WO2022002077A1

WO2022002077A1 - Aryl aromatic heterocyclic derivative and preparation method therefor and use thereof

Info

Publication number: WO2022002077A1
Application number: PCT/CN2021/103255
Authority: WO
Inventors: 李乐平; 李东升; 张翱; 李磊; 耿美玉; 谢作权; 丁春勇; 王玺渊; 宋子兰; 丁健; 沈安成; 张燕
Original assignee: 上海海和药物研究开发股份有限公司; 泰州海和药业有限公司
Priority date: 2020-06-30
Filing date: 2021-06-29
Publication date: 2022-01-06
Also published as: CN113861161A

Abstract

Disclosed in the present invention are an aryl aromatic heterocyclic derivative and preparation thereof and use thereof. The structure is as shown in formula I, and in this formula, the definitions of substituents are as stated in the description and the claims. The compound of the present invention can be used as a STING agonist, used for treatment of tumors and infectious diseases, or used as an immune composition or a vaccine adjuvant.

Description

A kind of aryl and aromatic heterocyclic derivative and its preparation method and use

technical field

The invention relates to the field of biomedicine, in particular to an aryl and aromatic heterocyclic derivative and a preparation method and application thereof.

Background technique

Innate immunity is the body's first line of defense against pathogen infection, and it plays a crucial role in inhibiting tumor growth and the pathogenesis of autoimmunity. In recent years, the cGAS-STING-TBK1 pathway has attracted widespread attention as an innate immune regulator. When the DNA sensor cGAS (cyclic GMP-AMP synthase) senses pathogen DNA, it induces the production of cGAMP (cyclic GMP-AMP), causing interferon gene stimulation Activation of stimulator of interferon genes (STING) recruits TANK-binding kinase 1 (TBK1) to phosphorylate interferon regulatory factor 3 (IRF3), induces type I interferon and cellular The production of factors, and through a series of cascade reactions, activate the adaptive immune system and activate T cells to play an anti-tumor immune role.

STING agonists not only induce the expression of type I interferon genes, but also play an important role in innate immune signaling pathways. It also activates immune-stimulatory cells including dendritic cells, alters the tumor microenvironment and induces the production of tumor-specific T cells, which in turn kill tumor cells. It has been shown that intratumoral or intravenous injection of STING agonists prevents primary tumor growth and distant lesions in different mouse tumor models, including B16 melanoma, 4T1 breast cancer, and CT26 colon cancer models . These findings indicate that the anti-tumor effect by activating STING has become one of the important strategies for anti-tumor immunotherapy.

So far, the research on STING small molecule agonists is still in its infancy, and few compounds have entered clinical trials. Among them, ADU-S100 (Phase II) developed by Aduro and MK1454 (Phase I) developed by Merck are both cyclic The dinucleotide analogs were administered by intratumoral injection. Such drugs have disadvantages such as large molecular weight, poor cell membrane permeability, negatively charged phosphate groups in their structures, and their phosphate bonds are easily hydrolyzed, and their pharmacokinetic properties are extremely poor, which severely limits their clinical use. In 2018, GSK reported the first intravenously administered benzimidazole STING agonist, but this class of compounds still suffers from serious metabolic problems. Therefore, it is necessary to further develop novel small molecules with simple structure, convenient synthesis, stable metabolism and high safety to activate interferon gene-stimulating protein and induce the production of type I interferon beta. Such STING agonists can be widely used in the treatment of tumors, infectious diseases, or as adjuvants for immune compositions or vaccines.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a compound represented by formula (I) and a preparation method thereof, as well as its use in anti-tumor and infectious diseases.

The first aspect of the present invention provides a compound represented by general formula (I), or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable compound thereof. Salt,

In the formula,

A ₁ and X ₁ are each independently N or CR _x ; R _x is H, halogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -LM; The substitution refers to being substituted by a substituent selected from the group consisting of halogen, hydroxyl, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, and 3-8 membered heterocyclyl;

W ₁ is NH, S or O; Y ₁ is N or CR _y ; R _y is H, -LM or absent;

R ₁ , R _{2 are} independently selected from halogen, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylacyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C4 alkylamido, substituted or unsubstituted C1-C4 alkylamino , -LM; _{the substitution in R 1} , R ₂ refers to being substituted by a substituent selected from Group A: one or more of halogen, hydroxyl, methoxy, amino, and carboxyl;

R ₃ is F, R ₄ is H, halogen, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; or R ₃ and R ₄ and the C atom to which they are attached form a 3-6 membered heterocyclic group or C3- C8 cycloalkyl; or R ₃ and R ₄ together form =O; or R ₄ is H, R ₃ and Y ₁ and the C atom between them form a 5-7 membered heterocyclic group; at this time Y ₁ is C ;

R ₅ , R ₆ , R ₇ , R ₈ are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or Unsubstituted C1-C4 alkanoylamino; said substitution means substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH ₂ , hydroxyl, C1-C4 alkyl, C1-C4 Alkoxy, amino, 3-6 membered heterocyclic group;

Or R ₅ , R ₆ and the connected carbon together form a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C3-C8 cycloalkyl group or a substituted or unsubstituted 3-8 membered heterocyclic group; the substitution refers to is substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, halogen;

Or R ₇ , R ₈ and the connected carbon together form a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C3-C8 cycloalkyl group or a substituted or unsubstituted 3-8 membered heterocyclic group; the substitution refers to is substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, halogen;

T ₁ is -C(O)R ₉ , -SO ₂ R ₉ ,

5-7-membered heteroaryl unsubstituted or substituted by substituents selected from group B, C1-C6 alkyl groups unsubstituted or substituted by substituents selected from group B; R _{9 is} selected from H, hydroxyl, C1- C6 alkoxy, -NHCO-(C1-C6 alkyl), C1-C6 alkyl unsubstituted or substituted by substituents selected from group B, amino group unsubstituted or substituted by substituents selected from group B, Unsubstituted or substituted 5-8-membered heteroaryl groups selected from B group substituents; B group substituents include: halogen, hydroxyl, C1-C6 alkyl, -SO ₂ CH ₃ ;

And when A ₁ , X ₁ , Y ₁ are CH, W ₁ is S, T ₁ is -C(O)R ₉ , and _{neither R 1} and R ₂ are -LM, R ₅ , R ₆ , R ₇ , R ₈ cannot be H at the same time;

And any two of R _{x in} _{A 1} and R _x , R ₁ , R ₂ , and R _y in X ₁ will not be -LM at the same time;

L is selected from -(CH ₂ ) _m -(Q) _i -(CH ₂ ) _n -, -O-(CH ₂ ) _m -(Q) _i -(CH ₂ ) _n -O-, -O-(CH ₂ ) _m -(Q) _i -(CH ₂ ) _n -, -(CH ₂ ) _m -(Q) _i -(CH ₂ ) _n -O-; m, n are independently selected from integers from 0 to 5 ; i is 0 or 1; and m, n, i are not 0 at the same time; Q is selected from -CH=CH-, -C≡C-, -C(O)-NH-, -NH-C(O)- , -N=CH-, O, 3-8-membered heterocyclic group, 3-8-membered heteroaryl;

M is selected from the following structures:

A ₂ and X ₂ are each independently N or CR _x '; R _x ' is H, halogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl; substituted or unsubstituted C1-C6 alkoxy; the Substitution refers to being substituted by a substituent selected from the group consisting of halogen, hydroxyl, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;

W ₂ is O, S, NH; Y ₂ is N or CR _y '; R _y ' is H or absent;

R ₁ ', R ₂ ' are independently selected from halogen, hydroxy, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C2-C4 alkynyl R _The substitution in 1 ', R ₂ ' refers to being substituted by one or more selected from halogen, hydroxyl and methoxy;

R ₃ ' is F, R ₄ ' is H, halogen, hydroxyl, C1-C4 alkyl or C1-C4 alkoxy; or R ₃ ' and R ₄ ' form a 3-6 membered heterocycle with the C atom to which they are attached or R ₃ ' and R ₄ ' together form =O; or R ₄ ' is H, R ₃ ' and Y ₂ and the C atom between them form a 5-7 membered heterocyclic group; at this time Y ₂ is C;

R ₅ ', R ₆ ', R ₇ ', R ₈ ' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy base, substituted or unsubstituted C1-C4 alkanoylamino; the substitution refers to being substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH ₂ , hydroxyl, C1-C4 alkyl , C1-C4 alkoxy, amino, 3-6 membered heterocyclic group;

Or R ₅ ', R ₆ ' and the connected carbon together form a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C3-C8 cycloalkyl group or a substituted or unsubstituted 3-8 membered heterocyclic group; the substitution Refers to being substituted by one or more substituents selected from the following: C1-C6 alkyl, hydroxyl, halogen;

Or R ₇ ', R ₈ ' and the connected carbon together form a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C3-C8 cycloalkyl group or a substituted or unsubstituted 3-8 membered heterocyclic group; the substitution Refers to being substituted by one or more substituents selected from the following: C1-C6 alkyl, hydroxyl, halogen;

T ₂ is -C(O)R ₉ , -SO ₂ R ₉ ,

5-7-membered heteroaryl unsubstituted or substituted by substituents selected from group B, C1-C6 alkyl groups unsubstituted or substituted by substituents selected from group B; R _{9 is} selected from H, hydroxyl, C1- C6 alkoxy, -NHCO-(C1-C6 alkyl), C1-C6 alkyl unsubstituted or substituted by substituents selected from group B, amino group unsubstituted or substituted by substituents selected from group B, 5-8-membered heteroaryl group unsubstituted or substituted by substituents selected from Group B;

T ₃ is a 5-7-membered heteroaryl group that is unsubstituted or substituted by a substituent selected from Group B;

Group B substituents include: halogen, hydroxyl, C1-C6 alkyl, -SO ₂ CH ₃ ;

T ₄ and T ₄ 'are each independently a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 5-7 membered heteroaryl, 3-6 membered substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C6 -C10 aryl, substituted or unsubstituted C3-C8 cycloalkyl; the substituted refers to being substituted by one or more of the following substituents: halogen, hydroxyl, amino, carboxyl, cyano, C1 -C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 3-8 membered heterocyclyl, C6-C10 aryl. In a preferred embodiment, A ₁ and X ₁ are each independently N or CR _x ; R _x is H, F, Cl, -LM; A ₂ and X ₂ are each independently N or CR _x '; R _x ' is H, F, Cl; Y ₁ is N or CR _y ; R _y is H, -LM or absent; Y ₂ is N or CH; W ₁ , W ₂ are each independently NH or S; R ₁ , R ₂ are each independently fluorine, chlorine, bromine or C1-C4 alkoxy, -LM; R ₁ ', R ₂ ' are each independently fluorine, chlorine, bromine or C1-C4 alkoxy; and in A ₁ Any two of R _x , R ₁ , R ₂ , and R _y in R _x , X ₁ cannot be -LM at the same time.

In a preferred example, R ₃ and R ₄ are both F; or R ₃ and R ₄ and the C atom to which they are attached form a 3-6-membered heterocyclic group or C3-C8 cycloalkyl; or R ₃ and R ₄ together Form =O; or R ₄ is H, R ₃ and Y ₁ and the C atom between them form a 5-7 membered heterocyclic group; at this time Y ₁ is C;

In a preferred example, both R ₃ ' and R ₄ ' are F; or R ₃ ' and R ₄ ' and the C atom to which they are attached form a 3-6-membered heterocyclic group or C3-C8 cycloalkyl; or R ₃ ' and R ₄ ' together form =O; or R ₄ ' is H, R ₃ ' and Y ₂ and the C atom between them form a 5-7 membered heterocyclic group; at this time Y ₂ is C;

In a preferred example, R ₅ , R ₆ , R ₇ , R ₈ are each independently H, halogen, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 Alkoxy; said substitution means substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH ₂ , hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino , 4-6 membered heterocyclic group;

Or R ₅ , R ₆ and the attached carbon together form -(CH=CH ₂ ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to the selected Substituted from one or more of the following substituents: C1-C6 alkyl, hydroxyl, halogen;

Or R ₇ , R ₈ and the attached carbon together form -(CH=CH ₂ ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to the selected Substituted from one or more of the following substituents: C1-C6 alkyl, hydroxyl, halogen;

R ₅ ', R ₆ ', R ₇ ', R ₈ ' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy base; the substitution refers to being substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH ₂ , hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, amino, 4 -6-membered heterocyclyl;

Or R ₅ ', R ₆ ' and the attached carbon together form -(CH=CH ₂ ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to is substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, halogen;

Or R ₇ ', R ₈ ' and the attached carbon together form -(CH=CH ₂ ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to Substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxy, halogen.

In a preferred embodiment, the compound described in formula (I) has a structure selected from the following:

Wherein, each substituent is as defined above.

In another preferred embodiment, the compound described in formula (I) has a structure selected from the following:

Wherein, A ₁ and X ₁ are each independently N or CR _x ; R _x is H, F, Cl, -LM; Y ₁ is N or CR _y ; R _y is H, -LM or absent; W ₁ is NH or S or O; R ₁ , R ₂ are each independently fluorine, chlorine, bromine or C1-C4 alkoxy, -LM; and R _{x in} _{A 1} , R _x , R ₁ , R in X ₁ _2. Any two of R _y will not be -LM at the same time.

in,

A ₁ , X ₁ , A ₂ , and X ₂ are each independently N or CR _x ; R _x is H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy said substitution refers to being substituted by a substituent selected from the group consisting of halogen, hydroxyl, C6-C10 aryl, C3-C8 cycloalkyl, 5-7-membered heteroaryl, and 3-8-membered heterocyclyl;

Y ₁ and Y ₂ are each independently N or CH; W ₁ and W ₂ are each independently NH or S; preferably, W ₁ and W ₂ are each independently S.

R ₁ , R _{2 are} independently selected from halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; _{the substitution in R 1} , R ₂ refers to being selected from halogen, hydroxyl , substituted by one or more of methoxy;

L is selected from -(CH ₂ ) _m -(Q) _i -(CH ₂ ) _n -, -O-(CH ₂ ) _m -(Q) _i -(CH ₂ ) _n -O-; m and n are independent is selected from an integer of 1-5; i is 0 or 1; Q is selected from -CH=CH-, -C≡C-, -C(O)-NH-, -NH-C(O)-, -N =CH-, O,

R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , T ₁ , R ₁ ′, R ₂ ′, R ₃ ′, R ₄ ′, R ₅ ′, R ₆ ′, R ₇ ′, R ₈ ', T ₂ and T ₃ are defined as above.

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

The first aspect of the present invention provides a compound represented by general formula (I), or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable compound thereof. Salt.

The compounds of the present invention possess asymmetric centers, chiral axes and chiral planes, and may exist as racemates, R-isomers or S-isomers. Those skilled in the art can obtain the R-isomer and/or S-isomer from the racemate by conventional technical means.

A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or its enantiomers, diastereomers, racemates and mixtures thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.

The present invention provides novel compounds, which can be used alone or mixed with pharmaceutically acceptable excipients (such as excipients, diluents, etc.) to prepare tablets, capsules, granules or syrups for oral administration, etc. . The pharmaceutical composition can be prepared according to conventional methods in pharmacy.

In another preferred embodiment, the pharmaceutical composition further comprises at least one other therapeutic agent. Preferably, the at least one other therapeutic agent contained in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulatory agents, antiallergic agents, antiemetic agents, pain relief agents, cytoprotective agents, and combinations thereof.

The third aspect of the present invention provides the compound represented by the general formula (I) described in the first aspect or the use of the pharmaceutical composition described in the second aspect, for preparing a STING agonist, an immune composition or a vaccine adjuvant;

Or for the prevention and/or treatment of STING-dependent type I interferon-related diseases.

In another preferred embodiment, the STING-dependent type I interferon-related diseases are tumors and infectious diseases.

In another preferred embodiment, the tumor is selected from the group consisting of: brain cancer and spine cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophagus cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer , hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell Tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline tract cancers, and cancers of unknown primary (ie, cancers in which metastatic cancer is found but the site of the original cancer is unknown).

In another preferred embodiment, the infectious disease is selected from: viral infections such as human immunodeficiency virus, herpes simplex virus, hepatitis B virus, hepatitis C virus; pathogenic microorganism infection.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification may be replaced by any alternative feature serving the same, equivalent or similar purpose. Due to space limitations, it is not repeated here.

detailed description

After extensive and in-depth research, the inventors of the present application have developed an arylheterocyclic derivative, especially a 4-(arylthiophene)-4,4-difluoro-polysubstituted butyric acid derivative thing. In the present invention, the multi-substituted derivatives obtained by performing multi-site modification on the aromatic ring and the aromatic heterocycle in the core structure of the aryl-aromatic heterocyclic derivative, or the side chain, can simultaneously activate the human source (human source) efficiently. ) STING (hSTING) and mouse STING (mSTING). For example, for 4-(arylthiophene)-4,4-difluoro-polysubstituted butyric acid derivatives, the present invention is based on the benzene ring, thiophene ring or butyric acid side of the benzothiophene core in the benzothiophene compound Multi-site modification of the chain, such as methyl or fluoride modification on the side chain of butyric acid, modification of the benzene ring and thiophene ring in the parent nucleus by halogen such as fluorine or -LM substituents to obtain multi-substituted derivatives , can efficiently activate both human STING (hSTING) and mouse STING (mSTING). In particular, the drug metabolism (PK) properties of the compound S1 substituted with both methyl and three fluorine atoms in the present invention are significantly improved, so that the compound can be administered orally, avoiding the development of special dosage forms in later studies. On this basis, the present invention has been completed.

the term

In the present invention, when the valence bond of the group has a wavy line

when, for example, in

, the wavy line indicates the point of attachment of this group to the rest of the molecule.

In the present invention, the halogen is F, Cl, Br or I.

In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.

In the present invention, the term "C1-C6" means having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C1-C8" means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "3-8 membered" means having 3-8 ring atoms, and so on "3-6 membered", etc.

In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety, for example, the term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, without limitation include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl and tert-butyl.

In the present invention, the term "alkoxy" denotes a -O-(C1-6 alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.

In the present invention, the term "alkenyl" denotes a straight-chain or branched-chain hydrocarbyl moiety containing at least one double bond, for example, the term "C ₂ -C ₆ alkenyl" means having 2 to 6 carbon atoms containing one double bond The linear or branched alkenyl groups include, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl, and the like.

In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety, for example, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, without limitation Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and the like. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

In the present invention, the term "heterocyclyl" refers to a cyclic group comprising at least one carbon atom and at least one (eg 1-3) ring heteroatoms selected from N, O, S, eg a 3-8 membered heteroatom Cyclic group, 3-6 membered heterocyclic group, etc; Cytidine, 1,2-dithietanyl, 1,3-dithietanyl, azepanyl, oxetanyl, and the like.

In the present invention, the term "5-7 membered heteroaryl" refers to a cyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, which contains in the ring at least one (eg 1-3) independently selected from Ring heteroatoms of N, O and S (eg N), the remaining ring atoms are carbon atoms; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, Thienyl, pyrimidinyl, 1,2,4-triazolyl, etc.; preferably five-membered heteroaryl, such as imidazolyl, isoxazolyl, 1,2,4-triazolyl, benzoxazole base, imidazopyridyl, triazolopyridyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolinyl, isoquinyl and the like.

Unless otherwise specified, alkyl, alkoxy, cycloalkyl, heterocyclyl, and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkene base, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocyclyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl , Heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkyl Imino, C1-C10 alkylsulfoimino, arylsulfoimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothio acyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl groups, heterocyclyl groups, heterocycloalkenyl groups, aryl groups and heteroaryl groups can also be condensed with each other.

In the present invention, the substitution is monosubstitution or polysubstitution, and the polysubstitution is disubstitution, trisubstitution, tetrasubstitution, or pentasubstitution. The disubstituted refers to having two substituents, and so on.

The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate acid, glutamate, glucuronate, lactate, glutamate or maleate. Similarly, salts can be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium, such as tetramethylammonium.

In another preferred embodiment, "pharmaceutically acceptable salt" refers to the salts formed by the compound of formula I with an acid selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, Nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid , Glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or sodium salts, magnesium salts formed by compounds of formula (I) and inorganic bases salts, potassium salts, calcium salts, aluminum salts, manganese salts or ammonium salts; or methylamine salts, ethylamine salts or ethanolamine salts formed by compounds of general formula (I) and organic bases.

The present invention is based on the multi-site modification of the aromatic ring and the aromatic heterocyclic ring in the core structure of the aryl-aromatic heterocyclic derivative, or the side chain to obtain multi-substituted derivatives, and these multi-substituted derivatives can simultaneously and efficiently Activates human STING (hSTING) and mouse STING (mSTING). In particular, in the series of benzothiophene compounds of the present invention, the benzene ring, the thiophene ring or the side chain of butyric acid in the benzothiophene core of the benzothiophene compound is modified at multiple sites, such as the side chain of butyric acid. Modifications such as methyl or halogenation such as fluorination are carried out, and the benzene ring and thiophene ring in the parent nucleus are modified with halogens such as fluorine or -LM substituents to obtain multi-substituted derivatives, which can efficiently activate human STING (human) STING ( hSTING) and mouse STING (mSTING). Specifically, the drug metabolism (PK) properties of the compound S1 substituted with both methyl and three fluorine atoms in the present invention are significantly improved, so that the compound can be administered orally, avoiding the development of special dosage forms in later studies. Specifically, the representative compounds of the present invention are compared with the known compound IA in which neither the parent nucleus nor the side chain is substituted with methyl and fluorine atoms, and the known compound IB with only methyl group but no substitution with fluorine atoms in the side chain. The advantages of S1 are reflected in:

1. The half-life T1/2 reaches 1.56 hours, which is 2.4 times that of compound IA and 2 times that of IB;

2. The exposure of oral administration is significantly increased, which is 7.5 times that of compound IA and 5.8 times that of IB;

3. The exposure of intravenous administration was significantly increased, which was 10.4 times that of compound IA and 7.2 times that of IB.

It can be seen that these compounds containing multiple special group substitutions at the same time not only show high agonistic activity to hSTING or mSTING, but also significantly improve the metabolic properties in rats, which makes the pharmacodynamics and safety of these compounds in vivo. Whether it is administered intravenously or orally, its efficacy is fully exposed at the time of evaluation, which has significant advantages and potential for further development compared with the STING inhibitors reported so far.

pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising the active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.

The "active ingredient" in the present invention refers to the compound of formula (I) in the present invention.

The "active ingredients" and pharmaceutical compositions of the present invention are used to prepare medicines for treating tumors and infectious diseases. The "active ingredients" and pharmaceutical compositions of the present invention can be used as STING agonists to activate STING.

The tumor is selected from the group consisting of: brain and spine cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer , gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, Malignant rhabdoid tumors, soft tissue sarcomas, midline tract cancers, and cancers of unknown primary (ie, cancers in which metastatic cancer is found but the site of the original cancer is unknown).

A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient/dose, more preferably 10-200 mg of active ingredient/dose. Preferably, the "one dose" is one tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

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

In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention may be administered alone or in combination with other therapeutic agents such as antineoplastic agents.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental method of unreceipted specific conditions in the following examples, usually according to conventional conditions (such as Sambrook et al., molecular cloning: conditions described in laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989)) or according to manufacturing conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Preferred embodiments and materials described herein are provided for illustrative purposes only.

Preparation of the compound of Example 1

1. Synthesis of compound S1

Step 1: Compound 1a (1eq) was dissolved in toluene in a sealed tube, rhodamine (1.1eq) and ammonium acetate (2eq) were added, and the temperature was raised to 160° C. to react for 20 minutes. After cooling, a large amount of solid was precipitated, and an appropriate amount of ethanol was added to dilute, and filtered. The filter cake was washed with water and then slurried with ethanol, and dried to obtain compound 1b. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24(s, 1H), 7.83(s, 1H), 7.17-7.07(m, 1H), 6.82(d, J=9.0Hz, 1H), 3.95(s, 6H).

Step 2: Compound 1b (1eq) was suspended in 2.5M aqueous sodium hydroxide (2.5eq) solution, heated to 75°C and reacted for 30 minutes, the reaction solution became clear. Add an appropriate amount of activated carbon, stir for 15 minutes, filter while hot. The filtrate was added dropwise to 6N hydrochloric acid in an ice bath, filtered after the solid was fully separated out, the filter cake was slurried with water, and dried to obtain compound 1c. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.64 (t, J=8.4 Hz, 1H), 6.80 (dd, J=9.0, 1.5 Hz, 1H), 4.67 (s, 1H) ,3.93(s,6H).

Step 3: The compound 1c (1eq) was placed in a sealed tube and dissolved in 1,4-dioxane, iodine element (1.5eq) was added, and the temperature was raised to 150° C. to react overnight. After cooling, the reaction solution was poured into water, an appropriate amount of saturated sodium thiosulfate solution was added dropwise to decolorize, extracted with ethyl acetate, and purified to obtain compound 1d. ¹ H NMR (400MHz, DMSO) δ 13.50(s, 1H), 7.92(s, 1H), 7.58(s, 1H), 3.91(s, 3H), 3.84(s, 3H).

Step 4: Compound 1d (1eq) was dissolved in N-methylpyrrolidone, silver carbonate (1.2eq) and o-phenanthroline (0.1eq) were added, and the temperature was raised to 170° C. to react for 1 hour. After the reaction solution was cooled, it was passed through celite, and the filtrate was extracted with ethyl acetate to purify to obtain compound 1e. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (d, J=5.5 Hz, 1H), 7.27 (d, J=4.5 Hz, 1H), 7.13 (s, 1H), 3.99-3.97 (m, 3H) ,3.94(s,3H).

Step 5: Suspend (S)-methylsuccinic anhydride (1.5eq) and aluminum chloride (2eq) in 1,2-dichloroethane, add compound 1e (1eq) in dichloromethane dropwise at -10°C Ethyl chloride solution. After the addition was completed, the temperature was raised to 45°C for overnight reaction. After cooling, it was poured into ice water, an appropriate amount of 4N hydrochloric acid was added, extracted with ethyl acetate, and purified to obtain mixtures 1f and 1g.

Step 6: Dissolve the mixture 1f and 1 g (1 eq) in anhydrous methanol, slowly add thionyl chloride (10 eq) under an ice bath, move to room temperature and react for 1 hour after the addition is complete. The solvent was removed, and the residual oil was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with salt, and dried over anhydrous sodium sulfate to obtain mixtures 1h and 1i.

Step 7: Under nitrogen protection, the mixtures 1j and 1k (1eq) were dissolved in ultra-dry dichloromethane, 1,3-propanedithiol (2eq) and boron trifluoride ether complex ( 1eq), the reaction was moved to room temperature for 48 hours after the reaction for 2 hours. The reaction was quenched with an appropriate amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, and purified to obtain pure products 1j and 1k.

Compound 1j: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (s, 1H), 7.02 (s, 1H), 3.96 (d, J=0.7 Hz, 3H), 3.93 (s, 3H), 3.41 (s ,3H),3.00–2.93(m,2H),2.87–2.71(m,4H),2.09–1.99(m,2H),1.97–1.87(m,1H),1.13(d,J=6.8Hz,3H ).

Compound 1k: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46(s, 1H), 7.02(s, 1H), 3.97(s, 3H), 3.93(s, 3H), 3.63(s, 3H), 3.04 –2.90(m,3H),2.76(d,J=14.9Hz,2H),2.70-2.65(m,1H),2.25(dd,J=15.8,10.7Hz,1H),2.04-1.98(m1H) ,1.94-1.82(m,1H),1.14(d,J=6.7Hz,3H).

Step 8: Compound 1j (1eq) was dissolved in ultra-dry dichloromethane, diethylaminosulfur trifluoride (20eq) was added, and the reaction was carried out at room temperature for 5 hours. Quenched with saturated ammonium chloride solution, extracted with dichloromethane, and purified to obtain compound 11. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.44(s, 1H), 7.07(s, 1H), 3.97(s, 3H), 3.94(s, 3H), 3.65(s, 3H), 2.96–2.80( m, 2H), 2.37–2.24 (m, 1H), 1.28 (d, J=6.8Hz, 3H).

Step 9: Dissolve compound 11 (1eq) in tetrahydrofuran, add an aqueous solution of lithium hydroxide monohydrate (3eq), react at room temperature for 3 hours, add 1N hydrochloric acid dropwise to adjust the pH to 6-7, extract with ethyl acetate, and purify to obtain Compound S1.

Compound S1: ¹ H NMR (400MHz, CDCl ₃ )δ7.47(s,1H), 7.08(s,1H), 3.97(s,3H), 3.94(s,3H), 2.98-2.83(m,2H) ,2.39-2.26(m,1H),1.34(d,J=6.6Hz,3H).

2. Synthesis of Compound S2

Step 1: Dissolve compound 1k (1 eq) in ultra-dry dichloromethane, add diethylaminosulfur trifluoride (20 eq), and react at room temperature for 5 hours. Quenched with saturated ammonium chloride solution, extracted with dichloromethane, and purified to give compound 2a. ¹ H NMR (400MHz, CDCl ₃ )δ7.45(s,1H), 7.08(s,1H), 3.98(s,3H), 3.95(s,3H), 3.69(s,3H), 2.89(br, 1H), 2.76(dd, J＝15.9, 3.9Hz, 1H), 2.31(dd, J＝16.1, 9.8Hz, 1H), 1.13(d, J＝6.9Hz, 3H).

Step 2: Compound 2a (1 eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (3 eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S2.

Compound S2: ¹ H NMR (400MHz, CDCl ₃ )δ7.45(s,1H), 7.08(s,1H), 3.98(s,3H), 3.94(s,3H), 2.93-2.85(m,1H) ,2.82(dd,J＝16.5,3.6Hz,1H),2.35(dd,J＝16.3,9.7Hz,1H),1.16(d,J＝6.9Hz,3H).

3. Synthesis of compound S3

The same compound S1 was synthesized except that (S)-methylsuccinic anhydride was replaced with itaconic anhydride.

Compound S3: ¹ H NMR (400MHz, CDCl ₃ )δ7.48(s,1H), 7.07(s,1H), 6.32(s,1H), 5.80(s,1H), 3.98(s,3H), 3.96 (s, 3H), 2.95–2.86 (m, 2H).

4. Synthesis of Compound S4

The same compound S2 was synthesized except that (S)-methylsuccinic anhydride was replaced with itaconic anhydride.

Compound S4: ¹ H NMR (400MHz, CDCl ₃ )δ7.51(s,1H), 7.12(s,1H), 6.77(s,1H), 5.91(s,1H), 3.99(s,3H), 3.98 (s,3H),3.02(s,2H).

5. Synthesis of Compound S5

Step 1: Suspend (S)-(-)-2-acetoxysuccinic anhydride (1.5eq) and aluminum chloride (2eq) in 1,2-dichloroethane and add dropwise at -10°C A solution of compound 1e (1 eq) in dichloroethane. After the dropwise addition, the temperature was raised to 45°C and the reaction was carried out overnight. After cooling, the reaction solution was poured into ice water, an appropriate amount of 4N hydrochloric acid was added, extracted with ethyl acetate, and purified to obtain mixtures 5a and 5b.

Step 2: Dissolve the mixtures 5a and 5b (1 eq) in anhydrous methanol, slowly add thionyl chloride (10 eq) under an ice bath, and react at room temperature for 1 hour after the addition. The solvent was removed, the residual oil was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with salt, dried over anhydrous sodium sulfate, and the solvent was removed to obtain mixtures 5c and 5d.

Step 3: Under nitrogen protection, mixtures 5c and 5d (1 eq) were dissolved in ultra-dry dichloromethane, 1,3-propanedithiol (2eq) and boron trifluoride ether complex ( 1eq), after adding the reaction for 2 hours, the reaction was moved to room temperature for 48 hours. The reaction was quenched with an appropriate amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, and purified to give pure products 5e and 5f.

Step 4: Compound 5e (1 eq) was dissolved in ultra-dry dichloromethane, diethylaminosulfur trifluoride (20 eq) was added, and the reaction was carried out at room temperature for 5 hours. Quenched with saturated ammonium chloride solution, extracted with dichloromethane, and purified to give compound 5f.

Step 5: Compound 5f (1 eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (5 eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S5.

Compound S5: ¹ H NMR (400MHz, CDCl ₃ )δ7.46(s,1H), 7.05(s,1H), 4.28-4.19(m,1H), 3.94(s,3H), 3.87(s,3H) ,2.41–2.38(m,2H).

6. Synthesis of compound S6

Step 1: Dissolve compound 5d (1 eq) in ultra-dry dichloromethane, add diethylaminosulfur trifluoride (20 eq), and react at room temperature for 5 hours. Quenched with saturated ammonium chloride solution, extracted with dichloromethane, and purified to give compound 6a.

Step 2: Compound 6a (1 eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (5 eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S6.

Compound S6: ¹ H NMR (400MHz, CDCl ₃ )δ7.44(s,1H), 7.08(s,1H), 4.79-4.65(m,1H), 3.95(s,3H), 3.86(s,3H) ,2.52–2.46(m,2H).

7. Synthesis of compound S7

Step 1: The mixtures 5a and 5b (1 eq) were dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (3 eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to give mixtures 7a and 7b.

Step 2: Dissolve the mixtures 7a and 7b (1 eq) in anhydrous methanol, slowly add thionyl chloride (10 eq) under an ice bath, move to room temperature and react for 1 hour after the addition is complete. The solvent was removed, the residual oil was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with salt, and dried over anhydrous sodium sulfate to obtain mixtures 7c and 7d.

Step 3: Under nitrogen protection, the mixtures 7c and 7d (1 eq) were dissolved in ultra-dry dichloromethane, 1,3-propanedithiol (2eq) and boron trifluoride ether complex ( 1eq), the reaction was moved to room temperature for 48 hours after the reaction for 2 hours. The reaction was quenched with an appropriate amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, and purified to give pure products 7e and 7f.

Step 4: Dissolve compound 7e (1 eq) in ultra-dry DCM, add diethylaminosulfur trifluoride (20 eq), react at room temperature for 5 hours, quench with saturated ammonium chloride solution, extract with dichloromethane, and purify to obtain Compound 7g.

Step 5: Compound 7g (1eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (3eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S7.

Compound S7: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46(s, 1H), 7.07(s, 1H), 4.81-3.78(m, 1H), 3.93(s, 3H), 3.86(s, 3H) ,2.85–2.76(m,2H).

8. Synthesis of Compound S8

The same compound S5 was synthesized except that (S)-(-)-2-acetoxysuccinic anhydride was replaced by (R)-(+)-2-acetoxysuccinic anhydride.

Compound S8: ¹ H NMR (400MHz, CDCl ₃ )δ7.44(s,1H), 7.06(s,1H), 4.29-4.22(m,1H), 3.93(s,3H), 3.86(s,3H) ,2.43–2.39(m,2H).

9. Synthesis of Compound S9

The same compound S7 was synthesized except that (S)-(-)-2-acetoxysuccinic anhydride was replaced with (R)-(+)-2-acetoxysuccinic anhydride.

Compound S9: ¹ H NMR (400MHz, CDCl ₃ )δ7.45(s,1H), 7.08(s,1H), 4.78-3.67(m,1H), 3.92(s,3H), 3.85(s,3H) ,2.86–2.78(m,2H).

10. Synthesis of compound S10

The same compound S1 was synthesized except that (S)-methylsuccinic anhydride was replaced by (S)-methoxysuccinic anhydride.

Compound S10: ¹ H NMR (400MHz, CDCl ₃ )δ7.41(s,1H), 7.14(s,1H), 4.48-4.40(m,1H), 3.92(s,3H), 3.86(s,3H) ,3.47(s,3H),2.89–2.79(m,2H).

11. Synthesis of compound S11

The same compound S2 was synthesized except that (S)-methylsuccinic anhydride was replaced by (S)-methoxysuccinic anhydride.

Compound S11: ¹ H NMR (400MHz, CDCl ₃ )δ7.52(s,1H), 7.13(s,1H), 5.05-4.99(m,1H), 3.93(s,3H), 3.86(s,3H) ,3.51(s,3H),2.74–2.63(m,2H).

12. Synthesis of compound S12

Step 1: Compound 7c (1 eq) was dissolved in tetrahydrofuran, and sodium hydride (2 eq) was added under ice bath to react for 2 hours. Then bromoacetonitrile (3eq) was added dropwise to react overnight. Quenched with water, extracted with ethyl acetate, and purified to obtain compound 12a.

Step 2: Add 33% hydrobromic acid in acetic acid solution to compound 12a (1 eq), and react at room temperature for 1 hour. The reaction solution was neutralized with an appropriate amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, and purified to obtain compound 12b.

Step 3: Under nitrogen protection, compound 12b (1eq) was dissolved in ultra-dry dichloromethane, 1,3-propanedithiol (2eq) and boron trifluoride ether complex (1eq) were added under ice bath , the reaction was moved to room temperature overnight after 2 hours of reaction. The reaction was quenched with an appropriate amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, and purified to give compound 12c.

Step 4: Compound 12c (1 eq) was dissolved in ultra-dry dichloromethane, diethylaminosulfur trifluoride (20 eq) was added, and the reaction was carried out at room temperature for 2 hours. Quenched with saturated ammonium chloride solution, extracted with dichloromethane, and purified to give compound 12d.

Step 5: Compound 12d (1 eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (3 eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S12.

Compound S12: ¹ H NMR (400MHz, CDCl ₃ )δ7.48(s,1H), 7.21(s,1H), 6.98(br,2H), 4.26-4.17(m,1H), 4.09(s,2H) ,3.91(s,3H),3.86(s,3H),2.85–2.75(m,2H).

13. Synthesis of compound S13

The same compound S1 was synthesized except that (S)-methylsuccinic anhydride was replaced with 2,2-dimethylsuccinic anhydride.

Compound S13: ¹ H NMR (400MHz, CDCl ₃ )δ7.46(s,1H), 7.16(s,1H), 3.90(s,3H), 3.83(s,3H), 2.64-2.51(m,2H) ,1.23(s,6H).

14. Synthesis of compound S14

Step 1: Compound 9c (1eq, intermediate of compound S8) was dissolved in N,N-dimethylformamide, ethyl 2-chloroacetate (1.5eq) and potassium carbonate (3eq) were added, and the temperature was raised to 60°C React overnight. Diluted with water, extracted with ethyl acetate, and purified to obtain compound 14a.

Step 2: Under nitrogen protection, compound 14a (1eq) was dissolved in ultra-dry dichloromethane, 1,3-propanedithiol (2eq) and boron trifluoride ether complex (1eq) were added under ice bath , reacted for 2 hours, moved to room temperature and reacted overnight, quenched the reaction with an appropriate amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, and purified to obtain compound 14b.

Step 3: Compound 14b (1 eq) was dissolved in ultra-dry dichloromethane, diethylaminosulfur trifluoride (20 eq) was added, and the reaction was carried out at room temperature for 6 hours. Quenched with saturated ammonium chloride solution, extracted with dichloromethane, and purified to give compound 14c.

Step 4: Compound 14c (1 eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (5 eq) was added, and the reaction was carried out at room temperature for 5 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S14.

Compound S14: ¹ H NMR (400MHz, CDCl ₃ )δ7.46(s,1H), 7.19(s,1H), 4.20-4.15(m,1H), 3.90(s,3H), 3.84(s,3H) ,3.70-3.56(m,4H),2.85-2.75(m,2H).

15. Synthesis of compound S15

The same compound S14 was synthesized except that 3-chloropropyl acetate was used to replace 2-chloroethyl acetate.

Compound S15: ¹ H NMR (400MHz, CDCl ₃ )δ7.48(s,1H), 7.18(s,1H), 4.52-4.48(m,1H), 3.92(s,3H), 3.87(s,3H) ,3.69-3.57(m,4H),2.76-2.63(m,2H),1.91-1.84(m,2H).

16. Synthesis of compound S16

Step 1: Suspend Z-aspartic anhydride (1.5eq) and aluminum chloride (2eq) in 1,2-dichloroethane, add compound 1e (1eq) in dichloroethane dropwise at -10°C Ethane solution. After the dropwise addition, the temperature was raised to 45°C and the reaction was carried out overnight. After cooling, the reaction solution was poured into ice water, an appropriate amount of 4N hydrochloric acid was added, extracted with ethyl acetate, and purified to obtain compound 16a.

Step 2: Dissolve compound 16a (1 eq) in anhydrous methanol, slowly add thionyl chloride (10 eq) under ice bath, move to room temperature and react for 1 hour after the addition is complete. The solvent was removed, the residual oil was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with salt, dried over anhydrous sodium sulfate, and the solvent was removed to obtain compound 16b.

Step 3: Under nitrogen protection, compound 16b (1eq) was dissolved in ultra-dry dichloromethane, 1,3-propanedithiol (2eq) and boron trifluoride ether complex (1eq) were added under ice bath , the reaction was moved to room temperature for 48 hours after the reaction for 2 hours. The reaction was quenched with an appropriate amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, and purified to give compound 16c.

Step 4: Compound 16c (1 eq) was dissolved in ultra-dry dichloromethane, diethylaminosulfur trifluoride (20 eq) was added, and the reaction was carried out at room temperature for 5 hours. Quenched with saturated ammonium chloride solution, extracted with dichloromethane, and purified to give compound 16d.

Step 5: Compound 16d (1 eq) was dissolved in anhydrous methanol, 10% Pd/C was added, hydrogen was usually pressed, and the reaction was carried out at room temperature for 6 hours. The reaction solution was passed through celite, and the solvent was removed from the filtrate to obtain compound 16e.

Step 6: Compound 16e (1 eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (3 eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S16.

Compound S16: ¹ H NMR (400MHz, CDCl ₃ )δ7.42(s,1H), 7.14(s,1H), 4.08-3.97(m,1H), 3.94(s,2H), 3.90(s,3H) ,3.84(s,3H),2.78–2.66(m,2H).

17. Synthesis of compound S17

Step 1: Under nitrogen protection, compound 16e (1eq) was dissolved in 1,4-dioxane, methylboronic acid (1.5eq), copper acetate (1.5eq), pyridine (4eq) were added, and the mixture was heated at 120°C The reaction was continued for 3 hours. Diluted with water, extracted with ethyl acetate, and purified to obtain compound 17a.

Step 2: Compound 17a (1 eq) was dissolved in tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (3 eq) was added, and the reaction was carried out at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, extracted with ethyl acetate, and purified to obtain compound S17.

Compound S17: ¹ H NMR (400MHz, CDCl ₃ )δ7.43(s,1H), 7.18(s,1H), 4.32-4.27(m,1H), 4.01(s,1H), 3.91(s,3H) ,3.85(s,3H),2.67–2.59(m,2H),2.39(s,3H).

18. Synthesis of compound S18

The same compound S1 was synthesized except that (S)-methyl succinic anhydride was replaced with cyclopropyl succinic anhydride.

Compound S18: ¹ H NMR (400MHz, CDCl ₃ )δ7.47(s,1H), 7.17(s,1H), 3.88(s,3H), 3.82(s,3H), 2.63-2.51(m,2H) ,1.28–1.16(m,4H).

19. Synthesis of compound S19

In addition to replacing 4-fluoro-5,6-dimethoxybenzothiophene with 5,6-dimethoxythiophene[2,3-b]pyridine-2-carboxylic acid (compound 19a, synthetic reference: WO 2019195063A1) -2-Carboxylic acid (compound 1d), other synthesis is the same as compound S1.

Compound S19: ¹ H NMR (400MHz, CDCl ₃ )δ7.88(s,1H), 7.56(s,1H), 4.03(s,3H), 3.89(s,3H), 3.01-2.85(m,2H) ,2.38–2.29(m,1H),1.32(d,J=6.8Hz,3H).

20. Synthesis of compound S20

In addition to replacing 4-fluoro-5,6-dimethoxybenzothiophene (compound 1e) with 6-bromo-5-methoxythiophene[3,2-b]pyridine (compound 20a, synthetic reference: WO 2019195063A1) , other synthesis is the same as compound S1.

Compound S20: ¹ H NMR (400MHz, CDCl ₃ )δ8.78(s,1H), 8.21(s,1H), 4.04(s,3H), 3.03-2.89(m,2H), 2.69-2.56(m, 1H), 1.35(d, J=6.9Hz, 3H).

21. Synthesis of compound S21

In addition to replacing 4-fluoro-5,6-dimethoxybenzothiophene-2 with 2,3-dimethoxythiophene[2,3-b]pyrazine-6-carboxylic acid (Synthesis reference: WO 2019195063A1) -Carboxylic acid (compound 1d), other synthesis is the same as compound S1.

Compound S21: ¹ H NMR (400MHz, CDCl ₃ )δ8.29(s,1H), 4.03(s,3H), 3.99(s,3H), 3.13-2.88(m,2H), 2.65-2.59(m, 1H), 1.28(d, J=6.7Hz, 3H).

22. Synthesis of compound S22

In addition to replacing 4-fluoro-5,6-dimethoxybenzothiophene with 5,6-dimethoxythiophene[3,2-b]pyridine-2-carboxylic acid (compound 22a, synthetic reference: WO 2019195063A1) -2-Carboxylic acid (compound 1d), other synthesis is the same as compound S1.

Compound S22: ¹ H NMR (400MHz, CDCl ₃ )δ7.92(s,1H), 7.41(s,1H), 4.03(s,3H), 3.98(s,3H), 3.13-2.89(m,2H) ,2.76–2.64(m,1H),1.36(d,J=6.6Hz,3H).

23. Synthesis of compound S23

In addition to substituting 5,6-dimethoxybenzothiophene-2-carboxylic acid (compound 23a) for 4-fluoro-5,6-dimethoxybenzothiophene-2-carboxylic acid (compound 1d), other syntheses Same as compound S1.

Compound S23: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.35(s, 1H), 7.25(s, 1H), 7.20(s, 1H), 3.95(s, 3H), 3.94(s, 3H), 2.89 (q, J=13.6Hz, 2H), 2.36–2.24 (m, 1H), 1.33 (d, J=6.8Hz, 3H).

24. Synthesis of compound S24

Step 1: The same compound S23 was synthesized except that (S)-methylsuccinic anhydride was replaced with succinic anhydride.

Step 2: Under nitrogen protection, compound 24e (1eq) was dissolved in N,N-dimethylformamide, 3-aminopropionitrile (1.2eq), 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (1.5eq), 1-hydroxybenzotriazole (1.5eq), N,N-diisopropylethylamine (4eq), react at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, and purified to obtain compound 24f.

Step 3: Under nitrogen protection, compound 24f (1 eq) and triphenylphosphine (2.5 eq) were dissolved in ultra-dry acetonitrile, cooled to 0 °C and stirred for about 10 minutes, and then diisopropyl azodicarboxylate was added dropwise Ester (2.5eq), after about 5 minutes, azidotrimethylsilane (3eq) was added dropwise, and after stirring at 0°C for about 1 hour, the temperature was raised to 50°C to react overnight. The reaction solution was cooled to 0°C, an appropriate amount of sodium nitrite aqueous solution was added and stirred for about 20 minutes, then an aqueous solution of ceric ammonium nitrate was added and stirred for 30 minutes, diluted with water, extracted with ethyl acetate, and purified to obtain compound S24.

Compound S24: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 7.26-7.24 (m, 1H), 7.21 (s, 1H), 4.55 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.25–3.18 (m, 2H), 3.09 (t, J=6.6Hz, 2H), 2.99 (ddd, J=23.0, 15.6, 7.7Hz, 2H).

25. Synthesis of compound S25

Step 1: Under nitrogen protection, compound S24 (1eq) was dissolved in ultra-dry dichloromethane, 1,8-diazabicycloundec-7-ene (7eq) was added, and the reaction was performed at room temperature for about 4 hours Diluted with water, extracted with ethyl acetate, and purified to obtain compound S25.

Compound S25: ¹ H NMR (400MHz, DMSO-d ₆ )δ7.65(s,1H), 7.62(s,1H), 7.42(s,1H), 3.84(s,3H), 3.82(s,3H) ,3.12(dd,J=9.2,6.5Hz,2H),2.99–2.83(m,2H).

26. Synthesis of compound H26

In a dry round-bottomed flask at room temperature, compound 24e (70 mg, 0.22 mmol), HATU (100 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (2 mL), and a solution of methylamine in tetrahydrofuran (4N) was added successively at room temperature. , 0.6mL). Stirring at room temperature, after reacting for 1 hour, it was directly concentrated, and then the obtained residue was purified by reverse phase to obtain the product H26 (67 mg, white solid), yield: 92.5%. LCMS (ESI): m/z 310.1 [M-19+H] ⁺ ;

¹ H-NMR (400MHz, DMSO-d ₆ ): 7.87-7.86(brs,1H), 7.60(s,1H), 7.59(s,1H), 7.41(s,1H), 3.83(s,3H), 3.81(s, 3H), 2.62-2.58(m, 2H), 2.55(s, 3H), 2.30-2.26(m, 2H).

27. Synthesis of compound H27

Compound 24d (60 mg, 0.18 mmol), (trifluoromethyl)trimethylsilane (258 mg, 1.82 mmol) was dissolved in tetrahydrofuran (20 mL) in a dry round-bottomed flask at room temperature, and the mixture was placed in a nitrogen atmosphere. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1 N, 0.02 mL) was added to a -78°C dry ice bath. After stirring at room temperature for 2 hours, 20 mL of water was added, extracted with ethyl acetate, and the organic phases were combined. Washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase system to obtain compound H27 (6 mg, white solid), yield: 9.1%. LCMS (ESI): m/z 367.0 [MH] ⁺ ;

¹ H-NMR (DMSO-d ₆ , 400MHz): 7.44(s, 1H), 7.43(s, 1H), 7.37(s, 1H), 3.90(s, 3H), 3.89(s, 3H), 2.46- 2.42(m,2H),1.98-1.94(m,2H).

28. Synthesis of compound H28

Step 1: To a solution of LiHMDS (9.08 mL, 9.08 mmol) in THF (30 mL) was added EtOAc (800 mg, 9.08 mmol) dropwise at -78 °C. After the dropwise addition was completed, the temperature was kept constant and stirring was continued for 1 hour. Compound 24d (300 mg, 0.9 mmol) was added dropwise to the above solution at -78°C. After stirring for 1 hour warmed to 0 ℃, the addition of saturated aqueous NH ₄ Cl quenched. Extracted with EtOAc, concentrated and purified to give compound 28a (100 mg, white waxy solid) in 28.5% yield. LCMS(ESI): m/z 386.2[M+H] ⁺ .

Step 2: To 1 mL of compound 28a (50 mg, 0.13 mmol) in ethanol, was added hydrazine hydrate (7 mg, 0.14 mmol) at room temperature. Under nitrogen protection, the mixture was stirred at room temperature for 2 hours. Purification by reverse phase HPLC gave H28 (6 mg, white solid) in 13.1% yield. LCMS(ESI): m/z 353.0[MH] ^- ;

¹ H NMR (400MHz, DMSO-d ₆ )δ7.63(s,1H), 7.61(s,1H), 7.42(s,1H), 5.36(s,1H), 3.83(s,3H), 3.82( s,3H),2.68–2.66(m,4H).

29. Synthesis of compound H29

The NH ₄ OH hydrochloride (10mg, 0.15mmol) was dissolved in MeOH / H in _{2 O (2mL, 1/1} ), maintaining the temperature at 0 ℃. 0.5 mL of aqueous NaOH (12 mg, 0.31 mmol) was added dropwise. After stirring for 5 minutes, 0.5 mL of compound 28a (60 mg, 0.15 mmol) in methanol was added. Under nitrogen protection, stirring was continued at 0°C for 2 hours. The reaction system was purified by reverse-phase HPLC to obtain H29 (16 mg, white solid) with a yield of 29.0%. LCMS(ESI): m/z354.1[MH] ^- ;

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64(s,1H),7.62(s,1H),7.42(s,1H),3.86-3.82(m,7H),2.78-2.66(m,4H) ).

30. Synthesis of compound H30

Compound H27 (90 mg, 0.24 mmol) and tetrahydrofuran (5 mL) were added to a dry three-necked flask at room temperature, placed in a nitrogen atmosphere, and a solution of lithium triethylborohydride in tetrahydrofuran (1N, 0.7 m) was added at -78°C. . After stirring at room temperature for 2 hours, 20 mL of water was added, extracted with ethyl acetate, and the organic phases were combined. It was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. After purification, the product H30 (6 mg, white solid) was obtained with a yield of 6.8%.

¹ H-NMR (400MHz, MeOD-d ₄ )δ7.44(s, 2H), 7.37(s, 1H), 4.00-3.98(m, 1H), 3.97-3.95(m, 6H), 2.58-2.53( m,2H),1.88-1.72(m,2H).

31. Synthesis of compound H31

Compound H27 (120 mg, 0.33 mmol), (trifluoromethyl)trimethylsilane (460 mg, 3.26 mmol) 3 mL of tetrahydrofuran were sequentially added to a dry round-bottomed flask at room temperature, placed under nitrogen, and a dry ice bath at -78 °C was placed. To this was added tetrabutylammonium fluoride in tetrahydrofuran (1 N, 0.03 mL). After stirring at room temperature for 2 hours, 20 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified to obtain H31 (15 mg, yellow solid), yield 10.4%. LCMS (ESI): m/z 436.9 [MH] ^- ;

¹ H NMR (MeOD-d ₄ , 400MHz) δ 7.45-7.44(m, 2H), 7.37(s, 1H), 3.90-3.89(m, 6H), 2.61-2.49(m, 2H), 2.15-2.11 (m,2H).

32. Synthesis of compound H32

Step 1: Compound 32a (10 g, 71.9 mmol) and N-bromosuccinimide (15.3 g, 86.3 mmol) were added to a dry single-necked bottle in turn, dissolved in dry N,N-dimethylformamide (20 mL), then reacted at room temperature overnight. Ethyl acetate was extracted, and the organic phase was dried, concentrated and purified to obtain compound 32b (12 g, yellow oil), yield: 80%. LCMS(ESI): m/z 219.9[M+H] ⁺ .

Step 2: Compound 32b (6 g, 27.6 mmol) was added to a dry three-necked flask, and dissolved in dry tetrahydrofuran (60 mL). Under nitrogen protection, n-butyllithium (20.4 mL, 33.2 mmol) was slowly added, reacted at -78 °C for 1 hour, then N,N-dimethylformamide (6 g, 82.8 mmol) was added, and reacted at -78 °C for 1 hour . Ethyl acetate was extracted, and the organic phase was dried, concentrated and purified to obtain compound 32c (3.1 g, yellow solid), yield: 80%. LCMS(ESI): m/z 168.2[M+H] ⁺ .

Step 3: Compound 32c (3.1 g, 18.5 mmol) was added successively in a dry single-necked flask, dissolved in methanol (30 mL), the reaction was stirred in an ice-water bath for 10 minutes, and then sodium borohydride (2.1 g, 55.6 mmol) was added , and react at room temperature for about an hour. Extracted with dichloromethane, the organic phase was dried, concentrated and purified to obtain compound 32d (1.3 g, yellow oil), yield: 43%. LCMS(ESI): m/z 170.2[M+H] ⁺ .

Step 4: Compound 32d (2.5 g, 14.8 mmol) and N-bromosuccinimide (3.9 g, 22.2 mmol) were sequentially added to a dry single-necked flask, dissolved in dry N,N-dimethylformaldehyde amide (20 mL), then reacted overnight at room temperature. Extracted with ethyl acetate, the organic phase was dried and concentrated, and separated on a silica gel column to obtain compound 32e (2.1 g, white solid), yield: 58%. LCMS(ESI): m/z 249.9[M+H] ⁺ .

Step 5: 32e (2.1 g, 8.5 mmol) was sequentially added to a dry single-necked bottle, and manganese dioxide (7.4 g, 85 mmol) was dissolved in dichloromethane (20 mL). Stir at room temperature for 2 hours. Filtration and concentration gave compound 32f (1.9 g, white solid). LCMS(ESI): m/z 246.0[M+H] ⁺ .

Step 6: Add 32f (2.4g, 9.79mmol), methyl thioglycolate (1.6g, 14.7mmol), potassium carbonate (4.1g, 29.4mmol) successively in a dry single-necked bottle to dissolve in N,N-dimethyl Formamide (20 mL) was stirred at 60°C for 5 hours. Ethyl acetate was extracted, and the organic phase was dried, concentrated and purified to obtain compound 32 g (1.7 g, white solid), yield: 54%. LCMS(ESI): m/z 254.0[M+H] ⁺ .

Step 7: Add 32 g (2.4 g, 9.79 mmol) and sodium hydroxide (1.7 g, 6.72 mmol) to a dry single-necked flask in sequence, dissolve in tetrahydrofuran (10 mL) and water (10 mL), and stir at room temperature for 12 hours. The pH was adjusted to 5-6 with HCl, and the filter cake was obtained by filtration for 32 h (1.28 g, white solid). Yield: 80%. LCMS(ESI): m/z 240.0[M+H] ⁺ .

Step 8: Add 32h (1.28g, 5.44mmol), 1,10-phenanthroline (979mg, 5.44mmol), silver carbonate (1.5g, 5.44mmol) to N-methylpyrrolidone successively in a dry single-necked bottle (15 mL) was stirred at 150°C for 2 hours. Ethyl acetate was extracted, and the organic phase was dried, concentrated and purified to obtain compound 32i (742 mg, white solid). Yield: 70%. LCMS(ESI): m/z 196.0[M+H] ⁺ .

Step 9: Compound 32i (700 mg, 3.59 mmol) was added to a dry three-necked flask, and dissolved in dry tetrahydrofuran (20 mL). Under nitrogen protection, n-butyllithium (3.4 mL, 5.39 mmol) was slowly added to react at -78°C for one hour, and then succinic anhydride (1.1 g, 10.78 mmol) was added to react at room temperature for one hour. The pH was adjusted to 5-6 with HCl, extracted with ethyl acetate, concentrated and purified to obtain compound 32j (200 mg, yellow solid), yield: 20%. LCMS(ESI): m/z 296.0[M+H] ⁺ .

Step 10: Add 32j (180 mg, 0.65 mmol) and chloroform (162 mg, 1.36 mmol) to a dry single-necked bottle in sequence, dissolve in methanol (15 mL), and stir at 80 degrees for 2 hours. Drying, concentration and purification gave compound 32k (140 mg, yellow solid), yield: 72%. LCMS(ESI): m/z 310.0[M+H] ⁺ .

Step 11: Add 32k (180mg, 0.65mmol), 1,3-propane dithiol (97 mg, 0.9mmol), boron trifluoride ether (128mg, 0.9mmol) to 10mL of tetrahydrofuran successively in a dry single-necked flask, Stir at room temperature for 16 hours. The organic phase was dried, concentrated and purified to obtain compound 32l (65 mg, white solid). Yield: 36%. LCMS(ESI): m/z 400.0[M+H] ⁺ .

Step 12: Add 32l (65mg, 0.16mmol) and diethylaminosulfur trifluoride (53mg, 0.33mmol) to a dry single-necked flask in sequence, dissolve in 5mL of dichloromethane, and stir at room temperature for 2 hours. The organic phase was dried, concentrated and purified to obtain compound 32m (35 mg, yellow solid). Yield: 70%. LCMS(ESI): m/z 332.0[M+H] ⁺ .

Step 13: Add 32m (35 mg, 0.1 mmol) and lithium hydroxide (3 mg, 0.3 mmol) to a dry single-necked flask in sequence, dissolve in tetrahydrofuran (3 mL) and water (3 mL), and stir at room temperature for 1 hour. The compound H32 (10 mg, white solid) was prepared, yield: 30%. LCMS (ESI): m/z 318.0 [M+H] ⁺ ;

¹ H NMR(DMSO-d ₆ , 400MHz)δ12.42(s,1H),7.75(s,1H),7.61(s,1H),3.76(s,3H),3.74(s,3H),2.62( t,J＝12.0Hz,2H),2.47(t,J＝12.0Hz,2H).

33. Synthesis of compound H33

The synthesis of H33 is similar to that of H32. Compound H33: white solid. LCMS (ESI): m/z 349.2[MH] ^- ; ¹ H NMR (400MHz, MeOD) δ 7.54(s, 1H), 7.52(s, 1H), 3.94(s, 3H), 3.86(s, 3H ),2.60-2.70(m,2H),2.52-2.56(m,2H).

The synthesis of intermediate 33d is as follows:

Step 1: Compound 33a (5.0 g, 27.2 mmol)) and 40 mL of 98% sulfuric acid were sequentially added to a dry single-necked flask, and heated to 95° C. to react for 4 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. After the organic phase was concentrated, it was stirred with silica gel and passed through a column (petroleum ether/ethyl acetate=5/1) to obtain the product 33b (3.95 g, white solid), yield: 85.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.16 (s, 1H), 7.34 (d, J=6.8 Hz, 1H), 6.66 (d, J=15.2 Hz, 1H), 5.28 (brs, 1H), 3.93(s,3H).

Step 2: Compound 33b (3.80 g, 22.35 mmol) and 40 mL of N,N-dimethylformamide were sequentially added to a dry single-necked flask, and NCS (2.97 g, 22.35 mmol) was added in batches. React overnight at room temperature. Ethyl acetate and water were added. After the organic phase was separated, it was dried over anhydrous sodium sulfate, filtered, and the solvent was removed. The product 33c (4.0 g, white solid) was obtained by stirring silica gel column (petroleum ether/ethyl acetate=5/1), yield: 87.7%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.34 (s, 1H), 6.63 (d, J=11.6 Hz, 1H), 5.79 (s, 1H), 3.99 (s, 3H).

Step 3: Compound 33c (4.0 g, 19.6 mmol), methyl iodide (8.35 g, 58.8 mmol), potassium carbonate (8.11 g, 58.8 mmol) and 40 mL of N,N-dimethylformamide were successively added to a dry single-necked flask . React overnight at room temperature. Ethyl acetate and water were added. After the organic phase was separated, it was dried over anhydrous sodium sulfate, filtered, and the solvent was removed. Purification gave the product 33d (3.52 g, white solid), yield: 82.4%. LCMS(ESI): m/z 219.1[M+H] ⁺ .

34. Synthesis of compound H34

24a (100mg, 0.34mmol), sodium hydride (16mg, 0.68mmol), trimethylsulfur iodide (138mg, 0.68mmol) were dissolved in dimethyl sulfoxide (10mL) and tetrahydrofuran ( 10 mL) and stirred at room temperature for 16 hours. Reverse phase preparation gave compound H34 (5 mg, white solid), yield: 4.5%. LCMS (ESI): m/z 309.1 [M+H] ⁺ ;

¹ H NMR (MeOD, 400MHz) δ 7.39(s, 1H), 7.30(s, 1H), 7.21(s, 1H), 3.95-3.91(m, 1H), 3.87(s, 6H), 3.81-3.78 (m,1H),2.68-2.56(m,4H).

35. Synthesis of compound H35

The synthesis of H35 is similar to that of H32.

Compound H35: white solid. LCMS (ESI): m/z 383.0 [MH] ^- ; ¹ H NMR (MeOD, 400 MHz) δ 7.69(s, 1H), 3.98(s, 3H), 3.95(s, 3H), 2.67-2.73(m ,2H),2.54-2.57(m,2H).

The synthesis of intermediate 35b is as follows:

Compound 35a (2.0 g, 6.99 mmol) and 15 mL of N,N-dimethylformamide were sequentially added to a dry single-necked flask, and N-chlorosuccinimide (0.93 g, 6.99 mmol) was added in batches. React overnight at room temperature. Ethyl acetate and water were added. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and purification afforded the product 35b (1.85 g, white solid), yield: 82.6%. ¹ H NMR (CDCl ₃ , 400MHz) δ 8.14 (s, 1H), 4.01 (s, 3H), 3.96 (s, 6H).

36. Synthesis of compound H37

In a dry round-bottomed flask, compound 24e (50 mg, 0.16 mmol), HATU (72 mg, 0.19 mmol), dissolved in N,N-dimethylformamide (3 mL), and ammonia in tetrahydrofuran (4N) were added successively at room temperature. , 0.4mL). After stirring at room temperature for 2 hours, it was directly concentrated and the resulting residue was purified by reverse phase to give the product H37 (21 mg, white solid), yield: 41.6%. LCMS(ESI): m/z 296[M-19] ⁺ ;

¹ H NMR(DMSO-d ₆ , 400MHz)δ7.60-7.59(brs,2H),7.41(s,1H),7.39(s,1H),6.89(s,1H),3.83-3.81(m,6H) ), 2.61-2.58(m, 2H), 2.30-2.26(m, 2H).

37. Synthesis of compound H38

The synthesis of H38 is similar to that of H32.

The synthesis of intermediate 38d is as follows:

Step 1: Add compound 38a (36.51 g, 245 mmol) and 600 mL of methanol into a dry single-neck flask, and stir at room temperature until compound 38a is completely dissolved. Move to an ice-water bath and stir, add sodium methoxide (119 g, 2.21 mol) in batches, and react at room temperature overnight. Dichloromethane was added to dilute, filtered, the organic phase was concentrated, water was added, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 38b (31 g, white solid), yield: 90.3%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.62 (s, 2H), 4.02 (s, 6H).

Step 2: Compound 38b (31 g, 221 mmol) and 300 mL of N,N-dimethylformamide were sequentially added to a dry single-necked flask, and NBS (47.2 g, 265 mmol) was added in batches. The reaction was carried out at 40 °C overnight, and ethyl acetate and water were added for extraction. After separation of the organic phase, it was dried and filtered. The crude product was purified to give product 38c (26.8 g, white solid), yield: 55.3%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 4.03 (s, 3H), 4.00 (s, 3H).

Step 3: Add 2, 2, 6, 6-tetramethylpiperidine (43 mL, 269.06 mmol) and anhydrous tetrahydrofuran (200 mL) into a dry three-necked flask in turn, stir at -78°C under nitrogen protection, slowly n-Butyllithium (107 mL, 269.06 mmol, 2.5 mol/L) was added dropwise, and after the addition, the temperature was maintained and stirred for 15 minutes, and then the temperature was raised to zero degrees Celsius and stirred for 20 minutes. The reaction solution was re-cooled to -78 ° C, compound 38c (26.8 g, 122.3 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) and slowly added to the reaction solution, and after the addition, the temperature was stirred for 1 hour, and then anhydrous N was added, N-dimethylformamide (9 mL) was added and the temperature was raised to 0°C and stirred for 20 minutes, glacial acetic acid (27 mL) was added, and the addition was completed overnight at room temperature. The reaction solution was stirred in an ice bath and quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain the product 38d (2.6 g, white solid), yield: 8.6%. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.17(s,1H), 4.15(s,3H), 4.11(s,3H).

38. Synthesis of compound H39

Step 1: Compound 24e (300 g, 0.95 mmol), N-methoxymethylamine hydrochloride (93 mg, 0.95 mmol) and diisopropylethylamine (490 mg, 0.95 mmol) were successively added to a dry single-necked round-bottomed flask at room temperature. 1.14 mmol). After cooling to 0 °C, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (432 mg, 1.14 mmol) was added to the above solution in portions. ), stirred at room temperature for 16 hours, added water, and extracted with ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified (petroleum ether/ethyl acetate=1/1) to obtain the crude product 39a (300 mg, yellow solid), yield : 88%. ¹ H NMR (400MHz, CDCl ₃ )δ7.37(s,1H), 7.26(s,1H), 7.21(s,1H), 3.98(s,1H), 3.94(s,3H), 3.68(s, 3H), 3.18(s, 3H), 2.72-2.65(m, 4H).

Step 2: Compound 39b (2.0 g, 29.41 mmol), pyridine (5 mL, 62.03 mmol) and anhydrous dichloromethane (30 mL) were sequentially added to a dry single-neck round bottom flask at room temperature. After cooling to 0°C, a dichloromethane solution of p-toluenesulfonyl chloride (6.9 g, 36.3 mmol) was slowly added dropwise to the above solution. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, added with water, and extracted with dichloromethane. The organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified (petroleum ether/ethyl acetate=1/1) to obtain the crude product 39c (4.5 g, white solid), Yield: 69%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.22 (s, 1H), 7.33 (d, J=8.0 Hz, 2H), 6.39 (s,1H),2.42(s,3H).

Step 3: Compound 39c (50 mg, 0.225 mmol) and anhydrous tetrahydrofuran (5 mL) were sequentially added to a dry three-necked round bottom flask at room temperature, replaced with nitrogen three times and cooled to -78°C. To the above solution was slowly added dropwise t-BuLi (0.19 mL, 1.3 N, 0.247 mmol) and stirred at the same temperature for 45 minutes, and then a solution of compound 39a (89 mg, 0.248 mmol) in anhydrous tetrahydrofuran was added dropwise to the above solution, Stirring was continued at -78°C for 1 hour, quenched with saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and used Prep-TLC preparation and purification, developed with PE/EA=1/1, to obtain 39d (25 mg, pale yellow solid), yield: 82.1%. Compound 39d was hydrolyzed by LiOH to give compound H39 (4.6 mg, white solid), yield: 5.6%. 39d: ¹ H NMR (CDCl ₃ , 400MHz) δ 8.01(d, J=8.4Hz, 2H), 7.68(s, 1H), 7.37-7.34(m, 3H), 7.26(s, 1H), 7.21( s,1H),6.67(s,1H),3.97(s,3H),3.95(s,3H),3.20-3.16(m,2H),2.82-2.74(m,2H),2.43(s,3H) .

H39: ¹ H NMR(CDCl ₃ , 400MHz) δ 10.7(brs, 1H), 7.62(s, 1H), 7.38(s, 1H), 7.26(s, 1H), 7.20(s, 1H), 6.68( s,1H),3.97(s,3H),3.94(s,3H),3.31-3.27(m,2H),2.83-2.71(m,2H).

39. Synthesis of compound H40

The synthesis of H40 is similar to that of H32.

The synthesis of intermediate 40d is as follows:

Step 1: Compound 1 2-fluoro-4-methoxybenzaldehyde 40a (10 g, 64.93 mmol) was added to a single-neck round-bottomed flask with 150 mL of methanol at room temperature, and then liquid bromine (15.58 g, 97.40 mmol) was added dropwise in an ice bath. mmol). After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours, quenched by adding sodium sulfite solution, then 200 mL of water was added, the solution was filtered, the solution was filtered, the filter cake was washed with water, and then the filter cake was removed from the solvent to obtain compound 40b (12 g, white solid), Yield: 79.31%. LCMS(ESI): m/z 233.0,235.0[M+H] ⁺ .

Step 2: Compound 40b (12 g, 51.50 mmol) and methyl 2-mercaptoacetate (6.0 g, 56.65 mmol) were added to a DMF single-neck round-bottomed flask containing 150 mL at room temperature, followed by potassium carbonate (10.66 g, 77.25 mmol) ). The reaction was heated at 60 °C for 5 h under argon protection, 150 mL of water was added, the solution was filtered, the filter cake was washed with water, and dried to obtain the crude compound 40c (13 g, white solid), yield: 84.14%. LCMS(ESI): m/z 301.0,303.0[M+H] ⁺ .

Step 2: In a 500mL single-neck flask filled with 150mL of tetrahydrofuran and 60mL of water, at room temperature, add compound 40c (13g, 43.19mmol) and lithium hydroxide (9.07g, 216mmol), stir at 50 ° C for 3 hours, and concentrate. The solution was added with dilute hydrochloric acid to adjust the pH to ~4, the filter cake of the filtered solution was washed with water three times, and the solvent was removed under reduced pressure to obtain the product compound 40d (8 g, white solid), yield: 64.54%. LCMS (ESI): m/z 287.0, 289.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.25 (s, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 3.93(s, 3H).

H40: yellow solid. LCMS (ESI): m/z 325.1, 327.1 [M+H-40] ⁺ ; ¹ H NMR (400 MHz, MeOD): δ 8.05(s, 1H), 7.58(s, 1H), 7.48(s, 1H ),3.94(s,3H),2.69-2.63(m,2H),2.55-2.52(m,2H).

40. Synthesis of compound H41

Step 1: Compound 24d (344 mg, 1.0 mmol) was dissolved in _{a mixed solvent of THF/H 2} O (1/1), then lithium hydroxide (72 mg, 3.0 mmol) was added, and the reaction was carried out at room temperature for half an hour. The pH was adjusted to 5-6 with hydrochloric acid, extracted with chloroform, and the organic phase was collected, dried, concentrated, and separated on a column to obtain compound 41a (165 mg, white solid) in a yield of 52%. LCMS (ESI): m/z 317.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35(s, 1H), 7.25(s, 1H), 7.20(s, 1H), 3.96( s,3H),3.94(s,3H),2.70–2.58(m,4H).

Step 2: Add compound 41a (30 mg, 0.094 mmol) and 1 drop of DMF to a dry three-necked round-bottomed flask filled with anhydrous dichloromethane at room temperature. After cooling to 0 °C, add oxalyl chloride (0.2 mmol) to the above solution. mL), the addition was completed, and the solution of 41b was obtained after stirring at 0 °C for 1 hour, which was directly used in the next reaction.

Step 3: N-methylmethanesulfonamide (12mg, 0.104mmol), catalytic amounts of 4-N,N-lutidine and triethyl pyridine were successively added at room temperature in a dry three-necked flask filled with anhydrous dichloromethane. Amine (29 mg, 0.284 mmol), cooled to 0°C under nitrogen protection, and added dropwise the above-prepared acid chloride solution to it, after the dropwise addition, stirred at room temperature for 1 hour, the reaction solution was diluted with water, extracted with dichloromethane, The organic phase was washed successively with water and saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by PREP-HPLC (hydrochloric acid system) to obtain the final compound H41 (10 mg, white solid), yield: 26%.

¹ H NMR (400MHz, CDCl ₃ , ): δ 7.34(s, 1H), 7.26(s, 1H), 7.21(s, 1H), 3.97(s, 3H), 3.95(s, 3H), 3.30( s,3H),3.24(s,3H),2.93-2.89(m,2H),2.75-2.71(m,2H).

41. Synthesis of compound H42

The synthesis of H42 is the same as that of compound H41.

H42 (white solid), ¹ H NMR (400MHz, MeOD): δ 7.46(s,1H), 7.45(s,1H), 7.37(s,1H), 3.90(s,3H), 3.89(s,3H) ),3.31(s,3H),2.65-2.54(m,4H).

42. Synthesis of Compounds H45 and H46

Step 1: Add compound 40g (2.0g, 5.58mmol) and allyltetrabutyl-15-stannane (4.33g, 11.17mmol) to a there-necked flask containing 50mL of 1,4 dioxane at room temperature , tetrakistriphenylphosphonium palladium (1.29 g, 1.12 mmol), stirred at 80 °C overnight under argon protection, added 150 mL of water, quenched with KF solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and purified. Compound 45a was obtained (1.5 g, white solid), yield: 84.43%. LCMS (ESI): m/z 319.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.27 (s, 1H), 7.73 (s, 1H), 7.62 (s, 1H) ,6.03-5.97(m,1H),5.09-5.05(m,2H),3.94(s,3H),3.60(s,3H),3.41(d,J＝6.8Hz,2H),3.34-3.31(m ,2H),2.69-2.66(t,J＝6.4Hz,2H).

Step 2: Add compound 45a (750 mg, 2.35 mmol) and Grubbs catalyst 2G catalyst (283 mg, 0.47 mmol) to a single-necked flask containing 50 mL of dichloromethane at room temperature, stir overnight at 50°C under argon protection, and prepare by prep-TLC Purification gave a mixture of compounds 45b and 45b' (600 mg, brown powder), yield: 80.0%. LCMS(ESI): m/z 595.2,609.2[M+H] ⁺ .

Step 3: Add the mixture (200mg, 0.33mmol) and palladium-carbon catalyst (50mg) of compound 45b and 45b' at room temperature in the single-necked flask filled with 100mL of dichloromethane, stir overnight under the protection of hydrogen, filter and combine the organic phases to obtain Mixture of crude 45c and 45c' (150 mg, white solid), yield: 74.76%. LCMS(ESI): m/z 597.2, 611.2 [M+H] ⁺ .

Step 4: A mixture of 45c and 45c' (150 mg, 0.24 mmol) and 1,3 propanedithiol (133 mg, 1.23 mmol) were added at room temperature to a single-necked flask containing 10 mL of tetrahydrofuran, and then boron trifluoride ether was added dropwise. solution 2mL. Stir overnight at 50°C under argon protection, add 50 mL of water, adjust pH with sodium bicarbonate solution, extract with ethyl acetate, combine the organic phases to remove the solvent, and purify to obtain a mixture of 45d and 45d' (80 mg, brown oil), yield: 46.47%. LCMS(ESI): m/z 701.3,687.3[M+H] ⁺ .

Step 5: Add 45d and 45d' (80mg, 0.11mmol) and DAST (184mg, 1.14mmol) dropwise to a single-necked flask containing 10mL of dichloromethane at room temperature, stir at room temperature for 1 hour under argon protection, add 50mL of The pH of the water was adjusted with sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined to remove the solvent. The residue was separated by thin layer chromatography and developed with petroleum ether/ethyl acetate=3/1 to obtain compounds 45e and 45e' (45 mg, brown oil), yield: 60.21%. LCMS(ESI): m/z 655.2,641.3[M+H] ⁺ .

Step 5: Add compounds 45e and 45e' (45 mg, 0.068 mmol) and lithium hydroxide (15 mg, 0.34 mmol) to a single-necked flask containing 10 mL of tetrahydrofuran and 2 mL of water at room temperature, stir overnight at room temperature, concentrate the solution, and use reverse phase Preparation, separation and purification to obtain compounds H45 and H46:

H45 (7 mg, yellow solid), yield: 16.20%. LCMS (ESI): m/z 627.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOD): δ 8.04 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.420 ( s,1H),7.37(s,2H),3.89(s,3H),3.85(s,3H),2.73-2.60(m,6H),2.58-2.51(m,4H),1.67(s,4H) ,1.32-1.29(m,2H).

H46 (3 mg, yellow solid), yield: 7.09%. LCMS (ESI): m/z 613.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOD): δ 8.06(s, 1H), 7.66(s, 1H), 7.57(s, 1H), 7.42( s,1H),7.38-7.37(m,2H),3.89(s,3H),3.87(s,3H),2.77-2.60(m,8H),2.58-2.51(m,2H),2.03-1.94( m,2H),1.67-1.59(m,2H).

43. Synthesis of compound H47

Step 1: In a dry three-necked flask, add compound 40g (800mg, 2.24mmol), bis-boronic acid pinacol ester (1.7g, 6.74mmol), [1,1'-bis(diphenylphosphino)diocene Iron]palladium dichloride (161 mg, 0.22 mmol), potassium acetate (161 mg, 0.22 mmol), dissolved in dry 1,4-dioxane (30 mL). The reaction system was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 16 hours. Ethyl acetate was extracted, the organic phase was dried and concentrated, and purified to obtain compound 47a (470 mg, yellow solid), yield: 52%. LCMS(ESI): m/z 323.0[M-82+H] ⁺ .

Step 2: Compound 47a (470 mg, 1.46 mmol) and hydrogen peroxide (99 mg, 2.92 mmol) were sequentially added to a dry single-necked flask, dissolved in dry ethanol (10 mL), and reacted at 80° C. for 2 hours. The organic phase was dried, concentrated and purified to obtain compound 47b (320 mg, yellow solid), yield: 75%. LCMS(ESI): m/z 295.4[M+H] ⁺ .

Step 3: Compound 47b (100 mg, 0.34 mmol), 1,3-dibromopropane (136 mg, 0.68 mmol), potassium carbonate (94 mg, 0.68 mmol) were added successively to a dry single-necked flask, dissolved in dry N,N - Dimethylformamide (10 mL), reacted at room temperature for 16 hours. Ethyl acetate was extracted, the organic phase was dried and concentrated, and the crude product was purified to obtain compound 47c (80 mg, yellow solid), yield: 75%. LCMS(ESI): m/z 415.3[M+H] ⁺ .

Step 4: Compound 47c (50 mg, 0.12 mmol), compound 47b (35 mg, 0.12 mmol), sodium hydride (6 mg, 0.24 mmol) were added successively to a dry single-necked flask, and the mixture was dissolved in dry N,N-dimethylformaldehyde. The amide (10 mL) was reacted at room temperature for 4 hours. Extracted with ethyl acetate, the organic phase was dried and concentrated, and separated on a silica gel column to obtain compound 47d (25 mg, yellow solid), yield: 34%. LCMS(ESI): m/z 628.8[M+H] ⁺ .

Step 5: 47d (25 mg, 0.04 mmol) was sequentially added to a dry single-necked flask, and lithium hydroxide (8 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and stirred at room temperature for two hours. Purification gave compound H47 (2 mg, white solid). Yield: 8%. LCMS(ESI): m/z 600.9[M+H] ⁺ .

44. Synthesis of compound H51

Step 1: In a dry three-necked flask at room temperature, compound 47b (500 mg, 1.70 mmol), 1,3-propanedithiol (184 mg, 3.40 mmol) were dissolved in dry tetrahydrofuran (10 mL), and boron trifluoride was added. ether solution (2 mL). Stir overnight at 50°C, add ice water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, evaporate to dryness to obtain crude product, and purify with Flash silica gel to obtain product 51a (180 mg, yellow solid), yield: 27.5%. LCMS(ESI): m/z 384.8[M+H] ⁺ .

Step 2: Compound 51a (180 mg, 0.47 mmol) was dissolved in dry dichloromethane (10 mL) in a dry 25 mL three-neck flask under ice bath condition, and diethylaminosulfur trifluoride (226 mg, 1.41 mmol) was added. After stirring in an ice bath for 3 hours, ice water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness to obtain a crude product, which was purified by silica gel plate preparation to obtain product 51b (80 mg, yellow oil), yield: 53.8%

Step 3: Compound 51b (80 mg, 0.25 mmol), potassium iodide (42 mg, 0.25 mmol) and cesium carbonate (162 mg, 0.50 mmol) were dissolved in dry N-methylpyrrolidone (10 mL) in a dry three-necked flask with ice bath , compound 47c (226 mg, 1.41 mmol) was added. After stirring at room temperature for 3 hours, the reaction solution was added to ice water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness to obtain a crude product, which was purified by silica gel plate preparation to obtain product 51c (80 mg, yellow solid), yield: 49.2%. LCMS(ESI): m/z 630.8[M-19+H] ⁺ .

Step 4: Compound 51c (80 mg, 0.12 mmol) was dissolved in tetrahydrofuran/water (3/1, 4 mL) in a dry three-necked flask under ice bath condition, and lithium hydroxide (12 mg, 0.49 mmol) was added. After stirring in an ice bath for 3 hours, the reaction solution was added with acetic acid to adjust the pH to about 7, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, evaporated to dryness to obtain the crude product, and then the crude product was purified to the obtained residue to obtain the product H51( 20 mg, yellow solid), yield: 26.7%. LCMS (ESI): m/z 623.1 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD-d ₄ ): δ 7.86(s, 1H), 7.60-7.27(m, 5H), 4.27-4.21(m, 4H), 3.84-3.82(m, 6H), 3.26- 3.23(m, 2H), 2.70-2.50(m, 6H), 2.33-2.28(m, 2H).

45. Synthesis of compound H59:

Step 1: Compound 61b (100 mg, 0.24 mmol), Compound 61a (95 mg, 0.32 mmol), anhydrous cesium carbonate (157 mg, 0.48 mmol), and potassium iodide (40 mg, 0.24 mmol) were added to a dry three-necked round-bottomed flask at room temperature. ) and N-methylpyrrolidone (4 mL). Stir at 20-25°C for 4 hours under nitrogen protection. Quenched with ice water, extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified (dichloromethane-dichloromethane:methanol=0-5 %) to give the product 59a (90 mg, pale yellow solid), yield: 59.6%. LCMS(ESI): m/z 629.3[M+H] ⁺ .

Step 2: Compound 59a (135 mg, 0.21 mmol), propanedithiol (91 mg, 0.84 mmol), boron trifluoride ether (120 mg, 0.84 mmol) and anhydrous tetrahydrofuran were added to a dry three-necked round-bottomed flask at room temperature. (4 mL). Stir at 20-25°C for 16 hours under nitrogen protection. Quenched with ice water, extracted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified (dichloromethane-dichloromethane/methanol). =0-2%) to give product 59b (130 mg, pale yellow solid), yield: 76.5%. LCMS(ESI): m/z[M+H] ⁺ .

Step 3: Compound 59b (130 mg, 0.16 mmol) and dichloromethane (4 mL) were sequentially added to a dry three-necked round bottom flask at room temperature. Under ice-water bath cooling, DAST (105 mg, 0.64 mmol) was added dropwise, and after the addition was completed, stirring was continued for 1 hour under ice-water bath cooling. Quenched with ice water, extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified (dichloromethane-dichloromethane/methanol). =0-2%) to give the product 59c (90 mg, yellow solid), yield: 83.3%.

Step 4: Compound 59c (90 mg, 0.13 mmol), tetrahydrofuran (4 mL) and water (1 mL) were sequentially added to a dry three-necked round bottom flask at room temperature. Lithium hydroxide hydrate (22 mg, 0.52 mmol) was added, and after the addition was complete, stirring was continued at 20-25° C. for 3-4 hours. Quenched with ice water, extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by prep-HPLC to obtain the product H59 (15 mg , pale yellow solid), yield: 17.9%. LCMS(ESI): m/z 643.1[MH] ^- .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ12.35(s, 2H), 7.67(s, 2H), 7.61(s, 2H), 7.43(s, 2H), 4.23(t, 4H), 3.83(d,6H), 2.63(td,4H), 2.45(t,4H), 2.31–2.18(m,2H).

46. Synthesis of compound H61

Step 1: In a dry three-necked flask containing 100 mL of dichloromethane, compound 24a (5.3 g, 17.2 mmol) and aluminum chloride (11.4 g, 86.0 mmol) were sequentially added under ice bath. After stirring at 0°C for 10 minutes, the reaction was carried out at room temperature for three hours. After the reaction was monitored by LC-MS, the reaction solution was slowly poured into 1M dilute hydrochloric acid, extracted twice with dichloromethane, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product , slurried with tetrahydrofuran and methyl tert-butyl ether (3/1, V/V) to obtain product 61a (2.5 g, white solid), yield: 49.4%. LCMS (ESI): m/z 551.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.88 (s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 6.07 (s, 1H), 3.98(s, 3H), 3.71(s, 3H), 3.32(t, 2H), 2.79(t, 2H).

Step 2: Compound 61a (220 mg, 0.75 mmol), 1,3-dibromopropane (182 mg, 0.90 mmol), anhydrous potassium carbonate (156 mg, 1.13 mmol) and anhydrous potassium carbonate (156 mg, 1.13 mmol) were added to a dry three-necked round-bottom flask at room temperature. N,N-Dimethylformamide (12 mL) was stirred at 20-25°C for 16 hours under nitrogen protection. Quenched with ice water, extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified (petroleum ether-petroleum ether: ethyl acetate=0-15 %) to obtain product 61b (180 mg, off-white solid), yield: 57.9%. LCMS(ESI): m/z 414.9[M+H] ⁺ .

Step 3: Compound 61b (40 mg, 0.096 mmol) and 4,4-difluoro-4-(6-hydroxy-5-methoxybenzone) were added to a single-necked flask containing 10 mL of N-methylpyrrolidone at room temperature [b]Thien-2-yl)butyric acid methyl ester (30mg, 0.096mmol), then add cesium carbonate (63mg, 0.192mmol), potassium iodide (16mg, 0.096mmol) stirring at room temperature overnight, add 50mL of water, ethyl acetate Extracted 3 times, combined the organic phases to remove the solvent, purified petroleum ether by thin layer chromatography: ethyl acetate=2:1 to obtain compound 61c (35 mg, yellow oil), yield: 55.86%. LCMS(ESI): m/z 631.3[M+H-20] ⁺ .

Step 4: Add compound 61c (35 mg, 0.054 mmol) and lithium hydroxide (23 mg, 0.54 mmol) to a single-necked flask containing 8 mL of tetrahydrofuran and 2 mL of water at room temperature, stir at room temperature for 4 hours, concentrate the solution, and reverse-phase preparation for separation and purification , to obtain H61 (6 mg, yellow solid), yield: 17.92%. LCMS (ESI): m/z 583.2 [M+H-40] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.20(s, 1H), 7.66(d, J=3.6Hz, 2H), 7.61(s, 1H), 7.49(s, 1H), 7.43(s ,1H),4.27-4.19(m,4H),3.86(s,3H),3.82(s,3H),3.27-3.24(m,4H),2.68-2.58(m,3H),2.46-2.43(m ,1H)2.29-2.25(m,2H).

47. Synthesis of compound H62:

Step 1: In a three-necked flask containing 20 mL of tetrahydrofuran, compound 61a (500 mg, 1.7 mmol), 1,2-dithiol (2 mL) and boron trifluoride ether (5 mL) were sequentially added at room temperature. The reaction was carried out overnight at room temperature, diluted with water, extracted twice with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (petroleum ether/ethyl acetate=5/1) gave the product 62a (460 mg, white solid), yield: 70.4%. LCMS(ESI): m/z 385.1[M+H] ⁺ .

Step 2: In a dry single-necked flask containing 15 mL of dichloromethane, compound 62a (400 mg, 1.04 mmol) and diethylaminosulfur trifluoride (251 mg, 1.56 mmol) were sequentially added at 0°C. After reacting at 0°C for 1 hour, it was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (petroleum ether/ethyl acetate=5/1) gave the product 62b (160 mg, white wax), yield: 40%. LCMS(ESI): m/z 297.1[M+HF] ⁺ .

Step 3: Compound 62b (30 mg, 0.063 mmol), 4-(6-(2-hydroxyethoxy)-5-methoxybenzothiophene- Methyl 2-yl)-4-oxobutanoate (32 mg, 0.063 mmol), diisopropylazodicarboxylate (58 mg, 0.28 mmol) and triphenylphosphine (75 mg, 0.28 mmol). The reaction was carried out overnight at room temperature, diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 62c (15 mg, yellow solid), yield: 24.8%. LCMS(ESI): m/z 617.0[M-F+H] ⁺ .

Step 4: In a dry single-necked flask containing 3 mL of tetrahydrofuran and 1 mL of water, compound 62c (15 mg, 0.024 mmol) and lithium hydroxide (4 mg, 0.094 mmol) were sequentially added at room temperature. After reacting at room temperature for three hours, the reaction solution was concentrated and purified to obtain product H62 (6 mg, yellow solid), yield: 40%. LCMS(ESI): m/z 569.1[M+H-2F] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.22(s, 1H), 7.73(d, J=4.8Hz, 2H), 7.63(s, 1H), 7.52(s, 1H), 7.46(s ,1H),4.47(s,4H),3.83(d,J＝8.0Hz,6H),3.28(d,J＝6.4Hz,2H),2.67-2.59(m,4H),2.51-2.44(m, 2H).

48. Synthesis of compound H83

Step 1: Compound 83a (250 mg, 0.65 mmol), allyl boronate (217 mg, 1.29 mmol), [1,1'-bis(diphenylphosphino) were sequentially added to a dry three-necked round-bottomed flask at room temperature ) ferrocene]palladium dichloride (47 mg, 0.06 mmol) and cesium carbonate (420 mg, 1.29 mmol) were dissolved in 1,4-dioxane (20 mL). Stir at 100°C for 4 hours under nitrogen protection. Cooled to room temperature, the reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain product 83b (100 mg, yellow solid), yield: 44.2%, LCMS (ESI): m /z 349.1[M+H] ⁺ .

Step 2: At room temperature, argon, compound 83b (100 mg, 0.29 mmol), 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H - Benzo[d]imidazole-5-carboxamide (101 mg, 0.29 mmol) and dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (174 mg, 0.29 mmol) in 20 mL of dichloro Stir in methane at 40°C for 16 hours. Purification gave compound 83c (50 mg, green solid), yield: 25.6%, LCMS (ESI): m/z 673.3 [M+H] ⁺ .

Step 3: Add compound 83c (20 mg, 0.03 mmol) and lithium hydroxide monohydrate (5 mg, 0.12 mmol) to a single-necked flask containing 1.5 mL of tetrahydrofuran and 0.5 mL of water at room temperature, stir at room temperature for 2 hours, concentrate, and prepare Purification gave compound H83 (1.02 mg, white solid), yield: 5.1%, LCMS (ESI): m/z 659.4 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ8.09(s,1H), 7.83-7.81(m,1H), 7.54-7.52(m,1H), 7.37(s,1H), 7.13(s,1H), 6.61(s, 1H), 6.02-6.01(m, 1H), 5.75-5.73(m, 1H), 5.39(t, J=4.4Hz, 2H), 4.61-4.57(m, 2H), 4.05-4.03( m, 2H), 3.89(s, 3H), 3.63(s, 3H), 2.66-2.63(m, 2H), 2.28(s, 3H), 2.21-2.17(m, 2H), 0.91-0.88(m, 3H).

49. Synthesis of compound H102

Step 1: Compound 102a (200 mg, 0.56 mmol), N,N-dimethylformamide (3 mL), 40 g (196 mg, 0.56 mmol), thiophene-2-carboxylate ( I) (11 mg, 0.06 mmol), triethylamine (113 mg, 1.12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4 mg, 0.06 mmol). It was replaced with nitrogen three times, heated to 65°C, and reacted for 8 hours. The reaction solution was concentrated under reduced pressure. Purification with HPLC phase gave the product 102b (20 mg, yellow solid), yield: 5.70%, LCMS (ESI): m/z 627.1 [M+H] ⁺ .

Step 2: Compound 102b (20 mg, 0.03 mmol), ethyl acetate (10 mL) and palladium/carbon catalyst (2 mg) were sequentially added to a dry single-necked flask at room temperature. The hydrogen was replaced 3 times, and the mixture was stirred at room temperature for 1 hour. Filtration and concentration gave product 102c (20 mg, yellow solid), yield: 99.36%, LCMS (ESI): m/z 631.1 [M+H] ⁺ .

Step 3: Compound 102c (20 mg, 0.03 mmol), sodium tetrahydrofuran (2 mL), water (0.5 mL) and lithium hydroxide monohydrate (4 mg, 0.09 mmol) were sequentially added to a dry single-necked flask at room temperature. The mixture was stirred at room temperature and reacted for 3 hours. The reaction solution was concentrated under reduced pressure. Purification with HPLC phase gave the product H102 (6.1 mg, yellow solid), yield: 22.35%, LCMS (ESI): m/z 617.1 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6): δ8.15(s, 1H), 8.00(s, 2H), 7.82-7.77(m, 2H), 7.58-7.56(m, 2H), 7.33(s, 1H), 6.45(s, 1H), 4.57-4.56(m, 2H), 4.29-4.25(m, 2H), 3.78(s, 3H), 3.26-3.23(m, 2H), 2.78-2.74(m, 2H), 2.61-2.58(m, 2H), 2.14-2.10(m, 5H), 1.33-1.29(m, 3H).

50. Synthesis of compound H103

Step 1: Add compound 103a (60 mg, 0.17 mmol), 4-(5-allyl-6-methoxybenzo[b]thiophene-2- yl)-4-oxobutyric acid methyl ester (54 mg, 0.17 mmol) and dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (102 mg, 0.17 mmol). Stir under argon at 40°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified (dichloromethane:methanol=10:1) to obtain compound 103b (30 mg, green solid), yield: 27.4%, LCMS (ESI): m/z 643.3 [M+H] ⁺ .

Step 2: Compound 103b (30 mg, 0.047 mmol) and Pd/C (10%, 10 mg) were added to a single-necked flask containing 10 mL of tetrahydrofuran at room temperature, and a hydrogen balloon was used to stir at room temperature for 2 hours, and the reaction solution was filtered through celite , the filtrate was concentrated to give crude compound 103c, LCMS (ESI): m/z 645.3 [M+H] ⁺ .

Step 3: Add compound 103c (0.047 mmol) and lithium hydroxide monohydrate (8 mg, 0.18 mmol) to a single-necked flask at room temperature, dissolve in tetrahydrofuran/water (2/1, 3 mL), stir at room temperature for 2 hours, and concentrate the reaction solution , purified to obtain compound H103 (4.5 mg, green solid), yield: 15.2%, LCMS (ESI): m/z 631.4 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ8.09(s, 1H), 7.92-7.89(m, 2H), 7.63(d, J=8.4Hz, 1H), 7.55-7.54(m, 1H), 7.30( s,1H),6.80(s,1H),4.67-4.65(m,2H),4.41-4.40(m,2H),3.77(s,3H),2.75-2.70(m,4H),2.33(s, 3H), 1.96-1.90(m, 2H), 1.74-1.71(m, 2H), 1.86-1.80(m, 2H), 1.46-1.42(m, 3H).

51. Synthesis of compound H104

Step 1: Compound 103a (200 mg, 0.57 mmol), ethyl acetate (20 mL), methanol (20 mL), palladium/barium sulfate (20 mg) and ethylenediamine (0.20 mL) were sequentially added to a dry single-necked flask at room temperature. The hydrogen was replaced three times, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, it was filtered. The filtrate was concentrated under reduced pressure to give the product 1-allyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-methyl Amide 104a (200 mg, white solid), yield: 99.43%. , LCMS (ESI): m/z 353.1 [M+H] ⁺ .

Step 2: Compound 104a (80 mg, 0.23 mmol), dichloromethane (10 mL), SM_1 (72 mg, 0.23 mmol, ) and Grubbs 1 (136 mg, 0.23 mmol) were sequentially added to a dry single-necked flask at room temperature. It was replaced with nitrogen three times, heated to 40°C, and reacted for 16 hours. The reaction solution was concentrated under reduced pressure. Purification with preparative plates (pure DCM) afforded product 104b (40 mg, yellow solid), yield: 27.41%, LCMS (ESI): m/z 643.0 [M+H] ⁺ .

Step 3: Compound 104b (40 mg, 0.06 mmol), sodium tetrahydrofuran (2 mL), water (0.5 mL) and lithium hydroxide monohydrate (13 mg, 0.31 mmol) were sequentially added to a dry single-necked flask at room temperature. The mixture was stirred at room temperature and reacted for 3 hours. The reaction solution was concentrated under reduced pressure. Purification by high performance liquid phase phase gave the product H104 (1.02 mg, yellow solid), yield: 2.61%, LCMS (ESI): m/z 629.1 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ12.84(s, 1H), 8.00-7.96(m, 3H), 7.81-7.78(m, 1H), 7.61(s, 1H), 7.57(s ,1H),7.53(d,J=8.4Hz,1H),7.33(s,1H),6.67(s,1H),5.99-5.90(m,1H),5.73-5.65(m,1H),4.85( d, J＝5.2Hz, 2H), 4.63-4.58(m, 2H), 3.81(s, 3H), 3.39-3.38(m, 2H), 3.26-3.23(m, 2H), 2.62-2.59(m, 2H), 2.14(s, 3H), 1.35-1.31(m, 3H).

52. Synthesis of compound H107

Step 1: Add compound 107a (550 mg, 1.54 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxo to a dry three-necked round-bottomed flask at room temperature. dioxaborolane (517mg, 3.08mmol), anhydrous potassium carbonate (426mg, 3.08mmol), Pd ( dppf) Cl 2 (110mg, 0.15mmol) and 1,4-dioxane (10mL). Stir at 100°C for 16 hours under nitrogen protection. Cooled to room temperature, the reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain product 107b (250 mg, yellow solid), yield: 51.0%, LCMS (ESI): m /z 319.2[M+H] ⁺ .

Step 2: Add compound 107b (100 mg, 0.31 mmol), compound 103a (111 mg, 0.31 mmol) and dichloro (o-isopropoxyphenylmethylene) to a single-necked flask containing 40 mL of dichloromethane at room temperature (Tricyclohexylphosphine)ruthenium (186 mg, 0.31 mmol). Stir under argon at 40°C for 16 hours. After the reaction solution was concentrated under reduced pressure, it was purified by thin layer chromatography (dichloromethane:methanol=10:1) to obtain compound 107c (40 mg, brown solid), yield: 20.1%, LCMS (ESI): m/z 643.4 [M+H] ⁺ .

Step 3: Compound 107c (40 mg, 0.062 mmol) and Pd/C (40 mg) were added at room temperature in a single-necked flask containing 10 mL of tetrahydrofuran, stirred at room temperature for 2 hours under hydrogen (15 psi), and the reaction solution was filtered through celite, The filtrate was concentrated to give compound 107d (30 mg, brown solid), yield: 74.8%, LCMS (ESI): m/z 645.4 [M+H] ⁺ .

Step 4: Add compound 107d (30 mg, 0.049 mmol) and lithium hydroxide monohydrate (10 mg, 0.245 mmol) to a single-necked flask containing 1.5 mL of tetrahydrofuran and 0.5 mL of water at room temperature, stir at room temperature for 2 hours, and concentrate the reaction solution The solution was separated and purified by reverse-phase preparation to obtain compound H107 (5.0 mg, white solid), yield: 16.1%, LCMS (ESI): m/z 631.4 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ 8.10 (s, 1H), 8.02 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.52 (s,1H),7.28(s,1H),6.84(s,1H),4.70-4.66(m,2H),4.45-4.39(m,2H),3.76(s,3H),2.77-2.72(m ,4H),2.35(s,3H),1.96-1.86(m,4H),1.76-1.71(m,2H),,1.48(t,J=7.0Hz,3H).

53. Synthesis of compound H108

Step 1: Compound 108a (200 mg, 0.83 mmol), methyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (246 mg, 0.83 mmol) , triphenylphosphine (505 mg, 1.66 mmol) and anhydrous tetrahydrofuran (20 mL), and under nitrogen protection, diisopropyl azodicarboxylate (335 mg, 1.66 mmol) was added dropwise under an ice bath, and the mixture was naturally returned to room temperature and stirred overnight. Quenched with ice water, extracted with ethyl acetate, washed the organic phase with water and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, concentrated and purified to obtain product 108b (120 mg, yellow solid), yield: 27.80%.

Step 2: At room temperature, compound 108b (100 mg, 0.29 mmol), palladium carbon (20 mg) in dichloromethane/methanol (30/10 mL) were stirred at room temperature for 5 hours under the protection of hydrogen. Filtration and concentration gave the product 108c (90 mg, yellow solid), yield: 77.87%.

Step 3: Compound 108c (90 mg, 0.19 mmol), cyanogen bromide (31 mg g, 0.29 mmol) in methanol (25 mL), stirred under nitrogen at 80°C for 3 hours. The organic phase was concentrated, 50 mL of water was added, extracted with ethyl acetate, the combined organic phases were concentrated under reduced pressure and purified to obtain the product 108d (50 mg, yellow solid), yield: 51.5%, LCMS: m/z 511.1 [M+H ] ⁺ .

Step 4: Compound 108d (50 mg, 0.10 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (24 mg, 0.15 mmol) in N,N-dimethylformamide (7 mL) ), then N,N-diisopropylethylamine (39 mg, 0.30 mmol) and HATU condensing agent (57 mg, 0.15 mmol) were added dropwise, and the mixture was stirred at room temperature overnight under nitrogen protection. The organic phase was concentrated, 50 mL of water was added, extracted with ethyl acetate, the combined organic phases were concentrated under reduced pressure and purified (dichloromethane: methanol=20:1) to obtain the product 108e (38 mg, brown solid), yield: 58.5%, LCMS :m/z 645.1[MH] ^- .

Step 5: Add compound 108e (38 mg, 0.06 mmol) and lithium hydroxide (13 mg, 0.30 mmol) to a single-necked flask containing 10 mL of tetrahydrofuran and 5 mL of water at room temperature, stir overnight at room temperature, concentrate the solution, and use reverse-phase preparation for separation and purification Obtained compound H108 (2.0 mg, brown solid) Yield: 5.3%, LCMS: m/z 633.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.81 (s, 1H), 8.28 (s, 1H), 8.10-7.93 (m, 3H), 7.75 (d, J=8.2 Hz, 1H), 7.62 -7.52(m, 2H), 7.35(d, J=12.0Hz, 2H), 6.59(s, 1H), 4.57-4.53(m, 2H), 4.43-4.40(t, J=5.6Hz, 2H), 4.14-4.10(t, J=5.6Hz, 2H), 3.86(s, 3H), 3.26-3.23(t, J=6.0Hz, 2H), 2.60-2.57(m, 2H), 2.33-2.29(m, 2H), 2.11(s, 3H), 1.33-1.29(t, J=7.2Hz, 3H).

54. Synthesis of compound H109

Step 1: Add compound 109a (10g, 49.7mmol) in a dry three-necked round-bottomed flask at room temperature, in 30mL of dichloromethane, then dropwise add oxalyl chloride (12.63g, 99.50mmol), stir at room temperature for 1 hour, For compound 1, the above solution was added dropwise to 50 mL of ammonia in tetrahydrofuran (100 mL). After the dropwise addition, the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated, 200 mL of water was added, filtered, the filter cake was washed twice with water, and the solid was removed from the solvent to obtain the product 109b (8.0 g, yellow solid), yield: 80.0%, LCMS (ESI): m/z 201.1 [M+ H] ⁺ .

Step 2: Compound 109b (5 g, 24.87 mmol) was sequentially added to 3-aminopropan-1-ol (50 mL) in a dry round-bottomed flask at room temperature, and stirred at room temperature for 4 hours. Quenched with ice water, added 200 mL of water, filtered, the filter cake was washed with a small amount (petroleum ether:ethyl acetate=2:1), the solid was removed the solvent to obtain the product 109c (5.1 g, yellow solid), yield: 84.10%, LCMS (ESI): m/z 240.1 [M+H] ⁺ .

Step 3: Compound 109c (200 mg, 0.83 mmol), 4-(6-hydroxy-5-methoxybenzo[b]thiophen-2-yl)-4-oxo were sequentially added to a dry three-necked round-bottomed flask at room temperature Methyl substituted butyrate (246 mg, 0.83 mmol), triphenylphosphine (505 mg, 1.66 mmol) and anhydrous tetrahydrofuran (20 mL), under nitrogen protection, was added dropwise diisopropyl azodicarboxylate (335 mg, 1.66 mg under ice bath) mmol) naturally returned to room temperature and stirred overnight. Quenched with ice water, extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified (petroleum ether:ethyl acetate=3:1) to obtain Product 109d (150 mg, yellow solid), yield: 34.80%, LCMS (ESI): m/z 516.2 [M+H] ⁺ .

Step 4: At room temperature, compound 109d (150 mg, 0.29 mmol) and palladium on carbon (20 mg) were sequentially added to a dry flask, and the mixture was stirred in dichloromethane/methanol 30 mL (3/1) under the protection of hydrogen for 5 hours at room temperature. The organic phase was filtered and concentrated, and the filtrate was concentrated under reduced pressure and purified (dichloromethane:methanol=20:1) to obtain the product 109e (110 mg, yellow solid), yield: 77.87%, LCMS (ESI): m/z 487.2 [M +H] ⁺ .

Step 5: At room temperature, compound 109e (110 mg, 0.227 mmol) and cyanogen bromide (36 mg, 0.34 mmol) were sequentially added to a dry flask in methanol (30 mL) and stirred at 80° C. for 3 hours under nitrogen protection. The organic phase was concentrated, 50 mL of water was added, extracted with ethyl acetate, the combined organic phases were concentrated under reduced pressure and purified (dichloromethane: methanol=20:1) to obtain the product 109f (70 mg, yellow solid), yield: 60.51%, LCMS (ESI): m/z 511.3 [M+H] ⁺ .

Step 6: Compound 6 (70 mg, 0.14 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (32 mg, 0.20 mmol) were sequentially added to a dry flask at room temperature, and the mixture was dissolved in N , N-dimethylformamide (10 mL), then N,N-diisopropylethylamine (54 mg, 0.42 mmol) and HATU condensing agent (76 mg, 0.20 mmol) were added dropwise at room temperature and stirred overnight under nitrogen protection. The organic phase was concentrated, 50 mL of water was added, extracted with ethyl acetate, the combined organic phases were concentrated under reduced pressure and purified (dichloromethane:methanol=20:1) to obtain 109g (50mg, brown solid) of the product, yield: 56.39%, LCMS(ESI): m/z647.3[M+H] ⁺ .

Step 7: Add compound 109g (50 mg, 0.077 mmol) and lithium hydroxide (17 mg, 0.39 mmol) to a single-necked flask containing 10 mL of tetrahydrofuran and 5 mL of water at room temperature, stir at room temperature overnight, concentrate the solution, and purify to obtain compound H109 (10 mg, brown solid), yield: 20.44%, LCMS (ESI): m/z 633.3 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6): δ8.18(s, 1H), 8.02-7.97(m, 2H), 7.77-7.74(m, 1H), 7.56(d, J=8.4Hz, 1H) ,7.48(d,J＝4.8Hz,2H),7.31(s,1H),6.59(s,1H),4.58-4.53(m,2H),4.43-4.40(t,J＝5.6Hz,2H), 4.17-4.15(t, J=5.6Hz, 2H), 3.98(s, 3H), 3.26-3.23(t, J=6.0Hz, 2H), 2.61-2.58(m, 2H), 2.54-2.51(m, 2H), 2.33-2.29(m, 2H), 2.11(s, 3H), 1.33-1.29(t, J=7.2Hz, 3H).

55. Synthesis of compound H110

Step 1: In a dry three-necked round-bottomed flask, compound 110a (600mg, 1.55mmol), allyltributylstannane (1.03g, 3.10mmol), tetrakistriphenylphosphonium palladium (901mg, 0.78mmol) were added successively at room temperature ) and 1,4-dioxane (15 mL). Stir at 90°C for 16 hours under nitrogen protection. Cooled to room temperature, the solvent was removed, and purification gave the product 110b (145 mg, yellow solid), yield: 26.9%, LCMS (ESI): m/z 349.1 [M+H] ⁺ .

Step 2: Add 20 mL of dichloromethane, compound 110b (120 mg, 0.34 mmol), compound 103a (121 mg, 0.34 mmol) and dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine) to the single-necked flask ) ruthenium (201 mg, 0.34 mmol). Stir under argon at 40°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified (dichloromethane: methanol=10:1) to obtain compound 110c (35 mg, yellow solid), yield: 15.3%, LCMS (ESI): m/z 673.4 [M+H] ⁺ .

Step 3: Add 2 mL of dichloromethane, compound 110c (20 mg, 0.03 mmol) and 10% Pd/C (20 mg) to a single-necked flask, stir at room temperature for 2 hours under hydrogen (15 psi), and filter the reaction solution through celite, The filtrate was concentrated to give compound 110d (15 mg, grey solid), yield: 74.8%, LCMS (ESI): m/z 675.3 [M+H] ⁺ .

Step 4: To a single-necked flask containing 1.5 mL of tetrahydrofuran and 0.5 mL of water, add compound 110d (15 mg, 0.022 mmol) and lithium hydroxide monohydrate (4.7 mg, 0.111 mmol), stir at room temperature for 1 hour, and concentrate the reaction Liquid-liquid, purified to obtain compound H110 (1.3 mg, white solid) Yield: 8.5%, LCMS (ESI): m/z 661.4 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ 7.98 (d, J=8.0Hz, 2H), 7.89-7.82 (m, 1H), 7.51 (d, J=8.4Hz, 1H), 7.25 (s, 1H) ,6.73(s,1H),5.35(d,J=4.7Hz,2H),3.87(s,3H),3.75(s,3H),3.06-3.02(m,2H),2.71-3.68(m,2H) ), 2.30(s, 3H), 2.19(t, J＝6.0Hz, 2H), 2.04-2.00(m, 4H), 1.82-1.77(m, 2H), 0.90(t, J＝0.8Hz, 3H) .

56. Synthesis of compound H111

Step 1: Compound 111a (180 mg, 0.33 mmol), compound 111b (97 mg, 0.33 mmol), potassium carbonate (91 mg, 0.66 mmol), potassium iodide (55 mg, 0.33 mmol) and NMP (5 mL) were sequentially added to a dry flask, The reaction was carried out at 80°C for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (ethyl acetate/methanol=10/1) gave the product 111c (100 mg, yellow solid, crude), LCMS (ESI): m/z 675.0 [M+H] ⁺ .

Step 2: Compound 111c (100 mg, 0.15 mmol), tetrahydrofuran (3 mL), water (1 mL), and lithium hydroxide monohydrate (32 mg, 0.75 mmol) were sequentially added to the flask, and the mixture was stirred at room temperature for 2 hours. Acetic acid (0.3 mL) was added, filtered and purified to give the product H111 (6 mg, white solid) Yield: 6.1%, LCMS (ESI): m/z 661.0 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6): δ12.85 (s, 1H), 8.13 (s, 1H), 8.00 (d, J=9.0Hz, 2H), 7.80 (dd, J=8.4, 1.5Hz ,1H),7.60(d,J=8.5Hz,1H),7.57(s,1H),7.42(s,1H),7.34(s,1H),6.64(s,1H),4.68-4.54(m, 2H), 4.26(t, J＝6.9Hz, 2H), 3.99(t, J＝6.3Hz, 2H), 3.81(s, 3H), 3.27-3.22(m, 2H), 2.63-2.56(m, 2H) ), 2.13(s, 3H), 1.92-1.78(m, 4H), 1.57-1.44(m, 2H), 1.35(t, J=7.1Hz, 3H).

57. Synthesis of compound H112

Step 1: Compound 112a (6.0 g, 29.91 mmol) dissolved in 100 mL of tetrahydrofuran and 4-amino-1-butanol (5.3 g, 59.83 mmol) was added to a single-necked flask. The mixture was heated under reflux and stirred overnight, cooled, concentrated and filtered to obtain crude compound 112b (5.0 g, yellow solid), yield: 66.0%, LCMS (ESI): m/z 254.1 [M+H] ⁺ .

Step 2: Add compound 112b (2.0 g, 7.90 mmol) and N-bromosuccinimide (1.7 g, 9.48 mmol) to a single-necked flask containing 40 mL of dichloromethane at room temperature, and then add triphenyl Phosphine (3.1 g, 11.85 mmol). The reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated, separated and purified by silica gel column to obtain compound 112c (1.2 g, yellow solid), yield: 48.1%, LCMS (ESI): m/z 318.0 [M+H] ⁺ .

Step 3: Compound 112c (300 mg, 0.95 mmol), 4-(5-hydroxy-6-methoxybenzo[b]thiophene-2- (280 mg, 0.95 mmol), potassium iodide (158 mg, 0.95 mmol), cesium carbonate (618 mg, 1.90 mmol). The reaction was carried out at 50°C for 4 hours, water was added, extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by TLC silica gel plate to obtain compound 112d (140 mg, yellow oil), yield: 27.8%, LCMS (ESI): m/z 530.2 [M +H] ⁺ .

Step 4: Compound 112d (140 mg, 0.26 mmol) was added to a single-necked flask, dissolved in 10 mL of methanol:dichloromethane=2:1 mixed solution, and then 10% wet palladium on carbon (20 mg) was added to the reaction solution. Under hydrogen balloon reaction conditions, the mixture was stirred at room temperature for 2 hours, filtered, and the filtrate was concentrated to obtain compound 112e (110 mg, yellow solid), yield: 84.7%, LCMS (ESI): m/z 500.3 [M+H] ⁺ .

Step 5: Compound 112e (110 mg, 0.22 mmol) and cyanogen bromide (35 mg, 0.33 mmol) were added to a single-necked flask containing 10 mL of methanol/water (1/1) at room temperature. The reaction was carried out at 60°C for 3 hours. The reaction solution was concentrated to obtain compound 112f (100 mg, yellow oil), yield: 86.6%, LCMS (ESI): m/z 525.2 [M+H] ⁺ .

Step 6: Add compound 112f (100 mg, 0.19 mmol), 1-ethyl-3-methyl-1H-pyrazole-5- to a single-necked flask containing 3 mL of N,N-dimethylformamide at room temperature Carboxylic acid (29 mg, 0.19 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (87 mg, 0.23 mmol), triethylamine (29 mg, 0.28 mmol). React at room temperature for 2 hours, add water, and extract with ethyl acetate, the organic phase is dried and concentrated, and purified to obtain compound 112g (56mg, yellow oil), yield: 44.6%, LCMS (ESI): m/z 661.3 [M+H] ⁺ .

Step 7: Add compound 112g (56 mg, 0.08 mmol) and lithium hydroxide monohydrate (14 mg, 0.34 mmol) to a single-necked flask containing 2 mL of methanol and 1 mL of water at room temperature, stir at room temperature for 3 hours, concentrate, and purify Obtained compound H112 (25 mg, white solid) Yield: 48.3%, LCMS (ESI): m/z 647.3 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ 8.13(s, 1H), 8.02-7.98(m, 2H), 7.82-7.80(m, 1H), 7.40-7.38(m, 2H), 6.84(s, 1H) ), 4.68-4.62(m, 4H), 4.19(t, J=6.0Hz, 2H), 3.80(s, 3H), 3.33(t, J=6.0Hz, 2H), 2.74-2.71(m, 2H) ,2.20-2.18(m,5H),1.99-1.97(m,2H),1.50-1.46(m,3H).

58. Synthesis of compound H113

Step 1: Add compound 113a (322 mg, 1.02 mmol), 4-(6-hydroxy-5-methoxybenzo[b]thiophene-2-) to a single-necked flask containing 5 mL of N-methylpyrrolidone at room temperature yl)-4-oxobutyric acid methyl ester (300 mg, 1.02 mmol), potassium iodide (169 mg, 1.02 mmol), cesium carbonate (664 mg, 2.04 mmol). React at room temperature for 4 hours, add water, and extract with ethyl acetate. The organic phase is dried and concentrated, and purified to obtain compound 113b (60 mg, yellow oil). Yield: 11.1%, LCMS (ESI): m/z 530.2 [M+H] ⁺ .

Step 2: Compound 113b (60 mg, 0.11 mmol) was added to a 25 mL single-necked flask, dissolved in 10 mL of methanol:dichloromethane=2:1 mixed solution, and then 10% wet palladium on carbon (15 mg) was added. Under a hydrogen balloon, the mixture was stirred at room temperature for 2 hours, filtered and concentrated to obtain compound 113c (40 mg, yellow oil), yield: 72.8%, LCMS (ESI): m/z 500.2 [M+H] ⁺ .

Step 3: Compound 113c (40 mg, 0.08 mmol) and cyanogen bromide (13 mg, 0.12 mmol) were added to a single-necked flask containing 5 mL of methanol/water (1/1) at room temperature. The reaction was carried out at 60°C for 3 hours. Concentration gave compound 113d (40 mg, yellow solid) yield: 95.2%, LCMS (ESI): m/z 525.2 [M+H] ⁺ .

Step 4: Add compound 113d (40 mg, 0.076 mmol), 1-ethyl-3-methyl-1H-pyrazole-5- to a single-necked flask containing 2 mL of N,N-dimethylformamide at room temperature Carboxylic acid (12 mg, 0.076 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (35 mg, 0.092 mmol), triethylamine (15 mg, 0.15 mmol). React at room temperature for 2 hours, add water, and extract with ethyl acetate. The organic phase is dried and concentrated, and purified to obtain compound 113e (25 mg, white solid), yield: 50.0%, LCMS (ESI): m/z 661.4 [M+H] ⁺ .

Step 5: Add compound 113e (25 mg, 0.038 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol) to a single-neck flask containing 2 mL of methanol and 1 mL of water at room temperature, stir at room temperature for 2 hours, concentrate, and purify to obtain the compound H113 (1.1 mg, white solid) Yield: 4.5%, LCMS (ESI): m/z 647.6 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ 8.09-8.08 (m, 2H), 8.02-8.01 (m, 1H), 7.61-7.60 (m, 1H), 7.40-7.39 (m, 2H), 6.81-6.80 (m,1H),4.68-4.67(m,2H),4.58-4.57(m,2H),4.22-4.21(m,2H),3.81(s,3H),3.36-3.35(m,2H),2.74 -2.71(m,2H),2.21-2.15(m,5H),1.98-1.97(m,2H),1.48-1.46(m,3H).

59. Synthesis of compound H114

Step 1: Compound 114a (4.40 g, 22.0 mmol), 5-aminopentan-1-ol (6.81 g, 66.0 mmol) and tetrahydrofuran (100 mL) were sequentially added to a dry single-necked flask, and the mixture was stirred under reflux for 16 hours. Cooled to room temperature, concentrated, and the crude product was purified by column chromatography (ethyl acetate:methanol = 10:1) to give product 114b (3.50 g, yellow solid) Yield: 59.5%, LCMS (ESI): m/z 268.2 [M +H] ⁺ .

Step 2: Compound 114b (2.67 g, 10.0 mmol), iron powder (2.23 g, 40.0 mmol), ammonium chloride (4.28 g, 80.0 mmol) and ethanol (80 mL) were sequentially added to the flask, and stirred at room temperature for 16 hours. Concentrated and the crude product was purified by column chromatography (ethyl acetate:methanol=10:1) to give product 114c (1.90 g, yellow solid) Yield: 80.2%, LCMS (ESI): m/z 238.2 [M+H] ⁺ .

Step 3: Compound 114c (1.90 g, 8.01 mmol), bromoacetonitrile (1.27 g, 12.01 mmol) methanol (30 mL) and water (300 mL) were sequentially added to the flask, and the reaction mixture was stirred at 60° C. for 16 hours. Concentration gave product 114d (2.30 g, yellow solid, crude), LCMS (ESI): m/z 263.2 [M+H] ⁺ .

Step 4: Compound 114d (2.30 g, 8.78 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1.35 g, 8.78 mmol), and triethylamine (2.66 g) were added to the flask in sequence g, 26.34 mmol), DMF (60 mL) and HBTU (3.99 g, 10.54 mmol). The reaction mixture was reacted at room temperature for 16 hours. Concentrated and the crude product was purified by column chromatography (ethyl acetate/methanol=10/1) to give the product 114e (1.30 g, white solid) Yield: 37.2%, LCMS (ESI): m/z 553.3 [M+H] ⁺ .

Step 5: In a dry 100 mL three-necked flask, compound 114e (1.20 g, 3.02 mmol), triethylamine (917 mg, 9.06 mmol), NMP (15 mL) and TsCl (1.17 g, 6.04 mmol) were sequentially added and stirred at room temperature for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/methanol=10/1) to give the product 114f (360 mg, white solid) Yield: 21.7%, LCMS (ESI): m/z 342.8 [M+H] ⁺ .

Step 6: Compound 114f (180 mg, 0.33 mmol), compound 7 (97 mg, 0.33 mmol), potassium carbonate (91 mg, 0.66 mmol), potassium iodide (55 mg, 0.33 mmol) and NMP (5 mL) were sequentially added to a dry flask, The reaction was carried out at 80°C for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/methanol=10/1) to give product 114g (100 mg, white solid, crude product), LCMS (ESI): m/z 675.1 [M+H] ⁺ .

Step 7: Compound 114 g (100 mg, 0.15 mmol), 3 mL of tetrahydrofuran, 1 mL of water, and lithium hydroxide monohydrate (32 mg, 0.75 mmol) were sequentially added to the flask, and the mixture was stirred at room temperature for 2 hours. Acetic acid 0.3 mL was added, filtered and purified to give the product H114 (10 mg, white solid), yield: 10.1%, LCMS (ESI): m/z 661.1 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6): δ8.19(s, 1H), 8.01(s, 2H), 7.81(d, J=8.2Hz, 1H), 7.60(d, J=8.4Hz, 1H) ), 7.54(s, 1H), 7.45(s, 1H), 7.35(s, 1H), 6.64(s, 1H), 4.66–4.56(m, 2H), 4.26(t, J=6.5Hz, 2H) ,4.03(t,J＝6.0Hz,2H),3.78(s,3H),3.27–3.24(m,2H),2.60(t,J＝6.1Hz,2H),2.13(s,3H),1.91– 1.80(m, 4H), 1.55–1.44(m, 2H), 1.35(t, J=7.0Hz, 3H).

60. Synthesis of compound H115

Step 1: Compound 115a (4.8 g, 42.86 mmol), diphenylphosphonate azide (14.1 g, 51.43 mmol), and triethylamine (8.67 g, 85.71 mmol) were sequentially added to a dry flask, and the mixture was heated at 80 °C. The reaction was carried out for 16 hours. The reaction solution was concentrated and purified to obtain the product 115b (2.8 g, colorless oil). Yield: 35.71%. ¹ H-NMR (400MHz, CDCl ₃ ): δ 4.73 (s, 1H), 3.25-3.21 (m, 2H), 2.24 (q, J=7.0, 2.6Hz, 2H), 1.77-1.65 (m, 2H) ),1.44(s,9H).

Step 2: Compound 115b (2.85g, 15.57mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborane (3g, 23.36mmol), schwartz's were added in order to a dry flask Reagent (770 mg, 3.14 mmol) and triethylamine (314 mg, 3.14 mmol) were reacted at 60° C. for 16 hours. Concentration and purification gave the product 115c (1.9 g, yellow oily liquid), yield: 39.25%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.60 (q, J=17.9, 6.4 Hz, 1H), 5.45 (d, J=18.0 Hz, 1H), 3.13-3.12 (m, 2H), 2.21- 2.16(m, 2H), 1.67-1.56(m, 2H), 1.44(s, 9H), 1.27(s, 12H).

Step 3: Compound 115c (520 mg, 1.67 mmol), 4-(3-bromo-5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxo were sequentially added to a dry flask Methyl butyrate (630 mg, 1.67 mmol), cesium carbonate (1.08 g, 3.36 mmol), 1,1-bis(diphenylphosphine)pyridinium palladium dichloride (123 mg, 0.17 mmol), 1,4- Dioxane (10 mL) was reacted at 100° C. for 2 hours under nitrogen protection. The reaction solution was concentrated and purified with silica gel to obtain the product 115d (660 mg, yellow oily liquid), yield: 80.01%, LCMS (ESI): m/z 436.1 [M+H-56] ⁺ .

Step 4: Compound 115d (660 mg, 1.34 mmol), 10% palladium on carbon (100 mg) and methanol (15 mL) were sequentially added to a dry flask, and reacted at room temperature overnight under hydrogen protection. Filtration, concentration of the filtrate and drying gave the product 115e (630 mg, brown solid) Yield: 95.16%, LCMS (ESI): m/z 394.2 [M+H-100] ⁺ .

Step 5: Compound 115e (630 mg, 1.28 mmol), hydrochloric acid/1,4-dioxane (1.3 mL, 5.11 mmol), 1,4-dioxane (3 mL) were added to a dry flask in sequence, and the room temperature The reaction was carried out for 3 hours. The reaction solution was concentrated to obtain the product 115f (450 mg, black solid), yield: 89.64%, LCMS (ESI): m/z 394.2 [M+H] ⁺ .

Step 6: Compound 115f (450 mg, 1.14 mmol), 4-chloro-3-nitrobenzamide (343 mg, 1.71 mmol), potassium carbonate (474 mg, 3.43 mmol) and N,N-dimethylformamide (8 mL) ), reacted at 100°C overnight. Add water and ethyl acetate for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified to obtain product 115g (220mg, yellow solid), yield: 34.49%, LCMS (ESI): m/z 558.2[M+H] ⁺ .

Step 7: Compound 115g (100mg, 0.18mmol), 10% palladium on carbon (40mg), methanol (5mL) and tetrahydrofuran (3mL) were sequentially added to a dry flask, and the reaction was carried out at room temperature overnight under hydrogen protection. Filtration, concentration of the filtrate and drying to give the product 115h (90 mg, black solid) Yield: 95.13%, LCMS (ESI): m/z 528.3 [M+H] ⁺ .

Step 8: Compound 115h (90 mg, 0.17 mmol), bromine cyanide (36 mg), methanol (1 mL) and water (1 mL) were sequentially added to a dry flask, and reacted at 70° C. for 2 hours under nitrogen protection. The reaction solution was concentrated to obtain the product 115i (80 mg, black solid), yield: 85.09%, LCMS (ESI): m/z 553.1 [M+H] ⁺ .

Step 9: Compound 115i (80 mg, 0.145 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (33 mg, 0.217 mmol), N,N-diisopropylethylamine (37 mg , 0.289 mmol), benzotriazole-1-tetramethyl hexafluorophosphate (82 mg, 0.217 mmol), N,N-dimethylformamide (2 mL), and reacted at 50° C. for 2 hours under nitrogen protection. Water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain product 115j (70 mg, black oily liquid), yield: 70.21%, LCMS (ESI): m/z 689.2 [M+H] ⁺ .

Step 10: Compound 115j (70 mg, 0.1 mmol), lithium hydroxide (12 mg, 0.3 mmol), tetrahydrofuran (1 mL) and water (1 mL) were sequentially added to a dry flask, and reacted at room temperature for 2 hours. The reaction solution was purified to obtain the product H115 (38 mg, white solid), yield: 56.15%, LCMS (ESI): m/z 675.1 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ8.00(d, J=1.2Hz, 1H), 7.99-7.95(m, 1H), 7.61-7.54(m, 2H), 7.45(s, 1H) ),7.36-7.27(m,1H),6.62(s,1H),4.60(q,J=6.9Hz,2H),4.23(t,J=7.0Hz,2H),3.82(s,3H),3.79 (s,3H),3.16-3.05(m,2H),2.99(t,J=7.5Hz,2H),2.71-2.58(m,2H),2.11(s,3H),1.87-1.80(m,2H) ),1.79-1.69(m,2H),1.50-1.37(m,2H),1.34(t,J=7.1Hz,3H).

61. Synthesis of compound H116

Step 1: Compound 116a (1.1 g, 4 mmol), 3-oxabicyclo[3.1.0]hexane-2,4-dione (670 mg, 6 mmol), and aluminum trichloride (1.06 mmol) were sequentially added to a dry flask g, 8 mmol) and 20 mL of dichloromethane, and reacted at room temperature for 2 days after the addition. Dilute hydrochloric acid and ethyl acetate were added to the reaction solution, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain crude product 116b (1.54 g), LCMS (ESI): m/z 387.0 [M+H] ⁺ .

Step 2: Compound 116b (1.54 g, 4 mmol), methyl iodide (568 mg, 8 mmol), potassium carbonate (552 mg, 8 mmol) and 10 mL of N,N-dimethylformamide were sequentially added to a dry flask. React overnight at room temperature. Water and ethyl acetate were added to the reaction solution, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and passed through a silica gel column to purify to obtain the product 116c (330 mg, yellow solid), yield: 20.57%.

¹ H-NMR (400MHz, CDCl ₃ ): δ 7.30(s, 1H), 7.20(s, 1H), 4.01(s, 3H), 3.99(s, 3H), 3.61(s, 3H), 3.06( td, J=8.3, 7.0Hz, 1H), 2.38 (td, J=8.5, 6.6Hz, 1H), 2.05–2.00 (m, 1H), 1.47 (td, J=8.3, 4.9Hz, 1H).

Step 3: Compound 116c (330 mg, 0.827 mmol), 4-tert-butyl(E)-(4-(4,4,5,5-tetramethyl-1,3,2-di) were sequentially added to a dry flask Oxaboran-2-yl)but-3-en-1-yl)carbamate (244 mg, 0.827 mmol), cesium carbonate (539 mg, 1.654 mmol), 1,1-bis(diphenylphosphine) ) ferrous palladium dichloride (60 mg, 0.08 mmol), 1,4-dioxane (8 mL), and reacted at 100° C. for 2 hours under nitrogen protection. The reaction solution was concentrated, passed through silica gel column, and purified to obtain product 116d (280 mg, yellow oily liquid), yield: 69.31%, LCMS (ESI): m/z 434.4 [M+H-56] ⁺ .

Step 4: Compound 116d (280 mg, 0.57 mmol), 10% palladium on carbon (50 mg) and methanol (10 mL) were sequentially added to a dry flask, and the reaction was carried out at room temperature overnight under the protection of hydrogen. After filtration, the filtrate was concentrated and dried to obtain the product 116d'. 4A was dissolved in hydrochloric acid/1,4-dioxane (3 mL) and stirred for 3 hours. The reaction solution was concentrated to obtain the product 116e (200 mg, yellow solid) Yield: 100%, LCMS (ESI): m/z 392.3 [M+H] ⁺ .

Step 5: Compound 116e (200 mg, 0.511 mmol), 4-chloro-3-nitrobenzamide (102 mg, 0.511 mmol), potassium carbonate (141 mg, 1.02 mmol) and N,N- Dimethylformamide (5 mL) was reacted at 100°C overnight. The reaction solution was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was mixed with silica gel and passed through a column to purify the product 116f (100 mg, yellow solid), yield: 35.23%, LCMS (ESI): m/z 556.2 [M+H] ⁺ .

Step 6: Compound 116f (100 mg, 0.18 mmol), 10% palladium on carbon (50 mg), methanol (3 mL) and tetrahydrofuran (3 mL) were sequentially added to a dry flask, and reacted at room temperature overnight under hydrogen protection. Filtration, concentrated filtrate and dried to obtain crude product 116g (100mg, brown solid)

Step 7: Compound 116g (100 mg, 0.19 mmol), bromine cyanide (30 mg), methanol (1 mL) and water (1 mL) were sequentially added to a dry flask, and reacted at 70° C. for 2 hours under nitrogen protection. The reaction solution was concentrated to obtain the product 116h (100 mg, black solid), yield: 97.27%, LCMS (ESI): m/z 551.3 [M+H] ⁺ .

Step 8: Compound 116h (100 mg, 0.182 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (56 mg, 0.363 mmol), N,N-dicarboxylate (56 mg, 0.363 mmol) were added to a dry flask Isopropylethylamine (70 mg, 0.545 mmol), benzotriazole-1-tetramethyl hexafluorophosphate (103 mg, 0.273 mmol), N,N-dimethylformamide (2 mL), under nitrogen for 50 °C for 2 hours. The reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was then purified to obtain product 116i (12 mg, white solid), and mixture 9A (11 mg, white solid) ), yield: 18.41%, LCMS (ESI): m/z 687.3 [M+H] ⁺ .

Step 9: Compound 116i (12 mg, 0.017 mmol), lithium hydroxide (3 mg, 0.052 mmol), tetrahydrofuran (1 mL) and water (1 mL) were sequentially added to a dry flask, and reacted at room temperature for 2 hours. The reaction solution was purified to obtain the product H116 (3.3 mg, white solid) Yield: 28.21%, LCMS (ESI): m/z 673.2 [M+H] ⁺ ,

¹ H-NMR (400MHz, MeOD-d ₄ ): δ 7.92(s, 1H), 7.80(d, J=8.4Hz, 1H), 7.40(d, J=8.5Hz, 1H), 7.36(s, 1H), 7.16(s, 1H), 6.62(s, 1H), 4.69-4.60(m, 2H), 4.28-4.17(m, 2H), 3.92(s, 3H), 3.77(s, 3H), 2.91 -2.80(m, 1H), 2.23(s, 3H), 2.18-2.10(m, 1H), 2.01-1.92(m, 2H), 1.82-1.71(m, 2H), 1.52-1.43(m, 2H) ,1.38(t,J＝7.0Hz,3H),1.33-1.25(m,1H).

62. Synthesis of compound H117

Step 1: Compound 117a (790 mg, 2.44 mmol), 1,3-dibromopropane (1.47 g, 7.32 mmol) and cesium carbonate (790 mg, 2.44 mmol) and N,N-dimethyl are added to a dry flask sequentially Formamide (15 mL) was added and reacted at 80°C for 3 hours. The reaction solution was concentrated, stirred with silica gel, and subjected to column chromatography (petroleum ether:ethyl acetate=10:1-6:1) to obtain the product 117b (680 mg, yellow solid) Yield: 62.6%, LCMS (ESI): m/z 446.0[M+H] ⁺ .

Step 2: Compound 117b (680 mg, 1.53 mmol), sodium azide (298 mg, 4.59 mmol) and 5 mL of dimethyl sulfoxide were sequentially added to a dry flask, and stirred at room temperature for 3 hours. After adding 20 mL of water, it was extracted with ethyl acetate. The organic phase was concentrated to give the product 117b as a yellow oil (430 mg, 69.1% yield), LCMS (ESI): m/z 408.1 [M+H] ⁺ .

Step 3: Compound 117c (430 mg, 1.05 mmol), 5% palladium on carbon (50 mg) and methanol (15 mL) were sequentially added to a dry flask, and the reaction was carried out at room temperature overnight under hydrogen protection. Filtration, concentration of the filtrate and drying gave the product 117d (370 mg, yellow oil) Yield: 92.0%, LCMS (ESI): m/z 382.1 [M+H] ⁺ .

Step 4: Compound 117d (370 mg, 0.97 mmol), 4-fluoro-3-nitro-benzamide (213 mg, 1.16 mmol), triethylamine (202 mg, 2 mmol) and 5 mL of tetrahydrofuran were sequentially added to a dry flask. The reaction was carried out at 50°C overnight. Concentration and column chromatography (petroleum ether:ethyl acetate=10:1-5:1) gave the product 117e (280 mg, yellow oil) Yield: 53.0%, LCMS (ESI): m/z 546.1 [M+H ] ⁺ .

Step 5: Compound 117e (280 mg, 0.514 mmol), 5% palladium on carbon (30 mg) and methanol (5 mL) were sequentially added to a dry flask, and the reaction was carried out at room temperature overnight under the protection of hydrogen. Filtration, concentration of the filtrate and drying gave the product 117f (210 mg, yellow oil) Yield: 79.5%, LCMS (ESI): m/z 516.2 [M+H] ⁺ .

Step 6: Compound 117f (80 mg, 0.145 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-thioisocyanate (80 mg, 0.408 mmol) and N,N-diisocyanate were added to a dry flask sequentially Methylformamide (4 mL); after stirring at room temperature for 5 minutes, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.408 mmol) and triethylamine (41 mg, 0.408mmol); After continuing the reaction at room temperature for 3 hours, add water and ethyl acetate for extraction, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain product 117g (100mg, yellow oily liquid), yield: 36.2%, LCMS (ESI): m/z 677.1 [M+H] ⁺ .

Step 7: Compound 117g (100 mg, 0.148 mmol), lithium hydroxide (19 mg, 0.444 mmol), tetrahydrofuran (5 mL) and water (2 mL) were sequentially added to a dry flask, and reacted at room temperature for 2 hours. The reaction solution was purified to obtain the product H117 (29 mg, white solid), yield: 29.6%, LCMS (ESI): m/z 663.1 [M+H] ⁺ ,

¹ H-NMR (400MHz, MeOD-d ₄ ): δ 8.11 (s, 1H), 7.96 (s, 1H), 7.84-7.81 (m, 1H), 7.53 (d, J=8.8Hz 1H), 7.13 (s,1H),6.54(s,1H),4.60(q,J＝6.9Hz,2H),4.49-4.41(m,4H),3.86(s,3H),3.81(s,3H),3.12- 3.09(m, 2H), 2.57-2.27(m, 4H), 2.07(s, 3H), 1.27(t, J=7.2Hz, 3H).

63. Synthesis of compound H118

Step 1: Compound 117a (800 mg, 2.47 mmol), 1,4-dibromopropane (1.593 g, 7.41 mmol), and cesium carbonate (802 mg, 2.47 mmol) and N,N-dimethylene were sequentially added to a dry flask Formamide (15 mL) was added and reacted at 80°C for 3 hours. The reaction solution was concentrated, stirred with silica gel, and subjected to column chromatography (petroleum ether:ethyl acetate=10:1-6:1) to obtain product 118a (420 mg, yellow solid) Yield: 36.9%, LCMS (ESI): m/z 461.0[M+H] ⁺ .

Step 2: Compound 118a (400 mg, 0.87 mmol), sodium azide (169 mg, 2.60 mmol) and 10 mL of dimethyl sulfoxide were sequentially added to a dry flask, and the mixture was stirred at room temperature for 3 hours. 20 mL of water was added and extracted with ethyl acetate. The organic phase was concentrated to give 118b as a yellow oil (300 mg, 81.5% yield), LCMS (ESI): m/z 422.1 [M+H] ⁺ .

Step 3: Compound 118b (300 mg, 0.713 mmol), 5% palladium on carbon (30 mg) and methanol (5 mL) were sequentially added to a dry flask, and the reaction was carried out at room temperature overnight under the protection of hydrogen. Filtration, concentration of the filtrate and drying gave the product 118c (270 mg, yellow oil) Yield: 95.7%, LCMS (ESI): m/z 396.1 [M+H] ⁺ .

Step 4: Compound 118c (270 mg, 0.68 mmol), 4-fluoro-3-nitro-benzamide (150 mg, 0.82 mmol), triethylamine (137 mg, 1.36 mmol) and 15 mL of tetrahydrofuran were sequentially added to a dry flask . The reaction was carried out at 50°C overnight. Concentration, column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to give product 118d (210 mg, yellow oil) Yield: 55.3%, LCMS (ESI): m/z 560.1 [M+ H] ⁺ .

Step 5: Compound 118d (210 mg, 0.376 mmol), 5% palladium on carbon (20 mg) and methanol (10 mL) were sequentially added to a dry flask, and the reaction was carried out at room temperature overnight under the protection of hydrogen. Filtration, concentration of the filtrate and drying gave the product 118e (180 mg, yellow oil) Yield: 90.4%, LCMS (ESI): m/z 530.2 [M+H] ⁺ .

Step 6: In a dry flask, compound 118e (180 mg, 0.34 mmol), 1-ethyl-3-methyl-1H-pyrazole-5-thioisocyanate (66 mg, 0.34 mmol) and N,N-diisocyanate were added sequentially Methylformamide (4 mL); after stirring at room temperature for 5 minutes, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol) and triethylamine (33 mg, 0.34mmol); After continuing to react at room temperature for 3 hours, water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain product 118f (120mg, yellow oily liquid), yield: 51.2%, LCMS (ESI): m/z 691.1 [M+H] ⁺ .

Step 7: Compound 118f (120 mg, 0.174 mmol), lithium hydroxide (22 mg, 0.522 mmol), tetrahydrofuran (5 mL) and water (2 mL) were sequentially added to a dry flask, and reacted at room temperature for 2 hours. The reaction solution was purified to obtain the product H118 (38 mg, white solid), yield: 32.4%, LCMS (ESI): m/z 677.1 [M+H] ⁺ ,

¹ H-NMR (400MHz, MeOD-d ₄ ): δ 8.12 (s, 1H), 8.02 (s, 1H), 7.91-7.89 (m, 1H), 7.64 (d, J=8.8Hz 1H), 7.24 (s,1H),6.80(s,1H),4.69(q,J＝6.9Hz,2H),4.49-4.45(m,4H),3.90(s,3H),3.85(s,3H),3.15- 3.12(m, 2H), 2.52-2.49(m, 2H), 2.21-2.14(m, 2H), 2.07(s, 3H), 2.05-2.03(m, 2H), 1.45(t, J=7.2Hz, 3H).

64. Synthesis of compound H119

Step 1: Add compound 119a (the synthesis method is similar to H116) (25mg, 0.037mmol) and Pd/C (10mg) at room temperature in a single-necked flask containing 10mL of tetrahydrofuran, and stir at room temperature for 3 hours under a hydrogen atmosphere (15psi) , the reaction solution was filtered through celite, and the filtrate was concentrated to obtain compound 119b (13.2 mg, brown solid), yield: 52.8%, LCMS (ESI): m/z 675.4 [M+H] ⁺ .

Step 2: Compound 119b (13.2 mg, 0.02 mmol) and lithium hydroxide monohydrate (3 mg, 0.08 mmol) were added to a single-necked flask containing 1.5 mL of tetrahydrofuran and 0.5 mL of water at room temperature, and stirred at room temperature for 2 hours. The reaction solution was concentrated, separated and purified by reverse-phase preparation to obtain compound H119 (3.2 mg, white solid), yield: 24.2%, LCMS (ESI): m/z 661.4 [M+H] ⁺ ,

¹ H NMR (400MHz, MeOD): δ8.07-8.06(m,1H), 7.93-7.91(m,1H), 7.64-7.62(m,1H), 7.36-7.34(m,1H), 7.14(s) ,1H),6.84(s,1H),4.69-4.68(m,2H),4.41-4.40(m,2H),3.92(s,3H),3.64(s,3H),3.28-3.26(m,2H) ), 3.14-3.11(m, 2H), 2.64-2.61(m, 2H), 2.36(s, 3H), 2.01-1.98(m, 2H), 1.76-1.75(m, 2H), 1.49-1.46(m , 3H).

65. Synthesis of compound H120

Step 1: Compound 120a (20.0 g, 104.1 mmol), dimethyl carbonate (120 mL) and NaH (7.50 g, 312.4 mmol) were sequentially added to a dry three-necked round-bottomed flask at room temperature. Heat to 90°C and stir for 2 hours. Cool to room temperature, add dichloromethane, adjust pH=2～3 with 3M hydrochloric acid, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, which is slurried with ethanol , to obtain product 120b (21.0 g, yellow solid), yield: 80.7%, ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18 (s, 1H), 6.92 (s, 1H), 3.99 (s, 3H) ,3.91(s,3H),3.79(s,3H),3.73(dd,J＝7.9,3.6Hz,1H),3.47(dd,J＝17.1,3.5Hz,1H),3.28(dd,J＝17.1 ,7.9Hz,1H).

Step 2: Compound 120b (8.0 g, 32.0 mmol), triethylsilylhydrogen (14.88 g, 128.0 mmol) and trifluoroacetic acid (30 mL) were heated to reflux and stirred for 16 hours. Cooled to room temperature, concentrated under reduced pressure, added ethyl acetate, washed with saturated sodium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified to give compound 120c (2.50 g, yellow solid), yield: 33.1%, ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.74 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H) ), 3.42-3.27(m, 1H), 3.25-3.11(m, 4H).

Step 3: Compound 120c (2.50 g, 10.6 mmol), methanol (60 mL) and 4M sodium hydroxide solution (10 mL) were stirred at room temperature for 16 hours. Concentrate under reduced pressure, add dichloromethane and water, and separate the layers. The aqueous phase is adjusted to pH<2 with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized (petroleum ether: dichloromethane) to give compound 120d (2.20 g, white solid), yield: 93.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.75 (s, 2H), 3.85 (s, 6H), 3.47-3.33 (m, 1H), 3.30-3.14 (m, 4H).

Step 4: Compound 120d (2.00g, 9.01mmol), CDI (2.19g, 13.51mmol) and acetonitrile (60mL) were stirred at room temperature for 1 hour and then added potassium 3-methoxy-3-oxomalonate (2.11g, 13.51g) mmol) and anhydrous magnesium chloride (1.29 g, 13.51 mmol), and stirred at room temperature for 16 hours. Concentrate under reduced pressure, add water, adjust pH=3-4 with 3M hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The crude product was purified (petroleum ether:ethyl acetate=1:1) to give compound 120e (2.00 g, white solid), yield: 79.9%. LCMS (ESI): m/z 279.1 [M+H] ⁺ .

Step 5: Compound 120e (2.00 g, 7.19 mmol), DMF (40 mL) and methyl chloroacetate (1.17 g, 10.78 mmol) were stirred at room temperature for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified (petroleum ether:ethyl acetate=1:1) to give compound 120f (1.00 g, yellow solid), yield: 39.7%. LCMS (ESI): m/z 349.0 [MH] ^- .

Step 6: Compound 120f (1.00 g, 2.85 mmol), potassium carbonate (3.94 g, 28.54 mmol), tetrahydrofuran (20 mL) and water (10 mL) were sequentially added to a dry three-necked round-bottomed flask at room temperature. Heat to 80°C and stir for 48 hours. Cooled to room temperature, the reaction solution was adjusted to pH=3-4 with 3M hydrochloric acid, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by HPLC to give compound H120 (280 mg, white solid), yield: 35.3%. LCMS (ESI): m/z 279.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ12.09(s, 1H), 6.80(s, 2H), 3.70(s, 6H), 3.56-3.45(m, 1H), 3.03(d, J=8.2 Hz, 4H), 2.76(t, J＝6.4Hz, 2H), 2.44(t, J＝6.4Hz, 2H).

66. Synthesis of compound H121

Compound H120 (50 mg, 0.18 mmol) was dissolved in 1,2-dichloroethane (5 mL), BAST (159 mg, 0.72 mmol) was added under an ice bath, and the mixture was stirred at room temperature for 3 hours. Ice water was added to the reaction solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by thin layer chromatography plate (PE:EA=1:1) to give compound H121 (14 mg, white solid), yield: 25.9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.74 (d, J=4.6 Hz, 2H), 3.86 (d, J=1.2 Hz, 6H), 3.19-3.00 (m, 4H), 2.97-2.72 (m ,2H),2.65-2.54(m,1H),2.47-2.36(m,1H),2.33-2.13(m,1H).

67. Synthesis of compound H122

Step 1: Compound 120a (9.60 g, 50.0 mmol) was dissolved in methanol (100 mL), and sodium borohydride (3.78 g, 100.0 mmol) was added in portions under ice bath. After stirring at room temperature for 3 hours, the solvent was concentrated under reduced pressure to remove the solvent, ethyl acetate was added, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product 122a (8.50 g, white solid), yield : 87.6%. ¹ H NMR (400MHz, CDCl ₃ ): δ 6.94 (s, 1H), 6.76 (s, 1H), 5.19 (s, 1H), 3.87 (d, J=2.5Hz, 6H), 3.07-2.93 (m ,1H),2.86-2.66(m,1H),2.57-2.43(m,1H),2.01-1.88(m,1H),1.87(d,J=4.3Hz,1H).

Step 2: Compound 122a (4.5 g, 23.17 mmol), chloroform (1 L) and p-toluenesulfonic acid monohydrate (23 mg, 0.12 mmol) were sequentially added to a dry three-necked round bottom flask at room temperature. The mixture was stirred at room temperature for 3 hours, washed with 10% aqueous potassium carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified (petroleum ether:ethyl acetate=3:1) to give compound 122b (1.50 g, yellow solid), yield: 36.7%. LCMS (ESI): m/z 177.2 [M+H] ⁺ .

Step 3: Add succinic anhydride (981 mg, 9.80 mmol), dichloromethane (100 mL) and aluminum trichloride (1.74 g, 13.06 mmol) to a dry three-necked round-bottomed flask successively under ice bath, stir for 0.5 hours and add Compound 122b (1.15 mg, 6.53 mmol). After stirring at room temperature for 3 hours, the reaction solution was poured into 3M hydrochloric acid, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by HPLC to give compound H122 (5 mg, white solid), yield: 0.3%. LCMS (ESI): m/z 277.1 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ 7.83 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 3.87 (d, J=5.5 Hz, 6H), 3.59 (s, 2H), 3.17 (t,J＝6.5Hz,2H),2.66(t,J＝6.4Hz,2H).

Example 2: Cell Screening Experiment of Compounds Activating Interferon Gene Stimulating Protein and Promoting IFN-β Expression

1. Human cell test of compound activation on STING

Detection method and principle: Human THP1-Blue-ISG cells are transferred with a reporter system containing IFN-β. The reporter system can induce the expression of downstream alkaline phosphatase. When the alkaline phosphatase is secreted outside the cell , OD650 can be measured by color reaction to reflect its content. When the compound is added to the cells, if the interferon gene-stimulating protein is activated, the expression of IFN-β can be promoted, thereby promoting the increase of the downstream alkaline phosphorylation secretion and the increase of the absorbance of the color reaction.

experiment method:

1. Add compound: 20 μL of compound diluted with physiological saline is added to each well of a 96-well cell culture plate, and the concentration of the compound is 100 μM, and two replicate wells are set. The positive control compound was ADU-S100 at a concentration of 100 μM. The unmedicated control group was added with 20 μL of normal saline containing 1% DMSO.

2. Add cells: THP1-Blue-ISG cell count, adjust the cell concentration to 5×10 ⁵ /mL, and add 180 μl of cells to each well for incubation. Therefore, the final volume of each test well is 200 μL, the content of DMSO is 0.1%, and the test concentration of the compound is 10 μM or 50 μM. The positive control compound was ADU-S100 with a final concentration of 10 μM, which was incubated for 24 hours for detection; 180 μL of culture solution was added to the blank group.

3. Detection of color reaction: After 24 hours, take 20 μL of culture solution from each well to a new 96-well plate, add 200 μL of color developing solution Quanti-Blue, and place it in an incubator at 37°C. After 0.5-2 hours, measure the OD650 value. .

4. Screening concentration of compounds: 10 μM.

5. Result analysis:

Wherein Compound OD650 is the OD650 value of the compound of the present invention, Blank OD650 is the OD650 value of the medium, and Control OD650 is the OD650 value of the control group without the present compound (only cells and 0.1% DMSO).

6. Result evaluation: when the activation multiple (Fold change) ≥ 2, it is valid.

Table 1. The ability of some compounds to activate hSTING in THP1 cells

Note: The structures of compound ADU-S100, compound IA and compound IB are as follows:

It can be seen from Table 1 that at 10 μM or 50 μM, most of the representative compounds of the present invention show a significant ability to activate the interferon gene-stimulating protein hSTING, and promote the expression of type I interferon. In particular, compounds S1, S3, S23, H45, H46, H47, H83, H112, H119, H120, H121, H122 have excellent activation properties for the interferon gene-stimulating protein hSTING, thereby promoting the expression of type I interferon, and then To achieve effective treatment of tumors and their complications.

Among them, some of the representative compounds have comparable or even stronger agonistic activity to the cyclic diglycoside compound ADU-S100 under clinical research or the reported known tool compound IA. In addition, there are some compounds that show weak to moderate agonistic activity of hSTING at experimental concentrations, but these compounds can mildly agonize the immune target and avoid excessive/strong agonism of the immune target. Toxic side effects.

2. Experiments on mouse-derived cells activated by compounds on STING

Detection method and principle: a mouse-derived Raw-lucia cell, which is transduced with a reporter system containing ISG. The reporter system induces activation of the ISG promoter and produces luciferase, which is present in the cell supernatant and can be quantified ^{by the luciferase detection reagent QUANTI-Luc™.} When the compound is added to the cells, if STING is activated, it can promote the expression of ISG, which in turn promotes the increase of downstream luciferase secretion.

Reagents, Consumables and Instruments:

In the experiment, Raw-lucia cells were purchased from InvivoGen, DMEM medium was purchased from Thermo Fisher Scientific, FBS was purchased from Gibco, Australia, luciferase detection reagent QUANTI-Luc ^{TM was} purchased from InvivoGen, and the microplate reader was a product from Envision. Functional microplate reader.

Compound formulation:

Compounds were centrifuged at 12 000 g for 5 min, DMSO was added to prepare a 10 mM stock solution, vortexed evenly, sonicated for 10 min, and then stored at -20°C.

experiment method:

1. Add cells: Count Raw-lucia cells, adjust the cell concentration to 5×10 ⁵ /mL, and add 180 μL of cells to each well for incubation.

2. Add compound: 20 μL of compound diluted with physiological saline was added to each well of the 96-well cell culture plate after the cells adhered to the wall, the concentration of the compound was 50 μM, the positive control compound was DMXAA, the concentration was 50 μM, and the control group was without DMSO. Physiological saline, each with 3 replicate wells. Incubate for 24h for detection.

3. Detection of color reaction: After 24 hours, take 20 μL of culture medium from each well to a new bottom light-transmitting 96-well plate, add ^{50 μL of luciferase detection reagent QUANTI-Luc™} , and measure the fluorescence value immediately (in the dark).

Screening concentration of compounds: 50 μM

5. Experimental batch: 2 times

6. Result analysis:

Fold Change=Compound Luminescence/Control Luminescence

7. Result evaluation: when Fold change ≥ 2, it is valid.

Table 2. The ability of some compounds to activate mSTING in Raw-lucia cells

Note: The structures of compound DMXAA, compound IA and compound IB are as follows:

As can be seen from Table 2, at the concentration of 50 μM or 100 μM, each representative compound of the present invention showed a significant ability to activate Raw-lucia cells.

Example 3 Study on drug metabolism (PK) properties of compound S1

In order to demonstrate the special group effect of the compound obtained by multiplying the benzene ring in the benzothiophene core of the benzothiophene compound of the present invention, the side chain of butyric acid is substituted by different substituents such as fluorine, methyl, etc., Merck (Merck) ) in the company's published patent PCT/US2017/054688, the side chain and the parent nucleus benzene ring do not contain methyl, fluorine atom-substituted compound IA, and the benzene ring in the benzothiophene core contains fluorine atoms, but the side chain only contains Metabolism of compound IB whose methyl group does not contain fluorine atom substitution, and representative compound S1 among the polysubstituted compounds described in this patent (the benzene ring and butyric acid side chain in the benzothiophene nucleus both contain F substitution) in rats properties were compared.

1. Dosing schedule

18 SD rats, male, weighing 200-220g, were randomly divided into 6 groups, 3 rats in each group, and IA/IB/S1 was administered orally or intravenously. The specific arrangement is shown in the following table:

The rats were fasted for 12 h before the test and had free access to water. 2h after the administration of unified food.

2. Blood collection time point and sample processing:

Oral administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;

Intravenous administration: 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;

At the above set time points, 0.3 mL of venous blood was collected from the retroocular venous plexus of rats, placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a –20°C refrigerator.

3. Sample testing and data analysis

The concentrations of IA, IB and S1 in rat plasma were determined by LC/MS/MS method.

The non-compartmental model of WinNonlin 6.3 software (Pharsight, USA) was used to calculate the pharmacokinetic parameters after administration.

The peak concentration _Cmax and the peak time _Tmax are measured values;

_{AUC 0-t} value of the area under the drug-time curve: calculated by trapezoidal method; AUC _0-∞ =AUC _0-t +C _t / _ke , C _t is the blood drug concentration at the last measurable time point, and _ke is elimination rate constant;

elimination half-life t _1/2 =0.693/ _ke ;

Clearance CL=D/AUC _0-∞ ;

Steady-state volume of distribution V _ss =CL×MRT

Absolute bioavailability F = (AUC _oral × D _intravenous ) / (AUC _intravenous × D _oral ) × 100%

4. The results are shown in Table 3.

Table 3. Comparison of pharmacokinetic properties of compound S1 with IA and IB in rats

(Dosage: p.o.3mg/kg, i.v.1mg/kg)

The above data show that, compared with compound S1, although Merck compound IA has strong activating activity on both murine and human STING, its metabolic properties are poor, with _{short half-life (T 1/2} ) and peak time (T _{max ).} ) and lower exposure (AUC), especially when administered intravenously (iv). Compared with compound IA, the pharmacokinetic properties of compound IB were improved to some extent by introducing fluorine atoms into the benzene ring in the core of dimethoxybenzothiophene, but the improvement effect was not significant. However, the present invention is based on the fluorination of the parent nucleus benzene ring of the benzothiophene compound, and the multi-site modification strategies such as methylation and fluorination of the butyric acid side chain to obtain a class of compounds with novel structures and multiple substitution structures. , its representative compound S1 has significantly improved properties compared to compounds IA and IB, which are embodied in:

The half-life T _1/2 reaches 1.56 hours, which is 2.4 times that of compound IA and 2 times that of IB (IA:IB:S1=0.656:0.783:1.56h);

The oral exposure was significantly increased, which was 7.5 times that of compound IA and 5.8 times that of IB (IA:IB:S1=3419:4363:25508h*ng/mL);

The intravenous exposure was significantly increased, which was 10.4 times that of compound IA and 7.2 times that of IB (IA:IB:S1=1646:2370:16674h*ng/mL).

It can be seen that the compounds substituted with methyl and polyfluorine groups not only have high activation ability to hSTING or mSTING, but also have significantly improved metabolic properties in rats, which makes the compounds enter the body. In the evaluation of pharmacodynamics and safety, whether it is administered intravenously or orally, its efficacy can be fully exposed, which has significant advantages and potential for further development compared with the STING inhibitors reported so far.

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

Claims

A compound represented by the general formula (I), or its enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt thereof,

In the formula,

A 1 and X 1 are each independently N or CR x ; R x is H, halogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -LM; The substitution refers to being substituted by a substituent selected from the group consisting of halogen, hydroxyl, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, and 3-8 membered heterocyclyl;

W 1 is NH, S or O; Y 1 is N or CR y ; R y is H, -LM or absent;

R 1 , R 2 are independently selected from halogen, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylacyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C4 alkylamido, substituted or unsubstituted C1-C4 alkylamino , -LM; the substitution in R 1 , R 2 refers to being substituted by one or more substituents selected from the following A group: halogen, hydroxyl, methoxy, amino, carboxyl;

R 3 is F, R 4 is H, halogen, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; or R 3 and R 4 and the C atom to which they are attached form a 3-6 membered heterocyclic group or C3- C8 cycloalkyl; or R 3 and R 4 together form =O; or R 4 is H, R 3 and Y 1 and the C atom between them together form a 5-7 membered heterocyclic group; at this time Y 1 is C;

R 5 , R 6 , R 7 , R 8 are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or Unsubstituted C1-C4 alkanoylamino; said substitution means substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH 2 , hydroxyl, C1-C4 alkyl, C1-C4 Alkoxy, amino, 3-6 membered heterocyclic group;

Or R 5 , R 6 and the connected carbon together form a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted 3-8 membered heterocyclic group; the substitution is Refers to being substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxyl, halogen;

Or R 7 , R 8 and the attached carbon together form a group selected from the group consisting of substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered hetero Cyclic group; the substitution refers to being substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxyl, halogen;

T 1 is -C(O)R 9 , -SO 2 R 9 ,
5-7-membered heteroaryl unsubstituted or substituted by substituents selected from group B, C1-C6 alkyl groups unsubstituted or substituted by substituents selected from group B; R 9 is selected from H, hydroxyl, C1- C6 alkoxy, -NHCO-(C1-C6 alkyl), C1-C6 alkyl unsubstituted or substituted by substituents selected from group B, amino group unsubstituted or substituted by substituents selected from group B, 5-8-membered heteroaryl group unsubstituted or substituted by substituents selected from B group; B group substituents include: halogen, hydroxyl, C1-C6 alkyl, -SO 2 CH 3 ;

And when A 1 , X 1 , Y 1 are CH, W 1 is S, T 1 is -C(O)R 9 , and neither R 1 and R 2 are -LM, R 5 , R 6 , R 7 , R 8 cannot be H at the same time;

And any two of R x in A 1 and R x , R 1 , R 2 , and R y in X 1 will not be -LM at the same time;

L is selected from -(CH 2 ) m -(Q) i -(CH 2 ) n -, -O-(CH 2 ) m -(Q) i -(CH 2 ) n -O-, -O-(CH 2 ) m -(Q) i -(CH 2 ) n -, -(CH 2 ) m -(Q) i -(CH 2 ) n -O-; m, n are independently selected from integers from 0 to 5 ; i is 0 or 1; and m, n, i are not 0 at the same time; Q is selected from -CH=CH-, -C≡C-, -C(O)-NH-, -NH-C(O)- , -N=CH-, O, 3-8-membered heterocyclic group, 3-8-membered heteroaryl;

M is selected from the following structures:

A 2 and X 2 are each independently N or CR x '; R x ' is H, halogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl; substituted or unsubstituted C1-C6 alkoxy; the Substituted refers to being replaced by a substituent selected from the group consisting of halogen, hydroxyl, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;

W 2 is O, S, NH; Y 2 is N or CR y '; R y ' is H or absent;

R 1 ', R 2 ' are independently selected from halogen, hydroxy, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C2-C4 alkynyl R The substitution in 1 ', R 2 ' refers to being substituted by one or more selected from halogen, hydroxyl and methoxy;

R 3 ' is F, R 4 ' is H, halogen, hydroxyl, C1-C4 alkyl or C1-C4 alkoxy; or R 3 ' and R 4 ' form a 3-6 membered heterocycle with the C atom to which they are attached or R 3 ' and R 4 ' together form =O; or R 4 ' is H, R 3 ' and Y 2 and the C atom between them form a 5-7 membered heterocyclic group; at this time Y 2 is C;

R 5 ', R 6 ', R 7 ', R 8 ' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy base, substituted or unsubstituted C1-C4 alkanoylamino; the substitution refers to being substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH 2 , hydroxyl, C1-C4 alkyl , C1-C4 alkoxy, amino, 3-6 membered heterocyclic group;

Or R 5 ', R 6 ' and the connected carbon together form a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C3-C8 cycloalkyl group or a substituted or unsubstituted 3-8 membered heterocyclic group; the substitution Refers to being substituted by one or more substituents selected from the following: C1-C6 alkyl, hydroxyl, halogen;

Or R 7 ', R 8 ' and the connected carbon together form a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C3-C8 cycloalkyl group or a substituted or unsubstituted 3-8 membered heterocyclic group; the substitution Refers to being substituted by one or more substituents selected from the following: C1-C6 alkyl, hydroxyl, halogen;

T 2 is -C(O)R 9 , -SO 2 R 9 ,
5-7-membered heteroaryl unsubstituted or substituted by substituents selected from group B, C1-C6 alkyl groups unsubstituted or substituted by substituents selected from group B; R 9 is selected from H, hydroxyl, C1- C6 alkoxy, -NHCO-(C1-C6 alkyl), C1-C6 alkyl unsubstituted or substituted by substituents selected from group B, amino group unsubstituted or substituted by substituents selected from group B, 5-8-membered heteroaryl group unsubstituted or substituted by substituents selected from Group B;

T 3 is a 5-7-membered heteroaryl group that is unsubstituted or substituted by a substituent selected from Group B;

Group B substituents include: halogen, hydroxyl, C1-C6 alkyl, -SO 2 CH 3 ;

T 4 and T 4 'are each independently a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 5-7 membered heteroaryl, 3-6 membered substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C6 -C10 aryl, substituted or unsubstituted C3-C8 cycloalkyl; the substituted refers to being substituted by one or more of the following substituents: halogen, hydroxyl, amino, carboxyl, cyano, C1 -C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 3-8 membered heterocyclyl, C6-C10 aryl.
The compound represented by the general formula (I) according to claim 1, or its enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt thereof, is characterized by,

A 1 , X 1 are each independently N or CR x ; R x is H, F, Cl, -LM;

A 2 , X 2 are each independently N or CR x '; R x ' is H, F, Cl;

Y 1 is N or CR y ; R y is H, -LM or absent; Y 2 is N or CH;

W 1 and W 2 are each independently NH or S;

R 1 and R 2 are each independently fluorine, chlorine, bromine or C1-C4 alkoxy, -LM;

R 1 ', R 2 ' are each independently fluorine, chlorine, bromine or C1-C4 alkoxy;

And any two of R x in A 1 , R x , R 1 , R 2 , and R y in X 1 will not be -LM at the same time.
The compound represented by the general formula (I) according to claim 1, or its enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt thereof, is characterized by,

R 3 and R 4 are both F; or R 3 and R 4 and the C atom to which they are attached form a 3-6 membered heterocyclyl or C3-C8 cycloalkyl; or R 3 and R 4 together form =O; or R 4 is H, R 3 and Y 1 and the C atom between them form a 5-7-membered heterocyclic group; at this time Y 1 is C;

Both R 3 ' and R 4 ' are F; or R 3 ' and R 4 ' form a 3-6-membered heterocyclic group or a C3-C8 cycloalkyl group with the C atom to which they are attached; or R 3 ' and R 4 ' together Form =O; or R 4 ' is H, R 3 ' and Y 2 and the C atom between them form a 5-7 membered heterocyclic group; in this case, Y 2 is C.
The compound represented by the general formula (I) according to claim 1, or its enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt thereof, is characterized by,

R 5 , R 6 , R 7 , R 8 are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; the Substituted means substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH 2 , hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, amino, 4-6 membered hetero ring base;

Or R 5 , R 6 and the attached carbon together form -(CH=CH 2 ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to the selected Substituted from one or more of the following substituents: C1-C6 alkyl, hydroxyl, halogen;

Or R 7 , R 8 and the attached carbon together form -(CH=CH 2 ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to the selected Substituted from one or more of the following substituents: C1-C6 alkyl, hydroxyl, halogen;

R 5 ', R 6 ', R 7 ', R 8 ' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy base; the substitution refers to being substituted by one or more substituents selected from the group consisting of halogen, -C(O)NH 2 , hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, amino, 4 -6-membered heterocyclyl;

Or R 5 ', R 6 ' and the attached carbon together form -(CH=CH 2 ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to is substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, halogen;

Or R 7 ', R 8 ' and the attached carbon together form -(CH=CH 2 ), substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution refers to Substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxy, halogen.
The compound of claim 1, characterized in that, having a structure selected from any of the following groups:

in,

A 1 , X 1 , A 2 , and X 2 are each independently N or CR x ; R x is H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy said substitution refers to being substituted by a substituent selected from the group consisting of halogen, hydroxyl, C6-C10 aryl, C3-C8 cycloalkyl, 5-7-membered heteroaryl, and 3-8-membered heterocyclyl;

Y 1 and Y 2 are each independently N or CH; W 1 and W 2 are each independently NH or S;

R 1 , R 2 are independently selected from halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; the substitution in R 1 , R 2 refers to being selected from halogen, hydroxyl , substituted by one or more of the methoxy groups;

L is selected from -O-(CH 2 ) m -(Q) i -(CH 2 ) n -O-, -(CH 2 ) m -(Q) i -(CH 2 ) n -; m and n are independent is selected from an integer of 1-5; i is 0 or 1; Q is selected from -CH=CH-, -C≡C-, -C(O)-NH-, -NH-C(O)-, -N =CH-, O,

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , T 1 , R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′, R 6 ′, R 7 ′, R 8 ', T 2 and T 3 are defined as in claim 1.
The compound of claim 1, wherein the compound is selected from the group consisting of:
A pharmaceutical composition, characterized in that, comprising:

The compound represented by general formula (I) according to any one of claims 1-6, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable an acceptable salt; and a pharmaceutically acceptable carrier.
Use of the compound represented by the general formula (I) according to any one of claims 1-6 or the pharmaceutical composition according to claim 7, characterized in that, for the preparation of STING agonists, immune compositions or vaccine adjuvants;

Or used for preparing a medicine for preventing and/or treating STING-dependent type I interferon-related diseases.
The use according to claim 8, wherein the STING-dependent type I interferon-related diseases are tumors and infectious diseases.
The use of claim 9, wherein the tumor is selected from the group consisting of brain and spine cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasal cancer Pharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, Thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline beam cancer and unknown primary cancer;

And the infectious disease is selected from the group consisting of human immunodeficiency virus infection, herpes simplex virus infection, hepatitis B virus infection, and hepatitis C virus infection.