CN110642874B

CN110642874B - Cell necrosis inhibitor and preparation method and application thereof

Info

Publication number: CN110642874B
Application number: CN201810676651.0A
Authority: CN
Inventors: 马大为; 王开亮; 夏尚华; 李征; 赵金龙; 李盈
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2018-06-26
Filing date: 2018-06-26
Publication date: 2023-03-28
Anticipated expiration: 2038-06-26
Also published as: CN110642874A

Abstract

The invention provides a cell necrosis inhibitor and a preparation method and application thereof, and particularly provides an inhibitor for inhibiting cell necrosis and/or human receptor interacting protein 1 kinase (RIP 1), wherein the inhibitor has a structure shown in formula I. The compounds and compositions comprising the same are useful for the prevention and/or treatment of diseases involving cell death and/or inflammation.

Description

Cell necrosis inhibitor and preparation method and application thereof

Technical Field

The invention relates to an inhibitor for inhibiting cell necrosis and/or human receptor interacting protein 1 kinase (RIP 1) and a preparation method and application thereof. The compounds and compositions comprising the same may be used in methods for the prevention and/or treatment of diseases involving cell death and/or inflammation.

Background

Programmed necrotic cell death, also known as programmed necrosis, is a novel mode of cell death discovered in recent years. Programmed necrosis is a highly inflammatory form of cell death and is considered to be an important pathological factor in a variety of degenerative and inflammatory diseases. The above diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel diseases, nephropathy, hepatopathy, and other various related diseases.

Tumor necrosis factor alpha (TNF- α) -induced NF- κ B activation plays a central role in the immune system and inflammatory responses. Receptor-interacting protein 1 (RIP 1) is a multifunctional signal transducer involved in mediating nuclear factor kb (NF-kb) activation, apoptosis and necrosis. The kinase activity of RIP1 is critically involved in mediating apoptosis, a caspase-independent necrotic cell death pathway.

Receptor-interacting protein 1 (RIP 1) is a cross-point that determines the life and death of cells, and plays an important role in the processes of cell survival, apoptosis, programmed necrosis, and the like. The role of RIP1 in cell signaling has been evaluated under different conditions, including TLR3, TLR4, TRAIL, FAS, but is best understood in mediating signaling downstream of the death receptor TNFR 1. TNFR engagement by TNF leads to oligomerization, recruitment of a variety of proteins, including linear K63-linked polyubiquitinated RIP1, TRAF2/5, tradd and cIAPs, to the cytoplasmic tail of the receptor. This RIP 1-dependent complex, termed complex I, as a scaffold protein (i.e., kinase independent), provides a platform for pro-survival signaling by activating the nfkb and MAP kinase pathways. In addition, TNF binding to its receptor (inhibited by, for example, a20 and CYLD proteins or cIAP) under conditions promoting RIP1 deubiquitination will result in receptor internalization and complex II or DISC (death inducing signal complex) formation. Formation of DISC (including RIP1, TRADD, FADD and caspase 8) leads to activation of caspase 8, and also initiates apoptotic cell death in a RIP1 kinase independent manner. Apoptosis is largely a quiescent form of cell death that is involved in such routine processes as development and cellular homeostasis.

Necrostatin-1, an inhibitor of RIP1 kinase known in the art, has been shown to be effective in the treatment of a variety of inflammatory diseases. Has protective effect on inflammatory bowel disease, psoriasis, photoreceptor necrosis induced by retinal detachment, retinitis pigmentosa, acute pancreatitis induced by bombesin and septicemia/Systemic Inflammatory Response Syndrome (SIRS). Neocriptin-1 is effective in relieving ischemic brain injury, retinal ischemia/reperfusion injury, huntington's disease, renal ischemia reperfusion injury, cisplatin-induced renal injury and traumatic brain injury. Other diseases or disorders that are regulated, at least in part, by RIP 1-dependent apoptosis, necrosis or cytokine production include hematologic and solid organ malignancies, bacterial and viral infections (including but not limited to tuberculosis and influenza), and lysosomal storage disorders (especially gaucher's disease). However, the existing cell necrosis inhibitors have various defects, such as unsatisfactory activity, poor pharmacokinetic properties or low oral bioavailability, and the like, and some defects can not penetrate through a blood brain barrier to enter a central nervous system, so that the further research and clinical application of the cell necrosis inhibitors are limited.

Therefore, the intensive research on RIP1 kinase to provide a new feasible target for clinical application and the development of a highly efficient selective small molecule RIP1 kinase activity inhibitor with clinical application value become the difficulty and hot spot of the current research. There remains a need in the art to provide novel compounds for the prevention and treatment of diseases involving cell death and/or inflammation.

Disclosure of Invention

It is an object of the present invention to provide novel compounds for the prevention and treatment of diseases involving cell death and/or inflammation.

In a first aspect of the present invention, there is provided a compound represented by the following formula (I), or an optical isomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein:

x is O, S or CH ₂ ；

The M ring has a structure shown as the following formula:

wherein, the A ring is selected from the following group: substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered heterocyclyl; wherein the heteroaryl or heterocyclyl has one or more heteroatoms in its ring backbone selected from the group consisting of: n, O or S;

n is selected from the group consisting of: 1.2 or 3;

b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered heterocyclyl;

l is selected from the group consisting of: o, S, NH, N (CH) ₃ ) Substituted or unsubstituted C ₁ -C ₆ Alkylene, substituted or unsubstituted C ₁ -C ₆ alkylene-O-, substituted or unsubstituted C ₁ -C ₆ alkylene-NH-, (substituted or unsubstituted C ₁ -C ₆ Alkylene radical) ₂ -N-, substituted or unsubstituted C ₃ -C ₆ Alkenylene, or substituted or unsubstituted C ₃ -C ₆ alkenylene-O-;

c is selected from the following group: H. substituted or unsubstituted (C) ₃ -C ₆ ) Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered heterocyclyl;

R ₁ selected from the group consisting of: H. substituted or unsubstituted C ₁ -C ₆ An alkyl group;

R ₂ is one or more substituents on the benzene ring selected from the group consisting of: H. halogen, halogen substituted or unsubstituted C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ An acyl group;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, cyano, alkyl, acyl, sulfonyl, hydroxy, amino, benzyl, oxy (A)＝O)、(C ₁ -C ₄ ) Alkyl, halo (C) ₁ -C ₄ ) Alkyl, (C) ₁ -C ₄ ) Alkoxy, halo (C) ₁ -C ₄ ) Alkoxy, nitro, (C) ₁ -C ₄ ) Alkyl C (O) -;

the configuration of each chiral center is independently R or S.

In another preferred embodiment, the M-ring has a structure selected from the group consisting of:

wherein +>

Indicates the attachment site.

In another preferred embodiment, the terminal moiety and the L substituent are attached to ring B at the 1,3 positions, respectively, on the B ring.

In another preferred embodiment, L is selected from the group consisting of: o, S, NH, N (CH) ₃ )、CH ₂ 、CH ₂ CH ₂ 、CH(CH ₃ )、CHF、CF ₂ 、CH ₂ O、CH ₂ N(CH ₃ )、CH ₂ NH or CH (OH).

In another preferred embodiment, the substituted or unsubstituted 5-6 membered heteroaryl is a group selected from the group consisting of: substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted tetrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiophene, substituted or unsubstituted furyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinoline.

In another preferred embodiment, the substituted or unsubstituted 5-6 membered heterocyclic group is a group selected from the group consisting of: substituted or unsubstituted morpholinyl, substituted or unsubstituted dihydropiperidinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted pyrrolinyl, substituted or unsubstituted tetrahydrothiophenyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted thietanyl, substituted or unsubstituted azetidine.

In another preferred embodiment, the compound of formula I has a structure as shown in formula I-1 or formula I-2 below:

in another preferred embodiment, said C is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 membered heteroaryl.

In another preferred embodiment, said C is substituted or unsubstituted phenyl.

In another preferred embodiment, L is substituted or unsubstituted C ₁ -C ₆ An alkylene group.

In another preferred embodiment, L is-CH ₂ -。

In another preferred embodiment, the A ring has 1-2 substituents.

In another preferred embodiment, the substituents on the ring a are selected from the group consisting of: halogen, C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ An acyl group.

In another preferred embodiment, X is O or S.

In another preferred embodiment, the ring A is a 5-membered ring having one or more N atoms in the ring skeleton.

In another preferred embodiment, the B ring is a 5-membered ring having one or more heteroatoms selected from the group consisting of: n or O.

In another preferred embodiment, the B ring is a 5-membered heteroaromatic ring.

In another preferred embodiment, R ₁ Is methyl.

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in another preferred embodiment, the B ring has a structure selected from the group consisting of:

in another preferred embodiment, the compound is selected from the group consisting of compounds RIP1-001 through RIP 1-116.

In another preferred embodiment, the compound is prepared by the following steps (a) or (b):

(a) Reacting a compound shown in a formula II with a compound shown in a formula III in an inert solvent in the presence of a condensation reagent and alkali to obtain a compound shown in a formula I; wherein R is H;

(b) Under the acidic condition, the compound of the formula II removes an amino protecting group, and then reacts with the compound of the formula III in an inert solvent in the presence of a condensation reagent and alkali to obtain the compound of the formula I; wherein R is an amino protecting group (preferably Boc); the remaining groups are as defined in the first aspect of the invention.

In another preferred embodiment, in the step (a), the inert solvent is selected from the group consisting of: DMF, DMSO, acetonitrile, THF, DCM, or combinations thereof.

In another preferred embodiment, in the step (a), the condensing agent is selected from the group consisting of: HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, pyBOP, or combinations thereof.

In another preferred embodiment, in the step (a), the base is selected from the group consisting of: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine, or a combination thereof.

In another preferred embodiment, in the step (b), the acidic condition refers to the presence of an acid selected from the group consisting of: hydrochloric acid, trifluoromethanesulfonic acid, or a combination thereof.

In another preferred embodiment, in the step (b), the solvent is selected from the group consisting of: DMF, DMSO, acetonitrile, THF, DCM, or combinations thereof.

In another preferred embodiment, in the step (b), the condensation reagent is selected from the group consisting of: HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, pyBOP, or combinations thereof.

In another preferred embodiment, in the step (b), the base is selected from the group consisting of: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine, or a combination thereof.

In another preferred example, the method further comprises the steps of: and (3) carrying out substitution on the compound of the formula I to obtain the substituted compound of the formula I.

In another preferred embodiment, the method further comprises the steps of:

reacting a compound of formula IIa with a compound of formula IIb in an inert solvent in the presence of a base to provide a compound of formula IIc.

In another preferred embodiment, the method further comprises the steps of:

in an alcohol solvent, under the action of hydrogen atmosphere and/or a metal catalyst, performing nitro reduction on the compound shown in the formula IIc, and then performing cyclization reaction in an inert solvent in the presence of a condensing agent and alkali to obtain a compound shown in the formula II';

wherein R' is an amino protecting group, preferably selected from the group consisting of: boc, SEM.

The remaining groups are as defined in the first aspect of the invention.

In another preferred embodiment, in the step (1), the alkali is selected from the group consisting of: cesium carbonate, potassium carbonate, naOH, naH, n-BuLi, KHMDS, or a combination thereof.

In another preferred embodiment, in the step (1), the solvent is selected from the group consisting of: DMF, DMSO, acetonitrile, THF, or a combination thereof.

In another preferred example, in the step (1), the reaction is carried out at-20 ℃ to 100 ℃.

In another preferred embodiment, in the step (2), the alcohol solvent: methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, or a combination thereof.

In another preferred embodiment, in the step (2), the metal catalyst is selected from the group consisting of: pd/C, or a combination thereof.

In another preferred embodiment, in the step (2), the inert solvent is selected from the group consisting of: DMF, DMSO, acetonitrile, THF, DCM, or combinations thereof.

In another preferred embodiment, in the step (2), the condensation reagent is selected from the group consisting of: HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, pyBOP, or a combination thereof.

In another preferred embodiment, in the step (2), the alkali is selected from the group consisting of: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine, or a combination thereof.

In another preferred embodiment, the inert solvent is selected from the group consisting of: DCM, chloroform, THF, or combinations thereof.

In another preferred embodiment, the base is selected from the group consisting of: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine, or a combination thereof.

In another preferred embodiment, the acetylation agent is selected from the group consisting of: acetyl chloride, acetic anhydride, or a combination thereof.

In another preferred example, the method further comprises: reacting a compound of formula II' with R in an inert solvent under the action of a base ₁ I, reacting to obtain the compound of formula II.

The definition of each functional group is as described in the first aspect of the present invention.

In another preferred embodiment, the inert solvent is selected from the group consisting of: DMF, 1, 4-dioxane, diethyl ether, acetone, or a combination thereof.

In another preferred embodiment, the base is selected from the group consisting of: triethylamine, potassium carbonate, naH, DIEA, pyridine, or combinations thereof.

In another preferred embodiment, the method further comprises the steps of: in an inert solvent, in the presence of a ketone catalyst and a ligand L, the compound shown in the formula IId and ammonia water are subjected to coupling reaction to obtain the compound shown in the formula IIe.

Said

Preferably is

Wherein R is ₃ Is methyl or trifluoromethyl, R ₁ ’、R ₂ ’、R ₃ ' may be a group of H, methyl, methoxy, phenyl, benzyl, phenoxy, naphthyl, etc., and the remaining functional groups are as defined in the first aspect of the invention.

In another preferred embodiment, the inert solvent is selected from the group consisting of: DMSO, DMF, 1, 4-dioxane, or a combination thereof.

In another preferred embodiment, the copper catalyst is selected from the group consisting of: cuI, cuCN, cuBr, cuCl, cu ₂ O, or a combination thereof.

In another preferred embodiment, the weight ratio of the ammonia water to the inert solvent is 1: 10 to 1: 1.

In another preferred embodiment, the copper catalyst is used in an amount of 0.5 to 20mol%.

In another preferred embodiment, the ligand L is used in an amount of 0.5 to 30mol%.

In another preferred embodiment, the reaction is carried out at 40 ℃ to 150 ℃.

In another preferred embodiment, the method further comprises the steps of: and (3) carrying out dehydration ring-closing reaction by using the compound of the formula IIe under acidic or basic conditions to obtain the compound of the formula II'.

Wherein R is ₃ Is methyl or trifluoromethyl, the remaining functional groups being as defined in the first aspect of the invention.

In another preferred embodiment, the acidic condition refers to the reaction system including an acid selected from the group consisting of: acetic acid, 15% sulfuric acid, or a combination thereof.

In another preferred embodiment, the alkaline condition refers to the reaction system including an alkali selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, potassium phosphate, or combinations thereof.

In another preferred embodiment, the reaction is carried out at room temperature (10-40 ℃) to 80 ℃.

In another preferred embodiment, the method further comprises the steps of: and (3) in an inert solvent, heating the compound of the formula IIf to react under the alkaline condition, dehydrating and closing the ring to obtain the compound of the formula II'.

Each functional group is as defined in the first aspect of the invention.

In another preferred embodiment, the alkaline conditions are selected from the group consisting of: potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or combinations thereof.

In another preferred embodiment, the reaction temperature is 60 ℃ to 120 ℃.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of formula I, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a combination thereof; and (b) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition is for use in treating or preventing a RIP1 kinase-mediated disease or disorder; preferably, the disease or condition is selected from the group consisting of: inflammatory bowel disease, crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, soJIA, systemic lupus erythematosus, sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of a solid organ, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, huntington's disease, alzheimer's disease, parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, wegener's granuloma, pulmonary sarcoidosis, behcet's disease, interleukin-1 converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, periodontitis.

In a third aspect of the invention, there is provided the use of a compound of formula I, as described in the first aspect of the invention, or a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, or mixtures thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a RIP1 kinase-mediated disease or condition; or for the preparation of a pharmaceutical composition for the treatment or prevention of a disease or disorder caused by apoptosis.

In another preferred embodiment, the disease or condition is selected from the group consisting of: inflammatory bowel disease, crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, soJIA, systemic lupus erythematosus, sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of a solid organ, sepsis, systemic inflammatory response syndrome, cerebrovascular accidents, myocardial infarction, huntington's disease, alzheimer's disease, parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, wegener's granuloma, pulmonary sarcoidosis, behcet's disease, interleukin-1 converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, periodontitis.

In a fourth aspect of the present invention, there is provided an intermediate compound represented by the following formula II:

wherein R is selected from the group consisting of: H. an amino protecting group (preferably Boc);

the remaining groups are as defined in the first aspect of the invention.

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

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it is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have found, through long-term and intensive studies, that a compound having a structure represented by formula I has a superior RIP1 inhibitory effect and thus can be used for treating various diseases associated with cell necrosis, and have completed the present invention based on the above findings.

Term(s) for

In the present invention, the alkyl group includes a linear or branched alkyl group, and the halogen is F, cl, br or I, preferably F or Br.

In particular, herein, unless otherwise specified, reference to an atom includes all isotopic forms thereof, for example, when referring to a "hydrogen atom," it is intended to refer to a hydrogen atom, a deuterium atom, a tritium atom, or a combination thereof. In the present invention, the abundance of each isotopic atom of a certain element may be a state in which the element naturally occurs in nature, or a state in which the element is isotopically enriched.

Specifically, in the present invention, when the number of carbon atoms of the group is not limited, it means a group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified.

The term "pharmaceutically acceptable solvate" refers to a solvate of the corresponding compound with water, ethanol, isopropanol, diethyl ether, acetone.

In the present invention, a "therapeutically effective amount" refers to a dose that achieves the desired therapeutic effect in a desired subject, but does not cause undue adverse effects. After the structures of the compounds of the present invention are disclosed, the above dosages can be generally determined by those skilled in the art according to actual needs.

A compound of formula I

Embodiments of the present invention provide compounds as inhibitors of cellular necrosis, which are provided as therapeutic agents for the treatment of various diseases associated with cellular necrosis, such as trauma, ischemia, stroke, myocardial infarction, infection, sepsis, parkinson's disease, alzheimer's disease, amyotrophic lateral sclerosis, huntington's disease, HIV-associated dementia, retinal degenerative diseases, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, inflammatory bowel disease, nephropathy, and others.

The heterocyclic amide with a brand-new three-fused ring structure provided by the invention can be used as a cell necrosis inhibitor, wherein part of compounds have good in-vivo and in-vitro cell necrosis inhibition effects, and have more beneficial treatment effects compared with the compound GSK2982772 which is currently in a clinical research stage and has certain structural similarity.

In one embodiment, compounds having the following structure (1) are provided:

wherein:

x is O, S or CH ₂ ；

The M ring has a structure shown as the following formula:

wherein, the A ring is selected from the following group: a substituted or unsubstituted 5-6 membered heteroaryl, a substituted or unsubstituted 5-6 membered heterocyclyl; wherein the heteroaryl or heterocyclyl has one or more heteroatoms in its ring backbone selected from the group consisting of: n, O or S;

n is selected from the group consisting of: 1.2 or 3;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, cyano, alkyl, acyl, sulfonyl, hydroxy, amino, benzyl, oxy (= O), (C) ₁ -C ₄ ) Alkyl, halo (C) ₁ -C ₄ ) Alkyl, (C) ₁ -C ₄ ) Alkoxy, halo (C) ₁ -C ₄ ) Alkoxy, nitro, (C) ₁ -C ₄ ) Alkyl C (O) -;

the configuration of each chiral center is independently R or S.

In another preferred embodiment, the terminal moiety and the L substituent are attached to ring A at the 1,3 positions, respectively, on the B ring.

preferred compounds of the invention have the structures listed below:

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preparation of Compounds of formula I

1. The compound of formula I can be prepared by the following method:

1) Amide condensation: removing the protective agent on the amino group of the fragment II under acidic condition, and condensing the fragment II with the fragment III to obtain a target compound

Some examples are as follows:

wherein, the solvent can be: DMF, DMSO, acetonitrile, THF, DCM, or combinations thereof

The condensing agent may be: HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, pyBOP or combinations thereof

The base may be: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine or a combination thereof

(b) Under the acidic condition, the compound of the formula II removes an amino protecting group, and then reacts with the compound of the formula III in an inert solvent in the presence of a condensation reagent and alkali to obtain the compound of the formula I; wherein R is an amino protecting group (preferably Boc); wherein each group is as defined above.

Wherein, the acid condition can be: hydrochloric acid, trifluoromethanesulfonic acid,

The solvent may be: DMF, DMSO, acetonitrile, THF, DCM, or combinations thereof.

The condensing agent may be: HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, pyBOP, or combinations thereof.

The base may be: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine, or a combination thereof.

2) The latter introduction of functional groups can be carried out by further introducing the common functional groups such as acyl, alkyl, etc. into the compound of formula I by conventional methods, for example:

2. type of fragment II and method of Synthesis

In the present invention, fragment II used includes:

the synthesis method of the fragment II comprises the following two types:

the first type: starting from a benzo five-membered ring, reacting with Boc-protected cysteine or Boc-protected serine, subsequently reducing a nitro group, and ring-closing to synthesize a third seven-membered ring

The reaction process is that the compound of formula IIa and the compound of formula IIb are reacted in an inert solvent in the presence of alkali to obtain the compound of formula IIc; then, in an alcohol solvent, under the action of hydrogen atmosphere and/or a metal catalyst, the compound of the formula IIc is subjected to nitro reduction, and then in an inert solvent, in the presence of a condensing agent and alkali, a cyclization reaction is carried out to obtain a compound of a formula II'; finally, the compound of formula II' is reacted with R under the action of a base ₁ I, reacting to obtain the compound of formula II.

The base is selected from the group consisting of: cesium carbonate, potassium carbonate, naOH, naH, n-BuLi, KHMDS, or a combination thereof.

The inert solvent is selected from the group consisting of: DMF, DMSO, acetonitrile, THF, or a combination thereof.

The reaction is carried out at-20 ℃ to 100 ℃.

The alcohol solvent is selected from the following group: methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, or a combination thereof.

The metal catalyst is selected from the following group: pd/C, or a combination thereof.

The condensation reagent is selected from the group consisting of: HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, pyBOP, or a combination thereof.

In the reaction from II' to II, the base is selected from the group consisting of: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine, or a combination thereof.

The second type: firstly, a benzo seven-membered ring is constructed, then a third five-membered ring is synthesized, and the key synthesis steps are as follows: in an inert solvent, in the presence of a ketone catalyst and a ligand L, carrying out coupling reaction on a compound shown in a formula IId and ammonia water to obtain a compound shown in a formula IIe; then, the compound of formula IIe is used for dehydration ring closing reaction under acidic or basic conditions to obtain the compound of formula II'.

Wherein L is preferably

R ₃ Is methyl or trifluoromethyl, R ₁ ’、R ₂ ’、R ₃ ' may be a group of H, methyl, methoxy, phenyl, benzyl, phenoxy, naphthyl, etc., the remaining functional groups being as defined in the first aspect of the invention.

The inert solvent is selected from the group consisting of: DMSO, DMF, 1, 4-dioxane, or a combination thereof.

The copper catalyst is selected from the group consisting of: cuI, cuCN, cuBr, cuCl, cu ₂ O, or a combination thereof.

The weight ratio of the ammonia water to the inert solvent is 1: 10 to 1: 1.

The dosage of the copper catalyst is 0.5-20mol%.

The dosage of the ligand L is 0.5-30mol%.

The reaction is carried out at 40 ℃ to 150 ℃.

The acidic condition refers to the reaction system comprising an acid selected from the group consisting of: acetic acid, 15% sulfuric acid, or a combination thereof.

The alkaline condition means that the reaction system comprises an alkali selected from the following group: sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, potassium phosphate, or combinations thereof.

The reactions of steps IIe to II "are carried out at room temperature (10-40 ℃) to 80 ℃.

The synthesis of a three-fused ring is shown below:

reacting a compound 25 with methyl chloroformate in dichloromethane at the temperature of between-5 ℃ and room temperature under alkaline conditions to obtain an intermediate 29, removing a trifluoroacetyl protective agent under alkaline conditions, protecting primary amino groups with Boc anhydride to obtain a compound 30, then performing coupling reaction on the compound of formula 30 and ammonia water in an inert solvent in the presence of a ketone catalyst and a ligand L to obtain a compound of formula 31, and further performing heating reaction under alkaline conditions to dehydrate and close rings to obtain a compound of formula II-10.

Pharmaceutically acceptable salts and solvates

The pharmaceutical forms of the compounds of the invention may include the compounds themselves, as well as other pharmaceutically acceptable variations, such as optical isomers, cis-trans isomers, and the like, or pharmaceutically acceptable salts or solvates.

Preferably, the pharmaceutically acceptable salts include (but are not limited to): inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; organic acid salts such as formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, and the like; alkyl sulfonates such as methylsulfonate, ethylsulfonate, and the like; aryl sulfonates such as benzenesulfonate, p-toluenesulfonate, and the like.

Preferably, the pharmaceutically acceptable solvates include (but are not limited to): the compound is a solvate of water, ethanol, isopropanol, diethyl ether, acetone and the like.

Use of compounds of formula I

Through research, the compound shown in the formula I has the inhibitory activity of RIP1 kinase, so that the compound shown in the formula I or any one or a mixture of several of tautomers, racemes, enantiomers, diastereoisomers, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of the derivative can be applied to preparation of an RIP1 kinase inhibitor.

Meanwhile, the inhibitor can be applied to the preparation of drugs for preventing or treating RIP1 kinase-related diseases. In particular, the compound can be applied to the preparation of medicines for preventing or treating the diseases of abnormal cell proliferation, morphological change, hyperkinesia, angiogenesis and tumor metastasis related to the EGFR.

In addition, the inhibitor can be applied to the preparation of medicaments for treating or preventing tumor growth and metastasis related to the epidermal growth factor receptor EGFR.

The active ingredient of the inhibitor disclosed by the patent is preferably any one or a mixture of several of specific compounds shown in the invention, or tautomers, racemes, enantiomers, diastereoisomers, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of the compounds shown in the invention.

Pharmaceutical composition and use thereof

Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of formula (I) above, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, optionally together with one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents. The auxiliary materials are, for example, odorants, flavoring agents, sweeteners, and the like.

The pharmaceutical composition provided by the invention preferably contains 1-99% by weight of active ingredients, and the preferred proportion is that the compound of the general formula I as the active ingredient accounts for 65-99% by weight of the total weight, and the rest is pharmaceutically acceptable carriers, diluents or solutions or salt solutions.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be presented in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

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 preparation formula comprises 0.05-200mg of the compound of the general formula I, and preferably, the unit dosage of the preparation formula comprises 0.1-100 mg of the compound of the general formula I.

The compounds and pharmaceutical compositions of the present invention may be administered to mammals in the clinical setting, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably oral. Most preferably, the daily dose is 0.01-200mg/kg body weight, and is administered once or in portions of 0.01-100mg/kg body weight. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually, the dosage is increased gradually starting from a small dosage until the most suitable dosage is found.

In a further aspect, the present invention provides a RIP1 kinase inhibitor comprising one or more compounds selected from the group consisting of compounds of formula I above, pharmaceutically acceptable salts, isomers or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents.

The compounds and compositions of the present invention may be used for the treatment and prevention of various diseases associated with cell necrosis (such as trauma, ischemia, stroke, myocardial infarction, infection, sepsis, parkinson's disease, alzheimer's disease, amyotrophic lateral sclerosis, huntington's disease, HIV-related dementia, retinal degenerative diseases, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, inflammatory bowel disease, nephropathy, and other diseases).

Therefore, the invention also provides the application of the compound shown in the general formula I, the pharmaceutically acceptable salt, the isomer or the mixture thereof in preparing medicaments for treating various diseases related to the activity of RIP1 kinase.

In a further aspect, the invention provides a method of treating a disease associated with RIP1 kinase activity or expression comprising administering to a patient in need of such treatment one or more compounds selected from the group consisting of a compound of formula I as described above, a pharmaceutically acceptable salt, isomer or mixture thereof.

Compared with the prior art, the invention has the main advantages that:

(1) Provides a compound with RIP1 kinase inhibitory activity and a novel structure, and compared with the existing similar compound, the compound has better apoptosis inhibition effect.

(2) The partial compounds of the invention have improved selectivity and pharmacokinetics compared to prior art compounds.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Example 1 preparation of Compound I (RIP 1-001-017, 019-0116) by condensation reaction

The method comprises the following steps:

compound II-1 (27.8mg, 0.08mmol) was placed in a 25mL single vial, to which was added 1mL TFA,4mL DCM, reacted at room temperature for 30min, TLC monitoring of the completion of the reaction, the solvent was removed under reduced pressure, dried under vacuum and redissolved in 4mL DMF, to which was added HATU (38mg, 0.1mmol), DIEA (51.7mg, 0.4mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid III-1 (20.3mg, 0.1mmol), reacted at room temperature overnight, TLC monitoring of the completion of the reaction, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, removing the solvent under reduced pressure, reverse phase column separation and freeze drying to obtain RIP1-001: white solid 14.0mg (40.4%)

By varying compound II and compound III (both known compounds, prepared by methods reported in the literature), compounds RIP1-002, RIP 1-013-RIP 1-017, RIP 1-019-RIP 1-020, RIP 1-026-RIP 1-030, RIP 1-036-RIP 1-040 and RIP 1-092-RIP 1-116 can also be prepared by method one.

The method 2 comprises the following steps:

30.0mg of II-1 was dissolved in 1mL of dichloromethane, 0.3mL of TFA was added, the mixture was stirred at room temperature for 3 hours, and dichloromethane and TFA were removed by rotary evaporation to obtain Boc-deprotected aminotrifluoroacetate.

17.7mg of the intermediate product after the removal of the Boc protecting group in the previous step is taken, 1mL of DMF is added for dissolution, 43.3mg of DIEA,19.3mg of EDCI and 13.6mg of HOBt are sequentially added, and the mixture is stirred at the normal temperature for 1 hour and then cooled to 0 ℃. The trifluoroacetate salt obtained in the previous step was dissolved in 1mL of DMF and then slowly added dropwise to the reaction solution. The reaction mixture was allowed to react overnight at room temperature, after completion of the reaction 10mL of water was slowly added, the mixture was stirred for 0.5 hour, 10mL of ethyl acetate was added and extracted, the ethyl acetate layer was collected, dried, spun-dried and separated by silica gel column (eluent: petroleum ether: ethyl acetate = 3: 1) to give 19.0mg of RIP1-003 in 66% yield.

By varying compound II and compound III, compounds RIP1-004 to RIP1-012, and RIP1-041 to RIP1-058, RIP1-061 to RIP1-088, they may also be prepared by method two.

The method 3 comprises the following steps:

compound II-4 (27.8mg, 0.06mmol) was placed in a 15mL sealed tube, to which was added 1mL of 3N HCl,0.5mL of EtOH, reaction at 100 ℃ for 2h, TLC monitoring of completion of the reaction, the solvent was removed under reduced pressure, dried under vacuum and redissolved in 4mL of DMF, to which was added HATU (28.5mg, 0.075mmol), DIEA (38.8mg, 0.3mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (15.2mg, 0.075mmol), reacted overnight at room temperature, TLC monitoring of completion of the reaction, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, removing the solvent under reduced pressure, reverse phase column separation and lyophilization to obtain RIP1-023: white solid 10mg (40%)

By varying compound II and compound III, compounds RIP1-021 through RIP1-025, RIP1-031 through RIP1-035, RIP1-059 through RIP1-060, and RIP1-089 through RIP1-091 can also be prepared by method three.

The synthesis methods of the prepared compounds RIP1-001 to RIP1-017 and RIP1-019 to RIP1-060 have the following yields and data:

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compound I test data:

RIP1-001：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.86(s，1H)，8.31(d，J＝7.8，1H)，7.63(s，1H)，7.49(s，1H)，7.31-7.26(m，2H)，7.25-7.17(m，5H)，6.50(s，1H)，4.83-4.76(m，1H)，4.08(s，2H)，3.76(dd，J＝11.1，6.9，1H)，3.46(s，3H)，2.83(t，J＝11.2，1H)；ESI-MS m/z 433.4(M+H) ⁺ .

RIP1-002：

¹ H NMR(400MHz，CDCl ₃ )δ(ppm)：2.79(t，J＝11.2Hz，1H)，3.45(s，3H)，3.75(s，3H)，3.76-3.80(m，1H)，4.06(s，2H)，，4.66-4.73(m，1H)，6.41(s，1H)，7.04-7.08(m，1H)，7.19-7.30(m，5H)，7.45(s，1H)，7.56(s，1H)，8.16(brs，1H)；ESI-MS(M+H) ⁺ ＝447.1.

RIP1-003：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.49(s，1H)，7.84(d，J＝7.4，1H)，7.71(s，1H)，7.54(s，1H)，7.34-7.29(m，3H)，7.28-7.24(m，1H)，7.21(d，J＝7.1，2H)，6.56-6.54(m，1H)，6.26(s，1H)，4.78-4.73(m，1H)，4.09(s，2H)，3.82(dd，J＝11.2，6.9，1H)，3.48(s，3H)，2.84(t，J＝11.2，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ173.86，169.89，158.15，158.01，137.99，135.24，129.36，128.88，128.74，127.31，126.83，119.90，117.90，116.81，103.06，101.54，49.68，38.12，37.19，33.16；MS-ESI：433.3(M+H) ⁺ .

RIP1-004：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.73(s，1H)，7.83(d，J＝0.4，1H)，7.76(s，1H)，7.68(s，1H)，7.52(s，1H)，7.37-7.31(m，3H)，7.28-7.26(m，1H)，7.21(dd，J＝7.7，1.5，2H)，7.03(d，J＝7.3，1H)，6.53-6.50(m，1H)，5.27(s，2H)，4.81-4.75(m，1H)，3.85(dd，J＝11.2，6.9，1H)，3.47(s，3H)，2.80(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ171.01，161.45，138.86，137.98，135.42，134.74，130.83，129.45，129.14，128.63，128.12，126.99，119.95，118.52，118.03，116.86，103.08，56.63，49.78，38.65，37.33；MS-ESI：432.4(M+H) ⁺ .

RIP1-005：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.75(s，1H)，7.66(s，1H)，7.59(d，J＝0.6，1H)，7.55(s，1H)，7.53(s，1H)，7.30-7.23(m，4H)，7.19(d，J＝7.3，1H)，7.08(d，J＝1.7，1H)，7.06(s，1H)，6.53-6.51(m，1H)，5.44(s，2H)，4.75-4.69(m，1H)，3.77(dd，J＝11.2，6.8，1H)，3.48(s，3H)，2.76(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.55，159.08，141.63，137.96，136.58，134.72，132.64，129.46，128.94，128.08，127.32，127.02，125.32，119.90，117.97，116.92，103.08，50.02，49.66，38.47，37.33，1.16；MS-ESI：432.4(M+H) ⁺ .

RIP1-006：

¹ H NMR(500MHz，CDCl ₃ )δ＝9.01(s，1H)，8.07(d，J＝8.0，1H)，7.65(s，1H)，7.48(s，1H)，7.47(d，J＝1.2，1H)，7.44(d，J＝1.3，1H)，7.36-7.31(m，3H)，7.23-7.22(m，1H)，7.13(dd，J＝7.6，1.7，2H)，6.48-6.45(m，1H)，5.08(s，2H)，4.83(ddd，J＝11.2，7.8，7.0，1H)，3.80(dd，J＝11.1，6.8，1H)，3.47(s，3H)，2.88(t，J＝11.2，1H)； ¹³ C NMR(125MHz，cdcl ₃ )δ170.79，161.75，138.15，137.17，137.13，135.27，134.70，129.39，129.27，128.74，127.60，126.93，122.47，119.90，117.99，116.74，102.86，51.44，49.37，38.68，37.27；MS-ESI：432.4(M+H) ⁺ .

RIP1-007：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.84(s，1H)，7.71(s，1H)，7.64(s，1H)，7.61(dt，J＝7.1，1.6，1H)，7.54(s，1H)，7.42(d，J＝7.2，1H)，7.35-7.25(m，5H)，7.19(t，J＝7.4，1H)，7.15(d，J＝7.1，2H)，6.53-6.51(m，1H)，4.88-4.81(m，1H)，4.00(s，2H)，3.94(dd，J＝11.1，6.8，1H)，3.50(s，3H)，2.85(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.95，166.48，141.85，140.53，137.95，134.79，134.04，132.55，129.46，129.01，128.86，128.70，127.82，127.07，126.42，124.99，119.89，118.08，116.86，103.00，50.35，41.87，38.55，37.32；MS-ESI：442.4(M+H) ⁺ .

RIP1-008：

¹ H NMR(500MHz，CDCl ₃ )δ＝9.03(s，1H)，8.22(d，J＝7.6，1H)，8.02(s，1H)，7.70(s，1H)，7.50(s，1H)，7.39-7.34(m，3H)，7.29-7.27(m，2H)，7.25(d，J＝1.8，1H)，6.49(s，1H)，5.36(s，2H)，4.87-4.81(m，1H)，3.92(dd，J＝11.2，6.9，1H)，3.49(s，3H)，2.85(t，J＝11.1，1H)； ¹³ CNMR(125MHz，CDCl ₃ )δ170.36，158.12，157.01，144.07，137.82，134.82，133.91，129.47，129.31，129.08，128.37，127.17，119.62，118.30，116.78，102.83，54.45，49.89，38.52，37.36；MS-ESI：433.4(M+H) ⁺ .

RIP1-009：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.84(d，J＝7.4，1H)，7.65(s，1H)，7.52(s，1H)，7.32(t，J＝7.3，2H)，7.28(s，1H)，7.21(d，J＝7.1，2H)，7.15(d，J＝3.1，1H)，6.48(d，J＝3.0，1H)，6.26(s，1H)，4.77-4.70(m，1H)，4.08(s，2H)，3.85-3.80(m，4H)，3.48(s，3H)，2.84(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ173.96，170.03，158.33，158.12，137.72，135.63，135.41，131.53，129.95，129.02，128.89，127.46，119.55，117.07，116.41，101.70，101.57，49.83，38.33，37.31，33.31，31.77；MS-ESI：447.4(M+H) ⁺ .

RIP1-010：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.82(s，1H)，7.75(s，1H)，7.64(s，1H)，7.51(s，1H)，7.37-7.31(m，3H)，7.23-7.20(m，2H)，7.14(d，J＝3.1，1H)，6.96(d，J＝7.3，1H)，6.47(d，J＝3.0，1H)，5.27(s，2H)，4.77-4.71(m，1H)，3.87-3.82(m，4H)，3.47(s，3H)，2.78(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ171.00，161.31，138.80，137.66，135.66，135.46，131.49，130.81，129.91，129.13，128.61，128.12，119.63，118.60，117.04，116.41，101.55，56.62，49.75，38.71，37.30，33.30；MS-ESI：446.4(M+H) ⁺ .

RIP1-011：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.66(s，1H)，7.63(s，1H)，7.59(d，J＝7.3，1H)，7.53(s，1H)，7.35(d，J＝7.1，1H)，7.34-7.25(m，4H)，7.19(t，J＝7.4，1H)，7.16(d，J＝1.2，1H)，7.15(d，J＝3.0，2H)，6.48(d，J＝3.7，1H)，4.83-4.77(m，1H)，4.00(s，2H)，3.91(dd，J＝11.1，6.8，1H)，3.84(s，3H)，3.50(s，3H)，2.82(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.97，166.28，141.78，140.56，137.68，135.67，134.16，132.43，131.50，129.92，129.01，128.81，128.69，127.81，126.40，124.97，119.63，117.06，116.42，101.56，50.29，41.87，38.60，37.27，33.29；MS-ESI：456.4(M+H) ⁺ .

RIP1-012：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.18(d，J＝7.5，1H)，7.99(s，1H)，7.65(s，1H)，7.51(s，1H)，7.39-7.34(m，3H)，7.27(d，J＝2.5，1H)，7.26(d，J＝2.0，1H)，7.15(d，J＝3.1，1H)，6.47(dd，J＝3.1，0.7，1H)，5.35(s，2H)，4.83-4.77(m，1H)，3.91(dd，J＝11.2，6.9，1H)，3.84(s，3H)，3.48(s，3H)，2.83(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.36，157.94，157.08，143.97，137.67，135.65，133.95，131.49，129.94，129.30，129.06，128.36，119.55，117.06，116.53，101.51，54.42，49.80，38.53，37.32，33.29；MS-ESI：447.4(M+H) ⁺ .

RIP1-013

¹ H NMR(400MHz，CDCl ₃ )δ8.03(s，1H)，7.89(s，1H)，7.68(s，1H)，7.37-7.21(m，5H)，4.87-4.74(m，1H)，4.13(s，2H)，3.87-3.74(m，1H)，3.50(s，3H)，2.99-2.87(m，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.0，158.2，138.8，138.6，135.9，134.2，128.8，127.2，126.1，123.8，117.5，116.8，49.5，37.5，37.3，33.2.ESI-MS：m/z 434.1(M+H) ⁺

RIP1-014

¹ H NMR(400MHz，CDCl ₃ )δ11.82(s，1H)，7.92(s，1H)，7.87(s，1H)，7.81(s，1H)，7.66(s，1H)，7.60-7.54(m，2H)，7.38-7.31(m，3H)，7.24-7.19(m，2H)，5.25(s，2H)，4.90(dt，J＝11.4，7.4Hz，1H)，3.79(dd，J＝11.3，6.8Hz，1H)，3.43(s，3H)，2.93(t，J＝11.4Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ171.0，162.1，139.1，138.6，138.5，135.3，134.7，131.1，129.1，128.6，128.2，126.0，123.9，118.0，116.8，116.8，56.6，49.6，37.7，37.6.ESI-MS：m/z 433.1(M+H) ⁺

RIP1-015

¹ H NMR(400MHz，CDCl ₃ )δ10.97(s，1H)，8.01(s，1H)，7.92(d，J＝7.1Hz，1H)，7.80(s，1H)，7.63(s，1H)，7.36-7.15(m，5H)，6.27(s，1H)，4.88-4.72(m，1H)，4.07(s，2H)，3.80(dd，J＝11.0，6.7Hz，1H)，3.47(s，3H)，2.89(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ174.2，169.7，158.5，158.1，138.9，138.7，135.3，135.0，129.0，128.9，127.5，126.5，124.2，117.0，116.9，101.7，49.6，37.6，37.5，33.3.ESI-MS：m/z 434.1(M+H) ⁺

RIP1-016

¹ H NMR(400MHz，CDCl ₃ )δ11.94(s，1H)，8.17(d，J＝8.2Hz，1H)，7.88(d，J＝0.7Hz，1H)，7.68(s，1H)，7.52(s，1H)，7.49(s，1H)，7.48(s，1H)，7.35-7.29(m，3H)，7.15-7.10(m，2H)，5.08(s，2H)，4.91(ddd，J＝11.4，8.0，7.0Hz，1H)，3.79(dd，J＝11.1，6.7Hz，1H)，3.43(s，3H)，2.96(t，J＝11.3Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.3，162.2，138.7，138.6，137.3，136.7，135.2，134.5，129.3，128.7，127.6，126.0，123.8，122.8，116.7，116.6，51.4，49.1，37.8，37.4.ESI-MS：m/z 433.1(M+H) ⁺

RIP1-017

¹ H NMR(400MHz，CDCl ₃ )δ11.61(br s，1H)，8.00(s，1H)，7.80-7.46(m，5H)，7.26-7.13(m，3H)，7.12-6.97(m，2H)，5.44(q，J＝15.0Hz，2H)，4.77(s，1H)，3.79-3.66(m，1H)，3.48(s，3H)，2.86(t，J＝11.0Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.5，159.4，141.8，138.7，136.5，134.8，133.0，128.9，128.1，127.3，126.3，125.1，124.0，117.0，116.9，53.6，50.2，49.4，37.6.ESI-MS：m/z 433.1(M+H) ⁺

RIP1-019

¹ H NMR(400MHz，CDCl ₃ +CD ₃ OD)δ7.99(s，1H)，7.92(s，1H)，7.81(s，1H)，7.64(s，1H)，7.38-7.30(m，3H)，7.25-7.19(m，2H)，5.58-5.45(m，2H)，4.78(dd，J＝11.3，6.7Hz，1H)，3.75(dd，J＝11.1，6.8Hz，1H)，3.46(s，3H)，2.91(t，J＝11.3Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ +CD ₃ OD)δ170.0，159.4，142.8，138.9，138.7，134.5，133.8，129.3，129.2，128.3，126.4，125.7，124.0，117.1，116.9，54.6，49.2，37.51，37.49.ESI-MS：m/z434.1(M+H) ⁺

RIP1-020

¹ H NMR(400MHz，CDCl ₃ +CD ₃ OD)δ8.07(s，1H)，8.02(s，1H)，7.89(s，1H)，7.66(s，1H)，7.40-7.33(m，3H)，7.29-7.26(m，2H)，5.37(s，2H)，4.82(dd，J＝11.2，6.8Hz，1H)，3.86(dd，J＝11.1，6.8Hz，1H)，3.49(s，3H)，2.88(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ +CD ₃ OD)δ170.1，158.1，156.6，144.2，138.8，138.6，134.4，133.8，129.3，129.1，128.3，126.1，123.9，117.5，116.8，54.4，49.6，49.5，37.52，37.47.ESI-MS：m/z 434.1(M+H) ⁺

RIP1-021

¹ H NMR(400MHz，CDCl ₃ )δ10.49(s，1H)，8.05(s，1H)，7.80(d，J＝6.3Hz，1H)，7.60(s，1H)，7.35-7.27(m，4H)，7.24-7.19(m，2H)，6.29(s，1H)，5.07-4.98(m，1H)，4.69(dd，J＝9.8，7.4Hz，1H)，4.24(dd，J＝11.1，9.9Hz，1H)，4.10(s，2H)，3.51(s，3H)； ¹³ CNMR(100MHz，CDCl ₃ )δ174.3，168.4，158.8，158.0，150.0，138.6，135.3，135.2，131.7，129.1，128.9，127.5，120.6，115.4，103.2，101.7，76.6，49.2，36.7，33.3.ESI-MS：m/z 418.0(M+H) ⁺

RIP1-022

¹ H NMR(400MHz，CDCl ₃ )δ11.00(br s，1H)，8.07-7.96(m，2H)，7.53(s，1H)，7.51-7.46(m，2H)，7.38-7.30(m，3H)，7.19-7.11(m，2H)，5.15-5.04(m，3H)，4.70-4.63(m，1H)，4.31-4.22(m，1H)，3.48(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ169.1，162.4，150.0，137.3，136.8，135.2，134.9，131.8，129.3，128.8，127.7，122.7，115.1，103.0，77.0，51.5，48.7，36.5.ESI-MS：m/z 417.1(M+H) ⁺

RIP1-023

¹ H NMR(400MHz，CDCl ₃ )δ8.00(s，1H)，7.56(s，1H)，7.31-7.27(m，2H)，7.26-7.17(m，4H)，5.01(dd，J＝11.2，7.4Hz，1H)，4.67-4.58(m，1H)，4.26-4.17(m，1H)，4.10(s，2H)，3.47(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ168.6，158.7，154.5，149.7，138.7，135.9，134.3，131.4，128.9，127.3，120.3，115.2，103.6，76.4，49.0，36.6，33.3.ESI-MS：m/z 418.1(M+H) ⁺

RIP1-024

¹ H NMR(400MHz，CDCl ₃ )δ10.93(br s，1H)，8.03(d，J＝6.8Hz，1H)，7.91(s，1H)，7.84(s，1H)，7.47(s，1H)，7.26(s，2H)，7.17(s，3H)，5.53-5.36(m，2H)，5.07-4.91(m，1H)，4.56(t，J＝8.5Hz，1H)，4.19(t，J＝10.4Hz，1H)，3.41(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ168.6，159.9，149.9，142.8，138.6，134.9，133.8，131.7，129.4，129.2，128.4，125.7，120.5，115.2，103.1，76.7，54.7，48.9，36.6.ESI-MS：m/z 418.1(M+H) ⁺

RIP1-025

¹ H NMR(400MHz，CDCl ₃ )δ11.54(br s，1H)，8.17-7.86(m，3H)，7.47(s，1H)，7.33-7.26(m，3H)，7.23-7.16(m，2H)，5.30(s，2H)，5.09-4.96(m，1H)，4.71(t，J＝8.2Hz，1H)，4.18(t，J＝10.3Hz，1H)，3.43(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ168.6，158.8，156.7，149.6，144.3，138.8，134.6，133.8，131.3，129.3，129.1，128.5，120.5，115.0，103.7，76.7，54.5，49.4，36.6.ESI-MS：m/z 418.1(M+H) ⁺

RIP1-026

¹ H NMR(400MHz，CDCl ₃ )δ11.81(s，1H)，8.24(s，1H)，8.08(s，1H)，7.81(s，1H)，7.51(s，1H)，7.41-7.34(m，3H)，7.33-7.27(m，2H)，5.38(s，2H)，4.88-4.75(m，1H)，3.96(dd，J＝10.7，6.7Hz，1H)，3.51(s，3H)，2.92(t，J＝11.1Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ169.7，158.5，156.7，144.3，139.9，139.2，134.8，133.7，129.4，129.2，128.5，127.4，121.3，118.3，115.2，54.6，49.8，37.6，37.4.ESI-MS：m/z 468.0(M+H) ⁺

RIP1-027

¹ H NMR(400MHz，CDCl ₃ )δ8.23(br s，1H)，7.81(s，1H)，7.54(s，1H)，7.29-7.26(m，1H)，7.25-7.20(m，4H)，4.70(dd，J＝11.2，6.8Hz，1H)，4.10(s，2H)，3.72(dd，J＝11.0，6.8Hz，1H)，3.47(s，3H)，2.86(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ169.8，158.4，139.9，139.4，135.8，134.6，129.0，128.9，127.9，127.3，121.2，118.4，115.3，49.5，37.6，37.2，33.2.ESI-MS：m/z 466.0(M-H) ^-

RIP1-028

¹ H NMR(400MHz，CDCl ₃ )δ11.69(s，1H)，8.16(d，J＝7.9Hz，1H)，7.68(s，1H)，7.51-7.44(m，3H)，7.37-7.31(m，3H)，7.17-7.10(m，2H)，5.12(d，J＝16.7Hz，2H)，4.87(dt，J＝11.5，7.2Hz，1H)，3.82(dd，J＝11.0，6.6Hz，1H)，3.47(s，3H)，2.97(t，J＝11.3Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.1，162.3，139.7，139.6，137.4，136.6，135.1，135.0，129.3，128.8，127.9，127.7，122.9，121.2，117.3，115.3，51.5，49.1，37.7，37.5.ESI-MS：m/z 467.0(M+H) ⁺

RIP1-029

¹ H NMR(400MHz，CDCl ₃ )δ10.90(br s，1H)，7.91(s，1H)，7.78(s，1H)，7.56(s，1H)，7.37-7.27(m，3H)，7.24-7.19(m，2H)，6.28(s，1H)，4.78(dd，J＝11.2，6.7Hz，1H)，4.09(s，2H)，3.81(dd，J＝11.1，6.7Hz，1H)，3.50(s，3H)，2.92(t，J＝11.3Hz，1H)； ¹³ CNMR(100MHz，CDCl ₃ )δ174.3，169.5，158.6，158.0，139.7，139.7，135.5，135.3，129.1，128.9，128.2，127.5，121.5，117.5，115.6，101.7，49.5，37.6，37.3，33.3.ESI-MS：m/z 468.0(M+H) ⁺

RIP1-030

¹ H NMR(400MHz，CDCl ₃ +CD ₃ OD)δ11.85(br s，1H)，8.19(d，J＝7.1Hz，1H)，7.91(s，1H)，7.80(s，1H)，7.57(s，1H)，7.41-7.31(m，3H)，7.26-7.19(m，2H)，5.57-5.46(m，2H)，4.84-4.68(m，1H)，3.76(dd，J＝10.7，6.7Hz，1H)，3.45(d，J＝29.4Hz，3H)，2.92(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ +CD ₃ OD)δ169.9，159.4，142.8，139.7，139.6，134.9，133.8，129.4，129.2，128.3，128.1，125.7，121.3，117.7，115.5，54.6，49.2，37.6，37.4.ESI-MS：m/z 468.1(M+H) ⁺

RIP1-031

¹ H NMR(400MHz，CDCl ₃ )δ11.05(s，1H)，8.03(d，J＝7.3Hz，1H)，7.53-7.46(m，2H)，7.43(s，1H)，7.39-7.30(m，3H)，7.18(s，1H)，7.17-7.11(m，2H)，5.21-5.04(m，3H)，4.72-4.63(m，1H)，4.29(dd，J＝11.3，9.9Hz，1H)，3.51(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ168.8，162.8，150.7，139.7，137.4，136.4，135.1，134.7，132.3，129.3，128.8，127.7，122.9，117.6，113.6，103.5，76.8，51.5，48.7，36.5.ESI-MS：m/z 451.1(M+H) ⁺

RIP1-032

¹ H NMR(400MHz，CDCl ₃ )δ11.53(s，1H)，8.15(d，J＝6.4Hz，1H)，8.08(s，1H)，7.46(s，1H)，7.40-7.28(m，5H)，5.37(s，2H)，5.07(dt，J＝11.1，6.9Hz，1H)，4.85(dd，J＝9.6，7.4Hz，1H)，4.35-4.25(m，1H)，3.52(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ168.4，159.0，156.5，150.3，144.4，139.9，134.4，133.7131.8，129.3，129.2，128.5，117.7，113.5，104.6，76.6，54.6，49.5，36.6.ESI-MS：m/z 452.1(M+H) ⁺

RIP1-033

¹ H NMR(400MHz，CDCl ₃ )δ11.38(br s，1H)，7.83(br s，1H)，7.40(s，1H)，7.30-7.11(m，6H)，6.24(s，1H)，5.07-4.93(m，1H)，4.67-4.55(m，1H)，4.21(t，J＝10.5Hz，1H)，4.02(s，2H)，3.45(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ174.4，168.2，159.1，157.8，150.8，139.7，135.2，135.1，132.3，129.0，128.9，127.5，117.8，114.0，103.8，101.7，76.4，49.1，36.7，33.3.ESI-MS：m/z 452.1(M+H) ⁺

RIP1-034

¹ H NMR(400MHz，CDCl ₃ +CD ₃ OD)δ7.45(s，1H)，7.32-7.12(m，6H)，5.05-4.92(m，1H)，4.61(t，J＝8.4Hz，1H)，4.22(t，J＝10.4Hz，1H)，4.08(s，2H)，3.46(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ +CD ₃ OD)δ168.5，158.8，150.5，139.9，135.7，134.3，132.0，128.84，128.80，127.2，117.6，113.7，104.2，76.3，49.0，36.6，33.1.ESI-MS：m/z 452.1(M+H) ⁺

RIP1-035

¹ H NMR(400MHz，CDCl ₃ )δ7.92(s，1H)，7.49(s，1H)，7.36-7.32(m，2H)，7.29-7.18(m，5H)，5.51(s，2H)，5.07-4.95(m，1H)，4.61(dd，J＝9.7，7.4Hz，1H)，4.29-4.20(m，1H)，3.49(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ168.6，159.8，150.6，142.3，139.8，134.3，133.8，132.1，129.2，129.0，128.1，125.8，117.5，113.8，103.9，76.3，54.4，48.6，36.5.ESI-MS：m/z 452.1(M+H) ⁺

RIP1-036

¹ H NMR(400MHz，CDCl ₃ )δ8.01(d，J＝7.7Hz，1H)，7.81(s，1H)，7.69(d，J＝1.8Hz，1H)，7.50(s，1H)，7.44(d，J＝7.7Hz，2H)，7.38-7.29(m，3H)，7.17-7.07(m，2H)，6.76(s，1H)，5.08(s，2H)，4.77(dt，J＝11.1，7.5Hz，1H)，3.79(dd，J＝11.0，6.8Hz，1H)，3.45(s，3H)，2.89(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.6，161.6，153.1，147.4，141.4，137.1，135.3，129.6，129.2，128.7，127.6，123.3，122.4，118.3，117.3，106.8，51.4，49.1，38.7，37.1.ESI-MS：m/z 433.1(M+H) ⁺

RIP1-037

¹ H NMR(400MHz，CDCl ₃ )δ8.15(d，J＝7.7Hz，1H)，8.02(s，1H)，7.82(s，1H)，7.70(d，J＝2.2Hz，1H)，7.50(s，1H)，7.38-7.32(m，3H)，7.27-7.22(m，2H)，6.77(dd，J＝2.1，0.9Hz，1H)，5.35(s，2H)，4.80(dt，J＝11.1，7.2Hz，1H)，3.89(dd，J＝11.2，6.9Hz，1H)，3.45(s，3H)，2.87(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.2，157.9，156.9，153.1，147.5，144.0，141.0，133.9，129.6，129.2，129.0，128.3，123.0，118.4，117.3，106.7，54.3，49.5，38.5，37.2.ESI-MS：m/z 434.1(M+H) ⁺

RIP1-038

¹ H NMR(400MHz，CDCl ₃ )δ7.87-7.79(m，2H)，7.71(d，J＝2.1Hz，1H)，7.52(s，1H)，7.35-7.19(m，5H)，6.79(d，J＝1.3Hz，1H)，6.27(s，1H)，4.74(dt，J＝11.2，7.2Hz，1H)，4.08(s，2H)，3.83(dd，J＝11.1，6.9Hz，1H)，3.46(s，3H)，2.88(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ174.0，169.9，158.2，158.1，153.1，147.5，141.1，135.3，129.7，129.0，128.9，127.4，123.1，118.4，117.4，106.8，101.7，49.6，38.3，37.2，33.3.ESI-MS：m/z 434.1(M+H) ⁺

RIP1-039

¹ H NMR(400MHz，CDCl ₃ )δ8.25(d，J＝7.9Hz，1H)，7.80(s，1H)，7.70(d，J＝2.1Hz，1H)，7.46(s，1H)，7.15(s，5H)，6.76(d，J＝1.3Hz，1H)，4.77(dt，J＝11.3，7.4Hz，1H)，4.06(s，2H)，3.74(dd，J＝11.2，6.9Hz，1H)，3.42(s，3H)，2.87(t，J＝11.3Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.4，158.7，153.1，147.5，141.1，136.1，129.8，128.9，128.7，127.0，123.0，118.3，117.4，106.8，49.6，38.3，37.3，32.9.ESI-MS：m/z 434.1(M+H) ⁺

RIP1-040

¹ H NMR(400MHz，CDCl ₃ )δ8.11(d，J＝7.5Hz，1H)，7.87(s，1H)，7.82(s，1H)，7.70(d，J＝1.7Hz，1H)，7.51(s，1H)，7.39-7.31(m，3H)，7.26-7.20(m，2H)，6.78(s，1H)，5.59-5.45(m，2H)，4.77(dt，J＝11.1，7.3Hz，1H)，3.81(dd，J＝11.1，6.9Hz，1H)，3.46(s，3H)，2.91(t，J＝11.2Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.2，159.1，153.1，147.5，143.1，141.3，133.9，129.7，129.4，129.2，128.3，125.4，123.2，118.3，117.3，106.8，54.6，49.3，38.5，37.2.ESI-MS：m/z 434.1(M+H) ⁺

RIP1-041：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.59(s，1H)，8.12(brs，1H)，7.72(s，1H)，7.55(s，1H)，7.34-7.27(m，6H)，6.56(s，1H)，4.77-4.70(m，1H)，4.23(s，2H)，3.84(dd，J＝11.2，6.9，1H)，3.49(s，3H)，2.84(t，J＝11.1，1H).MS-ESI：434.1(M+H) ⁺ .

RIP1-042：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.83(s，1H)，8.16(d，J＝7.8，1H)，7.86(s，1H)，7.67(s，1H)，7.51(s，1H)，7.37-7.33(m，3H)，7.26-7.21(m，3H)，6.50(s，1H)，5.51(d，J＝7.1，2H)，4.85-4.79(m，1H)，3.81(dd，J＝11.2，6.9，1H)，3.48(s，3H)，2.88(t，J＝11.2，1H)； ¹³ C NMR(125MHz，cdcl ₃ )δ170.33，159.19，143.19，138.10，134.68，133.93，129.45，129.37，129.17，128.31，127.00，125.44，119.89，118.01，116.83，102.98，54.59，49.56，38.48，37.33；MS-ESI：433.2(M+H) ⁺ .

RIP1-043：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.83(s，1H)，8.19(d，J＝7.4，1H)，7.72(s，1H)，7.53(s，1H)，7.39-7.34(m，5H)，7.31-7.29(m，1H)，6.54-6.52(m，1H)，5.79(s，2H)，4.86-4.81(m，1H)，3.92(dd，J＝11.2，6.9，1H)，3.49(s，3H)，2.85(t，J＝11.1，1H)； ¹³ C NMR(125MHz，cdcl ₃ )δ169.94，159.74，155.64，137.78，134.80，132.51，129.54，129.43，129.26，128.73，127.21，119.64，118.26，116.88，103.00，57.59，50.07，38.32，37.40；MS-ESI：434.1(M+H) ⁺ .

RIP1-044：

¹ H NMR(400MHz，CDCl ₃ )δ＝9.17(s，1H)，7.89(d，J＝7.8，1H)，7.66(s，1H)，7.49(s，1H)，7.23(t，J＝2.7，1H)，7.08(d，J＝7.8，2H)，6.98(d，J＝7.9，2H)，6.46(s，1H)，6.46(s，1H)，4.88-4.80(m，1H)，3.91(s，2H)，3.86(dd，J＝11.1，6.8，1H)，3.69(s，3H)，3.48(s，3H)，2.87(t，J＝11.2，1H)，2.30(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.84，161.46，144.46，143.36，137.92，136.61，134.74，133.66，129.58，129.36，128.34，127.05，119.66，118.07，116.69，106.81，102.72，77.48，77.16，76.84，49.50，38.65，37.27，37.12，31.56，21.12；MS-ESI：460.2(M+H) ⁺ .

RIP1-045：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.68(s，1H)，7.69(s，1H)，7.54(s，1H)，7.28(s，1H)，7.14-7.07(m，5H)，6.54(s，1H)，6.30(s，1H)，4.75-4.68(m，1H)，4.01(s，3H)，3.89(s，2H)，3.81(dd，J＝11.0，6.8，1H)，3.47(s，3H)，2.78(t，J＝11.1，1H)，2.33(s，3H)；MS-ESI：460.15(M+H) ⁺ .

RIP1-046：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.85(s，1H)，8.00(s，1H)，7.99(d，J＝8.4，1H)，7.68(s，1H)，7.52(s，1H)，7.35-7.31(m，2H)，7.30-7.25(m，3H)，6.50(s，1H)，4.83-4.77(m，1H)，4.10(s，2H)，3.83(dd，J＝11.1，6.8，1H)，3.49(s，3H)，2.87(t，J＝11.2，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.31，162.98，159.70，141.31，137.89，135.78，134.64，134.58，129.33，128.80，128.80，127.31，126.89，119.70，117.90，116.70，102.85，49.36，38.37，37.16，34.49；MS-ESI：433.1(M+H) ⁺ .

RIP1-047：

¹ H NMR(500MHz，CD ₃ OD)δ＝7.74(s，1H)，7.69(s，1H)，7.59(s，1H)，7.40(d，J＝3.1，1H)，7.34-7.29(m，2H)，7.26-7.21(m，3H)，6.55(dd，J＝3.1，0.7，1H)，4.10(s，2H)，3.94-3.90(m，1H)，3.64(dd，J＝11.2，6.9，1H)，3.45(s，3H)，2.95(t，J＝11.4，1H)；MS-ESI：432.1(M+H) ⁺ .

RIP1-048

¹ H NMR(500MHz，CDCl ₃ )δ＝8.15(d，J＝7.5，1H)，7.86(s，1H)，7.64(s，1H)，7.52(s，1H)，7.38-7.34(m，3H)，7.26-7.22(m，2H)，7.14(d，J＝2.8，1H)，6.47(d，J＝3.0，1H)，5.52(d，J＝7.6，2H)，4.81-1.74(m，1H)，3.82(s，3H)，3.80(dd，J＝7.0，4.2，1H)，3.48(s，3H)，2.87(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.30，159.10，143.24，137.88，135.60，133.96，131.45，129.92，129.38，129.18，128.32，125.43，119.69，117.06，116.37，101.54，54.60，49.56，38.52，37.30，33.29；MS-ESI：447.4(M+H) ⁺ .

RIP1-049

¹ H NMR(500MHz，CDCl ₃ )δ＝8.00(s，1H)，7.95(d，J＝7.6，1H)，7.65(s，1H)，7.53(s，1H)，7.37-7.32(m，2H)，7.31-7.27(m，3H)，7.15(d，J＝3.0，1H)，6.48(d，J＝3.0，1H)，4.79-4.73(m，1H)，4.11(s，2H)，3.85-3.81(m，4H)，2.86(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.47，163.01，159.70，141.36，137.83，136.05，135.63，134.85，131.47，129.94，128.94，127.44，119.65，119.54，117.06，116.40，101.55，49.45，38.56，37.26，34.65，33.30；MS-ESI：447.4(M+H) ⁺ .

RIP1-050：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.85(brs，1H)，7.60(s，1H)，7.50(s，1H)，7.34(d，J＝7.0，2H)，7.23(t，J＝7.3，2H)，7.20-7.16(m，2H)，7.14(d，J＝3.0，1H)，7.02(d，J＝5.9，1H)，6.47(d，J＝3.1，1H)，5.29(s，2H)，4.72-4.67(m，1H)，3.80(s，3H)，3.68(dd，J＝11.4，7.0，1H)，3.41(s，3H)，3.17(t，J＝11.4，1H)； ¹³ C NMR(126MHz，CDCl ₃ )δ171.54，159.75，148.15，137.59，135.62，131.65，129.99，129.25，129.17，128.78，128.60，127.73，119.59，117.19，116.18，101.75，101.54，53.56，50.53，49.68，37.71，33.29；MS-ESI：447.3(M+H) ⁺ .

RIP1-051：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.64(s，1H)，8.06(s，1H)，7.69(s，1H)，7.65(d，J＝7.3，1H)，7.56(s，1H)，7.32-7.30(m，1H)，7.25-7.19(m，5H)，6.57-6.55(m，1H)，5.82(d，J＝3.1，2H)，4.76-4.70(m，1H)，3.75(dd，J＝11.3，7.0，1H)，3.48(s，3H)，2.79(t，J＝11.2，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.38，156.74，137.78，135.46，134.75，134.24，129.92，129.57，128.78，128.31，128.05，127.16，119.75，118.03，117.03，103.24，53.28，50.04，38.17，37.49MS-ESI：433.1(M+H) ⁺ .

RIP1-052：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.02(s，1H)，7.64(s，1H)，7.54(s，1H)，7.41(d，J＝7.2，1H)，7.26-7.20(m，5H)，7.17(d，J＝3.0，1H)，6.50(d，J＝3.0，1H)，5.82(s，2H)，4.71-4.65(m，1H)，3.84(s，3H)，3.77(dd，J＝11.2，6.9，1H)，3.48(s，3H)，2.75(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.15，156.66，137.40，135.98，135.69，135.45，134.14，131.69，130.00，128.78，128.34，128.11，119.33，117.14，116.43，101.64，53.24，50.03，38.26，37.39，33.32；MS-ESI：447.3(M+H) ⁺ .

RIP1-054：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.62(s，1H)，7.57(s，1H)，7.53(s，1H)，7.52(s，1H)，7.27(s，1H)，7.26-7.23(m，2H)，7.16(d，J＝7.1，1H)，7.14(d，J＝2.9，1H)，7.07(d，J＝7.0，2H)，6.47(d，J＝3.0，1H)，5.44(s，2H)，4.71-4.65(m，1H)，3.81(s，3H)，3.77(dd，J＝11.1，6.7，1H)，3.47(s，1H)，2.75(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.53，159.00，141.58，137.61，136.60，135.62，132.56，131.51，129.90，128.91，128.06，127.35，127.27，119.52，117.06，116.35，101.55，49.97，49.63，38.50，37.26，33.25；MS-ESI：446.4(M+H) ⁺ .

RIP1-055：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.03(d，J＝7.7，1H)，7.63(s，1H)，7.50(s，1H)，7.45(s，1H)，7.43(s，1H)，7.35-7.30(m，3H)，7.13(d，J＝3.5，3H)，6.46(d，J＝3.0，1H)，5.07(s，2H)，4.80-4.75(m，1H)，3.82-3.78(m，4H)，3.47(s，3H)，2.86(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.77，161.55，138.01，137.24，137.06，135.56，135.31，131.33，129.86，129.23，128.69，127.57，122.37，119.81，117.00，116.33，101.48，51.40，49.30，38.69，37.21，33.25；MS-ESI：446.4(M+H) ⁺ .

RIP1-056：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.84(d，J＝7.6，1H)，7.64(s，1H)，7.51(s，1H)，7.14(d，J＝2.9，1H)，7.08(d，J＝7.8，2H)，6.98(d，J＝7.8，2H)，6.47(d，J＝3.0，1H)，6.45(s，1H)，4.81-4.75(m，1H)，3.90(s，2H)，3.86-3.82(m，4H)，3.69(s，3H)，3.48(s，3H)，2.84(t，J＝11.1，1H)，2.31(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.86，161.24，144.67，143.21，137.91，136.60，135.60，133.73，131.38，129.89，129.58，128.34，119.76，117.01，116.39，106.82，101.50，49.46，38.69，37.22，37.09，33.27，31.58，21.12；MS-ESI：474.4(M+H) ⁺ .

RIP1-057：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.63(s，1H)，7.52(s，1H)，7.14(d，J＝3.0，1H)，7.13-7.09(m，4H)，7.07(d，J＝7.3，1H)，6.47(d，J＝3.0，1H)，6.29(s，1H)，4.72-4.66(m，1H)，4.01(s，3H)，3.89(s，2H)，3.83-3.78(m，4H)，3.47(s，3H)，2.77(t，J＝11.1，1H)，2.33(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.44，158.73，150.97，137.56，136.44，136.02，135.64，135.30，131.55，129.94，129.42，128.74，119.42，117.01，116.37，105.91，101.57，49.71，39.07，38.45，37.18，34.20，33.26，21.17；MS-ESI：474.4(M+H) ⁺ .

RIP1-058：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.32(s，1H)，8.12(d，J＝7.4，1H)，7.65(s，1H)，7.53(s，1H)，7.36-7.29(m，4H)，7.16(d，J＝3.0，1H)，6.49(d，J＝3.0，1H)，4.74-4.68(m，1H)，4.23(s，2H)，3.86-3.81(m，4H)，3.48(s，3H)，2.85(t，J＝11.1，1H)；MS-ESI：448.4(M+H) ⁺ .

RIP1-059

¹ H NMR(400MHz，Methanol-d4)δ8.31(s，1H)，7.97(s，1H)，7.81(dd，J＝9.0，1.4Hz，1H)，7.79-7.73(m，2H)，7.61(d，J＝1.3Hz，1H)，7.39-7.24(m，6H)，5.26(s，1H)，5.22(s，2H)，4.69(dd，J＝11.5，6.9Hz，1H)，3.68(dd，J＝11.3，6.9Hz，1H)，3.46(s，3H)，2.98(t，J＝11.4Hz，1H)；ESI：m/z 433.1(M+H) ⁺ .RIP1-060

¹ H NMR(400MHz，Methanol-d4)δ8.55(s，1H)，8.32(s，1H)，7.97(s，1H)，7.76(s，1H)，7.36-7.34(m，4H)，7.33(d，J＝3.5Hz，5H)，5.44(s，2H)，5.42(s，1H)，4.71(dd，J＝11.6，6.9Hz，1H)，3.68(dd，J＝11.4，6.9Hz，1H)，3.45(s，2H)，3.15-2.95(m，1H)；ESI：m/z 434.1(M+H) ⁺ .RIP1-061：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.82(d，J＝7.0，1H)，7.38(brs，1H)，7.35-7.24(m，5H)，7.21(d，J＝7.3，2H)，6.27(s，1H)，4.99-4.93(m，1H)，4.66(dd，J＝9.4，7.9，1H)，4.22(t，J＝10.5，1H)，4.09(s，2H)，3.42(s，3H)，2.61(s，3H)；MS-ESI：432.1(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₃ H ₂₂ O ₄ N ₅ (M+H) ⁺ ：432.1666，Found：432.1662.

RIP1-062：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.87(s，1H)，7.79(s，1H)，7.37-7.27(m，4H)，7.24-7.20(m，3H)，7.17(d，J＝6.8，1H)，5.27(s，2H)，5.00-4.94(m，1H)，4.66(dd，J＝9.6，7.6，1H)，4.21(t，J＝10.5，1H)，3.40(s，3H)，2.57(s，3H)；MS-ESI：431.4(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₃ H ₂₃ O ₃ N ₆ (M+H) ⁺ ：431.1826，Found：431.1827.

RIP1-063：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.09(d，J＝7.3，1H)，7.91(s，1H)，7.36-7.31(m，3H)，7.29(s，1H)，7.25-7.20(m，3H)，5.51(d，J＝3.9，2H)，5.03-4.97(m，1H)，4.62(dd，J＝9.3，7.8，1H)，4.24(t，J＝0.5，1H)，3.39(s，3H)，2.56(s，3H)；MS-ESI：432.3(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₂ H ₂₂ O ₃ N ₇ (M+H) ⁺ ：432.1779，Found：432.1778.

RIP1-064：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.10(s，1H)，7.74(d，J＝7.0，1H)，7.37(s，1H)，7.30(s，1H)，7.26-7.18(m，5H)，5.80(s，2H)，5.05-4.97(m，1H)，4.65-4.53(m，1H)，4.20(t，J＝10.4，1H)，3.44(s，3H)，2.62(s，3H)；MS-ESI：432.4(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₂ H ₂₂ O ₃ N ₇ (M+H) ⁺ ：432.1779，Found：432.1779.

RIP1-065：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.04(s，1H)，7.94(d，J＝7.3，1H)，7.35-7.26(m，6H)，7.24(s，1H)，5.00-4.94(m，1H)，4.64(dd，J＝9.6，7.6，1H)，4.24(t，J＝10.5，1H)，4.11(s，2H)，3.41(s，3H)，2.58(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ168.70，163.42，160.70，153.52，146.05，141.68，136.01，135.52，134.61，131.65，128.96，128.92，128.67，127.51，109.29，107.33，77.16，49.14，36.31，34.60，14.95；MS-ESI：432.3(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₃ H ₂₂ O ₄ N ₅ (M+H) ⁺ ：432.1666，Found：432.1668.

RIP1-066：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.68-7.62(m，2H)，7.48(d，J＝6.5，1H)，7.39-7.27(m，4H)，7.24(d，J＝6.5，2H)，7.18(t，J＝7.3，1H)，7.15(d，J＝7.6，2H)，5.07-4.96(m，1H)，4.77(dd，J＝9.5，7.6，1H)，4.25(t，J＝10.4，1H)，4.00(s，2H)，3.44(s，3H)，2.55(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ169.13，167.46，153.51，146.01，142.09，140.34，133.42，132.99，131.31，129.02，128.96，128.72，127.82，126.49，125.02，109.75，109.71，106.91，106.87，77.41，50.00，41.83，36.38，14.96；MS-ESI：431.3(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₆ H ₂₅ O ₃ N ₄ (M+H) ⁺ ：431.1921，Found：432.1922.

RIP1-067：

¹ H NMR(500MHz，CD ₃ OD)δ＝7.76(s，1H)，7.63(s，1H)，7.51(s，1H)，7.36-7.27(m，4H)，7.24(d，J＝7.7，2H)，5.21(s，2H)，5.00-4.94(m，1H)，4.53(dd，J＝9.7，7.8，1H)，4.29(t，J＝10.6，1H)，3.43(s，3H)，2.58(s，3H)； ¹³ C NMR(125MHz，CD ₃ OD)δ171.00，164.12，155.23，147.60，139.43，137.54，136.79，133.32，130.05，129.42，128.86，124.35，110.26，110.25，108.27，108.24，78.21，52.01，50.22，36.48，14.35；MS-ESI：431.4(M+H) ⁺ ；HRMS(ESI)Calcd.forC ₂₃ H ₂₃ O ₃ N ₆ (M+H) ⁺ ：431.1826，Found：431.1829.

RIP1-068：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.18(d，J＝6.8，1H)，8.10(s，1H)，7.38-7.32(m，4H)，7.26-7.22(m，3H)，5.36(s，2H)，5.03-4.97(m，1H)，4.77(dd，J＝9.2，7.9，1H)，4.25(t，J＝10.4，1H)，3.42(s，3H)，2.56(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ168.59，159.01，156.58，153.60，145.85，144.35，133.69，131.17，129.35，129.17，128.33，109.89，109.84，107.10，107.05，77.36，54.54，49.69，36.35，14.92；MS-ESI：432.4(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₂ H ₂₂ O ₃ N ₇ (M+H) ⁺ ：432.1779，Found：432.1777.

RIP1-069：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.65(s，1H)，7.56(s，1H)，7.30-7.26(m，2H)，7.26-7.19(m，4H)，7.07(d，J＝1.3，1H)，7.06(s，1H)，5.44(s，2H)，4.98-4.91(m，1H)，4.60(dd，J＝9.7，7.6，1H)，4.23-4.09(m，1H)，3.41(s，3H)，2.57(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ169.19，159.69，153.28，146.06，141.71，136.46，132.94，131.44，128.97，128.16，127.25，125.03，109.68，109.66，107.23，107.22，77.36，50.14，49.18，36.39，15.06；MS-ESI：431.4(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₃ H ₂₃ O ₆ N ₃ (M+H) ⁺ ：431.1826，Found：431.1829.

RIP1-070：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.11(d，J＝6.9，1H)，7.41(s，1H)，7.34-7.26(m，6H)，4.99-4.93(m，1H)，4.68(dd，J＝9.6，7.8，1H)，4.26-4.20(m，4H)，3.43(s，3H)，2.61(s，3H)；MS-ESI：433.4(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₂ H ₂₁ O ₄ N ₆ (M+H) ⁺ ：433.1619，Found：433.1613.

RIP1-071：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.16(d，J＝6.7，1H)，7.40(s，1H)，7.39-7.33(m，5H)，7.29(s，1H)，5.80(s，2H)，5.06-5.00(m，1H)，4.77(dd，J＝9.6，7.7，1H)，4.25(t，J＝10.4，1H)，3.44(s，3H)，2.60(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ168.24，159.37，156.51，153.65，146.04，132.32，131.31，129.55，129.32，128.76，110.18，110.14，107.06，107.01，77.04，57.75，49.82，36.42，14.96；MS-ESI：433.3(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₁ H ₂₁ O ₃ N ₈ (M+H) ⁺ ：433.1731，Found：433.1733.

RIP1-072：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.86(d，J＝7.1，1H)，7.28(s，1H)，7.24(s，1H)，7.08(d，J＝7.8，2H)，6.98(d，J＝7.7，2H)，6.45(s，1H)，5.02-4.93(m，1H)，4.68(t，J＝8.6，1H)，4.24(t，J＝10.4，1H)，3.91(s，2H)，3.72(s，3H)，3.40(s，3H)，2.57(s，3H)，2.30(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ168.97，162.35，153.60，145.99，143.87，143.82，136.74，133.46，131.58，129.62，128.35，109.21，109.16，107.33，107.25，106.77，77.36，49.22，37.21，36.26，31.58，21.10，14.93；MS-ESI：459.4(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₅ H ₂₇ O ₃ N ₆ (M+H) ⁺ ：459.2139，Found：59.2141.

RIP1-073：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.37(s，1H)，7.26(s，1H)，7.13-7.08(m，5H)，6.36(s，1H)，4.96-4.89(m，1H)，4.64(dd，J＝9.6，7.6，1H)，4.16(t，J＝10.5，1H)，4.01(s，3H)，3.89(s，2H)，3.42(s，3H)，2.61(s，3H)，2.31(s，3H)； ¹³ C NMR(126MHz，CDCl ₃ )δ168.86，159.53，153.46，151.15，146.25，136.27，136.10，134.95，131.73，129.43，128.71，107.19，107.17，107.13，107.13，106.33，77.29，49.32，39.10，36.34，34.14，21.14，15.01；MS-ESI：459.4(M+H) ⁺ ；HRMS(ESI)Calcd.for C ₂₅ H ₂₇ O ₃ N ₆ (M+H) ⁺ ：459.2139，Found：459.2140.

RIP 1-074：

¹ H NMR(500MHz，CD ₃ OD)δ＝8.18(s，1H)，7.98(s，1H)，7.40-7.33(m，3H)，7.31-7.28(m，2H)，7.11(s，1H)，6.93(s，1H)，5.38(s，2H)，5.08-5.03(m，1H)，4.48(dd，J＝9.8，7.8，1H)，4.41(dd，J＝11.5，9.9，1H)，3.41(s，3H)；ESI-MSm/z 433.0(M+H) ⁺ .

RIP 1-075：

¹ H NMR(500MHz，CD ₃ OD)δ＝7.46-7.43(m，1H)，7.43-7.38(m，2H)，7.11(s，1H)，6.95(s，1H)，5.96(s，1H)，5.38-5.35(m，1H)，5.07(dd，J＝11.4，7.7，1H)，4.46(dd，J＝11.3，10.0，1H)，3.42(s，2H)；ESI-MS m/z 435.3(M+H) ⁺ .

RIP 1-076：

¹ H NMR(500MHz，CD ₃ OD)δ＝7.35-7.28(m，5H)，7.10(s，1H)，6.95(s，1H)，5.03(dd，J＝11.2，7.5，1H)，4.37(dd，J＝11.1，10.1，1H)，4.18(s，2H)，4.09-4.03(m，1H)，3.42(s，3H)；ESI-MS m/z 434.4(M+H) ⁺ .

RIP1-077：

¹ H NMR(400MHz，CDCl ₃ )δ＝7.86(d，J＝8.3，1H)，7.67(s，1H)，7.51-7.41(m，1H)，7.33-7.25(m，3H)，7.21(d，J＝7.0，2H)，6.27(s，1H)，5.02-4.86(m，1H)，4.73(dd，J＝11.6，5.7，1H)，4.27(t，J＝10.5，1H)，4.09(s，2H)，3.47(s，3H).HRMS(ESI)Calcd.for C ₂₃ H ₁₈ F ₃ N ₅ O ₄ (M+H) ⁺ ：486.1389，Found：486.1392.

RIP1-078：

¹ H NMR(500MHz，CDCl ₃ )δ＝12.22(s，1H)，8.23(s，2H)，7.90(s，1H)，7.65(s，1H)，7.40-7.34(m，4H)，7.27(d，J＝3.3，2H)，5.54(s，2H)，5.06-4.98(m，1H)，4.33(t，J＝10.5，1H)，3.67-3.33(m，4H)；HRMS(ESI)Calcd.for C ₂₂ H ₁₈ F ₃ N ₇ O ₃ Na(M+Na) ⁺ ：508.1321，Found：508.1315.

RIP1-079：

¹ H NMR(500MHz，CDCl ₃ )δ12.15(s，1H)，8.13(d，J＝6.5Hz，1H)，8.05(s，1H)，7.70(s，1H)，7.35(d，J＝7.2Hz，2H)，7.33-7.30(m，4H)，5.04-4.97(m，1H)，4.85-4.80(m，1H)，4.36(t，J＝10.4Hz，1H)，4.14(s，3H)，3.54(s，2H)；HRMS(ESI)Calcd.for C ₂₃ H ₁₈ F ₃ N ₅ O ₄ (M+H) ⁺ ：486.1389，Found：486.1390.

RIP1-080：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.84(d，J＝7.3，1H)，7.64(s，1H)，7.52(s，1H)，7.35-7.27(m，3H)，7.21(d，J＝7.5，2H)，7.15(d，J＝2.7，1H)，6.48(d，J＝2.9，1H)，6.26(s，1H)，4.77-4.70(m，1H)，4.08(s，2H)，3.86-3.77(m，4H)，3.47(s，3H)，2.84(t，J＝11.1，1H)； ¹³ CNMR(125MHz，CDCl ₃ )δ173.97，170.04，158.30，158.11，137.68，135.62，135.39，131.53，129.94，129.01，128.88，127.45，119.51，117.06，116.39，101.69，101.55，49.82，38.31，37.30，33.29，29.45；MS-ESI：447.3(M+H) ⁺ .

RIP1-081：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.12(d，J＝7.2，1H)，7.65(s，1H)，7.53(s，1H)，7.34-7.27(m，5H)，7.16(d，J＝3.0，1H)，6.49(d，J＝3.1，1H)，4.74-4.68(m，1H)，4.23(s，2H)，3.86-3.81(m，4H)，3.48(s，3H)，2.85(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ169.44，167.63，158.80，152.21，137.46，135.66，133.05，131.67，130.02，129.14，129.00，127.92，119.28，117.11，116.47，101.61，50.24，38.13，37.39，33.32，31.96；；MS-ESI：448.4(M+H) ⁺ .

RIP1-082：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.82(s，1H)，7.77(s，1H)，7.64(s，1H)，7.52(s，1H)，7.36-7.29(m，3H)，7.21(d，J＝7.3，2H)，7.14(d，J＝2.4，1H)，7.07(d，J＝7.2，1H)，6.47(d，J＝3.0，1H)，5.25(s，2H)，4.78-4.72(m，1H)，3.85-3.80(m，4H)，3.46(s，3H)，2.79(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ171.11，161.37，138.86，137.65，135.64，135.46，131.49，130.83，129.90，129.09，128.57，128.10，119.60，118.55，117.04，116.38，101.54，56.57，49.73，38.66，37.31，33.27；MS-ESI：446.4(M+H) ⁺ .

RIP1-083：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.83(s，1H)，7.78(s，1H)，7.61(s，1H)，7.54(s，1H)，7.37-7.28(m，7H)，7.22(d，J＝1.5，1H)，7.21(d，J＝3.1，2H)，7.16(d，J＝0.7，1H)，7.15(s，1H)，6.54(d，J＝3.1，1H)，5.32(s，2H)，5.25(s，2H)，4.82-4.75(m，1H)，3.78(dd，J＝11.2，6.9，1H)，3.45(s，3H)，2.78(t，J＝11.2，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ171.18，161.43，138.92，137.87，136.76，135.45，135.23，130.86，130.83，130.12，129.09，129.07，129.04，128.54，128.09，126.97，119.92，118.49，117.19，116.52，102.27，56.53，50.44，49.70，38.59，37.36，1.14；MS-ESI：522.4(M+H) ⁺ .

RIP1-084：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.15(d，J＝7.9，1H)，7.88(s，1H)，7.61(s，1H)，7.53(s，1H)，7.36-7.33(m，5H)，7.26-7.22(m，3H)，7.20(d，J＝3.0，1H)，7.15(d，J＝7.3，2H)，6.53(d，J＝3.1，1H)，5.51(d，J＝6.4，2H)，5.32(s，2H)，4.83-4.76(m，1H)，3.78(dd，J＝11.2，6.8，1H)，3.47(s，3H)，2.85(t，J＝11.2，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.31，159.09，143.19，138.04，136.77，135.15，133.95，130.82，130.10，129.32，129.10，129.06，128.26，128.06，126.96，125.43，119.94，117.17，116.48，102.23，54.53，50.42，49.49，38.45，37.32；；MS-ESI：523.4(M+H) ⁺ .

RIP1-085：

¹ H NMR(500MHz，CDCl ₃ )δ＝7.85(d，J＝7.7，1H)，7.61(s，1H)，7.54(d，J＝1.1，1H)，7.37-7.30(m，6H)，7.23-7.20(m，3H)，7.16(d，J＝7.6，2H)，6.55(s，1H)，6.27(s，1H)，5.33(s，2H)，4.79-4.73(m，1H)，4.08(s，2H)，3.79(dd，J＝11.3，6.5，1H)，3.47(s，3H)，2.81(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ173.96，170.04，158.28，158.11，137.89，136.75，135.36，135.20，130.91，130.15，129.10，128.99，128.86，128.10，127.43，126.98，119.82，117.20，116.54，102.27，101.67，50.45，49.79，38.26，37.34，33.26；；MS-ESI：523.4(M+H) ⁺ .

RIP1-086：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.18(d，J＝7.6，1H)，8.01(s，1H)，7.62(s，1H)，7.53(s，1H)，7.37-7.33(m，5H)，7.30(d，J＝7.0，1H)，7.26(t，J＝3.7，2H)，7.21(d，J＝3.1，1H)，7.17(d，J＝7.4，2H)，6.54(d，J＝3.1，1H)，5.35(s，2H)，5.33(s，2H)，4.86-4.80(m，1H)，3.87(dd，J＝11.1，7.0，1H)，3.47(s，3H)，2.81(t，J＝11.1，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.34，157.91，156.99，144.00，137.84，136.77，135.22，133.92，130.85，130.11，129.25，129.08，129.00，128.31，128.07，127.00，119.84，117.19，116.62，102.23，54.37，50.43，49.74，38.48，37.36；MS-ESI：523.5(M+H) ⁺ .

RIP1-087：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.00(s，1H)，7.95(d，J＝7.7，1H)，7.62(s，1H)，7.54(s，1H)，7.36-7.33(m，4H)，7.32(s，1H)，7.30-7.28(m，3H)，7.21(d，J＝3.1，1H)，7.16(d，J＝7.2，2H)，6.54(d，J＝3.1，1H)，5.33(s，2H)，4.81-4.75(m，1H)，4.10(s，2H)，3.79(dd，J＝11.0，6.9，1H)，3.48(s，3H)，2.83(t，J＝11.1，1H)； ¹³ C NMR(126MHz，CDC1 ₃ )δ170.45，163.02，159.69，141.37，138.01，136.78，135.99，135.20，134.80，130.84，130.13，129.10，128.91，128.09，127.90，127.41，126.97，119.94，117.18，116.53，102.26，50.45，49.41，38.50，37.29，34.61；MS-ESI：523.4(M+H) ⁺ .

RIP1-088：

¹ H NMR(500MHz，CDCl ₃ )δ＝8.04(d，J＝7.9，1H)，7.60(s，1H)，7.52(s，1H)，7.47(s，1H)，7.44(s，1H)，7.36-7.31(m，6H)，7.19(d，J＝2.2，1H)，7.15(d，J＝7.8，2H)，7.13(d，J＝7.0，2H)，6.53(d，J＝2.9，1H)，5.32(s，2H)，5.07(s，2H)，4.83-4.77(m，1H)，3.76(dd，J＝11.0，6.8，1H)，3.45(s，3H)，2.84(t，J＝11.2，1H)； ¹³ C NMR(125MHz，CDCl ₃ )δ170.77，161.52，138.16，137.13，137.02，136.80，135.23，135.12，130.71，130.05，129.20，129.04，128.66，128.02，127.56，126.95，122.43，120.07，117.13，116.45，102.20，51.38，50.39，49.29，38.59，37.25；；MS-ESI：522.3(M+H) ⁺ .

RIP1-089

¹ H NMR(400MHz，CD ₃ OD_SPE)δ8.30(s，1H)，8.00(d，J＝18.6Hz，1H)，7.75(s，1H)，7.26(dd，J＝18.8，6.7Hz，5H)，6.33(s，1H)，4.66(dd，J＝11.7，7.0Hz，1H)，4.11(s，2H)，3.69-3.51(m，1H)，3.43(s，3H)，3.30(dt，J＝3.3，1.6Hz，2H)，3.05(t，J＝11.5Hz，1H). ¹³ C NMR(101 MHz，CD ₃ OD_SPE)δ174.48(s)，170.74(s)，159.07(s)，157.90(s)，143.94(s)，141.00(s)，135.77(s)，128.47(s)，128.45(s)，126.85(s)，121.08(s)，49.89(s)，36.95(s)，36.10(s)，32.22(s).ESI：m/z 434.1(M+H) ^+· RIP1-090

¹ H NMR(400MHz，CD ₃ OD_SPE)δ8.30(s，1H)，7.94(s，1H)，7.74(s，1H)，7.25(dd，J＝14.0，6.9Hz，5H)，4.70(dd，J＝11.6，6.9Hz，1H)，4.12(s，2H)，3.66(dt，J＝16.1，8.1Hz，1H)，3.44(s，3H)，3.05-2.96(m，1H).ESI：m/z 434.1(M+H) ⁺ .RIP1-091

¹ H NMR(400MHz，CDCl ₃ )δ8.14(s，1H)，7.98(d，J＝2.0Hz，1H)，7.95(s，1H)，7.62(s，1H)，7.32(dt，J＝28.9，5.7Hz，5H)，5.54(s，2H)，4.81-4.71(m，1H)，3.76(dd，J＝10.9，7.1Hz，1H)，3.48(s，3H)，2.93(t，J＝11.3Hz，1H). ¹³ C NMR(101 MHz，CDCl ₃ )δ170.35(s)，159.33(s)，159.26(s)，143.32(s)，142.62(s)，142.59(s)，140.73(s)，139.38(s)，136.30(s)，133.76(s)，129.19(s)，129.01(s)，128.12(s)，125.65(s)，121.87(s)，121.19(s)，112.26(s)，63.44(s)，54.43(s)，38.09(s)，37.12(s).ESI：m/z 434.1(M+H) ⁺ .RIP1-092

¹ H NMR(400MHz，CDCl ₃ )δ8.96(dd，J＝4.2，1.5Hz，1H)，8.13(d，J＝8.4Hz，1H)，8.08(d，J＝8.8Hz，1H)，7.90(d，J＝8.8Hz，1H)，7.47(dd，J＝8.6，4.2Hz，1H)，7.24-7.15(m，5H)，4.77(dd，J＝10.5，7.4Hz，1H)，4.09(s，2H)，3.87(dd，J＝11.4，7.2Hz，1H)，3.46(s，2H)，3.38(s，3H)，3.03(t，J＝11.2Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ172.01，158.15，151.46，149.38，141.76，135.89，135.02，131.82，130.26，128.87，128.80，127.13，127.06，124.16，122.32，60.46，50.79，49.72，39.25，36.93，33.20.MS(ESI)：m/z 445.1(M+H) ⁺ .

RIP1-093

¹ H NMR(400MHz，CDCl ₃ )δ9.00(dd，J＝4.2，1.6Hz，1H)，8.19-8.13(m，2H)，8.10(dd，J＝8.8，0.5Hz，1H)，8.03(s，1H)，7.93(d，J＝8.7Hz，1H)，7.51(dd，J＝8.6，4.2Hz，1H)，7.39-7.34(m，3H)，7.29-7.25(m，2H)，5.37(s，2H)，4.84(dt，J＝10.7，7.4Hz，1H)，4.01(dd，J＝11.4，7.2Hz，1H)，3.42(s，3H)，3.03(t，J＝11.1Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ171.94，158.02，156.69，151.46，149.52，143.95，141.71，135.07，133.77，131.71，130.33，129.20，128.98，128.24，127.10，124.19，122.23，54.34，49.68，39.52，36.90.MS(ESI)：m/z 445.1(M+H) ⁺ .

RIP1-094

¹ H NMR(400MHz，CDCl ₃ )δ8.96(dd，J＝4.1，1.5Hz，1H)，8.15(d，J＝8.5Hz，1H)，8.05(d，J＝8.8Hz，1H)，7.99(d，J＝7.9Hz，1H)，7.90(d，J＝8.7Hz，1H)，7.51-7.41(m，3H)，7.36-7.28(m，3H)，7.15-7.09(m，2H)，5.07(s，2H)，4.77(dt，J＝10.9，7.5Hz，1H)，3.87(dd，J＝11.3，7.1Hz，1H)，3.38(s，3H)，3.04(t，J＝11.1Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ172.38，161.63，151.35，149.45，142.03，137.07，136.74，135.08，135.07，131.86，130.06，129.16，128.66，127.50，127.19，124.23，122.54，122.20，51.35，49.27，39.62，36.80.MS(ESI)：m/z 444.1(M+H) ⁺ .

RIP1-095

¹ H NMR(400MHz，CDCl ₃ )δ8.99(dd，J＝4.2，1.6Hz，1H)，8.18(dd，J＝8.5，0.6Hz，1H)，8.13-8.05(m，2H)，7.93(d，J＝8.7Hz，1H)，7.87(s，1H)，7.51(dd，J＝8.6，4.2Hz，1H)，7.38-7.34(m，3H)，7.27-7.22(m，2H)，5.53(d，J＝1.3Hz，2H)，4.79(dt，J＝10.9，7.4Hz，1H)，3.42(s，3H)，3.07(t，J＝11.1Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ171.86，159.14，151.44，149.50，142.86，141.91，135.03，133.75，131.77，130.22，129.28，129.11，128.22，127.10，125.42，124.21，122.25，54.52，49.45，39.45，36.86.MS(ESI)：m/z 445.1(M+H) ⁺ .

RIP1-096

¹ H NMR(400MHz，CDCl ₃ )δ9.00(dd，J＝4.1，1.5Hz，1H)，8.17(d，J＝8.1Hz，1H)，8.10(d，J＝8.8Hz，1H)，7.93(d，J＝8.7Hz，1H)，7.81(d，J＝7.4Hz，1H)，7.52(dd，J＝8.6，4.2Hz，1H)，7.35-7.18(m，5H)，6.26(s，1H)，4.75(dt，J＝10.7，7.3Hz，1H)，4.09(s，2H)，3.93(dd，J＝11.3，7.1Hz，1H)，3.42(s，3H)，3.03(t，J＝11.1Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ174.10，171.58，158.19，157.97，151.51，149.51，141.74，135.18，135.01，131.70，130.36，128.93，128.75，127.39，127.03，124.18，122.30，101.58，49.72，39.27，36.88，33.18.MS(ESI)：m/z 445.1(M+H) ⁺ .

RIP1-097

¹ H NMR(400MHz，MeOD)δ8.80(d，J＝3.5Hz，1H)，8.30(d，J＝8.3Hz，1H)，7.97(d，J＝9.0Hz，1H)，7.61-7.51(m，2H)，7.25-7.07(m，5H)，4.95(d，J＝7.7Hz，1H)，4.63-4.52(m，1H)，4.45(t，J＝9.9Hz，1H)，4.14-3.97(m，2H)，3.32(s，3H). ¹³ CNMR(100MHz，MeOD)δ171.13，149.77，149.28，145.94，132.31，130.26，129.57，128.49，128.36，126.82，125.23，124.19，121.90，77.28，49.09，36.43.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-098

¹ H NMR(400MHz，CDCl ₃ )δ8.96(dd，J＝4.2，1.6Hz，1H)，8.17-8.06(m，3H)，8.02(s，1H)，7.59(d，J＝9.0Hz，1H)，7.50(dd，J＝8.6，4.2Hz，1H)，7.41-7.36(m，3H)，7.29(dd，J＝7.1，2.4Hz，2H)，5.38(s，2H)，5.17(dt，J＝10.9，7.5Hz，1H)，4.85(dd，J＝9.9，7.6Hz，1H)，4.41-4.34(m，1H)，3.47(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ170.89，158.47，156.57，150.04，149.22，146.78，143.98，133.72，131.10，131.08，129.57，129.22，129.01，128.27，125.30，124.07，121.71，78.16，54.39，48.95，37.41.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-099

¹ H NMR(400MHz，CDCl ₃ )δ8.94(dd，J＝4.1，1.5Hz，1H)，8.12(dd，J＝20.9，8.5Hz，2H)，7.94(d，J＝7.5Hz，1H)，7.58(d，J＝9.0Hz，1H)，7.52-7.44(m，3H)，7.39-7.32(m，3H)，7.15(dd，J＝7.3，1.9Hz，2H)，5.16-5.06(m，3H)，4.76(dd，J＝9.9，7.6Hz，1H)，4.44-4.34(m，1H)，3.46(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ171.28，162.04，149.96，149.25，146.77，137.07，135.05，131.19，130.96，130.87，130.27，129.88，129.19，128.70，127.52，126.58，125.30，124.43，124.15，123.92，122.51，121.61，78.41，51.39，48.52，37.33.MS(ESI)：m/z 428.1(M+H) ⁺ .

RIP1-100

¹ H NMR(400MHz，CDCl ₃ )δ8.95(dd，J＝4.2，1.6Hz，1H)，8.19-8.13(m，1H)，8.11(d，J＝9.1Hz，1H)，8.05(d，J＝7.4Hz，1H)，7.89(s，1H)，7.58(d，J＝9.1Hz，1H)，7.49(dd，J＝8.6，4.2Hz，1H)，7.40-7.34(m，3H)，7.29-7.24(m，3H)，5.54(d，J＝4.1Hz，2H)，5.11(dt，J＝10.9，7.5Hz，1H)，4.78(dd，J＝9.9，7.6Hz，1H)，4.40(dd，J＝10.8，10.1Hz，1H)，3.47(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ170.80，159.56，150.04，149.20，146.78，142.75，133.71，131.14，131.00，129.74，129.31，129.14，128.26，125.45，125.24，124.10，121.70，78.13，54.55，48.74，37.40.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-101

¹ H NMR(400MHz，CDCl ₃ )δ8.96(dd，J＝4.2，1.6Hz，1H)，8.15(d，J＝7.9Hz，1H)，8.12(d，J＝9.4Hz，1H)，7.75(d，J＝7.1Hz，1H)，7.59(d，J＝9.1Hz，1H)，7.50(dd，J＝8.6，4.2Hz，1H)，7.36-7.27(m，3H)，7.25-7.20(m，2H)，6.28(s，1H)，5.07(dt，J＝10.9，7.4Hz，1H)，4.79(dd，J＝9.9，7.6Hz，1H)，4.45-4.32(m，1H)，4.10(s，2H)，3.47(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ174.17，170.51，158.63，157.86，150.10，149.17，146.79，135.16，131.14，131.06，129.57，128.94，128.77，127.40，125.19，124.05，121.75，101.59，49.03，37.41，33.20，29.33.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-102

¹ H NMR(400MHz，CDCl ₃ )δ9.30(s，1H)，8.59(d，J＝6.0Hz，1H)，8.22(d，J＝7.7Hz，1H)，7.94(d，J＝8.4Hz，1H)，7.83(d，J＝8.4Hz，1H)，7.59(d，J＝5.9Hz，1H)，7.25-7.18(m，5H)，4.77(dt，J＝10.8，7.5Hz，1H)，4.11(s，2H)，3.90(dd，J＝11.3，7.1Hz，1H)，3.40(s，3H)，3.07(t，J＝11.1Hz，1H). ¹³ C NMR(101 MHz，CDCl ₃ )δ171.58，153.09，144.48，140.90，135.87，133.17，131.66，131.47，129.76，128.89，128.83，128.29，127.17，116.00，100.00，77.25，49.55，39.17，36.59，33.25.MS(ESI)：m/z 445.0(M+H) ⁺ .

RIP1-103

¹ H NMR(400MHz，CDCl ₃ )δ9.34(s，1H)，8.64(d，J＝5.9Hz，1H)，8.18(d，J＝7.5Hz，1H)，8.04(s，1H)，7.97(d，J＝8.4Hz，1H)，7.85(d，J＝8.4Hz，1H)，7.60(d，J＝5.9Hz，1H)，7.41-7.33(m，3H)，7.27(d，J＝5.2Hz，2H)，5.37(s，2H)，4.91-4.78(m，1H)，4.02(dd，J＝11.3，7.1Hz，1H)，3.43(s，3H)，3.06(t，J＝11.1Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ171.60，158.03，156.64，153.19，144.62，143.97，140.85，133.73，133.21，131.64，131.47，129.79，129.21，129.00，128.24，128.23，115.91，54.36，49.55，39.37，36.56.MS(ESI)：m/z 445.0(M+H) ⁺ .

RIP1-104

¹ H NMR(400MHz，CDCl ₃ )δ9.33(s，1H)，8.62(d，J＝5.9Hz，1H)，8.02(d，J＝7.8Hz，1H)，7.94(d，J＝8.4Hz，1H)，7.84(d，J＝8.4Hz，1H)，7.61(d，J＝5.9Hz，1H)，7.46(d，J＝13.1Hz，2H)，7.39-7.30(m，3H)，7.18-7.09(m，2H)，5.09(s，2H)，4.79(dt，J＝10.9，7.4Hz，1H)，3.91(dd，J＝11.2，7.0Hz，1H)，3.41(s，3H)，3.09(t，J＝11.1Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ172.03，161.63，153.10，144.56，141.18，137.06，136.75，135.05，133.20，131.72，131.53，129.77，129.18，128.69，128.00，127.49，122.53，116.02，51.37，49.12，39.52，36.45.MS(ESI)：m/z 444.1(M+H) ⁺ .

RIP1-105

¹ H NMR(400MHz，CDCl ₃ )δ9.33(s，1H)，8.63(d，J＝6.0Hz，1H)，8.13(d，J＝7.7Hz，1H)，7.95(d，J＝8.4Hz，1H)，7.89-7.81(m，2H)，7.61(d，J＝6.0Hz，1H)，7.40-7.33(m，3H)，7.27-7.22(m，2H)，5.53(d，J＝1.8 Hz，2H)，4.79(dt，J＝10.9，7.3 Hz，1H)，3.92(dd，J＝11.3，7.0 Hz，1H)，3.43(s，3H)，3.10(t，J＝11.1 Hz，1H). ¹³ C NMR(100 MHz，CDCl ₃ )δ171.53，159.16，153.16，144.66，142.83，141.07，133.73，133.16，131.61，131.50，129.78，129.30，129.13，128.22，128.11，125.42，115.95，54.54，49.29，39.33，36.52.MS(ESI)：m/z 445.1(M+H) ⁺ .

RIP1-106

¹ H NMR(400 MHz，CDCl ₃ )δ9.34(s，1H)，8.65(d，J＝6.0 Hz，1H)，7.98-7.94(m，1H)，7.87-7.80(m，2H)，7.61(d，J＝6.0 Hz，1H)，7.35-7.27(m，3H)，7.24-7.19(m，2H)，6.26(s，1H)，4.75(dt，J＝10.9，7.3 Hz，1H)，4.09(s，2H)，3.94(dd，J＝11.3，7.1Hz，1H)，3.42(s，3H)，3.06(t，J＝11.1 Hz，1H). ¹³ C NMR(100 MHz，CDCl ₃ )δ174.13，171.24，158.20，157.94，153.21，144.73，140.90，135.17，133.13，131.53，131.45，129.78，128.93，128.76，128.23，127.40，115.88，101.57，49.56，39.14，36.54，33.18.MS(ESI)：m/z 445.0(M+H) ⁺ .

RIP1-107

¹ H NMR(400 MHz，CDCl ₃ )δ9.25(s，1H)，8.56(d，J＝6.0 Hz，1H)，8.11(d，J＝5.3Hz，1H)，7.96(d，J＝8.8 Hz，1H)，7.58(d，J＝6.0 Hz，1H)，7.43(d，J＝8.7 Hz，1H)，7.25-7.16(m，5H)，5.06(s，1H)，4.75(dd，J＝9.7，7.7 Hz，1H)，4.40(t，J＝10.5 Hz，1H)，4.12(s，2H)，3.45(s，3H). ¹³ C NMR(100 MHz，CDCl ₃ )δ170.42，158.63，152.90，152.36，143.92，135.85，132.00，129.55，129.07，128.89，128.83，127.20，127.18，123.58，115.79，77.93，48.81，37.08，33.24.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-108

¹ H NMR(400 MHz，CDCl ₃ )δ9.31(s，1H)，8.61(d，J＝6.0 Hz，1H)，8.10(d，J＝7.2Hz，1H)，8.03(s，1H)，8.00(d，J＝8.7 Hz，1H)，7.60(d，J＝6.0 Hz，1H)，7.48(d，J＝8.7Hz，1H)，7.43-7.34(m，3H)，7.32-7.27(m，2H)，5.38(s，2H)，5.14(dt，J＝10.9，7.4 Hz，1H)，4.86(dd，J＝9.9，7.5Hz，1H)，4.45-4.37(m，1H)，3.48(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ170.55，158.49，156.55，153.04，152.36，144.16，143.97，133.69，131.99，129.46，129.24，129.06，129.04，128.28，127.25，123.64，115.67，78.14，54.42，48.83，37.05.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-109

¹ H NMR(400 MHz，CDCl ₃ )δ9.22(s，1H)，8.52(d，J＝6.0 Hz，1H)，7.89(m，2H)，7.53(d，J＝5.9 Hz，1H)，7.40(dd，J＝9.4，6.4 Hz，3H)，7.28-7.22(m，J＝8.8 Hz，3H)，7.12-7.05(m，2H)，5.10-4.98(m，2H)，4.70(dd，J＝9.8，7.5 Hz，1H)，4.34(t，J＝10.5Hz，1H)，3.39(s，3H). ¹³ C NMR(100 MHz，CDCl ₃ )δ170.95，162.06，152.96，152.39，144.04，137.10，136.67，135.04，132.06，129.35，129.25，129.19，128.70，127.52，127.21，123.61，122.56，115.78，78.39，51.39，48.38，36.97.MS(ESI)：m/z 428.0(M+H) ⁺ .

RIP1-110

¹ H NMR(400 MHz，CDCl ₃ )δ9.29(s，1H)，8.60(d，J＝5.9 Hz，1H)，8.07(d，J＝7.1Hz，1H)，7.98(d，J＝8.7 Hz，1H)，7.89(s，1H)，7.61(d，J＝5.9Hz，1H)，7.47(d，J＝8.7Hz，1H)，7.42-7.33(m，3H)，7.29-7.22(m，2H)，5.65-5.46(m，2H)，5.10(dt，J＝10.9，7.4Hz，1H)，4.78(dd，J＝9.6，7.7Hz，1H)，4.43(t，J＝10.5Hz，1H)，3.48(s，3H). ¹³ CNMR(100MHz，CDCl ₃ )δ170.47，159.59，153.00，152.33，144.13，142.70，133.71，132.02，129.37，129.31，129.23，129.15，128.25，127.22，125.47，123.55，115.73，78.10，54.56，48.60，37.04.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-111

¹ H NMR(400MHz，CDCl ₃ )δ9.30(s，1H)，8.61(d，J＝6.0Hz，1H)，7.99(d，J＝8.7Hz，1H)，7.77(d，J＝7.0Hz，1H)，7.60(d，J＝6.0Hz，1H)，7.47(d，J＝8.7Hz，1H)，7.36-7.28(m，3H)，7.25-7.20(m，2H)，6.28(s，1H)，5.05(dt，J＝11.0，7.3Hz，1H)，4.80(dd，J＝9.9，7.4Hz，1H)，4.40(dd，J＝10.8，10.1Hz，1H)，4.10(s，2H)，3.48(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ174.21，170.18，158.65，157.82，153.04，152.30，144.20，135.15，131.97，129.50，129.07，128.95，128.78，127.41，127.23，123.51，115.67，101.57，77.88，48.89，37.05，33.20.MS(ESI)：m/z 429.1(M+H) ⁺ .

RIP1-112

¹ H NMR(400MHz，DMSO)δ11.10(s，1H)，8.29(s，1H)，7.43-7.01(m，9H)，6.27(s，1H)，4.79(d，J＝9.3Hz，1H)，4.49-4.16(m，2H)，4.05(s，2H)，3.44(s，3H).MS(ESI)：m/z 417.1(M+H) ⁺ .MS(ESI)：m/z 417.1(M+H) ⁺ .

RIP1-113

¹ H NMR(400MHz，CDCl ₃ )δ9.04(d，J＝91.0Hz，1H)，8.08(d，J＝17.6Hz，4H)，7.44-7.35(m，5H)，6.94(s，1H)，6.46(s，1H)，5.36(s，2H)，4.72(s，2H)，4.19(s，1H)，3.37(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ168.92，168.71，158.53，156.72，150.46，150.11，146.25，135.34，133.81，129.20，128.96，128.28，125.99，119.43，105.15，103.10，57.00，54.33，49.26，36.36.MS(ESI)：m/z 417.1(M+H) ⁺ .MS(ESI)：m/z 417.1(M+H) ⁺ .

RIP1-114

¹ H NMR(400MHz，CDCl ₃ )δ8.27(s，1H)，7.89(d，J＝7.2Hz，1H)，7.42-7.37(m，3H)，7.31-7.25(m，3H)，7.19-7.16(m，1H)，7.14(s，1H)，7.08(dd，J＝7.3，1.9Hz，2H)，6.47-6.44(m，1H)，5.02(s，2H)，4.99(dd，J＝7.5，3.6Hz，1H)，4.59(dd，J＝9.7，7.5Hz，1H)，4.15(dd，J＝11.0，9.8Hz，1H)，3.43(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ174.49，168.24，160.97，145.31，135.99，134.09，133.06，129.08，128.90，128.14，127.62，126.49，124.60，124.15，121.32，113.94，103.45，101.71，50.32，47.74，35.24，34.91.MS(ESI)：m/z 416.1(M+H) ⁺ .MS(ESI)：m/z 416.1(M+H) ⁺ .

RIP1-115

¹ H NMR(400MHz，CDCl ₃ )δ8.44(s，1H)，8.15-8.01(m，2H)，7.96-7.82(m，2H)，7.45-7.31(m，5H)，6.96(d，J＝6.5Hz，1H)，6.45(s，1H)，5.26(s，1H)，5.08(dd，J＝16.4，8.7Hz，2H)，4.65(s，2H)，3.37(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ168.88，159.57，150.15，146.56，142.94，135.17，133.78，129.29，129.10，128.25，125.36，119.51，118.72，104.95，102.90，99.99，57.17，54.51，49.02，36.52.MS(ESI)：m/z 417.1(M+H) ⁺ .MS(ESI)：m/z 417.1(M+H) ⁺ .

RIP1-116

¹ H NMR(400MHz，CDCl ₃ )δ8.37(s，1H)，7.77(d，J＝6.4Hz，2H)，7.38-7.29(m，5H)，6.96(d，J＝6.4Hz，1H)，6.46(d，J＝4.3Hz，1H)，6.31(d，J＝5.0Hz，1H)，6.28(d，J＝3.0Hz，1H)，5.13-4.97(m，2H)，4.31(t，J＝6.7Hz，1H)，4.09(s，2H)，3.38(s，3H). ¹³ CNMR(100MHz，CDCl ₃ )δ174.04，168.59，158.61，150.13，146.45，135.23，130.95，128.93，128.79，127.38，126.20，122.97，119.48，118.68，114.00，104.97，101.55，65.61，57.20，49.22，33.19.MS(ESI)：m/z 417.1(M+H) ⁺ .MS(ESI)：m/z 417.1(M+H) ⁺ .

example 2 Synthesis of Compounds RIP1-018

Compound RIP1-015 (13mg, 0.03mmol) was placed in a 25mL single vial, 5mL DCM, one drop of acetic anhydride, two drops of TEA were added, the reaction was carried out for 30min at room temperature, TLC was used to monitor the end of the reaction, the solvent was removed under reduced pressure, EA was extracted, washed with deionized water, saturated NaCl, na ₂ SO ₄ Drying, removing the solvent under reduced pressure, reverse phase column separation and freeze drying to obtain RIP1-018: white solid 10mg (70.7%).

RIP1-018： ¹ H NMR(400MHz，CDCl ₃ )δ8.87(s，1H)，8.17(s，1H)，7.86(d，J＝7.5Hz，1H)，7.70(s，1H)，7.38-7.29(m，3H)，7.27-7.23(m，2H)，6.32(s，1H)，4.82-4.72(m，1H)，4.12(s，2H)，3.86(dd，J＝11.1，6.8Hz，1H)，3.51(s，3H)，3.01-2.94(m，1H)，2.85(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ174.1，171.0，169.7，158.2，158.1，142.3，139.1，137.4，135.3，129.8，129.0，128.9，127.5，127.5，122.5，116.7，101.7，49.5，37.7，37.4，33.3，23.0.ESI-MS：m/z 476.1(M+H) ⁺

Example 3 Synthesis of Compound II-1

To a 500mL reaction flask was added 11.33g NaNO ₃ And 100mL H ₂ SO ₄ Stirring, and cooling to 0 ℃ under ice bath. 20.00g of Compound 1-1 was dissolved in 120mL of H ₂ SO ₄ In (1) mixing H of 1-1 ₂ SO ₄ The solution is slowly dripped into a reaction bottle, the temperature is kept at 0 ℃ for reaction for 1 hour after dripping, then the reaction solution is poured into 1L of ice water, the mixture is stirred for 0.5 hour and then filtered, and the filter cake is washed by water to be neutral. The filter cake was washed with 80mL of EtOH/H ₂ O (7: 3) is beaten for 0.5 hour, filtered and the filter cake is dried to obtain 18.83g of crude product of 2-1 with yield of 74 percent.

9.10g of 2-1, 13.24g of N-Boc-L-cysteine and 5.67g of NaHCO were added to the reaction flask in this order ₃ 200mL of EtOH was added, and the reaction was carried out at 70 ℃ for 8 hours. After the reaction was completed, the reaction mixture was cooled with stirring, a large amount of solid was precipitated, and 100mL of H was added ₂ O, continuing to stir for 0.5 hour to ensure that the product is fully separated out, filtering, and using 500mL of H for filter cakes ₂ And O is beaten for 0.5 hour, filtered, and a filter cake is dried to obtain 17.5g of a crude product of 3-1 with the yield of 95 percent. ¹ H NMR(500MHz，DMSO-d6)δ＝11.60(s，1H)，8.27(s，1H)，7.56(d，J＝8.4，1H)，6.96(s，1H)，4.34-4.28(m，1H)，3.70(s，3H)，3.58(dd，J＝13.0，3.8，1H)，3.31(dd，J＝12.8，10.8，1H)，1.37(s，9H)； ¹³ C NMR(125MHz，DMSO-d6)δ181.47，170.82，160.37，155.35，153.15，149.16，139.90，122.60，114.61，107.90，78.81，52.43，51.51，33.36，28.04；ESI-MS m/z 424.1(M-H) ^- Placing 10.00g3-1 into a 250mL reaction bottle, adding 80mL THF, stirring and dissolving, cooling to-10 deg.C, then slowly adding BH into the reaction solution ₃ 40mL of THF solution (1 mol/L), after adding, rising to room temperature for 2 hours reaction, transferring to 50 ℃ for reaction for 15min, cooling to 0 ℃, and slowly adding 10mL of H ₂ Quenching with O, stirring for 0.5 hr, rotary evaporating to remove most THF, dissolving the residue with ethyl acetate, extracting with water, collecting ethyl acetate layer, drying, rotary drying to obtain crude product, separating with silica gel column (eluent is ethyl acetate: petroleum ether = 1: 5) to obtain 6.6g 4-1,the yield thereof was found to be 71%. ¹ H NMR(500MHz，CD ₃ OD)δ＝8.40(s，1H)，7.59(s，1H)，7.43(d，J＝3.2，1H)，6.63(d，J＝3.1，1H)，4.39(dd，J＝8.3，5.0，1H)，3.68(s，3H)，3.49(dd，J＝13.8，5.0，1H)，3.26(dd，J＝13.8，8.5，1H)，1.39(s，9H)； ¹³ C NMR(125MHz，CD ₃ OD)δ172.95，157.70，143.95，140.05，129.85，127.13，125.92，120.12，113.10，104.46，80.86，61.53，52.89，28.61，14.46；ESI-MS m/z 394.1，433.4(M-H) ^- 3.00g of 4-1 was placed in a 100mL reaction flask, dissolved by adding 30mL THF, followed by 1.27g DIEA,2.07g Boc anhydride, with stirring, and heated to 50 ℃ for reaction overnight. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was spin-dried, extracted with ethyl acetate and water, and the ethyl acetate phase was collected, dried, spin-dried, and separated by silica gel column (eluent: ethyl acetate: petroleum ether = 1: 8) to obtain 5-1 g of compound (3.57 g), with a yield of 95%. ESI-MS M/z 496.3 (M + H) ⁺ .

3.50g of 5-1 was placed in a 100mL reaction flask, 20mL of THF was added to dissolve it, 0.89g of lithium hydroxide monohydrate was added ₂ And (3) stirring for 24 hours at normal temperature, adjusting the pH value to 4-5 by using 1mol/L HCl solution in an ice bath after the reaction is finished, removing most THF by rotary evaporation, extracting by using ethyl acetate and water, collecting an organic phase, drying, and performing rotary drying to obtain a crude product of 6-1.

And (3) taking the 6-1 crude product, adding 30mL of methanol for dissolving, pumping and exchanging argon for three times, adding 0.75g of Pd-C into the crude product under the argon atmosphere, introducing hydrogen under stirring, reacting for 24 hours at 25 ℃, filtering by using kieselguhr after the reaction is completed, removing palladium carbon, and spin-drying the filtrate to obtain the 7-1 crude product.

Taking the crude product of 7-1, adding 200mL of anhydrous THF for dissolving, adding 2.01g of DIEA, cooling to 0 ℃ under stirring, slowly adding 5.37g of HATU, raising the temperature to room temperature after the addition is finished, reacting overnight, and adding 10mL of H ₂ Stirring for 0.5h, removing most THF by rotary evaporation, adding ethyl acetate and water for extraction, collecting ethyl acetate layer, drying, rotary drying, and separating with silica gel column (eluent is petroleum ether: ethyl acetate = 6: 1) to obtain 1.85g of 8-1, and the total yield of three steps is 60%.

1.80g of 8-1 was placed in a 100mL reaction flask, and 15mL of DMF was added to dissolve1.76g of cesium carbonate was added, and the mixture was cooled to-5 ℃ with stirring, and then 0.68g of methyl iodide was slowly added thereto, and after completion of the addition, the mixture was warmed to room temperature and reacted at room temperature for 3 hours. After the reaction, 60mL of H was slowly added to the reaction solution ₂ O, with H ₂ A large amount of solid is separated out after the O is added, the mixture is continuously stirred for 0.5 hour after the O is added, the mixture is filtered, a filter cake is collected and dried to obtain 1.63g of II-1, and the yield is 88 percent. ¹ H NMR(500MHz，CDCl ₃ )δ＝8.42(s，1H)，8.31(s，1H)，7.64(d，J＝3.5，1H)，7.32(s，1H)，6.51(d，J＝3.6，1H)，5.65(d，J＝7.7，1H)，4.47-4.41(m，1H)，3.81(dd，J＝11.0，6.7，1H)，2.87(t，J＝11.4，1H)，1.69(s，9H)，1.38(s，9H)； ¹³ C NMR(125MHz，CDCl ₃ )δ172.51，154.70，149.32，134.71，133.57，132.01，128.14，122.58，122.02，116.02，106.92，80.16，50.40，39.06，38.74，28.39，28.26；ESI-MS m/z 448.2(M+H) ⁺ .

Example 4 Synthesis of Compound II-2

Placing 3g of 4-1 into a 100mL reaction bottle, adding 20mL of THF for dissolving, adding 0.96g of lithium hydroxide monohydrate ₂ And (3) stirring for 24 hours at normal temperature, adjusting the pH value to 4-5 by using 1mol/L HCl solution in an ice bath after the reaction is finished, removing most THF by rotary evaporation, extracting by using ethyl acetate and water, collecting an organic phase, drying, and performing rotary drying to obtain a crude product of 5-2. MS-ESI: for C ₁₆ H ₁₉ N ₃ O ₆ S(M)：381.1，Found.ESI-MS m/z 380.0433.4(M-H) ^- .

And (3) taking the crude product of 5-2, adding 30mL of methanol for dissolving, pumping and exchanging argon for three times, adding 0.81g of Pd-C into the crude product under the argon atmosphere, introducing hydrogen under stirring, reacting for 24 hours at 25 ℃, filtering by using kieselguhr after complete reaction, removing palladium carbon, and spin-drying the filtrate to obtain the crude product of 6-2. ESI-MS M/z 352.1 (M + H) ⁺ .

Taking the crude product of 6-2, adding 200mL anhydrous THF to dissolve, adding 2.15g DIEA, cooling to 0 deg.C under stirring, slowly adding 5.77g HATUAfter the addition, the reaction was warmed to room temperature overnight, and 10mL of H was added ₂ O stirring for 0.5 hours, rotary evaporating to remove most THF, adding ethyl acetate and water for extraction, collecting ethyl acetate layer, drying, rotary drying, and separating with silica gel column (eluent petroleum ether: ethyl acetate = 6: 1) to obtain 1.43g 7-2, with three-step total yield of 57%. ESI-MS M/z334.1 (M + H) ⁺ .

1.40g of 7-2 was placed in a 100mL reaction flask, and 15mL of DMF was added to dissolve it, 1.78g of cesium carbonate was added, and the mixture was cooled to-5 ℃ with stirring, and then 0.69g of methyl iodide was slowly added thereto, and after the completion of the addition, the mixture was warmed to room temperature, and reacted at room temperature for 3 hours. After the reaction, 60mL of H was slowly added to the reaction solution ₂ O, with H ₂ A large amount of solid is separated out when O is added, stirring is continued for 0.5h after the addition is finished, filtering is carried out, a filter cake is collected, and drying is carried out to obtain 1.25g of II-2, wherein the yield is 86%. ¹ H NMR(500MHz，CDCl ₃ )δ＝7.59(s，1H)，7.51(s，1H)，7.12(d，J＝2.9，1H)，6.46(d，J＝2.6，1H)，5.61(d，J＝7.6，1H)，4.41-4.32(m，1H)，3.79(s，3H)，3.68(dd，J＝11.0，6.7，1H)，3.45(s，3H)，2.75(t，J＝11.2，1H)，1.36(s，9H)； ¹³ C NMR(125MHz，CDCl ₃ )δ171.13，154.65，137.94，135.56，131.37，129.84，119.70，117.06，116.16，101.52，79.92，50.78，39.01，37.11，33.22，28.40；ESI-MS m/z 362.1(M+H) ⁺ .

Example 5 Synthesis of Compound II-3

NaNO ₃ (5100mg, 60mmol) was placed in a 500mL reaction flask, concentrated sulfuric acid 60mL was added dropwise thereto at 0 ℃, 6-fluoroindazole 1 (8167mg, 60mmol) was dissolved in 60mL concentrated sulfuric acid, and the resulting solution was slowly added dropwise to NaNO ₃ The reaction was carried out at 0 ℃ for 2.5 hours in the concentrated sulfuric acid solution of (3), and the completion of the reaction was monitored by TLC. Pouring the reaction solution into 500mL of ice-water mixture, filtering with filter paper, extracting the filtrate with EA, combining the organic phase and the solid phase obtained by filtering, and sequentially using saturated NaHCO ₃ Saturated NaCl wash, na ₂ SO ₄ Drying, concentrating, and separating by column chromatography(DCM) gave 2: light yellow solid 3300mg (30.3%).

Compound 2 (1449mg, 8mmol) was placed in a 250mL reaction flask and Boc was added thereto ₂ O (2095mg, 9.6 mmol), DMAP (195mg, 1.6 mmol), 100mL THF, reaction at room temperature for 2h, monitoring by TLC for completion of the reaction, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, and removing the solvent under reduced pressure to obtain the Boc protected intermediate. The intermediate was used in the next reaction without further purification and isolation. N-Boc-L-cysteine (2655mg, 12mmol), cs ₂ CO ₃ (7819mg, 24mmol) was placed in a 250mL reaction flask, 80mL of DMF was added at 0 deg.C and reacted for 15min, then a solution of Boc protected intermediate in DMF (20 mL) obtained in reaction a was slowly added dropwise, the reaction was allowed to proceed overnight at 0 deg.C, TLC was used to monitor the completion of the reaction, acidified with 0.2M HCl, EA was extracted, washed with deionized water, washed with saturated NaCl, washed with Na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 20: 1) separated 3: 2400mg (62.2%) of a pale yellow solid.

Placing compound 3 (2310mg, 4.8mmol) in a 250mL three-neck flask, pumping and replacing argon gas three times, adding Pd/C (4000mg, 10wt%) and MeOH (150 mL) under the argon atmosphere, pumping and replacing hydrogen three times, reacting at room temperature for 8h under the hydrogen atmosphere, monitoring the reaction by TLC, filtering by diatomite, removing the solvent under reduced pressure, redissolving by 40mL of DMF, adding HATU (1825mg, 4.8mmol), DIEA (1240mg, 9.6mmol), reacting at room temperature overnight, monitoring the reaction by TLC, extracting EA, washing by deionized water, washing by saturated NaCl, washing by Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, flash column chromatography (EA: PE = 1: 2) to give 4: yellowish solid 800mg (38%).

4 (434.5mg, 1mmol) was placed in a reaction flask, and Cs was added thereto ₂ CO ₃ (407.3mg, 1.25mmol) and 40mL of DMF were reacted at 0 ℃ for 10min, methyl iodide (177.4mg, 1.25mmol) was slowly added dropwise to the above solution, the reaction was carried out overnight at 0 ℃, TLC was used to monitor the completion of the reaction, EA was extracted, washed with deionized water, saturated NaCl, na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 2) to obtain II-3: pale yellow solid 417mg (93%)

II-3： ¹ H NMR(400MHz，CDCl ₃ )δ8.51(s，1H)，8.15(s，1H)，7.64(s，1H)，5.57(d，J＝7.9Hz，1H)，4.34(dt，J＝11.5，7.3Hz，1H)，3.69(dd，J＝11.0，6.6Hz，1H)，3.45(s，3H)，2.82(t，J＝11.3Hz，1H)，1.73(s，9H)，1.35(s，9H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.7，154.6，148.7，141.8，139.0，138.0，129.4，126.9，121.6，116.8，85.9，80.2，50.6，38.4，37.2，28.4，28.2.ESI-MS：m/z 471.1(M+H) ⁺

Tricyclic compound II-5,8 was obtained by the same synthetic method as in II-3 in this example using compound 8 as a starting material, and was synthesized as shown in example 7.

II-5

¹ H NMR(400MHz，CDCl ₃ )δ8.49(s，1H)，7.58(s，1H)，5.57(d，J＝7.9Hz，1H)，4.33(dt，J＝11.6，7.3Hz，1H)，3.68(dt，J＝14.1，7.1Hz，1H)，3.47(s，3H)，2.84(t，J＝11.3Hz，1H)，1.72(s，9H)，1.36(s，9H)； ¹³ C NMR(100MHz，CDCl ₃ )δ170.6，154.6，148.0，142.5，140.5，138.8，131.1，124.6，122.0，115.6，80.3，50.5，38.3，37.2，28.4，28.2.ESI-MS：m/z 505.1(M+Na) ⁺

Example 6 Synthesis of Compound II-4

NaNO ₃ (5100mg, 60mmol) was placed in a 500mL reaction flask, concentrated sulfuric acid 60mL was added dropwise thereto at 0 ℃, 6-fluoroindazole 1 (8167mg, 60mmol) was dissolved in 60mL concentrated sulfuric acid, and the resulting solution was slowly added dropwise to NaNO ₃ The reaction was carried out at 0 ℃ for 2.5 hours in the concentrated sulfuric acid solution of (3), and the completion of the reaction was monitored by TLC. Pouring the reaction solution into 500mL of ice-water mixture, filtering by using filter paper, extracting the filtrate by using EA, combining the organic phase and the solid phase obtained by filtering, and sequentially using saturated NaHCO ₃ Saturated NaCl wash, na ₂ SO ₄ Drying, concentration and column chromatography (DCM) gave 2: light yellow solid 3300mg (30.3%).

Compound 2 (1086.8mg, 6mmol) was placed in a 250mL reaction flask, to which Cs was added ₂ CO ₃ (2443mg, 7.5 mmol), to which 40mL of DMF was added at 0 ℃ and reacted for 15min, followed by slow dropwise addition of SEMCl (1.33mL, 7.5 mmol), transfer to room temperature reaction for 4h after completion of the dropwise addition, monitoring of the end of the reaction by TLC, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and column chromatography (EA: PE = 1: 8) to isolate 5: pale yellow solid 900mg (48.2%). ¹ H NMR(400MHz，CDCl ₃ )δ8.59(d，J＝6.9Hz，1H)，8.18(s，1H)，7.42(d，J＝10.7Hz，1H)，5.72(s，2H)，3.62-3.51(m，2H)，0.93-0.86(m，2H)，-0.06(s，9H)； ¹³ C NMR(100MHz，CDCl ₃ )δ154.8(d，J＝262.1Hz)，140.8(d，J＝11.5Hz)，134.0(d，J＝10.9Hz)，136.3，121.0，120.0，98.3(d，J＝26.1Hz)，78.5，67.2，17.8，-1.4.

N-Boc-L-serine (1026.1mg, 5 mmol), naH (400mg, 10mmol, 60wt%) were placed in a 250mL reaction flask, argon was exchanged three times, 50mL of DMF was added thereto at 0 ℃ and reacted for 15min, then a solution of 5 (778.5mg, 2.5 mmol) in DMF (10 mL) was slowly added dropwise, reacted overnight at 0 ℃, TLC was performed to monitor the substantial completion of the reaction, acidification with 0.2M HCl, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 20: 1) separation gave 6: 473mg (38.1%) of a pale yellow solid. ¹ H NMR(400MHz，CDCl ₃ )δ7.95(s，1H)，7.53(s，1H)，7.33(s，1H)，5.73-5.60(m，2H)，5.58-5.47(m，1H)，4.70-4.59(m，1H)，4.58-4.49(m，1H)，4.17-4.09(m，1H)，3.60-3.48(m，2H)，3.45(s，3H)，0.96-0.85(m，2H)，-0.08(s，9H)； ¹³ C NMR(100MHz，CDCl ₃ )δ169.4，155.1，150.0，138.2，134.0，132.2，121.9，115.3，103.1，80.3，78.0，66.6，49.9，36.4，28.3，17.7，-1.4.

Compound No. 6 (450mg, 0.9062mmol) was placed in a 100mL three-necked flask, argon was purged three times, pd/C (600mg, 10 wt%), meOH (30 mL) was added thereto under argon atmosphere, hydrogen was purged three times, the reaction was carried out at room temperature under hydrogen atmosphere for 4h, the completion of the reaction was monitored by TLC, and celite was suction-filteredAfter removing the solvent under reduced pressure and redissolving it in 20mL of DMF, HATU (380.2mg, 1mmol) and DIEA (234mg, 1.81mmol) were added to the above solution, the reaction was allowed to proceed overnight at room temperature, TLC was used to monitor the completion of the reaction, EA was extracted, washed with deionized water, saturated NaCl, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure and flash column chromatography (EA: PE = 1: 2) gave 7 as a brown solid (260mg, 64%).

Adding Cs to 7 ₂ CO ₃ (226.6mg, 0.6955 mmol) and 20mL of DMF at 0 deg.C for 10min, slowly dropwise adding methyl iodide (98.7mg, 0.6955 mmol) into the above solution, reacting at 0 deg.C overnight, monitoring by TLC to terminate the reaction, EA extracting, washing with deionized water, washing with saturated NaCl, and Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 2) to obtain II-4: 202mg (75.3%) of brown solid.

II-4： ¹ H NMR(400MHz，CDCl ₃ )δ7.95(s，1H)，7.53(s，1H)，7.33(s，1H)，5.72-5.62(m，2H)，5.54(d，J＝7.2Hz，1H)，4.65(dt，J＝11.2，7.3Hz，1H)，4.53(dd，J＝9.5，7.4Hz，1H)，4.18-4.08(m，1H)，3.57-3.49(m，2H)，3.45(s，3H)，1.36(s，9H)，0.95-0.86(m，2H)，-0.06(s，9H)； ¹³ C NMR(101 MHz，CDCl ₃ )δ169.4，155.1，150.0，138.2，133.96，132.2，121.9，115.3，103.1，80.3，78.0，66.6，49.9，36.4，28.3，17.7，-1.4.

Tricyclic compound II-6,8 was synthesized in the same manner as in example 2 to II-4 using compound 8 as a starting material in example 7.

II-6

¹ H NMR(400MHz，CDCl ₃ )δ7.48(s，1H)，7.32(s，1H)，5.65-5.58(m，2H)，5.50(d，J＝7.1Hz，1H)，4.65(dt，J＝11.3，7.2Hz，1H)，4.55(dd，J＝9.5，7.3Hz，1H)，4.21-4.12(m，1H)，3.62-3.54(m，2H)，3.49(s，3H)，1.38(s，9H)，0.97-0.88(m，2H)，-0.02(s，9H)； ¹³ C NMR(100MHz，CDCl ₃ )δ169.2，155.1，151.0，139.3，134.1，133.1，119.1，114.0，103.6，80.2，78.1，77.3，66.9，49.8，36.3，28.2，17.7，-1.4.

Example 7 Synthesis of Compound 8

Compound 2 (2000mg, 11mmol) was placed in a 250mL reaction flask, 50mL of EtOH and NaOCl (20mL, 55mmol) were added thereto, the reaction was carried out overnight at room temperature, TLC was used to monitor the completion of the reaction, 1N HCl was acidified, EA was extracted, deionized water was washed, saturated NaCl was washed, na was used as a solvent, and the mixture was purified by filtration, washed with water, and the mixture was concentrated with sodium chloride and dried with sodium sulfate ₂ SO ₄ Drying, removing the solvent under reduced pressure, and column chromatography (EA: PE = 1: 4) to isolate 8: light yellow solid 2000mg 84.3%).

8： ¹ H NMR(400MHz，CD ₃ OD_SPE)δ8.41(d，J＝6.9Hz，1H)，7.42(d，J＝11.1Hz，1H)； ¹³ C NMR(101 MHz，CD ₃ OD_SPE)δ156.2(d，J＝260.0Hz)，143.4(d，J＝12.2Hz)，137.7，135.2(d，J＝11.6Hz)，120.2，116.8，99.8(d，J＝26.4Hz).

Example 8 Synthesis of Compound II-7

NaNO ₃ (5100mg, 60mmol) was placed in a 500mL reaction flask, concentrated sulfuric acid 60mL was added dropwise thereto at 0 ℃, 4-fluoro-2-hydroxyacetophenone 9 (9248mg, 60mm0l) was dissolved in 60mL concentrated sulfuric acid, and the resulting solution was slowly added dropwise to NaNO ₃ The reaction was carried out at 0 ℃ for 2.5 hours in the concentrated sulfuric acid solution of (3), and the completion of the reaction was monitored by TLC. Pouring the reaction solution into 500mL of ice-water mixture, filtering with filter paper, extracting the filtrate with EA, combining the organic phase and the solid phase obtained by filtering, and sequentially using saturated NaHCO ₃ Saturated NaCl wash, na ₂ SO ₄ Drying, concentration and column chromatography (EA: PE = 1: 20) gave 10: pale yellow solid 4570mg (38.2%). ¹ H NMR(400MHz，CDCl ₃ )δ13.02(s，1H)，8.65(d，J＝8.3Hz，1H)，6.83(d，J＝12.2Hz，1H)，2.72(s，3H)； ¹³ C NMR(100MHz，CDCl ₃ )δ203.2，168.5(d，J＝14.5Hz)，161.9，159.2，130.6，116.0(d，J＝2.5Hz)，107.6(d，J＝23.0Hz)，26.9.

CuBr ₂ (1898mg, 8.5mmol) was placed in a 250mL reaction flask, 50mL of ethyl acetate was added, the mixture was heated to reflux, a solution of 10 (995.7mg, 5 mmol) in chloroform (50 mL) was added to the above reaction solution, and after completion of the reflux reaction for 24 hours, the reaction solution was discolored to produce a pale gray solid, TLC monitored for 10 major conversion, and after filtration with celite, the solvent was removed under reduced pressure, and column chromatography (EA: PE = 1: 20 to 1: 10) gave 11: brown solid 833mg (60%). ¹ H NMR(400MHz，CDCl ₃ )δ8.37(d，J＝7.3Hz，1H)，7.77(d，J＝2.3Hz，1H)，7.41(d，J＝10.6Hz，1H)，6.90(dd，J＝2.2，0.7Hz，1H)； ¹³ C NMR(100MHz，CDCl ₃ )δ156.8(d，J＝12.4Hz)，155.3，152.7，148.6(d，J＝3.7Hz)，123.6(d，J＝2.1Hz)，119.2(d，J＝1.8Hz)，107.3(d，J＝1.2Hz)，101.5(d，J＝25.8Hz).

Compound 11 (5004mg, 18mmol) was placed in a 500mL reaction flask, 180mL of THF was added thereto, followed by slow addition of DIEA (3mL, 18mmol), room temperature reaction was 45min, completion of the reaction was monitored by TLC, and NaBH was added to the solution ₄ (2723mg, 72mmol), reaction at room temperature for 8h, and reaction completion was monitored by TLC. The reaction was quenched by slow addition of methanol, solvent removed under reduced pressure and redissolved with 50mL MeOH, followed by addition of 25mL of 4N HCl and heating to 75 deg.C, and 3h after TLC monitoring the end of the reaction. EA extraction, deionized water washing, saturated NaCl washing, na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and column chromatography (EA: PE = 1: 10) to isolate 12: yellow solid: 1200mg (36.8%)

N-Boc-L-cysteine(2660mg，12mmol)，Cs ₂ CO ₃ (7819mg, 24mmol) was placed in a 250mL reaction flask, 40mL of DMF was added thereto at 0 ℃ and reacted for 15min, followed by slow dropwise addition of a solution of 12 (1086mg, 6mmol) in DMF (10 mL), reaction at 0 ℃ for 24h, TLC to monitor completion of the reaction, acidification of 0.2M HC1, EA extraction, washing with deionized water, washing with saturated NaC1, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 20: 1) isolated 13: pale yellow solid 2780mg (qunt.). ¹ H NMR(400MHz，CDCl ₃ )δ8.30(s，1H)，7.64(d，J＝2.0Hz，1H)，7.54(s，1H)，6.75(d，J＝1.9Hz，1H)，5.70(s，1H)，4.50(s，1H)，3.60-3.49(m，1H)，3.35(s，1H)，1.35(s，9H)； ¹³ C NMR(100MHz，CDCl ₃ )δ175.1，157.2，155.9，147.8，143.5，132.4，124.9，119.7，110.4，107.1，80.5，53.5，36.1，28.4.ESI-MS：m/z 383.1(M+H) ⁺

Compound 13 (956mg, 2.5mmol) was placed in a 100mL reaction flask, and Fe (698mg, 12.5mmol), NH was added thereto ₄ Cl (267mg, 5mmol) followed by 24mL EtOH,6mL H ₂ O, reaction at 50 ℃ for 4h, and monitoring the reaction by TLC. Filtering with diatomaceous earth, removing solvent under reduced pressure, redissolving with 60mL DMF, adding HATU (950mg, 2.5 mmol), DIE (0.83mL, 5 mmol), reacting at room temperature overnight, monitoring reaction completion by TLC, extracting with EA, washing with deionized water, washing with saturated NaCl, and Na ₂ SO ₄ Drying, removal of solvent under reduced pressure and flash column chromatography (EA: PE = 1: 3) gave 14 as a tan solid (500mg, 59.8%).

14 (1500mg, 4.5mmol) was placed in a reaction flask, and Cs was added thereto ₂ CO ₃ (17599mg, 5.4mmol) and 60mL DMF, reacting at 0 ℃ for 10min, slowly and dropwise adding methyl iodide (766.5mg, 5.4mmol) into the solution, reacting at 0 ℃ overnight, monitoring the reaction by TLC, extracting EA, washing by deionized water, washing by saturated NaC1, and carrying out Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 4) to obtain II-7: 1320mg (84.2%) of white solid.

II-7： ¹ H NMR(400MHz，CDCl ₃ )δ7.78(s，1H)，7.69(d，J＝2.1Hz，1H)，7.52(s，1H)，6.77(d，J＝1.3Hz，1H)，5.58(d，J＝7.8Hz，1H)，4.37(dt，J＝11.3，7.5Hz，1H)，3.70(dd，J＝11.1，6.7Hz，1H)，3.44(s，3H)，2.79(t，J＝11.2Hz，1H)，1.37(s，9H)； ¹³ C NMR(101 MHz，CDCl ₃ )δ171.0，154.6，153.1，147.4，141.4，129.6，123.3，118.1，117.4，106.7，80.0，50.7，39.0，37.0，28.4.

Example 9 Synthesis of Compound II-8

NaNO ₃ (2520 mg, 30mmol) was placed in a 500mL reaction flask, concentrated sulfuric acid 30mL, 6-fluorobenzoimidazole 15 (29mg, 30mmol) was added dropwise thereto at 0 ℃ to dissolve in 30mL concentrated sulfuric acid, and the resulting solution was slowly added dropwise to NaNO ₃ The reaction was carried out at 0 ℃ for 2.5 hours in the concentrated sulfuric acid solution of (3), and the completion of the reaction was monitored by TLC. The reaction solution was poured into 500mL of an ice-water mixture, naCO ₃ Adjusting pH of saturated aqueous solution to alkalinity, EA extracting, na ₂ SO ₄ Drying, removing solvent under reduced pressure to obtain brown solid powder, and directly performing next reaction without column chromatography separation.

Compound 16 (2300mg, 12.7mmol) was placed in a 50mL reaction flask, and Cs was added thereto ₂ CO ₃ (5200mg, 15.9mmol), 20mL of DMF was added at 0 ℃ and the reaction was carried out for 15min, then SEMCl (2.8mL, 15.9mmol) was slowly added dropwise, after the addition, the reaction was carried out at room temperature for 4h, TLC was used to monitor the reaction completion, EA extraction, saturated NaCl washing, na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 8) to obtain a pair of isomers 17 and 17', which are close to 1: 1 and cannot be separated by column chromatography: 900mg of a pale yellow solid.

N-Boc-L-cysteine(284mg，1.3mmol)，Cs ₂ CO ₃ (837mg, 2.6 mmol) was placed in a 50mL reaction flask and 10mL of DMF was added at room temperature and reacted for 15min, followed by slow dropwise addition of a DMF (2 mL) solution of a mixture of 17 and 17' and reaction overnight at room temperature, TLC monitoring of the end of the reaction, acidification with 0.2M HCl, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 10: 1) separated a pair of isomeric compounds 18 and 18': pale yellow solid 140.6mg (86%).

Compound 18+18' (330mg, 0.64mmol) is placed in a 250mL three-necked bottle, argon is pumped out for three times, and Fe powder (180mg, 3.2mmol) and NH are added into the three-necked bottle under argon atmosphere ₄ Cl (172.2mg, 3.2mmol), ethanol 12.5mL, deionized water 10mL, reflux reaction for 3 hours, TLC to monitor reaction completion, suction filtration on celite, anhydrous Na ₂ SO ₄ Drying, and removing solvent under reduced pressureObtaining a crude product of a pair of isomers 19+ 19'.

Adding HATU (293mg, 0.8mmol) and DIEA (181mg, 1.4mmol) into DMF solution of 19+19', reacting at room temperature overnight, monitoring the reaction by TLC, extracting EA, washing with deionized water, washing with saturated NaCl, and washing with Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, flash column chromatography (EA: PE = 1: 2) to obtain a pair of isomers 20+20': yellowish solid 240mg (38%).

Taking 20+20' (240mg, 0.52mmol) and placing in a reaction bottle, adding Cs into the reaction bottle ₂ CO ₃ (202mg, 0.62mmol) and 10mL of DMF at 0 deg.C for 10min, slowly adding iodomethane (88mg, 0.62mmol) dropwise to the above solution, reacting at 0 deg.C overnight, TLC monitoring reaction completion, EA extraction, washing with deionized water, washing with saturated NaCl, and Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 2) to give a pair of isomers II-8 and II-8': pale yellow solid 120mg (93%). After the protecting groups of the pair of intermediates are removed, a common intermediate compound can be obtained to carry out the final condensation reaction.

Data of II-8+, II-8': ESI: m/z 479.2 (M + H) ⁺

Example 10 Synthesis of Compound II-9

Adding 8g of the compound 21 into a 250mL single-neck bottle provided with a rotor, adding 50mL of dichloromethane for dissolving, adding 12mL of trifluoroacetic acid under stirring, stirring for 1 hour at room temperature, carrying out rotary evaporation, removing dichloromethane and trifluoroacetic acid, adding 80mL of water into the residue for extraction, adjusting the pH to 8-9, extracting with ethyl acetate, collecting an organic phase, extracting with saturated saline, drying with anhydrous sodium sulfate, carrying out suction filtration, and carrying out rotary drying to obtain 22.8g of the compound which is brown solid; ESI-MS m/z ( ⁷⁹ Br)271.0and( ⁸¹ Br)273.0(M+H) ⁺ .

In a 250mL single-necked flask equipped with a rotor were added 5.5g of Compound 22,3.93g of N, N-diisopropylethylamine, and 5.75g of trifluoroacetic anhydride in this order. AddingDissolving in 50mL of dichloromethane, stirring at room temperature for 8 hours, adding 50mL of water for extraction after the reaction is completed, collecting a dichloromethane layer, extracting with saturated saline solution, drying with anhydrous sodium sulfate, filtering to remove anhydrous sodium sulfate, spin-drying, and separating with a silica gel column (eluent is petroleum ether: ethyl acetate = 7: 1) to obtain 7.30g of compound 23, wherein the yield is 98%; ESI-MS m/z ( ⁷⁹ Br)367.1and( ⁸¹ Br)369.1(M+H) ⁺ .

Adding 60mL of trifluoroacetic anhydride into a 250mL double-mouth bottle provided with a thermometer and a rotor, cooling to-30 ℃, adding 7g of the compound 23, dissolving under stirring, slowly dropwise adding 1.4g of concentrated nitric acid, and after dropwise adding, controlling the temperature not to exceed-10 ℃ and continuing to react for 4 hours. After the reaction is completed, the reaction solution is poured into 300mL of ice water, stirring is carried out fully, a large amount of solid is separated out, suction filtration is carried out, a filter cake is washed to be neutral by water, collection and drying are carried out, 24.70g of the compound is obtained, the compound is yellow solid, and the yield is 96%. EI-MS m/z: ( ⁷⁹ Br)411and( ⁸¹ Br)413(M) ⁺ .

Adding 7g of compound 24,7.6g of iron powder, 100mL of saturated ammonium chloride aqueous solution and 100mL of ethanol into a 250mL single-neck bottle provided with a rotor in sequence, heating to 90 ℃, reacting for 5 hours, filtering with diatomite in an auxiliary manner after the reaction is completed, washing a filter cake with 150mL of dichloromethane for three times, collecting filtrate, carrying out rotary evaporation to remove most of ethanol and dichloromethane, adjusting the pH of residual liquid to 8-9 with saturated sodium carbonate, extracting with 300mL of dichloromethane for three times, collecting an organic phase, washing with saturated sodium bicarbonate once, washing with saturated water, drying with anhydrous sodium sulfate, filtering, carrying out rotary drying, and separating with a silica gel column (the eluent is petroleum ether: ethyl acetate = 8: 1) to obtain 4.02g of white solid, namely the compound 25. The yield is 62 percent; ESI-MS m/z ( ⁷⁹ Br)382.1and( ⁸¹ Br)384.0(M+H) ⁺ .

In a 250mL two-necked flask equipped with a thermometer and a rotor, 4g of the compound 25,1.83g of N, N-diisopropylethylamine was added thereto, 40mL of methylene chloride was dissolved with stirring, and the reaction solution was cooled to-10 ℃. Dissolving 1.06g of acetyl chloride in 10mL of dichloromethane, slowly dropwise adding the dichloromethane solution of the acetyl chloride into the reaction solution, keeping the temperature of the reaction solution not to exceed-5 ℃ in the dropwise adding process, and reacting after the dropwise adding is finishedSlowly heating the solution to room temperature, reacting overnight, adding 50mL of water after the reaction is completed, quenching, extracting, collecting an organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating and purifying by using a silica gel column (eluent is petroleum ether: ethyl acetate = 4: 1) to obtain 3.19g of a white solid, namely the compound 26. The yield thereof was found to be 72%. ¹ H NMR(500MHz，CDCl ₃ )δ＝8.34(s，1H)，7.62(s，1H)，7.55(d，J＝6.3，1H)，7.39(s，1H)，4.88-4.82(m，1H)，4.70(dd，J＝9.8，7.4，1H)，4.22(dd，J＝10.9，10.1，1H)，3.39(s，3H)，2.26(s，3H)； ¹³ C NMR(125MHz，CDCl ₃ )δ168.38，167.73，156.74(q，J＝38.4)，149.71，135.40，131.81，126.45，115.78，115.57(q，J＝287.6)，108.53，77.41，77.16，76.91，76.35，49.75，35.76，25.04；ESI-MS m/z 424.1( ⁷⁹ Br)and426.1( ⁸¹ Br)(M+H) ⁺ .

Sequentially adding 3g of compound 26,3g of anhydrous potassium carbonate into a 100mL single-neck bottle with a stirrer, adding 15mL of tetrahydrofuran and 15mL of water for dissolving, stirring overnight at room temperature, adding 2.31g of Boc anhydride into a reaction solution after the reaction is completed, stirring for 5 hours at room temperature, adding 30mL of water and 30mL of dichloromethane for extraction, collecting an organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain 3g of a white solid, namely compound 27, wherein the yield is 99%; ESI-MS m/z ( ⁷⁹ Br)428.0and( ⁸¹ Br)429.9(M+H) ⁺ .

CuI (19.0 mg,0.1 mmol), N were added to a 10mL Schlenk tube equipped with a rotator in this order ¹ ，N ² -bis (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (42.0 mg, 0.1mmol), compound 27 (0.856g, 2mmol) and K ₃ PO ₄ (0.424g, 2mmol), adding 0.28g of 25% ammonia water solution and 2mL of DMSO into a Schlenk tube by using a syringe in sequence under the protection of argon, sealing, heating the reaction solution to 60 ℃ for reacting for 24 hours, cooling to room temperature after the reaction is completed, diluting the reaction solution by using 30mL of ethyl acetate, filtering with the assistance of kieselguhr, washing a filter cake by using ethyl acetate, distilling the filtrate under reduced pressure, and separating and purifying the residual residue by using a silica gel column (a developing agent is dichloromethane: methanol = 30: 1) to obtain brown solid0.59g of this compound was obtained as compound 28, and the yield was 81%. ESI-MS: for C ₁₇ H ₂₄ N ₄ O ₅ (M)：364.1，Found.ESI-MS m/z 365.1(M+H) ⁺ .

Adding 1g of the compound 28 into a 50mL single-neck bottle with a stirrer, adding 15mL of acetic acid, heating to 80 ℃, reacting for 1 hour, cooling to room temperature after the reaction is completed, adding 50mL of water, extracting with ethyl acetate, collecting an organic phase, washing with a saturated sodium bicarbonate solution, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, spinning, and separating and purifying the residual residues with a silica gel column (a developing agent is dichloromethane: methanol = 25: 1) to obtain 0.74g of a light yellow solid, namely the key intermediate II-9, wherein the yield is 78%. ¹ H NMR(400MHz，CDCl ₃ )δ＝7.29(s，1H)，7.21(s，1H)，5.62(d，J＝7.3，1H)，4.65-4.56(m，1H)，4.51(dd，J＝9.4，7.5，1H)，4.14(t，J＝10.4，1H)，3.38(s，3H)，2.55(s，3H)，1.38(s，9H)； ¹³ C NMR(100MHz，CDCl ₃ )δ169.49，155.56，153.52，149.54，146.13，136.19，131.83，109.50，107.07，80.67，77.84，50.25，36.20，28.34，14.94；ESI-MS m/z 347.0(M+H) ⁺ ；ESI-HRMS Calcd.for C ₁₇ H ₂₃ O ₄ N ₄ (M+H) ⁺ ：347.1714，found：347.1717.

Example 11 Synthesis of Compound II-10

In a 250mL two-necked flask equipped with a thermometer and a rotor, 4g of the compound 25,1.83g of N, N-diisopropylethylamine was added thereto, 40mL of methylene chloride was dissolved with stirring, and the reaction solution was cooled to-5 ℃. Dissolving 1.29g of acetyl chloride in 10mL of dichloromethane, slowly dropwise adding a dichloromethane solution of the acetyl chloride into the reaction solution, keeping the temperature of the reaction solution not more than 0 ℃ in the dropwise adding process, slowly heating the reaction solution to room temperature after the dropwise adding is finished, reacting overnight, adding 50mL of water after the reaction is finished, quenching, extracting, collecting an organic phase, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and carrying out rotary spinningAfter drying, the extract was purified by silica gel column separation (eluent petroleum ether: ethyl acetate = 4: 1) to obtain 3.19g of a white solid, i.e., compound 29. The yield is 67%; ESI-MS m/z 440.2 ( ⁷⁹ Br)and 442.2( ⁸¹ Br)(M+H) ⁺ .

Sequentially adding 3g of compound 29,3g of anhydrous potassium carbonate into a 100mL single-mouth bottle with a stirrer, adding 15mL of tetrahydrofuran and 15mL of water for dissolving, stirring overnight at room temperature, adding 2.30g of Boc anhydride into a reaction solution after the reaction is completed, stirring for 5 hours at room temperature, adding 30mL of water and 30mL of dichloromethane for extraction, collecting an organic phase, washing with distilled saturated salt water, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain 3g of white solid, namely compound 30, wherein the yield is 99%; ESI-MS m/z 465.8 ( ⁷⁹ Br)and 467.8( ⁸¹ Br)(M+Na) ⁺ .

CuI (19.0 mg,0.1 mmol), N were added to a 10mL Schlenk tube equipped with a rotator in this order ¹ ，N ² -bis (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (42.0 mg, 0.1mmol), compound 30 (0.888g, 2mmol) and K ₃ PO ₄ (0.424g, 2mmol), adding 0.28g of 25% ammonia water solution and 2mL of DMSO into a Schlenk tube by using a syringe in sequence under the protection of argon, sealing, heating the reaction solution to 70 ℃ for reacting for 24 hours, cooling to room temperature after the reaction is completed, diluting the reaction solution by using 30mL of ethyl acetate, filtering with the assistance of diatomite, washing a filter cake by using ethyl acetate, distilling the filtrate under reduced pressure, and separating and purifying the residual residue by using a silica gel column (a developing agent is dichloromethane: methanol = 30: 1) to obtain 0.40g of brown solid, namely the compound 31, wherein the yield is 53%. ESI-MS M/z 381.1 (M + H) ⁺ .

Adding 1g of compound 31, 1mL of DMSO and 1.67g of potassium phosphate into a 25mL single-neck flask with a stirrer, heating to 100 ℃, reacting for 5 hours, cooling to room temperature after the reaction is completed, adding 50mL of water, extracting with ethyl acetate, collecting an organic phase, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating and purifying the residual residues with a silica gel column (a developing agent is dichloromethane: methanol = 20: 1) to obtain 0.69g of light yellow solid, namely compound II-10, wherein the yield is 78%; ¹ H NMR(500MHz，CDCl ₃ )δ＝10.58(s，1H)，10.46(s，1H)，6.88(s，1H)，6.62(s，1H)，5.72(d，J＝7.1，1H)，4.64-4.59(m，1H)，4.58-4.50(m，1H)，4.21-4.09(m，1H)，3.32(s，3H)，1.44(s，9H)；ESI-MS m/z371.1

example 12 Synthesis of Compound II-11

In a 250mL two-necked flask equipped with a thermometer and a rotor, 4g of compound 25,1.83g of N, N-diisopropylethylamine was dissolved in 40mL of dichloromethane with stirring, and the reaction solution was cooled to-20 ℃. Dissolving 2.9g of trifluoroacetic anhydride in 10mL of dichloromethane, slowly dropwise adding a dichloromethane solution of the trifluoroacetic anhydride into the reaction solution, keeping the temperature of the reaction solution not to exceed-10 ℃ in the dropwise adding process, slowly heating the reaction solution to room temperature after the dropwise adding is finished, reacting overnight, adding 50mL of water after the reaction is completed, quenching, extracting, collecting an organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating and purifying with a silica gel column (eluent is petroleum ether: ethyl acetate = 4: 1) to obtain 4.20g of a white solid, namely the compound 32. The yield thereof was found to be 84%. ESI-MS m/z475.8 ( ⁷⁹ Br)and 477.8( ⁸¹ Br)(M-H) ^- .

CuI (19.0 mg,0.1 mmol), N were added to a 10mL Schlenk tube equipped with a rotator in this order ¹ ，N ² -bis (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (42.0mg, 0.1mmol), compound 32 (0.956g, 2mmol) and K3PO4 (0.424g, 2mmol) were sequentially added with 0.28g of 25% ammonia water solution and 2mL of DMSO to a Schlenk tube under the protection of argon, sealed, reacted at room temperature for 24 hours, after completion of the reaction, 5mL of acetic acid was added, stirring was continued for 8 hours, the reaction solution was diluted with 40mL of ethyl acetate, filtration was assisted with celite, the filter cake was washed with ethyl acetate, the filtrate was distilled under reduced pressure, and the remaining residue was separated and purified with a silica gel column (dichloromethane: methanol = 30: 1 as a developing agent) to obtain 0.40g of a brown solid, namely compound 33, in 51% yield. ¹ H NMR(500MHz，cdcl ₃ )δ＝10.39(s，1H)，7.75(s，1H)，7.59(s，1H)，7.39(s，1H)，4.87-4.79(m，1H)，4.79-4.72(m，1H)，4.24(t，J＝9.0，1H)，3.53(s，3H)；ESI-MS m/z 397.0(M+H) ⁺ .

In a single-neck flask equipped with a rotor, 0.4g of Compound 33 was charged, 4mL of tetrahydrofuran was added and dissolved with stirring, and then 0.42g of anhydrous K was added ₂ CO ₃ ，4mL H ₂ O, stirring overnight at room temperature, adding 15mL of ethyl acetate and 15mL of H after the reaction is complete ₂ Extracting, collecting an organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, and spin-drying to obtain a compound II-110.3g with a yield of 99%; ¹ H NMR(400MHz，DMSO-d6)δ＝7.74(s，1H)，7.45(s，1H)，4.28(dd，J＝9.9，7.6，1H)，3.99(dd，J＝11.4，10.1，1H)，3.68(dd，J＝11.5，7.6，1H)，3.37(s，3H)；ESI-MS m/z 301.3(M+H) ⁺

example 13 Synthesis of Compound II-14

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NaNO ₃ (5.2 g, 61.1mmol) was placed in a 500mL reaction flask, concentrated sulfuric acid 60mL, 6-chloroquinoline (10.0 g, 61.1mmol) dissolved in 60mL concentrated sulfuric acid was added dropwise thereto at 0 deg.C and the resulting solution was slowly added dropwise to NaNO ₃ The reaction was carried out at 0 ℃ for 2h in the concentrated sulfuric acid solution of (2), and the end of the reaction was monitored by TLC. Pouring the reaction solution into 500mL of ice-water mixture, filtering with filter paper, extracting the filtrate with EA, combining the organic phase and the solid phase obtained by filtering, and sequentially using saturated NaHCO ₃ Saturated NaCl wash, na ₂ SO ₄ Drying, concentration and column chromatography (EA: PE = 1: 8) gave 35: pale yellow solid 11.2g (88%). ¹ H NMR(400MHz，CDCl ₃ )δ9.01(dd，J＝4.2，1.5Hz，1H)，8.19(d，J＝9.1Hz，1H)，8.04(d，J＝8.6Hz，1H)，7.75(d，J＝9.1Hz，1H)，7.59(dd，J＝8.7，4.2Hz，1H).

N-Boc-L-cysteine(3.5g，15.8mmol)，Cs ₂ CO ₃ (10.3 g,31.6 mmol) was placed in a 250mL reaction flask, 40mL of DMF was added thereto at 0 ℃ and reacted for 15min, followed by slowly dropping a solution of Compound 35 (2.2 g,10.5 mmol) in DMF (20 mL) at 0 ℃24h, TLC monitoring of the end of the reaction, acidification with 0.2M HCl, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 20: 1) isolated 36: light yellow solid 4.2g (qunt.). ¹ H NMR(400MHz，CDCl ₃ )δ8.83-8.67(m，1H)，8.05(d，J＝9.1Hz，1H)，7.88(d，J＝8.5Hz，1H)，7.74(d，J＝9.1Hz，1H)，7.34(dd，J＝8.7，4.5Hz，1H)，5.74(d，J＝6.8Hz，1H)，4.74(dd，J＝6.3，3.1Hz，1H)，3.99(dd，J＝15.0，2.5Hz，1H)，3.60(dd，J＝15.0，3.6Hz，1H)，1.48(s，9H).

Compound 36 (2.0g, 5.09mmol) was placed in a 100mL reaction flask, and Fe (1.42g, 25.4mmol), NH, was added thereto ₄ Cl (0.43g, 8.14mmol), followed by 40mL EtOH,10mL H ₂ O, reacting at 50 ℃ for 2h, and monitoring the reaction completion by TLC. Filtering with diatomaceous earth, removing solvent under reduced pressure and redissolving with 80mL DMF, adding HATU (2.3 g, 6.11mmol), DIEA (1.77mL, 10.2mmol), reacting at room temperature for 30min, monitoring by TLC, extracting EA, washing with deionized water, washing with saturated NaCl, and washing with Na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, flash column chromatography (EA: PE = 1: 3) afforded a pale yellow solid 37 (1.2g, 68% for 2steps).

Compound 37 (1.0g, 2.9mmol) was taken and placed in a reaction flask, and Cs was added thereto ₂ CO ₃ (1.1g, 3.48mmol) and 60mL DMF at 0 deg.C for 10min, slowly adding methyl iodide (494mg, 3.48mmol) dropwise into the above solution, reacting at 0 deg.C for 3h, monitoring by TLC for reaction completion, extracting by EA, washing with deionized water, washing with saturated NaCl, washing with Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 4) to obtain compound II-14: white solid 0.95g (91%). ¹ H NMR(400MHz，CDCl ₃ )δ8.98(dd，J＝4.2，1.6Hz，1H)，8.18(d，J＝8.5Hz，1H)，8.05(d，J＝8.7Hz，1H)，7.88(d，J＝8.7Hz，1H)，7.52(dd，J＝8.6，4.2Hz，1H)，5.59(d，J＝7.8Hz，1H)，4.38(dt，J＝10.6，7.6Hz，1H)，3.82(dd，J＝11.2，7.0Hz，1H)，3.39(s，3H)，2.91(dd，J＝19.8，8.7Hz，1H)，1.36(s，9H). ¹³ C NMR(100MHz，CDCl ₃ )δ172.66，154.45，151.37，149.42，141.92，134.89，131.82，130.13，127.13，124.21，122.23，80.18，50.78，39.98，36.76，28.26.

Example 14 Synthesis of Compound II-15

N-Boc-L-serine (3.25g, 15.8mmol), naH (0.76g, 31.65mmol, 60wt%) were placed in a 250mL reaction flask, argon gas was evacuated three times, under an argon atmosphere, 50mL of DMF was added thereto at 0 ℃ and reacted for 30min, then a solution of 2 (2.2 g, 10.55mmol) in DMF (10 mL) was slowly added dropwise, reacted overnight at 0 ℃, TLC monitored that the reaction was substantially complete, acidification with 0.2M HCl, EA extraction, deionized water washing, saturated NaCl washing, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 20: 1) gave 38: pale yellow solid 2.1g (53%). ¹ H NMR(400MHz，MeOD)δ8.89(m，1H)，8.26(d，J＝9.1Hz，1H)，8.17(d，J＝8.1Hz，1H)，7.89(d，J＝9.0Hz，1H)，7.69(m，1H)，4.68(s，2H)，4.60(s，1H)，1.46(s，9H).

Compound 38 (1.92g, 5.09mmol) was placed in a 100mL reaction flask, to which Fe (1.42g, 25.4 mmol), NH was added ₄ Cl (0.43g, 8.14mmol) followed by 40mL EtOH,10mL H ₂ O, reacting at 50 ℃ for 2h, and monitoring the reaction by TLC. Filtering with diatomaceous earth, removing solvent under reduced pressure and redissolving with 80mL DMF, adding HATU (2.3 g, 6.11mmol), DIEA (1.77mL, 10.2mmol), reacting at room temperature for 30min, monitoring by TLC, extracting EA, washing with deionized water, washing with saturated NaC1, and eluting with Na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, flash column chromatography (EA: PE = 1: 3) gave a pale yellow solid 39 (1.1g, 66% for 2steps).

Compound 39 (1.0 g, 3.04mmol) was taken in a reaction flask, and Cs was added thereto ₂ CO ₃ (1.48g, 4.56mmol) and 60mL DMF at 0 deg.C for 10min, slowly adding methyl iodide (518mg, 3.65mmol) dropwise to the above solution, reacting at 0 deg.C for 3h, monitoring by TLC for reaction completion, extracting by EA, washing with deionized water, washing with saturated NaC1, and adding Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 4) to obtain compound II-15: white solid 0.96g (92%). ¹ H NMR(400MHz，CDCl ₃ )δ8.90(dd，J＝4.1，1.4Hz，1H)，8.12(d，J＝8.4Hz，1H)，8.04(d，J＝9.1Hz，1H)，7.51(d，J＝9.1Hz，1H)，7.46(dd，J＝8.6，4.2Hz，1H)，5.54(d，J＝6.7Hz，1H)，4.73-4.59(m，2H)，4.31-4.20(m，1H)，3.41(s，3H)，1.35(s，9H). ¹³ C NMR(100MHz，CDCl ₃ )δ171.59，154.95，149.94，149.15，146.67，131.16，130.89，129.73，125.11，124.08，121.63，80.30，78.72，49.94，37.26，28.21.

Example 15 Synthesis of Compound II-16

NaNO ₃ (5.2 g, 61.1mmol) was placed in a 500mL reaction flask, concentrated sulfuric acid 60mL was added dropwise thereto at 0 ℃, 6-chloroisoquinoline 40 (10.0 g, 61.1mmol) was dissolved in 60mL concentrated sulfuric acid, and the resulting solution was slowly added dropwise to NaNO ₃ The reaction was carried out at 0 ℃ for 2h in the concentrated sulfuric acid solution of (3), and the completion of the reaction was monitored by TLC. Pouring the reaction solution into 500mL of ice-water mixture, filtering with filter paper, extracting the filtrate with EA, combining the organic phase and the solid phase obtained by filtering, and sequentially using saturated NaHCO ₃ Saturated NaCl wash, na ₂ SO ₄ Drying, concentration and column chromatography (EA: PE = 1: 8) gave 41: pale yellow solid 11.2g (88%). ¹ H NMR(400MHz，CDCl ₃ )δ9.36(s，1H)，8.73(d，J＝6.0Hz，1H)，8.11(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.56(d，J＝6.0Hz，1H).

N-Boc-L-cysteine(3.5g，15.8mmol)，Cs ₂ CO ₃ (10.3 g,31.6 mmol) was placed in a 250mL reaction flask, 40mL DMF was added thereto at 0 ℃ and reacted for 15min, then a solution of Compound 41 (2.2 g,10.5 mmol) in DMF (20 mL) was slowly added dropwise, reaction was carried out at 0 ℃ for 24h, TLC monitored for reaction completion, acidification with 0.2M HCl, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying and removing under reduced pressureDesolvation and column chromatography (DCM: meOH = 20: 1) gave 42: light yellow solid 4.2g (qunt.). ¹ H NMR(400MHz，CDCl ₃ )δ8.52(s，1H)，8.32(d，J＝6.3Hz，1H)，7.94(d，J＝8.8Hz，1H)，7.77(d，J＝8.8Hz，1H)，7.44(d，J＝6.3Hz，1H)，5.69(d，J＝6.9Hz，1H)，4.68(m，1H)，3.97(d，J＝14.7Hz，1H)，3.55(dd，J＝15.0，4.4Hz，1H)，1.47(s，9H).

Compound 42 (2.0g, 5.09mmol) was placed in a 100mL reaction flask, and Fe (1.42g, 25.4mmol), NH, was added thereto ₄ Cl (0.43g, 8.14mmol), followed by 40mL EtOH,10mL H ₂ O, reacting at 50 ℃ for 2h, and monitoring the reaction by TLC. Filtering with Celite, removing solvent under reduced pressure and redissolving with 80mL DMF, adding HATU (2.3 g, 6.11mmol), DIEA (1.77mL, 10.2mmol), reacting at room temperature for 30min, monitoring reaction by TLC, extracting EA, washing with deionized water, washing with saturated NaCl, washing with Na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, flash column chromatography (EA: PE = 1: 3) afforded a pale yellow solid 43 (1.2g, 68% for 2steps).

Compound 43 (1.0 g, 2.9mmol) was placed in a reaction flask, and Cs was added thereto ₂ CO ₃ (1.1g, 3.48mmol) and 60mL DMF at 0 deg.C for 10min, slowly adding methyl iodide (494mg, 3.48mmol) dropwise into the above solution, reacting at 0 deg.C for 3h, monitoring by TLC for reaction completion, extracting with EA, washing with deionized water, washing with saturated NaCl, and Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 4) to obtain compound II-16: white solid 0.95g (91%). ¹ H NMR(400MHz，CDCl ₃ )δ9.31(s，1H)，8.64(d，J＝6.0Hz，1H)，7.91(d，J＝8.4Hz，1H)，7.78(d，J＝8.4Hz，1H)，7.62(d，J＝6.0Hz，1H)，5.63(d，J＝7.7Hz，1H)，4.37(m，1H)，3.82(dd，J＝11.1，7.0Hz，1H)，3.39(s，3H)，2.95(dd，J＝12.5，9.7Hz，1H)，1.35(s，9H). ¹³ C NMR(100MHz，CDCl ₃ )δ172.29，154.43，153.10，144.60，141.08，133.02，131.67，131.49，129.73，128.01，116.00，80.25，50.62，39.84，36.41，28.26.

Example 16 Synthesis of Compound II-17

N-Boc-L-serine (3.25g, 15.8mmol), naH (0.76g, 31.658 mmol, 60wt%) were placed in a 250mL reaction flask, argon was evacuated three times, under an argon atmosphere, 50mL DMF was added thereto at 0 ℃ and reacted for 30min, then a 10 (2.2 g, 10.55mmol) solution in DMF (10 mL) was slowly added dropwise, the reaction was allowed to proceed overnight at 0 ℃, TLC monitored for substantial completion of the reaction, acidification with 0.2M HCl, EA extraction, deionized water washing, saturated NaCl washing, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 20: 1) separated 44: pale yellow solid 2.1g (53%).

Compound 44 (1.92g, 5.09mmol) was placed in a 100mL reaction flask, to which Fe (1.42g, 25.4 mmol), NH was added ₄ Cl (0.43g, 8.14mmol), followed by 40mL EtOH,10mL H ₂ O, reacting at 50 ℃ for 2h, and monitoring the reaction by TLC. Filtering with diatomaceous earth, removing solvent under reduced pressure and redissolving with 80mL DMF, adding HATU (2.3 g, 6.11mmol), DIEA (1.77mL, 10.2mmol), reacting at room temperature for 30min, monitoring by TLC, extracting EA, washing with deionized water, washing with saturated NaCl, and washing with Na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, flash column chromatography (EA: PE = 1: 3) gave a pale yellow solid 45 (1.1g, 66% for 2steps).

Compound 45 (1.0 g, 3.04mmol) was taken in a reaction flask, and Cs was added thereto ₂ CO ₃ (1.48g, 4.56mmol) and 60mL DMF at 0 deg.C for 10min, slowly adding methyl iodide (518mg, 3.65mmol) dropwise into the above solution, reacting at 0 deg.C for 3h, monitoring by TLC for reaction completion, extracting EA, washing with deionized water, washing with saturated NaCl, and Na ₂ SO ₄ Drying, removing the solvent under reduced pressure, and separating by column chromatography (EA: PE = 1: 4) to obtain compound II-17: white solid 0.96g (92%). ¹ H NMR(400MHz，CDCl ₃ )δ9.27(s，1H)，8.60(d，J＝6.0Hz，1H)，7.94(d，J＝8.8Hz，1H)，7.60(d，J＝6.0Hz，1H)，7.42(d，J＝8.7Hz，1H)，5.53(d，J＝6.2Hz，1H)，4.76-4.60(m，2H)，4.36-4.25(m，1H)，3.44(s，3H)，1.38(s，9H). ¹³ C NMR(100MHz，CDCl ₃ )δ171.24，154.94，152.95，152.31，144.12，132.01，129.26，129.21，127.13，123.44，115.74，80.40，78.75，49.79，36.92，28.23.

Example 17 Synthesis of Compound II-18

Compound 2-1 (9.48g, 45.12mmol) was dissolved in 90mL of THF solvent, and 135.6mL of BH was added at 0 ℃ under argon ₃ (1M in THF) and then warmed to room temperature for 2 hours, TLC checked for completion, quenched with 1M HCl, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography (EA/PE = 1: 3) to give 6.0g of compound 46 in 74% yield.

Compound 46 (6.0g, 33.3mmol) and NaH (1.68g, 41.64mmol) were mixed and dissolved in 120mL of DMF solvent at 0 ℃ and reacted at that temperature for 30min. Subsequently SEMCl (8.82ml, 49.98mmol) was added for overnight reaction, TLC checked for completion, 1M HCl was added to quench the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated column chromatography (EA/PE = 1: 8) afforded 8.22g of compound 47 in 80% yield. ¹ H NMR(400MHz，CDCl ₃ )δ8.46(d，J＝7.2Hz，1H)，7.48-7.20(m，2H)，6.71(dd，J＝3.4，0.7Hz，1H)，5.50(s，2H)，3.52(dd，J＝8.6，7.7Hz，2H)，0.97-0.92(m，2H)，-0.00(s，9H). ¹³ C NMR(100MHz，CDCl ₃ )δ155.46，152.91，140.01，139.90，132.89，132.86，125.77，121.15，121.14，105.86，100.31，100.05，77.66，67.93，19.17，0.00.

N-Boc-L-serine (4.96g, 24.15mmol), t-BuOK (7.23g, 64.5mmol) were placed in a 250mL reaction flask, argon gas was evacuated three times under an argon atmosphere, 50mL of DMF was added thereto at 0 ℃ and reacted for 30min, then a solution of 47 (5.0g, 16.1mmol) in DMF (30 mL) was slowly added dropwise, reacted overnight at 0 ℃, TLC monitored that the reaction was substantially completed, acidification with 0.2M HCl, EA extraction, washing with deionized water, washing with saturated NaCl, na ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (DCM: meOH = 20: 1) isolated 48: 1.67g (21%) of a pale yellow solid,

dissolving compound 48 (1.67 g) in 40mL of methanol, adding 167mg of Pd/C, reacting at room temperature in a hydrogen-loaded atmosphere for 3h, monitoring the reaction by TLC, filtering with diatomite to remove Pd/C, distilling under reduced pressure to remove the solvent, dissolving the obtained crude product in 40mL of DMF, adding DIPEA and HATU, reacting at room temperature for 1h, after TLC shows that the reaction is complete, adding water, extracting with ethyl acetate, concentrating, and performing flash column chromatography (EA/PE = 1: 3) to obtain 1.0g of compound 48, wherein the yield of the two steps is 66%.

Compound 49 (1.0 g, 2.23mmol) was placed in a reaction flask, to which Cs was added ₂ CO ₃ (1.09g, 3.36mmol) and 20mL of DMF, reacting at 0 ℃ for 10min, slowly dropwise adding methyl iodide (380mg, 2.68mmol) into the solution, reacting at 0 ℃ for 3h, monitoring by TLC to finish the reaction, extracting with EA, washing with deionized water, washing with saturated NaCl, washing with Na and sodium chloride, and purifying with sodium hydroxide ₂ SO ₄ Drying, removal of the solvent under reduced pressure, column chromatography (EA: PE = 1: 8) isolated compound 50: white solid 0.96g (93%). ¹ H NMR(400MHz，CDCl ₃ )δ7.44(s，1H)，7.29(s，1H)，7.21(d，J＝3.2Hz，1H)，6.50(d，J＝3.1Hz，1H)，5.57(d，J＝6.8Hz，1H)，5.50-5.39(m，2H)，4.70(dt，J＝11.0，7.3Hz，1H)，4.59(dd，J＝9.5，7.5Hz，1H)，4.15(dd，J＝10.9，9.8Hz，1H)，3.54-3.47(m，5H)，1.41(s，9H)，1.00-0.91(m，2H)，0.00(s，9H). ¹³ C NMR(100Hz，CDCl ₃ )δ171.03，156.49，147.69，136.09，131.71，130.81，127.63，116.59，105.00，103.74，81.39，79.21，77.27，67.38，51.47，37.56，29.65，19.06，0.00.

Compound 50 (0.9 g, 1.95mmol) was dissolved in 15mL of anhydrous THF solvent under argon protection, and 13.65mL of TBAF (1M in THF) solution was added and reacted at 70 ℃ for 4 hours. After the reaction was completed, the THF solvent was removed, water was added, ethyl acetate was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and flash column chromatography (EA/PE = 1: 3) was performed to obtain 210mg of compound II-18 with a yield of 33%. ESI-MS M/z 330.1 (M-H) ^- .

Example 18 Effect of Compounds of formula I on TNF-induced apoptosis of FADD-specific Jurkat cells

Because the N terminal of the RIP1 is a serine/threonine specific kinase domain, the kinase domain can catalyze the self-phosphorylation of the RIP1 at the serine/threonine residue site; the C-terminus is a death domain through which Fas, tumor necrosis factor receptor 1 (TNFR 1), and the like can interact. Also, this domain is associated with death domain adaptor proteins, such as TNF receptor-associated death domain (TRADD), fas-associated death domain (FADD). In addition, studies have shown that the mitochondrial inner membrane gap protein analog Smac accelerates the necrosis process, and that co-induction of necrosis in vitro using high doses of TNF, smac analogs and the pan-caspase inhibitor z-VAD-FMK may bypass or mask the mitochondrial role in the execution of necrosis.

The bioassay protocol used was: effect of compound on TNF-induced apoptosis of FADD (Fas associated death domain) -deleted Jurkat cells.

In order to verify the inhibition effect of the compound of the invention on the apoptosis at the cellular level and select the cell type with the RIP1 pathway closely related, namely FADD specific Jurkat cell (human peripheral blood leukemia T cell line), two different stimulation modes are respectively adopted: the biological activity of the compound in inhibiting apoptosis is obtained by measuring chemiluminescence values to calculate cell viability by using Tumor Necrosis Factor (TNF) alone or in combination with mitochondrially-derived cysteine aspartate activator (SMAC).

Experimental conditions and procedures: FADD specificity Jurkat cells (human source peripheral blood leukemia T cell strain) are cultured in vitro, after the cells grow to the logarithmic growth phase, the cells are collected, centrifuged at 1000rpm for 5min, supernatant is discarded, and the cell concentration is adjusted to 4.44X105/mL. In a white 384-well cell culture plate, 50nl of drug in DMSO or pure DMSO control were added per well, with three replicates per drug concentration. Cells were seeded into 384-well plates at 45. Mu.l per well. The stimulation group was added 5. Mu.l of TNF (40 ng/mL) or TNF (10 ng/mL) + SM164 (25 nM) diluted in cell culture medium per well, placed in a cell culture chamber (37 ℃,5% ₂ ) In (1)After 20h incubation, 20. Mu.l of cell Titer-Glo solution was added to each well, incubated at room temperature for 30min, and chemiluminescence (luminescence) was measured to measure intracellular ATP levels. Compound EC50 values were calculated using Prism Graphpad statistical software with unstimulated DMSO control wells at 100% cell viability.

The compound numbers and structures in the test examples are the same as those in the specification, 7-Cl-O-Nec-1 and GSK2982772 are positive controls, and the results are shown in the following table:

TABLE 1 RIP1 inhibitors in vitro bioactivity test results

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The results show that the compounds of the present application have similar or better activity than the positive control compounds, especially in the case of TNF in combination with a mitochondria-derived cysteine aspartate activator (SMAC), a proportion of the compounds of the present application show a significant advantage in the inhibition of programmed cell necrosis over existing RIP inhibitors.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.

Claims

1. A compound of the following formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

wherein the compound of formula I has a structure shown as formula I-1 below:

x is O, S or CH ₂ ；

n is 1;

and the ring A, ring B and ring C are a combination selected from any one of the following groups (1) to (8):

(1) Ring A is a substituted or unsubstituted 5-6 membered heteroaryl; b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl;

(2) Ring A is a substituted or unsubstituted 5-6 membered heterocyclyl; b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl;

(3) Ring A is a substituted or unsubstituted 5-6 membered heteroaryl; b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl;

(4) Ring A is a substituted or unsubstituted 5-6 membered heterocyclic group; b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl;

(5) Ring A is a substituted or unsubstituted 5-6 membered heteroaryl; b is selected from the following group: substituted or unsubstitutedPhenyl, substituted or unsubstituted 5-6 membered heteroaryl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl;

(6) Ring A is a substituted or unsubstituted 5-6 membered heterocyclic group; b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl;

(7) Ring A is a substituted or unsubstituted 5-6 membered heteroaryl; b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl;

(8) Ring A is a substituted or unsubstituted 5-6 membered heterocyclic group; b is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl; c is selected from the following group: H. substituted or unsubstituted C ₃ -C ₆ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heterocyclyl;

l is selected from the group consisting of: substituted or unsubstituted C ₁ -C ₆ An alkylene group;

R ₂ is one or more substituents on the benzene ring selected from the group consisting of: h;

wherein the heteroaryl or heterocyclyl has one or more heteroatoms in its ring backbone selected from the group consisting of: n, O or S;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, cyano, hydroxy, amino, benzyl, oxy (= O), C ₁ -C ₄ Alkyl, halo (C) ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Alkoxy, halo C ₁ -C ₄ Alkoxy, nitro, C ₁ -C ₄ Alkyl C (O) -;

the configuration of each chiral center is independently R or S.

2. The compound of claim 1, wherein C is substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl.

3. The compound of claim 1, wherein L is substituted or unsubstituted C ₁ An alkylene group.

4. The compound of claim 1, wherein the a ring is a 5-membered ring having one or more N atoms in the ring backbone.

5. The compound of claim 1, wherein L is CH ₂ 。

6. A process for the preparation of a compound according to claim 1, which is prepared by the following steps (a) or (b):

(b) Under the acidic condition, the compound of the formula II removes an amino protecting group, and then reacts with the compound of the formula III in an inert solvent in the presence of a condensation reagent and alkali to obtain the compound of the formula I; wherein R is an amino protecting group; the remaining groups are as defined in claim 1.

7. A pharmaceutical composition comprising (a) a therapeutically effective amount of an optical isomer of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a combination thereof; and (b) a pharmaceutically acceptable carrier.

8. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a mixture thereof, according to claim 1, for the preparation of a pharmaceutical composition for the treatment or prevention of a RIP1 kinase-mediated disease or condition; or for the preparation of a pharmaceutical composition for the treatment or prevention of a disease or disorder caused by apoptosis.

9. The use of claim 8, wherein the disease or condition is selected from the group consisting of: inflammatory bowel disease, crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, soJIA, systemic lupus erythematosus, sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of a solid organ, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, huntington's disease, alzheimer's disease, parkinson's disease, allergic diseases, asthma, multiple sclerosis, type I diabetes, wegener's granuloma, pulmonary sarcoidosis, behcet's disease, interleukin-1 converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, periodontitis.

10. The use of claim 8, wherein the disease or condition is selected from the group consisting of: ulcerative colitis, autoimmune hepatitis,

11. An intermediate compound of formula II:

wherein R is selected from the group consisting of: H. an amino protecting group;

the remaining groups are as defined in claim 1.

12. An intermediate compound selected from the group consisting of:

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