CN118574832A

CN118574832A - Tri-fused ring compound, preparation, pharmaceutical composition and application thereof

Info

Publication number: CN118574832A
Application number: CN202280089566.9A
Authority: CN
Inventors: 郑乾刚; 江相清; 曾庆龙; 许明; 刘景�; 朱继东
Original assignee: Shanghai Yituo Pharmaceutical Technology Co ltd
Current assignee: Shanghai Yituo Pharmaceutical Technology Co ltd
Priority date: 2022-01-19
Filing date: 2022-01-19
Publication date: 2024-08-30
Also published as: WO2023137634A1

Abstract

The invention provides a tricyclic compound shown in the following formula I, and preparation, a pharmaceutical composition and application thereof. The compounds provided by the invention can be used as inhibitors of YAP/TAZ and TEAD interactions, and can be used for treating or preventing diseases mediated by YAP/TAZ and TEAD interactions.

Description

Tri-fused ring compound, preparation, pharmaceutical composition and application thereof

Technical Field

The invention relates to a tricyclic compound, preparation, a pharmaceutical composition and application thereof.

Background

The Hippo pathway is involved in regulating cell growth, proliferation and apoptosis, and plays an important role in regulating organ size, carcinogenesis, tissue regeneration, stem cell and precursor cell regeneration and differentiation, etc. It was found that in mammals, the pathway has a tumor-inhibiting effect, and that abnormal activation of major effector molecules in the pathway is closely related to the occurrence and development of various tumors. In addition, the Hippo pathway interacts with other pathways such as Wnt, notch, hedgehog, MAPK/ERK to co-regulate cell fate. The deregulation of this pathway has also a significant impact on other diseases besides tumours.

The Hippo signaling pathway is highly conserved during evolution, the core of which in mammalian cells is a kinase chain consisting of MST1/2 (membrane of Ste20-LIKE KINASE, the homologous gene in Drosophila is Hippo) and LATS1/2 (large tumor suppressor 1/2, the homologous gene in Drosophila is Warts) protein kinases, and their adaptor proteins SAV1 and Mob1 (Mps one binder kinase activator-like 1A and 1B, the homologous gene in Drosophila is Mats). The kinase chain is capable of phosphorylating the transcriptional coactivators YAP (Yes-Associated Protein) and TAZ (trans-formation co-activator with PDZ binding motif, also called WWTR 1) (corresponding to Yorkie in Drosophila).

LATS1/2, the core component of the mammalian Hippo pathway, belongs to the Dbf2-realted (NDR) family of kinases. Activated by binding to the scaffold protein Mob 1A/B. LATS1/2 can also be activated directly after phosphorylation by MST 1/2. LATS1/2 kinase is capable of phosphorylating multiple sites on the downstream effector YAP, with phosphorylation at Ser127 having a key role in YAP inhibition. The phosphorylated YAP at position 127 of Ser binds to 14-3-3 protein in the cytoplasm, is trapped in the cytoplasm, and cannot undergo nuclear transcription, thereby inhibiting pro-proliferative and anti-apoptotic activities of YAP. Similarly, LATS1/2 kinase is capable of phosphorylating multiple sites on the transcription factor TAZ, with Ser89 phosphorylation having a key role in TAZ inhibition. Phosphorylated TAZ will be retained or sequestered in the cytoplasm. At the same time, phosphorylated YAP or TAZ may be further recognized and degraded by the ubiquitin enzyme scfβ -TRCP. Thus, if the Hippo pathway is "on", YAP and/or TAZ are inactivated by phosphorylation and remain in the cytoplasm. Conversely, if the Hippo pathway is "off," YAP and/or TAZ will dephosphorylate activated and often found to be localized in the nucleus.

YAP acts as a transcription factor and does not itself contain a DNA binding region. Activated YAP must bind to transcription factors after entering the nucleus to function together. The most tightly bound transcription factor after YAP enters the nucleus is TEAD. TEAD family proteins of human origin include TEAD1/TEAD2/TEAD3/TEAD4.YAP together with TEAD (or other transcription factors such as Smad1, RUNX, erbB4 and p 73) can initiate transcription of a range of downstream genes including CTGF (connectivetissuegrowthfactor), gli2, birc5, birc2, FGF1 (fibroblast growth factor 1) and AREG (amphiregulin). Like YAP, non-phosphorylated TAZ enters the nucleus where it binds to various DNA binding transcription factors, such as PPARγ(peroxisome proliferation-activated receptorγ)、TTF-1(thyroid transcription factor-1)、Pax3、TBX5、RUNX、TEAD1 and Smad2/3/4. Most genes expressed by YAP or TAZ transcription factor complex activation are associated with cell growth and proliferation.

Based on the foregoing, the Hippo-YAP pathway regulates organ size and normal physiological functions by regulating cell proliferation and apoptosis, and is tightly regulated in normal physiological conditions. Protein kinase inactivation or YAP activation of the Hippo pathway promotes tumorigenesis. In fact, aberrant activation of the Hippo pathway is a major event in the development of a variety of malignant tumors, and elevated levels of YAP or TAZ and increased nuclear localization are found in tumors including non-small cell lung cancer, breast cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, prostate cancer, mesothelioma and skin cancer.

Malignant Pleural Mesothelioma (MPM) is a rare breast malignancy, the clinical manifestations are often nonspecific and occult, and many patients are already in the advanced stages of the disease at the time of diagnosis. The unresectable MPM treatment means of the operation is extremely limited, the current first-line pemetrexed/platinum treatment effect is unsatisfactory, the overall median survival rate of about one year can be obtained, and the clinical requirement is relatively large and unsatisfied. Abnormal activation of the Hippo-YAP pathway is present in approximately 70% of patients with MPM, is considered an important cancer driver, and reduction of Hippo-YAP pathway activity by biological means and chemical small molecules shows good tumor growth inhibition activity, indicating that Hippo-YAP is a potential target for treatment of MPM.

Lung cancer is one of the cancer species with the highest mortality rate in the world at present, and a plurality of treatment means including targeted treatment and immunotherapy exist clinically at present, but the problem of low response rate or recurrence is faced. In recent years, various researches show that YAP signal paths can generate drug resistance to lung cancer drugs such as EGFR inhibitors through mechanisms of mediating tumor cell dormancy, resisting apoptosis and the like, and the inhibition of Hippo-YAP signal paths can improve the sensitivity of tumor cells to EGFR targeted drugs, so that a combined strategy can be adopted clinically, and the treatment effect is improved.

Liver cancer is a high-incidence cancer species in China, the current clinical treatment means break through very limited, and great unmet clinical demands exist. YAP is an important gene for regulating the occurrence and development of liver cancer, and various in vivo experiments show that independent overexpression of YAP or knockout of upstream regulatory factor MST1-2 in mouse liver can cause the occurrence of hepatocellular carcinoma without introducing other oncogenes; meanwhile, in an established liver cancer mouse model, the expression of YAP is knocked down, so that the tumor can be obviously inhibited, the tumor cells are promoted to differentiate into liver parenchymal-like cells with functions, and meanwhile, along with the recovery of liver functions, YAP is a potential target for treating liver cancer.

Mutations in KRas are widely found in Pancreatic Ductal Adenocarcinoma (PDAC), and means for targeting KRas are believed to have broad clinical application prospects in PDAC. In a PDAC mouse model, targeting KRAS can inhibit tumor growth and face tumor recurrence at the same time, and research shows that YAP can induce EMT (epithelial-mesenchymal transition) by regulating Fos and plays an important role in the tumor; knocking down YAP expression in recurrent tumors can re-inhibit tumor growth. The targeting YAP has potential clinical application prospect in pancreatic duct adenocarcinoma.

Inhibitors of targeted BRAF and MEK have wide clinical application in a variety of tumors including melanoma, colon cancer, and thyroid cancer, but also face the problem of relapse resistance after administration. Studies show that the Hippo-YAP is used as a path for promoting the growth of tumor cells, overactivation occurs in a plurality of drug-resistant tumor models, and the inhibition of the activity of the Hippo-YAP can obviously improve the sensitivity to BRAF/MEK inhibitors, so that the Hippo-YAP has potential of drug combination in clinic.

In vitro, the overexpression of YAP or TAZ by mammalian epithelial cells results in transformation of the cells. Enhanced YAP/TAZ transcriptional activity induces EMT (epithelial-mesenchymal transition) and confers characteristics to stem cells breast cancer cells.

In summary, a therapeutic strategy targeting the Hippo-Yap pathway would be highly likely to provide a new approach for the treatment of a variety of tumors. The development of specific small molecules damages the interaction between YAP/TAZ and TEAD, weakens the transcriptional activity of YAP, thereby inhibiting the tumor generation of Hippo pathway abnormality, and being expected to become a new strategy for tumor treatment, and having wider clinical application prospect.

Disclosure of Invention

The first aspect of the present invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof:

Wherein:

A ₁ is selected from N or CR _a;

A ₂ is selected from NH, O, or CR _bR _c;

a ₃ is selected from N or CR ₃;

a ₄ is selected from N or CR ₄;

A ₅ is selected from N or CR ₅;

R ₁ is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

r ₂ is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R ₃、R ₄ and R _s are each independently selected from H, hydroxy, halo, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy;

R _a is selected from H, hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy;

R _b and R _c are each independently selected from: H. hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; and

Ring a is a 5-8 membered carbocyclyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl, optionally substituted with 1-3 substituents selected from hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy.

In a second aspect, the invention provides a pharmaceutical composition comprising a I, II or III compound according to any one of the embodiments of the invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof, and a pharmaceutically acceptable carrier or excipient.

In a third aspect, the invention provides the use of a I, II or III compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug or metabolite of any embodiment of the invention in the manufacture of a medicament for the treatment or prophylaxis of a disease mediated by YAP/TAZ interaction with TEAD.

In a fourth aspect, the invention provides a method of treating or preventing a disease mediated by YAP/TAZ interaction with TEAD comprising administering to a subject in need thereof a therapeutically effective amount of a compound I, II or III according to any one of the embodiments of the invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

The compounds described herein generally contain one axial chiral, including a pair of axial chiral isomers. In some embodiments, the axial chirality of the compounds described herein is in the S configuration. In some embodiments, the axial chirality of the compounds described herein is in the R configuration.

A detailed description of the various aspects of the invention is described below.

Detailed Description

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute a preferred technical solution.

I. Terminology

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety unless otherwise indicated. The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting, and may be open, semi-closed, and closed. In other words, the term also includes the meaning of "consisting essentially of …" or "consisting of …".

Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods, unless specifically defined, terms used herein in analytical chemistry, organic synthetic chemistry, and related descriptions of drugs and pharmaceutical chemistry are known in the art, the above techniques and methods may be generally performed according to a number of general and more specific references cited and discussed in the present specification, according to conventional methods well known in the art in this specification, groups and substituents thereof may be selected by one of ordinary skill in the art to provide stable moieties and compounds in this specification.

When a substituent is described by a conventional formula written from left to right, the substituent is also included from left to right

Chemically equivalent substituents are obtained when writing structural formulae right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.

In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

"Hydroxy" refers to an-OH group.

"Hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl (-OH).

"Carbonyl" refers to a-C (=o) -group.

"Nitro" means-NO ₂.

"Cyano" refers to-CN.

"Amino" means-NH ₂.

"Acyl" refers to-COR wherein R is H or alkyl, such as C _1-5 alkyl.

"Substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, aryl, heteroaryl, heterocyclyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino, heteroarylamino, and arylamino groups. In some embodiments herein, a "substituted amino" is represented as-NR 'R ", wherein R' and R" are each independently selected from H, amino, and substituted or unsubstituted alkyl.

"Carboxy" refers to-COOH.

In the present application, as part of a group or other group (e.g., as in a halogen (e.g., fluorine, chlorine, bromine, or iodine) -substituted alkyl group, etc.), the term "alkyl" refers to a straight or branched hydrocarbon chain radical that is fully saturated, consisting of only carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and being attached to the remainder of the molecule by a single bond, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, etc. The alkyl groups of the various embodiments of the present application are preferably C1-C4 alkyl groups.

In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 20 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.

In the present application, as part of a group or other group, the term "cycloalkyl" means a stable non-aromatic mono-or polycyclic hydrocarbon group (e.g., alkyl, alkenyl, or alkynyl) consisting only of carbon atoms and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, such as 3,4, 5,6,7, or 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the present specification, carbon atoms in the cycloalkyl group may optionally be oxidized. In a preferred embodiment, the cyclic hydrocarbon group is cycloalkyl, preferably C3-C8 cycloalkyl. Examples of cyclic hydrocarbyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanedienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [ 2.2.2.2 ] alkenyl, bicyclo [3.1.1] octadienyl, and the like, and adamantyl groups.

In the present application, the term "heterocyclyl" as part of a group or other group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms (e.g., 2, 3, 4,5,6,7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, heterocyclyl groups are preferably stable 4-to 12-membered, 5-to 12-membered, or 4-to 9-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 9-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups described in various embodiments herein include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrazolidinyl, phthalimidyl, dioxothiomorpholine and the like.

In the present application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having from 6 to 18 carbon atoms (preferably from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms, for example 6, 7, 8, 9 or 10 carbon atoms). For the purposes of the present application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups described in the various embodiments herein include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In the present application, the term "heteroaryl" as part of a group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms, for example 1,2, 3, 4,5,6,7, 8, 9 or 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups described in the various embodiments herein include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthazinyl, [1,2,4] triazolo [4,3-b ] pyridazine, [1,2,4] triazolo [4,3-a ] pyrazine, [1,2,4] triazolo [4,3-c ] pyrimidine, [1,2,4] triazolo [4,3-a ] pyridine, imidazo [1,2-b ] pyridazine, imidazo [1,2-a ] pyrazine, and the like.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

In the present application, "optionally" or "optionally" means that the subsequently described event or condition may or may not occur, and that the description includes both cases where the event or condition occurs and where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups. The "optional" substituents described in the claims and the description of the application include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.

It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto-protecting groups include-C (O) -R "(wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl esters, aryl esters or aralkyl esters.

Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, t.w. and p.g.m. wuts, protective Groups in Organi Synthesis, (1999), 4th Ed, wiley. The protecting group may also be a polymeric resin.

For the avoidance of doubt, in the present invention, the wedge bond drawn compound (e.g. compound 67 of example thirty three) is a single configuration compound of defined absolute stereochemistry.

II compounds

The present invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof:

Wherein:

A ₁ is selected from N or CR _a;A ₂ is selected from NH, O or CR _bR _c;A ₃ is selected from N or CR ₃;A ₄ is selected from N or CR ₄;A ₅ is selected from N or CR ₅;R ₁ is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; r ₂ is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; r ₃、R ₄ and R _s are each independently selected from H, hydroxy, halo, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; r _a is selected from H, hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; r _b and R _c are each independently selected from: H. hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; and ring A is a 5-8 membered carbocyclyl, 4-8 membered heterocyclyl or 5-or 6 membered heteroaryl, optionally substituted with 1-3 substituents selected from hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy.

In formula I and the formulae described below, unless otherwise indicated, the alkyl group is preferably a C _1-6 alkyl group, more preferably a C _1-4 alkyl group; the alkoxy group is preferably a C _1-6 alkoxy group, more preferably a C _1-4 alkoxy group; The cycloalkyl is preferably C _3-8 cycloalkyl; the aryl group is preferably a 6-14 membered aryl group; the heteroaryl is preferably a 5-12 membered heteroaryl, more preferably a 5-9 membered heteroaryl; the heterocyclic group is preferably a 4-12 membered heterocyclic group, more preferably a 4-9 membered heterocyclic group; preferably, the heteroatoms in the heterocyclyl and heteroaryl groups include nitrogen, oxygen and/or sulfur, the number of heteroatoms being 1,2 or 3. Unless otherwise indicated, when the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups are substituted, their number of substituents may be 1 to 6, and may each be independently selected from: halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, hydroxy, C _1-4 alkoxy, Halogenated C _1-4 alkoxy, carboxyl, amino, cyano, optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, hydroxy, C _1-4 alkoxy, Halo C _1-4 alkoxy, carboxyl, amino and cyano substituents substituted 6-14 membered aryl, 5-12 membered heteroaryl and 4-12 membered heterocyclyl, and NR 'R' -C (O) - (CH ₂) _n -, etc., wherein R 'and R' are each independently H, amino or substituted or unsubstituted C _1-4 alkyl, n is an integer of 0 to 4; when the amino group is substituted, the substituent may be 1 or 2 substituents selected from the group consisting of C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 acyl and halogenated C _1-4 alkyl, Or1 is optionally substituted with 1 to 3 groups selected from halogen, C _1- ₄ alkyl, halogenated C _1-4 alkyl, hydroxy, C _1-4 alkoxy, halo C _1-4 alkoxy, carboxyl, amino and cyano substituted 6-14 membered aryl, 5-12 membered heteroaryl or 4-12 membered heterocyclyl. Preferably, the preferred substituents for each alkyl and alkoxy group are 1-6 substituents selected from halogen, hydroxy, NR ₁₂R ₁₃ and cyano, wherein each of R ₁₂ and R ₁₃ is independently selected from H, C _1-4 acyl and C _1-4 alkyl.

In particular, in formula I, a ₁ is N. In some embodiments, a ₁ is CR _a, wherein R _a is selected from H and substituted or unsubstituted C _1-4 alkyl.

In some embodiments, ring A is a 5-8 membered saturated carbocycle or a 4-8 membered heterocyclyl in formula I. In particular, ring A is a 4-8 membered nitrogen containing heterocyclic group, which optionally further contains 1 or2 heteroatoms selected from N and O, preferably further optionally contains 1 or2 nitrogen atoms when A ₁ is N. In a further preferred embodiment, ring a is a piperidine ring, in particular the ring nitrogen atom of the piperidine ring is a ₁. In other preferred embodiments, ring a is a piperazine ring, in particular, one ring nitrogen atom of the piperazine ring is a ₁. In some embodiments, ring a is a 5-or 6-membered heteroaryl, preferably containing 1 or2 nitrogen atoms, wherein 1 nitrogen atom is located at position a ₁. In some embodiments, ring a is a benzene ring.

The substituents on ring a are preferably selected from hydroxy, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy; more preferably, the substituents on ring a are selected from substituted or unsubstituted C _1-4 alkyl groups. Preferably, the alkyl is substituted with 1-6 substituents selected from the group consisting of hydroxy, halogen, and NR ₁₂R ₁₃, wherein each of R ₁₂ and R ₁₃ is independently selected from the group consisting of H and C _1-4 alkyl.

In certain embodiments, in formula I, a ₂ is CR _bR _c, wherein, preferably, R _b and R _c of a ₂ are each independently H and C _1-4 alkyl, more preferably both are H. In some embodiments, a ₂ is NH or O.

In certain embodiments, in formula I, a ₃ is CR ₃; preferred R ₃ groups are H, halogen, C _1-4 alkoxy, cyano and substituted or unsubstituted C _1-4 alkyl, more preferably halogen. In certain embodiments, when the C _1-4 alkyl is substituted, the substituents may be 1 to 3 substituents selected from the group consisting of halogen, hydroxy, and amino.

In formula I, a preferred A ₄ is CR ₄; preferred R ₄ groups are H, halogen, C _1-4 alkoxy, cyano and substituted or unsubstituted C _1-4 alkyl, more preferably halogen. Preferably, when the C _1-4 alkyl group is substituted, the substituent may be 1 to 3 substituents selected from halogen, hydroxy and amino.

In certain embodiments, in formula I, R ₃ and R ₄ are each independently halogen.

In formula I, a preferred A ₅ is CR ₅; preferred R ₅ groups are H, halogen, cyano, C _1-4 alkoxy and substituted or unsubstituted C _1-4 alkyl, more preferably H. In certain embodiments, when the C _1-4 alkyl is substituted, the substituents may be 1 to 3 substituents selected from the group consisting of halogen, hydroxy, and amino.

In some embodiments, in formula I, any 1 or any two of a ₃、A ₄ and a ₅ are N, the remainder are the corresponding CR ₃、CR ₄ or CR ₅.

In formula I, in certain embodiments, R ₁ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl. In certain embodiments, when a substituent-bearing group, the substituent on R ₁ can be 1-3 substituents selected from halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, and-NR ₁₂R ₁₃, wherein R ₁₂ and R ₁₃ are each independently H or C _1-4 alkyl. In certain embodiments, the cycloalkyl is C _3-8 cycloalkyl; preferred aryl groups are aryl groups having 6 to 14 ring carbon atoms; preferred heteroaryl groups are those having 5 to 12 ring atoms, more preferably those having at least a ring nitrogen atom in the heteroatom; preferred heterocyclyl groups are those having 4 to 9 ring atoms. In certain embodiments, R ₁ is unsubstituted 6-14 membered aryl, such as phenyl, or 6-14 membered aryl optionally substituted with 1-3 substituents selected from hydroxy, halogen, C _1-4 alkyl, and C _1-4 alkoxy, such as phenyl.

In formula I, preferred R ₂ is H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl. in certain embodiments, when the alkyl is substituted, the substituents may be 1-5 selected from halogen, hydroxy, carboxy, cyano, and-NR ₁₂R ₁₃, where R ₁₂ and R ₁₃ are each independently H or C _1-4 alkyl. In certain embodiments, the substituted or unsubstituted alkyl is a substituted or unsubstituted C _1-4 alkyl, preferably an unsubstituted C _1-4 alkyl or a halogenated C _1-4 alkyl. In some embodiments, R ₂ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl. Preferred cycloalkyl groups are C _3-8 cycloalkyl groups; preferred aryl groups are 6-14 membered aryl groups, more preferably phenyl; preferred heteroaryl groups are those having 5 to 12 ring atoms, more preferably those having at least a ring nitrogen atom in the heteroatom, including but not limited to pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl, indolyl, pyridazinyl, and the like; preferred heterocyclyl groups are heterocyclyl groups having 4 to 9 ring atoms, more preferably heterocyclyl groups containing ring nitrogen and/or oxygen and/or sulfur atoms, such as morpholinyl, piperidinyl, piperazinyl, indolinyl, pyrrolidinyl, azetidinyl. When substituted, the substituent on R ₂ may be 1-3 groups selected from hydroxy, carboxy, halogen, cyano, NR 'R' -C (O) - (CH ₂) _n -, substituted or unsubstituted C _1- ₄ alkyl, A substituted or unsubstituted C _1-4 alkoxy group, a substituted or unsubstituted 4-9 membered heterocyclic group, and a substituted or unsubstituted amino group, wherein R' and R "are each independently selected from H and a substituted or unsubstituted C _1-4 alkyl group, and n is an integer of 0 to 4; In certain embodiments, the alkyl groups, when substituted, may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, and amino; preferably, when the alkoxy group is substituted, the substituent may be 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino, halogenated C _1-4 alkyl, and substituted or unsubstituted 5-12 membered heteroaryl; in some embodiments, when the aforementioned heterocyclyl is substituted, the substituents thereof may be 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino, C _1-4 alkyl, and halo C _1-4 alkyl; In certain embodiments, the amino group, when substituted, may have 1 substituted or unsubstituted 4-9 membered heterocyclic group, or1 or2 substituents selected from substituted or unsubstituted C _1-4 alkyl and C _1-4 acyl, preferably the heterocyclic group is a 4-9 membered heterocyclic group containing N, O and or S, including tetrahydrofuranyl, tetrahydropyranyl, Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, dioxothiomorpholinyl and the like, wherein the substituents on the heterocyclyl may be 1 or 2 substituents selected from halogen, C _1-4 alkyl and amino, and the substituents on the alkyl may be 1 or 2 substituents selected from halogen, hydroxy and amino.

In formula I, preferably, when R ₃、R ₄、R ₅、R _a、R _b、R _c and the alkyl and alkoxy groups in the definition of ring a are substituted, their respective substituents may be 1 to 3 amino groups selected from halogen, hydroxy, carboxy or optionally substituted by 1 or 2C _1-4 alkyl groups, and the amino groups in the definition of these groups may be substituted by 1 or 2C _1-4 alkyl groups.

Some exemplary compounds of formula I have the structure shown in formula II below:

Wherein R ₁ is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted cycloalkyl; r ₂ is selected from H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted cycloalkyl; r ₃、R ₄ and R _s are each independently selected from H, hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; r ₁₁ is H or substituted or unsubstituted alkyl.

In certain embodiments, in formula II, R ₁ is a group having a substituent, the substituent is 1-3 substituents selected from halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, and-NR ₁₂R ₁₃, wherein R ₁₂ and R ₁₃ are each independently H or C _1-4 alkyl. Preferred R ₁ is a substituted or unsubstituted 6-14 membered aryl or a substituted or unsubstituted 5-12 membered heteroaryl; preferred substituents on R ₁ are selected from one or more of hydroxy, halogen, C _1-4 alkyl, and C _1-4 alkoxy. More preferred R ₁ is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl group such as pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl, pyridazinyl and the like; preferably, when a group having a substituent, the substituent is selected from one or more of a hydroxyl group, a halogen, a C _1-4 alkyl group, and a C _1-4 alkoxy group.

In some embodiments, in formula II, R ₂ is a group having a substituent, the substituent is 1-3 groups selected from hydroxy, carboxy, halogen, cyano, NR 'R' -C (O) - (CH ₂) _n -, substituted or unsubstituted C _1-4 alkyl, Substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted 4-9 membered heterocyclyl (e.g., nitrogen-, sulfur-, and/or oxygen-containing 4-9 membered heterocyclyl including tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and dioxothiomorpholinyl, and the like), and substituted or unsubstituted amino, wherein R 'and R' are each independently selected from H, amino, and substituted or unsubstituted C _1-4 alkyl, n is an integer of 0 to 4; Preferably, when the alkyl group is substituted, the substituent may be 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxyl and amino; in certain embodiments, the alkoxy groups, when substituted, may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino, halogenated C _1-4 alkyl, and substituted or unsubstituted 5-12 membered heteroaryl groups; preferably, when the heterocyclic group is substituted, the substituent may be 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino, C _1-4 alkyl and halogenated C _1-4 alkyl; In certain embodiments, the amino group, when substituted, may be substituted or unsubstituted 4-9 membered heterocyclyl (e.g., an oxygen-containing 4-9 membered heterocyclyl such as tetrahydrofuranyl, tetrahydropyranyl, or a nitrogen-containing 4-9 membered heterocyclyl such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or a sulfur-containing 4-9 membered heterocyclyl, and the like), substituted or unsubstituted C _1-4 alkyl, or C _1-4 acyl. the aryl, heteroaryl, and heterocyclyl have the definitions described herein. In some embodiments, R ₂ is a substituted or unsubstituted 6-14 membered aryl (e.g., phenyl), a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl (e.g., pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrrolyl, triazolyl, pyrazinyl, indolyl, pyridazinyl, and the like), a substituted or unsubstituted 4-9 membered nitrogen and/or oxygen and/or sulfur containing heterocyclyl (e.g., azetidinyl, morpholinyl, pyrrolidinyl, indolinyl, piperidinyl, piperazinyl, and the like), or a substituted or unsubstituted C _3-8 cycloalkyl, The substituents on these aryl, heteroaryl, heterocyclyl and cycloalkyl groups are preferably 1 to 3 substituents selected from the group consisting of: halogen, NR 'R' -C (O) - (CH ₂) _n -, C _1-4 alkyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, carboxy and amino, C _1-4 alkoxy which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halogenated C _1-4 alkyl, Unsubstituted 4-9 membered heterocyclyl (preferably heterocyclyl containing N and O and/or S), and unsubstituted or substituted with 1 or 2 substituents selected from C _1-4 alkyl and C _1-4 acyl, or 1-9 membered heterocyclyl (e.g. an oxygen-containing 4-9 membered heterocyclyl, such as tetrahydrofuranyl, tetrahydropyranyl; Or a nitrogen-containing 4-9 membered heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like; or a sulfur-containing 4-9 membered heterocyclic group such as thiomorpholinyl). In other embodiments, R ₂ in formula II is H, halogen, C _1-4 alkyl, or halogenated C _1-4 alkyl.

In certain embodiments, in formula II, R ₃ is H, halogen, C _1-4 alkoxy, and C _1-4 alkyl, particularly halogen and C _1-4 alkyl.

In certain embodiments, in formula II, R ₄ is H, halogen, C _1-4 alkoxy, and C _1-4 alkyl, particularly halogen.

In some embodiments, in formula II, R ₅ is H, halogen, C _1-4 alkoxy, and C _1-4 alkyl, in particular, H.

In some embodiments, in formula II, R ₃ and R ₄ are each independently halogen and R ₅ is H.

In certain embodiments, in formula II, R ₁₁ is H or C _1-6 alkyl optionally substituted with 1-3 substituents selected from halogen and hydroxy, in particular R ₁₁ is H.

In some embodiments, in the compounds of formula I and formula II, when R ₂ is substituted cycloalkyl, aryl, heteroaryl, or heterocyclyl, the number of substituents is at least two; preferably, at least one, more preferably at least two substituents are located in ortho-position. In some embodiments, the at least two substituents include at least halogen and the NR 'R' -C (O) - (CH ₂) _n -), preferably the substituents further comprise one selected from the group consisting of the substituted or unsubstituted C _1-4 alkyl group, a substituted or unsubstituted C _1-4 alkoxy group, a substituted or unsubstituted heterocyclic group, and a substituted or unsubstituted amino group.

In some preferred embodiments of formula II, R ₁ is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl, such as pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl, and pyridazinyl, and the like, wherein when a group having substituents is present, the number of substituents is 1-3 and is selected from hydroxy, halogen, C _1-4 alkyl, and C _1-4 alkoxy, Preferred R ₁ is unsubstituted phenyl; R ₂ is a 4-9 membered heterocyclyl, preferably a 4-9 membered heterocyclyl containing N and/or O and/or S, including azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl and piperazinyl, said heterocyclyl optionally being substituted with 1-3 substituents selected from halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, c _1-4 alkoxy, halo C _1-4 alkoxy, carboxy and NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H and C _1-4 alkyl, n is an integer from 0 to 4, preferably the substituent is the carboxy group or NR 'R' -C (O) - (CH ₂) _n -, and preferably the substituent is located ortho to, and/or is linked to the remainder of the compound of formula II through the ring nitrogen atom of the heterocyclic group when the heterocyclic group is a nitrogen-containing heterocyclic group; R ₃ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H and halogen; r ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen; R ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H; preferably, R ₃ and R4 are each independently halogen, R ₅ is H; r ₁₁ is H or C _1-6 alkyl optionally substituted with 1 to 3 substituents selected from halogen and hydroxy, preferably H.

In still other embodiments of formula II, R ₁ is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl, such as pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl, pyridazinyl, and the like, wherein when substituted, the number of substituents is 1-3 and is selected from the group consisting of halogen, C _1-4 alkyl, and C _1-4 alkoxy, Preferred R ₁ is unsubstituted phenyl; R ₂ is a 5-12 membered heteroaryl, preferably an N-containing 5-12 membered heteroaryl, including pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like, optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1- ₄ alkoxy, halo C _1-4 alkoxy, carboxyl and NR 'R' -C (O) - (CH ₂) _n -, Wherein R 'and R' are each independently selected from H and C _1-4 alkyl, n is an integer from 0 to 4, preferred substituents are the halogen, C _1-4 alkyl or NR 'R' -C (O) - (CH ₂) _n -, and preferably, the substituents are ortho and/or, when the heterocyclic group is a nitrogen-containing heterocyclic group, are attached to the remainder of the compound of formula II through the ring nitrogen atom of the heterocyclic group; R ₃ is H, halo, C _1-4 alkoxy and C _1-4 alkyl, preferably H and halo; r ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen; R ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H; preferably, R ₃ and R ₄ are each independently halogen, R ₅ is H; r ₁₁ is H or C _1-6 alkyl optionally substituted with 1 to 3 substituents selected from halogen and hydroxy, preferably H.

Further preferred compounds of the compounds of formula I have the structure shown in formula III below:

Wherein:

R ₁、R ₃-R _s is as described in any one of the embodiments of formulas I or II above;

B ₁ is C or N; b ₂ is CR ₆ or N; b ₃ is CR ₇ or N; b ₄ is CR ₈ or N; b ₅ is CR ₉ or N; b ₆ is CR ₁₀ or N;

R ₆ is selected from H, halogen, C _1-4 alkyl, C _1-4 alkoxy, cyano, carboxyl, NR ₁₂R ₁₃, and NR 'R' -C (O) - (CH ₂) _n -, wherein R ₁₂ and R ₁₃ are each independently selected from H, C _1-4 acyl and substituted or unsubstituted C _1-4 alkyl, and n is an integer from 0 to 4;

R ₇ is H, halogen, NR ₁₂R ₁₃、C _1-4 alkoxy or C _1-4 alkyl;

R ₈ is H, halogen or C _1-4 alkyl;

r9 is H, halogen, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted 4-9 membered heterocyclyl (e.g., nitrogen and/or oxygen and/or sulfur containing 4-9 membered heterocyclyl including tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, dioxothiomorpholinyl, and the like), or substituted or unsubstituted amino; in some embodiments, the alkyl groups, when substituted, may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, and amino; preferably, when the alkoxy group is substituted, the substituent may be 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino, halogenated C _1-4 alkyl, and substituted or unsubstituted 5-12 membered heteroaryl; in some embodiments, the heterocyclyl, when substituted, may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino, C _1-4 alkyl, and halo C _1-4 alkyl; preferably, when the amino group is substituted, the substituent may be a substituted or unsubstituted 4-9 membered heterocyclic group (e.g., an oxygen-containing 4-9 membered heterocyclic group such as tetrahydrofuranyl, tetrahydropyranyl; or a nitrogen-containing 4-9 membered heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.; or a sulfur-containing 4-9 membered heterocyclic group such as thiomorpholinyl) or a substituted or unsubstituted C _1-4 alkyl group (e.g., hydroxy or halogen-substituted C _1-4 alkyl); or R ₇ and R ₈, or R ₈ and R ₉ together with the C to which they are each attached form a 5 membered nitrogen containing saturated or unsaturated heterocycle, such as pyrrolyl or pyrrolidinyl;

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

R ₁₁ is H or substituted or unsubstituted C _1-4 alkyl, preferably H; and

R ₁₂ and R ₁₃ are each independently H or substituted or unsubstituted C _1-4 alkyl.

In certain embodiments, in formula III, B ₁ is CH; B ₂ is CR ₆;B ₃, CR ₇;B ₄, CR ₈;B ₅, CR ₉;B ₆, and CR ₁₀. Preferred R ₆ is halogen, C _1-4 alkyl, C _1-4 alkoxy, cyano, NR ₁₂R ₁₃ or NR 'R' -C (O) - (CH ₂) _n -, Wherein R ₁₂ and R ₁₃ are each independently selected from H, C _1-4 acyl and substituted or unsubstituted C _1-4 alkyl, n is an integer of 0 to 4. Preferred R ₇ is H or NR ₁₂R ₁₃, more preferably H or NH ₂. Preferred R ₈ is H. Preferred R ₉ is: the aforementioned substituted or unsubstituted C _1-4 alkyl group, substituted or unsubstituted C _1-4 alkoxy group, unsubstituted 4-9 membered heterocyclic group (preferably 4-9 membered heterocyclic group containing N and O and/or S), or substituted or unsubstituted amino group, More preferably: c _1-4 alkyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, carboxy and amino, C _1-4 alkoxy which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halogenated C _1-4 alkyl, Unsubstituted morpholinyl, thiomorpholinyl and tetrahydropyranyl, or amino which is unsubstituted or substituted with 1 or 2C _1-4 alkyl groups or with 1 to 9 membered heterocyclyl groups, preferably 5 to 12 membered oxygen containing heterocyclyl groups such as oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and the like. Preferred R ₁₀ is halogen. Preferred R ₁₁ is H or C _1-4 alkyl optionally substituted with 1-3 groups selected from hydroxy and halogen.

In some preferred embodiments of formula III, B ₁ is CH; B ₂ is CR ₆;B ₃, CR ₇;B ₄, CR ₈;B ₅, CR ₉;B ₆, CR ₁₀;R ₆, NR 'R' -C (O) - (CH ₂) _n -, Wherein R 'and R' are each independently selected from H, amino, and C _1-4 alkyl optionally substituted with 1-2 substituents selected from hydroxy and halogen, n is an integer from 0-4; R ₇ and R ₈ are H; R ₉ is C _1- ₄ alkyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, carboxy and amino, or C _1-4 alkoxy which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halogenated C _1-4 alkyl, Or amino which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halo C _1-4 alkyl; r ₁₀ is halogen; r ₁₁ is H. Further, in these preferred embodiments, R ₁ is a substituted or unsubstituted phenyl group, preferably, when a group having substituents, the number of substituents is 1, 2 or 3, selected from the group consisting of hydroxy, halogen, C _1-4 alkyl and C _1-4 alkoxy; R ₃ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen and C _1-4 alkyl; R ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen; r ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H. Preferably, R ₃ and R ₄ are each independently halogen and R ₅ is H.

In some preferred embodiments of formula III, B ₁ is CH; B ₂ is CR ₆;B ₃ is N or CR ₇;B ₄ is N or CR ₈;B ₅ is N or CR ₉;B ₆ is CR ₁₀;R ₆ is NR 'R' -C (O) - (CH ₂) _n -, Wherein R 'and R' are each independently selected from H, amino, and C _1-4 alkyl optionally substituted with 1-2 substituents selected from hydroxy and halogen, n is an integer from 0-4; R ₇ and R ₈ are H; r ₉ is C _1-4 alkyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, carboxy and amino, or C _1-4 alkoxy which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halogenated C _1- ₄ alkyl, Or amino which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halo C _1-4 alkyl; r ₁₀ is halogen; r ₁₁ is H. Further, in these preferred embodiments, R ₁ is a substituted or unsubstituted phenyl group, preferably, when a group having substituents, the number of substituents is 1, 2 or 3, selected from the group consisting of hydroxy, halogen, C _1-4 alkyl and C _1-4 alkoxy; R ₃ is H, halogen, C _1- ₄ alkoxy and C _1-4 alkyl, preferably halogen and C _1-4 alkyl; R ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen; r ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H. Preferably, R ₃ and R ₄ are each independently halogen and R ₅ is H.

In some embodiments, the compound of formula I has a structure shown in formula IV below:

Wherein:

R ₁、R ₃-R ₅ and R ₁₁ are as described in any one of the embodiments of formulas I or II above;

each m is independently 1,2 or 3;

X is CH ₂, O or NH;

r _d is H, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, carboxyl or NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H and C _1-4 alkyl, n is an integer from 0 to 4, and the number of R _d may be 1,2 or 3.

In some embodiments, in formula IV, R _d is located ortho to the nitrogen atom to which the heterocyclyl is attached to the remainder of formula IV.

In some embodiments, in formula IV, R _d is H, carboxyl, or NR' R "-C (O) - (CH ₂) _n -.

In some embodiments, in formula IV, the X-containing heterocycle is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

In certain embodiments, in formula IV, R ₁ is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl, such as pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl, and pyridazinyl, and the like, wherein when a group having substituents is present, the number of substituents is 1-3 and is selected from halogen, C _1-4 alkyl, and C _1-4 alkoxy, Preferred R ₁ is unsubstituted phenyl; R ₃ is H, halogen, C _1-4 alkoxy and C _1- ₄ alkyl, preferably H and halogen; R ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen; r ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H; Preferably, R ₃ and R ₄ are each independently halogen, R ₅ is H; r ₁₁ is H or C _1-6 alkyl optionally substituted with 1-3 substituents selected from halogen and hydroxy, preferably H; x is CH ₂, O or NH; r _d is H, carboxyl or NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H and C _1-4 alkyl, and n is an integer from 0 to 4.

In a preferred embodiment of the formulae I, II, III and IV according to the invention, in the NR ' R ' -C (O) - (CH ₂) _n -, n is 0 and R ' are each independently H and C _1-4 alkyl.

In some embodiments, the compound of formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof: the formula I has a structural formula shown in the following formula V:

In formula V, B ₁、B ₃-B ₅、R ₁、R ₃-R ₅、R ₁₁ is as described in any one of the embodiments of formulae I, II or III previously;

R ₆ is selected from H, halogen, alkyl, carboxyl, NR ₁₂R ₁₃, and NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H, amino, and substituted or unsubstituted alkyl, n is an integer from 0 to 4;

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

R ₁₂ and R ₁₃ are each independently H, C _1-4 acyl or substituted or unsubstituted C _1-4 alkyl; preferably, the alkyl group is substituted with 1 to 6 substituents selected from hydroxy and halogen, or unsubstituted;

Wherein R ₆ and R ₁₀ are not simultaneously H.

In some embodiments, the compound of formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof: the formula I has a structural formula shown in the following formula VI:

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

Wherein R ₆ and R ₁₀ are not simultaneously H.

In some embodiments, the compound of formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof: the formula I has a structural formula shown in the following formula VII:

In formula VI, R ₁、R ₃-R _s、R ₇-R ₉、R ₁₁ is as described in any one of the embodiments of formulae I, II or III previously;

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

Wherein R ₆ and R ₁₀ are not simultaneously H.

In some embodiments, the compound of formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof: the formula I has a structural formula shown in the following formula VIII:

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

Wherein R ₆ and R ₁₀ are not simultaneously H.

In certain embodiments of the present invention, there is provided a compound, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug, or metabolite thereof, characterized in that said compound is selected from the group consisting of:

Also included herein are pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substituents, polymorphs, prodrugs or metabolites of the compounds of each formula described above.

Herein, "stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.

When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.

"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example GeRald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3：341-63,2010;Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128.

The invention also includes all suitable isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof. Isotopic variations of the compounds of the present invention or pharmaceutically acceptable salts thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N and O, such as ²H、 ³H、 ¹¹C、 ¹³C、 ¹⁴C、 ¹⁵N、 ¹⁷O、 ¹⁸O、 ³⁵S、 ¹⁸F、 ³⁶Cl and ¹²⁵ I. Isotopic variants of the compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared by conventional techniques using suitable isotopic variants of suitable reagents.

In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.

By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

Pharmaceutically acceptable salts of the compounds of the invention preferably include the hydrochloride salts (e.g., compounds 1-4, 7-23, 26-29, 33-38, 41, 46, 48-49), formate salts (e.g., compounds 30-32, 39-40, 44-45) and hydrobromide salts (e.g., compound 43). Examples of prodrugs of the compounds of the present invention may include simple esters of carboxylic acid-containing compounds (e.g., esters obtained by condensation with C _1-4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (e.g., esters obtained by condensation with C _1-4 carboxylic acids, C _3-6 diacids, or anhydrides thereof, such as succinic anhydride and fumaric anhydride, according to methods known in the art); imines of amino-containing compounds (e.g., imines obtained by condensation with C _1-4 aldehydes or ketones according to methods known in the art); carbamates of amino-containing compounds, such as those described by Leu et al (J.Med. Chem.,42:3623-3628 (1999)) and Greenwald et al (J.Med. Chem.,42:3657-3667 (1999)). Aldols or ketals of alcohol-containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

III preparation of the Compounds

Representative compounds of the present invention, compounds of formula II may be prepared by the following method:

Wherein X ₁、X ₂ is halogen; PG ₁ and G ₂ P are protecting groups; LG ₁ is a leaving group; r ₁-R ₅ and R ₁₁ are as defined for formula II.

In the reaction flow:

starting from II-a, converting the iodo compound into aldehyde in an inert solvent by using a format reagent/DMF to obtain II-b; the grignard reagent is preferably an isopropyl grignard reagent, and the inert solvent is preferably toluene;

II-b is reduced to II-c in polar proton solvent by reducing agent; the reducing agent is preferably sodium borohydride, and the polar proton solvent is preferably a methanol/tetrahydrofuran mixed solvent;

II-c is subjected to halogenated/methanesulfonic acid esterification/p-toluenesulfonic acid esterification to obtain II-d; the halogenating agent is preferably NBS/triphenylphosphine, and the solvent is preferably halogenated alkane;

alkylating II-e under the action of strong alkali to obtain II-f; the strong base is LDA, and the ether solvent is tetrahydrofuran;

Removing the protecting group PG ₁ from the II-f to obtain II-g; the protecting group PG ₁ is BOC, the deprotection condition is trifluoroacetic acid and other acids, and the solvent is halogenated alkane;

II-g is subjected to strong base ring closure to obtain II-h; the strong base is preferably sodium hydride, and the solvent is preferably DMAc;

reducing the amide by using reducing agents such as borane and the like to obtain II-i; the solvent is preferably tetrahydrofuran;

In the presence of alkali and palladium catalyst, the bromine in II-i is replaced by duplex boron pinacol ester to obtain boron ester II-j; the palladium catalyst is preferably PdCl ₂ dppf, the base is preferably potassium phosphate, and the solvent is preferably p-toluene;

The boron ester II-j and the aromatic halogenide R ₂-X ₂ are catalyzed by Pd catalyst and phosphorus ligand to carry out coupling reaction in alkali and inert solvent to obtain II-k; the Pd catalyst is preferably Pd ₂(dba) ₃, the phosphorus ligand is preferably XantPhos, the alkali is preferably potassium phosphate, and the solvent is preferably toluene/water mixed solvent;

II-k removing the protecting group PG ₂ to obtain II-l, wherein the protecting group is preferably benzyl, the deprotection condition is preferably chloroethyl chloroformate, and the solvent is preferably halogenated alkane;

Finally, carrying out reductive amination reaction on II-l and aldehyde compounds in a polar solvent to obtain a compound of a formula II; the reducing agent used is preferably sodium cyanoborohydride and the solvent is preferably methanol.

Other compounds of the invention can be prepared under the same or similar reaction conditions by referring to the schemes or examples described above, using the corresponding reactants.

IV pharmaceutical composition, method and use

The compounds of formulas I, II and III of the present invention, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substituents, polymorphs, prodrugs and metabolites thereof are inhibitors of YAP/TAZ interaction with TEAD, more particularly inhibitors of YAP interaction with TEAD. Accordingly, the compounds of formulas I, II and III, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs and metabolites thereof of the invention are useful for treating or preventing diseases mediated by YAP/TAZ and TEAD interactions. As used herein, "disease mediated by YAP/TAZ interaction with TEAD" refers to a disease in which YAP/TAZ interaction with TEAD is involved in the occurrence and/or development of a disease, and which may be accomplished for relief, treatment and/or prevention purposes by inhibiting the expression and/or activity of YAP and TEAD or by inhibiting or blocking YAP-TEAD protein interactions. In the present invention, diseases mediated by YAP/TAZ interaction with TEAD include, but are not limited to, lung cancer (e.g., non-small cell lung cancer), breast cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, prostate cancer, mesothelioma, pancreatic cancer, melanoma, colon cancer, thyroid cancer, skin cancer, and the like.

In some embodiments, the disease mediated by YAP/TAZ interaction with TEAD is Malignant Pleural Mesothelioma (MPM), a rare breast malignancy. Abnormal activation of the Hippo-YAP pathway is present in about 70% of patients with MPM, and is considered to be an important cancer driving gene, and reduction of Hippo-YAP pathway activity by biological means and chemical small molecules shows good tumor growth inhibition activity.

In some embodiments, the disease mediated by YAP/TAZ interaction with TEAD is Pancreatic Ductal Adenocarcinoma (PDAC).

YAP signal channels can generate drug resistance to various anticancer targeting drugs by mediating tumor cell dormancy, resisting apoptosis and other mechanisms, and inhibiting Hippo-YAP signal channels can improve the sensitivity of tumor cells to the targeting drugs; in addition, hippo-YAP acts as a pathway for promoting tumor cell growth, and excessive activation occurs in multiple drug-resistant tumor models, and inhibition of its activity can significantly increase the sensitivity of therapeutic cells to related inhibitors. Thus, in some embodiments, the I, II and III compounds of the invention, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substituents, polymorphs, prodrugs, and metabolites thereof, are useful for increasing the sensitivity of a therapeutic cell to a targeted drug (e.g., EGFR inhibitors, BRAF-targeted inhibitors, MEK-targeted inhibitors, etc.), increasing the therapeutic effect of such tumor-targeted drugs.

Accordingly, the present invention provides a method of treating or preventing a disease mediated by YAP/TAZ interaction with TEAD as described herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound I, II or III of the invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

As used herein, "subject" or "individual" refers to a mammal, particularly a primate, more particularly a human.

The terms "prevent" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition; the term also includes: preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder. "treatment" and other similar synonyms include the following meanings: (i) inhibiting the disease or disorder, i.e., inhibiting its progression; (ii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or (iii) alleviating symptoms caused by the disease or condition.

The terms "effective amount," "therapeutically effective amount," "administered amount," "pharmaceutically effective amount" as used herein refer to an amount of at least one agent or compound that is sufficient to, upon administration, alleviate to some extent one or more symptoms of the disease or disorder being treated. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a I, II or III compound disclosed herein, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof, required to provide clinically significant relief from the condition. The amount of administration may be determined according to age, sex, disease and severity of the subject, etc. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. Methods of administration known in the art may be used in the present invention. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. The skilled artisan is familiar with the techniques of administration that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa. In a preferred embodiment, the I, II or III compound of the invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof, is administered orally.

The I, II or III compounds of the invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substituents, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof, can be used in combination with other compounds having pharmacological activity, especially in combination for the treatment of cancer. For example, I, II or III compounds of the invention, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof, or pharmaceutical compositions thereof, may be administered simultaneously, sequentially or separately in combination with one or more drugs selected from the group consisting of: chemotherapeutic agents such as mitotic inhibitors like taxane, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, other anticancer agents like cisplatin, 5-fluorouracil or 5-fluoro-2-4 (1 h,3 h) -pyrimidinedione (5 FU), flutamide or gemcitabine etc. In some embodiments, the inventive compounds of formula I, pharmaceutically acceptable salts and isomers thereof, or pharmaceutical compositions containing the inventive compounds of formula I, pharmaceutically acceptable salts and isomers thereof, may also be used in the treatment of cancer with tumor immunotherapeutic agents known in the art, such as anti-PD 1 antibodies and the like. Or a compound of the invention I, II or III, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof, may also be used in combination with conventional radiation therapy.

Herein, "combination", "pharmaceutical combination", "combination" or "combination therapy" and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients, or a combination of two or more different therapeutic approaches. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.

The invention also provides a pharmaceutical composition comprising a compound I, II or III of the invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, and a pharmaceutically acceptable carrier or excipient.

In the present application, "pharmaceutical composition" refers to a formulation containing I, II or III compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug or metabolite thereof, and a medium commonly accepted in the art for delivery of a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity. The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of a compound of the application I, II or III, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug, or metabolite thereof, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an undesirable manner with any of the components contained in the composition. "pharmaceutically acceptable carrier or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

In some embodiments, the active ingredient of the pharmaceutical compositions of the present invention may contain, in addition to the present I, II or III compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug or metabolite thereof, other known anticancer agents including, but not limited to, taxane, vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4 (1 h,3 h) -pyrimidinedione (5 FU), flutamide, gemcitabine, and the like.

The present invention relates to the use of a compound I, II or III of the invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof, in the treatment or prevention of a YAP/TAZ and TEAD interaction mediated disease described herein, or in the manufacture of a medicament for the treatment or prevention of a YAP/TAZ-TEAD interaction mediated disease described herein. The present invention also provides a I, II or III compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof, of the present invention for use in the treatment or prevention of a disease mediated by YAP/TAZ and TEAD interactions described herein.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

The starting materials used in the examples described below are commercially available from chemical suppliers such as Aldrich, TCI, ALFA AESAR, pichia, an Naiji, and the like, or may be synthesized by known methods.

Synthesis of intermediate A1: 8-chloro-7-fluoro-10 a-phenyl-9- (4, 5-tetramethyl-1, 3, 2-dioxaboren-2-yl) -3,4, 10, 10 a-tetrahydropyrazin [1,2-a ] indole-2 (1H) -carbonic acid tert-butyl ester

Step one: 1, 3-dibromo-5-fluoro-2-iodobenzene (7.50 g,19.7 mmol) and toluene (45 mL) were sequentially added to a dry three-necked flask under nitrogen atmosphere, and isopropyl magnesium chloride (12.8 mL,25.6mmol, 2.0M) was added dropwise at-30℃and the resulting brown solution was stirred at-30℃for 30 minutes. DMF (4.75 g,65.0 mmol) was then added to the solution, the reaction was warmed to 0℃naturally over 30 minutes and stirring was continued for 30 minutes at 0 ℃. The dot plate showed that the reaction was complete. The reaction solution was poured into a saturated ammonium chloride solution to quench. The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether) to obtain yellow solid A-1 (4.10 g, yield: 73.9%).

¹H NMR(400MHz,CDCl ₃)δ10.22(s，1H)，7.43(d，J＝7.6Hz，2H)。

Step two: to a dry single-necked flask, compound A-1 (4.10 g,14.5 mmol), tetrahydrofuran (40 mL), methanol (6 mL), and sodium borohydride (399 mg,8.70 mmol) were sequentially added. The reaction solution was stirred at 20℃for 0.5 hours. Dot panels showed complete reaction. The reaction solution was concentrated under reduced pressure. The concentrate was diluted with water and the aqueous phase was extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give yellow solid A-2 (4.12 g, crude).

¹H NMR(400MHz,CDCl ₃)δ7.68(d，J＝8.4Hz，2H)，5.22(t，J＝5.2Hz，1H)，4.70(d，J＝5.2Hz，2H)。

Step three: to a dry single vial at 20℃was added compound A-2 (4.12 g,14.5 mmol), dichloromethane (60 mL), triphenylphosphine (4.56 g,17.4 mmol) and NBS (3.10 g,17.4 mmol) in sequence. The reaction solution was stirred at 20℃for 0.5 hours. Dot panels showed complete reaction. The reaction solution was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether) to give white solid A (4.40 g, yield: 87.5%).

¹H NMR(400MHz,CDCl ₃)δ7.34(d，J＝7.6Hz，2H)，4.79(s，2H)。

Step four: ethyl 2-bromo-2-phenylacetate (13 g,53.48mmol,1.0 eq), (2-aminoethyl) carbamic acid tert-butyl ester (9.42 g,58.82mmol,1.1 eq) was dissolved in ethanol (130 mL) followed by triethylamine (8.12 g,80.21mmol,1.5 eq) and stirring at 60℃for 12 hours, TLC showed complete reaction and new spot formation, the reaction solution was dried under reduced pressure, placed in water and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure to give A1-1 (14 g, crude) as a yellow oil.

Step five: a1-1 (14 g,43.42 mmol) was dissolved in dichloromethane (90 mL) and trifluoroacetic acid (30 mL) was added, followed by reaction at 20deg.C for 2h, TLC showed complete reaction of starting material and formation of new spots, the reaction solution was dried under reduced pressure, placed in water, pH was adjusted to neutral with saturated aqueous NaHCO ₃ and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give A1-2 (10 g, crude) as a yellow oil.

Step six: a1-2 (9.65 g,43.41 mmol) was dissolved in ethanol (100 mL) and heated to 85deg.C, triethylamine (6.59 g,65.12 mmol) was added and reacted at this temperature for 12h, TLC showed complete reaction of starting material and new spots, the reaction solution was dried under reduced pressure, placed in water, pH was adjusted to neutrality with saturated aqueous NaHCO ₃ and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give A1-3 (5.6 g, crude) as a white solid.

1H NMR(400MHz,DMSO)δ7.82(s,1H),7.45-7.18(m,5H),4.35(s,1H),3.92 (s,1H),3.35-3.25(m,1H),3.19(dt,J＝11.7,3.9Hz,1H),2.99-2.81(m,2H).

Step seven: compounds A1-3 (4.67 g,26.5 mmol) were suspended in dioxane (100 mL) and Boc ₂ O anhydride (5.78 g,26.5 mmol) was added and the mixture heated at 90℃for 1 hour. After completion of the spot-plate reaction, the mixture was filtered while it was still hot, the filtrate was concentrated under reduced pressure, and the crude product was slurried in (petroleum ether: ethyl acetate=10:1) to give pale pink solid A1-4 (6.82 g, yield: 93%).

¹H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.38-7.29(m,5H),5.46-5.15(brs,1H),3.80-3.70(brs,1H),3.25-3.15(m,3H),1.36(s,9H).

Step eight: compound A1-4 (6.82 g,24.7 mmol) was dissolved in tetrahydrofuran (120 mL) and 60% sodium hydrogen (1.09 g,27.2 mmol) was added in one portion at 20℃and stirred for 5 min. Benzyl bromide (4.83 g,28.4 mmol) was then added and stirred overnight. The reaction was followed by spot-plating, quenched with methanol (5 mL) and diluted with water (80 mL). The solvent was removed by concentration under reduced pressure. The residue was extracted twice with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (methanol/dichloromethane=6/100) to give colorless viscous liquid A1-5 (7 g, yield: 77%).

1H NMR(400MHz,DMSO-d6)δ7.44-7.18(m,10H),5.51(brs,1H),4.70(d,J＝16Hz,1H),4.49(d,J＝16Hz,1H),3.81(brs,1H),3.45-3.18(m,3H),1.37(s,9H).

Step nine: to a solution of compounds A1-5 (3.59 g,9.80 mmol) in tetrahydrofuran (40 mL) was added dropwise lithium diisopropylamide (6.4 mL,12.7mmol, 2.0M) at-50deg.C. The reaction solution was stirred at-30℃for 1 hour. Then, the temperature was lowered to-50℃and a solution of Compound A (3.40 g,9.8 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture. The reaction solution was gradually warmed to 20℃and stirred for a further 12 hours. After the reaction, adding saturated ammonium chloride solution to quench. The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give A1-6 (6.10 g, yield: 98.4%) as a white solid.

¹H NMR(400MHz,CDCl ₃)δ7.49-7.41(m,2H),7.39-7.33(m,2H),7.32-7.21(m,6H),7.05-6.95(m,2H),4.65-4.50(m,2H),4.40-4.20(m,1H),4.17-4.05(m,1H),3.80-3.70(m,1H),3.65-3.50(m,1H),3.25-3.10(m,1H),2.80-2.60(m,1H),1.10(s,9H).

Step ten: to a solution of A1-6 (6.10 g,9.65 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (20 mL). The reaction solution was stirred at 30℃for 2 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. To the concentrated residue was added saturated sodium bicarbonate solution (60 mL), and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give yellow solid A1-7 (5.10 g, yield: 99.2%).

¹H NMR(400MHz,CDCl ₃)δ7.45-7.38(m,2H),7.35-7.20(m,10H),4.96(d,J＝14.4 Hz,1H),4.44(d,J＝14.8Hz,1H),4.13(d,J＝14.8Hz,1H),3.80(d,J＝14.8Hz,1H),3.40-3.30(m,1H),3.00-2.70(m,3H),2.50-2.10(m,2H).

Step eleven: in a dry single vial were added compound A1-7 (5.10 g,9.58 mmol), DMA (50 mL), and sodium hydride (768 mg,19.2mmol,60% in mineral oil) in sequence. The reaction solution was stirred at 100℃for 6 hours. After the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give white solid A1-8 (4.0 g, yield: 92.6%).

¹H NMR(400MHz,CDCl ₃)δ7.65-7.55(m,2H),7.40-7.35(m,2H),7.34-7.22(m,4H),7.14-7.06(m,2H),6.63(dd,J＝9.2,2.0Hz,1H),6.17(dd,J＝9.6,2.0Hz,1H),4.83(d,J＝14.8Hz,1H),4.44(d,J＝14.8Hz,1H),4.29(dd,J＝16.8,0.8Hz,1H),3.56-3.45(m,1H),3.40-3.30(m,2H),3.13-2.96(m,2H).

Step twelve: in a dry single vial were added, in order, compounds A1-8 (4.0 g,8.86 mmol), tetrahydrofuran (40 mL), and borane dimethyl sulfide (35.5 mL,70.9mmol, 2M). The reaction solution was stirred at 65℃for 20 hours. The reaction solution was quenched with methanol, and then concentrated to dryness under reduced pressure. The resulting residue was dissolved in methanol (40 mL) and 4N dioxane hydrochloride (20 mL), and the reaction solution was stirred at 20℃for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, saturated sodium bicarbonate solution (150 mL) was added, and extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give colorless oil A1-9 (4.10 g, crude).

Step thirteen: in a dry single vial were added in sequence compound A1-9 (4.10 g,8.86 mmol), 1, 2-dichloroethane (40 mL) and 2-chloroethyl chloroformate (3.17 g,22.2 mmol). The reaction solution was stirred at 80℃for 16 hours. The reaction solution was concentrated to dryness under reduced pressure. The obtained residue was dissolved in methanol and stirred at 75 degrees for 1.5 hours. After the completion of the reaction, the solution was concentrated under reduced pressure to give compound 6 (3.10 g, crude product) as a yellow oil.

Step fourteen: to a dry single vial was added compound 6 (3.08 g,8.86 mmol), dichloromethane (50 mL), triethylamine (3.58 g,35.4 mmol) and Boc ₂ O (2.90 g,13.3 mmol) in sequence. The reaction solution was stirred at 20℃for 1 hour and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give A1-10 (3.10 g, yield: 78.3%) as a white solid.

¹H NMR(400MHz,CDCl ₃)δ7.70-7.50(m,2H),7.42-7.34(m,2H),7.32-7.26(m,1H),6.53(dd,J＝9.2,2.0Hz,1H),6.25-6.10(m,1H),4.80-4.50(m,1H),4.00-4.36(m,1H),3.50-2.80(m,6H),1.50-1.30(m,9H).

Fifteen steps: in a dry single-port flask, compound A1-10 (1.0 g,2.24 mmol), acetonitrile (20 mL) and NCS (299 mg,2.24 mmol) were added sequentially. The reaction solution was stirred at 20℃for 4 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give white solid A1-11 (700 mg, yield: 64.8%).

¹H NMR(400MHz,CDCl ₃)δ7.65-7.50(m,2H),7.42-7.34(m,2H),7.33-7.27(m,1H),6.40-6.20(m,1H),4.80-4.50(m,1H),4.00-4.36(m,1H),3.50-2.80(m,6H),1.50-1.25(m,9H).

Step sixteen: in a dry three-necked flask, compound A1-11 (600 mg,1.25 mmol), bis-pinacolato borate (635 mg,2.50 mmol), xylene (10 mL), pd (dppf) Cl ₂·CH ₂Cl ₂ (102 mg,0.125 mmol), and potassium pivalate (526 mg,3.75 mmol) were added sequentially. The reaction solution was stirred for 12 hours at 100℃under nitrogen. After the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give A1 (470 mg, yield: 71.1%) as a white solid.

¹H NMR(400MHz,CDCl ₃)δ7.70-7.50(m,2H),7.42-7.34(m,2H),7.33-7.27(m,1H),6.40-6.20(m,1H),4.75-4.45(m,1H),4.00-4.36(m,1H),3.40-2.80(m,6H),1.50-1.36(m,9H),1.35-1.27(m,12H).

Synthesis of intermediate A2: 8-chloro-7-fluoro-10 a- (3-methoxyphenyl) -9- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3,4, 10, 10 a-tetrahydropyrazino [1,2-a ] indole-2 (1H) -carbonate tert-butyl ester

Step one: to a solution of 3-benzyloxybenzaldehyde (A2-1, 45g,212.3 mmol) in methylene chloride (900 mL) was added dropwise tetraisopropyl titanate (24 g,84.9 mmol) under argon atmosphere at 0 ℃. TMSCN (84.2 g,849.2 mmol) was added after slowly warming to room temperature. Stirring for 4h at room temperature. TLC showed complete reaction and quenched by addition of aqueous hydrochloric acid (20 ml,1.5 m) at 0 ℃. Water (270 mL) was added and extracted with ethyl acetate (3X 200 mL). The organic phases were combined, washed with water (2X 100 mL), and saturated brine (100 mL). Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether=1:6) to give 2- (3- (benzyloxy) phenyl) -2-hydroxyacetonitrile (A2-2, 44g, yield: 86.8%) as a tan oil.

¹H NMR(400MHz，DMSO-d6)，δppm 7.30～7.15(m，6H)，6.97～6.87(m，3H)，5.56(d，J＝6.0Hz，1H)，4.95(s，2H)。

Step two: 2- (3- (benzyloxy) phenyl) -2-hydroxyacetonitrile (44 g,183.9 mmol) was dissolved in HCl/MeOH (4N, 500 ml). The reaction was stirred at 80℃for 14h. TLC confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure to near dryness. The residue was taken up in water (400 mL) and extracted with ethyl acetate (3 x 300 mL). The organic phases were combined, washed with water (2 x 150 mL), saturated brine (100 mL). Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether=1:4) to give methyl 2- (3- (benzyloxy) phenyl) -2-glycolate (A2-3, 37.3g, yield: 74.5%) as a tan solid.

¹H NMR(400MHz,DMSO-d6),δppm 7.46～7.24(m,6H),7.04～6.93(m,3H),5.11(s,1H),5.08(s,2H),3.60(s,3H).

Step three: to a solution of methyl 2- (3- (benzyloxy) phenyl) -2-glycolate (37.3 g,137.0 mmol) in dichloromethane (100 mL) was added SOCl ₂ (18 g,150.7 mmol). The temperature is raised to 60 ℃ and the reaction is carried out for 5 hours. TLC showed complete reaction and the reaction concentrated under reduced pressure. To the residue was added water (100 mL) and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. Ethyl acetate extraction (3 x 400 ml). The organic phases were combined, washed with water (2 x 200 ml), and saturated brine (3 x 200 ml). Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether=1:5) to give methyl 2- (3- (benzyloxy) phenyl) -2-chloroacetate (A2-4, 35.5g, yield: 89.1%) as an off-white solid.

¹H NMR(400MHz,CDCl ₃),δ7.38～7.19(m,6H),7.06(t,J＝2.0Hz,1H),7.00(d,J＝7.6Hz,1H),6.92～6.89(m,1H),5.26(s,1H),5.00(s,2H),3.69(s,3H).

Step four: to a solution of methyl 2- (3- (benzyloxy) phenyl) -2-chloroacetate (35.5 g,122.1 mmol) in methanol (350 mL) was added triethylamine (18.5 g,183.2 mmol) and N-t-butoxycarbonyl-1, 2-ethylenediamine (25.4 g,158.6 mmol). Heating to 60 ℃ and stirring to react for 18h. TLC and LCMS showed complete reaction. The reaction solution was concentrated under reduced pressure. The residue was taken up in water (600 mL) and extracted with ethyl acetate (3 x 200 mL). The organic phases were combined and washed with saturated brine (3X 200 mL). Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give methyl 2- ((2- ((tert-butoxycarbonyl) amino) ethyl) amino) -2- (3- (benzyloxy) phenyl) acetate (A2-5, 30.5g, yield: 60.3%) as a pale white oil.

LCMS：m/z 415[M+H] ⁺

Step five: to a solution of methyl 2- ((2- ((tert-butoxycarbonyl) amino) ethyl) amino) -2- (3- (benzyloxy) phenyl) acetate (30.0 g,72.4 mmol) in dichloromethane (300 mL) was added dropwise trifluoroacetic acid (60 mL). The reaction was carried out at 20℃for 2h. The reaction solution was concentrated to dryness under reduced pressure. The residue was added ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (300 mL). The organic phase was collected and the aqueous phase was extracted with ethyl acetate (3 x 150 ml). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure to give crude methyl 2- ((2-aminoethyl) amino) -2- (3- (benzyloxy) phenyl) acetate (A2-6, 27.0 g) which was used directly in the next reaction.

LCMS：m/z 315.3[M+H] ⁺

¹H NMR(400MHz,DMSO-d ₆)：δppm 7.47～7.45(m,2H),7.40(t,J＝7.2Hz,2H),7.35～7.33(m,1H),7.29～7.25(m,1H),7.11(s,1H),7.00～6.97(m,2H),5.09(s,2H),4.42(s, 1H),3.60(s,3H),2.88～2.84(m,2H),2.65～2.59(m,2H).

Step six: to a solution of methyl 2- ((2-aminoethyl) amino) -2- (3- (benzyloxy) phenyl) acetate (27.0 g,85.85 mmol) in ethanol (50 mL) was added triethylamine (13.0 g,128.77 mmol). The reaction was stirred at 85℃for 3h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (100 mL), washed with water (3X 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 3- (3- (benzyloxy) phenyl) piperazin-2-one (A2-7, 17.0g, two step yield: 83%) which was used directly in the next reaction.

LCMS：m/z 283.1[M+H] ⁺

Step seven: to a solution of 3- (3- (benzyloxy) phenyl) piperazin-2-one (17.0 g,60.3 mmol) in1, 4-dioxane (150 ml) was added di-tert-butyl dicarbonate (14.5 g,66.3 mmol) and triethylamine (18.3 g,180.8 mmol). Stirring at 90℃for 1.5h. The reaction mixture was concentrated to dryness, and diethyl ether (100 mL) was added thereto, followed by stirring and beating, and the mixture was filtered to give tert-butyl 2- (3- (benzyloxy) phenyl) -3-oxopiperazine-1-carboxylate (A2-8, 18.0g, yield: 78.2%) as a white solid.

LCMS：m/z 765.4[2M+H] ⁺

¹H NMR：(400MHz,CDCl ₃),δppm 7.42-7.25(m,6H),7.06-7.01(m,2H),6.93(dd,J＝8.0,2.4Hz,1H),5.65(s,1H),5.06(s,2H),4.00(s,1H),3.50～3.47(m,1H),3.29～3.22(m,2H),1.45(s,9H).

Step eight: to a solution of tert-butyl 2- (3- (benzyloxy) phenyl) -3-oxopiperazine-1-carboxylate (5.0 g,13.1 mmol) in tetrahydrofuran (75 mL) was added NaH (60% dispersed in oil, 785mg,19.6 mmol) under argon atmosphere at 20 ℃. Benzyl bromide (3.4 g,19.62 mmol) was added after stirring for 30min. The reaction was stirred in the greenhouse for 16h. The reaction mixture was diluted with ethyl acetate (100 mL) and poured into ice water (150 mL). The organic phase was collected and the aqueous phase was extracted with ethyl acetate (3 x 100 ml). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/10 to 1/5) to give 4-benzyl-2- (3- (benzyloxy) phenyl) -3-oxopiperazine-1-carboxylic acid tert-butyl ester (A2-9, 3.8g, yield: 61.5%) as a colorless transparent oil.

LCMS：m/z 473.2[M+H] ⁺

¹H NMR(400MHz,CDCl ₃),δppm 7.42～7.24(m,12H),7.03～7.00(m,2H),6.93(dd,J＝8.4,2.4Hz,1H),5.07(s,2H),4.84(d,J＝14.4Hz,1H),4.48(m,1H),3.87(s,1H),3.34～3.23(m,2H),3.18～3.14(m,1H),1.44(s,9H).

Step nine: LDA (2.0M in THF,14.9mL,29.8mmol) was added dropwise to a solution of tert-butyl 4-benzyl-2- (3- (benzyloxy) phenyl) -3-oxopiperazine-1-carboxylate (10.8 g,22.9 mmol) in tetrahydrofuran (150 mL) at-50℃under argon. After the dripping, stirring for 1h at about-30 ℃. A solution of 1, 3-dibromo-2- (bromomethyl) -5-fluorobenzene (7.2 g,20.8 mmol) in tetrahydrofuran (50 mL) was added dropwise after cooling to-50 ℃. Naturally heating to room temperature, and stirring to react for 16h. The reaction solution was poured into ice water (150 mL). Ethyl acetate extraction (3 x 150 mL), saturated brine washing (150 mL), drying over anhydrous sodium sulfate, filtration, concentration, and purification by silica gel column chromatography (ethyl acetate/petroleum ether=1/100 to 1/4) gave tert-butyl 4-benzyl-2- (3- (benzyloxy) phenyl) -2- (2, 6-dibromo-4-fluorobenzyl) -3-oxopiperazine-1-carboxylate (A2-10, 13.0g, yield: 77.0%).

LCMS：m/z 739.3[M+H] ⁺

¹H NMR(400MHz,CDCl ₃)：δppm 7.52～7.29(m,7H),7.26～7.20(m,4H),7.09～7.05(m,2H),7.00～6.99(m,2H),6.90～6.87(m,1H),5.09～5.02(m,2H),4.58～4.53(m,2H),4.27(s,1H),4.12(d,J＝14.4Hz,1H),3.77～3.71(m,1H),3.52(s,1H),3.19～3.13(m,1H),2.72～2.70(m,1H),1.13(s,9H).

Step ten: to a solution of tert-butyl 4-benzyl-2- (3- (benzyloxy) phenyl) -2- (2, 6-dibromo-4-fluorobenzyl) -3-oxopiperazine-1-carboxylate (13.0 g,17.6 mmol) in dichloromethane (85 mL) was added trifluoroacetic acid (45 mL) dropwise. The reaction was carried out at 30℃for 2 hours. Concentrating under reduced pressure to dry. The residue was taken up in dichloromethane (200 mL) and saturated aqueous sodium bicarbonate (300 mL). The aqueous phase was extracted with dichloromethane (3 x 150 ml). The organic phases were combined, dried over saturated brine (150 mL), filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/100 to 1/3) to give 1-benzyl-3- (3- (benzyloxy) phenyl) -3- (2, 6-dibromo-4-fluorobenzyl) piperazin-2-one (A2-11, 10.5g, yield: 93.4%).

LCMS：m/z 639.0[M+H] ⁺

¹H NMR(400MHz,CDCl ₃)：δppm7.41～7.30(m,10H),7.23～7.21(m,2H),7.17～7.13(m,1H),7.09～7.08(m,1H),7.04～7.02(m,1H),6.89～6.87(m,1H),4.98～4.88(m,3H),4.41(d,J＝14.4Hz,1H),4.08(d,J＝14.8Hz,1H),3.77(d,J＝14.4Hz,1H),3.36～3.29(m,1H),2.99～2.94(m,2H),2.44(s,1H).

Step eleven: 1-benzyl-3- (3- (benzyloxy) phenyl) -3- (2, 6-dibromo-4-fluorobenzyl) piperazin-2-one (3.0 g,4.70 mmol) was dissolved in trifluoroacetic acid (50 mL). Heating to 60 ℃ and stirring to react for 2h. The reaction mixture was concentrated to dryness under reduced pressure, diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogencarbonate (400 mL), washed with saturated brine (2X 400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate: petroleum ether) to give 1-benzyl-3- (2, 6-dibromo-4-fluorobenzyl) -3- (3-hydroxyphenyl) piperazin-2-one (A2-12, 2.1g, yield: 82%) as a white solid.

¹H NMR(400MHz,DMSO-d ₆)：δppm 9.15(s,1H),7.56(d,J＝8.0Hz,2H),7.35～7.24(m,5H),7.01(t,J＝8.0Hz,1H),6.87(t,J＝2.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.62(dd,J＝8.0,2.0Hz,1H),4.79(d,J＝14.8Hz,1H),4.43(d,J＝14.8Hz,1H),3.87(d,J＝14.4Hz,1H),3.68(d,J＝14.4Hz,1H),3.36～3.29(m,1H),2.92～2.89(m,1H),2.79～2.76(m,2H),2.58～2.54(m,1H).

Step twelve: to a solution of 1-benzyl-3- (2, 6-dibromo-4-fluorobenzyl) -3- (3-hydroxyphenyl) piperazin-2-one (1.9 g,3.47 mmol) and potassium carbonate (1.4 g,10.40 mmol) in MeCN (30 mL) was added dimethyl sulfate (525 mg,4.16 mmol). The reaction was heated to 60℃and stirred for 4h. The reaction was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (100 mL), saturated brine (2X 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate: petroleum ether) to give 1-benzyl-3- (2, 6-dibromo-4-fluorobenzyl) -3- (3-methoxyphenyl) piperazin-2-one (A2-13, 1.16g, yield: 60%) as a white solid.

LCMS：m/z 563.3[M+H] ⁺

¹H NMR(400MHz,DMSO-d ₆)：δppm 7.57(d,J＝8.0Hz,2H),7.35～7.24(m,5H),7.14(t,J＝8.0Hz,1H),6.98(d,J＝8.0Hz,1H),6.91(t,J＝2.0Hz,1H),6.81(dd,J＝8.0,2.0Hz,1H),4.83(d,J＝14.4Hz,1H),4.39(d,J＝14.8Hz,1H),3.90(d,J＝14.4Hz,1H),3.68(d,J＝14.0Hz,1H),3.60(s,3H),3.40～3.32(m,1H),2.94～2.89(m,2H),2.81～2.76(m,1H),2.57～2.50(m,1H).

¹⁹F NMR(376MHzDMSO-d ₆)：δ-113.37.

The remaining steps are as follows: referring to the synthesis method of the intermediate A1, A2-13 is used for replacing A1-7, and a six-step reaction is carried out to obtain the intermediate A2.

Synthesis of intermediate A3: 8-chloro-7-fluoro-10 a- (3-fluorophenyl) -9- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3,4, 10, 10 a-tetrahydropyrazino [1,2-a ] indole-2 (1H) -carbonate tert-butyl ester

Step one: to a solution of methyl 3-fluoro-phenylacetate (25.00 g,148.66 mmol) in carbon tetrachloride (250 mL) under argon was added N-bromosuccinimide (34.40 g,193.26 mmol) and azobisisobutyronitrile (9.76 g,59.46 mmol). Heated to 70 ℃ and reacted for 20 hours. LCMS monitored the reaction. The reaction solution was concentrated under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate=40/1 to 20/1) to give methyl 2-bromo-2- (3-fluorophenyl) acetate (A3-2, 35.6g, yield: 96.9%) as a yellow liquid.

¹H NMR(400MHz,CDCl ₃)：δppm 7.34～7.27(m，3H)，7.05(s，1H)，5.32(s，1H)，3.80(s，3H)。

¹⁹FNMR(376MHz,CDCl ₃)δppm-111.72。

The remaining steps are as follows: referring to the synthesis method of the intermediate A1, A3-2 is used for replacing 2-bromo-2-phenyl ethyl acetate, and thirteen steps of reactions are carried out to obtain the intermediate A3.

Synthesis of intermediate A4: 8-chloro-10 a- (3-chlorophenyl) -7-fluoro-9- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3,4, 10, 10 a-tetrahydropyrazino [1,2-a ] indole-2 (1H) -carbonate tert-butyl ester

Referring to the synthesis method of the intermediate A3, A4-1 is used for replacing A3-1, and fourteen steps of reactions are carried out to obtain the intermediate A4.

Synthesis of intermediate A5: 2-benzyl-8-chloro-7-fluoro-10 a- (pyridin-3-yl) -9- (4, 5-tetramethyl-1, 3, 2-dioxabor-2-yl) -1,2,3,4, 10, 10 a-tetrahydropyrazino [1,2-a ] indole

Step one to step nine: referring to the synthesis method of the intermediate A3, A5-1 is used for replacing A3-1, and nine steps of reactions are carried out to obtain the intermediate A5-10.

Step ten: in a dry single vial were added compound A5-10 (585 mg,1.29 mmol), tetrahydrofuran (10 mL), and borane dimethyl sulfide (5.2 mL,10.3mmol, 2M) in sequence. The reaction solution was stirred at 35℃for 50 hours. The reaction solution was quenched with methanol, and then concentrated to dryness under reduced pressure. The resulting residue was dissolved in methanol (10 mL) and 4N dioxane hydrochloride (2 mL), and the reaction solution was stirred at 20℃for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, and extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:1) to give a colorless oil A5-11 (350 mg, yield: 61.9%).

¹H NMR(400MHz,CDCl ₃)δ8.70-8.60(m,1H),8.54(dd,J＝4.8,1.6Hz,1H),7.71-7.64(m,1H),7.40-7.20(m,6H),6.53(dd,J＝9.2,2.4Hz,1H),6.16(dd,J＝10.0,2.0Hz,1H),3.56(d,J＝12.8Hz,1H),3.43-3.29(m,2H),3.26-3.13(m,2H),2.86(d,J＝1.6Hz,2H),2.68-2.58(m,1H),2.40(d,J＝12.0Hz,1H),2.36-2.25(m,1H).

Step eleven: in a dry single-port flask, compound A5-11 (450 mg,1.03 mmol), acetonitrile (20 mL) and NCS (138 mg,1.03 mmol) were added sequentially. The reaction solution was stirred at 60℃for 12 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:1) to give A5-12 (310 mg, yield: 63.7%) as a white solid.

¹H NMR(400MHz,CDCl ₃)δ8.67-8.61(m,1H),8.55(dd,J＝4.8,1.6Hz,1H),7.71- 7.64(m,1H),7.38-7.19(m,6H),6.29(dd,J＝9.6Hz,1H),3.57(d,J＝13.2Hz,1H),3.41-3.28(m,2H),3.27-3.12(m,2H),2.90(d,J＝1.2Hz,2H),2.68-2.58(m,1H),2.40(d,J＝12.4Hz,1H),2.35-2.24(m,1H).

Step twelve: in a dry three-necked flask, compound A5-12 (310 mg, 0.650 mmol), bis-pinacolato borate (333 mg,1.31 mmol), xylene (6 mL), pd (dppf) Cl ₂·CH ₂Cl ₂ (54 mg,0.066 mmol) and potassium pivalate (276 mg,1.97 mmol) were sequentially added. The reaction solution was stirred for 12 hours at 100℃under nitrogen. After the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give yellow oil A5 (250 mg, crude).

LCMS：m/z 520.3[M+H] ⁺。

Synthesis of intermediate A6: 8-chloro-7-methoxy-10 a-phenyl-9- (4, 5-tetramethyl-1, 3, 2-dioxaboren-2-yl) -3,4, 10, 10 a-tetrahydropyrazin [1,2-a ] indole-2 (1H) -carbonic acid tert-butyl ester

Step one: in a single vial was added compound A1-11 (200 mg,0.42 mmol) and sodium methoxide solution (6 mL, 5.4M). The mixture was heated to 80 ℃ and reacted overnight. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 ml x 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give yellow oil A6-1 (250 mg, crude).

LCMS：m/z 493/495[M+H] ⁺。

Step two: referring to the synthesis method of the intermediate A1, A6-1 is used for replacing A1-11, and the intermediate A6 is obtained by a one-step reaction.

Synthesis of intermediate A7: 7-fluoro-8-methyl-10 a-phenyl-9- (4, 5-tetramethyl-1, 3, 2-dioxaboren-2-yl) -3,4, 10, 10 a-tetrahydropyrazin [1,2-a ] indole-2 (1H) -carbonic acid tert-butyl ester

Step one: in a three-necked flask, compound A1-10 (390 mg,0.87 mmol) and anhydrous tetrahydrofuran (5 mL) were added. LDA (0.865 mL,2M,1.73 mmol) was added dropwise at-50 ℃. The mixture was reacted at-50℃for 45 minutes. Methyl iodide (246 mg,1.73 mmol) was then added dropwise. The resulting mixture was stirred at-50 ℃ for one hour, then warmed to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (30 ml x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a yellow oil, and the resulting residue was purified by silica gel chromatography (ethyl acetate: petroleum ether=1/3) to give A7-1 (280 mg,0.630mmol, 72.79%).

LCMS：m/z 461/463[M+H] ⁺。

Step two: referring to the synthesis method of the intermediate A1, A7-1 is used for replacing A1-11, and the intermediate A7 is obtained by a one-step reaction.

Synthesis of intermediate B1: 2-bromo-3-fluoro-4-hydroxybenzonitrile

Step one: to a round bottom flask was added dichloromethane (20 mL), 2-bromo-3, 4-difluorobenzoic acid (B1-1, 2g,8.44mmol,1.0 eq), HATU (4.83 g,12.7mmol,1.5 eq), triethylamine (5.5 mL,42.2mmol,5.0 eq) and ammonium chloride (1.35 g,25.3mmol,3.0 eq) in sequence at 25 ℃. The yellow reaction solution was stirred at this temperature for 12 hours. TLC showed the reaction was complete. Water (30 mL) and dichloromethane (30 mL. Times.3) were added, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate: petroleum ether=1/10) to give 2-bromo-3, 4-difluorobenzamide (B1-2, 1.8g, yield: 90%) as a white solid.

¹H NMR(400MHz,DMSO_d6)δ7.95(s,1H),7.70(s,1H),7.53(ddd,J＝10.0,8.8,7.6Hz,1H),7.31(ddd,J＝8.8,5.2,2.0Hz,1H).

Step two: tetrahydrofuran (20 mL), 2-bromo-3, 4-difluorobenzamide (B1-2, 1.8g,7.63mmol,1.0 eq), triethylamine (2.12 mL,15.3mmol,2.0 eq) and trifluoroacetic anhydride (2.39 g,11.4mmol,1.5 eq) were added sequentially to the round bottom flask at 25 ℃. The yellow reaction solution was stirred at this temperature for 12 hours. TLC showed the reaction was complete. Water (30 mL) and dichloromethane (30 mL) were added and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles removed under reduced pressure. The resulting residue was purified by silica gel chromatography (0 to 6% gradient of ethyl acetate: petroleum ether) to give 2-bromo-3, 4-difluorobenzonitrile (B1-3, 1.5g, yield: 90%) as a white solid.

¹H NMR(400MHz,CDCl ₃)δ7.50(ddd，J＝8.8，4.8，2.0Hz，1H)，7.33-7.24(m，1H)。

Step three: to a round bottom flask was added dimethyl sulfoxide (11.5 mL), 2-bromo-3, 4-difluorobenzonitrile (B1-3, 1.5g,6.88mmol,1.0 eq), potassium carbonate (4.75 g,34.4mmol,5.0 eq) and acetohydroxamic acid (1.55 g,20.6mmol,3.0 eq) in sequence. The yellow reaction solution was warmed to 80 degrees celsius and stirred for 4 hours. TLC showed the reaction was complete. The filtrate was suction filtered under reduced pressure, the pH was adjusted to 5 with dilute hydrochloric acid (0.5N), extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the volatiles were removed under reduced pressure. The resulting residue was purified by silica gel chromatography (0 to 20% gradient of ethyl acetate: petroleum ether) to give 2-bromo-3-fluoro-4-hydroxybenzonitrile (B1, 1.0g, yield: 67.1%) as a yellow solid.

Synthesis of intermediate B2: 2-bromo-4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3-fluorobenzonitrile

Step one: tetrahydrofuran (20 mL), 2- ((tert-butyldimethylsilyl) oxy) ethan-1-ol (B2-1, 1.76g,10.0mmol,1.0 eq), imidazole (2.04 g,30.0mmol,3.0 eq), triphenylphosphine (3.93 g,15.0mmol,1.5 eq) and elemental iodine (3.04 g,12.0mmol,1.2 eq) were added sequentially to the round bottom flask at 20 ℃. The pale yellow reaction solution was stirred at this temperature for 2 hours. TLC showed the reaction was complete. The volatiles were removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether) to give t-butyl (2-iodoethoxy) dimethylsilane (B2-2, 2.4g, yield: 83.9%) as a yellow oil.

¹H NMR(400MHz，DMSO_d6)δ3.90-3.76(m，2H)，3.27-3.13(m，2H)，0.99-0.83(m，9H)，0.16-0.03(m，6H)。

Step two: to a dry single vial was added compound B1 (500 mg,2.31 mmol), DMF (10 mL), compound B2-2 (727 mg,2.54 mmol) and potassium carbonate (428 mg,4.62 mmol) in sequence. The reaction solution was stirred at 80℃for 12 hours. The reaction was diluted with water and the aqueous phase was extracted 2 times with petroleum ether/ethyl acetate (1/1, 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B2 (700 mg, yield: 80.9%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ7.41(dd,J＝8.4,1.6Hz,1H),7.03(dd,J＝8.8,7.6Hz,1H),4.19(d,J＝4.8Hz,2H),4.01(d,J＝5.2Hz,2H),0.89(s,9H),0.09(s,6H).

Synthesis of intermediate B3: 2-bromo-4- (2- (((tert-butyldimethylsilyl) oxy) ethoxy) -3-fluorobenzoic acid methyl ester

Step one: to a round bottom flask was added, in order, anhydrous methanol (42 mL), 2-bromo-3, 4-difluorobenzoic acid (B1-1, 3.3g,14.8mmol,1.0 eq) at 25℃followed by addition of thionyl chloride (7 mL). The yellow reaction solution was stirred at this temperature for 4 hours. TLC showed the reaction was complete. The volatiles were removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether) to give methyl 2-bromo-3, 4-difluorobenzoate (B3-1, 3.4g, yield: 92.6%) as a yellow oil.

Step two: the synthesis of step three referred to intermediate B1 gave methyl 2-bromo-3-fluoro-4-hydroxybenzoate (B3-2, 3.5g, yield: 93.5%) as a yellow solid.

¹H NMR(400MHz，DMSO_d6)δ11.18(s，1H)，7.58(dd，J＝8.8，1.6Hz，1H)，7.02(t，J＝8.4Hz，1H)，3.80(s，3H)。

Step three: the synthesis of step two, referred to intermediate B2, gave methyl 2-bromo-4- (2- (((tert-butyldimethylsilyl) oxy) ethoxy) -3-fluorobenzoate (B3, 1.44g, yield: 88.3%) as a colorless oil.

Synthesis of intermediate B4: 2- (3-bromo-4-cyano-2-fluorophenoxy) acetic acid ethyl ester

Step one: to a dry single-port flask were added compound B1 (500 mg,2.31 mmol), DMF (10 mL), ethyl bromoacetate (463 mg,2.77 mmol) and potassium carbonate (618 mg,4.62 mmol) in this order. The reaction solution was stirred at 20℃for 12 hours. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give B4 (650 mg, yield: 93.1%) as a white solid.

¹H NMR(400MHz,CDCl ₃)δ7.42(dd,J＝8.8,2.0Hz,1H),6.89(dd,J＝8.8,7.6Hz,1H),4.77(s,2H),4.28(q,J＝7.2Hz,2H),1.30(t,J＝7.2Hz,3H).

Synthesis of intermediate B5: 2-bromo-4- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3-fluorobenzonitrile

Step one: to a dry single-necked flask were added sequentially compound B1-3 (1.0 g,4.59 mmol), diethyl malonate (883 mg,5.51 mmol), DMF (10 mL), and potassium carbonate (1.27 g,9.18 mmol). The reaction solution was stirred at 35℃for 12 hours. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B5-1 (1.60 g, yield: 97.6%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ7.61(dd,J＝8.4,6.4Hz,1H),7.50(dd,J＝8.4,1.6Hz,1H),5.00(s,1H),4.34-4.16(m,4H),1.33-1.25(m,6H).

Step two: to a dry single-necked flask, compound B5-1 (1.60 g,4.47 mmol), dimethyl sulfoxide (16 mL), water (0.8 mL), and lithium chloride (379 mg,8.94 mmol) were sequentially added. The reaction solution was stirred at 85℃for 36 hours. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B5-2 (1.0 g, yield: 78.1%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ7.48-7.43(m,1H),7.39-7.33(m,1H),4.19(q,J＝7.2Hz,2H),3.75(s,2H),1.27(t,J＝7.2Hz,3H).

Step three: to a dry single-necked flask, compound B5-2 (150 mg,0.524 mmol), ethanol (5 mL) and sodium borohydride (40 mg,1.05 mmol) were sequentially added. The reaction solution was stirred at 20℃for 36 hours. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=2:1) to give B5-3 (100 mg, yield: 78.1%) as a white solid.

¹H NMR(400MHz,CDCl ₃)δ7.43(dd,J＝8.0,0.8Hz,1H),7.35(dd,J＝7.6,6.4Hz,1H),3.92(t,J＝6.4Hz,2H),3.05-2.95(m,2H).

Step four: to a dry single-necked flask, compound B5-3 (100 mg,0.410 mmol), methylene chloride (3 mL), DMF (1 mL), t-butyldimethylchlorosilane (93 mg, 0.616 mmol) and N, N-diisopropylethylamine (106 mg, 0.630 mmol) were added sequentially. The reaction solution was stirred at 20℃for 1 hour. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B5 (103 mg, yield: 70.1%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ7.40(dd,J＝8.0,1.2Hz,1H),7.31(dd,J＝8.0,6.4Hz,1H),3.84(t,J＝6.4Hz,2H),2.96-2.90(m,2H),0.83(s,9H),-0.042(s,6H).

Synthesis of intermediate B6: 2-bromo-4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) -3-fluorobenzonitrile

According to the synthesis method of the compound B2, tert-butyl- (3-iodopropoxy) dimethyl silane is used for replacing the compound B2-2 to perform one-step reaction to obtain a crude compound B6, which is directly used for the next reaction.

Synthesis of intermediate B7: 2-bromo-3-fluoro-4-morpholinyl benzonitrile

According to the synthesis method of the reference compound B5-1, morpholine is used for replacing diethyl malonate, and the crude compound B7 is obtained through one-step reaction and is directly used for the next reaction.

Synthesis of intermediate B8: 2-bromo-4- (1, 1-thiomorpholinyl) -3-fluorobenzonitrile

According to the synthesis method of the reference compound B5-1, 1-sulphur dioxide substituted morpholine is used for replacing diethyl malonate, and a one-step reaction is carried out to obtain a crude compound B8 which is directly used for the next reaction.

Synthesis of intermediate B9: 2-bromo-3-fluoro-4- ((tetrahydro-2H-pyran-4-yl) amino) benzonitrile

According to the synthesis method of the reference compound B5-1, 4-aminotetrahydropyran is used for replacing diethyl malonate, and a one-step reaction is carried out to obtain a crude compound B9 which is directly used for the next reaction.

Synthesis of intermediate B10: (S) -2-bromo-4- (2- ((tert-butyldimethylsilyl) oxy) propoxy) -3-fluorobenzonitrile

Step one: to a dry single vial were added, in order, L-methyl lactate (1.0 g,9.61 mmol), methylene chloride (15 mL), t-butyldimethylchlorosilane (1.88 g,12.5 mmol), triethylamine (1.46 g,14.4 mmol), and 4-dimethylaminopyridine (117 mg,0.961 mmol). The reaction solution was stirred at 20℃for 12 hours. The reaction mixture was diluted with water and extracted 2 times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B10-1 (1.70 g, yield: 81.0%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ4.33(q,J＝6.8Hz,1H),3.72(s,3H),1.40(d,J＝6.8Hz,3H),0.90(s,9H),0.08(d,J＝10.8Hz,6H).

Step two: to a dry single-necked flask at 0℃was added compound B10-1 (1.70 g,7.78 mmol), tetrahydrofuran (20 mL) and diisobutylaluminum hydride (13.0 mL,19.5mmol, 1.5M) in this order. The reaction solution was stirred at 25℃for 2 hours. The reaction was quenched by addition of 1.0M sodium potassium tartrate solution (30 mL) at 0deg.C and stirring was continued for 30min at 25deg.C. The resulting mixture was extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B10-2 (1.10 g, yield: 74.3%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ4.00-3.80(m,1H),3.50(dd,J＝10.8,3.6Hz,1H),3.36(dd,J＝10.8,6.4Hz,1H),1.12(d,J＝6.4Hz,3H),0.90(s,9H),0.09(s,6H).

Step three: to a dry single-necked flask at 0℃was added compound B10-2 (500 mg,2.63 mmol), methylene chloride (10 mL), triethylamine (798 mg,7.89 mmol) and methanesulfonic anhydride (688 mg,3.95 mmol) in this order. The reaction solution was stirred at 25℃for 2 hours. The reaction mixture was diluted with water and extracted 2 times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B10-3 (540 mg, yield: 76.5%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ4.10-3.90(m,3H),3.02(s,3H),1.19(d,J＝6.0Hz,3H),0.89(s,9H),0.09(s,6H).

Step four: to a dry single vial was added in order compound B1 (200 mg,0.926 mmol), DMF (6 mL), compound B10-3 (274 mg,1.02 mmol), sodium iodide (274 mg,1.85 mmol) and potassium carbonate (256 mg,1.85 mmol). The reaction solution was stirred at 80℃for 12 hours. The reaction mixture was diluted with water and extracted 2 times with petroleum ether/ethyl acetate (1/1, 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B10 (100 mg, yield: 27.8%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ7.42(dd,J＝8.8,2.0Hz,1H),6.98(dd,J＝8.4,7.2Hz,1H),4.28-4.18(m,1H),4.00-3.85(m,2H),1.25(d,J＝6.0Hz,3H),0.88(s,9H),0.08(d,J＝17.6Hz,6H).

Synthesis of intermediate B11: (R) -2-bromo-4- (2- ((tert-butyldimethylsilyl) oxy) propoxy) -3-fluorobenzonitrile

Referring to the synthesis method of the compound B10, the compound D-methyl lactate is used for replacing the compound L-methyl lactate, and the compound B11 is obtained through four-step reaction.

Synthesis of intermediate B12: 4- (2- (benzyloxy) ethoxy) -2-bromo-3-fluorobenzoic acid methyl ester

Colorless oil B12 (1.32 g, yield: 85.7%) was synthesized with reference to the synthesis method of intermediate B3.

Synthesis of intermediate B13: 5-bromo-6-cyano-4-fluoroindole-1-carboxylic acid tert-butyl ester

Step one: to a 500mL round bottom flask was added B13-1 (6.5 g,27.8mmol,1.0 eq), DMF-DMA (13 mL,61.1mmol,2.2 eq), triethylamine (4.25 mL,61.1mmol,2.2 eq) and DMF (25 mL) in sequence, followed by warming to 110℃and stirring for 3 hours. TLC showed complete reaction, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (150 mL), saturated aqueous sodium thiosulfate (150 mL), saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in acetic acid/toluene (100 mL/150 mL), reduced iron powder (31 g, 55mmol,20.0 eq) was added and then warmed to 100℃and stirred for 1 hour. Cooled, filtered, the reaction was poured into ice water and extracted with ethyl acetate (150 ml x 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-40% ethyl acetate/petroleum ether) to give B13-2 (3.7 g, yield: 60%) as a yellow solid.

¹H NMR(400MHz,CDCl ₃)δ8.27(s,1H),7.35(t,J＝1.2Hz,1H),7.17(dd,J＝3.2,2.4Hz,1H),6.96(dd,J＝9.6,1.4Hz,1H),6.61(ddd,J＝3.2,2.2,1.0Hz,1H).

Step two: to a dry three-necked flask, compound B13-2 (3.7G, 17.3mmol,1.0 eq), zinc cyanide (1.34G, 11.42mmol,0.66 eq) and t-BuXPhos-Pd-G3 (686 mg,0.86mmol,0.05 eq) were added sequentially under nitrogen, and then THF/H ₂ O (10 mL/50 mL) was added and the reaction stirred at 40℃for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (0-40% ethyl acetate/petroleum ether) to give B13-3 (2.85 g, yield: 93%) as a yellow solid.

LCMS：[M+H] ⁺＝161。

Step three: to a dry round bottom flask under nitrogen protection was added compound B13-3 (0.68 g,4.25mmol,1.0 eq), triethylsilane (1 mL,26.6mmol,6.25 eq) and tetrahydrofuran (6 mL) in sequence and the reaction stirred at 60℃for 5 hours. TLC showed complete reaction, the reaction was dried by spinning, diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to give B13-4 (566 mg, yield: 82.2%) as a yellow solid.

LCMS：[M+H] ⁺＝163。

Step four: to a dry round bottom flask, compound B13-4 (560 mg,3.47mmol,1.0 eq) and acetonitrile (10 mL) were added sequentially with ice-bath cooling, followed by dropwise addition of a solution of NBS (611 mg,3.47mmol,1.0 eq) in acetonitrile (10 mL). The reaction solution was stirred at 0℃for 0.5 hours. TLC showed complete reaction, diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (60 mL), saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-30% ethyl acetate/petroleum ether) to give B13-5 (423 mg, yield: 59.6%) as a white solid.

F-NMR(400MHz，CDCl ₃)：-108.80；

¹H NMR(400MHz,CDCl ₃)δ6.63(S，1H)，3.72(t，J＝8.8Hz，2H)，3.18(m，2H)。

Step five: to a dry round bottom flask, compound B13-5 (50 mg,0.2mmol,1.0 eq) and dichloromethane (4 mL) were added sequentially with ice-bath cooling, followed by (Boc) ₂ O (66 mg,0.3mmol,1.5 eq) and DMAP (24.4 mg,0.2mmol,1.0 eq). The reaction solution was stirred at room temperature for 2 hours. TLC showed complete reaction and the reaction concentrated. The resulting residue was purified by silica gel chromatography (0-20% ethyl acetate/petroleum ether) to give B13 (50 mg, yield: 73%) as a white solid.

LCMS：m/z＝340.95[M+H] ⁺。

Synthesis of intermediate B14: 6-bromo-5-cyano-7-fluoro-1H-indole-1-carboxylic acid tert-butyl ester

Step one: acetonitrile (20 mL), aqueous ammonia (20 mL), and B1-3 (2.18 g,10.0mmol,1.0 eq) were added sequentially to a 60mL pressure-resistant bottle, then warmed to 60℃and stirred for 16 hours. TLC showed complete reaction, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B14-2 (1.9 g, yield: 88.4%) as a white solid.

Step two: to a dry single vial was added acetic acid (20 mL), B14-2 (21.0 g,4.65mmol,1.0 eq) and NIS (1.57 g,6.98mmol,1.5 eq) in sequence. The reaction solution was stirred at 25 degrees celsius for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (35 ml×3). The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate (100 mL), saturated aqueous sodium thiosulfate (100 mL), saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-15% ethyl acetate/petroleum ether) to give B14-3 (1.3 g, yield: 81.8%) as a yellow solid.

¹H NMR(400MHz,CDCl ₃)δ7.71(d，J＝1.6Hz，1H)，4.79(s，2H)。

Step three: tetrahydrofuran (20 mL), B14-3 (1.5 g,4.4mmol,1.0 eq), diphenylphosphine palladium dichloride (154 mg,0.22mmol,0.05 eq), cuprous iodide (84 mg,0.44mmol,0.1 eq) and triethylamine (1.22 mL,8.8mmol,2.0 eq) were added sequentially to a dry three-necked flask under nitrogen, and ethynyl trimethylsilane (682 uL,4.84mmol,1.1 eq) was added dropwise with stirring. The reaction solution was stirred at 25 degrees celsius for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (45 ml×3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in anhydrous methanol (20 mL), then potassium carbonate (1.22 g,8.8mmol,2.0 eq) was added, the reaction mixture was stirred for 2 hours, after completion of the reaction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-13% ethyl acetate/petroleum ether) to give B14-4 (700 mg, yield: 66.7%) as a yellow solid.

¹H NMR(400MHz，DMSO_d6)δ7.65(d，J＝1.2Hz，1H)，6.79(s，2H)，4.68(s，1H)。

Step four: pyridine (10 mL), compound B14-4 (700 mg,2.93mmol,1.0 eq) and CpRuCl (PPh ₃) ₂ (233 mg,0.29mmol,0.1 eq)) were added sequentially to a dry three-necked flask under nitrogen protection, the reaction was stirred at 90℃for 12 hours, after completion of the reaction, the reaction was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (0-13% ethyl acetate/petroleum ether) to give B14-5 (170 mg, yield: 24.3%) as a yellow solid.

¹H NMR(400MHz，DMSO_d6)δ12.46(s，1H)，8.13(s，1H)，7.78-7.57(m，1H)，6.72(d，J＝1.6Hz，1H).

Step five: to a dry single-necked flask were successively added dichloromethane (2 mL), B14-5 (70 mg,0.29mmol,1.0 eq), boc ₂ O (96 mg,0.44mmol,1.5 eq), triethylamine (82 uL,0.59mmol,2.0 eq) and N, N-lutidine (4 mg,0.03mmol,0.1 eq). The reaction solution was stirred at 25 degrees celsius for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (0-7.2% ethyl acetate/petroleum ether) to give B14 (94 mg, yield: 94.9%) as a white solid.

LCMS：m/z＝339.16(M+H) ⁺。

Synthesis of intermediate B15: 6- (2- ((tert-Butyldimethylsilanyloxy) ethoxy) -5-fluoro-4-iodonicotinonitrile

Step one: to a solution of 2-amino-3-fluoropyridine (B15-1, 40.0g,356.79 mmol) in DMF (400 mL) was added NBS (64.1 g,360.36 mmol) under an ice-water bath. The reaction was stirred at room temperature for 4 hours. The reaction solution was poured into an ice saturated aqueous sodium sulfite solution (1200 mL), filtered, and the cake was washed with water, followed by purification by silica gel chromatography (ethyl acetate/petroleum ether=1/20 to 1/5) to give 5-bromo-3-fluoropyridin-2-amine (B15-2, 60.7g, yield: 89%) as a white solid.

¹H NMR(400MHz,CDCl ₃)：δppm 7.93(d,J＝1.6Hz,1H),7.38(dd,J＝10.0,2.0Hz,1H),4.66(br,2H).

Step two: 5-bromo-3-fluoropyridin-2-amine (B15-2, 74.50g,390.05 mmol) was dissolved in tetrahydrofuran (260 mL) and water (1000 mL), zn (CN) ₂ (30.22 g,257.45 mmol) was added and the mixture was purged 3 times with argon under vacuum. t-BuXPhos-Pd G3 (6.80G, 8.56 mmol) was added and replaced 3 more times with argon under vacuum. The reaction was carried out at 40℃for 15 hours. The reaction was slowly poured into ice water (1.0L), extracted with ethyl acetate (3 x 400 mL), the insoluble material was filtered off over celite, and the residue was rinsed with tetrahydrofuran (300 mL). The organic phases were combined, washed with saturated brine (2×500 ml), dried and concentrated over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/20 to 1/1) to give 6-amino-5-fluoronicotinonitrile (B15-3, 28.53g, yield: 53.3%) as a pale yellow powder.

LCMS：m/z 138.5[M+H] ⁺。

Step three: 6-amino-5-fluoronicotinonitrile (B15-3, 28.53g,208.10 mmol) was dissolved in acetone (290 mL) and tert-butanol (145 mL), and DMAP (82.84 g,677.9 mmol) was added. (Boc) ₂ O (200.39 g,919.26 mmol) was added slowly and reacted at 60℃for 12 hours. The reaction solution was concentrated to near dryness, applied by wet method, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/100 to 1/15) to give tert-butyl N- (3-fluoro-5-cyanopyridin-2-yl) -N- [ (2-methylpropan-2-yl) oxycarbonyl ] carbamate (B15-4, 58.32g, yield: 83.1%) as a white solid.

¹H NMR(400MHz,CDCl ₃)：δppm 8.60(s，1H)，7.75(d，J＝7.2Hz，1H)，1.44(s，18H)。

Step four: tert-butyl N- (3-fluoro-5-cyanopyridin-2-yl) -N- [ (2-methylpropan-2-yl) oxycarbonyl ] carbamate (B15-4, 58.32g,172.85 mmol) was dissolved in tetrahydrofuran (630 mL), iodine (87.72 g,345.64 mmol) was added, nitrogen blanket, and the temperature was lowered to-65 ℃. LDA (2.0M in THF,440mL,888.00mmol) was added dropwise. After the completion of the dropping, the mixture was stirred for 10 minutes, and then the mixture was allowed to react at room temperature for 16 hours. The reaction solution was slowly poured into ice water (1.0L), ethyl acetate (3 x 400 ml) was added for extraction, the organic phase was washed with saturated brine (2 x 500 ml), concentrated by organic phase drying, purified by column chromatography on silica gel (0-10% ethyl acetate/petroleum ether), and slurried with dichloromethane/petroleum ether (1/50) to give tert-butyl (5-cyano-3-fluoro-4-iodopyridin-2-yl) carbamate (B15-5, 23.27g, yield: 37.1%) as a pale yellow powder.

¹H NMR(400MHz，DMSO-d6)δppm：10.27(s，1H)，8.52(s，1H)，1.46(s，9H)。

Step five: to a solution of tert-butyl (5-cyano-3-fluoro-4-iodopyridin-2-yl) carbamate (B15-5, 32.06g,88.29 mmol) in dichloromethane (360 mL) was added dropwise trifluoroacetic acid (130 mL) at 0deg.C. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated to remove most of the solvent and trifluoroacetic acid. Ethyl acetate (60 mL) was added to dilute, and poured into a saturated aqueous sodium carbonate solution (500 mL), the aqueous phase was extracted with ethyl acetate (3×200 mL), and the organic phase was washed with saturated brine (100 mL), dried, and concentrated to give 6-amino-5-fluoro-4-iodonicotinonitrile (B15-6, 19.08g, yield: 82.2%) as an off-white solid.

LCMS：m/z：264.2[M+H] ⁺。

¹H NMR(400MHz,CDCl ₃)δ8.20(s，1H)。

Step six: 6-amino-5-fluoro-4-iodonicotinonitrile (B15-6, 4.58g,17.43 mmol) was dissolved in tetrafluoroboric acid (150 mL), cooled to-10℃and NaNO ₂ (3.32 g,48.13 mmol) was added in portions for 2 hours. The reaction solution was poured into an aqueous solution of sodium glacial carbonate (800 mL), stirred for 5 minutes, extracted with ethyl acetate (3×200 mL), and the organic phase was washed with saturated brine (100 mL), dried, concentrated, and purified by silica gel column chromatography (0-5% ethyl acetate/petroleum ether) to give 5, 6-difluoro-4-iodonicotinonitrile (B15-7, 1.47g, yield: 31.7%) as a white solid.

¹H NMR(400MHz,CDCl ₃)：δppm8.22(s，1H)。

Step seven: 2- ((tert-Butyldimethylsilanyloxy) ethyl-1-hydroxy (B15-7, 72mg,0.40 mmol) was dissolved in tetrahydrofuran (8 mL), cooled to 0deg.C, sodium hydrogen (32 mg,0.76mmol, 60%) was added in portions and reacted for 30 minutes. Then, a solution of 5, 6-difluoro-4-iodonicotinonitrile (100 mg,0.37 mmol) in tetrahydrofuran (2 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. The reaction was poured into ice water (20 mL), stirred for 5min, extracted with ethyl acetate (3×20 mL), and the organic phase was washed with saturated brine (20 mL), dried, concentrated, and purified (ethyl acetate/petroleum ether=1/20) over a silica gel plate to give 6- (2- ((tert-butyldimethylsilyloxy) ethoxy) -5-fluoro-4-iodonicotinonitrile (B15, 40mg, yield: 25%).

¹H NMR(400MHz,CDCl ₃)：δppm8.03(s,1H),4.45(t,J＝8.0Hz,2H),3.90(t,J＝8.0Hz,2H),0.81(s,9H),0.01(s,6H).

Synthesis of intermediate B16: 2-bromo-3-fluoro-4- (methylamino) benzonitrile

To a 60mL pressure-resistant bottle was added sequentially a methylamine ethanol solution (5 mL) and B1-3 (400 mg,1.83mmol,1.0 eq) followed by heating to 100℃and stirring for 16 hours. TLC showed complete reaction, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B16 (400 mg, yield: 95.2%) as a white solid.

Synthesis of intermediate B17: 3, 4-difluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoic acid methyl ester

In a dry three-necked flask, compound B1-1 (310 mg,1.25 mmol), bis-pinacolato borate (636 mg,2.50 mmol), xylene (10 mL), pd (dppf) Cl ₂·CH ₂Cl ₂ (100 mg,0.12 mmol) and potassium pivalate (520 mg,3.75 mmol) were sequentially added. The reaction solution was stirred for 12 hours at 100℃under nitrogen. After the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give B17 (220 mg, yield: 60.1%) as a white solid

Synthesis of intermediate B18: 3-fluoro-4-methoxy-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoic acid methyl ester

Step one: synthesis of reference Compound B4 Compound B18-1 was synthesized via a one-step reaction.

Step two: synthesis of reference Compound B17 intermediate Compound B18 was synthesized via a one-step reaction.

Synthesis of intermediate B19: 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole-5-carboxylic acid methyl ester

Synthesis of reference Compound B17, intermediate Compound B19 was synthesized via a one-step reaction.

Synthesis of intermediate B20: 2-bromo-4- (difluoromethoxy) -3-fluorobenzonitrile

Step one: to a round bottom flask was added, in order, N-dimethylformamide (15 mL), 2-bromo-3-fluoro-4-hydroxybenzonitrile (B1, 1.0g,4.63mmol,1.0 eq), cesium carbonate (3.01 g,9.26mmol,2.0 eq) and sodium chlorodifluoroacetate (1.06 g,6.94mmol,1.5 eq). The yellow reaction solution was warmed to 90 degrees celsius and stirred for 6 hours (with gas evolved). TLC showed the reaction was complete. The filtrate was extracted with water (50 mL) and ethyl acetate (20 mL x 3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica gel chromatography (to 6% gradient of ethyl acetate: petroleum ether) to give 2-bromo-4- (difluoromethoxy) -3-fluorobenzonitrile (B20, 0.54g, yield: 43.9%) as a yellow liquid.

¹H NMR(400MHz,CDCl ₃)δ7.54-7.46(m，1H)，7.34(dd，J＝8.0，7.2Hz，1H)，6.65(t，J＝71.6Hz，1H)。

Synthesis of intermediate C1: 2-tert-Butyldimethylsiloxy-acetaldehyde

To a dry single-necked flask were added 2-t-butyldimethylsilyloxy ethanol (1.0 g,5.67 mmol), methylene chloride (40 mL), and dess-Martin oxidant (3.61 g,8.51 mmol) in this order. The reaction solution was stirred at 25℃for 1 hour. After completion of the reaction, a saturated sodium bicarbonate solution (30 mL) and a saturated sodium thiosulfate solution (30 mL) were added to the reaction solution, and the resulting mixture was stirred at 25℃for 30 minutes. Extraction with dichloromethane was performed 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give C1 (700 mg, yield: 70.9%) as a colorless oil.

¹H NMR(400MHz,CDCl ₃)δ9.70(s，1H)，4.22(s，2H)，0.93(s，9H)，0.11(s，6H)。

Embodiment one: synthesis of Compound 1

8-Methyl-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indole

Step one: HMPA (3.0 mL) and LDA (7.7 mL,15.4mmol, 2.0M) were dissolved in anhydrous tetrahydrofuran (100 mL), and a solution of A1-5 (1.7 g,4.64 mmol) in tetrahydrofuran (25 mL) was slowly dropped at-60℃after completion of the dropping, the reaction solution was warmed to-30℃and stirred for 30 minutes, then stirred for another 30 minutes at-60℃and then a solution of Compound 1-1 (2.20 g,8.35 mmol) in tetrahydrofuran (10 mL) was dropped at-60 ℃. After completion of the dropwise addition, the reaction mixture was stirred at-60 ℃ for 2 hours, quenched with saturated ammonium chloride (30 mL), extracted with ethyl acetate (60 ml×3), and the organic layer was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=10/1) to give the product compound 1-2 (1.8 g, yield: 71%) as a brown oil.

Step two: compound 1-2 (2.6 g,4.73 mmol) was dissolved in ethyl acetate (3 mL), HCl (4M, etOAc,10 mL) was added and stirred at room temperature for an additional 1 hour, the reaction solution was adjusted to pH=8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL. Times.2), the organic phase was washed with saturated sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated to give product 1-3 (1.1 g, yield: 51%) as a colorless oil.

Step three: compound 1-3 (1.1 g,2.45 mmol) was dissolved in DMA (4 mL), sodium hydrogen (254 mg,7.34mmol,60% mixture of mineral oils) was added at 0deg.C, the reaction was stirred at 100deg.C for another 6 hours, quenched with water (10 mL) and extracted with ethyl acetate (60 mL. Times.3), and the organic layer was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to give product 1-4 (180 mg, yield: 20%) as a pale yellow oil.

Step four: compounds 1 to 4 (180 mg,0.488 mmol) were dissolved in tetrahydrofuran (3 mL), borane tetrahydrofuran (3 mL,3mmol, 1M) was added at 0deg.C, the reaction was stirred for an additional 20h at 60deg.C, quenched with methanol (4 mL), concentrated, the solid was dissolved in methanol (4 mL) and 4N HCl/dioxane (20 mL), the mixture was stirred for 1h at room temperature, concentrated, pH=8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL. Times.2), the organic phase was washed with saturated sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated and isolated by column chromatography (Petroleum ether/ethyl acetate=5/1) to give products 1 to 5 (120 mg, yield: 69%) as colorless oil.

Step five: compounds 1 to 5 (120 mg, 0.399 mmol) were dissolved in 1, 2-dichloroethane (4 mL), 1-chloroethylchloroformate (121 mg,0.846 mmol) was added, the reaction was stirred for a further 2 hours at 70℃and concentrated, after dissolution of the solid in methanol (6 mL), the mixture was stirred for a further 1 hour at 40℃and concentrated, adjusted to pH=8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL. Times.2), the organic phase was washed with saturated sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated and subjected to Prep-TLC separation (dichloromethane/methanol=20/1) to give the product 8-methyl-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indole (compound 1, 83mg, yield: 93%) as a colourless oil.

¹HNMR(400MHz,CDCl ₃)7.59(d,J＝8.0Hz,2H),7.41(t,J＝8.0Hz,2H),7.29(d,J＝4.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.86(s,1H),6.44(d,J＝8.0Hz,1H),3.47(d,J＝12.0Hz,2H),3.25-3.14(m,2H),2.94-2.89(m,2H),2.83(d,J＝16.0Hz,1H),2.69(d,J＝12Hz,1H),2.26(s,3H).

LC-MS[M+1] ⁺＝265.3

The following compounds were synthesized according to the reference and the synthetic procedure for compound 1, respectively:

example 2: synthesis of Compound 6

9-Bromo-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indole

Step one: in a dry single vial were added in sequence compound A1-9 (4.10 g,8.86 mmol), 1, 2-dichloroethane (40 mL) and 2-chloroethyl chloroformate (3.17 g,22.2 mmol). The reaction solution was stirred at 80℃for 16 hours. The reaction solution was concentrated to dryness under reduced pressure. The obtained residue was dissolved in methanol and stirred at 75 degrees for 1.5 hours. After the completion of the reaction, the solution was concentrated under reduced pressure to give a yellow oil (compound 6,3.10 g).

LC-MS[M+1] ⁺＝347.0。

Example 3: synthesis of Compound 7

9-Bromo-8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indole

To a one-necked flask, compound A1-11 (5 mg,0.008 mmol), methanol (2 mL) and dioxane hydrochloride (1 mL, 4.0M) were successively added, and the reaction mixture was stirred at 20℃for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was lyophilized to give a white solid (compound 7,3.6mg, hydrochloride, yield: 89%).

LC-MS[M+1] ⁺＝381.0。

Example 4: synthesis of Compound 8

4- (7-Fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) morpholin

Step one: to the reaction flask were successively added compound A-10 (20 mg,0.045 mmol), morpholine (3.89 mg,0.045 mmol), cesium carbonate (29.13 mg,0.089 mmol), XPhos Pd G3 (3.81 mg,0.04 mmol) and1, 4-dioxane (2 mL), and the reaction mixture was stirred overnight at 100℃under nitrogen. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give 8-1 (8 mg, yield: 39.45%) as a yellow solid.

Step two: the synthesis of reference compound 7 gives compound 8 in one step.

¹H NMR(400MHz,CD3OD)δ7.70-7.67(m,3H),7.57-7.53(m,4H),4.16-4.13(m,4H),3.77-3.72(m,2H),3.64-3.55(m,6H),3.46-3.39(m,2H),3.10-3.06(m,2H).

LC-MS[M+1] ⁺＝354.19。

The following compounds were synthesized according to the reference and the synthetic procedure for compound 8, respectively:

example 5: synthesis of Compound 15

8-Chloro-7-fluoro-9, 10 a-diphenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indole

Step one: to the reaction flask were successively added Compound A-11 (20 mg,0.042 mmol), phenylboronic acid (6.15 mg,0.050 mmol), potassium carbonate (11.61 mg,0.084 mmol), water (0.5 mL), 1, 4-dioxane (2.5 mL), and tetrakis triphenylphosphine palladium (4.85 mg, 0.004mmol), and the reaction solution was stirred at 100℃for 2 hours under nitrogen. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give 15-1 (19 mg, yield: 95.57%) as a yellow solid.

LCMS：m/z 479.2[M+H] ⁺。

Step two: to a one-necked flask, compound 15-1 (19 mg,0.040 mmol), methanol (5 mL) and a hydrogen chloride dioxane solution (1 mL,4 mmol) were successively added, and the reaction mixture was stirred at 25℃for 3 hours. The solvent was removed under reduced pressure to give compound 15 (12 mg, yield: 65.57%) as a yellow solid.

¹H NMR(400MHz,CD3OD)δ7.55-7.52(m,2H),7.43-7.38(m,3H),7.32-7.20(m,5H),6.69(d,J＝12Hz,1H),3.91-3.80(m,2H),3.45-3.37(m,1H),3.27-3.21(m,1H),3.13-3.07(m,1H),2.97-2.94(m,1H),2.71-2.66(m,2H).

LC-MS：m/z 379.1[M+H] ⁺。

The following compounds were synthesized according to the reference and the synthetic procedure for compound 15, respectively:

Example 6: synthesis of Compound 30

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -N-methylbenzamide

Step one: synthesis of reference Compound 15-1, one-step reaction gives Compound 30-2.

LCMS：m/z 537.2[M+H] ⁺。

Step two: to a solution of compound 30-2 (100 mg,0.18 mmol) in methanol (5 mL) was added NaOH (40 mg,1 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was adjusted to ph=6 with dilute hydrochloric acid. Ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product 30-3 (105 mg).

Step three: the compound 30-4 is obtained by one-step reaction of the synthesis of the reference compound B1-2.

LCMS：m/z 522.2[M+H] ⁺。

Step four: the synthesis of reference compound 15 was carried out in one step to give compound 30.

¹H NMR(400MHz,CD3OD)δ7.65-7.57(m,4H),7.51-7.37(m,4H),7.32-7.30(m,1H),6.69(d,J＝8Hz,1H),4.01-3.92(m,2H),3.68-3.66(m,1H),3.51-3.48(m,1H),3.23-3.17(m,1H),3.06-3.04(m,1H),2.86-2.66(m,1H),2.76-2.72(m,1H).

LC-MS：m/z 422.1[M+H] ⁺

The following compounds were synthesized according to the reference and the synthetic procedure for compound 30, respectively:

Embodiment seven: synthesis of Compound 41

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -4- (difluoromethoxy) -3-fluorobenzamide hydrochloride

Step one: to the reaction flask were successively added compound A1 (130 mg, 0.248 mmol), compound B20 (65 mg, 0.248 mmol), potassium phosphate (131 mg, 0.015 mmol), toluene (5 mL), water (1 mL), pd2 (dba) 3 (23 mg,0.025 mmol) and NiXantPhos (27 mg,0.049 mmol), and the reaction was stirred under nitrogen at 100deg.C for 6 hours. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give 41-1 (16 mg, yield: 11.0%) as a white solid and 42-1 (19 mg, yield: 13.1%) as a white solid.

LCMS：m/z 588.2[M+H] ⁺。

Step two: to a one-necked flask, compound 41-1 (16 mg,0.027 mmol), methanol (4 mL), copper acetate (20 mg,0.108 mmol) and diethylhydroxylamine (96 mg,1.08 mmol) were successively added, and the reaction mixture was stirred at 20℃for 12 hours. After the reaction, the reaction solution was concentrated by filtration. The resulting residue was purified by thin layer chromatography (petroleum ether/ethyl acetate=1:1) to give 41-2 (5 mg, yield: 31.3%) as a white solid.

LCMS：m/z 606.2[M+H] ⁺。

Step three: to a one-necked flask, compound 41-2 (5 mg,0.008 mmol), methanol (2 mL) and dioxane hydrochloride (1 mL, 4.0M) were successively added, and the reaction mixture was stirred at 20℃for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was lyophilized to give compound 41 (3.7 mg, hydrochloride, yield: 82.2%) as a white solid.

¹H NMR(400MHz,DMSO-d6)87.72(s,1H),7.62-7.55(m,2H),7.54-7.34(m,5H),7.28-7.18(m,1H),7.04(d,J＝10.8Hz,1H),4.05-3.90(m,2H),3.55-3.40(m,1H),3.14-2.98(m,2H),2.78-2.70(m,1H),2.64-2.56(m,1H).

LC-MS：m/z 506.1[M+H] ⁺。

Example eight: synthesis of Compound 42

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -4- (difluoromethoxy) -3-fluorobenzamide hydrochloride

Referring to the synthesis method of compound 41, compound 42 was obtained by performing a two-step reaction using compound 42-1 instead of compound 41-1.

¹H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.42(d,J＝8.8Hz,2H),7.03-6.91(m,3H),6.89-6.83(m,2H),6.82-6.76(m,1H),6.96(d,J＝10.4Hz,1H),3.50-3.30(m,2H),3.00-2.87(m,1H),2.67-2.58(m,1H),2.45-2.25(m,1H);

LC-MS：m/z 506.1[M+H] ⁺。

Example nine: synthesis of Compound 43

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B2 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 43.

¹H NMR(400MHz,DMSO-d6)δ7.61-7.51(m,3H),7.49-7.41(m,2H),7.40-7.31(m,2H),7.30-7.22(m,1H),7.06-6.94(m,2H),5.00(d,J＝10.8Hz,1H),4.20-4.07(m,2H),4.00-3.87(m,2H),3.82-3.73(m,2H),3.33-3.25(m,1H),3.10-2.80(m,3H),2.68(d,J＝16.4Hz,1H),2.59-2.51(m,1H);

LC-MS：m/z 500.1[M+H] ⁺。

Example ten: synthesis of Compound 44

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Referring to the synthesis method of compound 41, compound 44 was obtained by performing a two-step reaction using compound 44-1 instead of compound 41-1.

¹H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.65-7.55(m,2H),7.49-7.41(m,3H),7.40-7.33(m,1H),7.30-7.20(m,1H),7.14(s,1H),7.02(d,J＝10.4Hz,1H),4.91(t,J＝5.6Hz,1H),4.14-4.02(m,2H),4.00-3.88(m,2H),3.75-3.65(m,2H),3.30-3.26(m,1H),3.20-3.10(m,1H),3.00-2.75(m,3H),2.44-2.36(m,1H).

LC-MS：m/z 500.1[M+H] ⁺。

Example eleven: synthesis of Compound 45

2- (4-Carbamoyl-3- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -2-fluorophenoxy) acetic acid

Step one and step two: referring to the synthesis of compound 41-2, compound B4 was used instead of compound B20 and XantPhos was used instead of NiXantPhos to give compound 45-2.

Step three: to a single-necked flask, compound 45-2 (100 mg,0.156 mmol), tetrahydrofuran (1 mL), methanol (1 mL), water (1 mL) and lithium hydroxide monohydrate (66 mg,1.56 mmol) were successively added, and the reaction mixture was stirred at 20℃for 1 hour. The reaction mixture was adjusted to ph=5 with 0.5N dilute hydrochloric acid. The mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 45-3 (90 mg, yield: 93.8%) as an off-white solid.

LC-MS：m/z 614.2[M+H] ⁺。

Step four: to a one-necked flask, compound 45-3 (90 mg,0.147 mmol), methanol (2.5 mL), and dioxane hydrochloride (1.0 mL, 4M) were successively added, and the reaction mixture was stirred at 20℃for 1 hour. The reaction mixture was adjusted to ph=8 with saturated sodium bicarbonate solution. The mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane/methanol=10:1) to give 45-4 (50 mg, yield: 61.0%) as an off-white solid and 46-1 (30 mg, yield: 36.6%) as an off-white solid.

LC-MS：m/z 528.1[M+H] ⁺。

Step five: to a single-necked flask, compound 45-4 (50 mg,0.095 mmol), tetrahydrofuran (1 mL), methanol (1 mL), water (1 mL) and sodium hydroxide (60 mg,1.50 mmol) were successively added, and the reaction mixture was stirred at 20℃for 1 hour. The reaction mixture was adjusted to ph=6 with 0.5N dilute hydrochloric acid. The mixture was concentrated to dryness, the residue was diluted with dichloromethane/methanol (10:1, 5 mL) and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure to give 45 (16 mg, yield: 30.8%) as an off-white solid.

¹H NMR(400MHz,DMSO-d6)δ7.60-7.52(m,3H),7.48-7.40(m,2H),7.38-7.31(m,2H),7.14(t,J＝8.4Hz,1H),7.05-6.95(m,2H),4.95-4.75(m,2H),4.00-3.85(m,2H),3.30-3.25(m,1H),3.10-2.95(m,2H),2.72-2.62(m,1H),2.60-2.52(m,1H).

LC-MS：m/z 514.1[M+H] ⁺。

Embodiment twelve: synthesis of Compound 46

2- (4-Carbamoyl-3- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -2-fluorophenoxy) acetic acid

Referring to the synthesis method of compound 45, compound 46 was obtained by performing a one-step reaction using compound 46-1 instead of compound 45-4.

¹H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.70-7.64(m,2H),7.55-7.39(m,4H),7.26-7.16(m,2H),7.02(d,J＝10.4Hz,1H),4.80(s,2H),4.07-3.95(m,2H),3.30-3.25(m,1H),3.24-3.15(m,1H),3.06-2.82(m,3H),2.51-2.42(m,1H).

LC-MS：m/z 514.1[M+H] ⁺。

Embodiment thirteen: synthesis of Compound 47

(2S) -2- (8-chloro-7-fluoro-2- (2-hydroxyethyl) -10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Step one: to a one-necked flask, compound 44 (10 mg,0.019 mmol), compound C1 (5 mg,0.029 mmol), methylene chloride (1 mL) and sodium triacetylborohydride (6 mg,0.029 mmol) were successively added, and the reaction mixture was stirred at 20℃for 2 hours. The reaction mixture was diluted with water and extracted 2 times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (petroleum ether/ethyl acetate=1:1) to give 47-1 (7 mg, yield: 75.0%) as an off-white solid.

LC-MS：m/z 658.3[M+H] ⁺。

Step two: to a one-necked flask, compound 47-1 (9 mg,0.014 mmol), methanol (2.0 mL) and dioxane hydrochloride (1.0 mL, 4M) were successively added, and the reaction mixture was stirred at 20℃for 1 hour. The reaction solution was concentrated under reduced pressure and lyophilized to give 47 (5.5 mg, hydrochloride, yield: 67.9%) as an off-white solid.

¹H NMR(400MHz,DMSO-d6)δ9.27(s,1H),7.78(s,1H),7.65-7.55(m,2H),7.50-7.33(m,4H),7.30-7.15(m,2H),7.06(d,J＝10.0Hz,1H),5.50-5.30(m,1H),4.35-4.20(m,1H),4.15-3.95(m,3H),3.87-3.76(m,1H),3.75-3.65(m,2H),3.55-3.45(m,2H),3.22-3.04(m,4H),2.95-2.80(m,1H),2.46-2.39(m,1H).

LC-MS：m/z 544.2[M+H] ⁺。

Fourteen examples: synthesis of Compound 48

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethyl) benzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B5 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 48.

¹H NMR(400MHz,DMSO-d6)δ9.60-9.20(m,1H),9.50-9.10(m,1H),7.61-7.54(m,3H),7.50-7.40(m,3H),7.39-7.34(m,1H),7.33-7.29(m,1H),7.12(s,1H),7.01(d,J＝10.4Hz,1H),4.86-4.78(m,1H),4.02-3.90(m,2H),3.70-3.60(m,2H),3.10-2.75(m,3H),2.87-2.77(m,2H),2.70-2.55(m,2H).

LC-MS：m/z 484.2[M+H] ⁺。

Example fifteen: synthesis of Compound 49

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethyl) benzamide hydrochloride

Referring to the synthesis of compound 41, compound 49 was obtained by performing a one-step reaction using compound 49-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ9.64-9.48(m,1H),8.40-8.22(m,1H),7.85(s,1H),7.65-7.55(m,2H),7.49-7.34(m,5H),7.26(s,1H),7.02(d,J＝10.4Hz,1H),4.90-4.50(m,1H),4.02-3.89(m,2H),3.58-3.48(m,2H),3.20-3.10(m,1H),3.00-2.78(m,3H),2.76-2.69(m,2H),2.43-2.35(m,1H).

LC-MS：m/z 484.2[M+H] ⁺。

Example sixteen: synthesis of Compound 50

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (3-hydroxypropyl) benzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B6 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 50.

¹H NMR(400MHz,DMSO-d6)δ7.60-7.50(m,3H),7.48-7.42(m,2H),7.41-7.32(m,2H),7.26(t,J＝8.4Hz,1H),7.04-6.94(m,2H),4.63(t,J＝5.2Hz,1H),4.25-4.10(m,2H),4.00-3.90(m,2H),3.62-3.54(m,2H),3.10-2.86(m,3H),2.75-2.65(m,1H),2.60-2.50(m,1H),1.98-1.86(m,2H).

LC-MS：m/z 514.2[M+H] ⁺。

Example seventeenth: synthesis of Compound 51

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (3-hydroxypropyl) benzamide hydrochloride

Referring to the synthesis method of compound 41, compound 51 was obtained by performing a one-step reaction using compound 51-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.65-7.55(m,2H),7.49-7.41(m,3H),7.40-7.33(m,1H),7.25(t,J＝8.4Hz,1H),7.13(s,1H),7.01(d,J＝10.8Hz,1H),4.55(t,J＝5.2Hz,1H),4.20-4.06(m,2H),4.00-3.87(m,2H),3.54-3.44(m,2H),3.15(d,J＝13.6Hz,1H),3.00-2.75(m,3H),2.45-2.35(m,1H),1.90-1.78(m,2H).

LC-MS：m/z 514.2[M+H] ⁺。

Example eighteenth: synthesis of Compound 52

2- (4-Carbamoyl-3- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -2-fluorophenyl) acetic acid hydrochloride

Step one, step two and step three: referring to the synthesis method of the compound 45-3, the compound B5-2 is used for replacing the compound B4, and the compound 52-3 is obtained through three-step reaction.

Step four: to a single-necked flask, compound 52-3 (18 mg,0.048 mmol), dioxane (2.0 mL) and dioxane hydrochloride (1.0 mL, 4M) were successively added, and the reaction solution was stirred at 20℃for 2 hours. The reaction solution was concentrated under reduced pressure and lyophilized to give yellow solid 52 (14 mg, hydrochloride).

¹H NMR(400MHz,DMSO-d6)δ12.57(brs,1H),7.66-7.54(m,1H),7.52-7.42(m,3H),7.40-7.33(m,3H),7.30-7.23(m,1H),7.22-7.12(m,1H),6.92-6.80(m,1H),3.76-3.68(m,2H),3.67-3.61(m,1H),3.58-3.53(m,1H),3.52-3.45(m,3H),3.44-3.38(m,3H).

LC-MS：m/z 498.1[M+H] ⁺。

Example nineteenth: synthesis of Compound 53

2- (4-Carbamoyl-3- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -2-fluorophenyl) acetic acid hydrochloride

Referring to the synthesis method of compound 52, compound 53 was obtained by performing a two-step reaction using compound 53-1 instead of compound 52-2.

¹H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.70(s,1H),7.49-7.29(m,6H),7.28-7.20(m,1H),6.74(d,J＝10.8Hz,1H),3.60-3.51(m,2H),3.50-3.45(m,1H),3.44-3.38(m,1H),3.35-3.25(m,1H),3.10-2.92(m,2H),2.72-2.62(m,2H),2.60-2.53(m,1H),2.32-2.22(m,1H).

LC-MS：m/z 498.1[M+H] ⁺。

Example twenty: synthesis of Compound 54

2- ((9R) 8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4-morpholinium benzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B7 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 54.

¹H NMR(400MHz,DMSO-d6)δ9.78-9.62(m,1H),8.42-8.15(m,1H),7.61-7.55(m,2H),7.51(brs,1H),7.48-7.42(m,2H),7.40-7.32(m,2H),7.10(t,J＝8.4Hz,1H),7.03-6.97(m,2H),4.04-3.90(m,2H),3.82-3.70(m,4H),3.40-3.28(m,1H),3.17-3.09(m,2H),3.08-2.88(m,5H),2.71-2.62(m,1H),2.61-2.52(m,1H).

LC-MS：m/z 525.2[M+H] ⁺。

Example twenty-one: synthesis of Compound 55

2- ((9S) 8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4-morpholinium benzamide hydrochloride

Referring to the synthesis method of compound 41, compound 55 was obtained by performing a one-step reaction using compound 55-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ9.70-9.55(m,1H),8.40-8.25(m,1H),7.78(s,1H),7.64-7.56(m,2H),7.49-7.41(m,3H),7.40-7.33(m,1H),7.18-7.05(m,2H),7.01(d,J＝10.8Hz,1H),4.00-3.90(m,2H),3.72-3.62(m,4H),3.35-3.25(m,1H),3.20-3.10(m,1H),3.05-2.75(m,7H),2.45-2.36(m,1H).

LC-MS：m/z 525.2[M+H] ⁺。

Example twenty two: synthesis of Compound 56

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -4- (1, 1-thiomorpholinyl) -3-fluorobenzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B8 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 56.

¹H NMR(400MHz,DMSO-d6)δ9.70(brs,1H),8.34(brs,1H),7.62-7.52(m, 3H),7.50-7.42(m,2H),7.40-7.33(m,2H),7.25(t,J＝8.4Hz,1H),7.07-6.97(m,2H),4.00-3.90(m,2H),3.63-3.52(m,4H),3.34-3.25(m,5H),3.05-2.85(m,3H),2.75-2.65(m,1H),2.63-2.53(m,1H).

LC-MS：m/z 573.1[M+H] ⁺。

Example twenty-three: synthesis of Compound 57

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -4- (1, 1-thiomorpholinyl) -3-fluorobenzamide hydrochloride

Referring to the synthesis method of compound 41, compound 57-1 was used instead of compound 41-2, and a one-step reaction was performed to obtain compound 57.

¹H NMR(400MHz,DMSO-d6)δ9.57(brs,1H),8.32(brs,1H),7.82(s,1H),7.65-7.55(m,2H),7.50-7.33(m,4H),7.28-7.14(m,2H),7.03(d,J＝10.8Hz,1H),4.00-3.90(m,2H),3.54-3.42(m,4H),3.30-3.10(m,6H),3.30-2.75(m,3H),2.47-2.40(m,1H).

LC-MS：m/z 573.1[M+H] ⁺。

Example twenty-four: synthesis of Compound 58

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- ((tetrahydro-2H-pyran-4-yl) amino) benzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B9 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 58.

¹H NMR(400MHz,DMSO-d6)δ9.76-9.58(m,1H),8.40-8.25(m,1H),7.65-7.55(m,2H),7.50-7.41(m,2H),7.40-7.26(m,3H),6.98(d,J＝10.4Hz,1H),6.90-6.70(m,2H),5.90-5.75(m,1H),4.00-3.80(m,4H),3.64-3.52(m,1H),3.50-3.38(m,3H),3.10-2.85(m,3H),2.72-2.62(m,1H),2.56-2.50(m,1H),1.95-1.75(m,2H),1.65-1.45(m,2H).

LC-MS：m/z 539.2[M+H] ⁺。

Example twenty-five: synthesis of Compound 59

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- ((tetrahydro-2H-pyran-4-yl) amino) benzamide hydrochloride

Referring to the synthesis method of compound 41, compound 59 was obtained by performing a one-step reaction using compound 59-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.50-7.42(m,2H),7.40-7.20(m,5H),6.91(brs,1H),6.80(t,J＝8.4Hz,1H),6.71(d,J＝10.8Hz,1H),5.68-5.60(m,1H),3.89-3.78(m,2H),3.60-3.45(m,5H),3.10-3.00(m,1H),2.98-2.90(m,1H),2.73-2.64(m,1H),2.63-2.55(m,3H),2.35-2.25(m,2H),2.35-2.25(m,1H),1.86-1.72(m,2H), 1.54-1.35(m,2H).

LC-MS：m/z 539.2[M+H] ⁺。

Example twenty-six: synthesis of Compound 60

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- ((S) -2-hydroxypropoxy) benzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B10 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 60.

¹H NMR(400MHz,DMSO-d6)δ9.85-12.70(m,1H),8.43-8.25(m,1H),7.61-7.52(m,3H),7.47-7.41(m,2H),7.40-7.32(m,2H),7.30-7.22(m,1H),7.05-6.97(m,2H),4.06-3.88(m,5H),3.75-3.63(m,0.5H),3.52-3.45(m,0.5H),3.10-2.85(m,3H),2.70(d,J＝16.4Hz,1H),2.60-2.50(m,1H),1.18(d,J＝2.0Hz,3H).

LC-MS：m/z 514.2[M+H] ⁺。

Example twenty-seventh: synthesis of Compound 61

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- ((S) -2-hydroxypropoxy) benzamide hydrochloride

Referring to the synthesis method of compound 41, compound 61 was obtained by performing a one-step reaction using compound 61-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ9.80-9.64(m,1H),8.42-8.27(m,1H),7.80(s,1H),7.64-7.57(m,2H),7.48-7.41(m,3H),7.40-7.33(m,1H),7.30-7.22(m,1H),7.17(brs,1H),7.02(d,J＝10.4Hz,1H),4.00-3.85(m,5H),3.75-3.63(m,0.5H),3.52-3.43(m,0.5H),3.19-3.07(m,1H),3.00-2.75(m,3H),2.44-2.36(m,1H),1.13-1.08(m,3H).

LC-MS：m/z 514.2[M+H] ⁺。

Example twenty-eight: synthesis of Compound 62

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- ((R) -2-hydroxypropoxy) benzamide hydrochloride

Referring to the synthesis of compound 41, a three-step reaction was performed using compound B11 instead of compound B20 and XantPhos instead of NiXantPhos to give compound 62.

¹H NMR(400MHz,DMSO-d6)δ9.64-9.46(m,1H),8.40-8.25(m,1H),7.61-7.52(m,3H),7.48-7.41(m,2H),7.40-7.32(m,2H),7.30-7.22(m,1H),7.05-6.97(m,2H),5.00(brs,1H),4.06-3.88(m,5H),3.75-3.63(m,0.5H),3.52-3.43(m,0.5H),3.10-2.85(m,3H),2.70(d,J＝16.0Hz,1H),2.60-2.50(m,1H),1.18(d,J＝2.0Hz,3H).

LC-MS：m/z 514.2[M+H] ⁺。

Example twenty-nine: synthesis of Compound 63

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- ((R) -2-hydroxypropoxy) benzamide hydrochloride

Referring to the synthesis method of compound 41, compound 63 was obtained by performing a one-step reaction using compound 63-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ9.53-9.40(m,1H),8.41-8.23(m,1H),7.80(s,1H),7.64-7.57(m,2H),7.48-7.41(m,3H),7.40-7.33(m,1H),7.30-7.22(m,1H),7.17(brs,1H),7.02(d,J＝10.4Hz,1H),4.00-3.85(m,5H),3.75-3.63(m,0.5H),3.52-3.43(m,0.5H),3.19-3.07(m,1H),3.00-2.75(m,3H),2.44-2.36(m,1H),1.13-1.08(m,3H).

LC-MS：m/z 514.2[M+H] ⁺。

Example thirty: synthesis of Compound 64

6- ((9R) 8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -7-fluoro-1H-indole-5-carboxamide

Step one and step two: referring to the synthesis of compound 41-2, compound B14 was used instead of compound B20 and XantPhos was used instead of NiXantPhos to perform a two-step reaction to give compound 64-2 and compound 65-1.

Step three: to a one-necked flask, compound 64-2 (12 mg,0.018 mmol), methylene chloride (2 mL) and trifluoroacetic acid (1 mL) were successively added, and the reaction mixture was stirred at 20℃for 2 hours. The reaction solution was concentrated under reduced pressure. To the resulting residue was added saturated sodium bicarbonate solution (6 mL), and extracted 2 times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and lyophilized to give 64 as a white solid (5 mg, yield: 58.1%).

¹H NMR(400MHz,DMSO-d6)δ11.87(s,1H),7.63(s,1H),7.55-7.40(m,4H),7.39-7.30(m,2H),7.26-7.19(m,1H),6.90(brs,1H),6.74(d,J＝10.8Hz,1H),6.63-6.58(m,1H),3.62-3.50(m,1H),3.40-3.31(m,2H),3.15-3.00(m,1H),2.86(d,J＝12.8Hz,1H),2.75-2.65(m,1H),2.60-2.50(m,2H),2.43-2.35(m,1H).

LC-MS：m/z 479.1[M+H] ⁺。

Example thirty-one: synthesis of Compound 65

6- ((9S) 8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -7-fluoro-1H-indole-5-carboxamide

Referring to the synthesis method of compound 64, compound 65-1 was used instead of compound 64-2, and a one-step reaction was performed to obtain compound 65.

¹H NMR(400MHz,DMSO-d6)δ11.77(s,1H),7.68(s,1H),7.61(brs,1H),7.50-7.41(m,3H),7.38-7.30(m,2H),7.26-7.19(m,1H),7.11(brs,1H),6.73(d,J＝10.4Hz,1H),6.63-6.58(m,1H),3.62-3.50(m,1H),3.33-3.29(m,2H),3.13-2.97(m,2H),2.75-2.55(m,3H),2.34-2.25(m,1H).

LC-MS：m/z 479.1[M+H] ⁺。

Example thirty-two: synthesis of Compound 66

2- ((9 R,10 ar) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Step one: in a dry single-necked flask, compound A1-10 (1.50 g,3.35 mmol), acetonitrile (20 mL), and NCS (447 mg,3.35 mmol) were sequentially added. The reaction solution was stirred at 60℃for 1 hour. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give a white solid (1.0 g). The obtained product was separated by SFC to obtain white solid 66-1 (500 mg, yield: 31.1%) and white solid 68-1 (500 mg, yield: 31.1%).

LC-MS：m/z 481.1[M+H] ⁺。

Step two: referring to the synthesis method of compound A1, compound 66-2 was synthesized using compound 66-1 instead of compound A1-11.

Step three to step five: referring to the synthesis of compound 41, compound 66 was obtained by performing a three-step reaction using compound 66-2 instead of compound a 20.

¹H NMR(400MHz,DMSO-d6)δ9.80-9.60(m,1H),8.45-8.25(m,1H),7.61-7.51(m,3H),7.48-7.42(m,2H),7.41-7.33(m,2H),7.30-7.22(m,1H),7.05-6.98(m,2H),5.30-4.70(m,1H),4.20-4.07(m,2H),4.02-3.89(m,2H),3.82-3.73(m,2H),3.33-3.25(m,1H),3.10-2.80(m,3H),2.70(d,J＝16.0Hz,1H),2.59-2.51(m,1H).

LC-MS：m/z 500.1[M+H] ⁺。

Example thirty-three: synthesis of Compound 67

2- ((9 S,10 ar) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Referring to the synthesis of compound 41, compound 67 was obtained by performing a one-step reaction using compound 67-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ9.57-9.43(m,1H),8.41-8.23(m,1H),7.81(s,1H),7.65-7.55(m,2H),7.49-7.41(m,3H),7.40-7.33(m,1H),7.30-7.22(m,1H),7.15(brs,1H),7.02(d,J＝10.4Hz,1H),5.10-4.75(m,1H),4.15-4.03(m,2H),4.00-3.89(m,2H),3.73-3.65(m,2H),3.32-3.25(m,1H),3.20-3.07(m,1H),3.00-2.75(m,3H),2.44-2.36(m,1H).

LC-MS：m/z 500.1[M+H] ⁺。

Example thirty-four: synthesis of Compound 68

2- ((9 R,10 as) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Referring to the synthesis of compound 43, compound 68 was obtained by performing a four-step reaction using compound 68-1 instead of compound A1-11.

¹H NMR(400MHz,DMSO-d6)δ9.72-9.55(m,1H),8.45-8.20(m,1H),7.61-7.52(m,3H),7.48-7.42(m,2H),7.41-7.33(m,2H),7.30-7.22(m,1H),7.05-6.98(m,2H),5.20-4.80(m,1H),4.20-4.07(m,2H),4.02-3.89(m,2H),3.82-3.73(m,2H),3.33-3.25(m,1H),3.10-2.85(m,3H),2.70(d,J＝16.0Hz,1H),2.59-2.51(m,1H).

LC-MS：m/z 500.1[M+H] ⁺。

Example thirty-five: synthesis of Compound 69

2- ((9 S,10 as) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Referring to the synthesis of compound 41, compound 69 was obtained by performing a one-step reaction using compound 69-1 instead of compound 41-2.

¹H NMR(400MHz,DMSO-d6)δ9.58-9.43(m,1H),8.41-8.23(m,1H),7.81(s,1H),7.65-7.55(m,2H),7.49-7.41(m,3H),7.40-7.33(m,1H),7.30-7.22(m,1H),7.15(brs,1H),7.02(d,J＝10.4Hz,1H),5.05-4.80(m,1H),4.15-4.03(m,2H),4.01-3.89(m,2H),3.73-3.65(m,2H),3.32-3.25(m,1H),3.20-3.07(m,1H),3.00-2.75(m,3H),2.44-2.36(m,1H).

LC-MS：m/z 500.1[M+H] ⁺。

Example thirty-six: synthesis of Compound 70

5- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -4-fluoroindole-6-carboxamide formate salt

Referring to the synthesis of compound 43, two steps of reaction were performed to obtain compounds 70-2 and 70-3.

Synthesis of Compound 70: 70-2 (25 mg,0.037mmol,1.0 eq) was dissolved in dichloromethane (1 mL) at 25℃and trifluoroacetic acid (1 mL) was added. After stirring the yellow reaction for 12 hours, LCMS showed product formation. The reaction solution was concentrated under reduced pressure to remove the solvent, and then prepared (0.05% formic acid/MeCN/H ₂ O) to give 70 (16 mg, yield: 82.9%) as a white solid.

¹H NMR(400MHz,DMSO_d6)δ9.08(s,1H),8.52(s,1H),8.16(s,1H),7.86(s,1H),7.57-7.43(m,3H),7.38(t,J＝7.6Hz,2H),7.31-7.10(m,2H),6.80(d,J＝10.8Hz,1H),4.27(s,1H),4.06-4.02(m,2H),3.64-3.60(m,2H),3.50-3.40(m,2H),3.27-3.16(m,2H),3.17-3.07(m,1H),2.86(d,J＝12.8Hz,1H),2.81-2.67(m,1H),2.63-2.59(m,1H).

LC-MS：m/z 481.1[M+H] ⁺。

Example thirty-seven: synthesis of Compound 71

5- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -4-fluoroindole-6-carboxamide formate salt

Referring to the synthesis of example thirty, a one-step reaction was performed using intermediate 70-3 instead of 70-2 to give compound 71 (10 mg, yield: 64.5%).

¹H NMR(400MHz,DMSO_d6)δ9.10(s,1H),8.50(s,1H),8.18(s,1H),7.90(s,1H),7.67(d,J＝21.6Hz,1H),7.53(s,1H),7.44(d,J＝7.6Hz,2H),7.36(t,J＝7.6Hz,2H),7.24(s,1H),6.74(d,J＝10.8Hz,1H),4.21(s,1H),4.05-3.87(m,2H),3.79(d,J＝7.2Hz,1H),3.55(d,J＝12.4Hz,1H),3.15-2.98(m,2H),2.97(s,1H),2.78-2.61(m,2H),2.58(d,J＝8.8Hz,1H),2.35-2.23(m,1H).

LC-MS：m/z 481.1[M+H] ⁺。

Example thirty-eight: synthesis of Compound 72.

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) -N-methylbenzamide formate salt

Step one: referring to step one of the synthesis of compound 43, compound 72-1 was synthesized by substituting intermediate B12 for B2 (yellow solid, 20mg, yield: 74.1%).

Step two: to a 15mL pressure-resistant bottle were added 72-1 (20 mg,0.028mmol,1.0 eq) and a solution of methylamine in ethanol (1 mL). Heating to 100℃and stirring for 24 hours, TLC showed that a new spot had formed, the reaction solution was concentrated under reduced pressure, and the residue was purified using a preparative plate (petroleum ether/ethyl acetate=3/1) to give 72-2 (4 mg, yield: 20%) as a colorless oil.

Step three: 72-2 (4 mg,0.006mmol,1.0 eq) was dissolved in dichloromethane (500 uL), cooled to 70 ℃ below zero using a dry ice acetone bath, and then boron tribromide (18 uL,0.018mmol,3.0 eq) was added. Stirring at low temperature for thirty minutes, LCMS showed product formation. The reaction was quenched by the addition of methanol (1 mL) at low temperature, concentrated under reduced pressure, and the residue was separated by preparative HPLC (formic acid system) to give crude compound 72 (1 mg, yield: 33.3%) as a white solid.

LC-MS：m/z 514.1[M+H]+。

Example thirty-nine: synthesis of Compound 73.

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -N-ethyl-3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Step one: compounds 73-1 (yellow solid, 80 mg) and 73-2 (yellow solid, 80 mg) were synthesized according to the procedure of Synthesis step one of Compound 43.

Step two: 73-1 (80 mg,0.11mmol,1.0 eq) was dissolved in tetrahydrofuran (500 uL), methanol (500 uL) and water (500 uL), followed by addition of lithium hydroxide monohydrate (14 mg,0.33mmol,3.0 eq). The reaction was allowed to react at 25℃for 12 hours, and TLC showed completion. The reaction was extracted with water (10 mL) and methyl tert-butyl ether (5 mL x 3), the aqueous phase was adjusted to acidic (ph=4) with dilute hydrochloric acid (2N), and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and volatiles were removed under reduced pressure to give 73-3 (90 mg, crude) as a yellow solid.

Step three: to a round bottom flask was added dichloromethane (10 mL), 73-3 (33 mg,0.055mmol,1.0 eq), ethylamine hydrochloride (9 mg,0.11mmol,2.0 eq), triethylamine (30 uL,0.22mmol,4.0 eq) and TBTU (35 mg,0.11mmol,2.0 eq) in sequence at 25 ℃. The pale yellow reaction was stirred at this temperature for 1.5 hours, and LCMS detected the formation of product. The volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography (0 to 2.7% gradient of methanol: dichloromethane) to give 73-4 (27 mg, yield: 79.4%) as a white solid.

LC-MS：m/z 528.1[M-Boc+H] ⁺。

Step four: 73-4 (27 mg,0.043mmol,1.0 eq) was dissolved in methanol (1 mL) at 25 degrees Celsius, then hydrochloric acid/dioxane solution (1 mL, 4M) was added and stirred for two hours, LCMS showed complete reaction. The reaction solution was concentrated under reduced pressure to give 73 (21 mg, yield: 87.5%) as a white solid.

¹H NMR(400MHz,DMSO_d6)δ9.52(d,J＝11.2Hz,1H),8.38-8.23(m,2H),7.55-7.50(m,2H),7.39(t,J＝7.6Hz,2H),7.32-7.28(m,2H),7.20(t,J＝8.4Hz,1H),6.96(d,J＝10.4Hz,1H),4.07-3.95(m,2H),3.88(t,J＝13.2Hz,2H),3.63(t,J＝4.8Hz,2H),3.23-2.92(m,5H),2.90-2.76(m,2H),2.73(d,J＝16.0Hz,1H),2.33(d,J＝16.0Hz,1H),0.96(t,J＝7.2Hz,3H).

LC-MS：m/z 528.1[M+H] ⁺。

Example forty: synthesis of Compound 74.

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -N-ethyl-3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Compound 74: the synthesis of reference compound 73 was performed in three steps to give compound 74 (21 mg, yield: 87.5%).

¹H NMR(400MHz,DMSO_d6)δ9.73(d,J＝10.0Hz,1H),8.34(d,J＝10.8Hz,1H),8.07(t,J＝5.6Hz,1H),7.56(d,J＝7.6Hz,2H),7.45(t,J＝7.6Hz,2H),7.37(d,J＝7.2Hz,1H),7.32-7.19(m,2H),7.01(d,J＝10.4Hz,1H),4.14(dtd,J＝15.2,10.0,4.8Hz,2H),3.97(t,J＝13.2Hz,2H),3.77(dd,J＝11.2,6.4Hz,2H),3.37-3.23(m,2H),2.95 (tdd,J＝20.0,15.2,9.2Hz,5H),2.76-2.55(m,2H),0.75(t,J＝7.2Hz,3H).

LC-MS：m/z 528.1[M+H] ⁺。

Example forty-one: synthesis of Compound 75.

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) -N- (2-hydroxyethyl) benzamide hydrochloride

Compound 75: the synthesis of reference compound 73 was performed in two steps to give compound 75 (22 mg, yield: 81.5%).

¹H NMR(400MHz,DMSO_d6)δ9.58(d,J＝10.8Hz,1H),8.4-8.25(m,1H),8.12(t,J＝5.6Hz,1H),7.52(d,J＝7.6Hz,2H),7.43-7.35(m,3H),7.30(t,J＝7.2Hz,1H),7.21(t,J＝8.4Hz,1H),6.96(d,J＝10.4Hz,1H),4.09-3.97(m,2H),3.89(t,J＝13.2Hz,2H),3.63(t,J＝4.8Hz,2H),3.18-3.06(m,6H),2.96(dd,J＝14.4,10.2Hz,1H),2.86(s,2H),2.73(t,J＝12.0Hz,1H),2.33(d,J＝15.6Hz,1H).

LC-MS：m/z 544.1[M+H] ⁺。

Examples forty-two: synthesis of Compound 76.

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) -N- (2-hydroxyethyl) benzamide hydrochloride

Compound 76: the synthesis of reference compound 73 was performed in two steps to give compound 76 (22 mg, yield: 81.5%).

¹H NMR(400MHz,DMSO_d6)δ9.77(s,1H),8.51-8.13(m,1H),8.02(s,1H),7.56(d,J＝7.6Hz,2H),7.45(t,J＝7.6Hz,2H),7.38-7.18(m,3H),7.00(d,J＝10.4Hz,1H),5.03(s,1H),4.57(s,1H),4.13(dd,J＝11.2,5.2Hz,2H),3.96(t,J＝15.2Hz,2H),3.78(s, 2H),3.16-2.92(m,7H),2.76-2.64(m,1H).

LC-MS：m/z 544.1[M+H] ⁺。

Example forty-three: synthesis of Compound 77.

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzohydrazide hydrochloride

Step one: to a 15mL pressure-resistant bottle were added 73-1 (30 mg,0.56mmol,1.0 eq), hydrazine hydrate (1 mL) and ethanol (1 mL). The temperature was raised to 100℃and stirred for 12 hours, TLC showed completion of the reaction and the reaction solution was concentrated under reduced pressure to give 77-1 (30 mg, crude) as a white solid.

Step two: white solid 77 (15 mg, yield: 66.1%) was synthesized according to the procedure of step four of compound 73.

¹H NMR(400MHz,DMSO_d6)δ11.02(s,1H),9.88(s,2H),8.33(d,J＝10.4Hz,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝8.4Hz,1H),7.44(t,J＝7.6Hz,2H),7.39-7.30(m,2H),7.02(d,J＝10.4Hz,1H),4.17(dt,J＝10.4,5.3Hz,2H),3.96(t,J＝14.0Hz,2H),3.78(t,J＝4.8Hz,2H),3.12-2.89(m,4H),2.74(d,J＝16.0Hz,1H),2.52(d,J＝15.6Hz,1H).

LC-MS：m/z 515.1[M+H] ⁺。

Example forty-four: synthesis of Compound 78.

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzoyl hydrazine hydrochloride

Compound 78: the synthesis of reference compound 77 was performed to synthesize white solid 78 (15 mg, yield: 66.1%).

¹H NMR(400MHz,DMSO_d6)δ9.46(s,1H),8.21(s,1H),7.45(d,J＝7.6Hz,2H),7.41-7.27(m,3H),7.23(dd,J＝15.6,7.6Hz,2H),6.72(d,J＝10.8Hz,1H),4.13-3.99(m,3H),3.72-3.67(m,2H),3.55(d,J＝13.6Hz,2H),3.36(d,J＝12.8Hz,2H),3.09-3.00(m,1H),2.95(d,J＝12.8Hz,1H),2.75-2.66(m,1H),2.60(t,J＝11.6Hz,2H),2.33-2.25(m,1H).

LC-MS：m/z 515.1[M+H] ⁺。

Example forty-five: synthesis of Compound 79.

2- ((9R) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzoic acid formate salt

Step one: 73-1 (30 mg,0.56mmol,1.0 eq) was dissolved in methanol (1 mL) and then added to a hydrochloric acid/dioxane (1 mL, 4M) solution and stirred at 25℃for 12 hours, LCMS showed product formation. The reaction solution was concentrated under reduced pressure to give 79-1 (24 mg, crude product) as a yellow solid.

LC-MS：m/z 515.1[M+H] ⁺。

Step two: white solid 79 (15 mg, yield: 50.0%) was synthesized according to the method of the synthesis step two of compound 73.

¹H NMR(400MHz,DMSO_d6)δ8.25(s,1H),7.72(d,J＝8.4Hz,1H),7.46(d,J＝7.6Hz,2H),7.35(t,J＝7.6Hz,2H),7.30-7.19(m,2H),6.74(d,J＝10.8Hz,1H),4.16(s,2H),3.81-3.74(m,2H),3.57(d,J＝13.6Hz,1H),3.41(d,J＝12.8Hz,1H),3.15-3.01(m,2H),2.84(d,J＝12.8Hz,1H),2.69(d,J＝10.4Hz,1H),2.57(d,J＝9.6Hz,1H),2.45-2.33(m,2H).

LCMS：m/z 500.1[M+H] ⁺。

Example forty-six: synthesis of Compound 80.

2- ((9S) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzoic acid formate salt

Compound 80: the synthesis of reference compound 79 was performed to synthesize white solid 80 (12 mg, yield: 52.9%) in two steps.

¹H NMR(400MHz,DMSO_d6)δ8.19(s,1H),7.78(d,J＝8.6Hz,1H),7.46(d,J＝8.0Hz,2H),7.36(t,J＝7.6Hz,2H),7.30-7.16(m,2H),6.75(d,J＝10.8Hz,1H),4.11(dd,J＝9.6,4.8Hz,2H),3.71(t,J＝4.8Hz,2H),3.58(d,J＝13.6Hz,2H),3.41(d,J＝12.8Hz,2H),3.12-3.03(m,2H),2.89(d,J＝13.2Hz,1H),2.76-2.57(m,2H),2.46(s,1H),2.33(d,J＝16.0Hz,1H).

LC-MS：m/z 500.1[M+H] ⁺。

Example forty-seventh: synthesis of Compound 81.

(2R) -2- (8-chloro-7-fluoro-10 a- (3-methoxyphenyl) -1,2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Compound 81: referring to the synthesis of compound 43, three-step reaction was performed to synthesize white solid 81 (45 mg, purity: 80%, yield: 94.7%) using intermediate A2 instead of A1.

¹H NMR(400MHz,DMSO_d6)δ10.35(s,1H),8.39(s,1H),7.56(s,1H),7.45-7.32(m,2H),7.27(s,1H),7.10(s,2H),7.00(d,J＝10.4Hz,2H),6.95-6.85(m,1H),5.07(s,1H),4.14(d,J＝4.8Hz,2H),3.95(d,J＝13.6Hz,2H),3.77(s,4H),3.73-3.62(m,1H),3.53-3.44(m,1H),2.89(s,2H),2.66(s,1H),2.54(d,J＝12.4Hz,1H).

LCMS：m/z 530.1[M+H] ⁺。

Example forty-eight: synthesis of Compound 82.

(2S) -2- (8-chloro-7-fluoro-10 a- (3-methoxyphenyl) -1,2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide

Compound 82: white solid 82 (18 mg, yield: 78.3%) was synthesized according to the synthesis method of compound 81.

¹H NMR(400MHz,DMSO)δ7.78(s,1H),7.48-7.38(m,1H),7.36-7.23(m,3H),7.17-7.10(m,3H),6.99(d,J＝10.4Hz,1H),6.90(dd,J＝8.0,2.0Hz,1H),4.09(dt,J＝10.0,5.2Hz,2H),3.93(d,J＝14.0Hz,2H),3.76(s,3H),3.68(dt,J＝16.0,8.0Hz,2H),3.37(s,2H),3.07(d,J＝13.6Hz,1H),2.96-2.76(m,3H),2.39(d,J＝16.0Hz,1H).

LCMS：m/z 530.1[M+H] ⁺。

Examples forty-nine: synthesis of Compound 83.

(2S) -2- (8-chloro-7-fluoro-10 a- (3-hydroxyphenyl) -1,2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrobromide

Step one: to a 4mL reaction flask was added sequentially anhydrous dichloromethane (1 mL) and 82 (15 mg,0.026mmol,1.0 eq) at 25deg.C, followed by dropwise addition of boron tribromide (20 mg,0.079mmol,3.0 eq) for one hour. LCMS showed product formation, quenched by the addition of methanol (1 mL), filtered, and the filtrate was separated by preparative HPLC (formic acid system) to give 83 (4 mg, yield: 25%) as a white solid.

¹H NMR(400MHz,DMSO_d6)δ9.30(s,1H),8.19(s,1H),7.58(s,1H),7.40(d,J＝8.4Hz,1H),7.32-7.08(m,3H),6.88-6.78(m,2H),6.72(d,J＝10.8Hz,1H),6.62(dd,J＝8.0,2.0Hz,1H),4.89(s,1H),4.16-4.00(m,2H),3.70(t,J＝4.8Hz,2H),3.54(d,J＝13.6Hz,2H),3.11-3.02(m,2H),2.92(d,J＝13.2Hz,1H),2.61(d,J＝16.0Hz,3H),2.30(s,1H).

LCMS：m/z 516.1[M+H] ⁺。

Example fifty: synthesis of Compound 84

(4R) - (8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -5-fluoro-6- (2-hydroxyethoxy) nicotinamide formate salt

Compound 84: referring to the synthesis of compound 43, three-step reaction was performed to synthesize white solid 84 (2 mg, yield: 52.9%) using intermediate B15 instead of B2.

¹H NMR(400MHz,Methanol-d4)δ8.46(s,1H),8.29(s,1H),7.63-7.56(m,2H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),6.77(d,J＝10.2Hz,1H),4.57-4.44(m,2H),3.94-3.74(m,4H),3.46-3.35(m,2H),3.09(d,J＝12.7Hz,1H),2.91(d,J＝13.3Hz,1H),2.78(d,J＝16.0Hz,1H),2.61(dd,J＝16.0,2.0Hz,1H).

LCMS：m/z 501.1[M+H] ⁺。

Example fifty-one: synthesis of Compound 85

(4S) - (8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazine [1,2-a ] indol-9-yl) -5-fluoro-6- (2-hydroxyethoxy) nicotinamide formate salt

Compound 85: white solid 85 (2 mg, yield: 52.9%) was synthesized according to the method of compound 84.

¹H NMR(400MHz,Methanol-d4)δ8.43(s,1H),8.25(s,1H),7.63-7.56(m,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),6.77(d,J＝10.2Hz,1H),4.59-4.53(m,2H),3.97-3.91(m,2H),3.83(t,J＝14.1Hz,2H),3.51-3.39(m,1H),3.21(d,J＝13.5Hz,1H),3.11-3.05(m,1H),2.91(d,J＝12.9Hz,1H),2.81-2.66(m,2H).

LCMS：m/z 501.1[M+H] ⁺。

Example fifty two: synthesis of Compound 86

(2R) -2- (8-chloro-10 a- (3-chlorophenyl) -7-fluoro-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Compound 86: referring to the synthesis of compound 43, three-step reaction was performed to synthesize white solid 86 (11 mg, purity: 80%, yield: 77.2%) using intermediate A4 instead of A1.

¹H NMR(400MHz,DMSO_d6)δ10.16(d,J＝9.2Hz,1H),8.51(d,J＝9.6Hz,1H),7.61(s,1H),7.54(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.39(dd,J＝15.6,7.3Hz,2H),7.27(t,J＝8.4Hz,1H),7.01(d,J＝10.4Hz,2H),4.12(dt,J＝10.0,4.8Hz,2H),3.96(d,J＝14.0Hz,2H),3.71-3.63(m,2H),3.54-3.42(m,1H),3.34-3.23(m,1H),2.97-2.88(m,3H),2.76-2.72(m,1H).

LCMS：m/z 534.1[M+H] ⁺。

Example fifty-three: synthesis of Compound 87

(2S) -2- (8-chloro-10 a- (3-chlorophenyl) -7-fluoro-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide

Compound 87: reference to the synthetic method of Compound 86, white solid 87 (8 mg, yield: 70.2%) was synthesized from Compound 86-3.

¹H NMR(400MHz,DMSO_d6)δ9.45(s,1H),8.41(s,1H),7.79(s,1H),7.66(s,1H),7.58(d,J＝7.6Hz,1H),7.50-7.39(m,2H),7.28(d,J＝8.4Hz,1H),7.13(s,1H),7.02(d,J＝10.4Hz,1H),4.09(d,J＝6.4Hz,2H),3.96(s,2H),3.70(t,J＝4.8Hz,2H),3.46(dd,J＝14.4,8.0Hz,2H),3.18-3.08(m,1H),2.97(d,J＝11.6Hz,1H),2.85(d,J＝16.0Hz,1H),2.45(s,1H).

LCMS：m/z 534.1[M+H] ⁺。

Example fifty-four: synthesis of Compound 88

(2R) -2- (8-chloro-7-fluoro-10 a- (3-fluorophenyl) -1,2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Compound 88: referring to the synthesis of compound 43, three-step reaction was performed to synthesize white solid 88 (24 mg, yield: 90.6%) using intermediate A3 instead of A1.

¹H NMR(400MHz,DMSO_d6)δ10.09(s,1H),8.47(s,1H),7.55(s,1H),7.52-7.44(m,1H),7.44-7.34(m,2H),7.30-7.24(m,1H),7.17(t,J＝8.4Hz,1H),7.00(d,J＝10.4Hz,1H),5.03(s,1H),4.12(dt,J＝10.8,5.6Hz,2H),3.95(d,J＝13.6Hz,2H),3.76(s,2H),2.90(d,J＝10.8Hz,3H),2.75-2.49(m,3H).

LCMS：m/z 518.1[M+H] ⁺。

Example fifty-five: synthesis of Compound 89

(2S) -2- (8-chloro-7-fluoro-10 a- (3-fluorophenyl) -1,2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (2-hydroxyethoxy) benzamide hydrochloride

Compound 89: a white solid 89 (18 mg, yield: 79.3%) was synthesized according to the method of compound 88.

¹H NMR(400MHz,DMSO)δ9.52(s,1H),8.32(s,1H),7.72(s,1H),7.39(dd,J＝7.6,4.8Hz,4H),7.20(s,3H),6.95(d,J＝10.4Hz,1H),4.02(d,J＝6.0Hz,2H),3.95-3.82(m,2H),3.63(t,J＝4.8Hz,3H),3.45-3.35(m,1H),3.12-3.02(m,1H),2.90(d,J＝12.8Hz,1H),2.77(d,J＝15.9Hz,1H),2.37(d,J＝15.6Hz,1H).

LCMS：m/z 518.1[M+H] ⁺。

Example fifty-six: synthesis of Compound 90

2- ((9 R,10 as) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (methylamino) benzamide

Step one: to the reaction flask were successively added compound A1 (25 mg,0.047 mmol), compound B16 (11 mg,0.047 mmol), potassium phosphate (60 mg,0.284 mmol), 1, 4-dioxane (1 mL), toluene (1 mL), water (0.4 mL), ruPhos-Pd-G3 (4 mg,0.005 mmol) and RuPhos (2 mg,0.005 mmol), and the reaction was stirred under nitrogen at 100℃for 6 hours. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=4:1) to give 90-1 (26 mg, yield: 96.1%) as a yellow solid.

LCMS：m/z 551.2[M+H] ⁺。

Step two: referring to the synthesis method of the compound 41-2, the compound 90-1 is used to replace the compound 41-1, and the compound 90-2 and the compound 91-1 are obtained through a one-step reaction.

LCMS：m/z 569.2[M+H] ⁺。

Step three: referring to the synthesis method of compound 41, compound 90 was obtained by performing a one-step reaction using compound 90-2 instead of compound 41-2.

¹H NMR(400MHz,Methanol-d4)δ7.53-7.50(m,2H),7.38-7.34(m,3H),7.30-7.26(m,1H),6.72-6.67(m,2H),3.94-3.81(m,2H),3.41-3.34(m,2H),3.17-3.07(m,1H),2.92-2.87(m,1H),2.82(s,3H),2.66-2.60(m,2H).

LC-MS：m/z 469.1[M+H] ⁺。

Example fifty-seven: synthesis of Compound 91

2- ((9 S,10 as) -8-chloro-7-fluoro-10 a-phenyl-1, 2,3,4, 10, 10 a-hexahydropyrazino [1,2-a ] indol-9-yl) -3-fluoro-4- (methylamino) benzamide

Referring to the synthesis method of compound 41, compound 91 was obtained by performing a one-step reaction using compound 91-1 instead of compound 41-2.

¹H NMR(400MHz,Methanol-d4)δ7.53-7.52(m,2H),7.41-7.37(m,3H),7.31-7.27(m,1H),6.73-6.67(m,2H),3.84-3.79(m,2H),3.43-3.36(m,2H),3.13-3.08(m,1H),2.94-2.91(m,1H),2.75(s,3H),2.72-2.68(m,1H)2.55-2.50(m,1H).

LC-MS：m/z 469.1[M+H] ⁺。

Test case one: YAP-TEAD protein interaction HTRF experiments

1. His-TEAD1 protein was added to 384-well assay plates to a final concentration of 10nM, using buffer as background signal well. And 3 times of dilution is carried out on the compound to be tested, and 10 concentration gradients are arranged for uniform mixing. A volume of test compound was added to each well, 2 replicates were set for each concentration, and the final DMSO concentration was controlled at 1%. Incubate for 20 minutes at room temperature. The amino acid sequence of TAED1 (209-426) used in this step is SEQ ID NO:1 is shown as follows:

2. The Bio-YAP peptide was added to each well to a final concentration of 50nM, mixed well and incubated for 10 min at room temperature. The amino acid sequence of the YAP peptide (60-100) part of the Bio-YAP peptide used in this step is shown in SEQ ID NO:2 is shown as follows:

3. Anti-His-Eucryptate gold and streptavidin-XL 665 were diluted according to instructions and mixed in equal proportions. A volume of detection reagent was added to the wells and incubated for 1 hour at room temperature.

4. Signals were detected using a Envision (Perkin Elmer) microplate reader at 320nM excitation and 665nM and 620nM emissions.

5. The signal is calculated by the ratio Em665/Em620 x 10000. Percent (%) inhibition was calculated by the following formula:

Inhibition% = (1- (cpd _{Signal signal} -background _{Signal signal})/(DMSO _{Signal signal} -background _{Signal signal})) = (100)

The semi-inhibitory concentration IC ₅₀ was calculated using GRAPHPAD PRISM software.

The ICs ₅₀ of each compound that block YAP-TEAD protein interactions are shown in table one, where letter a represents IC ₅₀ of less than 0.5uM; letter B represents IC ₅₀ from 0.5uM to 5uM; letter C represents IC ₅₀ to 50uM and letter D represents IC50 greater than 50uM.

List one

Numbering of compounds	Activity (uM)	Numbering of compounds	Activity (uM)
Compound 1	C	Compound 47	B
Compound 2	C	Compound 48	C
Compound 3	C	Compound 49	A
Compound 4	C	Compound 50	C
Compound 5	C	Compound 51	A
Compound 6	C	Compound 52	C
Compound 7	C	Compound 53	A
Compound 8	C	Compound 54	C
Compound 9	C	Compound 55	C

Compound 10	C	Compound 56	C
Compound 11	C	Compound 57	C
Compound 12	C	Compound 58	C
Compound 13	C	Compound 59	C
Compound 14	C	Compound 60	C
Compound 15	C	Compound 61	A
Compound 16	C	Compound 62	C
Compound 17	C	Compound 63	B
Compound 18	C	Compound 64	C
Compound 19	C	Compound 65	B
Compound 20	C	Compound 66	C
Compound 21	C	Compound 67	A
Compound 22	C	Compound 68	C
Compound 23	C	Compound 69	A
Compound 24	C	Compound 70	B
Compound 25	C	Compound 71	B
Compound 26	C	Compound 72	A
Compound 27	C	Compound 73	A
Compound 28	C	Compound 74	B
Compound 29	C	Compound 75	A
Compound 30	C	Compound 76	B
Compound 31	B	Compound 77	C
Compound 32	B	Compound 78	A
Compound 33	B	Compound 79	C
Compound 34	C	Compound 80	C
Compound 35	C	Compound 81	B
Compound 36	B	Compound 82	B
Compound 37	B	Compound 83	A
Compound 38	B	Compound 84	B
Compound 39	B	Compound 85	A

Compound 40	C	Compound 86	B
Compound 41	C	Compound 87	B
Compound 42	A	Compound 88	B
Compound 43	C	Compound 89	A
Compound 44	A	Compound 90	C
Compound 45	C	Compound 91	A
Compound 46	A

Test case two: YAP/TEAD reporter inhibition experiments

This example detects inhibition of the target by compounds by signals containing the reporter gene in the YAP/TEAD reporter stable cell line SF 268-YAP-Luc.

The sequence comprising 6 tandem YAP/TEAD binding sites and a basic transcription promoter was constructed on the Promega company vector pGL 4.76. The constructed reporter gene vector was transfected into SF268 cells (NCI DCTD tumor/cell line repository) and screened with 0.5. Mu.g/ml hygromycin to obtain SF268-YAP-Luc stable strain.

SF268-YAP-Luc cells were seeded in 96-well plates, and cells were seeded at a cell density of 3000 cells per well into 96-well plates in a volume of 100. Mu.L per well (cell culture medium composition ：RPMI1640(Gibco-A10491-01)+10％FBS(Gibco-10099-141C)+1％Penicillin-Streptomycin(5,000U/mL,Gibco-15070-063)), was placed in a 5% carbon dioxide incubator at 37℃overnight.

The next day, the compound to be tested is diluted 3 times, and 8 concentration gradients are set; a volume of DMSO (control) or test compound (treatment) was added to each well, 2 replicates were set for each concentration, and the final DMSO concentration was controlled to no higher than 0.5%. Culturing in a 5% carbon dioxide incubator at 37 ℃ for 24 hours. Cell seeding and compound treatment were performed on two identical parallel plates.

Control and treatment group reporter gene signals were detected using Renila-Glo Luciferase ASSAY SYSTEM kit (Promega, E2720). 70ul Renila-Glo was added to each well, mixed well and incubated at room temperature for 10 minutes. UsingMultilabel PLATE READER (PERKIN ELMER) reads the signal.

Cell viability was measured in control and treatment groups using CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7570). 50ul CellTiter-Glo was added to each well, mixed well and incubated for 10 minutes at room temperature. UsingMultilabel PLATE READER (PERKIN ELMER) reads the signal.

Analyzing the signal of Renila luciferase corrected for cell viability, calculating the inhibition rate of the compound to the reporter gene, the inhibition percentage (%) being calculated by the following formula:

inhibition% = (1- (compound treated well Renila signal/DMSO treated well Renila signal)/(compound treated well CTG signal/DMSO treated well CTG signal)) × 100

IC ₅₀ values for the inhibitory activity of the compounds on Renila luciferase signals were calculated using GRAPHPAD PRISM software.

Compound blocking YAP reporter gene expression IC ₅₀ is shown in table two, where letter a represents IC ₅₀ less than 0.5uM; letter B represents IC ₅₀ from 0.5uM to 5uM; letter C represents IC ₅₀ greater than 5uM.

Watch II

Test case three: cell proliferation inhibition assay

In this example, intracellular ATP was quantitatively determined by using CellTiter-Glo luminescence cell viability assay kit to determine the number of viable cells in culture.

The first step: MSTO-211H (ATCC, CRL-2081 ^TM) or NCI-H2052 (ATCC, CRL-5915 ^TM) cells were seeded in 96-well plates, the cells were seeded at a cell density of 1500 cells per well into 96-well plates, the volume per well was 100. Mu.L, and incubated overnight at 37℃in a 5% carbon dioxide incubator. The culture medium is as follows: RPMI1640 medium (GIBCO-A10491-01) +10% FBS (GIBCO-10099141C) +1% pen/Strep (GIBCO-15070-063).

And a second step of: the compound treats the cells. 3 times dilution is carried out on the compound to be tested, and 9 concentration gradients are arranged in total; a volume of DMSO (control) or test compound (treatment) was added to each well, 2 replicates were set for each concentration, and the final DMSO concentration was controlled to no higher than 0.5%. The cells were incubated at 37℃in a 5% carbon dioxide incubator for 96 hours.

And a third step of: cell viability was measured in control and treatment groups using CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7570). 50ul CellTiter-Glo was added to each well, mixed well and incubated for 10 minutes at room temperature. UsingMultilabel PLATE READER (PERKIN ELMER) reads the signal.

Percent (%) inhibition was calculated by the following formula:

Inhibition% = (1-compound treated wells CTG signal/DMSO treated wells CTG signal) ×100

IC ₅₀ values for compounds that inhibited cell proliferation activity CTG signaling were calculated using GRAPHPAD PRISM software.

Compound-on-cell proliferation inhibitory activity IC ₅₀ is shown in table three, wherein letter a represents IC ₅₀ of less than 1uM; letter B represents IC ₅₀ from 1uM to 5uM; letter C represents IC ₅₀ greater than 5uM.

Watch III

Claims

A compound of formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof:

Wherein:

A ₁ is selected from N or CR _a;

A ₂ is selected from NH, O, or CR _bR _c;

a ₃ is selected from N or CR ₃;

a ₄ is selected from N or CR ₄;

A ₅ is selected from N or CR ₅;

R ₁ is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

r ₂ is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R ₃、R ₄ and R ₅ are each independently selected from H, hydroxy, halo, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy;

r _a is selected from H, hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; and

R _b and R _c are each independently selected from: H. hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy;

Wherein ring A is a 5-8 membered carbocyclyl, 4-8 membered heterocyclyl or 5-or 6 membered heteroaryl, optionally substituted with 1-3 substituents selected from hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 1,

Ring A is a 5-8 membered saturated carbocycle or a 4-8 membered heterocyclyl; preferably, ring A is a 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N, preferably A ₁ is N; and/or

A ₂ is CR _bR _c wherein R _b and R _c are each independently H and C _1-4 alkyl, more preferably both H; and/or

A ₃ is CR ₃,R ₃ is H, halogen, C _1-4 alkoxy, cyano and substituted or unsubstituted C _1-4 alkyl, more preferably H, C _1-4 alkyl or halogen; and/or

A ₄ is CR ₄,R ₄ is H, halogen, C _1-4 alkoxy, cyano and substituted or unsubstituted C _1-4 alkyl, more preferably H, halogen or C _1-4 alkoxy; and/or

A ₅ is CR ₅,R ₅ is H, halogen, C _1-4 alkoxy, cyano and substituted or unsubstituted C _1-4 alkyl, more preferably H; and/or

R ₁ is substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted 6-14 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, or substituted or unsubstituted 4-9 membered heterocyclyl; wherein, when a group having a substituent, the substituent on R ₁ is 1 to 3 substituents selected from halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy and-NR ₁₂R ₁₃, wherein R ₁₂ and R ₁₃ are each independently H or C _1-4 alkyl; and/or

R ₂ is H, halogen, C _1-4 alkyl, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted 6-14 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, or substituted or unsubstituted 4-9 membered heterocyclyl; wherein, when a group having a substituent is used, the substituent on R ₂ is 1 to 3 substituents selected from cyano, hydroxy, carboxyl, halogen, NR 'R' -C (O) - (CH ₂) _n -, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heterocyclyl and substituted or unsubstituted amino, wherein R 'and R' are each independently selected from H, amino and substituted or unsubstituted alkyl, and n is an integer of 0 to 4.
A compound according to claim 1 or claim 2, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug or metabolite thereof, wherein when R ₃、R ₄、R ₅、R _a、R _b、R _c and the alkyl and alkoxy groups in the definition of ring a are substituted, each of their substituents is independently 1 to 3 substituents selected from halogen, hydroxy, carboxy and amino optionally substituted by 1 or 2C _1-4 alkyl groups; and R ₃、R ₄、R ₅、R _a、R _b、R _c and the amino group in the definition of ring a are each independently amino groups optionally substituted with 1 or 2C _1-4 alkyl groups.
The compound of claim 1, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof, wherein the compound of formula I has a structure represented by formula II:

In the method, in the process of the invention,

R ₁ is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted cycloalkyl;

R ₂ is selected from H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted cycloalkyl;

R ₃、R ₄ and R ₅ are each independently selected from H, hydroxy, halo, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; and

R ₁₁ is H or substituted or unsubstituted alkyl.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 4,

R ₁ is a substituted or unsubstituted 6-14 membered aryl or a substituted or unsubstituted 5-12 membered heteroaryl; wherein, when R ₁ is a group with substituent, the substituent is 1-3 substituents selected from halogen, hydroxy, alkyl, alkoxy and-NR ₁₂R ₁₃, wherein, R ₁₂ and R ₁₃ are each independently H or C _1-4 alkyl; and/or

R ₂ is a substituted or unsubstituted 6-14 membered aryl, a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl, a substituted or unsubstituted 4-9 membered nitrogen and/or oxygen containing heterocyclyl, or a substituted or unsubstituted C _3-8 cycloalkyl; wherein R ₂ is a substituent group, the substituent groups are 1-3 substituents selected from cyano, hydroxy, carboxy, halogen, NR 'R' -C (O) - (CH ₂) _n -, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted heterocyclyl and substituted or unsubstituted amino, wherein R 'and R' are each independently selected from H, amino and substituted or unsubstituted C _1-4 alkyl, n is an integer from 0 to 4, and/or

R ₃ is H, halogen, C _1-4 alkoxy or C _1-4 alkyl; and/or

R ₄ is H, halogen, C _1-4 alkoxy or C _1-4 alkyl; and/or

R ₅ is H, halogen, C _1-4 alkoxy or C _1-4 alkyl; and/or

R ₁₁ is H or C _1-4 alkyl optionally substituted with 1-3 substituents selected from halogen and hydroxy.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 4,

R ₁ is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl, preferably a 5-12 membered nitrogen containing heteroaryl selected from: pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl and pyridazinyl; wherein, when R ₁ is a group having a substituent, the number of the substituent is 1 to 3, selected from the group consisting of hydroxyl, halogen, C _1-4 alkyl and C _1-4 alkoxy; preferably, R ₁ is unsubstituted phenyl;

R ₂ is a 4-9 membered heterocyclyl, preferably a 4-9 membered heterocyclyl containing N and/or O, preferably selected from: azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl and piperazinyl; wherein the heterocyclyl is optionally substituted with 1 to 3 substituents selected from halogen, C _1-4 alkyl, haloc _1-4 alkyl, C _1-4 alkoxy, haloc 1 _- alkoxy, carboxy and NR ' R "-C (O) - (CH ₂) _n", wherein R ' and R "are each independently selected from H and C _1-4 alkyl, n is an integer from 0 to 4, the preferred substituent is carboxy or NR ' R" -C (O) - (CH ₂) _n ", and preferably the substituent is in the ortho position, and/or when the heterocyclyl is a nitrogen-containing heterocyclyl, the ring nitrogen atom through the heterocyclyl is attached to the remainder of the compound of formula II;

R ₃ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H and halogen;

R ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen;

R ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H;

Preferably, R ₃ and R ₄ are each independently halogen, R ₅ is H;

R ₁₁ is H or C _1-6 alkyl optionally substituted with 1 to 3 substituents selected from halogen and hydroxy, preferably H.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 4,

R ₁ is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl; preferably, the heteroaryl is selected from: pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl and pyridazinyl; wherein, when R ₁ is a group having a substituent, the number of the substituent is 1 to 3, selected from the group consisting of hydroxyl, halogen, C _1-4 alkyl and C _1-4 alkoxy; preferred R ₁ is unsubstituted phenyl;

R ₂ is a 5-12 membered heteroaryl, preferably an N-containing 5-12 membered heteroaryl, preferably selected from: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl; wherein the heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, C _1-4 alkyl, haloc _1-4 alkyl, C _1-4 alkoxy, haloc _1-4 alkoxy, carboxy and NR ' R "-C (O) - (CH ₂) _n", wherein R ' and R "are each independently selected from H and C _1-4 alkyl, n is an integer from 0 to 4, the preferred substituents are halogen, C _1-4 alkyl or NR ' R" -C (O) - (CH ₂) _n ", and preferably the substituents are in the ortho position and/or are attached to the rest of the compound of formula II through the ring nitrogen atom of the heterocyclyl when the heterocyclyl is a nitrogen-containing heterocyclyl;

R ₃ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H and halogen;

R ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen;

R ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H;

Preferably, R ₃ and R ₄ are each independently halogen, R ₅ is H;

R ₁₁ is H or C _1-6 alkyl optionally substituted with 1 to 3 substituents selected from halogen and hydroxy, preferably H.
The compound of claim 1, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof, wherein the compound of formula I has a structure represented by formula III:

Wherein:

R ₁、R ₃-R ₅ is as defined in claim 1;

B ₁ is C or N;

B ₂ is CR ₆ or N;

B ₃ is CR ₇ or N;

b ₄ is CR ₈ or N;

B ₅ is CR ₉ or N;

B ₆ is CR ₁₀ or N;

R ₆ is selected from H, halogen, C _1-4 alkyl, C _1-4 alkoxy, cyano, carboxyl, NR ₁₂R ₁₃, and NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H, amino, and substituted or unsubstituted C _1-4 alkyl, and n is an integer from 0 to 4;

R ₇ is H, halogen, NR ₁₂R ₁₃、C _1-4 alkoxy or C _1-4 alkyl;

R ₈ is H, halogen or C _1-4 alkyl;

R ₉ is H, halogen, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted amino; or R ₇ and R ₈, or R ₈ and R ₉ together with the C to which they are each attached form a5 membered nitrogen containing saturated or unsaturated heterocyclic ring, such as pyrrolyl or pyrrolidinyl;

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

R ₁₁ is H or substituted or unsubstituted C _1-4 alkyl;

R ₁₂ and R ₁₃ are each independently H, C _1-4 acyl or substituted or unsubstituted C _1-4 alkyl.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 8,

B ₁ is CH; and/or

B ₂ is CR ₆; and/or

B ₃ is CR ₇; and/or

B ₄ is CR ₈; and/or

B ₅ is CR ₉; and/or

B ₆ is CR ₁₀; and/or

R ₆ is H, halogen, C _1-4 alkyl, C _1-4 alkoxy, cyano, NR ₁₂R ₁₃ or NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H, amino and substituted or unsubstituted C _1-4 alkyl, n is an integer from 0 to 4, and/or

R ₇ is H or NR ₁₂R ₁₃;

R ₈ is H; and/or

R ₉ is substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _1-4 alkoxy, 4-9 membered heterocyclyl, or substituted or unsubstituted amino; and/or

R ₁₀ is halogen; and/or

R ₁₁ is H or C _1-4 alkyl optionally substituted with 1-3 groups selected from hydroxy and halogen;

wherein R ₁₂ and R ₁₃ are each independently H, C _1-4 acyl or substituted or unsubstituted C _1-4 alkyl.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 8,

B ₁ is CH; b ₂ is CR ₆;B ₃, CR ₇;B ₄, CR ₈;B ₅, CR ₉;B ₆, CR ₁₀;

R ₆ is NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H, amino and C _1-4 alkyl optionally substituted with 1-2 substituents selected from hydroxy and halogen, n is an integer from 0-4;

R ₇ and R ₈ are H;

R ₉ is H, halogen, C _1-4 alkyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, carboxy and amino, or C _1-4 alkoxy which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halogenated C _1-4 alkyl, or unsubstituted 4-9 membered heterocyclyl, or amino substituted by 1 or 2C _1-4 alkyl;

R ₁₀ is H or halogen;

R ₁₁ is H.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 8,

B ₁ is CH; b ₂ is CR ₆;B ₃ is N or CR ₇;B ₄ is N or CR ₈;B ₅ is N or CR ₉;B ₆ is CR ₁₀;

R ₆ is NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H, amino and C _1-4 alkyl optionally substituted with 1-2 substituents selected from hydroxy and halogen, n is an integer from 0-4;

R ₇ and R ₈ are H;

R ₉ is H, halogen, C _1-4 alkyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, carboxy and amino, or C _1-4 alkoxy which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, carboxy, amino and halogenated C _1-4 alkyl, or unsubstituted 4-9 membered heterocyclyl, or amino substituted by 1 or 2C _1-4 alkyl;

R ₁₀ is halogen;

R ₁₁ is H.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug or metabolite thereof of claim 10 or 11,

R ₁ is a substituted or unsubstituted phenyl, preferably when the phenyl is substituted, the number of substituents is 1,2 or 3, selected from hydroxy, halogen, C _1-4 alkyl and C _1-4 alkoxy;

R ₃ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen and C _1-4 alkyl;

R ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen;

R ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H;

Preferably, R ₃ and R ₄ are each independently halogen and R ₅ is H.
The compound of claim 1, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof, wherein the compound of formula I has a structure represented by formula IV:

Wherein:

R ₁、R ₃-R ₅ is as defined in claim 1; r ₁₁ is as defined in claim 4;

each m is independently 1,2 or 3;

X is CH ₂, O or NH;

r _d is H, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, carboxyl or NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H and C _1-4 alkyl, n is an integer from 0 to 4, and the number of R _d may be 1,2 or 3.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 13,

R _d is located ortho to the nitrogen atom to which the heterocyclyl is attached to the remainder of formula IV; and/or

R _d is H, carboxyl or NR 'R' -C (O) - (CH ₂) _n -; and/or

The heterocyclic group containing X is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
The compound, pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite thereof of claim 13,

R ₁ is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen containing heteroaryl; wherein the heteroaryl is selected from: pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl and pyridazinyl; wherein when R ₁ is a group having substituents, the number of substituents is 1-3, selected from the group consisting of hydroxy, halogen, C _1-4 alkyl and C _1-4 alkoxy, preferably R ₁ is unsubstituted phenyl;

R ₃ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H and halogen;

R ₄ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably halogen;

R ₅ is H, halogen, C _1-4 alkoxy and C _1-4 alkyl, preferably H;

Preferably, R ₃ and R ₄ are each independently halogen, R ₅ is H;

R ₁₁ is H or C _1-6 alkyl optionally substituted with 1-3 substituents selected from halogen and hydroxy, preferably H;

X is CH ₂, O or NH;

r _d is H, carboxyl or NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H and C _1-4 alkyl, and n is an integer from 0to 4.
The compound of claim 1, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof, wherein the compound of formula I has a structure represented by formula V or VI:

In the method, in the process of the invention,

R ₁、R ₃-R ₅ is as defined in claim 1;

B ₁ is C or N;

B ₃ is CR ₇ or N;

b ₄ is CR ₈ or N;

B ₅ is CR ₉ or N;

R ₆ is selected from H, halogen, alkyl, carboxyl, NR ₁₂R ₁₃, and NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H, amino, and substituted or unsubstituted alkyl, n is an integer from 0 to 4;

R ₇ is H, halogen or C _1-4 alkyl;

R ₈ is H, halogen or C _1-4 alkyl;

R ₉ is H, halogen, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted amino; or R ₇ and R ₈, or R ₈ and R ₉ together with the C to which they are each attached form a5 membered nitrogen containing saturated or unsaturated heterocyclic ring, such as pyrrolyl or pyrrolidinyl;

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

R ₁₁ is H or substituted or unsubstituted C _1-4 alkyl;

R ₁₂ and R ₁₃ are each independently H, C _1-4 acyl or substituted or unsubstituted C _1-4 alkyl;

Wherein R ₆ and R ₁₀ are not simultaneously H.
The compound of claim 1, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof, wherein the compound of formula I has a structure represented by formula VII or VIII:

In the method, in the process of the invention,

R ₁、R ₃-R ₅ is as defined in claim 1;

R ₆ is selected from H, halogen, alkyl, carboxyl, NR ₁₂R ₁₃, and NR 'R' -C (O) - (CH ₂) _n -, wherein R 'and R' are each independently selected from H, amino, and substituted or unsubstituted alkyl, n is an integer from 0 to 4;

R ₇ is H, halogen or C _1-4 alkyl;

R ₈ is H, halogen or C _1-4 alkyl;

R ₉ is H, halogen, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted amino; or R ₇ and R ₈, or R ₈ and R ₉ together with the C to which they are each attached form a5 membered nitrogen containing saturated or unsaturated heterocyclic ring, such as pyrrolyl or pyrrolidinyl;

r ₁₀ is H, halogen, alkyl or halogenated C _1-4 alkyl;

R ₁₁ is H or substituted or unsubstituted C _1-4 alkyl;

R ₁₂ and R ₁₃ are each independently H, C _1-4 acyl or substituted or unsubstituted C _1-4 alkyl;

Wherein R ₆ and R ₁₀ are not simultaneously H.
The compound of claim 1, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof, wherein the compound of formula I is selected from the group consisting of:
A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, and a pharmaceutically acceptable carrier or excipient.
Use of a compound of any one of claims 1-18, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug, or metabolite thereof, in the manufacture of a medicament for treating or preventing a disease mediated by YAP/TAZ interaction with TEAD; preferably, the disease mediated by YAP/TAZ interaction with TEAD is cancer; more preferably, the YAP/TAZ interaction with TEAD mediated disease is selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, prostate cancer, mesothelioma, pancreatic cancer, melanoma, colon cancer, thyroid cancer and skin cancer.