 1
The use according to claim 1, characterized in that the compound is compound 5-11, 15-16, 56-62, 65, 67-171 in Table 1.
A method for preparing peptidomimetic compounds according to claim 1, characterized in that it includes the steps:

Step (1): react compound Ia and compound Ib in an inert solvent in the presence of a condensing agent to obtain compound Ic;

Step (2): react compound Ic in a mixed solution of an inert solution and an acidic solution to obtain compound Id;

Step (3): react compound Ie and compound Id in an inert solvent in the presence of a condensing agent to obtain compound If;

Step (4): react compound If in a mixed solution of an inert solution and an acidic solution to obtain compound Ig;

Step (5): react compound Ih and compound Ig in an inert solvent in the presence of a condensing agent to obtain compound Ii;

Step (6): In an inert solvent, compound Ii undergoes a reduction reaction with a reducing agent to obtain compound Ij;

Step (7): In an inert solvent, compound Ij undergoes an oxidation reaction with an oxidizing agent to obtain compound Ik;

Step (8): In an inert solvent, compound Ik and compound IL are reacted in the presence of triphenylphosphine to obtain compound Im;

Step (9): In an inert solvent, compound Ik and compound In are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Io;

Step (10): In an inert solvent, compound Ik and compound Ip are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Iq;

Step (11): In an inert solvent, compound Ik and compound Ir are reacted in the presence of a base to obtain compound Is;

Step (12): In a polar solvent, compound Ik reacts with sulfite to obtain compound It; in an inert solvent, compound It reacts with acid anhydride to obtain compound Iu;

Step (13): In a polar solvent, compound Ii is reacted with ammonia water to obtain compound Iv; in an anhydrous inert solvent, compound Iv is reacted with an acid anhydride to obtain compound Iw;

Step (14): In a polar solvent, compound Ii is hydrolyzed under alkaline conditions to obtain compound Ix; in an inert solvent, compound Ix is condensed with N-methyl-N-methoxyamine hydrochloride. React to obtain compound Iy; in an inert solvent, compound Iy reacts with Grignard reagent to obtain compound Iz;

Step (15): In an inert solvent, compound Ix reacts with compound Iα in the presence of a base to obtain compound Iβ; in an inert solvent, compound Iβ reacts in the presence of an oxidizing agent to obtain compound Iγ; in an inert solvent, compound Iγ React with compound Iδ in the presence of a base to obtain compound Iε;

Step (16): In an inert solvent, in the presence of a catalytic amount of acid, compound Ik reacts with an alcoholic solvent to obtain compound Iζ; compound Ik is stirred in the corresponding alcoholic solvent to obtain compound Iη;

Among them, R 1 , R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14. The definitions of m, n, X and Y are the same as those in claim 1.
A pharmaceutical composition, characterized by comprising (a) a therapeutically effective amount of a peptidomimetic compound represented by general formula (I), or its racemate, cis-trans isomers, enantiomers, Diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof, and (b) a pharmaceutically acceptable carrier or excipient, wherein the formula (I ) is as described in claim 1.
The use of a pharmaceutical composition as claimed in claim 10, characterized in that it is used to prepare (a) SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV and/or Novel. Such as viral 3CL protease inhibitors; (b) 3C protease inhibitors of RNA viruses EV71 and/or EV68; and (c) treatment and/or prevention, mitigation of SARS-CoV-2 and/or SARS-CoV and/or Drugs for diseases caused by MERS-CoV and/or FIPV, and/or RNA viruses EV71 and/or EV68, and/or norovirus infections.
A treatment and/or prevention, mitigation of SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA virus EV71 and/or EV68 and/or norovirus infection A method for related diseases, characterized by comprising the steps of: administering to a subject in need a safe and effective amount of a peptidomimetic compound represented by general formula I, or its racemate, cis-trans isomer, or enantiomer isomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof, wherein the peptidomimetic compound represented by the general formula I is as claimed in the claims As mentioned in 1.
A method for inhibiting the activity of 3CL protease of SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV and/or norovirus, characterized by comprising the steps of: converting general formula I to Peptide compounds, or their racemates, cis-trans isomers, enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or Their combination contacts SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or the 3CL protease of norovirus, thereby inhibiting SARS-CoV-2 and/or the activity of 3CL protease of SARS-CoV and/or MERS-CoV and/or norovirus, wherein the peptidomimetic compound of general formula I is as described in claim 1.
A method for inhibiting the activity of 3C protease of RNA virus EV71 and/or EV68, which is characterized by comprising the steps of: adding the peptidomimetic compound represented by general formula I, or its racemate, cis-trans isomer, Enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof contact the 3C protease of RNA viruses EV71 and/or EV68, thereby inhibiting Activity of 3C protease of RNA virus EV71 and/or EV68, wherein the peptoid compound of general formula I is as described in claim 1.
A peptidomimetic compound according to claim 1, or its racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically active metabolite, pharmaceutically acceptable Salts, solvates, prodrugs, or combinations thereof,

in,

R 1 , R 2 , R 2 ', R 3 , R 4 , R 4 ', m, n are as defined in claim 1.