Tricyclic compounds, their preparation, pharmaceutical compositions and uses

Abstract

The present application provides a tri-cyclic compound represented by the following formula I, preparation, pharmaceutical composition and application. The compound provided by the present application can be used as an inhibitor of YAP / TAZ and TEAD interaction, for treating or preventing diseases mediated by YAP / TAZ and TEAD interaction.

Description

Technical Field

[0001] This invention relates to tricyclic compounds, their preparation, pharmaceutical compositions, and applications. Background Technology

[0002] The Hippo pathway is involved in regulating cell growth, proliferation, and apoptosis, playing a crucial role in controlling organ size, cancer development, tissue regeneration, and the renewal and differentiation of stem cells and progenitor cells. Studies have found that this pathway has tumor-suppressive effects in mammals, and aberrant activation of key effector molecules within the pathway is closely related to the development and progression of various tumors. Furthermore, the Hippo pathway interacts with other pathways such as Wnt, Notch, Hedgehog, and MAPK / ERK to jointly regulate cell fate. Dysregulation of this pathway also has significant implications for diseases beyond cancer.

[0003] The Hippo signaling pathway is highly conserved throughout evolution. The core of the Hippo signaling pathway in mammalian cells consists of a kinase chain composed of MST1 / 2 (a member of Ste20-like kinase, homologous to Hippo in Drosophila) and LATS1 / 2 (large tumor suppressor 1 / 2, homologous to Warts in Drosophila), along with their adaptor proteins SAV1 and Mob1 (Mps one binder kinase activator-like 1A and 1B, homologous to Mats in Drosophila). This kinase chain can phosphorylate the transcriptional coactivators YAP (Yes-Associated Protein) and TAZ (Transcription co-activator with PDZ binding motif, also known as WWTR1) (corresponding to Yorkie in Drosophila).

[0004] The core components of the mammalian Hippo pathway, LATS1 / 2, belong to the Dbf2-realized (NDR) family of kinases. They are activated by binding to the cytoskeletal proteins Mob1A / B. LATS1 / 2 can also be directly activated by phosphorylation of MST1 / 2. LATS1 / 2 kinases can phosphorylate multiple sites on the downstream effector YAP, with Ser127 phosphorylation playing a crucial role in YAP inhibition. Ser127 phosphorylated YAP binds to the 14-3-3 protein in the cytoplasm, becoming trapped there and unable to enter the nucleus to perform transcriptional functions, thus inhibiting YAP's pro-proliferative and anti-apoptotic activities. Similarly, LATS1 / 2 kinases can phosphorylate multiple sites on the transcription factor TAZ, with Ser89 phosphorylation playing a crucial role in TAZ inhibition. Phosphorylated TAZ is retained or isolated in the cytoplasm. Simultaneously, phosphorylated YAP or TAZ can be further recognized and degraded by the ubiquitinase SCFβ-TRCP. Therefore, if the Hippo pathway is "on", YAP and / or TAZ are phosphorylated and inactivated, remaining in the cytoplasm. Conversely, if the Hippo pathway is "off", YAP and / or TAZ are dephosphorylated and activated, and are often found localized in the cell nucleus.

[0005] YAP, as a transcription factor, does not contain a DNA-binding region itself. Activated YAP must bind to transcription factors after entering the nucleus to perform transcriptional functions. The transcription factor with which YAP binds most tightly after entering the nucleus is TEAD. Human TEAD family proteins include TEAD1 / TEAD2 / TEAD3 / TEAD4. YAP, along with TEAD (or other transcription factors such as Smad1, RUNX, ErbB4, and p73), can initiate the transcription of a series of downstream genes, including CTGF (connective tissue growth factor), Gli2, Birc5, Birc2, FGF1 (fibroblast growth factor 1), and AREG (amphiregulin). Like YAP, unphosphorylated TAZ enters the nucleus, where it binds to various DNA-binding transcription factors, such as PPARγ (peroxisome proliferation-activated receptor γ), TTF-1 (thyroid transcription factor-1), Pax3, TBX5, RUNX, TEAD1, and Smad2 / 3 / 4. Most genes activated by the YAP or TAZ transcription factor complex are associated with cell growth and proliferation.

[0006] As previously mentioned, the Hippo-YAP pathway regulates cell proliferation and apoptosis, as well as organ size and normal physiological function, and is strictly regulated under normal physiological conditions. Inactivation of Hippo pathway protein kinases or activation of YAP promotes tumorigenesis. In fact, aberrant activation of the Hippo pathway is a major event in the development and progression of many malignant tumors. Increased expression levels and nuclear localization of YAP or TAZ have been 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.

[0007] Malignant pleural mesothelioma (MPM) is a rare malignant tumor of the chest, with clinical manifestations that are often nonspecific and insidious, and many patients are diagnosed at an advanced stage. Treatment options for surgically unresectable MPM are extremely limited; current first-line pemetrexed / platinum-based therapy is unsatisfactory, achieving only a median overall survival of about one year, indicating a significant unmet clinical need. Aberrant activation of the Hippo-YAP pathway is present in approximately 70% of MPM patients and is considered a key cancer driver gene. Reducing Hippo-YAP pathway activity through biological methods and small chemical molecules has shown good inhibitory activity against tumor growth, suggesting that Hippo-YAP is a potential therapeutic target for MPM.

[0008] Lung cancer is one of the leading causes of cancer death worldwide. Currently, various treatments are available in clinical practice, including targeted therapy and immunotherapy, but all face challenges such as low response rates or recurrence. Recent studies have shown that the YAP signaling pathway can mediate tumor cell dormancy and resistance to apoptosis, leading to drug resistance to lung cancer drugs such as EGFR inhibitors. Inhibiting the Hippo-YAP signaling pathway can increase the sensitivity of tumor cells to EGFR-targeted drugs, suggesting that a combination strategy could be used clinically to improve treatment outcomes.

[0009] Liver cancer is a prevalent cancer in China, and current clinical treatments have limited breakthroughs, leaving a significant unmet clinical need. YAP is an important gene regulating the development and progression of liver cancer. Multiple in vivo experiments have shown that overexpression of YAP alone or knockout of its upstream regulator MST1-2 in mouse liver, without the introduction of other oncogenes, can induce hepatocellular carcinoma. Furthermore, in established mouse models of liver cancer, knockdown of YAP expression can significantly inhibit tumor growth and promote the differentiation of tumor cells into functional hepatocellular-like cells, accompanied by recovery of liver function, suggesting that YAP is a potential therapeutic target for liver cancer.

[0010] KRas mutations are widespread in pancreatic ductal adenocarcinoma (PDAC), and targeting KRas is considered to have broad clinical application prospects in PDAC. In a mouse model of PDAC, targeting KRas can inhibit tumor growth, but tumor recurrence is also a concern. Studies have shown that YAP plays an important role by regulating Fos and inducing EMT (epithelial-mesenchymal transition); knocking down YAP expression in recurrent tumors can suppress tumor growth again. This suggests that targeting YAP also has potential clinical application prospects in pancreatic ductal adenocarcinoma.

[0011] Inhibitors targeting BRAF and MEK have wide clinical applications in various tumors, including melanoma, colon cancer, and thyroid cancer, but they also face the challenge of preventing recurrence after treatment. Studies have shown that Hippo-YAP, as a pathway that promotes tumor cell growth, is overactivated in multiple drug-resistant tumor models. Inhibiting its activity can significantly improve sensitivity to BRAF / MEK inhibitors, suggesting its potential for combination therapy in clinical practice.

[0012] In vitro, overexpression of YAP or TAZ in mammalian epithelial cells leads to cell transformation. Enhanced YAP / TAZ transcriptional activity induces EMT (epithelial-mesenchymal transition) and confers characteristics of stem cell breast cancer cells.

[0013] In conclusion, therapeutic strategies targeting the Hippo-Yap pathway hold great promise for providing new insights into the treatment of various cancers. Developing specific small molecules to disrupt the interaction between YAP / TAZ and TEAD, thereby weakening YAP transcriptional activity and inhibiting the development of tumors with abnormal Hippo pathways, holds promise as a novel cancer treatment strategy with broad clinical application prospects. Summary of the Invention

[0014] The first aspect of this invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof:

[0015]

[0016]

[0017] In the formula:

[0018] A1 is selected from N or CR a ;

[0019] A2 is selected from NH, O, or CR. b R c ;

[0020] A3 is selected from N or CR3;

[0021] A4 is selected from N or CR4;

[0022] A5 is selected from N or CR5;

[0023] R1 is selected from H, hydroxyl, 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 heterocyclic.

[0024] R2 is selected from H, hydroxyl, 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 heterocyclic.

[0025] R3, R4 and R5 are each independently selected from H, hydroxyl, halogen, carboxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy.

[0026] R a Selected from H, hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy;

[0027] R b and R c Each group is independently selected from: H, hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; and

[0028] Ring A is a 5-8 membered carbocyclic group, a 4-8 membered heterocyclic group, or a 5 or 6 membered heteroaryl group, optionally substituted by 1-3 substituents selected from hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy groups.

[0029] A second aspect of the present invention provides a pharmaceutical composition comprising a compound I, II or III as described in any embodiment of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug or metabolite, and a pharmaceutically acceptable carrier or excipient.

[0030] A third aspect of the present invention provides the use of the I, II or III compounds, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope substitutes, polymorphs, prodrugs or metabolites of any embodiment of the present invention in the preparation of medicaments for the treatment or prevention of diseases mediated by the interaction between YAP / TAZ and TEAD.

[0031] A fourth aspect of the present invention provides a method for treating or preventing diseases mediated by the interaction of YAP / TAZ and TEAD, comprising administering to a desired subject a therapeutically effective amount of any of the I, II or III compounds of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug or a metabolite, or a pharmaceutical composition thereof.

[0032] The compounds described herein typically possess axial chirality, comprising a pair of axially chiral isomers. In some embodiments, the compounds described herein have an S-configuration of axial chirality. In some embodiments, the compounds described herein have an R-configuration of axial chirality.

[0033] The invention is described in detail below. Detailed Implementation

[0034] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as embodiments) can be combined with each other to form preferred technical solutions.

[0035] I. Terminology

[0036] Unless otherwise defined, all technical terms herein have the same meanings as commonly understood by one of ordinary skill in the art. Unless otherwise stated, all references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0037] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this application, unless specifically stated otherwise, the singular is used to include the plural. It must be noted that unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that unless otherwise stated, “or” or “or” means “and / or”. Furthermore, the term “comprising” and other forms such as “including,” “containing,” and “containing” are not limiting and can be open-ended, semi-closed, or closed. In other words, the term also includes the meaning of “substantially constituted by” or “composed of.”

[0038] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0039] When a substituent is described using a conventional chemical formula written from left to right, the substituent also includes those derived from...

[0040] Chemically equivalent substituents obtained when writing structural formulas from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0041] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to alkyl groups having a total of 1 to 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0042] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0043] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0044] "Hydroxy group" refers to the -OH group.

[0045] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group (-OH) as defined below.

[0046] "Carbonyl" refers to the -C(=O)- group.

[0047] "Nitro" refers to -NO2.

[0048] "Cyano" refers to -CN.

[0049] "Amino" refers to -NH2.

[0050] "Acyl" refers to -COR, where R is H or an alkyl group, such as C. 1-5 alkyl.

[0051] "Substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, aryl, heteroaryl, heterocyclic, or heteroaryl groups as defined below, such as monoalkylamino, dialkylamino, alkylamide, aralkylamino, heteroarylalkylamino, heteroarylamino, and arylamino. In some embodiments herein, "substituted amino" is represented as -NR'R", where R' and R" are each independently selected from H, an amino group, and a substituted or unsubstituted alkyl group.

[0052] The "carboxyl group" refers to -COOH.

[0053] In this application, as a group or part of other groups (e.g., in alkyl groups substituted with halogens (e.g., fluorine, chlorine, bromine, or iodine), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group composed only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl. The alkyl groups in various embodiments of the present invention are preferably C1-C4 alkyl groups.

[0054] In this application, as part of a group or other group, the term "alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of 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 connected to the rest of the molecule by single bonds, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0055] In this application, as part of a group or other group, the term "cycloalkyl group" refers to a stable non-aromatic monocyclic or polycyclic alkyl group (e.g., alkyl, alkenyl, or alkynyl) consisting only of carbon and hydrogen atoms. It may include fused ring systems, bridged ring systems, or spirocyclic 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 may be saturated or unsaturated and may be linked to the rest of the molecule via a single bond through any suitable carbon atom. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkyl group may optionally be oxidized. In a preferred embodiment, the cycloalkyl group is a cycloalkyl group, preferably a C3-C8 cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 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, and 5,6,7,8,9,10-hexahydro-benzocyclo Octenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.

[0056] In this application, as part of a group or other group, the term "heterocyclic 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 otherwise specifically indicated in this specification, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or more ring system, which may include fused ring systems, bridged ring systems, or spirocyclic systems; the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be connected to the remainder of the molecule via a carbon atom or heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the connection point with the remainder of the molecule is a non-aromatic ring atom. For the purposes of this invention, the heterocyclic group is preferably a stable 4- to 12-membered, 5- to 12-membered, or 4- to 9-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a stable 5- to 9-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups described in the various embodiments herein include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, aziridine, pyranyl, tetrahydropyranyl, thiaranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, quinazinyl, thiazoalkyl, isothiazyl, isoxazylalkyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrazolyl, phthalimide, dioxothiomorpholinyl, etc.

[0057] In this application, as a group or part of other groups, the term "aryl" refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, such as 6, 7, 8, 9, or 10 carbon atoms). For the purposes of this invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be fused with cycloalkyl or heterocyclic groups as defined above, provided that the aryl group is connected to the rest of the molecule via single bonds through atoms on the aromatic ring. Examples of aryl groups described in the embodiments herein include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.

[0058] In this application, the term "arylalkyl" refers to an alkyl group as defined above that has been replaced by an aryl group as defined above.

[0059] In this application, as part of a group or other group, the term "heteroaryl" means a 5- to 16-membered conjugated cyclic group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or more cyclic system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the remainder of the molecule via a single bond from an atom on the aromatic ring. The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of this invention, the heteroaryl group is preferably a stable 5- to 1.2-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered aromatic group containing 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, thiopheneyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolithyl, triazolyl, tetrazolyl, triazinyl, inazinyl, isoindolyl, indazoleyl, isoindazoleyl, purinyl, quinolinyl, isoquinolinyl, diazonyl, naphthidyl, quinoxolinyl, pteridyl, carbazolyl, carbazolyl, phenanthridine, phenanthroxolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiazolyl Phenoyl, oxarizolyl, cyclolinyl, quinazolinyl, phenylthiol, indene, o-diazaphenyl, isoxazolyl, phenoxazinyl, phenthiazinyl, 4,5,6,7-tetrahydrobenzo[b]thiophene, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyrazine, [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-a]pyridine, imidazo[1,2-b]pyrazine, imidazo[1,2-a]pyrazine, etc.

[0060] In this application, the term "heteroarylalkyl" refers to an alkyl group as defined above that has been replaced by a heteroaryl group as defined above.

[0061] In this application, "optionally" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups. The substituents referred to as "optionally" in the claims and specification of this invention include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclic hydrocarbon, and optionally substituted heterocyclic group.

[0062] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0063] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acids. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (where R is alkyl, aryl, or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl esters, aryl esters, or aralkyl esters.

[0064] Protecting groups can 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 detailed in Greene, TW & PGMUTS, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymer resins.

[0065] To avoid any ambiguity, in this invention, compounds plotted by wedge bonds (such as compound 67 in Example 33) are single-configuration compounds with an absolutely defined stereochemical structure.

[0066] II.Compounds

[0067] This invention provides compounds of Formula I, pharmaceutically acceptable salts thereof, or their enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites:

[0068]

[0069] In the formula:

[0070] A1 is selected from N or CR a A2 is selected from NH, O or CR. b R c A3 is selected from N or CR3; A4 is selected from N or CR4; A5 is selected from N or CR5; R1 is selected from H, hydroxyl, 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 heterocyclic; R2 is selected from H, hydroxyl, 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 heterocyclic; R3, R4, and R5 are each independently selected from H, hydroxyl, halogen, carboxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; R a Selected from H, hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; R b and R c Each is independently selected from: H, hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy; and ring A is a 5-8 membered carbocyclic group, a 4-8 membered heterocyclic group or a 5 or 6 membered heteroaryl group, optionally substituted by 1-3 substituents selected from hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy.

[0071] Unless otherwise stated, in Formula I and the various structural formulas described below, the alkyl group is preferably C10. 1-6 Alkyl, more preferably C 1-4 Alkyl; the alkoxy group is preferably C. 1-6 Alkoxy, more preferably C 1-4 alkoxy; the cycloalkyl group is preferably C10. 3-8 The alkyl group is preferably a 6-14-membered aryl group; the heteroaryl group is preferably a 5-12-membered heteroaryl group, more preferably a 5-9-membered heteroaryl group; the heterocyclic group is preferably a 4-12-membered heterocyclic group, more preferably a 4-9-membered heterocyclic group; preferably, the heteroatoms in the heterocyclic group and heteroaryl group include nitrogen, oxygen and / or sulfur, and the number of heteroatoms is 1, 2 or 3. Unless otherwise stated, when the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic groups are substituted, the number of their substituents can be 1-6, and each can be independently selected from: halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4Alkoxy, carboxyl, amino, cyano groups, optionally with 1-3 selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Substituents of alkoxy, carboxyl, amino, and cyano groups include 6-14 aryl, 5-12 heteroaryl, and 4-12 heterocyclic groups, as well as NR'R”-C(O)-(CH2). n - etc., where R' and R” are each independently H, amino, or substituted or unsubstituted C. 1-4 Alkyl group, n is an integer from 0 to 4; when the amino group is substituted, the substituent can be one or two selected from C10. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Acyl and halogenated C 1-4 Alkyl substituents, or one optional substituent selected from 1-3 halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 The alkyl, carboxyl, amino, and cyano groups are substituted with 6-14-membered aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic groups. Preferably, the preferred substituents for each alkyl and alkoxy group are 1-6 selected from halogens, hydroxyl groups, and NR groups. 12 R 13 and cyano substituents, wherein the R 12 and R 13 Each is independently selected from H and C 1-4 Acyl and C 1-4 alkyl.

[0072] Specifically, in Equation I, A1 is N. In some implementations, A1 is CR. a Ra is selected from H and substituted or unsubstituted C. 1-4 alkyl.

[0073] In some embodiments, in Formula I, ring A is a 5-8 membered saturated carbide ring or a 4-8 membered heterocyclic group. Specifically, ring A is a 4-8 membered nitrogen-containing heterocyclic group, and when A1 is N, the nitrogen-containing heterocyclic group optionally also contains one or two heteroatoms selected from N and O, and preferably also optionally contains one or two nitrogen atoms. In a further preferred embodiment, ring A is a piperidine ring, and specifically, the cyclic nitrogen atom of the piperidine ring is A1. In other preferred embodiments, ring A is a piperazine ring, and specifically, one cyclic nitrogen atom of the piperazine ring is A1. In some embodiments, ring A is a 5- or 6-membered heteroaryl group, preferably containing one or two nitrogen atoms, wherein one nitrogen atom is located at the A1 position. In some embodiments, ring A is a benzene ring.

[0074] The substituents on ring A are preferably selected from hydroxyl, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy groups; more preferably, the substituents on ring A are selected from substituted or unsubstituted C groups. 1-4 Alkyl group. Preferably, the alkyl group is composed of 1-6 alkyl groups selected from hydroxyl, halogen, and NR. 12 R 13 Substituents of R, wherein R 12 and R 13 Each is independently selected from H and C 1-4 alkyl.

[0075] In some implementations, in Formula I, A2 is CR b R c Preferably, A2's R b and R c Each is independent of H and C 1-4 Alkyl groups, more preferably H. In some embodiments, A2 is NH or O.

[0076] In some embodiments, in Formula I, A3 is CR3; preferably, R3 is H, halogen, or C. 1-4 Alkoxy, cyano, and substituted or unsubstituted C 1-4 Alkyl, more preferably halogen. In some embodiments, when the C 1-4 When an alkyl group is substituted, the substituent can be one to three substituents selected from halogens, hydroxyl groups, and amino groups.

[0077] In Formula I, A4 is preferably CR4; R4 is preferably H, halogen, or C. 1-4 Alkoxy, cyano, and substituted or unsubstituted C 1-4 Alkyl groups, more preferably halogens. Preferably, when the C... 1-4 When an alkyl group is substituted, the substituent can be one to three substituents selected from halogens, hydroxyl groups, and amino groups.

[0078] In some implementations, R3 and R4 in Formula I are each a halogen.

[0079] In Formula I, A5 is preferably CR5; R5 is preferably H, halogen, cyano, or C. 1-4 Alkoxy and substituted or unsubstituted C 1-4 Alkyl, more preferably H. In some embodiments, when the C 1-4 When an alkyl group is substituted, the substituent can be one to three substituents selected from halogens, hydroxyl groups, and amino groups.

[0080] In some implementations, in Formula I, any one or any two of A3, A4 and A5 are N, and the rest are the corresponding CR3, CR4 or CR5.

[0081] In Formula I, in some embodiments, R1 is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocyclic group. In some embodiments, when it is a substituent group, the substituent on R1 may be 1-3 selected from halogens, hydroxyl groups, C... 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and -NR 12 R 13 Substituents, wherein R 12 and R 13 Each can be H or C independently. 1-4 Alkyl group. In some embodiments, the cycloalkyl group is C10. 3-8 Cycloalkyl; preferably, the aryl group is an aryl group having 6 to 14 ring carbon atoms; preferably, the heteroaryl group is a heteroaryl group having 5 to 12 ring atoms, more preferably, the heteroaryl group having at least a ring nitrogen atom among the heteroatoms; preferably, the heterocyclic group is a heterocyclic group having 4 to 9 ring atoms. In some embodiments, R1 is an unsubstituted 6-14 membered aryl group, such as phenyl, or optionally surrounded by 1-3 atoms selected from hydroxyl, halogen, C 1-4 Alkyl and C 1-4 Alkoxy substituents are 6-14 aryl groups, such as phenyl.

[0082] In Formula I, R2 is preferably H, a substituted or unsubstituted alkyl group, a halogen, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group. In some embodiments, when the alkyl group is substituted, the substituent can be 1-5 selected from halogens, hydroxyl groups, carboxyl groups, cyano groups, and -NR groups. 12 R 13 , where R 12 and R 13 Each can be H or C independently. 1-4 Alkyl group. In some embodiments, the substituted or unsubstituted alkyl group is a substituted or unsubstituted C14 group. 1-4 Alkyl groups, preferably unsubstituted C4 groups 1-4 Alkyl or halogenated C 1-4 Alkyl group. In some embodiments, R2 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group. Preferred cycloalkyl groups are C10 and C20. 3-8Cycloalkyl; preferably, the aryl group is a 6-14 membered aryl group, more preferably a phenyl group; preferably, the heteroaryl group is a heteroaryl group having 5 to 12 ring atoms, more preferably a heteroaryl group that includes at least a cyclic nitrogen atom among the heteroatoms, including but not limited to pyridinyl, pyrimidinyl, pyrazolyl, pyrrolithyl, imidazolyl, triazolyl, pyrazinyl, indolyl, and pyridazinyl; preferably, the heterocyclic group is a heterocyclic group having 4 to 9 ring atoms, more preferably a heterocyclic group containing a cyclic nitrogen and / or oxygen atom and / or sulfur atom, such as morpholinyl, piperidinyl, piperazinyl, dihydroindolyl, pyrrolithyl, and azacyclic butyl. When it is a substituent group, the substituent on R2 can be 1 to 3 selected from hydroxyl, carboxyl, halogen, cyano, NR'R”-C(O)-(CH2). n - C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted C 1-4 The substituents of the alkoxy group, the substituted or unsubstituted 4-9 membered heterocyclic group, and the substituted or unsubstituted amino group, wherein R' and R" are each independently selected from H and the substituted or unsubstituted C. 1-4 Alkyl group, where n is an integer from 0 to 4; in some embodiments, when the alkyl group is substituted, the substituent may be 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups; preferably, when the alkoxy group is substituted, the substituent may be 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 Alkyl groups and substituted or unsubstituted 5-12-membered heteroaryl groups; in some embodiments, when the aforementioned heterocyclic group is substituted, the substituent can be 1-5 groups selected from hydroxyl, halogen, carboxyl, amino, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents; in some embodiments, when the amino group is substituted, the substituent may be one substituted or unsubstituted 4-9 membered heterocyclic group, or one or two C groups selected from substituted or unsubstituted groups. 1-4 Alkyl and C 1-4 The substituent on the acyl group, preferably, is a 4-9 membered heterocyclic group containing N, O, and / or S, including tetrahydrofuranyl, tetrahydropyranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and dioxothiomorpholinyl, etc., wherein the substituent on the heterocyclic group can be one or two selected from halogens, C 1-4 Substituents on alkyl and amino groups, wherein the substituents on the alkyl group may be one or two substituents selected from halogens, hydroxyl groups and amino groups.

[0083] In Formula I, preferably, R3, R4, R5, R a R b R c When the alkyl and alkoxy groups defined in ring A are substituted, their respective substituents can be 1-3 selected from halogens, hydroxyl groups, carboxyl groups, or optionally replaced by 1 or 2 carbon atoms. 1-4Alkyl-substituted amino groups, where the amino group in the definition can be occupied by one or two carbon atoms. 1-4 Alkyl substitution.

[0084] Some exemplary compounds of Formula I have the structure shown in Formula II:

[0085]

[0086] In the formula, R1 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, and substituted or unsubstituted cycloalkyl; R2 is selected from H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, and substituted or unsubstituted cycloalkyl; R3, R4, and R5 are each independently selected from H, hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy; R 11 It is H or a substituted or unsubstituted alkyl group.

[0087] In some embodiments, when R1 in Formula II is a substituent group, the substituent is 1-3 substituents selected from halogens, hydroxyl groups, C... 1-4 Alkyl, C 1-4 Alkoxy and -NR 12 R 13 Substituents, wherein R 12 and R 13 Each can be H or C independently. 1-4 Alkyl group. Preferably, R1 is a substituted or unsubstituted 6-14-membered aryl group or a substituted or unsubstituted 5-12-membered heteroaryl group; preferably, the substituent on R1 is selected from hydroxyl, halogen, C... 1-4 Alkyl and C 1-4 One or more of the alkoxy groups. More preferably, R1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-12 member nitrogen-containing heteroaryl group, such as pyridinyl, pyrimidinyl, pyrazolyl, pyrroleyl, imidazoleyl, triazolyl, pyrazinyl, and pyridazinyl; preferably, when it is a substituent group, the substituent is selected from hydroxyl, halogen, C 1-4 Alkyl and C 1-4 One or more of the alkoxy groups.

[0088] In some embodiments, when R2 in Formula II is a substituent group, the substituent is one to three groups selected from hydroxyl, carboxyl, halogen, cyano, NR'R”-C(O)-(CH2). n - C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted C 1-4The substituents of the alkoxy group, substituted or unsubstituted 4-9 membered heterocyclic group (such as nitrogen-containing, sulfur-containing and / or oxygen-containing 4-9 membered heterocyclic groups, including tetrahydrofuranyl, tetrahydropyranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and dioxothiomorpholinyl, etc.) and substituted or unsubstituted amino groups, wherein R' and R" are each independently selected from H, amino and substituted or unsubstituted C. 1-4 Alkyl group, where n is an integer from 0 to 4; preferably, when the alkyl group is substituted, the substituents can be 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups; in some embodiments, when the alkoxy group is substituted, the substituents can be 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 Alkyl groups and substituted or unsubstituted 5-12-membered heteroaryl groups; preferably, when the heterocyclic group is substituted, the substituent can be 1-5 groups selected from hydroxyl, halogen, carboxyl, amino, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents; in some embodiments, when the amino group is substituted, the substituent may be a substituted or unsubstituted 4-9 membered heterocyclic group (such as oxygen-containing 4-9 membered heterocyclic groups, such as tetrahydrofuranyl, tetrahydropyranyl; or nitrogen-containing 4-9 membered heterocyclic groups, such as aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholinyl; or sulfur-containing 4-9 membered heterocyclic groups, etc.), substituted or unsubstituted C 1-4 Alkyl, or C 1-4 Acyl group. The aryl, heteroaryl, and heterocyclic groups have the definitions described herein. In some embodiments, R2 is a substituted or unsubstituted 6-14 member aryl group (e.g., phenyl), a substituted or unsubstituted 5-12 member nitrogen-containing heteroaryl group (e.g., pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrrolithyl, triazolyl, pyrazinyl, indolyl, and pyridazinyl), a substituted or unsubstituted 4-9 member nitrogen- and / or oxygen- and / or sulfur-containing heterocyclic group (e.g., azahexacyclic butyl, morpholinyl, pyrrolithyl, dihydroindolyl, piperidinyl, and piperazinyl), or a substituted or unsubstituted C 3-8 Cycloalkyl groups, preferably 1-3 substituents selected from the group consisting of halogens, NR'R”-C(O)-(CH2). n - Unsubstituted or substituted C with 1-3 substituents selected from halogen, hydroxyl, carboxyl and amino groups. 1-4 Alkyl group, unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 C substituted with alkyl substituents 1-4 Alkoxy groups, unsubstituted 4-9 membered heterocyclic groups (preferably heterocyclic groups containing N and O and / or S), and unsubstituted groups or groups selected from 1 or 2 C atoms. 1-4 Alkyl and C 1-4An amino group substituted with an acyl group or a 4-9 membered heterocyclic group (such as an oxygen-containing 4-9 membered heterocyclic group, such as tetrahydrofuranyl or tetrahydropyranyl; or a nitrogen-containing 4-9 membered heterocyclic group, such as aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, etc.; or a sulfur-containing 4-9 membered heterocyclic group, such as thiomorpholinyl). In some other embodiments, R2 in Formula II is H, a halogen, or C. 1-4 Alkyl or halogenated C 1-4 alkyl.

[0089] In some implementations, in Formula II, R3 is H, halogen, or C. 1-4 Alkoxy and C 1-4 Alkyl groups, particularly halogens and C 1-4 alkyl.

[0090] In some implementations, in Formula II, R4 is H, halogen, or C. 1-4 Alkoxy and C 1-4 Alkyl groups, in particular, are halogens.

[0091] In some implementations, in Formula II, R5 is H, halogen, or C. 1-4 Alkoxy and C 1-4 Alkyl, specifically, H.

[0092] In some implementations, in Formula II, R3 and R4 are each halogens, and R5 is H.

[0093] In some implementations, in Formula II, R 11 C is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 Alkyl groups, in particular, R 11 For H.

[0094] In some embodiments, when R2 in compounds of formulas I and II is a substituted cycloalkyl, aryl, heteroaryl, or heterocyclic group, the number of substituents is at least two; preferably, at least one, more preferably, at least two substituents are located in the ortho position. In some embodiments, the at least two substituents include at least a halogen and the NR'R”-C(O)-(CH2). n - Preferably, the substituent further includes C selected from the substituted or unsubstituted groups. 1-4 Alkyl, substituted or unsubstituted C 1-4 One of the alkoxy group, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted amino group.

[0095] In some preferred embodiments of Formula II, R1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-12 member nitrogen-containing heteroaryl group, such as pyridyl, pyrimidinyl, pyrazolyl, pyrroloyl, imidazolyl, triazolyl, pyrazinyl, and pyridazinyl, wherein, when it is a substituent group, the number of substituents is 1-3, and they are selected from hydroxyl, halogen, C 1-4 Alkyl and C 1-4 The alkoxy group, preferably R1, is an unsubstituted phenyl group; R2 is a 4-9 membered heterocyclic group, preferably a 4-9 membered heterocyclic group containing N and / or O and / or S, including azirrobutyl, oxobutyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazineyl, wherein the heterocyclic group is optionally surrounded by 1-3 groups selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, carboxyl, and NR'R”-C(O)-(CH2) n - Substituents, wherein R' and R" are each independently selected from H and C. 1-4 Alkyl group, n is an integer from 0 to 4, and the preferred substituent is the carboxyl group or NR'R”-C(O)-(CH2). n - Preferably, the substituent is located in the ortho position, and / or when the heterocyclic group is a nitrogen-containing heterocyclic group, it is connected to other parts of the compound of formula II through the cyclic nitrogen atom of the heterocyclic group; R3 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl groups, preferably H and halogens; R4 is H, halogen, or C. 1-4 Alkoxy and C 1-4 Alkyl group, preferably halogen; R5 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl group, preferably H; preferably, R3 and R4 are each independently halogenated, and R5 is H; R 11 C is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 Alkyl group, preferably H.

[0096] In other embodiments of Formula II, R1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-12 member nitrogen-containing heteroaryl group, such as pyridyl, pyrimidinyl, pyrazolyl, pyrroloyl, imidazolyl, triazolyl, pyrazinyl, and pyridazinyl, wherein, when it is a substituent group, the number of substituents is 1-3, and they are selected from halogens, C 1-4 Alkyl and C 1-4The alkoxy group, preferably R1, is an unsubstituted phenyl group; R2 is a 5-12-membered heteroaryl group, preferably an N-containing 5-12-membered heteroaryl group, including pyrrole, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, etc., wherein the heteroaryl group is optionally surrounded by 1-3 atoms selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C1-4 alkoxy, halogenated C 1-4 Alkoxy, carboxyl, and NR'R”-C(O)-(CH2) n - Substituents, wherein R' and R" are each independently selected from H and C. 1-4 Alkyl group, n is an integer from 0 to 4, and the preferred substituents are the halogen and C. 1-4 Alkyl or NR'R”-C(O)-(CH2) n - Preferably, the substituent is located in the ortho position, and / or when the heterocyclic group is a nitrogen-containing heterocyclic group, it is connected to other parts of the compound of formula II through the cyclic nitrogen atom of the heterocyclic group; R3 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl groups, preferably H and halogens; R4 is H, halogen, or C. 1-4 Alkoxy and C 1-4 Alkyl group, preferably halogen; R5 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl group, preferably H; preferably, R3 and R4 are each independently halogenated, and R5 is H; R 11 C is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 Alkyl group, preferably H.

[0097] Further preferred compounds of Formula I have the structure shown in Formula III:

[0098]

[0099] In the formula:

[0100] R1, R3-R5 are as described in any embodiment of Formula I or II above;

[0101] B1 is C or N; B2 is CR6 or N; B3 is CR7 or N; B4 is CR8 or N; B5 is CR9 or N; B6 is CR 10 Or N;

[0102] R6 is selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, cyano, carboxyl, NR 12 R 13 And NR'R”-C(O)-(CH2) n -, where R12 and R 13 Each is independently selected from H and C 1-4 Acyl groups and substituted or unsubstituted C 1-4 Alkyl group, where n is an integer from 0 to 4;

[0103] R7 represents H, halogen, and NR. 12 R 13 C 1-4 Alkoxy or C 1-4 alkyl;

[0104] R8 is H, halogen, or C. 1-4 alkyl;

[0105] R9 is H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 1-4 The alkyl group may contain an alkoxy group, a substituted or unsubstituted 4-9 membered heterocyclic group (such as a 4-9 membered heterocyclic group containing nitrogen and / or oxygen and / or sulfur, including tetrahydrofuranyl, tetrahydropyranyl, azacyclobutane, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, and dioxothiomorpholinyl, etc.), or a substituted or unsubstituted amino group; in some embodiments, when the alkyl group is substituted, the substituent may be 1-5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups; preferably, when the alkoxy group is substituted, the substituent may be 1-5 substituents selected from hydroxyl, halogen, carboxyl, amino, halogenated C groups. 1-4 Alkyl groups and substituted or unsubstituted 5-12-membered heteroaryl groups; in some embodiments, when the heterocyclic group is substituted, the substituent can be 1-5 groups selected from hydroxyl, halogen, carboxyl, amino, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents; preferably, when the amino group is substituted, the substituent can be a substituted or unsubstituted 4-9 membered heterocyclic group (such as oxygen-containing 4-9 membered heterocyclic groups, such as tetrahydrofuranyl, tetrahydropyranyl; or nitrogen-containing 4-9 membered heterocyclic groups, such as aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, etc.; or sulfur-containing 4-9 membered heterocyclic groups, such as thiomorpholinyl) or a substituted or unsubstituted C 1-4 Alkyl groups (such as hydroxyl or halogen-substituted C4 groups) 1-4 Alkyl); or R7 and R8, or R8 and R9 together with their respective attached C to form a 5-membered nitrogen-containing saturated or unsaturated heterocycle, such as pyrrolidinyl or pyrrolidinyl;

[0106] R 10 H, halogen, alkyl or halogenated C 1-4 alkyl;

[0107] R 11 H or substituted or unsubstituted C 1-4 Alkyl groups, preferably H; and

[0108] R 12 and R 13 Each can be independently either H or substituted or unsubstituted C. 1-4 alkyl.

[0109] In some implementations, in Formula III, B1 is CH; B2 is CR6; B3 is CR7; B4 is CR8; B5 is CR9; and B6 is CR 10 The preferred R6 is halogen, C. 1-4 Alkyl, C 1-4 Alkoxy, cyano, NR 12 R 13 Or NR'R”-C(O)-(CH2) n -, where R 12 and R 13 Each is independently selected from H and C 1-4 Acyl groups and substituted or unsubstituted C 1-4 Alkyl group, where n is an integer from 0 to 4. Preferably, R7 is H or NR. 12 R 13 More preferably, it is H or NH2. Preferably, R8 is H. Preferably, R9 is: the aforementioned substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 1-4 The alkoxy group, an unsubstituted 4-9 membered heterocyclic group (preferably a 4-9 membered heterocyclic group containing N and O and / or S), or a substituted or unsubstituted amino group, more preferably: an unsubstituted or C-shaped group substituted with 1-3 substituents selected from halogens, hydroxyl groups, carboxyl groups, and amino groups. 1-4 Alkyl group, unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 C substituted with alkyl substituents 1-4 Alkyl group, unsubstituted morpholino group, thiomorpholino group, and tetrahydropyrano group, or unsubstituted or with 1 or 2 carbon atoms. 1-4 Alkyl groups or amino groups substituted with one 4-9 membered heterocyclic group (preferably a 5-12 membered oxygen-containing heterocyclic group, such as oxobutyl, tetrahydrofuranyl, tetrahydropyranyl, etc.). Preferred R 10 It is a halogen. Preferred R 11 H or C optionally substituted with 1-3 C atoms selected from hydroxyl and halogen. 1-4 alkyl.

[0110] In some preferred embodiments of Formula III, B1 is CH; B2 is CR6; B3 is CR7; B4 is CR8; B5 is CR9; and B6 is CR 10 R6 is NR'R”-C(O)-(CH2) n - where R' and R” are each independently selected from H, amino, and C, optionally substituted with 1-2 substituents selected from hydroxyl and halogen. 1-4Alkyl group, n is an integer from 0 to 4; R7 and R8 are H; R9 is an unsubstituted C group or a C group substituted with 1 to 3 substituents selected from halogen, hydroxyl, carboxyl and amino groups. 1-4 Alkyl groups, or unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 C substituted with alkyl substituents 1-4 Alkoxy group, either unsubstituted or surrounded by 1-3 groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C. 1-4 Alkyl-substituted amino groups; R 10 It is a halogen; R 11 For H. Further, in these preferred embodiments, R1 is a substituted or unsubstituted phenyl group, preferably, when it is a substituent group, the number of substituents is 1, 2, or 3, selected from hydroxyl, halogen, C 1-4 Alkyl and C 1-4 alkoxy group; R3 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl groups, preferably halogens and C 1-4 Alkyl; R4 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl group, preferably halogen; R5 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl group, preferably H. Preferably, R3 and R4 are each halogens, and R5 is H.

[0111] In some preferred embodiments of Formula III, B1 is CH; B2 is CR6; B3 is N or CR7; B4 is N or CR8; B5 is N or CR9; B6 is CR 10 R6 is NR'R”-C(O)-(CH2) n - where R' and R” are each independently selected from H, amino, and C, optionally substituted with 1-2 substituents selected from hydroxyl and halogen. 1-4 Alkyl group, n is an integer from 0 to 4; R7 and R8 are H; R9 is an unsubstituted C group or a C group substituted with 1 to 3 substituents selected from halogen, hydroxyl, carboxyl and amino groups. 1-4 Alkyl groups, or unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 C substituted with alkyl substituents 1-4 Alkoxy group, either unsubstituted or surrounded by 1-3 groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C. 1-4 Alkyl-substituted amino groups; R 10 It is a halogen; R 11 For H. Further, in these preferred embodiments, R1 is a substituted or unsubstituted phenyl group, preferably, when it is a substituent group, the number of substituents is 1, 2, or 3, selected from hydroxyl, halogen, C 1-4Alkyl and C 1-4 alkoxy group; R3 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl groups, preferably halogens and C 1-4 Alkyl; R4 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl group, preferably halogen; R5 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl group, preferably H. Preferably, R3 and R4 are each halogens, and R5 is H.

[0112] In some embodiments, the compound of formula I has the structure shown in formula IV:

[0113]

[0114] In the formula:

[0115] R1, R3-R5 and R 11 As described in any of the embodiments of Formula I or II above;

[0116] Each m can be 1, 2, or 3 independently;

[0117] X is CH2, O, or NH;

[0118] R d For 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)-(CH2) n - where R' and R” are each independently selected from H and C. 1-4 Alkyl group, n is an integer from 0 to 4; R d The quantity can be 1, 2 or 3.

[0119] In some implementations, in formula IV, R d It is located adjacent to the nitrogen atom that is connected to the rest of Formula IV.

[0120] In some implementations, in formula IV, R d It can be H, carboxyl, or NR'R”-C(O)-(CH2). n -

[0121] In some embodiments, in Formula IV, the heterocycle containing X is an azo-heterocyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl.

[0122] In some embodiments, in Formula IV, R1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-12 member nitrogen-containing heteroaryl group, such as pyridyl, pyrimidinyl, pyrazolyl, pyrroloyl, imidazolyl, triazolyl, pyrazinyl, and pyridazinyl, etc., wherein when it is a substituent group, the number of substituents is 1-3, and they are selected from halogens, C 1-4 Alkyl and C 1-4 Alkoxy group, preferably R1 is an unsubstituted phenyl group; R3 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl groups, preferably H and halogens; R4 is H, halogen, or C. 1-4 Alkoxy and C 1-4 Alkyl group, preferably halogen; R5 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl group, preferably H; preferably, R3 and R4 are each independently halogenated, and R5 is H; R 11 The C- group is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 Alkyl group, preferably H; X is CH2, O or NH; R d It can be H, carboxyl, or NR'R”-C(O)-(CH2). n - where R' and R” are each independently selected from H and C. 1-4 Alkyl group, where n is an integer from 0 to 4.

[0123] In preferred embodiments of formulas I, II, III, and IV of the present invention, the NR'R”-C(O)-(CH2) n In the given information, n is 0, and R' and R” are independently defined as H and C, respectively. 1-4 alkyl.

[0124] The compounds described herein typically possess axial chirality, comprising a pair of axially chiral isomers. In some embodiments, the compounds described herein have an S-configuration of axial chirality. In some embodiments, the compounds described herein have an R-configuration of axial chirality.

[0125] In some embodiments, the compound of formula I, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof, wherein formula I has the structural formula shown in formula V:

[0126]

[0127] In formula V, B1, B3-B5, R1, R3-R5, R 11 As described in any of the embodiments in Formula I, II or III above;

[0128] R6 is selected from H, halogen, alkyl, carboxyl, and NR. 12 R 13 And NR'R”-C(O)-(CH2) n -, where R' and R” are each independently selected from H, amino, and substituted or unsubstituted alkyl groups, and n is an integer from 0 to 4;

[0129] R 10 H, halogen, alkyl or halogenated C 1-4 alkyl;

[0130] R 12 and R 13 Each is independent of H and C 1-4 Acyl or substituted or unsubstituted C 1-4 Alkyl group; preferably, the alkyl group is substituted with 1-6 substituents selected from hydroxyl and halogen, or is unsubstituted;

[0131] Among them, R6 and R 10 They are not both H.

[0132] In some embodiments, the compound of formula I, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof, wherein formula I has the structural formula shown in formula VI:

[0133]

[0134] In formula V, B1, B3-B5, R1, R3-R5, R 11 As described in any of the embodiments in Formula I, II or III above;

[0135] R6 is selected from H, halogen, alkyl, carboxyl, and NR. 12 R 13 And NR'R”-C(O)-(CH2) n -, where R' and R” are each independently selected from H, amino, and substituted or unsubstituted alkyl groups, and n is an integer from 0 to 4;

[0136] R 10 H, halogen, alkyl or halogenated C 1-4 alkyl;

[0137] R 12 and R 13 Each is independent of H and C 1-4 Acyl or substituted or unsubstituted C 1-4 Alkyl group; preferably, the alkyl group is substituted with 1-6 substituents selected from hydroxyl and halogen, or is unsubstituted;

[0138] Among them, R6 and R 10They are not both H.

[0139] In some embodiments, the compound of formula I, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, tautomers, solvates, isotope-substituted derivatives, polymorphs, prodrugs, or metabolites thereof, wherein formula I has the structural formula shown in formula VII:

[0140]

[0141] In equation VI, R1, R3-R s R7-R9, R 11 As described in any of the embodiments in Formula I, II or III above;

[0142] R6 is selected from H, halogen, alkyl, carboxyl, and NR. 12 R 13 And NR'R”-C(O)-(CH2) n -, where R' and R” are each independently selected from H, amino, and substituted or unsubstituted alkyl groups, and n is an integer from 0 to 4;

[0143] R 10 H, halogen, alkyl or halogenated C 1-4 alkyl;

[0144] R 12 and R 13 Each is independent of H and C 1-4 Acyl or substituted or unsubstituted C 1-4 Alkyl group; preferably, the alkyl group is substituted with 1-6 substituents selected from hydroxyl and halogen, or is unsubstituted;

[0145] Among them, R6 and R 10 They are not both H.

[0146] In some embodiments, the compound of formula I, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof, wherein formula I has the structural formula shown in formula VIII:

[0147]

[0148] In equation VI, R1, R3-R5, R7-R9, R 11 As described in any of the embodiments in Formula I, II or III above;

[0149] R6 is selected from H, halogen, alkyl, carboxyl, and NR. 12 R 13 And NR'R”-C(O)-(CH2) n-, where R' and R” are each independently selected from H, amino, and substituted or unsubstituted alkyl groups, and n is an integer from 0 to 4;

[0150] R 10 H, halogen, alkyl or halogenated C 1-4 alkyl;

[0151] R 12 and R 13 Each is independent of H and C 1-4 Acyl or substituted or unsubstituted C 1-4 Alkyl group; preferably, the alkyl group is substituted with 1-6 substituents selected from hydroxyl and halogen, or is unsubstituted;

[0152] Among them, R6 and R 10 They are not both H.

[0153] In certain embodiments of the present invention, the following compounds, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof are provided, characterized in that the compounds are selected from:

[0154]

[0155]

[0156]

[0157] This article also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites of the aforementioned compounds.

[0158] In this article, "stereoisomer" refers to a compound composed of identical atoms bonded by the same bonds, but with different three-dimensional structures. This invention will cover various stereoisomers and mixtures thereof.

[0159] When the compounds of the present invention contain alkene double bonds, unless otherwise stated, the compounds of the present invention are intended to contain E- and Z-geometric isomers.

[0160] "Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomer forms of the compounds of this invention are also included within the scope of this invention.

[0161] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers, and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention aims to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present invention may select racemic, diastereomer, or enantiomer 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.

[0162] Conventional techniques for preparing / separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures 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; AMStalcup, 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.

[0163] This invention also includes all suitable isotopic variants of the compounds of the invention or pharmaceutically acceptable salts thereof. An isotopic variant of the compounds of the invention or pharmaceutically acceptable salts thereof is defined as one in which at least one atom is replaced by an atom having the same number of atoms but a different atomic mass than those commonly found in nature. Isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 35 S, 18F, 36 Cl and 125 I. Isotopic variants of the compounds described in this invention or of their pharmaceutically acceptable salts can be prepared using conventional techniques and appropriate isotopic variants with suitable reagents.

[0164] In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0165] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecenoate, glycolate, gluconate, lactate, sebate, 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-aminosalicylic acid, and naphthalenedisulfonate. These salts can be prepared using methods known in this field.

[0166] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that maintain 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, and aluminum salts. 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 amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0167] Pharmaceutically acceptable salts of the compounds of the present invention preferably include 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 compounds containing carboxylic acids (e.g., by reacting with C according to methods known in the art). 1-4 Esters obtained by alcohol condensation; esters of compounds containing hydroxyl groups (e.g., obtained by reacting with C according to methods known in the art). 1-4 Carboxylic acid, C 3-6 esters obtained by condensation of diacids or their anhydrides, such as succinic anhydride and fumaric anhydride; imines of compounds containing amino groups (e.g., obtained by condensation with C according to methods known in the art). 1-4 Imines obtained by condensation of aldehydes or ketones; urethanes of compounds containing amino groups, such as those esters described by Leu et al. (J.Med.Chem., 42: 3623-3628 (1999)) and Greenwald et al. (J.Med.Chem., 42: 3657-3667 (1999)); aldol acetals or ketal acetals of compounds containing alcohols (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0168] III. Compound Preparation

[0169] Representative compounds of this invention, compounds of formula II, can be prepared by the following method:

[0170]

[0171] In the formula, X1 and X2 are halogens; PG1 and G2P are protecting groups; LG1 is a leaving group; R1-R5 and R 11 As defined in Equation II.

[0172] In the above reaction process:

[0173] Starting from II-a, the iodide is converted to an aldehyde using Grignard reagent / DMF in an inert solvent to obtain II-b; the preferred Grignard reagent is isopropyl Grignard reagent, and the preferred inert solvent is toluene;

[0174] II-b is reduced to II-c by a reducing agent in a polar protic solvent; sodium borohydride is preferred as the reducing agent, and a methanol / tetrahydrofuran mixed solvent is preferred as the polar protic solvent.

[0175] II-c is halogenated / methanesulfonated / p-toluenesulfonated to obtain II-d; the preferred halogenating agent is NBS / triphenylphosphine, and the preferred solvent is a haloalkane;

[0176] II-d is alkylated to II-e under the action of a strong base to obtain II-f; the strong base is preferably LDA, and the ether solvent is preferably tetrahydrofuran;

[0177] II-f is deprotected by the protecting group PG1 to obtain II-g; the protecting group PG1 is preferably BOC, the deprotection conditions are preferably acids such as trifluoroacetic acid, and the solvent is preferably a haloalkane;

[0178] II-g is cyclized with a strong base to obtain II-h; the strong base is preferably sodium hydride, and the solvent used is preferably DMAc;

[0179] II-h is obtained by reducing the amide with a reducing agent such as borane to obtain II-i; the preferred solvent is tetrahydrofuran;

[0180] In the presence of a base and a palladium catalyst, bis-boron pinacol ester replaces bromine in II-i to obtain boron ester II-j; the palladium catalyst is preferably PdCl2dppf, the base is preferably potassium phosphate, and the solvent is preferably p-toluene;

[0181] Boron ester II-j and aromatic halide R2-X2 are coupled in an alkaline and inert solvent via a Pd catalyst and a phosphorus ligand to yield II-k; the Pd catalyst is preferably Pd2(dba)3, the phosphorus ligand is preferably XantPhos, the base is preferably potassium phosphate, and the solvent is preferably a toluene / water mixture.

[0182] II-k is deprotected by the protecting group PG2 to obtain II-1, wherein the protecting group is preferably benzyl, the deprotection conditions are preferably ethyl chloroformate, and the solvent is preferably a haloalkane;

[0183] Finally, II-1 reacts with an aldehyde compound in a polar solvent via a reductive amination reaction to obtain compound II; the reducing agent is preferably sodium cyanoborohydride, and the solvent is preferably methanol.

[0184] Other compounds of the present invention can be prepared by referring to the above process or the preparation examples in the embodiments, using corresponding reactants, under the same or similar reaction conditions.

[0185] IV. Pharmaceutical Compositions, Methods, and Applications

[0186] The compounds of formulas I, II, and III of this invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, and metabolites are inhibitors of the interaction between YAP / TAZ and TEAD, and more specifically, inhibitors of the interaction between YAP and TEAD. Therefore, the compounds of formulas I, II, and III of this invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, and metabolites can be used to treat or prevent diseases mediated by the interaction between YAP / TAZ and TEAD. In this document, "diseases mediated by the interaction between YAP / TAZ and TEAD" refers to diseases in which the interaction between YAP / TAZ and TEAD is involved in the occurrence and / or development of the disease, and for which relief, treatment, and / or prevention can be achieved by inhibiting the expression and / or activity of YAP and TEAD or by inhibiting or blocking the YAP-TEAD protein interaction. In this invention, diseases mediated by the interaction between YAP / TAZ and TEAD include, but are not limited to, lung cancer (such as 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, and skin cancer.

[0187] In some implementations, the YAP / TAZ-TEAD interaction mediates malignant pleural mesothelioma (MPM), a rare type of thoracic malignancy. Aberrant activation of the Hippo-YAP pathway is present in approximately 70% of MPM patients and is considered a key cancer driver gene. Reducing Hippo-YAP pathway activity through biological methods and small chemical molecules has shown promising inhibitory effects on tumor growth.

[0188] In some implementations, the disease mediated by the interaction between YAP / TAZ and TEAD is pancreatic ductal adenocarcinoma (PDAC).

[0189] The Hippo-YAP signaling pathway can induce resistance to various anticancer targeted drugs through mechanisms such as mediating tumor cell dormancy and resisting apoptosis. Inhibiting the Hippo-YAP signaling pathway can improve the sensitivity of tumor cells to targeted drugs. Furthermore, as a pathway that promotes tumor cell growth, Hippo-YAP is overactivated in multiple drug-resistant tumor models; inhibiting its activity can significantly improve the sensitivity of therapeutic cells to relevant inhibitors. Therefore, in some embodiments, the I, II, and III compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substitutes, polymorphs, prodrugs, and metabolites can be used to improve the sensitivity of therapeutic cells to targeted drugs (such as EGFR inhibitors, BRAF-targeting inhibitors, MEK-targeting inhibitors, etc.), thereby enhancing the therapeutic efficacy of these tumor-targeting drugs.

[0190] Therefore, the present invention provides a method for treating or preventing diseases mediated by the interaction of YAP / TAZ and TEAD as described herein, the method comprising administering to a desired subject a therapeutically effective amount of a compound of the present invention (I, II, or III), a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug, or a metabolite thereof, or a pharmaceutical composition thereof.

[0191] The “object” or “individual” referred to in this article refers to mammals, especially primates, and more specifically, humans.

[0192] As used herein, the terms “prevention” and “avoidance” include reducing the likelihood of the occurrence or worsening of a disease or condition in a patient; the term also includes preventing the occurrence of a disease or condition in mammals, particularly when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it. “Treatment” and other similar synonyms include the following meanings: (i) suppressing a disease or condition, i.e., curbing its development; (ii) alleviating a disease or condition, i.e., bringing the state of the disease or condition to an end; or (iii) reducing the symptoms caused by the disease or condition.

[0193] As used herein, the terms “effective amount,” “therapeutic effective amount,” “dosage,” and “pharmaceutical effective amount” refer to the amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an “effective amount” for treatment is the amount of a composition comprising, for example, a pharmaceutically acceptable salt of, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope-substituted product, a polymorph, a prodrug, or a metabolite of one of the compounds disclosed herein, which is required to provide significant symptom relief in a clinical setting. Dosage may be determined based on factors such as the subject’s age, sex, the nature and severity of the disease. Effective amounts suitable for any individual case may be determined using techniques such as dose escalation testing.

[0194] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. Methods of administration known in the art are applicable to this invention. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, and intra-arterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques applicable to 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 compounds of this invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites, or pharmaceutical compositions thereof, are administered orally.

[0195] The I, II, or III compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites, or pharmaceutical compositions thereof, may be used in combination with other pharmacologically active compounds, particularly for the treatment of cancer. For example, the I, II, or III compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, metabolites, or pharmaceutical compositions thereof may be administered simultaneously, sequentially, or separately with one or more drugs selected from: chemotherapeutic agents, such as mitotic inhibitors like taxane, vinblastine, paclitaxel, docetaxel, vinblastine, vinblastine, vinorelbine, or vinflunine; other anticancer agents such as cisplatin, 5-fluorouracil, or 5-fluoro-2-4(1H,3H)-pyrimidinidone (5FU), flutamide, or gemcitabine, etc. In some embodiments, the inventive I compounds of the present invention, their pharmaceutically acceptable salts and isomers, or pharmaceutical compositions containing the inventive I compounds of the present invention, their pharmaceutically acceptable salts and isomers may also be used in conjunction with tumor immunotherapy drugs known in the art, such as anti-PD1 antibodies, for the treatment of cancer. Alternatively, compounds of the present invention I, II or III, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope substitutes, polymorphs, prodrugs or metabolites, or pharmaceutical compositions thereof may also be used in combination with conventional radiotherapy.

[0196] In this article, terms such as "combination therapy," "drug combination therapy," "combined medication," or "combination treatment" refer to drug therapy achieved by mixing or combining more than one active ingredient. This includes fixed and non-fixed combinations of active ingredients, or combinations of two or more different treatment modalities. 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 "non-fixed combination" refers to the simultaneous, combined, or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0197] The present invention also provides a pharmaceutical composition comprising the I, II or III compound of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug or metabolite, and a pharmaceutically acceptable carrier or excipient.

[0198] In this application, "pharmaceutical composition" refers to a formulation containing a compound I, II, or III, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope-substituted product, a polymorph, a prodrug, or a metabolite, and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating the absorption of the active ingredient and the exertion of its biological activity. As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound I, II, or III of this invention, its pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope-substituted product, a polymorph, a prodrug, or a metabolite, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting adversely with any component contained in the composition. "Pharmaceutically acceptable carriers or excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0199] In some embodiments, the active ingredient of the pharmaceutical composition of the present invention may contain, in addition to the compounds of the present invention, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope substitutes, polymorphs, prodrugs or metabolites, other known anticancer agents, including but not limited to taxane, vinblastine, paclitaxel, docetaxel, vinblastine, vinblastine, vinorelbine, vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4(1H,3H)-pyrimidinidone (5FU), flutamide and gemcitabine, etc.

[0200] This invention relates to the use of the I, II, or III compounds of this invention, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof, or pharmaceutical compositions thereof, in the treatment or prevention of diseases mediated by the YAP / TAZ-TEAD interaction described herein, or in the preparation of medicaments for the treatment or prevention of diseases mediated by the YAP / TAZ-TEAD interaction described herein. This invention also provides for the treatment or prevention of diseases mediated by the YAP / TAZ-TEAD interaction described herein, the I, II, or III compounds of this invention, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof, or pharmaceutical compositions thereof.

[0201] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0202] The starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidex, and Energie, or can be synthesized by known methods.

[0203] Synthesis of intermediate A1: 8-chloro-7-fluoro-10a-phenyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-3,4,10,10a-tetrahydropyrazine[1,2-a]indole-2(1H)-tert-butyl carbonate

[0204]

[0205] Step 1: Under nitrogen protection, 1,3-dibromo-5-fluoro-2-iodobenzene (7.50 g, 19.7 mmol) and toluene (45 mL) were added sequentially to a dry three-necked flask. Isopropyl magnesium chloride (12.8 mL, 25.6 mmol, 2.0 M) was added dropwise at -30 °C. The resulting brown solution was stirred at -30 °C for 30 minutes. Then, DMF (4.75 g, 65.0 mmol) was added to the solution. The reaction mixture was allowed to warm naturally to 0 °C over 30 minutes and stirred at 0 °C for another 30 minutes. TLC showed the reaction was complete. The reaction mixture was quenched in a saturated ammonium chloride solution. 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 residue was purified by silica gel chromatography (petroleum ether) to give a yellow solid A-1 (4.10 g, yield: 73.9%).

[0206] 1 H NMR (400MHz, CDCl3) δ 10.22 (s, 1H), 7.43 (d, J = 7.6Hz, 2H).

[0207] Step 2: Compound A-1 (4.10 g, 14.5 mmol), tetrahydrofuran (40 mL), methanol (6 mL), and sodium borohydride (329 mg, 8.70 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 20 °C for 0.5 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with water, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid A-2 (4.12 g, crude product).

[0208] 1 H NMR (400MHz, CDCl3) δ7.68 (d, J=8.4Hz, 2H), 5.22 (t, J=5.2Hz, 1H), 4.70 (d, J=5.2Hz, 2H).

[0209] Step 3: 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) were added sequentially to a dry single-necked flask at 20°C. The reaction mixture was stirred at 20°C for 0.5 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether) to give a white solid A (4.40 g, yield: 87.5%).

[0210] 1 H NMR (400MHz, CDCl3) δ7.34 (d, J=7.6Hz, 2H), 4.79 (s, 2H).

[0211] Step 4: Ethyl 2-bromo-2-phenylacetate (13 g, 53.48 mmol, 1.0 eq) and tert-butyl (2-aminoethyl)carbamate (9.42 g, 58.82 mmol, 1.1 eq) were dissolved in ethanol (130 mL), and then triethylamine (8.12 g, 80.21 mmol, 1.5 eq) was added and stirred at 60 °C for 12 hours. TLC showed that the starting material reacted completely and new spots were formed. The reaction solution was evaporated to dryness under reduced pressure, placed in water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain Al-1 (14 g, crude product) as a yellow oil.

[0212] Step 5: Dissolve A1-1 (14g, 43.42mmol) in dichloromethane (90mL) and add trifluoroacetic acid (30mL). Then react at 20℃ for 2h. TLC showed that the starting material reacted completely and new spots were formed. The reaction solution was evaporated to dryness under reduced pressure, placed in water, and the pH was adjusted to neutral with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain A1-2 (1.0g, crude product) as a yellow oil.

[0213] Step 6: Dissolve A1-2 (9.65 g, 43.41 mmol) in ethanol (100 mL) and heat to 85 °C. Add triethylamine (6.59 g, 65.12 mmol) and react at this temperature for 12 h. TLC shows that the starting material reacts completely and new spots are formed. The reaction solution is evaporated to dryness under reduced pressure, placed in water, and the pH is adjusted to neutral with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic phase is dried with anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain A1-3 (5.6 g, crude product) as a white solid.

[0214] 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).

[0215] Step 7: Compound A1-3 (4.67 g, 26.5 mmol) was suspended in dioxane (100 mL), and Boc2O anhydride (5.78 g, 26.5 mmol) was added. The mixture was heated at 90°C for 1 hour. The reaction was monitored by TLC until completion. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. The crude product was slurried in petroleum ether:ethyl acetate = 10:1 to give a light pink solid A1-4 (6.82 g, yield: 93%).

[0216] 1H NMR (400MHz, DMSO-d6) δ 8.27 (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).

[0217] Step 8: Compound A1-4 (6.82 g, 24.7 mmol) was dissolved in tetrahydrofuran (120 mL), and 60% sodium hydroxide (1.09 g, 27.2 mmol) was added in one go at 20°C, with stirring for 5 minutes. Then benzyl bromide (4.83 g, 28.4 mmol) was added and stirred overnight. The reaction was monitored by TLC until complete, quenched with methanol (5 mL), and diluted with water (80 mL). Most of 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 subjected to silica gel column chromatography (methanol / dichloromethane = 6 / 100) to give a colorless viscous liquid A1-5 (7 g, yield: 77%).

[0218] 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).

[0219] Step 9: At -50°C, add 6.4 mL of diisopropylaminolithium solution (12.7 mmol, 2.0 M) dropwise to a tetrahydrofuran (40 mL) solution of compound A1-5 (3.59 g, 9.80 mmol). Stir the reaction mixture at -30°C for 1 hour. Then cool to -50°C and add a tetrahydrofuran (10 mL) solution of compound A (3.40 g, 9.8 mmol). Gradually heat the reaction mixture to 20°C and continue stirring for 12 hours. After the reaction is complete, quench with saturated ammonium chloride solution. Extract the resulting mixture with ethyl acetate. Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give a white solid A1-6 (6.10 g, yield: 98.4%).

[0220] 1H NMR (400MHz, CDCl3) 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).

[0221] Step 10: Add 20 mL of trifluoroacetic acid to a solution of A1-6 (6.10 g, 9.65 mmol) in dichloromethane (40 mL). Stir the reaction mixture at 30 °C for 2 hours. After the reaction is complete, concentrate the reaction mixture to dryness under reduced pressure. Add 60 mL of saturated sodium bicarbonate solution to the concentrated residue and extract with ethyl acetate. Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a yellow solid A1-7 (5.10 g, yield: 99.2%).

[0222] 1 H NMR (400MHz, CDCl3) δ7.45-7.38 (m, 2H), 7.35-7.20 (m, 10H), 4.96 (d, J=14.4Hz, 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).

[0223] Step 11: Compound A1-7 (5.10 g, 9.58 mmol), DMA (50 mL), and sodium hydride (768 mg, 19.2 mmol, 60% in mineral oil) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 100 °C for 6 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give a white solid A1-8 (4.0 g, yield: 92.6%).

[0224] 1H NMR (400MHz, CDCl3) 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).

[0225] Step 12: Compound A1-8 (4.0 g, 8.86 mmol), tetrahydrofuran (40 mL), and borane dimethyl sulfide (35.5 mL, 70.9 mmol, 2 M) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 65 °C for 20 hours. The reaction mixture was quenched with methanol and then concentrated to dryness under reduced pressure. The residue was dissolved in methanol (40 mL) and 4N dioxane hydrochloride (20 mL), and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, saturated sodium bicarbonate solution (150 mL) was added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oily substance A1-9 (4.10 g, crude product).

[0226] Step 13: In a dry single-necked flask, compound A1-9 (4.10 g, 8.86 mmol), 1,2-dichloroethane (40 mL), and 2-chloroethyl chloroformate (3.17 g, 22.2 mmol) were added sequentially. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in methanol and stirred at 75 °C for 1.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a yellow oily compound 6 (3.10 g, crude product).

[0227] Step Fourteen: Compound 6 (3.08 g, 8.86 mmol), dichloromethane (50 mL), triethylamine (3.58 g, 35.4 mmol), and Boc₂O (2.90 g, 13.3 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 20 °C 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 a white solid Al-10 (3.10 g, yield: 78.3%).

[0228] 1H NMR (400MHz, CDCl3) 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).

[0229] Step 15: Compound A1-10 (1.0 g, 2.24 mmol), acetonitrile (20 mL), and NCS (299 mg, 2.24 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 20 °C for 4 hours. The reaction mixture 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 A1-11 (700 mg, yield: 64.8%).

[0230] 1 H NMR (400MHz, CDCl3) 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).

[0231] Step 16: In a dry three-necked flask, compound A1-11 (600 mg, 1.25 mmol), bis-pinacolborate (635 mg, 2.50 mmol), xylene (10 mL), Pd(dppf)Cl2·CH2Cl2 (102 mg, 0.125 mmol), and potassium pentovalinate (526 mg, 3.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid A1 (470 mg, yield: 71.1%).

[0232] 1H NMR (400MHz, CDCl3) 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).

[0233] Synthesis of intermediate A2: 8-chloro-7-fluoro-10a-(3-methoxyphenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-tert-butyl carbonate

[0234]

[0235] Step 1: Under argon protection, tetraisopropyl titanate (24 g, 84.9 mmol) was added dropwise to a solution of 3-benzyloxybenzaldehyde (A2-1, 45 g, 212.3 mmol) in dichloromethane (900 mL) at 0 °C. After slowly raising the temperature to room temperature, TMSCN (84.2 g, 849.2 mmol) was added. The mixture was stirred at room temperature for 4 h. TLC showed the reaction was complete. The reaction was quenched by adding an aqueous solution of hydrochloric acid (20 mL, 1.5 M) at 0 °C. Water (270 mL) was added, and the mixture was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with water (2 × 100 mL), and then washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 1:6) to give a yellowish-brown oily substance, 2-(3-(benzyloxy)phenyl)-2-hydroxyacetonitrile (A2-2, 44 g, yield: 86.8%).

[0236] 1 H 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).

[0237] Step 2: Dissolve 44 g (183.9 mmol) of 2-(3-(benzyloxy)phenyl)-2-hydroxyacetonitrile in HCl / MeOH (4N, 500 mL). Stir the reaction mixture at 80 °C for 14 h. Confirm the reaction is complete by TLC. Concentrate the reaction mixture under reduced pressure to near dryness. Add water (400 mL) to the residue and extract with ethyl acetate (3 x 300 mL). Combine the organic phases, wash with water (2 x 150 mL), and wash with saturated brine (100 mL). Dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (ethyl acetate:petroleum ether = 1:4) to give methyl 2-(3-(benzyloxy)phenyl)-2-hydroxyacetate (A2-3, 37.3 g, yield: 74.5%).

[0238] 1 H 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).

[0239] Step 3: Add SOCl2 (18 g, 150.7 mmol) to a solution of methyl 2-(3-(benzyloxy)phenyl)-2-hydroxyacetate (37.3 g, 137.0 mmol) in dichloromethane (100 mL). Heat to 60 °C and react for 5 h. TLC showed complete reaction; concentrate the reaction solution under reduced pressure. Add water (100 mL) to the residue and adjust the pH to 8 with saturated sodium bicarbonate solution. Extract with ethyl acetate (3 x 400 mL). Combine the organic phases, wash with water (2 x 200 mL), and wash with saturated brine (3 x 200 mL). Dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (ethyl acetate:petroleum ether = 1:5) to give a pale white solid methyl 2-(3-(benzyloxy)phenyl)-2-chloroacetate (A2-4, 35.5 g, yield: 89.1%).

[0240] 1 H NMR (400MHz, CDCl3), 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).

[0241] Step 4: Add triethylamine (18.5 g, 183.2 mmol) and N-tert-butoxycarbonyl-1,2-ethylenediamine (25.4 g, 158.6 mmol) to a methanol (350 mL) solution of methyl 2-(3-(benzyloxy)phenyl)-2-chloroacetate (35.5 g, 122.1 mmol). Heat to 60 °C and stir for 18 h. TLC and LCMS showed the reaction was complete. Concentrate the reaction solution under reduced pressure. Extract the residue with ethyl acetate (3 x 200 mL) after adding water (600 mL). Combine the organic phases and wash with saturated brine (3 x 200 mL). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to give a light white oily substance, methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-(3-(benzyloxy)phenyl)acetate (A2-5, 30.5 g, yield: 60.3%).

[0242] LCMS: m / z 415 [M+H] +

[0243] Step 5: Add 60 mL of trifluoroacetic acid dropwise 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). React at 20 °C for 2 h. Concentrate the reaction solution to dryness under reduced pressure. Add 150 mL of ethyl acetate and 300 mL of saturated sodium bicarbonate aqueous solution to the residue. Collect the organic phase, and extract the aqueous phase with ethyl acetate (3 x 150 mL). Combine the organic phases, wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain crude methyl 2-((2-aminoethyl)amino)-2-(3-(benzyloxy)phenyl)acetate (A2-6, 27.0 g), which can be used directly in the next step of the reaction.

[0244] LCMS: m / z 315.3 [M+H] +

[0245] 1 H NMR (400MHz, DMSO-d6): 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).

[0246] Step Six: Add triethylamine (13.0 g, 128.77 mmol) to a 50 mL ethanol solution of methyl 2-((2-aminoethyl)amino)-2-(3-(benzyloxy)phenyl)acetate (27.0 g, 85.85 mmol). Stir the reaction mixture at 85 °C for 3 h. Concentrate the reaction solution under reduced pressure, dilute the residue with ethyl acetate (100 mL), wash with water (3 x 100 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude 3-(3-(benzyloxy)phenyl)piperazin-2-one (A2-7, 17.0 g, two-step yield: 83%), which is directly used in the next step of the reaction.

[0247] LCMS: m / z 283.1 [M+H] +

[0248] Step 7: Add di-tert-butyl dicarbonate (14.5 g, 66.3 mmol) and triethylamine (18.3 g, 180.8 mmol) to a solution of 3-(3-(benzyloxy)phenyl)piperazin-2-one (17.0 g, 60.3 mmol) in 1,4-dioxane (150 mL). Stir at 90 °C for 1.5 h. Concentrate the reaction solution to dryness, add diethyl ether (100 mL), stir and slurry, and filter to obtain a white solid 2-(3-(benzyloxy)phenyl)-3-oxoperazin-1-carboxylic acid tert-butyl ester (A2-8, 18.0 g, yield: 78.2%).

[0249] LCMS: m / z 765.4 [2M+H] +

[0250] 1 H NMR: (400MHz, CDCl3), 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).

[0251] Step 8: Under argon protection, at 20°C, add NaH (60% dispersed in oil, 785 mg, 19.6 mmol) to a tetrahydrofuran (75 mL) solution of 2-(3-(benzyloxy)phenyl)-3-oxoperazine-1-carboxylic acid tert-butyl ester (5.0 g, 13.1 mmol). After stirring for 30 min, add benzyl bromide (3.4 g, 19.62 mmol). Stir the reaction mixture at room temperature for 16 h. Dilute the reaction solution with ethyl acetate (100 mL) and pour it into ice water (150 mL). Collect the organic phase, and extract the aqueous phase with ethyl acetate (3 x 100 mL). Combine the organic phases, wash with saturated brine (200 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) to give a colorless, transparent oily tert-butyl 4-benzyl-2-(3-(benzyloxy)phenyl)-3-oxoperazine-1-carboxylic acid (A2-9, 3.8 g, yield: 61.5%).

[0252] LCMS: m / z 473.2 [M+H] +

[0253] 1 H NMR (400MHz, CDCl3), 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, 1.H), 3.87(s, 1H), 3.34~3.23(m, 2H), 3.18~3.14(m, 1H), 1.44(s, 9H).

[0254] Step 9: Under argon protection, at -50°C, add LDA (2.0 M in THF, 14.9 mL, 29.8 mmol) dropwise to a tetrahydrofuran (150 mL) solution of 4-benzyl-2-(3-(benzyloxy)phenyl)-3-oxoperazine-1-carboxylic acid tert-butyl ester (10.8 g, 22.9 mmol). After the addition is complete, stir at approximately -30°C for 1 h. Cool to -50°C and add a tetrahydrofuran (50 mL) solution of 1,3-dibromo-2-(bromomethyl)-5-fluorobenzene (7.2 g, 20.8 mmol). Allow to rise naturally to room temperature and stir for 16 h. Pour the reaction mixture into an ice bath (150 mL). Extracted with ethyl acetate (3 x 150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 100 to 1 / 4) to give 4-benzyl-2-(3-(benzyloxy)phenyl)-2-(2,6-dibromo-4-fluorobenzyl)-3-oxoperazine-1-carboxylic acid tert-butyl ester (A2-10, 13.0 g, yield: 77.0%).

[0255] LCMS: m / z 739.3 [M+H] +

[0256] 1 H NMR (400MHz, CDCl3): 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).

[0257] Step 10: Add trifluoroacetic acid (45 mL) dropwise to a solution of 4-benzyl-2-(3-(benzyloxy)phenyl)-2-(2,6-dibromo-4-fluorobenzyl)-3-oxoperazine-1-carboxylic acid tert-butyl ester (13.0 g, 17.6 mmol) in dichloromethane (85 mL). React at 30 °C for 2 h. Concentrate to dryness under reduced pressure. Add dichloromethane (200 mL) and saturated sodium bicarbonate aqueous solution (300 mL) to the residue. Extract the aqueous phase again with dichloromethane (3 x 150 mL). Combine the organic phases, wash with saturated brine (150 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify 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, 10.5 g, yield: 93.4%).

[0258] LCMS: m / z 639.0 [M+H] +

[0259] 1 H NMR (400MHz, CDCl3): 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), 3-7 7(d, J=14.4Hz, 1H), 3.36~3.29(m, 1H), 2.99~2.94(m, 2H), 2.44(s, 1H).

[0260] Step 11: Dissolve 3.0 g (4.70 mmol) of 1-benzyl-3-(3-(benzyloxy)phenyl)-3-(2,6-dibromo-4-fluorobenzyl)piperazin-2-one in 50 mL of trifluoroacetic acid. Heat to 60 °C and stir for 2 h. Concentrate the reaction solution to dryness under reduced pressure, dilute with 300 mL of ethyl acetate, wash with 400 mL of saturated sodium bicarbonate solution, wash with 2 x 400 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel chromatography (0 to 50% gradient of ethyl acetate: petroleum ether) to obtain a white solid 1-benzyl-3-(2,6-dibromo-4-fluorobenzyl)-3-(3-hydroxyphenyl)piperazin-2-one (A2-12, 2.1 g, yield: 82%).

[0261] 1 H NMR (400MHz, DMSO-d6): 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).

[0262] Step 12: Dimethyl sulfate (525 mg, 4.16 mmol) was added to a MeCN (30 mL) 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). The reaction mixture was heated to 60 °C and stirred for 4 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (100 mL), washed with saturated brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate:petroleum ether) to obtain a white solid 1-benzyl-3-(2,6-dibromo-4-fluorobenzyl)-3-(3-methoxyphenyl)piperazin-2-one (A2-13, 1.16 g, yield: 60%).

[0263] LCMS: m / z 563.3 [M+H] +

[0264] 1 H NMR (400MHz, DMSO-d6): 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=8.0H z, 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).

[0265] 19 F NMR (376MHz, DMSO-d6): δ-113.37.

[0266] Remaining steps: Referring to the synthesis method of intermediate A1, replace A1-7 with A2-13 and carry out a six-step reaction to obtain intermediate A2.

[0267] Synthesis of intermediate A3: 8-chloro-7-fluoro-10a-(3-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-tert-butyl carbonate

[0268]

[0269] Step 1: Under argon protection, N-bromosuccinimide (34.40 g, 193.26 mmol) and azobisisobutyronitrile (9.76 g, 59.46 mmol) were added to a carbon tetrachloride (250 mL) solution of methyl 3-fluorophenylacetate (25.00 g, 148.66 mmol). The reaction was heated to 70 °C and reacted for 20 h. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 40 / 1 to 20 / 1) to give a yellow liquid methyl 2-bromo-2-(3-fluorophenyl)acetate (A3-2, 35.6 g, yield: 96.9%).

[0270] 1 H NMR (400MHz, CDCl3): δppm 7.34~7.27 (m, 3H), 7.05 (s, 1H), 5.32 (s, 1H), 3.80 (s, 3H).

[0271] 19 FNMR (376MHz, CDCl3) δppm-111.72.

[0272] Remaining steps: Referring to the synthesis method of intermediate A1, replace ethyl 2-bromo-2-phenylacetate with A3-2 and carry out thirteen steps of reaction to obtain intermediate A3.

[0273] Synthesis of intermediate A4: 8-chloro-10a-(3-chlorophenyl)-7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-tert-butyl carbonate

[0274]

[0275] Referring to the synthesis method of intermediate A3, A4-1 was used instead of A3-1, and a fourteen-step reaction was carried out to obtain intermediate A4.

[0276] Synthesis of intermediate A5: 2-Benzyl-8-chloro-7-fluoro-10a-(pyridin-3-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1,2,3,4,10,10a-tetrahydropyrazino[1,2-a]indole

[0277]

[0278] Steps one through nine: Following the synthesis method of intermediate A3, replace A3-1 with A5-1 and carry out a nine-step reaction to obtain intermediate A5-10.

[0279] Step 10: Compound A5-10 (585 mg, 1.29 mmol), tetrahydrofuran (10 mL), and borane dimethyl sulfide (5.2 mL, 10.3 mmol, 2 M) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 35 °C for 50 hours. The reaction mixture was quenched with methanol and then concentrated to dryness under reduced pressure. The residue was dissolved in methanol (10 mL) and 4N dioxane hydrochloride (2 mL), and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless oily substance A5-11 (350 mg, yield: 61.9%).

[0280] 1H NMR (400MHz, CDCl3) 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).

[0281] Step 11: Compound A5-11 (450 mg, 1.03 mmol), acetonitrile (20 mL), and NCS (138 mg, 1.03 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give a white solid A5-12 (310 mg, yield: 63.7%).

[0282] 1 H NMR (400MHz, CDCl3) 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).

[0283] Step 12: In a dry three-necked flask, compound A5-12 (310 mg, 0.656 mmol), bis-pinacolborate (333 mg, 1.31 mmol), xylene (6 mL)Pd(dppf)Cl2·CH2Cl2 (54 mg, 0.066 mmol), and potassium pentovalinate (276 mg, 1.97 mmol) were added sequentially. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily substance A5 (250 mg, crude product).

[0284] LCMS: m / z 520.3 [M+H] + .

[0285] Synthesis of intermediate A6: 8-chloro-7-methoxy-10a-phenyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-3,4,10,10a-tetrahydropyrazine[1,2-a]indole-2(1H)-tert-butyl carbonate

[0286]

[0287] Step 1: Add compound A1-11 (200 mg, 0.42 mmol) and sodium methoxide solution (6 mL, 5.4 M) to a single-necked flask. Heat the mixture to 80 °C and react overnight. Quench the reaction solution with saturated ammonium chloride solution, extract with ethyl acetate (50 mL * 2), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a yellow oily substance A6-1 (250 mg, crude product).

[0288] LCMS: m / z 493 / 495 [M+H] + .

[0289] Step 2: Referring to the synthesis method of intermediate A1, replace A1-11 with A6-1 and carry out a one-step reaction to obtain intermediate A6.

[0290] Synthesis of intermediate A7: 7-fluoro-8-methyl-10a-phenyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-3,4,10,10a-tetrahydropyrazine[1,2-a]indole-2(1H)-tert-butyl carbonate

[0291]

[0292] Step 1: Compound A1-10 (390 mg, 0.87 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a three-necked flask. LDA (0.865 mL, 2 M, 1.73 mmol) was added dropwise at -50 °C. The mixture was allowed to react at -50 °C for 45 minutes. Then iodomethane (246 mg, 1.73 mmol) was added dropwise. The resulting mixture was stirred at -50 °C for one hour, then brought to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (30 mL * 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oil. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1 / 3) to give A7-1 (280 mg, 0.630 mmol, 72.79%).

[0293] LCMS: m / z 461 / 463[M+H]+ .

[0294] Step 2: Referring to the synthesis method of intermediate A1, replace A1-11 with A7-1 and carry out a one-step reaction to obtain intermediate A7.

[0295] Synthesis of intermediate B1: 2-bromo-3-fluoro-4-hydroxybenzonitrile

[0296]

[0297] Step 1: At 25°C, dichloromethane (20 mL), 2-bromo-3,4-difluorobenzoic acid (B1-1, 2 g, 8.44 mmol, 1.0 eq), HATU (4.83 g, 12.7 mmol, 1.5 eq), triethylamine (5.5 mL, 42.2 mmol, 5.0 eq), and ammonium chloride (1.35 g, 25.3 mmol, 3.0 eq) were added sequentially to a round-bottom flask. The yellow reaction solution was stirred at this temperature for 12 hours. TLC showed that the reaction was complete. The mixture was extracted with water (30 mL) and dichloromethane (30 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. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1 / 10) to give a white solid 2-bromo-3,4-difluorobenzamide (B1-2, 1.8 g, yield: 90%).

[0298] 1 H 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).

[0299] Step 2: At 25°C, tetrahydrofuran (20 mL), 2-bromo-3,4-difluorobenzoamide (B1-2, 1.8 g, 7.63 mmol, 1.0 eq), triethylamine (2.12 mL, 15.3 mmol, 2.0 eq), and trifluoroacetic anhydride (2.39 g, 11.4 mmol, 1.5 eq) were added sequentially to a round-bottom flask. The yellow reaction mixture was stirred at this temperature for 12 hours. TLC showed that the reaction was complete. The mixture was extracted with water (30 mL) and dichloromethane (30 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 residue was purified by silica gel chromatography (0 to 6% gradient of ethyl acetate: petroleum ether) to give a white solid 2-bromo-3,4-difluorobenzonitrile (B1-3, 1.5 g, yield: 90%).

[0300] 1 H NMR (400MHz, CDCl3) δ7.50 (ddd, J=8.8, 4.8, 2.0Hz, 1H), 7.33-7.24 (m, 1H).

[0301] Step 3: Add dimethyl sulfoxide (11.5 mL), 2-bromo-3,4-difluorobenzonitrile (B1-3, 1.5 g, 6.88 mmol, 1.0 eq), potassium carbonate (4.75 g, 34.4 mmol, 5.0 eq), and acetylhydroxamic acid (1.55 g, 20.6 mmol, 3.0 eq) sequentially to a round-bottom flask. Heat the yellow reaction solution to 80°C and stir for 4 hours. TLC showed the reaction was complete. Filter under reduced pressure, adjust the pH of the filtrate to 5 with dilute hydrochloric acid (0.5 N), extract with ethyl acetate (50 mL * 3), wash the organic phase with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and remove volatiles under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% gradient of ethyl acetate: petroleum ether) to give a yellow solid 2-bromo-3-fluoro-4-hydroxybenzonitrile (B1, 1.0 g, yield: 67.1%).

[0302] Synthesis of intermediate B2: 2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluorobenzonitrile

[0303]

[0304] Step 1: At 20°C, tetrahydrofuran (20 mL), 2-((tert-butyldimethylsilyl)oxy)ethane-1-ol (B2-1, 1.76 g, 10.0 mmol, 1.0 eq), imidazole (2.04 g, 30.0 mmol, 3.0 eq), triphenylphosphine (3.93 g, 15.0 mmol, 1.5 eq), and elemental iodine (3.04 g, 12.0 mmol, 1.2 eq) were added sequentially to a round-bottom flask. The pale yellow reaction solution was stirred at this temperature for 2 hours. TLC showed that the reaction was complete. The volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether) to give a yellow oily substance, tert-butyl(2-iodoethoxy)dimethylsilane (B2-2, 2.4 g, yield: 83.9%).

[0305] 1 H NMR (400MHz, DMSO_d6) δ 3.90-3.76 (m, 2H), 3.27-3.13 (m, 2H), 0.99-0.83 (m, 9H), 0.16-0.03 (m, 6H).

[0306] Step 2: Compound B1 (500 mg, 2.31 mmol), DMF (10 mL), compound B2-2 (727 mg, 2.54 mmol), and potassium carbonate (638 mg, 4.62 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with water, and the aqueous phase was extracted twice 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 residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily substance B2 (700 mg, yield: 80.9%).

[0307] 1 H NMR (400MHz, CDCl3) 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).

[0308] Synthesis of intermediate B3: Methyl 2-bromo-4-(2-(((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluorobenzoate

[0309]

[0310] Step 1: At 25°C, anhydrous methanol (42 mL), 2-bromo-3,4-difluorobenzoic acid (B1-1, 3.3 g, 14.8 mmol, 1.0 eq), and then thionyl chloride (7 mL) were added dropwise to a round-bottom flask. The yellow reaction solution was stirred at this temperature for 4 hours. TLC showed that the reaction was complete. The volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether) to give a yellow oily methyl 2-bromo-3,4-difluorobenzoate (B3-1, 3.4 g, yield: 92.6%).

[0311] Step 2: Following the synthesis method of intermediate B1 in Step 3, methyl 2-bromo-3-fluoro-4-hydroxybenzoate (B3-2, 3.5 g, yield: 93.5%) was obtained as a yellow solid.

[0312] 1 H NMR (400MHz, DMSO_d6) δ 11.18 (s, 1H), 7.58 (dd, J=8.8, 1.6Hz, 1H), 7.02 (t, J=8.4Hz, 1H), 3.80 (s, 3H).

[0313] Step 3: Following the synthesis method of intermediate B2 in Step 2, a colorless oily compound methyl 2-bromo-4-(2-(((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluorobenzoate (B3, 1.44 g, yield: 88.3%) was obtained.

[0314] Synthesis of intermediate B4: Ethyl 2-(3-bromo-4-cyano-2-fluorophenoxy)acetate

[0315]

[0316] Step 1: Compound B1 (500 mg, 2.31 mmol), DMF (10 mL), ethyl bromoacetate (463 mg, 2.77 mmol), and potassium carbonate (638 mg, 4.62 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give a white solid B4 (650 mg, yield: 93.1%).

[0317] 1 H NMR (400MHz, CDCl3) 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).

[0318] Synthesis of intermediate B5: 2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluorobenzonitrile

[0319]

[0320] Step 1: 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) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 35 °C for 12 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily substance B5-1 (1.60 g, yield: 97.6%).

[0321] 1H NMR (400MHz, CDCl3) 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).

[0322] Step 2: 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 added sequentially to a dry single-necked flask. The reaction mixture was stirred at 85 °C for 36 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily compound B5-2 (1.0 g, yield: 78.1%).

[0323] 1 H NMR (400MHz, CDCl3) 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).

[0324] Step 3: Compound B5-2 (150 mg, 0.524 mmol), ethanol (5 mL), and sodium borohydride (40 mg, 1.05 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 20 °C for 36 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2:1) to give a white solid B5-3 (100 mg, yield: 78.1%).

[0325] 1 H NMR (400MHz, CDCl3) 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).

[0326] Step 4: Compound B5-3 (100 mg, 0.410 mmol), dichloromethane (3 mL), DMF (1 mL), tert-butyldimethylchlorosilane (93 mg, 0.615 mmol), and N,N-diisopropylethylamine (106 mg, 0.820 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily substance B5 (103 mg, yield: 70.1%).

[0327] 1 H NMR (400MHz, CDCl3) 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).

[0328] Synthesis of intermediate B6: 2-bromo-4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-3-fluorobenzonitrile

[0329]

[0330] Following the synthetic method of compound B2, tert-butyl-(3-iodopropoxy)dimethylsilane was used instead of compound B2-2 to carry out a one-step reaction to obtain crude compound B6, which was directly used in the next step of the reaction.

[0331] Synthesis of intermediate B7: 2-bromo-3-fluoro-4-morpholinobenzonitrile

[0332]

[0333] Following the synthetic method of compound B5-1, morpholine was used instead of diethyl malonate to carry out a one-step reaction to obtain crude compound B7, which was directly used in the next step of the reaction.

[0334] Synthesis of intermediate B8: 2-bromo-4-(1,1-thiomorpholino)-3-fluorobenzonitrile

[0335]

[0336] Following the synthetic method of compound B5-1, 1,1-thiomorpholine dioxide was used instead of diethyl malonate in a one-step reaction to obtain crude compound B8, which was then directly used in the next step of the reaction.

[0337] Synthesis of intermediate B9: 2-bromo-3-fluoro-4-((tetrahydro-2H-pyran-4-yl)amino)benzonitrile

[0338]

[0339] Following the synthetic method of compound B5-1, 4-aminotetrahydropyran was used instead of diethyl malonate to carry out a one-step reaction to obtain crude compound B9, which was directly used in the next step of the reaction.

[0340] Synthesis of intermediate B10: (S)-2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-3-fluorobenzonitrile

[0341]

[0342] Step 1: L-methyl lactate (1.0 g, 9.61 mmol), dichloromethane (15 mL), tert-butyldimethylchlorosilane (1.88 g, 12.5 mmol), triethylamine (1.46 g, 14.4 mmol), and 4-dimethylaminopyridine (117 mg, 0.961 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oil, B10-1 (1.70 g, yield: 81.0%).

[0343] 1 H NMR (400MHz, CDCl3) 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).

[0344] Step 2: Compound B10-1 (1.70 g, 7.78 mmol), tetrahydrofuran (20 mL), and diisobutylaluminum hydride (13.0 mL, 19.5 mmol, 1.5 M) were added sequentially to a dry single-necked flask at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched at 0°C with 1.0 M sodium potassium tartrate solution (30 mL), and stirring was continued at 25°C for 30 minutes. The resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily compound B10-2 (1.10 g, yield: 74.3%).

[0345] 1H NMR (400MHz, CDCl3) 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).

[0346] Step 3: Compound B10-2 (500 mg, 2.63 mmol), dichloromethane (10 mL), triethylamine (798 mg, 7.89 mmol), and methanesulfonic anhydride (688 mg, 3.95 mmol) were added sequentially to a dry single-necked flask at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily substance B10-3 (540 mg, yield: 76.5%).

[0347] 1 H NMR (400MHz, CDCl3) 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).

[0348] Step 4: 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) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with water and extracted twice 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 residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily substance B10 (100 mg, yield: 27.8%).

[0349] 1 H NMR (400MHz, CDCl3) δ7.42 (dd, J=8.8, 2.0Hz, 1H), 6.98 (dd, J=8.4, 7.2Hz, 1H), 4.28-4.1 8 (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).

[0350] Synthesis of intermediate B11: (R)-2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-3-fluorobenzonitrile

[0351]

[0352] Following the synthetic method of compound B10, compound B11 was obtained by replacing compound L-methyl lactate with compound D-methyl lactate in a four-step reaction.

[0353] 1 H NMR (400MHz, CDCl3) δ7.42 (dd, J=8.8, 2.0Hz, 1H), 6.98 (dd, J=8.4, 7.2Hz, 1H), 4.28-4.1 8 (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).

[0354] Synthesis of intermediate B12: Methyl 4-(2-(benzyloxy)ethoxy)-2-bromo-3-fluorobenzoate

[0355]

[0356] Colorless oily compound B12 (1.32 g, yield: 85.7%) was synthesized using the same method as intermediate B3.

[0357] Synthesis of intermediate B13: tert-butyl 5-bromo-6-cyano-4-fluoroindole-1-carboxylic acid

[0358]

[0359] Step 1: Add B13-1 (6.5 g, 27.8 mmol, 1.0 eq), DMF-DMA (13 mL, 61.1 mmol, 2.2 eq), triethylamine (4.25 mL, 61.1 mmol, 2.2 eq), and DMF (25 mL) sequentially to a 500 mL round-bottom flask. Heat to 110°C and stir for 3 hours. TLC showed the reaction was complete. Dilute the reaction mixture with water (50 mL) and extract with ethyl acetate (50 mL x 3). Wash the combined organic phases with saturated sodium bicarbonate aqueous solution (150 mL), saturated sodium thiosulfate aqueous solution (150 mL), and saturated brine (150 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Dissolve the residue in acetic acid / toluene (100 mL / 150 mL), add reduced iron powder (31 g, 555 mmol, 20.0 eq), and heat to 100°C and stir for 1 hour. Cool, filter, pour the reaction mixture into ice water, and extract with ethyl acetate (150 mL * 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to give a yellow solid B13-2 (3.7 g, yield: 60%).

[0360] 1 H NMR (400MHz, CDCl3) δ 8.27 (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).

[0361] Step 2: Under nitrogen protection, compound B13-2 (3.7 g, 17.3 mmol, 1.0 eq), zinc cyanide (1.34 g, 11.42 mmol, 0.66 eq), and t-BuXPhos-Pd-G3 (686 mg, 0.86 mmol, 0.05 eq) were added sequentially to a dry three-necked flask, followed by the addition of THF / H2O (10 mL / 50 mL). The reaction mixture was stirred at 40 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to give a yellow solid B13-3 (2.85 g, yield: 93%).

[0362] LCMS: [M+H] + =161.

[0363] Step 3: Under nitrogen protection, compound B13-3 (0.68 g, 4.25 mmol, 1.0 eq), triethylsilane (1 mL, 26.6 mmol, 6.25 eq), and tetrahydrofuran (6 mL) were added sequentially to a dry round-bottom flask. The reaction mixture was stirred at 60 °C for 5 hours. TLC showed that the reaction was complete. The reaction mixture was evaporated to dryness, diluted with water (10 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give a yellow solid B13-4 (566 mg, yield: 82.2%).

[0364] LCMS: [M+H] + =163.

[0365] Step 4: Under ice bath cooling, compound B13-4 (562 mg, 3.47 mmol, 1.0 eq) and acetonitrile (10 mL) were added sequentially to a dry round-bottom flask, followed by dropwise addition of an acetonitrile solution of NBS (617 mg, 3.47 mmol, 1.0 eq) (10 mL). The reaction mixture was stirred at 0 °C for 0.5 h. TLC showed that the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (60 mL), saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give a white solid B13-5 (423 mg, yield: 59.6%).

[0366] F-NMR (400MHz, CDCl3): -108.80;

[0367] 1 H NMR (400MHz, CDCl3) δ 6.63 (S, 1H), 3.72 (t, J = 8.8Hz, 2H), 3.18 (m, 2H).

[0368] Step 5: Under ice bath cooling, compound B13-S (50 mg, 0.2 mmol, 1.0 eq) and dichloromethane (4 mL) were added sequentially to a dry round-bottom flask, followed by (Boc)₂O (66 mg, 0.3 mmol, 1.5 eq) and DMAP (24.4 mg, 0.2 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete, and the reaction mixture was concentrated. The resulting residue was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to give a white solid B13 (50 mg, yield: 73%).

[0369] LCMS: m / z = 340.95 [M+H] + .

[0370] Synthesis of intermediate B14: tert-butyl 6-bromo-5-cyano-7-fluoro-1H-indole-1-carboxylate

[0371]

[0372] Step 1: Acetonitrile (20 mL), ammonia (20 mL), and B1-3 (2.18 g, 10.0 mmol, 1.0 eq) were added sequentially to a 60 mL pressure-resistant flask. The mixture was then heated to 60 °C and stirred for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid B14-2 (1.9 g, yield: 88.4%).

[0373] Step 2: Acetic acid (20 mL), B14-2 (21.0 g, 4.65 mmol, 1.0 eq), and NIS (1.57 g, 6.98 mmol, 1.5 eq) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (35 mL x 3). The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (100 mL), saturated sodium thiosulfate aqueous solution (100 mL), and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-15% ethyl acetate / petroleum ether) to give a yellow solid B14-3 (1.3 g, yield: 81.8%).

[0374] 1 H NMR (400MHz, CDCl3) δ7.71 (d, J=1.6Hz, 1H), 4.79 (s, 2H).

[0375] Step 3: Under nitrogen protection at 25°C, tetrahydrofuran (20 mL), B14-3 (1.5 g, 4.4 mmol, 1.0 eq), diphenylphosphine dichloride (154 mg, 0.22 mmol, 0.05 eq), cuprous iodide (84 mg, 0.44 mmol, 0.1 eq), and triethylamine (1.22 mL, 8.8 mmol, 2.0 eq) were added dropwise with stirring. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, 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 residue was dissolved in anhydrous methanol (20 mL), and then potassium carbonate (1.22 g, 8.8 mmol, 2.0 eq) was added. The reaction mixture was stirred for 2 hours. After the reaction was complete, the mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-13% ethyl acetate / petroleum ether) to give a yellow solid B14-4 (700 mg, yield: 66.7%).

[0376] 1 H NMR (400MHz, DMSO_d6) δ7.65 (d, J=1.2Hz, 1H), 6.79 (s, 2H), 4.68 (s, 1H).

[0377] Step 4: Under nitrogen protection, pyridine (10 mL), compound B14-4 (700 mg, 2.93 mmol, 1.0 eq), and CpRuCl(PPh3)2 (233 mg, 0.29 mmol, 0.1 eq) were added sequentially to a dry three-necked flask. The reaction mixture was stirred at 90 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-13% ethyl acetate / petroleum ether) to give a yellow solid B14-5 (170 mg, yield: 24.3%).

[0378] 1 H 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).

[0379] Step 5: Add dichloromethane (2 mL), B14-5 (70 mg, 0.29 mmol, 1.0 eq), Boc2O (96 mg, 0.44 mmol, 1.5 eq), triethylamine (82 μL, 0.59 mmol, 2.0 eq), and N,N-dimethylpyridine (4 mg, 0.03 mmol, 0.1 eq) sequentially to a dry single-necked flask. Stir the reaction mixture at 25°C for 1 hour. After the reaction is complete, concentrate the reaction mixture under reduced pressure. Purify the residue by silica gel chromatography (0-7.2% ethyl acetate / petroleum ether) to give a white solid B14 (94 mg, yield: 94.9%).

[0380] LCMS: m / z = 339.16(M+H) + .

[0381] Synthesis of intermediate B15: 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-fluoro-4-iodofumonitrile

[0382]

[0383] Step 1: NBS (64.1 g, 360.36 mmol) was added to a DMF (400 mL) solution of 2-amino-3-fluoropyridine (B15-1, 40.0 g, 356.79 mmol) under ice-water bath conditions. The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was poured into an ice-cold saturated sodium sulfite aqueous solution (1200 mL), filtered, the filter cake was washed with water, and purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 5) to give a white solid 5-bromo-3-fluoropyridine-2-amine (B15-2, 60.7 g, yield: 89%).

[0384] 1 H NMR (400MHz, CDCl3): δppm 7.93 (d, J=1.6Hz, 1H), 7.38 (dd, J=10.0, 2.0Hz, 1H), 4.66 (br, 2H).

[0385] Step 2: Dissolve 5-bromo-3-fluoropyridine-2-amine (B15-2, 74.50 g, 390.05 mmol) in tetrahydrofuran (260 mL) and water (1000 mL), add Zn(CN)2 (30.22 g, 257.45 mmol), and purge with argon gas three times. Add t-BuXPhos-Pd G3 (6.80 g, 8.56 mmol), and purge with argon gas three more times. React at 40 °C for 15 hours. Slowly pour the reaction solution into ice water (1.0 L), add ethyl acetate (3 x 400 mL) for extraction, filter out the insoluble matter with diatomaceous earth, and wash the residue with tetrahydrofuran (300 mL). The organic phases were combined, washed with saturated brine (2 x 500 mL), dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 1) to give a pale yellow powder 6-amino-5-fluoronicotinonitrile (B15-3, 28.53 g, yield: 53.3%).

[0386] LCMS: m / z 138.5 [M+H] + .

[0387] Step 3: Dissolve 6-amino-5-fluoronicotinonitrile (B15-3, 28.53 g, 208.10 mmol) in acetone (290 mL) and tert-butanol (145 mL), and add DMAP (82.84 g, 677.9 mmol). Slowly add (Boc)20 (200.39 g, 919.26 mmol), and react at 60 °C for 12 hours. Concentrate the reaction solution to near dryness, load it onto a silica gel column for purification (ethyl acetate / petroleum ether = 1 / 100 to 1 / 15) to give a white solid N-(3-fluoro-5-cyanopyridin-2-yl)-N-[(2-methylpropane-2-yl)oxycarbonyl] tert-butyl carbamate (B15-4, 58.32 g, yield: 83.1%).

[0388] 1 H NMR (400MHz, CDCl3): δppm 8.60 (s, 1H), 7.75 (d, J = 7.2Hz, 1H), 1.44 (s, 18H).

[0389] Step 4: Dissolve N-(3-fluoro-5-cyanopyridin-2-yl)-N-[(2-methylpropane-2-yl)oxycarbonyl] tert-butyl carbamate (B15-4, 58.32 g, 172.85 mmol) in tetrahydrofuran (630 mL), add iodine (87.72 g, 345.64 mmol), and under nitrogen protection, cool to -65 °C. Add LDA (2.0 M in THF, 440 mL, 888.00 mmol) dropwise. After the addition is complete, stir for 10 minutes, then allow to rise to room temperature and react for 16 hours. The reaction solution was slowly poured into ice water (1.0 L), and extracted with ethyl acetate (3*400 mL). The organic phase was washed with saturated brine (2*500 mL), dried and concentrated, and purified by silica gel column chromatography (0-10% ethyl acetate / petroleum ether). The mixture was then slurried with dichloromethane / petroleum ether (1 / 50) to obtain a light yellow powder (5-cyano-3-fluoro-4-iodopyridin-2-yl) tert-butyl carbamate (B15-5, 23.27 g, yield: 37.1%).

[0390] 1 H NMR (400MHz, DMSO-d6) δppm: 10.27 (s, 1H), 8.52 (s, 1H), 1.46 (s, 9H).

[0391] Step 5: Trifluoroacetic acid (130 mL) was added dropwise to a solution of (5-cyano-3-fluoro-4-iodopyridin-2-yl)carbamate tert-butyl (B15-5, 32.06 g, 88.29 mmol) in dichloromethane (360 mL) at 0 °C. The reaction was allowed to proceed at room temperature for 2 hours. Most of the solvent and trifluoroacetic acid were concentrated from the reaction solution. The solution was diluted with ethyl acetate (60 mL) and poured into a saturated sodium carbonate aqueous 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 a white solid 6-amino-5-fluoro-4-iodonicotinonitrile (B15-6, 19.08 g, yield: 82.2%).

[0392] LCMS: m / z: 264.2 [M+H] + .

[0393] 1 H NMR (400MHz, CDCl3) δ8.20 (s, 1H).

[0394] Step Six: Dissolve 6-amino-5-fluoro-4-iodonicotinonitrile (B15-6, 4.58 g, 17.43 mmol) in tetrafluoroboric acid (150 mL), cool to -10 °C, and add NaNO2 (3.32 g, 48.13 mmol) in portions. React for 2 hours. Pour the reaction solution into an aqueous sodium carbonate solution (800 mL), stir for 5 minutes, extract with ethyl acetate (3 x 200 mL), wash the organic phase with saturated brine (100 mL), dry, concentrate, and purify by silica gel column chromatography (0-5% ethyl acetate / petroleum ether) to give a white solid 5,6-difluoro-4-iodonicotinonitrile (B15-7, 1.47 g, yield: 31.7%).

[0395] 1 H NMR (400MHz, CDCl3): δppmS.22 (s, 1H).

[0396] Step 7: Dissolve 2-((tert-butyldimethylsilyl)oxy)ethyl-1-hydroxy (B15-7, 72 mg, 0.40 mmol) in tetrahydrofuran (8 mL), cool to 0 °C, and add sodium hydroxide (32 mg, 0.76 mmol, 60%) in portions, reacting for 30 minutes. Then add dropwise a tetrahydrofuran solution (2 mL) of 5,6-difluoro-4-iodonicotinonitrile (100 mg, 0.37 mmol), stirring at room temperature for 2 hours. Pour the reaction solution into ice water (20 mL), stir for 5 minutes, extract with ethyl acetate (3 x 20 mL), wash the organic phase with saturated brine (20 mL), dry, concentrate, and purify by silica gel plate (ethyl acetate / petroleum ether = 1 / 20) to obtain an oily substance 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-fluoro-4-iodonicotinonitrile (B15, 40 mg, yield: 25%).

[0397] 1 H NMR (400MHz, CDCl3): δppm 8.03 (s, 1H), 4.45 (t, J=8.0Hz, 2H), 3.90 (t, J=8.0Hz, 2H), 0.81 (s, 9H), 0.01 (s, 6H).

[0398] Synthesis of intermediate B16: 2-bromo-3-fluoro-4-(methylamino)benzonitrile

[0399]

[0400] A 5 mL solution of methylamine ethanol and B1-3 (400 mg, 1.83 mmol, 1.0 eq) were added sequentially to a 60 mL pressure-resistant flask. The mixture was then heated to 100 °C and stirred for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid B16 (400 mg, yield: 95.2%).

[0401] Synthesis of intermediate B17: Methyl 3,4-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)benzoate

[0402]

[0403] Compound B1-1 (310 mg, 1.25 mmol), bis-pinacolborate (636 mg, 2.50 mmol), xylene (10 mL), Pd(dppf)Cl2·CH2Cl2 (100 mg, 0.12 mmol), and potassium pentovalinate (520 mg, 3.75 mmol) were added sequentially to a dry three-necked flask. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid B17 (220 mg, yield: 60.1%).

[0404] Synthesis of intermediate B18: Methyl 3-fluoro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)benzoate

[0405]

[0406] Step 1: Referring to the synthesis of compound B4, compound B18-1 was synthesized in one step.

[0407] Step 2: Referring to the synthesis of compound B17, intermediate compound B18 was synthesized in one step.

[0408] Synthesis of intermediate B19: Methyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-IH-pyrazole-5-carboxylate

[0409]

[0410] Referring to the synthesis of compound B17, intermediate compound B19 was synthesized in one step.

[0411] Synthesis of intermediate B20: 2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile

[0412]

[0413] Step 1: Add N,N-dimethylformamide (15 mL), 2-bromo-3-fluoro-4-hydroxybenzonitrile (BI, 1.0 g, 4.63 mmol, 1.0 eq), cesium carbonate (3.01 g, 9.26 mmol, 2.0 eq), and sodium dichlorofluoroacetate (1.06 g, 6.94 mmol, 1.5 eq) sequentially to a round-bottom flask. Heat the yellow reaction solution to 90°C and stir for 6 hours (gas is released). TLC shows the reaction is complete. Filter under reduced pressure, extract the filtrate with water (50 mL) and ethyl acetate (20 mL x 3), wash the organic phase with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, and remove volatiles under reduced pressure. The residue was purified by silica gel chromatography (to a 6% gradient of ethyl acetate: petroleum ether) to give a yellow liquid 2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (B20, 0.54 g, yield: 43.9%).

[0414] 1 H NMR (400MHz, CDCl3) δ7.54-7.46 (m, 1H), 7.34 (dd, J=8.0, 7.2Hz, 1H), 6.65 (t, J=71.6Hz, 1H).

[0415] Synthesis of intermediate C1: 2-tert-butyldimethylsiloxyacetaldehyde

[0416]

[0417] 2-tert-butyldimethylsiloxyethanol (1.0 g, 5.67 mmol), dichloromethane (40 mL), and Dysmartin oxidant (3.61 g, 8.51 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was confirmed by TLC, saturated sodium bicarbonate solution (30 mL) and saturated sodium thiosulfate solution (30 mL) were added to the reaction mixture, and the resulting mixture was stirred at 25 °C for 30 minutes. The mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily substance C1 (700 mg, yield: 70.9%).

[0418] 1H NMR (400MHz, CDCl3) δ9.70 (s, 1H), 4.22 (s, 2H), 0.93 (s, 9H), 0.11 (s, 6H).

[0419] Example 1: Synthesis of Compound 1

[0420] 8-Methyl-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

[0421]

[0422] Step 1: Dissolve HMPA (3.0 mL) and LDA (7.7 mL, 15.4 mmol, 2.0 M) in anhydrous tetrahydrofuran (100 mL). Slowly add a tetrahydrofuran (25 mL) solution of A1-5 (1.7 g, 4.64 mmol) at -60 °C. After the addition is complete, heat the reaction solution to -30 °C and stir for 30 minutes. Then stir for another 30 minutes at -60 °C. Finally, add a tetrahydrofuran (10 mL) solution of compound 1-1 (2.20 g, 8.35 mmol) at -60 °C. After the addition was complete, the reaction solution was stirred at -60°C for 2 hours. The reaction solution was quenched with saturated ammonium chloride (30 mL) and then extracted with ethyl acetate (60 mL * 3). The organic layer was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain product compounds 1-2 (1.8 g, yield: 71%), which were brown oily substances.

[0423] Step 2: Dissolve compounds 1-2 (2.6 g, 4.73 mmol) in ethyl acetate (3 mL), add HCl (4 M, EtOAc, 10 mL) solution, stir for 1 hour at room temperature, adjust the pH of the reaction solution to 8 with saturated sodium bicarbonate solution, extract with ethyl acetate (50 mL * 2), wash the organic phase with saturated sodium chloride (20 mL * 2), dry with anhydrous sodium sulfate, filter, and concentrate to obtain product 1-3 (1.1 g, yield: 51%) as a colorless oil.

[0424] Step 3: Dissolve compounds 1-3 (1.1 g, 2.45 mmol) in DMA (4 mL), add sodium hydride (294 mg, 7.34 mmol, 60% mineral oil mixture) at 0 °C, stir the reaction solution at 100 °C for 6 hours, quench with water (10 mL), and then extract with ethyl acetate (60 mL * 3). After concentrating the organic layer, perform column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain product 1-4 (180 mg, yield: 20%) as a pale yellow oil.

[0425] Step 4: Dissolve compounds 1-4 (180 mg, 0.488 mmol) in tetrahydrofuran (3 mL), add borane tetrahydrofuran (3 mL, 3 mmol, 1 M) at 0 °C, stir the reaction mixture at 60 °C for 20 hours, quench with methanol (4 mL), concentrate, dissolve the solid in methanol (4 mL) and 4N HCl / dioxane (20 mL), stir the mixture at room temperature for 1 hour, concentrate, adjust pH to 8 with saturated sodium bicarbonate solution, extract with ethyl acetate (50 mL * 2), wash the organic phase with saturated sodium chloride (20 mL * 2), dry with anhydrous sodium sulfate, filter, concentrate and separate by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain product 1-5 (120 mg, yield: 69%) as a colorless oil.

[0426] Step 5: Dissolve compounds 1-5 (120 mg, 0.339 mmol) in 1,2-dichloroethane (4 mL), add 1-chloroethyl chloroformate (121 mg, 0.846 mmol), stir the reaction solution at 70 °C for 2 hours, concentrate, dissolve the solid in methanol (6 mL), stir the mixture at 40 °C for 1 hour, concentrate, adjust the pH to 8 with saturated sodium bicarbonate solution, extract with ethyl acetate (30 mL * 2), wash the organic phase with saturated sodium chloride (20 mL * 2), dry with anhydrous sodium sulfate, filter, concentrate and separate by Prep-TLC (dichloromethane / methanol = 20 / 1) to give the product 8-methyl-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (compound 1, 83 mg, yield: 93%) as a colorless oil.

[0427] 1 HNMR (400MHz, CDCl3) 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).

[0428] LC-MS[M+1] + =265.3

[0429] The following compounds were synthesized according to the references and the synthetic steps of compound 1:

[0430]

[0431] Example 2: Synthesis of Compound 6

[0432] 9-Bromo-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

[0433]

[0434] Step 1: Compound A1-9 (4.10 g, 8.86 mmol), 1,2-dichloroethane (40 mL), and 2-chloroethyl chloroformate (3.17 g, 22.2 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in methanol and stirred at 75 °C for 1.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a yellow oily substance (compound 6, 3.10 g).

[0435] LC-MS[M+1] + =347.0.

[0436] Example 3: Synthesis of Compound 7

[0437] 9-Bromo-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

[0438]

[0439] Compound A1-11 (5 mg, 0.008 mmol), methanol (2 mL), and dioxane hydrochloride (1 mL, 4.0 M) were added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was lyophilized to give a white solid (compound 7, 3.6 mg, hydrochloride, yield: 89%).

[0440] LC-MS[M+1] + =381.0.

[0441] Example 4: Synthesis of Compound 8

[0442] 4-(7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)morpholine

[0443]

[0444] Step 1: 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, 0.004 mmol), and 1,4-dioxane (2 mL) were added sequentially to the reaction flask. The reaction solution was protected with nitrogen and stirred overnight at 100 °C. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give a yellow solid 8-1 (8 mg, yield: 39.45%).

[0445] Step 2: Referring to the synthesis of compound 7, compound 8 is obtained in a one-step reaction.

[0446] 1 H 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).

[0447] LC-MS[M+1] + =354.1.9.

[0448] The following compounds were synthesized according to the references and the synthetic steps of compound 8:

[0449]

[0450]

[0451] Example 5: Synthesis of Compound 15

[0452] 8-Chloro-7-fluoro-9,10a-diphenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

[0453]

[0454] Step 1: 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, 0.004 mmol) were added sequentially to the reaction flask. The reaction solution was protected with nitrogen and stirred at 100 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give a yellow solid 15-1 (19 mg, yield: 95.57%).

[0455] LCMS: m / z 479.2 [M+H] + .

[0456] Step 2: Compound 15-1 (19 mg, 0.040 mmol), methanol (5 mL), and dioxane hydrochloride solution (1 mL, 4 mmol) were added sequentially to a single-necked flask. The reaction mixture was stirred at 25 °C for 3 hours. The solvent was removed under reduced pressure to obtain a yellow solid compound 15 (12 mg, yield: 65.57%).

[0457] 1 H 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).

[0458] LC-MS: m / z 379.1 [M+H] + .

[0459] The following compounds were synthesized according to the references and the synthetic steps of compound 15:

[0460]

[0461]

[0462]

[0463] Example 6: Synthesis of Compound 30

[0464] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-N-methylbenzamide

[0465]

[0466] Step 1: Referring to the synthesis of compound 15-1, compound 30-2 is obtained in one step.

[0467] LCMS: m / z 537.2 [M+H] + .

[0468] Step 2: Add NaOH (40 mg, 1 mmol) to a methanol (5 mL) solution of compound 30-2 (100 mg, 0.18 mmol). Stir the mixture overnight at room temperature. Adjust the pH of the reaction solution to 6 with dilute hydrochloric acid. Extract with ethyl acetate, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product 30-3 (105 mg).

[0469] Step 3: Referring to the synthesis of compound B1-2, a one-step reaction was carried out to obtain compound 30-4.

[0470] LCMS: m / z 522.2 [M+H] + .

[0471] Step 4: Referring to the synthesis of compound 15, a one-step reaction is carried out to obtain compound 30.

[0472] 1 H 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).

[0473] LC-MS: m / z 422.1 [M+H] +

[0474] The following compounds were synthesized according to the references and the synthetic steps of compound 30:

[0475]

[0476]

[0477] Example 7: Synthesis of Compound 41

[0478] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-4-(difluoromethoxy)-3-fluorobenzamide hydrochloride

[0479]

[0480] Step 1: Compound A1 (130 mg, 0.246 mmol), compound B20 (65 mg, 0.246 mmol), potassium phosphate (131 mg, 0.615 mmol), toluene (5 mL), water (1 mL), Pd2(dba)3 (23 mg, 0.025 mmol), and NiXantPhos (27 mg, 0.049 mmol) were added sequentially to the reaction flask. The reaction mixture was stirred at 100 °C for 6 hours under nitrogen protection. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residues were purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give white solid 41-1 (16 mg, yield: 11.0%) and white solid 42-1 (19 mg, yield: 13.1%).

[0481] LCMS: m / z 588.2 [M+H] + .

[0482] Step 2: 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 added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 12 hours. After the reaction was complete, the reaction mixture was filtered and concentrated. The residue was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to give a white solid 41-2 (5 mg, yield: 31.3%).

[0483] LCMS: m / z 606.2 [M+H] + .

[0484] Step 3: Compound 41-2 (5 mg, 0.008 mmol), methanol (2 mL), and dioxane hydrochloride (1 mL, 4.0 M) were added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was lyophilized to give a white solid, compound 41 (3.7 mg, hydrochloride, yield: 82.2%).

[0485] 1H NMR (400MHz, DMSO-d6) δ7.72 (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(1m, 1H), 3.14-2.98(m, 2H), 2.78-2.70(m, 1H), 2.64-2.56(m, 1H).

[0486] LC-MS: m / z 506.1 [M+H] + .

[0487] Example 8: Synthesis of Compound 42

[0488] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-4-(difluoromethoxy)-3-fluorobenzamide hydrochloride

[0489]

[0490] Following the synthetic method of compound 41, compound 42-1 was used instead of compound 41-1 to carry out a two-step reaction to obtain compound 42.

[0491] 1 H 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);

[0492] LC-MS: m / z 506.1 [M+H] + .

[0493] Example 9: Synthesis of Compound 43

[0494] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0495]

[0496] Following the synthetic method of compound 41, compound 43 was obtained by replacing compound B20 with compound B2 and NiXantPhos with XantPhos in a three-step reaction.

[0497] 1 H 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);

[0498] LC-MS: m / z 500.1 [M+H] + .

[0499] Example 10: Synthesis of Compound 44

[0500] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0501]

[0502] Following the synthetic method of compound 41, compound 44-1 was used instead of compound 41-1, and a two-step reaction was carried out to obtain compound 44.

[0503] 1 H 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).

[0504] LC-MS: m / z 500.1 [M+H]+ .

[0505] Example 11: Synthesis of Compound 45

[0506] 2-(4-carbamoyl-3-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,1.0a-hexahydropyrazine[1,2-a]indol-9-yl)-2-fluorophenoxy)acetic acid

[0507]

[0508] Steps 1 and 2: Following the synthesis method of compound 41-2, compound B4 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to carry out a two-step reaction to obtain compound 45-2.

[0509] Step 3: 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 added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was adjusted to pH 5 with 0.5 N dilute hydrochloric acid. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a grayish-white solid 45-3 (90 mg, yield: 93.8%).

[0510] LC-MS: m / z 614.2 [M+H] + .

[0511] Step 4: Compound 45-3 (90 mg, 0.147 mmol), methanol (2.5 mL), and dioxane hydrochloride (1.0 mL, 4 M) were added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol = 10:1) to give a grayish-white solid 45-4 (50 mg, yield: 61.0%) and a grayish-white solid 46-1 (30 mg, yield: 36.6%).

[0512] LC-MS: m / z 528.1 [M+H] + .

[0513] Step 5: 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 added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction mixture was adjusted to 6 with 0.5 N dilute hydrochloric acid. The mixture was concentrated to dryness, and the residue was diluted with dichloromethane / methanol (10:1, 5 mL). The resulting suspension was filtered. The filtrate was concentrated under reduced pressure to give a grayish-white solid 45 (16 mg, yield: 30.8%).

[0514] 1 H 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).

[0515] LC-MS: m / z 514.1 [M+H] + .

[0516] Example 12: Synthesis of Compound 46

[0517] 2-(4-carbamoyl-3-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-2-fluorophenoxy)acetic acid

[0518]

[0519] Following the synthetic method of compound 45, compound 46-1 was used instead of compound 45-4 to carry out a one-step reaction to obtain compound 46.

[0520] 1 H 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).

[0521] LC-MS: m / z 514.1 [M+H] + .

[0522] Example 13: Synthesis of Compound 47

[0523] (2S)-2-(8-chloro-7-fluoro-2-(2-hydroxyethyl)-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0524]

[0525] Step 1: Compound 44 (10 mg, 0.019 mmol), compound C1 (5 mg, 0.029 mmol), dichloromethane (1 mL), and sodium triacetylborohydride (6 mg, 0.029 mmol) were added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to give a grayish-white solid 47-1 (7 mg, yield: 75.0%).

[0526] LC-MS: m / z 658.3 [M+H] + .

[0527] Step 2: Compound 47-1 (9 mg, 0.014 mmol), methanol (2.0 mL), and dioxane hydrochloride (1.0 mL, 4 M) were added sequentially to a single-necked flask. The reaction solution was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure and lyophilized to obtain a grayish-white solid 47 (5.5 mg, hydrochloride, yield: 67.9%).

[0528] 1 H 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).

[0529] LC-MS: m / z 544.2 [M+H] + .

[0530] Example 14: Synthesis of Compound 48

[0531] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethyl)benzamide hydrochloride

[0532]

[0533] Following the synthetic method of compound 41, compound 48 was obtained by replacing compound B20 with compound B5 and NiXantPhos with XantPhos in a three-step reaction.

[0534] 1 H 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), 3.7 0-3.60(m,2H), 3.10-2.75(m,3H), 2.87-2.77(m,2H), 2.70-2.55(m,2H).

[0535] LC-MS: m / z 484.2 [M+H] + .

[0536] Example 15: Synthesis of Compound 49

[0537] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethyl)benzamide hydrochloride

[0538]

[0539] Following the synthetic method of compound 41, compound 49-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 49.

[0540] 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=10.4 Hz, 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).

[0541] LC-MS: m / z 484.2 [M+H] + .

[0542] Example 16: Synthesis of Compound 50

[0543] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(3-hydroxypropyl)benzamide hydrochloride

[0544]

[0545] Following the synthetic method of compound 41, compound 50 was obtained by replacing compound B20 with compound B6 and NiXantPhos with XantPhos in a three-step reaction.

[0546] 1 H 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).

[0547] LC-MS: m / z 514.2 [M+H] + .

[0548] Example 17: Synthesis of Compound 51

[0549] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(3-hydroxypropyl)benzamide hydrochloride

[0550]

[0551] Following the synthetic method of compound 41, compound 51-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 51.

[0552] 1 H NMR (400MHz, DMSO-d6) δ7.78 (s, 1H), 7.65-7.55 (m, 2H), 7.49-7.41 (m, 3H), 7.4 0-7.33 (m, 1H), 7.25 (t, J=8.4Hz, 1H), 7.13 (s, 1H), 7.01 (d, J=10.8Hz, 1H), 4.5 5(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).

[0553] LC-MS: m / z 514.2 [M+H] + .

[0554] Example 18: Synthesis of Compound 52

[0555] 2-(4-carbamoyl-3-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-2-fluorophenyl)acetate hydrochloride

[0556]

[0557] Steps 1, 2, and 3: Following the synthesis method of compound 45-3, compound B5-2 was used instead of compound B4 to carry out a three-step reaction to obtain compound 52-3.

[0558] Step 4: Compound 52-3 (18 mg, 0.048 mmol), dioxane (2.0 mL), and dioxane hydrochloride (1.0 mL, 4 M) were added sequentially to a single-necked flask. The reaction solution was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure and lyophilized to obtain a yellow solid 52-3 (14 mg, hydrochloride).

[0559] 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).

[0560] LC-MS: m / z 498.1 [M+H] + .

[0561] Example 19: Synthesis of Compound 53

[0562] 2-(4-carbamoyl-3-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-2-fluorophenyl)acetate hydrochloride

[0563]

[0564] Following the synthetic method of compound 52, compound 53-1 was used instead of compound 52-2 to carry out a two-step reaction to obtain compound 53.

[0565] 1 H 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).

[0566] LC-MS: m / z 498.1 [M+H] + .

[0567] Example 20: Synthesis of Compound 54

[0568] 2-((9R)8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-morpholinobenzamide hydrochloride

[0569]

[0570] Following the synthetic method of compound 41, compound 54 was obtained by replacing compound B20 with compound B7 and NiXantPhos with XantPhos in a three-step reaction.

[0571] 1 H NMR (400MHz, DMSO-d6) δ9.78-9.62 (m, 1H), 8.42-8.15 (m, 1H), 7.61-7.55 (m, 2 H), 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).

[0572] LC-MS: m / z 525.2 [M+H] + .

[0573] Example 21: Synthesis of Compound 55

[0574] 2-((9S)8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-morpholinobenzamide hydrochloride

[0575]

[0576] Following the synthetic method of compound 41, compound 55-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 55.

[0577] 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), 3.3 5-3.25 (m, 1H), 3.20-3.10 (m, 1H), 3.05-2.75 (m, 7H), 2.45-2.36 (m, 1H).

[0578] LC-MS: m / z 525.2 [M+H] + .

[0579] Example 22: Synthesis of Compound 56

[0580] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-4-(1,1-thiomorpholino)-3-fluorobenzamide hydrochloride

[0581]

[0582] Following the synthetic method of compound 41, compound 56 was obtained by replacing compound B20 with compound B8 and NiXantPhos with XantPhos in a three-step reaction.

[0583] 1 H 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).

[0584] LC-MS: m / z 573.1 [M+H] + .

[0585] Example 23: Synthesis of Compound 57

[0586] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-4-(1,1-thiomorpholino)-3-fluorobenzamide hydrochloride

[0587]

[0588] Following the synthetic method of compound 41, compound 57-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 57.

[0589] 1 H 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, 2 H), 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).

[0590] LC-MS: m / z 573.1 [M+H] + .

[0591] Example 24: Synthesis of Compound 58

[0592] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-((tetrahydro-2H-pyran-4-yl)amino)benzamide hydrochloride

[0593]

[0594] Following the synthetic method of compound 41, compound 58 was obtained by replacing compound B20 with compound B9 and NiXantPhos with XantPhos in a three-step reaction.

[0595] 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).

[0596] LC-MS: m / z 539.2 [M+H] + .

[0597] Example 25: Synthesis of Compound 59

[0598] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-((tetrahydro-2H-pyran-4-yl)amino)benzamide hydrochloride

[0599]

[0600] Following the synthetic method of compound 41, compound 59-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 59.

[0601] 1 H 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).

[0602] LC-MS: m / z 539.2 [M+H] + .

[0603] Example 26: Synthesis of Compound 60

[0604] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1.,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide hydrochloride

[0605]

[0606] Following the synthetic method of compound 41, compound 60 was obtained by replacing compound B20 with compound B10 and NiXantPhos with XantPhos in a three-step reaction.

[0607] 1 H 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).

[0608] LC-MS: m / z 514.2 [M+H] + .

[0609] Example 27: Synthesis of Compound 61

[0610] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide hydrochloride

[0611]

[0612] Following the synthetic method of compound 41, compound 61-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 61.

[0613] 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).

[0614] LC-MS: m / z 514.2 [M+H] + .

[0615] Example 28: Synthesis of Compound 62

[0616] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-((R)-2-hydroxypropoxy)benzamide hydrochloride

[0617]

[0618] Following the synthetic method of compound 41, compound 62 was obtained by replacing compound B20 with compound B11 and NiXantPhos with XantPhos in a three-step reaction.

[0619] 1 H 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).

[0620] LC-MS: m / z 514.2 [M+H] + .

[0621] Example 29: Synthesis of Compound 63

[0622] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-((R)-2-hydroxypropoxy)benzamide hydrochloride

[0623]

[0624] Following the synthetic method of compound 41, compound 63-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 63.

[0625] 1 H 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).

[0626] LC-MS: m / z 514.2 [M+H] + .

[0627] Example 30: Synthesis of Compound 64

[0628] 6-((9R)8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-7-fluoro-1H-indol-5-carboxamide

[0629]

[0630] Steps 1 and 2: Following the synthesis method of compound 41-2, compound B14 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to carry out a two-step reaction to obtain compounds 64-2 and 65-1.

[0631] Step 3: Compound 64-2 (12 mg, 0.018 mmol), dichloromethane (2 mL), and trifluoroacetic acid (1 mL) were added sequentially to a single-necked flask. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution (6 mL) was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure and lyophilized to give a white solid 64 (5 mg, yield: 58.1%).

[0632] 1 H 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).

[0633] LC-MS: m / z 479.1 [M+H] + .

[0634] Example 31: Synthesis of Compound 65

[0635] 6-((9S)8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl-7-fluoro-1H-indol-5-carboxamide

[0636]

[0637] Following the synthetic method of compound 64, compound 65-1 was used instead of compound 64-2 to carry out a one-step reaction to obtain compound 65.

[0638] 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).

[0639] LC-MS: m / z 479.1 [M+H] + .

[0640] Example 32: Synthesis of Compound 66

[0641] 2-((9R,10aR)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1.,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0642]

[0643] Step 1: Compound A1-10 (1.50 g, 3.35 mmol), acetonitrile (20 mL), and NCS (447 mg, 3.35 mmol) were added sequentially to a dry single-necked flask. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture 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 give white solid 66-1 (500 mg, yield: 31.1%) and white solid 68-1 (500 mg, yield: 31.1%).

[0644] LC-MS: m / z 481.1 [M+H] + .

[0645] Step 2: Following the synthesis method of compound A1, use compound 66-1 instead of compound A1.-11 to synthesize compound 66-2.

[0646] Steps 3 to 5: Following the synthesis method of compound 41, compound 66-2 was used to replace compound A20, and a three-step reaction was carried out to obtain compound 66.

[0647] 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).

[0648] LC-MS: m / z 500.1 [M+H] + .

[0649] Example 33: Synthesis of Compound 67

[0650] 2-((9S,10aR)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0651]

[0652] Following the synthetic method of compound 41, compound 67-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 67.

[0653] 1 H 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), 3.73-3.6 5(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).

[0654] LC-MS: m / z 500.1 [M+H] + .

[0655] Example 34: Synthesis of Compound 68

[0656] 2-((9R,10aS)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0657]

[0658] Following the synthetic method of compound 43, compound 68-1 was used instead of compound A1-11, and a four-step reaction was carried out to obtain compound 68.

[0659] 1 H NMR (400MHz, DMS0-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=1.6.0Hz, 1H), 2.59-2.51 (m, 1H).

[0660] LC-MS: m / z 500.1 [M+H] + .

[0661] Example 35: Synthesis of Compound 69

[0662] 2-((9S,10aS)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0663]

[0664] Following the synthetic method of compound 41, compound 69-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 69.

[0665] 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), 3.73-3.6 5(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).

[0666] LC-MS: m / z 500.1 [M+H] + .

[0667] Example 36: Synthesis of Compound 70

[0668] 5-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-4-fluoroindol-6-carboxamide carboxylate

[0669]

[0670] Following the synthetic method of compound 43, a two-step reaction was carried out to obtain compounds 70-2 and 70-3.

[0671] Synthesis of compound 70: 70-2 (25 mg, 0.037 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) at 25°C, followed by the addition of trifluoroacetic acid (1 mL). After stirring the yellow reaction solution for 12 hours, LC-MS showed product formation. The solvent was removed by concentration under reduced pressure, and the solution was then prepared (0.05% formic acid / MeCN / H₂O) to give a white solid 70 (16 mg, yield: 82.9%).

[0672] 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), 3.27-3.1.6 (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).

[0673] LC-MS: m / z 481.1 [M+H] + .

[0674] Example 37: Synthesis of Compound 71

[0675] 5-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-4-fluoroindol-6-carboxamide carboxylate

[0676]

[0677] Following the synthetic method of Example 30, intermediate 70-3 was used instead of 70-2 for a one-step reaction to obtain compound 71 (10 mg, yield: 64.5%).

[0678] 1 H NMR (400MHz, DMSO_d6) δ9.10 (s, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.67 (d, J=21.6 Hz, 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=1 0.8Hz, 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).

[0679] LC-MS: m / z 481.1 [M+H]+ .

[0680] Example 38: Synthesis of compound 72.

[0681] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide carboxylate

[0682]

[0683] Step 1: Following the method of synthesizing compound 43, use intermediate B12 instead of B2 to synthesize compound 72-1 (yellow solid, 20 mg, yield: 74.1%).

[0684] Step 2: Add 72-1 (20 mg, 0.028 mmol, 1.0 eq) and methylamine ethanol solution (1 mL) to a 15 mL pressure-resistant bottle. Heat to 100 °C and stir for 24 hours. TLC shows the formation of new spots. Concentrate the reaction solution under reduced pressure. Purify the residue using a preparative plate (petroleum ether / ethyl acetate = 3 / 1) to obtain a colorless oily substance 72-2 (4 mg, yield: 20%).

[0685] Step 3: Dissolve 72-2 (4 mg, 0.006 mmol, 1.0 eq) in dichloromethane (500 μL), cool to -70°C using a dry ice-acetone bath, and then add boron tribromide (18 μL, 0.018 mmol, 3.0 eq). Stir at low temperature for 30 minutes; LC-MS showed product formation. Quench the reaction with methanol (1 mL) at low temperature, concentrate under reduced pressure, and separate the residue by preparative HPLC (formic acid system) to obtain a white solid crude compound 72 (1 mg, yield: 33.3%).

[0686] LC-MS: m / z 514.1[M+H]+.

[0687] Example 39: Synthesis of compound 73.

[0688] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-N-ethyl-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0689]

[0690] Step 1: Compounds 73-1 (yellow solid, 80 mg) and 73-2 (yellow solid, 80 mg) were synthesized by following the same method as in Step 1 of the synthesis of compound 43.

[0691] Step 2: Dissolve 73-1 (80 mg, 0.11 mmol, 1.0 eq) in tetrahydrofuran (500 μL), methanol (500 μL), and water (500 μL), then add lithium hydroxide monohydrate (14 mg, 0.33 mmol, 3.0 eq). The reaction solution was reacted at 25°C for 12 hours, and TLC showed that the reaction was complete. The reaction solution was extracted with water (10 mL) and methyl tert-butyl ether (5 mL x 3). The aqueous phase was adjusted to acidity (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 the volatiles were removed under reduced pressure to obtain a yellow solid 73-3 (90 mg, crude product).

[0692] Step 3: At 25°C, dichloromethane (10 mL), 73-3 (33 mg, 0.055 mmol, 1.0 eq), ethylamine hydrochloride (9 mg, 0.11 mmol, 2.0 eq), triethylamine (30 μL, 0.22 mmol, 4.0 eq), and TBTU (35 mg, 0.11 mmol, 2.0 eq) were added sequentially to a round-bottom flask. The pale yellow reaction solution was stirred at this temperature for 1.5 hours, and LC-MS detected the formation of products. The volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography (0 to 2.7% methanol:dichloromethane gradient) to give a white solid 73-4 (27 mg, yield: 79.4%).

[0693] LC-MS: m / z 528.1 [M-Boc+H] + .

[0694] Step 4: Dissolve 73-4 (27 mg, 0.043 mmol, 1.0 eq) in methanol (1 mL) at 25°C, then add hydrochloric acid / dioxane solution (1 mL, 4 M), stir for two hours, and LC-MS shows that the reaction is complete. The reaction solution is concentrated under reduced pressure to give a white solid 73 (21 mg, yield: 87.5%).

[0695] 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).

[0696] LC-MS: m / z 528.1 [M+H] + .

[0697] Example 40: Synthesis of compound 74.

[0698] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-N-ethyl-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0699]

[0700] Compound 74: Compound 74 (21 mg, yield: 87.5%) was obtained by a three-step reaction following the synthetic method of Compound 73.

[0701] 1 H 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), 7.5 6 (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=10.4 HZ, 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).

[0702] LC-MS: m / z 528.1 [M+H] + .

[0703] Example 41: Synthesis of compound 75.

[0704] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-(2-hydroxyethyl)benzamide hydrochloride

[0705]

[0706] Compound 75: Compound 75 (22 mg, yield: 81.5%) was obtained by two-step reaction following the synthetic method of Compound 73.

[0707] 1 H 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=1 0.4Hz, 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).

[0708] LC-MS: m / z 544.1 [M+H] + .

[0709] Example 42: Synthesis of compound 76.

[0710] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-(2-hydroxyethyl)benzamide hydrochloride

[0711]

[0712] Compound 76: Compound 76 was obtained by a two-step reaction following the synthetic method of Compound 73 (22 mg, yield: 81.5%).

[0713] 1 H 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).

[0714] LC-MS: m / z 544.1 [M+H] + .

[0715] Example 43: Synthesis of compound 77.

[0716] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzohydrazine hydrochloride

[0717]

[0718] Step 1: Add 73-1 (30 mg, 0.56 mmol, 1.0 eq), hydrazine hydrate (1 mL), and ethanol (1 mL) to a 15 mL pressure-resistant bottle. Heat to 100 °C and stir for 12 hours. TLC shows that the reaction is complete. Concentrate the reaction solution under reduced pressure to obtain a white solid 77-1 (30 mg, crude product).

[0719] Step 2: Synthesize white solid 77 (15 mg, yield: 66.1%) by following the method in step 4 of compound 73.

[0720] 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).

[0721] LC-MS: m / z 515.1 [M+H] + .

[0722] Example 44: Synthesis of compound 78.

[0723] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzoylhydrazine hydrochloride

[0724]

[0725] Compound 78: A white solid 78 (15 mg, yield: 66.1%) was synthesized by a two-step reaction following the synthesis method of compound 77.

[0726] 1 H 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), 3.7 2-3.67 (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).

[0727] LC-MS: m / z 515.1 [M+H] + .

[0728] Example 45: Synthesis of compound 79.

[0729] 2-((9R)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzoic acid formate

[0730]

[0731] Step 1: Dissolve 73-1 (30 mg, 0.56 mmol, 1.0 eq) in methanol (1 mL), then add it to hydrochloric acid / dioxane (1 mL, 4 M) solution. Stir at 25°C for 12 hours. LC-MS showed product formation. Concentrate the reaction solution under reduced pressure to obtain a yellow solid 79-1 (24 mg, crude product).

[0732] LC-MS: m / z 515.1 [M+H] + .

[0733] Step 2: White solid 79 (15 mg, yield: 50.0%) was synthesized by following the method in Step 2 of the synthesis of compound 73.

[0734] 1 H 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).

[0735] LCMS: m / z 500.1 [M+H] + .

[0736] Example 46: Synthesis of compound 80.

[0737] 2-((9S)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzoic acid formate

[0738]

[0739] Compound 80: A white solid 80 (12 mg, yield: 52.9%) was synthesized by a two-step reaction following the synthesis method of compound 79.

[0740] 1 H NMR (400MHz, DMSO_d6) δ8.19 (s, 1H), 7.78 (d, J = 8.6Hz, 1H), 7.46 (d, J = 8.0Hz, 2H), 7.3 6(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, 2 H), 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).

[0741] LC-MS: m / z 500.1 [M+H] + .

[0742] Example 47: Synthesis of compound 81.

[0743] (2R)-2-(8-chloro-7-fluoro-10a-(3-methoxyphenyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0744]

[0745] Compound 81: Following the synthetic method of Compound 43, intermediate A2 was used instead of A1 to synthesize white solid 81 (45 mg, purity: 80%, yield: 94.7%) in three steps.

[0746] 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), 5.0 7 (s, 1H), 4.14 (d, J = 4.8Hz, 2H), 3.95 (d, J = 13.6Hz, 2H), 3.77 (s, 4H), 3.73-3.6 2 (m, 1H), 3.53-3.44 (m, 1H), 2.89 (s, 2H), 2.66 (s, 1H), 2.54 (d, J=12.4Hz, 1H).

[0747] LCMS: m / z 530.1 [M+H] + .

[0748] Example 48: Synthesis of compound 82.

[0749] (2S)-2-(8-chloro-7-fluoro-10a-(3-methoxyphenyl)-1,2,3,4,10,10a-hexahydropyrazino[[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide

[0750]

[0751] Compound 82: White solid 82 (18 mg, yield: 78.3%) was synthesized using the same method as compound 81.

[0752] 1 H NMR (400MHz, DMSO) 67.78 (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).

[0753] LCMS: m / z 530.1 [M+H] + .

[0754] Example 49: Synthesis of compound 83.

[0755] (2S)-2-(8-chloro-7-fluoro-10a-(3-hydroxyphenyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrobromide

[0756]

[0757] Step 1: At 25°C, anhydrous dichloromethane (1 mL) and 82 (15 mg, 0.026 mmol, 1.0 eq) were added sequentially to a 4 mL reaction flask, followed by the dropwise addition of boron tribromide (20 mg, 0.079 mmol, 3.0 eq). The reaction was allowed to proceed for one hour. LC-MS showed product formation. The reaction was quenched by adding methanol (1 mL), filtered, and the filtrate was separated by preparative-grade HPLC (formic acid system) to obtain a white solid 83 (4 mg, yield: 25%).

[0758] 1 H 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).

[0759] LCMS: m / z 516.1 [M+H] + .

[0760] Example 50: Synthesis of Compound 84

[0761] (4R)-(8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide carboxylate

[0762]

[0763] Compound 84: Following the synthetic method of Compound 43, intermediate B15 was used instead of B2 to synthesize white solid 84 (2 mg, yield: 52.9%) in three steps.

[0764] 1 H NMR (400MHz, Methanol-d4) 68.46 (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).

[0765] LCMS: m / z 501.1 [M+H] + .

[0766] Example 51: Synthesis of Compound 85

[0767] (4S)-(8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-9-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide carboxylate

[0768]

[0769] Compound 85: White solid 85 (2 mg, yield: 52.9%) was synthesized by the same method as compound 84.

[0770] 1 H NMR (400MHz, Methanol-d4) δ8.43 (s, 1H), 8.25 (s, 1H), 7.63-7.56 (m, 2H), 7.4 6(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).

[0771] LCMS: m / z 501.1 [M+H] + .

[0772] Example 52: Synthesis of Compound 86

[0773] (2R)-2-(8-chloro-10a-(3-chlorophenyl)-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0774]

[0775] Compound 86: Following the synthetic method of Compound 43, intermediate A4 was used instead of A1 to synthesize white solid 86 (11 mg, purity: 80%, yield: 77.2%) in three steps.

[0776] 1 H 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).

[0777] LCMS: m / z 534.1 [M+H] + .

[0778] Example 53: Synthesis of Compound 87

[0779] (2S)-2-(8-chloro-10a-(3-chlorophenyl)-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide

[0780]

[0781] Compound 87: White solid 87 (8 mg, yield: 70.2%) was synthesized from compound 86-3 using the same method as compound 86.

[0782] 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, 8.0H z, 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).

[0783] LCMS: m / z534.1[M+H] + .

[0784] Example 54: Synthesis of Compound 8S

[0785] (2R)-2-(8-chloro-7-fluoro-10a-(3-fluorophenyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0786]

[0787] Compound 88: Following the synthetic method of Compound 43, intermediate A3 was used instead of A1 to synthesize white solid 88 (24 mg, yield: 90.6%) in three steps.

[0788] 1 H 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).

[0789] LCMS: m / z 518.1 [M+H] + .

[0790] Example 55: Synthesis of Compound 89

[0791] (2S)-2-(8-chloro-7-fluoro-10a-(3-fluorophenyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide hydrochloride

[0792]

[0793] Compound 89: White solid 89 (18 mg, yield: 79.3%) was synthesized using the same method as compound 88.

[0794] 1 H 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, 1 H), 2.90 (d, J=12.8Hz, 1H), 2.77 (d, J=15.9Hz, 1H), 2.37 (d, J=15.6Hz, 1H).

[0795] LCMS: m / z 518.1 [M+H] + .

[0796] Example 56: Synthesis of Compound 90

[0797] 2-((9R,10aS)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(methylamino)benzamide

[0798]

[0799] Step 1: 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) were added sequentially to the reaction flask. The reaction mixture was stirred at 100 °C for 6 hours under nitrogen protection. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 4:1) to give a yellow solid 90-1 (26 mg, yield: 96.1%).

[0800] LCMS: m / z 551.2 [M+H] + .

[0801] Step 2: Following the synthesis method of compound 41-2, use compound 90-1 instead of compound 41-1 to carry out a one-step reaction to obtain compound 90-2 and compound 91-1.

[0802] LCMS: m / z 569.2 [M+H] + .

[0803] Step 3: Following the synthesis method of compound 41, use compound 90-2 instead of compound 41-2 to carry out a one-step reaction to obtain compound 90.

[0804] 1 H 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).

[0805] LC-MS: m / z 469.1 [M+H] + .

[0806] Example 57: Synthesis of Compound 91

[0807] 2-((9S,10aS)-8-chloro-7-fluoro-10a-phenyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-9-yl)-3-fluoro-4-(methylamino)benzamide

[0808]

[0809] Following the synthetic method of compound 41, compound 91-1 was used instead of compound 41-2 to carry out a one-step reaction to obtain compound 91.

[0810] 1 H 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).

[0811] LC-MS: m / z 469.1 [M+H] + .

[0812] Test Example 1: YAP-TEAD Protein-Protein Interaction HTRF Experiment

[0813] 1. Add His-TEAD1 protein to a 384-well white plate to a final concentration of 10 nM, using buffer as the background signal well. Perform a 3-fold dilution of the analyte, creating 10 concentration gradients and mixing thoroughly. Add a specific volume of the analyte to each well, with two replicates for each concentration. The final concentration of DMSO is controlled at 1%. Incubate at room temperature for 20 minutes. The amino acid sequence of TAED1 (209-426) used in this step is shown in SEQ ID NO: 1.

[0814]

[0815] 2. Add Bio-YAP peptide to each well to a final concentration of 50 nM, mix well, and incubate at room temperature for 10 minutes. The amino acid sequence of the YAP peptide (60-100) portion of the Bio-YAP peptide used in this step is shown in SEQ ID NO: 2:

[0816]

[0817] 3. Dilute Anti-His-Eu cryptate gold and streptavidin-XL665 according to the instructions and mix them in equal proportions. Add a certain volume of the test reagent to the well and incubate at room temperature for 1 hour.

[0818] 4. Using an Envision (Perkin Elmer) microplate reader, detect the signal at excitation light of 320 nM, emission light of 665 nM, and emission light of 620 nM.

[0819] 5. Calculate the signal using the ratio of Em665 / Em620*10000. The suppression percentage (%) is calculated using the following formula:

[0820] Inhibition % = (1-(cpd) 信号 -background 信号 ) / (DMSO 信号 -background 信号 ))*100

[0821] Half-inhibition concentration IC 50 The values ​​were calculated using GraphPad Prism software.

[0822] IC50 of each compound blocking YAP-TEAD protein interaction 50 As shown in Table 1, where the letter A represents IC. 50 Less than 0.5µm; the letter B represents IC. 50 The range is from 0.5µM to 5µM; the letter C represents IC. 50 The range is from 5µM to 50µM, with the letter D indicating that IC50 is greater than 50µM.

[0823] Table 1

[0824]

[0825]

[0826]

[0827] Test Example 2: YAP / TEAD Reporter Gene Repression Experiment

[0828] In this embodiment, the inhibitory effect of a compound on a target is detected by using the signal of the reporter gene in the stable cell line SF268-YAP-Luc containing the YAP / TEAD reporter gene.

[0829] A sequence containing six tandem YAP / TEAD binding sites and a basic transcription promoter was constructed into the Promega vector pGLA.76. The constructed reporter gene vector was transfected into SF268 cells (NCI DCTDtumor / cell line repository) and selected with 0.5 μg / ml hygromycin to obtain stable SF268-YAP-Luc cells.

[0830] SF268-YAP-Luc cells were seeded into 96-well plates at a density of 3000 cells per well, with a volume of 100 μL per well (cell culture medium composition: RPMI 1640 (Gibco-A10491-01) + 10% FBS (Gibco-10099-141C) + 1% Penicillin-Streptomycin (5,000 U / mL, Gibco-15070-063)). The plates were incubated overnight at 37°C in a 5% CO2 incubator.

[0831] On the second day, the test compound was diluted 3-fold, resulting in 8 concentration gradients. A specific volume of DMSO (control group) or the test compound (treatment group) was added to each well, with two replicates for each concentration. The final concentration of DMSO was controlled to be no higher than 0.5%. Cells were incubated at 37°C with 5% CO2 for 24 hours. Two identical parallel plates were prepared for cell seeding and compound treatment.

[0832] The reporter gene signal in the control and treatment groups was detected using the Renila-Glo Luciferase assay system kit (Promega, E2720). 70 μL of Renila-Glo was added to each well, mixed, and incubated at room temperature for 10 minutes. Multilabel Plate Reader (Perkin Elmer) reads signals.

[0833] Cell viability in the control and treatment groups was assessed using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570). 50 μL of CellTiter-Glo was added to each well, mixed well, and incubated at room temperature for 10 minutes. Multilabel Plate Reader (Perkin Elmer) reads signals.

[0834] The cell viability-corrected signal of Renila luciferase was analyzed, and the inhibition rate of the compound on the reporter gene was calculated. The inhibition percentage (%) was obtained using the following formula:

[0835] Inhibition rate % = (1 - (Renila signal from compound-treated well / Renila signal from DMSO-treated well) / (CTG signal from compound-treated well / CTG signal from DMSO-treated well)) * 100

[0836] The IC50 of the compound's inhibitory activity against Renila luciferase signaling was calculated using Graphpad Prism software.50 value.

[0837] IC50 of compounds blocking YAP reporter gene expression 50 As shown in Table 2, the letter A in the table represents IC. 50 Less than 0.5µm; the letter B represents IC. 50 The range is from 0.5µM to 5µM; the letter C represents IC. 50 Greater than 5uM.

[0838] Table 2

[0839]

[0840] Test Example 3: Cell Proliferation Inhibition Experiment

[0841] In this embodiment, the CellTiter-Glo luminescence assay kit was used to quantify intracellular ATP and detect the number of live cells in the culture.

[0842] Step 1: Inoculate MSTO-211H (ATCC, CRL-2081) into 96-well plates. TM ) or NCI-H2052 (ATCC, CRL-5915) TM Cells were seeded at a density of 1500 cells per well into 96-well plates, with a volume of 100 μL per well, and incubated overnight at 37°C in a 5% CO2 incubator. The culture medium was: RPMI 1640 medium (GIBCO-A10491-01) + 10% FBS (GIBCO-10099141C) + 1% Pen / Strep (GIBCO-15070-063).

[0843] Step 2: Cell treatment with compounds. The test compounds were diluted 3-fold, resulting in 9 concentration gradients. A certain volume of DMSO (control group) or the test compound (treatment group) was added to each well, with two replicates for each concentration. The final concentration of DMSO was controlled to be no higher than 0.5%. The cells were incubated at 37°C in a 5% CO2 incubator for 96 hours.

[0844] Step 3: Cell viability in the control and treatment groups was assessed using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570). 50 μL of CellTiter-Glo was added to each well, mixed well, and incubated at room temperature for 10 minutes. Multilabel Plate Reader (Perkin Elmer) reads signals.

[0845] The inhibition percentage (%) is calculated using the following formula:

[0846] Inhibition rate % = (1 - CTG signal of compound-treated well / CTG signal of DMSO-treated well) * 100

[0847] The IC50 of the compound on the inhibition of CTG signaling in cell proliferation was calculated using Graphpad Prism software. 50 value.

[0848] The compound's inhibitory activity on cell proliferation IC 50 As shown in Table 3, the letter A represents IC. 50 Less than 1µM; the letter B represents IC 50 The range is from 1µM to 5µM; the letter C represents IC. 50 Greater than 5uM.

[0849] Table 3

[0850] sequence list <110> Shanghai Yituo Pharmaceutical Technology Co., Ltd. <120> Tricyclic compounds, their preparation, pharmaceutical compositions and applications <130> 220367 1PCWO <160> 2 <170> PatentIn version 3.5 <210> 1 <211> 226 <212> PRT <213> Artificial Sequence <220> <223> TAED1 amino acid sequence from position 209 to 426 <400> 1 Arg Ser Ile Gly Thr Thr Lys Leu Arg Leu Val Glu Phe Ser Ala Phe 1 5 10 15 Leu Glu Gln Gln Arg Asp Pro Asp Ser Tyr Asn Lys His Leu Phe Val 20 25 30 His Ile Gly His Ala Asn His Ser Tyr Ser Asp Pro Leu Leu Glu Ser 35 40 45 Val Asp Ile Arg Gln Ile Tyr Asp Lys Phe Pro Glu Lys Lys Gly Gly 50 55 60 Leu Lys Glu Leu Phe Gly Lys Gly Pro Gln Asn Ala Phe Phe Leu Val 65 70 75 80 Lys Phe Trp Ala Asp Leu Asn Cys Asn Ile Gln Asp Asp Ala Gly Ala 85 90 95 Phe Tyr Gly Val Thr Ser Gln Tyr Glu Ser Ser Glu Asn Met Thr Val 100 105 110 Thr Cys Ser Thr Lys Val Cys Ser Phe Gly Lys Gln Val Val Glu Lys 115 120 125 Val Glu Thr Glu Tyr Ala Arg Phe Glu Asn Gly Arg Phe Val Tyr Arg 130 135 140 Ile Asn Arg Ser Pro Met Cys Glu Tyr Met Ile Asn Phe Ile His Lys 145 150 155 160 Leu Lys His Leu Pro Glu Lys Tyr Met Met Asn Ser Val Leu Glu Asn 165 170 175 Phe Thr Ile Leu Leu Val Val Thr Asn Arg Asp Thr Gln Glu Thr Leu 180 185 190 Leu Cys Met Ala Cys Val Phe Glu Val Ser Asn Ser Glu His Gly Ala 195 200 205 Gln His His Ile Tyr Arg Leu Val Lys Asp His Ile Tyr Arg Leu Val 210 215 220 Lys Asp 225 <210> 2 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> YAP is 60‐100 years old <400> 2 Asp Ser Glu Thr Asp Leu Glu Ala Leu Phe Asn Ala Val Met Asn Pro 1 5 10 15 Lys Thr Ala Asn Val Pro Gln Thr Val Pro Met Arg Leu Arg Lys Leu 20 25 30 Pro Asp Ser Phe Phe Lys Pro Pro Glu 35 40

Claims

1. The compound represented by Formula II, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers: (II) In the formula, R1 is a substituted or unsubstituted phenyl group; when R1 is a substituent group, the substituent is 1-3 selected from halogens, hydroxyl groups, C... 1-4 Alkyl and C 1-4 Alkoxy; R2 is selected from H, substituted or unsubstituted C. 1-6 Alkyl, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted 5-12-membered heteroaryl and substituted or unsubstituted 4-12-membered heterocyclic groups; When R2 is a substituent, the substituent is one to three substituents selected from the group consisting of: hydroxyl, carboxyl, halogen, cyano, NR'R''-C(O)-(CH2). n - C, optionally substituted with 1-5 substituents selected from hydroxyl, halogen, carboxyl and amino groups. 1-4 Alkyl groups, optionally surrounded by 1 to 5 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 Alkyl substituents substituted C 1-4 Alkyl groups, optionally surrounded by 1-5 groups selected from hydroxyl, halogen, carboxyl, amino, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents of 4-9 membered heterocyclic groups, and optionally selected from 4-9 membered heterocyclic groups, C 1-4 Alkyl and C 1-4 The acyl group is substituent for the amino group; wherein, R' and R'' are each independently selected from H, amino, and C, optionally substituted with 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl group, where n is an integer from 0 to 4; R3 represents H, halogen, or C. 1-4 Alkoxy and C 1-4 alkyl; R4 represents H, halogen, and C. 1-4 Alkoxy and C 1-4 alkyl; R5 represents H, halogen, and C. 1-4 Alkoxy and C 1-4 Alkyl; and R 11 H or any 1-6 selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Substituents of alkoxy, carboxyl, amino, and cyano groups on C 1-6 alkyl; The heteroatoms in the heterocyclic and heteroaryl groups include 1, 2, or 3 N, O, and / or S atoms.

2. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The 4-9 membered heterocyclic groups that serve as substituents for R2 are selected from tetrahydrofuranyl, tetrahydropyranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and dioxothiomorpholinyl.

3. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, When the substituent on R2 is an amino group substituted with a 4-9 membered heterocyclic group, the 4-9 membered heterocyclic group is selected from tetrahydrofuranyl, tetrahydropyranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl.

4. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is a phenyl group, a substituted or unsubstituted 5-12 membered nitrogen-containing heteroaryl group, or a substituted or unsubstituted 4-9 membered nitrogen- and / or oxygen- and / or sulfur-containing heterocyclic group, wherein the substituents on the phenyl group, the 5-12 membered nitrogen-containing heteroaryl group, or the 4-9 membered nitrogen- and / or oxygen- and / or sulfur-containing heterocyclic group are 1-3 substituents selected from the group consisting of: halogens, NR'R''-C(O)-(CH2). n - Unsubstituted or substituted C with 1-3 substituents selected from halogen, hydroxyl, carboxyl and amino groups. 1-4 Alkyl group, unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 C substituted with alkyl substituents 1-4 Alkoxy groups, unsubstituted 4-9 membered heterocyclic groups, and unsubstituted or selected from 1 or 2 C groups. 1-4 Alkyl and C 1-4 An acyl substituent or an amino group substituted with a 4-9 membered heterocyclic group.

5. The compound of claim 4, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, In R2, the substituted or unsubstituted 5-12 nitrogen-containing heteroaryl group is selected from pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrroloyl, triazolyl, pyrazinyl, indolyl, and pyridazinyl.

6. The compound of claim 4, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, In R2, the substituted or unsubstituted 4-9 member heterocyclic groups containing nitrogen and / or oxygen and / or sulfur are selected from nitrogen-heterocyclic butyl, morpholino, pyrrolidinyl, dihydroindolyl, piperidinyl, and piperazine.

7. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is H, halogen, or C. 1-4 Alkyl or halogenated C 1-4 alkyl.

8. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that: R3 is selected from halogens and C. 1-4 Alkyl; and / or, R4 is a halogen; and / or, R5 is H.

9. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 and R4 are halogens, and R5 is hydrogen.

10. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R 11 C is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 alkyl.

11. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R 11 For H.

12. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, When R2 is a substituted phenyl, heteroaryl, or heterocyclic group, the number of substituents is at least two.

13. The compound of claim 12, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, At least two substituents are located in adjacent positions.

14. The compound of claim 12, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, At least two substituents include at least a halogen and the NR'R''-C(O)-(CH2). n - 15. The compound of claim 14, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The substituent further includes one of the substituents selected from the group consisting of: C groups optionally substituted with 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl groups, optionally surrounded by 1 to 5 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 Alkyl substituents substituted C 1-4 Alkyl groups, optionally surrounded by 1-5 groups selected from hydroxyl, halogen, carboxyl, amino, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents of 4-9 membered heterocyclic groups, and optionally selected from 4-9 membered heterocyclic groups, C 1-4 Alkyl and C 1-4 An amino group substituted with an acyl group.

16. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R1 is a substituted or unsubstituted phenyl group, wherein when R1 is a substituent group, the number of substituents is 1-3, selected from hydroxyl, halogen, C 1-4 Alkyl and C 1-4 Alkoxy; R2 is a 4-9 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1-3 elements selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, carboxyl, and NR'R''-C(O)-(CH2) n - Substituents, wherein R' and R'' are each independently selected from H and C. 1-4 Alkyl group, where n is an integer from 0 to 4; R3 is selected from H, halogens, and C. 1-4 Alkoxy and C 1-4 alkyl; R4 is selected from H, halogens, and C. 1-4 Alkoxy and C 1-4 alkyl; R5 is selected from H, halogens, and C. 1-4 Alkoxy and C 1-4 alkyl; R 11 The C- group is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 alkyl.

17. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R1 is an unsubstituted phenyl group.

18. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is a 4-9 membered heterocyclic group containing N and / or O.

19. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is selected from aziridine, oxadiidine, tetrahydrofuranyl, pyrrolidine, tetrahydropyranyl, piperidinyl, and piperazine.

20. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is optionally selected from carboxyl groups and NR'R''-C(O)-(CH2). n - Substituents replace 4-9 membered heterocyclic groups.

21. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The substituent of R2 is located ortho to the position where R2 is connected to other parts of the compound of formula II, and / or when R2 is a nitrogen-containing heterocyclic group, it is connected to other parts of the compound of formula II through the cyclic nitrogen atom of R2.

22. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 is selected from H and halogens.

23. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R4 is a halogen.

24. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R5 is H.

25. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 and R4 are halogens, and R5 is hydrogen.

26. The compound of claim 16, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R 11 For H.

27. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R1 is a substituted or unsubstituted phenyl group; wherein, when R1 is a substituent group, the number of substituents is 1-3, selected from halogens, C 1-4 Alkyl and C 1-4 Alkoxy; R2 is a 5-12-membered heteroaryl group; wherein, the heteroaryl group is optionally surrounded by 1-3 groups selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, carboxyl, and NR'R''-C(O)-(CH2) n - Substituents, wherein R' and R'' are each independently selected from H and C. 1-4 Alkyl group, where n is an integer from 0 to 4; R3 is selected from H, halogens, and C. 1-4 Alkoxy and C 1-4 alkyl; R4 is selected from H, halogens, and C. 1-4 Alkoxy and C 1-4 alkyl; R5 is selected from H, halogens, and C. 1-4 Alkoxy and C 1-4 alkyl; R 11 The C- group is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 alkyl.

28. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R1 is an unsubstituted phenyl group.

29. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is a 5-12 membered heteroaryl group containing N.

30. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is selected from pyrrole, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

31. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R2 is randomly selected from 1-3 elements chosen from halogens, C 1-4 Alkyl groups and NR'R''-C(O)-(CH2) n - Substitution of substituents.

32. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The substituent of R2 is located adjacent to the position where R2 is connected to other parts of the compound of formula II, and / or when the heteroaryl is a nitrogen-containing heteroaryl, it is connected to other parts of the compound of formula II through the cyclic nitrogen atom of the heteroaryl.

33. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 is selected from H and halogens.

34. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R4 is a halogen.

35. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R5 is H.

36. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 and R4 are halogens, and R5 is hydrogen.

37. The compound of claim 27, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R 11 For H.

38. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound of formula II has the structure shown in formula III: (III) In the formula: R1, R3-R5 are as defined in claim 1; B1 is either C or N; B2 is either CR6 or N; B3 is either CR7 or N; B4 is either CR8 or N; B5 is either CR9 or N; B6 is CR 10 Or N; R6 is selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, cyano, carboxyl, NR 12 R 13 and NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted by 1-5 substituents selected from halogen, hydroxyl, carboxyl, and amino groups. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 represents H, halogen, and NR. 12 R 13 C 1-4 Alkoxy or C 1-4 alkyl; R8 is H, halogen, or C. 1-4 alkyl; R9 is H, a halogen, and C, optionally substituted with 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl groups, optionally surrounded by 1 to 5 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 Alkyl substituents substituted C 1-4 Alkyl groups, optionally surrounded by 1-5 groups selected from hydroxyl, halogen, carboxyl, amino, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents of 4-9 membered heterocyclic groups, or optionally selected from 4-9 membered heterocyclic groups and C 1-4 An amino group substituted with an alkyl group; or R7 and R8, or R8 and R9 together with their respective attached Cs to form a 5-membered nitrogen-containing saturated or unsaturated heterocycle; R 10 H, halogen, alkyl or halogenated C 1-4 alkyl; R 11 H or any 1-6 selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Substituents of alkoxy, carboxyl, amino, and cyano groups on C 1-4 alkyl; R 12 and R 13 Each is independent of H and C 1-4 Acyl or C 1-4 alkyl.

39. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, In R9, the 4-9 membered heterocyclic group is a 4-9 membered heterocyclic group containing nitrogen and / or oxygen and / or sulfur.

40. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, In R9, the 4-9 membered heterocyclic groups are selected from tetrahydrofuranyl, tetrahydropyranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, and dioxothiomorpholinyl.

41. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, In R9, when the amino group is optionally substituted with a 4-9 membered heterocyclic group, the 4-9 membered heterocyclic group is selected from tetrahydrofuranyl, tetrahydropyranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, and thiomorpholinyl.

42. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R7 and R8, or R8 and R9 together with their respective C atoms, form pyrrole or pyrrolealkyl groups.

43. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, B1 is CH; B2 is CR6; B3 is CR7; B4 is CR8; B5 is CR9; B6 is CR 10 ; R6 represents H, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, cyano, NR 12 R 13 Or NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted by 1-5 substituents selected from halogen, hydroxyl, carboxyl, and amino groups. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 is either H or NR 12 R 13 ; R8 is H; R9 is a C group optionally substituted with 1 to 5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl groups, optionally surrounded by 1 to 5 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 Alkyl substituents substituted C 1-4 Alkyl groups, optionally surrounded by 1-5 groups selected from hydroxyl, halogen, carboxyl, amino, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents of 4-9 membered heterocyclic groups, or optionally selected from 4-9 membered heterocyclic groups and C 1-4 Alkyl substituents substituted amino groups; R 10 It is a halogen; R 11 H or C optionally substituted with 1-3 C atoms selected from hydroxyl and halogen. 1-4 alkyl; Among them, R 12 and R 13 Each is independent of H and C 1-4 Acyl or C 1-4 alkyl.

44. The compound of claim 43, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R7 is H or NH2.

45. The compound of claim 43, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, In R9, the 4-9 member heterocyclic group is a 4-9 member heterocyclic group containing N and O, N and S, or N, O and S.

46. ​​The compound of claim 43, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R9 is an unsubstituted C group or a C group substituted with 1-3 substituents selected from halogen, hydroxyl, carboxyl, and amino groups. 1-4 Alkyl group, unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 Alkyl substituents substituted C 1-4 Alkyl group, unsubstituted morpholino group, unsubstituted thiomorpholino group, unsubstituted tetrahydropyrano group, or unsubstituted or with 1 or 2 carbon atoms. 1-4 Alkyl groups or amino groups substituted with a 4-9 membered heterocyclic group.

47. The compound of claim 46, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, When R9 is an amino group substituted with a 4-9 membered heterocyclic group, the 4-9 membered heterocyclic group is selected from oxobutane, tetrahydrofuranyl, and tetrahydropyranyl.

48. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, B1 is CH; B2 is CR6; B3 is CR7; B4 is CR8; B5 is CR9; B6 is CR 10 ; R6 is NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted with 1-2 substituents selected from hydroxyl and halogen. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 and R8 are H; R9 is H, a halogen, an unsubstituted C or a C substituted with 1-3 substituents selected from halogen, hydroxyl, carboxyl, and amino groups. 1-4 Alkyl group, unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 C substituted with alkyl substituents 1-4 Alkoxy group, unsubstituted 4-9 membered heterocyclic group, amino group substituted with one 4-9 membered heterocyclic group, or amino group substituted with one or two carbon atoms. 1-4 Alkyl-substituted amino groups; R 10 It is H or halogen; R 11 For H.

49. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, B1 is CH; B2 is CR6; B3 is N or CR7; B4 is N or CR8; B5 is N or CR9; B6 is CR 10 ; R6 is NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted with 1-2 substituents selected from hydroxyl and halogen. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 and R8 are H; R9 is H, a halogen, an unsubstituted C or a C substituted with 1-3 substituents selected from halogen, hydroxyl, carboxyl, and amino groups. 1-4 Alkyl group, unsubstituted or with 1-3 C groups selected from hydroxyl, halogen, carboxyl, amino, and halogenated C groups. 1-4 C substituted with alkyl substituents 1-4 Alkoxy group, unsubstituted 4-9 membered heterocyclic group, amino group substituted with one 4-9 membered heterocyclic group, or amino group substituted with one or two carbon atoms. 1-4 Alkyl-substituted amino groups; R 10 It is a halogen; R 11 For H.

50. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 is selected from halogens and C. 1-4 alkyl.

51. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R4 is a halogen.

52. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R5 is H.

53. The compound of claim 38, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 and R4 are halogens, and R5 is hydrogen.

54. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound of formula II has the structure shown in formula IV: (IV) In the formula: R1, R3-R5 and R 11 As described in claim 1; Each m can be 1, 2, or 3 independently; X is CH2, O, or NH; R d For 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)-(CH2) n - where R' and R'' are each independently selected from H and C. 1-4 Alkyl group, n is an integer from 0 to 4; R d The quantity is 1, 2 or 3.

55. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R d Located at the ortho position of the nitrogen atom connected to the remainder of Formula IV; and / or R d It can be H, carboxyl, or NR'R''-C(O)-(CH2). n -; and / or The heterocyclic group containing X is a nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl.

56. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R 11 The C- group is H or unsubstituted or optionally substituted with 1-3 substituents selected from halogens and hydroxyl groups. 1-6 alkyl; X is CH2, O, or NH; R d It can be H, carboxyl, or NR'R''-C(O)-(CH2). n - where R' and R'' are each independently selected from H and C. 1-4 Alkyl group, where n is an integer from 0 to 4.

57. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R1 is an unsubstituted phenyl group.

58. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 is selected from H and halogens.

59. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R4 is a halogen.

60. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R5 is H.

61. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R3 and R4 are halogens, and R5 is hydrogen.

62. The compound of claim 54, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, R 11 For H.

63. The compound according to any one of claims 1-62, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The NR'R''-C(O)-(CH2) n In the given condition, n is 0, and R' and R'' are independently H and C, respectively. 1-4 alkyl.

64. The compound according to any one of claims 1-62, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound contains an axial chirality.

65. The compound of claim 64, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound has an axial chirality of S configuration; or, the compound has an axial chirality of R configuration.

66. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound of formula II has the structure shown in formula V: （V） In the formula, R1, R3-R5 are as defined in claim 1; B1 is either C or N; B3 is either CR7 or N; B4 is either CR8 or N; B5 is either CR9 or N; R6 is selected from H, halogens, and C. 1-4 Alkyl, carboxyl, NR 12 R 13 and NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted by 1-5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 is H, halogen, or C. 1-4 alkyl; R8 is H, halogen, or C. 1-4 alkyl; R9 is as defined in any one of claims 38-49; R 10 H, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 11 H or arbitrarily selected from 1-6 halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Substituents of alkoxy, carboxyl, amino, and cyano groups on C 1-4 alkyl; R 12 and R 13 Each is independent of H and C 1-4 Acyl or C 1-4 alkyl; Among them, R6 and R 10 They are not both H.

67. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound of formula II has the structure shown in formula VI: (VI) In the formula, R1, R3-R5 are as defined in claim 1; B1 is either C or N; B3 is either CR7 or N; B4 is either CR8 or N; B5 is either CR9 or N; R6 is selected from H, halogens, and C. 1-4 Alkyl, carboxyl, NR 12 R 13 and NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted by 1-5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 is H, halogen, or C. 1-4 alkyl; R8 is H, halogen, or C. 1-4 alkyl; R9 is as defined in any one of claims 38-49; R 10 H, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 11 H or arbitrarily selected from 1-6 halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Substituents of alkoxy, carboxyl, amino, and cyano groups on C 1-4 alkyl; R 12 and R 13 Each is independent of H and C 1-4 Acyl or C 1-4 alkyl; Among them, R6 and R 10 They are not both H.

68. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound of formula II has the structure shown in formula VII: (VII) In the formula, R1, R3-R5 are as defined in claim 1; R6 is selected from H, halogens, and C. 1-4 Alkyl, carboxyl, NR 12 R 13 and NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted by 1-5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 is H, halogen, or C. 1-4 alkyl; R8 is H, halogen, or C. 1-4 alkyl; R9 is as defined in any one of claims 38-49; R 10 H, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 11 H or arbitrarily selected from 1-6 halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Substituents of alkoxy, carboxyl, amino, and cyano groups on C 1-4 alkyl; R 12 and R 13 Each is independent of H and C 1-4 Acyl or C 1-4 alkyl; Among them, R6 and R 10 They are not both H.

69. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound of formula II has the structure shown in formula VIII: (VIII) In the formula, R1, R3-R5 are as defined in claim 1; R6 is selected from H, halogens, and C. 1-4 Alkyl, carboxyl, NR 12 R 13 and NR'R''-C(O)-(CH2) n - where R' and R'' are each independently selected from H, amino, and C, optionally substituted by 1-5 substituents selected from hydroxyl, halogen, carboxyl, and amino groups. 1-4 Alkyl group, where n is an integer from 0 to 4; R7 is H, halogen, or C. 1-4 alkyl; R8 is H, halogen, or C. 1-4 alkyl; R9 is as defined in any one of claims 38-49; R 10 H, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 11 H or arbitrarily selected from 1-6 halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Substituents of alkoxy, carboxyl, amino, and cyano groups on C 1-4 alkyl; R 12 and R 13 Each is independent of H and C 1-4 Acyl or C 1-4 alkyl; Among them, R6 and R 10 They are not both H.

70. The compound of claim 1, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, or tautomers, characterized in that, The compound of formula II is selected from: and .

71. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any one of claims 1-70, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

72. The use of any compound of claims 1-70, a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof in the preparation of a medicament for the treatment or prevention of diseases mediated by the interaction between YAP / TAZ and TEAD.

73. The application as described in claim 72, characterized in that, The disease mediated by the interaction between YAP / TAZ and TEAD is cancer.

74. The application as described in claim 72, characterized in that, The diseases mediated by the interaction between YAP / TAZ and TEAD are 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.

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