Compound and medical use thereof

Abstract

The present application provides a compound having a structure represented by formula I or an enantiomer, a diastereoisomer, a racemate, a tautomer, a stereoisomer, a geometric isomer, an N-oxide, a metabolite thereof, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isotope-labeled compound, or a prodrug thereof. The present application also provides medical use of the compound or the enantiomer, the diastereoisomer, the racemate, the tautomer, the stereoisomer, the geometric isomer, the N-oxide, the metabolite thereof, or of the pharmaceutically acceptable salt, the ester, the solvate, the hydrate, the isotope-labeled compound, or the prodrug thereof.

Description

Compounds and their medicinal uses Technical Field

[0001] This application belongs to the field of pharmaceuticals, specifically relating to a compound and its pharmaceutical uses. Background Technology

[0002] The Hippo pathway has become an effective target for treating hyperproliferative disorders and diseases, particularly cancer (SASmith et al., J. Med. Chem. 2019, 62, 1291-1305; KCLin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. Kim et al., Cells (2019), 8, 468; KF Harvey et al., Nature Reviews Cancer, Vol. 13, 246–257 (2013)). The Hippo signaling pathway regulates many biological processes, including cell proliferation, survival, differentiation, organ size, and tissue homeostasis. This pathway consists of a complex cascade of serine / threonine protein kinases, including serine / threonine kinase 3 (STK3) and STK4. The complex formed by these kinases and the adaptor protein salvador homologue 1 (SAV1) can phosphorylate and activate effector proteins, LATS1 / 2. Upon activation, LATS1 / 2 binds to MOB kinase activator 1A / B (MOB1A / B) and inhibits the transcriptional cofactor yes-associated protein (YAP1) and transcriptional coactivators with PDZ-binding motifs (TAZ or WWTR1). When the Hippo pathway is "off," phosphorylated YAP / TAZ remains in the cytoplasm and may undergo protein degradation. When the Hippo pathway is "on," unphosphorylated YAP / TAZ enters the nucleus and binds to the transcription factor TEA DNA-binding protein (TEAD1-4). Dysregulation of the Hippo pathway leads to increased YAP / TAZ activity, which is associated with tumors, excessive proliferation, cell invasion, metastasis, and chemoresistance.

[0003] The TEAD transcription factor family are the ultimate effector factors of the Hippo pathway. They regulate the expression of target genes (Kras, Braf, Ctgf, Cyr6, Axl, Myc, etc.) by integrating and coordinating multiple signal transduction pathways (including Hippo, Wnt, TGFβ, and EGFR), thereby mediating tumor growth, metastasis, and tissue homeostasis. Numerous clinical studies have found that TEAD is highly expressed in various solid tumors, including prostate cancer, gastric cancer, breast cancer, germ cell tumors, head and neck squamous cell carcinoma, and renal cell carcinoma. Due to its high correlation with clinicopathological parameters of human malignancies, TEAD can serve as a prognostic biomarker for solid tumors. The Hippo pathway, as an important anti-tumor target discovered in the last decade, may benefit from inhibitors targeting TEAD-YAP, which may more effectively and directly correct dysregulated Hippo signaling pathways compared to those targeting upstream regulators, thus achieving the goal of tumor treatment.

[0004] Therefore, by targeting YAP, TAZ, or TEAD, thereby inhibiting the protein-protein interaction between YAP-TEAD, TAZ-TEAD, or other functional proteins and TEAD, it is possible to prevent and / or treat cancers and other hyperproliferative conditions and diseases associated with Hippo pathway dysfunction. Summary of the Invention

[0005] To address one of the aforementioned technical problems in the prior art, this application provides a compound and its pharmaceutical use. The compound of this application can prevent and / or treat cancers and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction by targeting YAP, TAZ, or TEAD, inhibiting protein-protein interactions between YAP-TEAD, TAZ-TEAD, or other functional proteins and TEAD, or protein-protein interactions between other functional proteins and YAP / TAZ.

[0006] In a first aspect of this application, a compound is provided having the structure shown in Formula I or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof.

[0007] Ring A is selected from: bond, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, phenyl;

[0008] Cycloyl group B is selected from: C4-C8 cycloalkyl, 5-10 heteroaryl, C 6-10 Aryl, C5-C6 cycloalkyl phenyl, C5-C6 cycloalkyl 5-6 heteroaryl, 5-6 heterocyclic phenyl, 5-6 heterocyclic 5-6 heteroaryl;

[0009] The ring C is selected from: C4-C6 cycloalkyl, 4-6 heterocyclic, 5-12 bridged cycloalkyl, 5-12 spirocyclic, 5-12 fused cycloalkyl, 5-10 heteroaryl, C6-C 10 Aryl;

[0010] R 1 R 2 R 3 Each of the following is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, and O;

[0011] Each R a Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -CONHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently substituted by 1-3 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=; or two adjacent R a The components are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, and O=.

[0012] Each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, SF5; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, and O=;

[0013] Each R cIndependently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=;

[0014] Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-, -N(R) Y1 )-、-P(=O)(R Y1 )-; where each R Y1 Whether the same or different, each is independently selected from: hydrogen, C1-C4 alkyl;

[0015] Y 2 Selected from: bond, -C(=O)-, -S(=O)2-, -N(R) Y2 )-、-C1-C4 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl;

[0016] L 1 Selected from: key, -N(R) L1 )-、-C1-C4 alkylene-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl;

[0017] L 2 Selected from: key, -N(R) L2 )-、-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl;

[0018] L 3 Selected from: key, -N(R) L3 )-、-C1-C4 alkylene-; wherein R L3 Selected from: hydrogen, C1-C4 alkyl;

[0019] Indicates a triple bond, double bond, or key; when When representing a triple bond, R 2 and R 3 Does not exist; when When representing a key, structural unit express

[0020] n, m, and p are each independently selected from: 0, 1, 2, 3, 4, and 5.

[0021] In a second aspect of this application, a pharmaceutical composition is provided comprising the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs thereof; and a pharmaceutically acceptable carrier or diluent.

[0022] In a third aspect of this application, the use of the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application for the preparation of a medicament for treating cancer is provided; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

[0023] In a fourth aspect of this application, the use of the compound described herein or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described herein for the preparation of a medicament for inhibiting cancer progression is provided.

[0024] In a fifth aspect of this application, the use of the compound described herein or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described herein for the preparation of a medicament for treating diseases or conditions associated with increased TEAD expression is provided.

[0025] In a sixth aspect of this application, the use of the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application for the preparation of a medicament for treating a disease or condition related to TEAD activity; wherein, inhibition of TEAD activity would be beneficial to the disease or condition.

[0026] In a seventh aspect of this application, the use of the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application in the preparation of a medicament for treating diseases or conditions associated with the Hippo pathway; wherein inhibition of the Hippo pathway would be beneficial to the disease or condition.

[0027] In some embodiments, the disease or condition is a proliferative disease; preferably, the proliferative disease is cancer.

[0028] In some implementations, the cancer is a YAP confined to the cell nucleus of the cancer cell.

[0029] In some embodiments, the TEAD overexpression, increased TEAD expression, or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression, or increased TEAD1 activity; and / or

[0030] The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD2 overexpression, increased TEAD2 expression, or increased TEAD2 activity; and / or

[0031] The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD3 overexpression, increased TEAD3 expression, or increased TEAD3 activity; and / or

[0032] The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD4 overexpression, increased TEAD4 expression, or increased TEAD4 activity.

[0033] In the eighth aspect of this application, the use of the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application for the preparation of a medicament having activity of binding to TEAD and blocking the interaction between YAP / TEAD is provided.

[0034] In the ninth aspect of this application, the use of the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, prodrugs, or pharmaceutical compositions described in this application for the preparation of a medicament for treating a disease or condition; said disease or condition is a disease or condition related to a protein that interacts with TEAD; preferably, said disease or condition related to a protein that interacts with TEAD includes, but is not limited to, cancer, metabolic diseases, inflammatory diseases, or neurodegenerative diseases; more preferably, said cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, melanoma, and melanoma. Cancers include fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper respiratory and digestive tract cancer, colorectal cancer, urinary tract cancer, or colon cancer; preferably, the cancers are selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, stomach cancer, breast cancer, or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, or undifferentiated carcinoma; even more preferably, the brain cancers include, but are not limited to, glioma; the head and neck cancers include, but are not limited to, head and neck squamous cell carcinoma; the lung cancers include, but are not limited to, lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma, or non-small cell lung cancer; the stomach cancers include, but are not limited to, gastric adenocarcinoma; the breast cancers include, but are not limited to, ductal breast cancer, breast cancer, or HR+ breast cancer; and the prostate cancers include, but are not limited to, prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.

[0035] In a tenth aspect of this application, a method is provided for inhibiting the interaction between TEAD and YAP; or for preventing and / or treating diseases mediated by the nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to antitumor drugs; or for reversing tumor cell resistance to antitumor drugs, comprising contacting the cells with or administering to the subject the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application;

[0036] According to some implementation methods, the subject is a mammal.

[0037] In other embodiments, the subject is a human.

[0038] In the eleventh aspect of this application, the use of the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application in inhibiting the interaction between TEAD and YAP; or in preventing and / or treating diseases mediated by the nuclear transcription factor TEAD; or in non-therapeuticly reversing anti-tumor drug resistance in tumor cells; or in reversing anti-tumor drug resistance in tumor cells is provided.

[0039] In a twelfth aspect of this application, a method of treating cancer in a patient is provided, comprising administering to the patient the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, prodrugs, or pharmaceutical compositions described in this application. Preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

[0040] In a thirteenth aspect of this application, there is a method for inhibiting cancer progression in a patient, comprising administering to the patient a compound of this application or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or a pharmaceutical composition of this application. Preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

[0041] In the fourteenth aspect of this application, a method is provided for treating a patient suffering from a disease or condition associated with increased TEAD expression, comprising administering to the patient the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application.

[0042] In the fifteenth aspect of this application, a method is provided for treating a patient suffering from a disease or condition associated with increased TEAD activity, comprising using the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or pharmaceutical compositions described in this application.

[0043] In a sixteenth aspect of this application, a method of treating a disease or symptom is provided, comprising administering to the patient a compound described in this application or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or a pharmaceutical composition described in this application.

[0044] In the seventeenth aspect of this application, a method for treating a disease or symptom is provided, wherein inhibition of the Hippo pathway would be beneficial to said disease or symptom, comprising administering to said patient a compound described in this application or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or pharmaceutical composition described in this application.

[0045] According to some embodiments, the disease or condition is a cell proliferation disorder; preferably, the cell proliferation disorder is cancer.

[0046] According to some implementations, the cancer is a cancer in which YAP is confined to the cell nucleus.

[0047] According to some implementations, the TEAD overexpression, increased TEAD expression, or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression, or increased TEAD1 activity; and / or

[0048] The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD2 overexpression, increased TEAD2 expression, or increased TEAD2 activity; and / or

[0049] The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD3 overexpression, increased TEAD3 expression, or increased TEAD3 activity; and / or

[0050] The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD4 overexpression, increased TEAD4 expression, or increased TEAD4 activity.

[0051] Another aspect of this application relates to methods for the preparation, separation, and purification of the compounds shown in this application.

[0052] Any embodiment of any aspect of this application may be combined with other embodiments, as long as they do not contradict each other. Furthermore, any technical feature in any embodiment of any aspect of this application may be applied to the same technical feature in other embodiments, as long as they do not contradict each other.

[0053] The foregoing description only outlines certain aspects of this application, but is not limited to them. These and other aspects will be described in more detail and in full below. All references in this specification are incorporated herein by reference in their entirety. Attached Figure Description

[0054] Figure 1 shows the inhibitory effect of compound 1 in test example 2 on downstream target genes of YAP in NCI-H226 cells.

[0055] Figure 2 shows the inhibitory effects of compound 2 and control compound VT103 on downstream target genes of YAP in NCI-H226 cells in test example 2, with compound 2 showing a significantly better inhibitory effect than control compound VT103.

[0056] Figure 3 shows the inhibitory effect of the mixture of compounds 3 and 4 in test example 2 on downstream target genes of YAP in NCI-H226 cells.

[0057] Figure 4 shows the inhibitory effects of compound 4 in test example 2 and control compound VT103 on downstream target genes of YAP in NCI-H226 cells, with compound 4 showing a significantly better inhibitory effect than control compound VT103.

[0058] Figure 5 shows the inhibitory effect of compound 9 in test example 2 on downstream target genes of YAP in NCI-H226 cells.

[0059] Figure 6 shows the inhibitory effect of compound 10 in test example 2 on downstream target genes of YAP in NCI-H226 cells.

[0060] Figure 7 shows the inhibitory effect of compound 13 in test example 2 on downstream target genes of YAP in NCI-H226 cells.

[0061] Figure 8 shows the inhibitory effects of compound 92 in test example 2 and control compound BPI-460372 on downstream target genes of YAP in NCI-H226 cells. The inhibitory effect of compound 92 was significantly better than that of control compound BPI-460372.

[0062] Figure 9 shows the inhibitory effects of compound 129 and control compound BPI-460372 on downstream target genes of YAP in NCI-H226 cells in test example 2. The inhibitory effect of compound 129 was significantly better than that of control compound BPI-460372.

[0063] Figure 10 shows the inhibitory effect of compound 14 in test example 4 on downstream target genes of YAP in mice with MSTO-211H cells transplanted subcutaneously.

[0064] Figure 11 shows the inhibitory effect of compound 65 in test example 4 on downstream target genes of YAP in mice with MSTO-211H cells transplanted subcutaneously.

[0065] Figure 12 shows that compound 65 in test example 5, at a dose of 30 mg / kg, effectively inhibited tumor growth in a mouse subcutaneous xenograft model of NCI-H226 cells, without any change in mouse body weight.

[0066] Figure 13 shows that compound 65 in test example 6 is a pan-TEAD inhibitor, and under the same administration concentration, compound 65 significantly inhibits the YAP / TEAD interaction better than the control compound VT103. Detailed Implementation

[0067] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of this application. Furthermore, descriptions of well-known structures and technologies are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and technologies have also been described in numerous publications.

[0068] definition

[0069] Certain embodiments of this application will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. This application is intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of this application as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice this application. This application is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0070] It should be further appreciated that some features of this application, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of this application, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0071] Unless otherwise stated, all technical terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. All patents and publications related to this application are incorporated herein by reference in their entirety.

[0072] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this application, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0073] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles concerning one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or employed in the embodiments described.

[0074] The term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0075] The terms "patient" or "subject" refer to a person (including adults and children) or other animal. In some implementations, "patient" refers to a person.

[0076] The terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this application but do not exclude other contents.

[0077] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0078] The term "enantiomer" refers to two non-overlapping but mirror-image isomers of a compound.

[0079] The term "diastereomer" refers to a stereoisomer that has two or more chiral neutral molecules that are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatography, for example, HPLC.

[0080] The terms “racemate,” “racemic mixture,” or “racemic mixture” refer to an equimolar mixture of two enantiomers that lack optical activity.

[0081] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds in this application are within the scope of this application.

[0082] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and hindered isomers, etc.

[0083] The term "geometric isomers," also known as "cis-trans isomers," refers to isomers that cannot rotate freely due to the double bond (including the double bond, C=N double bond, and N=N double bond in alkenes) or the single bond of a cyclic carbon atom.

[0084] In the general formula compounds and specific compounds of this application, the group " Can be with The terms "cis," "trans," and "mixtures" are used interchangeably to refer to compounds. Specifically, when the isomer designation (e.g., isomer 1 or isomer 2) is provided below the compound's structural formula, it indicates that the compound is either cis or trans. When no isomer designation is provided below the compound's structural formula, it indicates that the compound is a mixture of cis and trans configurations. For example, compound 3... and compound 4 Compounds 3 and 4 are in cis configuration. and trans configuration One of them, and the two are different, while compound 112 If the word "isomer" is not indicated below the structural formula, it means that it is a mixture of cis and trans configurations.

[0085] The stereochemical definitions and rules used in this application generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they have the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0086] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this application may exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0087] Depending on the choice of starting materials and methods, the compounds of this application may exist as one or a mixture of possible isomers, such as racemic mixtures and diastereomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0088] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0089] Racemic mixtures of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating their diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0090] The term "nitrogen oxide" refers to the oxidation of one or more nitrogen atoms to form N-oxides when a compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th ed., Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0091] The term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A compound's metabolite can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this application. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this application includes metabolites of compounds, including metabolites produced by sufficient contact of the compound of this application with mammals for a period of time.

[0092] The term "pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated. Preferably, "pharmaceutical acceptable" as used herein means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly in humans.

[0093] The term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of this application. Pharmaceutically acceptable salts are well-known in the field, as described in SMBerge et al., J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts include salts formed by the compound with an acid, including, but not limited to, inorganic acid salts (such as hydrochlorides, hydrobromic acids, phosphates, sulfates, nitrates, and perchlorates) and organic acid salts (such as acetates, glycolic acids, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, and sulfosalicylates), or salts obtained by other methods described in the literature, such as ion exchange. More pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, gluconate, glycerophosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts also include salts formed by compounds with bases, including but not limited to, inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C) salts). 1-4 Alkyl salts, alkali metal or alkaline earth metal salts including sodium, lithium, potassium, calcium, magnesium, etc. This application also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C44, etc. 1-8 Sulfonates and aromatic sulfonates. Organic base salts (such as primary, secondary, and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, and basic ion exchange resin salts)). Certain organic amine salts include, for example, isopropylamine salts, benzathine salts, cholinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, and tromethamine salts.

[0094] Pharmaceutically acceptable acid addition salts can be formed by the reaction of the compounds of this application with inorganic or organic acids, and pharmaceutically acceptable base addition salts can be formed by the reaction of the compounds of this application with inorganic or organic bases. The pharmaceutically acceptable salts of this application can be synthesized using conventional chemical methods from a parent compound and its basic or acidic components. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other lists of suitable salts can be found in, for example, “Remington’s Pharmaceutical Sciences”, 20th edition, Mack Publishing Company, Easton, Pa. (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0095] The term "solvent" refers to an association formed by one or more solvent molecules with the compound of this application. The solvent may be water, acetic acid, diethyl ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixture of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, or tert-butanol. Sec-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixture of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropanol, methanol, butanone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-propanone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, cumene, or mixtures thereof, etc.

[0096] The term "hydrate" refers to an associative compound formed by one or more water molecules and the compound of this application.

[0097] Furthermore, the compounds disclosed in this application, including their salts, can also be obtained in their hydrated form or in the form of a solvent containing them (e.g., ethanol, DMSO, etc.) for crystallization. The compounds disclosed in this application can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this application is intended to include both solvated and unsolvated forms.

[0098] The term "ester" is represented by the formula -OC(O)R' or -C(O)OR', where R' can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described in this application.

[0099] The term "isotope-labeled compound" refers to compounds in this application that are labeled with isotopes. They are identical to those compounds described in this application except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Exemplary isotopes may also be introduced in the compounds of this application, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0100] Other isotopically labeled compounds of this application containing the aforementioned isotopic label and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this application. Isotopically labeled compounds of this application, such as radioisotopically labeled compounds, are also included. 3 H and 14 The incorporation of tritium into the compounds of this application can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds, i.e., 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. Additionally, isotopes with higher mass numbers, such as deuterium, are used. 2 H substitution can offer therapeutic advantages such as greater metabolic stability, including increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some situations.

[0101] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages due to increased metabolic stability. These advantages include, for example, an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this application is considered a substituent. The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. As used in this application, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of the specified isotope and its native abundance. If the substituents of the compounds in this application are designated as deuterium, the compounds have an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of this application include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0102] As used in this application, the term "prodrug" refers to the conversion of a compound into the compound represented by Formula I in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds in this application can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C14) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this application contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent hydroxyl group. A complete discussion of prodrugs can be found in the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270; and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0103] Unless otherwise expressly indicated, the descriptive terms “each…independently”, “…each…independently”, and “…independently” used in this application are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0104] The terms “optional,” “optionally,” or “arbitrarily” mean that the event or situation subsequently described may, but is not necessarily, occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, “optionally replaced by…” means that the replacement may or may not exist.

[0105] When the terms “independent” and “arbitrarily” are used together, for example, “independently and arbitrarily replaced by…”, it means that specific options are replaced by or not replaced by each other without affecting each other.

[0106] The term "unsaturated" or "unsaturated" means that a portion contains one or more degrees of unsaturation.

[0107] In various parts of this specification, the substituents of the compounds disclosed in this application are disclosed according to the type or scope of the groups. In particular, this application includes every independent secondary combination of each member of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0108] Linking substituents are described in various parts of this application. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0109] The term "heteroatom" refers to O, S, N, P, B, and Si, including any oxidation state of S, N, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NRT (like NRT in N-substituted pyrrolidinyl, where RT is a substituent on N). In some embodiments, the heteroatoms involved in this application are nitrogen, oxygen, and sulfur. In the compounds involved in this application, when multiple heteroatoms are contained, the compounds constituted conform to the covalent and compositional rules of organic compounds, that is, compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent and compositional rules of organic compounds.

[0110] The term "heterocyclic group" or "heterocycle" refers to a monovalent or polyvalent monocyclic or polycyclic (e.g., bicyclic or tricyclic) system containing a carbon atom and a heteroatom. The heteroatom has the meaning as described in this application. A heterocyclic group can be fully saturated or contain one or more degrees of unsaturation, wherein at least one ring is not an aromatic ring and the whole is not aromatic; when the heterocyclic group is a polycyclic system, at least one ring is a non-aromatic ring. In one embodiment, the heterocyclic group is a 4-12 membered ring, such as a 4-12 membered saturated or partially unsaturated heterocyclic group (a carbon atom and a heteroatom selected from N, O, P, S, B, Si, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO2, PO, PO2, preferably a carbon atom and a heteroatom selected from N, O, and S). In one embodiment, the saturated or partially unsaturated heterocyclic group is selected from: saturated monocyclic heterocyclic groups, saturated bicyclic heterocyclic groups, saturated tricyclic heterocyclic groups, partially unsaturated monocyclic heterocyclic groups, partially unsaturated bicyclic heterocyclic groups, and partially unsaturated tricyclic heterocyclic groups. A bicyclic heterocyclic group represents a heterocyclic group of a bicyclic system. A monocyclic heterocyclic group represents a heterocyclic group of a monocyclic system. A 5-12 membered heterocyclic group represents a heterocyclic group with 5-12 ring atoms. A 6-12 membered heterocyclic group represents a heterocyclic group with 6-12 ring atoms. A 7-8 membered heterocyclic group represents a heterocyclic group with 7-8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include heterocyclic groups of spirocyclic, fused, and bridged rings.

[0111] The term "spiroheterocyclic group" or "heterospirocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), and the ring atoms are selected from N, O, and S(O). m The ring may contain B (where m is an integer from 0 to 2) heteroatoms (preferably N, O, or S), with the remaining ring atoms being carbon. One or more rings may contain one or more double bonds, but the ring as a whole is not aromatic. The rings are preferably 6 to 12-membered. Depending on the number of rings, the rings can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic spirocyclic groups, with bicyclic being preferred. Based on the number of non-shared atoms on the rings, examples of spirobicyclic rings include, but are not limited to: spiro[3.2]bicyclic rings, spiro[3.3]bicyclic rings, spiro[3.4]bicyclic rings, spiro[3.5]bicyclic rings, spiro[4.4]bicyclic rings, spiro[4.5]bicyclic rings, spiro[5.5]bicyclic rings, spiro[6.3]bicyclic rings, spiro[6.4]bicyclic rings, and spiro[6.5]bicyclic rings.

[0112] The term "fused heterocyclic group" or "heterofused cyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein at least one ring is not an aromatic ring and the whole is not aromatic, and one or more ring atoms are selected from N, O, and S(O). m The heteroatom is B (where m is an integer from 0 to 2) (preferably N, O, or S), and the remaining ring atoms are carbon. It is preferably 6 to 12-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, with bicyclic being preferred. Examples of fused bicyclic heterocycles, depending on the number of fused monocyclic atoms, include, but are not limited to, 4-membered heterocycles with 4-membered heterocycles, 5-membered heterocycles with 4-membered heterocycles, 5-membered heterocycles with 5-membered heterocycles, 6-membered heterocycles with 4-membered heterocycles, 6-membered heterocycles with 5-membered heterocycles, 6-membered heterocycles with 6-membered heterocycles, 7-membered heterocycles with 4-membered heterocycles, 7-membered heterocycles with 5-membered heterocycles, 7-membered heterocycles with 6-membered heterocycles, 7-membered heterocycles with 7-membered heterocycles with 7-membered heterocycles, 8-membered heterocycles with 4-membered heterocycles, 8-membered heterocycles with 5-membered heterocycles, and 8-membered heterocycles with 6-membered heterocycles.

[0113] The term "bridged heterocyclic group" or "heterobridged cyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. One or more rings may contain one or more double bonds, at least one of which is not an aromatic ring and the group as a whole is not aromatic. One or more ring atoms are selected from N, O, and S(O). m The heteroatom is B (where m is an integer from 0 to 2) (preferably N, O, or S), and the remaining ring atoms are carbon. It is preferably 6 to 12-membered. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, with bicyclic being preferred. Based on the number of non-shared atoms on the ring, examples of bridged bicyclic rings include, but are not limited to: bridged [2.1.1] bicyclic ring, bridged [2.2.1] bicyclic ring, bridged [2.2.2] bicyclic ring, bridged [3.1.1] bicyclic ring, bridged [3.2.1] bicyclic ring, bridged [3.2.2] bicyclic ring, bridged [3.3.1] bicyclic ring, bridged [3.3.2] bicyclic ring, bridged [3.3.3] bicyclic ring, bridged [4.1.1] bicyclic ring, bridged [4.2.1] bicyclic ring, bridged [4.2.2] bicyclic ring, bridged [4.3.1] bicyclic ring, bridged [4.3.2] bicyclic ring, bridged [4.4.1] bicyclic ring, or bridged [4.4.2] bicyclic ring.

[0114] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing carbon atoms. A cycloalkyl group may be fully saturated or contain one or more degrees of unsaturation, wherein at least one ring is not an aromatic ring and the entire group is not aromatic. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C1. 3-6Saturated or partially unsaturated cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc. In one embodiment, the saturated or partially unsaturated cycloalkyl group is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. C 4-7 Cycloalkyl refers to cycloalkyl groups with 4-7 ring atoms. C 3-6 Cycloalkyl refers to cycloalkyl groups with 3 to 6 ring atoms.

[0115] The terms "heteroaryl" or "heteroaromatic ring" refer to aromatic systems containing heteroatoms, including monocyclic, bicyclic, and tricyclic rings. The term "heteroaryl" may be used interchangeably with "heteroaromatic ring" or "heteroaromatic compound." Heteroatoms are defined as described in this application. In some embodiments, a heteroaryl is a heteroaryl consisting of 5-10 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-10-membered heteroaryl; a heteroaryl is a heteroaryl consisting of 5-8 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-8-membered heteroaryl; in some embodiments, a heteroaryl is a heteroaryl consisting of 5-7 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-7-membered heteroaryl. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-6 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 6 membered heteroaryl group.

[0116] The term "aryl" or "aromatic ring" refers to aromatic carbocyclic systems that are monocyclic, bicyclic, or tricyclic. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". 6-10 Aryl refers to an aryl group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl groups.

[0117] The term "alkyl" or "alkyl group" refers to a carbon-containing, saturated, straight-chain or branched hydrocarbon group. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C64-C64. 1-6 Alkyl group; in another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C64-C44-C6 ... 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C64-C ... 1-3Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups.

[0118] The term "alkenyl" refers to a straight-chain or branched monovalent or polyvalent hydrocarbon group containing carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group contains 2-6 carbon atoms, i.e., a C2-C6 alkenyl; in another embodiment, the alkenyl group contains 2-4 carbon atoms, i.e., a C2-C4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0119] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing a carbon atom, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp triple bond. In one embodiment, the alkynyl group comprises 2-6 carbon atoms, i.e., a C2-C6 alkynyl; in another embodiment, the alkynyl group comprises 2-4 carbon atoms, i.e., a C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0120] The term "alkoxy group" indicates that an alkyl group is attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this application. In one embodiment, the alkoxy group contains 1-6 carbon atoms, i.e., C64-C ... 1-6 Alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C 1-4 Alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C6 1-3 Alkyl group.

[0121] The term "alkylamino" indicates that an alkyl group is attached to the rest of the molecule via a nitrogen atom, wherein the alkyl group has the meaning as described in this application. In one embodiment, the alkylamino group contains 1-6 carbon atoms, i.e., C64-C ... 1-6 Alkylamino; in particular, C 1-6 Alkylamino groups include -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl group 2. In another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., C14... 1-4 Alkylamino groups, including -NH(C 1-4 alkyl) and -N(C) 1-4 Alkyl group 2; In another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C 1-3Alkylamino, which includes -NH(C 1-3 alkyl) and -N(C 1-3 alkyl)2.

[0122] The term "hydrogen" refers to 1 H; "deuterium" refers to 2 H.

[0123] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0124] The term "amino" refers to -NH2.

[0125] The term "hydroxy" refers to -OH.

[0126] The term "cyano" refers to -CN.

[0127] The term "nitro" refers to -NO2.

[0128] The term "carboxyl" refers to HO(C=O)-.

[0129] The term "oxo" refers to O=, that is, when the substituent is O=, O is connected to the substituted group by a double bond.

[0130] In this application document, when it is mentioned that a group is substituted by a substituent, it means that a suitable group is substituted at a reasonable position. For example, for oxo, when there is a description: R is alkyl, aryl, and the alkyl and aryl are each optionally independently substituted by 0, 1, 2, 3 substituents selected from halogens, hydroxy, oxo, it can be reasonably understood that oxo only occurs at a suitable position on the alkyl.

[0131] The terms "comprising", "including", "containing" are inclusive or open-ended and do not exclude additional unmentioned elements or components from the drug (or in the case of a method, steps). The phrase "consisting of..." does not include any element, step or component not specified in the drug (or in the case of a method, steps). The phrase "consisting essentially of..." means the specified materials and those materials that do not substantially affect the basic and novel properties of the drug (or in the case of a method, steps).

[0132] As described herein, the ring system formed by connecting the substituent R to the ring center by a bond (as shown in the following figure) represents that the substituent R is substituted at any substitutable or any reasonable position on the A ring or B ring. For example, formula f represents any possible substituted position on the A ring or B, as shown by formulas f1 - f8:

[0133] As described herein, the ring system formed by connecting the substituent to the ring center by a bond, such as (R x ) n, representing n substituents R x It can be substituted at any substituted position on the ring. For example, formula a represents that the benzene ring can be substituted by n R groups. x replace.

[0134] When the substituent is a ring, and the bond connecting the substituted part to the molecule is attached to the center of the ring of the substituent, forming a ring system (as shown in the figure below), it represents any reasonable position on the substituent connected to the substituted part. For example, formula b is represented as formulas b1-b5:

[0135] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position, i.e., the various substitutions are independent of each other. Those skilled in the art will understand that the combinations of substituents contemplated in this application are those that are stable or chemically feasible.

[0136] As used in this article, when a group is selected from the bond, it means that the position of the group does not contain an actual atom or group, and the groups (or structural units) on both sides are directly connected by chemical bonds. For example, when Y 2 When selected from the key, Y 1 It is directly bonded to the ring C.

[0137] As used herein, "having the following structures" means "selected from the following structures," for example, "in some embodiments, It has the following structure: "In some implementations, " indicates " Selected from the following structures:

[0138] Description of the compounds in this application

[0139] This application describes compounds that are used to prepare inhibitors of the interaction between TEAD and YAP; or to prepare drugs for the prevention and / or treatment of diseases mediated by the nuclear transcription factor TEAD; or to non-therapeuticly reverse anti-tumor drug resistance in tumor cells; or to prepare drugs for reversing anti-tumor drug resistance in tumor cells. The preparation methods for the compounds described in this application are simple and easy to implement, the processes are stable, and they are suitable for industrial production. Therefore, the compounds provided in this application have superior druggability compared to existing similar compounds.

[0140] Specifically, this application provides a compound having the structure shown in Formula I or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof.

[0141] Ring A is selected from: bond, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, phenyl;

[0142] Cycloyl group B is selected from: C4-C8 cycloalkyl, 5-10 heteroaryl, C 6-10 Aryl, C5-C6 cycloalkylphenyl, C5-C6 cycloalkyl5-6 heteroaryl, 5-6 heterocyclic phenyl, 5-6 heterocyclic 5-6 heteroaryl; preferably, ring B is selected from phenyl, pyridyl, and cyclohexyl;

[0143] The ring C is selected from: C4-C6 cycloalkyl, 4-6 heterocyclic, 5-12 bridged cycloalkyl, 5-12 spirocyclic, 5-12 fused cycloalkyl, 5-10 heteroaryl, C6-C 10 Aryl;

[0144] R 1 R 2 R 3 Each of the following is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, and O;

[0145] Each R a Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, C 3-6 Substitution of cycloalkyl groups; or two adjacent R groups. aThe components are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, and O=.

[0146] Each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, SF5; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, and O=;

[0147] Each R c Independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=;

[0148] Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-, -N(R) Y1 )-、-P(=O)(R Y1 )-; where each R Y1 Whether the same or different, each is independently selected from: hydrogen, C1-C4 alkyl;

[0149] Y 2 Selected from: bond, -C(=O)-, -S(=O)2-, -N(R) Y2 )-、-C1-C4 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl;

[0150] L 1 Selected from: key, -N(R) L1 )-、-C1-C4 alkylene-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl;

[0151] L 2 Selected from: key, -N(R) L2 )-、-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl;

[0152] L 3 Selected from: key, -N(R)L3 )-、-C1-C4 alkylene-; wherein R L3 Selected from: hydrogen, C1-C4 alkyl;

[0153] Indicates a triple bond, double bond, or key; when When representing a triple bond, R 2 and R 3 Does not exist; when When representing a key, structural unit express

[0154] n, m, and p are each independently selected from: 0, 1, 2, 3, 4, and 5.

[0155] In some embodiments, ring A is selected from: 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenyl;

[0156] Cyclone B is selected from: 5-10 heteroaryl groups, C 6-10 Aryl, C5-C6 cycloalkylphenyl, C5-C6 cycloalkyl5-6 heteroaryl, 5-6 heterocyclic phenyl, 5-6 heterocyclic 5-6 heteroaryl; preferably, ring B is selected from phenyl;

[0157] The ring C is selected from: C4-C6 cycloalkyl, 4-6 heterocyclic, 5-12 bridged cycloalkyl, 5-12 spirocyclic, 5-12 fused cycloalkyl, 5-10 heteroaryl, C6-C 10 Aryl;

[0158] R 1 R 2 R 3 Each of the following is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, and O;

[0159] Each R a Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, C 3-6Substitution of cycloalkyl groups; or two adjacent R groups. a The components are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, and O=.

[0160] Preferably; each R a Independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from 1-3 of the following: deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C 3-6 Substitution of cycloalkyl groups; or two adjacent R groups. a The compounds are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1, 2, or 3 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, and O=.

[0161] Each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, SF5; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally each independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, and O; preferably, each R b Independently selected from: C1-C6 alkyl, C1-C6 alkoxy, SF5; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1-6 substituents selected from deuterium and halogen;

[0162] Each R cIndependently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=; preferably, each R c Independently selected from: hydrogen, deuterium, and halogens;

[0163] Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-;

[0164] Y 2 Selected from: key, -N(R) Y2 )-、-C1-C4 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl;

[0165] L 1 Selected from: key, -N(R) L1 )-、-C1-C4 alkylene-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl;

[0166] L 2 Selected from: key, -N(R) L2 )-、-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl;

[0167] L 3 Selected from: key, -N(R) L3 )-、-C1-C4 alkylene-; wherein R L3 Selected from: hydrogen, C1-C4 alkyl;

[0168] Indicates a triple bond or a double bond; when When representing a triple bond, R 2 and R 3 It does not exist;

[0169] n, m, and p are each independently selected from: 0, 1, 2, 3, 4, and 5.

[0170] In some implementations, each R a Independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from 1-3 of the following: deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C 3-6Substitution of cycloalkyl groups; or two adjacent R groups. a The components are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1, 2, or 3 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, and O=.

[0171] In some implementations, each R b Independently selected from: C1-C6 alkyl, C1-C6 alkoxy, SF5; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1-6 substituents selected from deuterium and halogen.

[0172] In some implementations, each R c Independently selected from: hydrogen, deuterium, halogens.

[0173] In some embodiments, ring A is selected from 5-6 membered heteroaryl, 5-6 membered saturated heterocyclic group, 5-6 membered partially unsaturated heterocyclic group, and phenyl.

[0174] In some embodiments, ring A is selected from phenyl, 5-6-membered heteroaryl; the heteroatom of the 5-6-membered heteroaryl is selected from N, O and S, and the number of heteroatoms is selected from 1, 2 and 3.

[0175] In some embodiments, ring A is selected from 5-6-membered heteroaryl groups; the heteroatoms of the 5-6-membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is selected from 1 and 2.

[0176] In some embodiments, ring A is selected from 5-6-membered heteroaryl groups; the 5-6-membered heteroaryl group has 1 or 2 N heteroatoms and 0 or 1 heteroatoms selected from O and S.

[0177] In some implementations... It has the following structure:

[0178] in,

[0179] X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9X 10 Each is independently selected from: CH, N;

[0180] E 1 E 2 E 3 E 4 E 5 E 6 Each is independently selected from: CH2, NH, O, S.

[0181] In some implementations... It has the following structure:

[0182] Among them, X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 Each is independently selected from: CH, N;

[0183] E 1 E 2 Each is independently selected from: CH2, NH, O, S.

[0184] In some implementations... It has the following structure:

[0185] X 1 X 2 X 3 X 4 Each is independently selected from: CH, N;

[0186] X 9 X 10 Each is independently selected from: CH, N;

[0187] E 1 and E 3 Each is independently selected from: CH2, NH, O, S;

[0188] E 2 Selected from: CH, N.

[0189] In some implementations... It has the following structure:

[0190] Wherein, p' is selected from 0, 1, 2, 3 or 4. Preferably, p and p' are each independently selected from 0 or 1; more preferably, p and p' are both selected from 0.

[0191] In some implementations... It has the following structure:

[0192] In some implementations... It has the following structure:

[0193] Wherein, p' is selected from 0, 1, 2, 3 or 4. Preferably, p and p' are each independently selected from 0 or 1; more preferably, p and p' are both selected from 0.

[0194] In some implementations... It has the following structure:

[0195] In some implementations... It has the following structure:

[0196] In some implementations... It has the following structure:

[0197] In some implementations... It has the following structure:

[0198] In some implementations... It has the following structure:

[0199] In some implementations... It has the following structure:

[0200] Among them, R aaEach is independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl;

[0201] p1 is independently selected from: 0, 1, 2.

[0202] In some implementations... It has the following structure:

[0203] Among them, p1 is independently selected from: 0, 1, 2.

[0204] In some implementations... It has the following structure:

[0205] In some implementations... It has the following structure:

[0206] In some implementations... It has the following structure:

[0207] In some implementations... It has the following structure:

[0208] In some implementations... It has the following structure:

[0209] Preferably, It has the following structure:

[0210] Among them, R aaEach is independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl;

[0211] p1 is independently selected from 0, 1, and 2. Preferably, p1 is selected from 0 or 1; more preferably, p1 is 0.

[0212] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl.

[0213] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0214] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 alkoxy.

[0215] In some implementations, R aa Each is independently selected from C1-C4 alkoxy groups.

[0216] In some implementations, R aaEach is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0217] In some implementations, R aa Selected from

[0218] In some implementations, R aa Each is independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0219] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, or methoxy.

[0220] In some implementations, R aa Each is independently selected from: hydrogen or deuterium.

[0221] In some embodiments, the ring C is a C4-C6 saturated cycloalkyl, a 4-6 membered saturated heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-12 membered bridged carbocyclic group, a 5-12 membered spirocarbocyclic group, a 5-12 membered fused carbocyclic group, a 5-12 membered bridged heterocyclic group, a 5-12 membered spiroheterocyclic group, a 5-12 membered heterofused cyclic group, a 5-10 membered heteroaryl group, or a C6-C6 cycloalkyl group. 10 Aryl.

[0222] In some embodiments, the ring C is a C4-C6 saturated cycloalkyl group, a 4-6 membered saturated heterocyclic group, a C4-C6 partially unsaturated cycloalkyl group, a 4-6 membered partially unsaturated heterocyclic group, a 5-12 membered bridged carbocyclic group, a 5-12 membered bridged heterocyclic group, a 5-12 membered spirocyclic group, a 5-12 membered fused heterocyclic group, a 5-10 membered heteroaryl group, or a C6-C6 cycloalkyl group. 10 Aryl.

[0223] In some embodiments, the ring C is a C4-C6 saturated cycloalkyl group, a 4-6 membered saturated heterocyclic group, a C4-C6 partially unsaturated cycloalkyl group, a 4-6 membered partially unsaturated heterocyclic group, a 5-12 membered bridged carbocyclic group, a 5-12 membered bridged heterocyclic group, a 5-12 membered spirocyclic group, a 5-12 membered fused heterocyclic group, a 5-10 membered heteroaryl group, or a C6-C6 cycloalkyl group. 10 Aryl.

[0224] In some embodiments, the ring C is selected from 4-6 member saturated heterocyclic groups, 5-12 member spiroheterocyclic groups, 5-10 member heteroaryl groups, and C6-C... 10 Aryl.

[0225] In some embodiments, the ring C is selected from 4-6 membered saturated heterocyclic groups, 5-10 membered heteroaryl groups, and C6-C6 saturated heterocyclic groups. 10 Aryl, 7-11 membered spiroheterocyclic group.

[0226] In some embodiments, the ring C is selected from 4-6 membered saturated heterocyclic groups, 5-6 membered heteroaryl groups, phenyl groups, and 7-9 membered spiroheterocyclic groups. In some embodiments, the ring C is selected from 4-6 membered saturated heterocyclic groups, and the heteroatom is selected from nitrogen.

[0227] In some implementations... It has the following structure:

[0228] in,

[0229] c1 and c2 are each independently selected from: 0 and 1;

[0230] c3, c4, c5, and c6 are each independently selected from: 0, 1, and 2;

[0231] c7, c8, c9, and c10 are each independently selected from: 1 and 2.

[0232] In some implementations... It has the following structure: c7, c8, c9, and c10 are each independently selected from: 1 and 2.

[0233] In some implementation schemes, It has the following structure:

[0234] c1 and c2 are each independently selected from 0 and 1.

[0235] In some implementations... It has the following structure:

[0236] In some implementations... It has the following structure:

[0237] Among them, c1 and c2 are each independently selected from 0 and 1.

[0238] In some implementations... It has the following structure:

[0239] Among them, c1 and c2 are each independently selected from 0 and 1.

[0240] In some implementations... It has the following structure:

[0241] Among them, R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2.

[0242] In some implementations... It has the following structure:

[0243] Among them, R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2.

[0244] In some implementations... It has the following structure: Among them, R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2.

[0245] In some implementations... Selected from Preferred Among them, R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2.

[0246] In some implementations... Selected from The key marked with "1" is connected to Y. 2 The key marked with "2" is connected to ring L. 3 ;

[0247] R ccEach is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2.

[0248] In some implementations... Selected from The key marked with "1" is connected to Y. 2 The key marked with "2" is connected to ring L. 3 ;

[0249] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2.

[0250] In some implementations... Selected from

[0251] R cc Each is independently selected from: hydrogen, deuterium, fluorine, methyl, and n1 is independently selected from: 0, 1, 2.

[0252] In some implementations... Selected from

[0253] R cc Each is independently selected from: hydrogen, deuterium, fluorine, methyl, and n1 is independently selected from: 0, 1, 2.

[0254] In some implementations, R cc Each is independently selected from: hydrogen, deuterium, fluorine, and methyl.

[0255] In some implementations, n1 is independently selected from 0, 1, and 2, and preferably, n1 is 0.

[0256] In some embodiments, ring B is selected from 5-10 member heteroaryl groups, C 6-10 Aryl, C 4-8 Cycloalkyl.

[0257] In some embodiments, ring B is selected from 5-6 membered heteroaryl groups, C 6-8 Aryl, C 5-7 Cycloalkyl.

[0258] In some embodiments, ring B is selected from 6-membered azirroaryl, phenyl, and cyclohexyl.

[0259] In some implementations... It has the following structure:

[0260] In some implementations... for

[0261] In some implementations... It has the following structure:

[0262] In some implementations... It has the following structure:

[0263] In some implementations... It has the following structure:

[0264] In some implementations, each R b It is independently selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0265] In some implementations, each R b Independently selected from: C1-C6 haloalkyl, C1-C6 haloalkoxy.

[0266] In some implementations, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0267] In some implementations, each R b Independently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl.

[0268] In some implementations, each R b Independently selected from: trifluoromethyl, -OCF3.

[0269] In some implementations, m is 0, 1, or 2.

[0270] In some implementations, m is 1.

[0271] In some implementations, R 1 R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl, C1-C4 alkoxy are optionally independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, or O.

[0272] In some implementations, R 1R 2 Each is independently selected from hydrogen, C1-C6 alkyl, C1-C4 alkylamino, C1-C4 alkyl-; R 3 Selected from hydrogen or halogens (e.g., F).

[0273] In some implementations, R 1 R 2 Each is independently selected from hydrogen or C1-C6 alkyl; R 3 Selected from hydrogen or halogens (e.g., F).

[0274] In some implementations, R 1 R 2 All are hydrogen; R 3 It is a halogen (e.g., F).

[0275] In some implementations, structural units for

[0276] In some implementations, structural units for

[0277] In some implementations, each R a Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino; wherein the -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino are optionally each independently separated by 1-3 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, O=, C 3-6 Cycloalkyl substitution; or two adjacent Rs a The groups are linked to form C4-C6 saturated cycloalkyl, 4-6 saturated heterocyclic groups, C4-C6 partially unsaturated cycloalkyl, 4-6 partially unsaturated heterocyclic groups, 5-6 heteroaryl groups, and phenyl groups; wherein the C4-C6 saturated cycloalkyl, 4-6 saturated heterocyclic groups, C4-C6 partially unsaturated cycloalkyl, 4-6 partially unsaturated heterocyclic groups, 5-6 heteroaryl groups, and phenyl groups are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, or O= groups.

[0278] In some implementations, each R aIndependently selected from: hydrogen, deuterium, halogen, cyano, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino; wherein the -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino are optionally each independently substituted by 1-3 deuterium, halogen, hydroxyl, cyano, C1-C4 alkylamino groups; or two adjacent R groups. a They can be linked together to form C4-C6 saturated cycloalkyl groups, 4-6 saturated heterocyclic groups, C4-C6 partially unsaturated cycloalkyl groups, 4-6 partially unsaturated heterocyclic groups, 5-6 heteroaryl groups, and phenyl groups.

[0279] In some implementations, R a Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0280] In some implementations, each R a Independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0281] In some implementations, each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, SF5; wherein the C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino are optionally each independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, or O.

[0282] In some implementations, each R bIndependently selected from: C1-C4 alkyl, C1-C4 alkoxy, SF5; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally each independently substituted with 1-6 deuterium or halogen.

[0283] In some implementations, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0284] In some implementations, each R b Independently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl.

[0285] In some implementations, each R c Independently selected from: hydrogen, deuterium, halogen, C1-C4 alkyl; wherein the C1-C4 alkyl is optionally substituted with 1-6 deuterium, halogen, amino, hydroxyl, cyano, or O=.

[0286] In some implementations, each R c Independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl.

[0287] In some implementations, Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-.

[0288] In some implementations, Y 1 Selected from: -C(=O)-, -S(=O)2-.

[0289] In some implementations, Y 1 It is -C(=O)-.

[0290] In some implementations, Y 1 Selected from: -N(R) Y1 )-、-P(=O)(R Y1 )-; where each R Y1 They are either the same or different, and are each independently selected from: hydrogen, C1-C4 alkyl.

[0291] In some implementations, each R Y1 They may be the same or different, each independently selected from: hydrogen, methyl, or ethyl.

[0292] In some implementations, Y 2 Selected from: key, -N(R) Y2 )-、-C1-C2 alkylene-; wherein R Y2Selected from: hydrogen, C1-C4 alkyl.

[0293] In some implementations, Y 2 For key.

[0294] In some implementations, R Y2 Selected from: hydrogen, methyl, or ethyl.

[0295] In some implementations, Y 2 Selected from: -C(=O)-, -S(=O)2-.

[0296] In some implementations, L 1 Selected from key; L 2 Selected from key; L 3 Selected from key.

[0297] In some embodiments, the compounds of this application have the structure shown in formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13 or II-14, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs;

[0298] in,

[0299] X 1 X 2 X 3 X 4 Each is independently selected from: CH, N;

[0300] X 9 X 10 Each is independently selected from: CH, N;

[0301] E 1 and E 3 Each is independently selected from: CH2, NH, O, S;

[0302] E 2 E 4 and E 5 Independently selected from: CH, N;

[0303] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0304] n1 is independently selected from: 0, 1, 2;

[0305] c1 and c2 are each independently selected from: 0 and 1;

[0306] c7, c8, c9, and c10 are each independently selected from: 1 and 2;

[0307] Other symbols such as R 1 R 2 R 3 L 1 L 2 L 3 Y 1 Y 2 R a R b m and p have the definitions described in this article.

[0308] In some implementations, X 1 X 4 Let N, X 2 X 3 For CH, or X 1 X 2 X 3 For CH, X 4 Let N be the number of elements in the array.

[0309] In some implementations, E 1 Selected from NH, O, and S.

[0310] In some implementations, n1 is 0.

[0311] In some embodiments, c1 and c2 are 0. In some embodiments, the compounds of this application have the structure shown in formula II-1-1, II-2-1, II-3-1 or II-4-1, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs;

[0312] in,

[0313] X 1 X 2 X 3 X 4 Each is independently selected from: CH, N;

[0314] X 9 X 10 Each is independently selected from: CH, N;

[0315] E 1 and E 3Each is independently selected from: CH2, NH, O, S;

[0316] E 2 Independently selected from: CH, N;

[0317] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0318] n1 is independently selected from: 0, 1, 2;

[0319] c1 and c2 are each independently selected from: 0 and 1;

[0320] Other symbols such as R 1 R 2 R 3 L 1 L 2 L 3 Y 1 Y 2 R a R b m and p have the definitions described in this article.

[0321] In some implementations, X 1 X 4 Let N, X 2 X 3 For CH, or X 1 X 2 X 3 For CH, X 4 Let N be the number of elements in the array.

[0322] In some implementations, E 1 Selected from NH, O, and S.

[0323] In some implementations, n1 is 0.

[0324] In some implementations, c1 and c2 are 0. In some implementations, p is 0 or 1.

[0325] In some implementations, m is 0 or 1.

[0326] In some implementations, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0327] In some implementations, each R bIndependently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl.

[0328] In some implementations, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0329] In some embodiments, the compound has a structure represented by formula III-1, III-2, III-3, III-4, III-5 or III-6 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

[0330] in,

[0331] X 1 X 2 X 3 X 4 Each is independently selected from: CH, N;

[0332] X 9 X 10 Each is independently selected from: CH, N;

[0333] E 1 and E 3 Each is independently selected from: CH2, NH, O, S;

[0334] E 2 Independently selected from: CH, N;

[0335] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0336] n1 is independently selected from: 0, 1, 2;

[0337] c1 and c2 are each independently selected from: 0 and 1;

[0338] Other symbols such as R 1 R 2 R 3 L 1 L 2 L 3 Y 2 R a R b m and p have the definitions described in this article.

[0339] In some implementations, X 1 X 4 Let N, X 2 X 3 For CH, or X 1 X 2 X 3 For CH, X 4 Let N be the number of elements in the array.

[0340] In some implementations, E 1 Selected from NH, O, and S.

[0341] In some implementations, n1 is 0.

[0342] In some embodiments, c1 and c2 are 0. In some embodiments, the compound has the structure shown in formula iii-1, iii-2, iii-3, iii-4, iii-5, iii-6, iii-7, iii-8, iii-9, iii-10, iii-11, iii-12, iii-13, iii-14, iii-15, iii-16, iii-17, iii-18, iii-19, iii-20 or iii-21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

[0343] in,

[0344] X 1 X 2 X 3 X 4 Each is independently selected from: CH, N;

[0345] X 9 X 10 Each is independently selected from: CH, N;

[0346] E 1 and E 3 Each is independently selected from: CH2, NH, O, S;

[0347] E 2 E 4 and E 5 Independently selected from: CH, N;

[0348] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0349] n1 is independently selected from: 0, 1, 2;

[0350] c1 and c2 are each independently selected from: 0 and 1;

[0351] c7, c8, c9, and c10 are each independently selected from: 1 and 2;

[0352] Other symbols such as R 1 R 2 R 3 L 1 L 2 L 3 R Y1 R Y2 R a R b p has the definition described in this article.

[0353] In some implementations, X 1 X 4 Let N, X 2 X 3 For CH, or X 1 X 2 X 3 For CH, X 4 Let N be the number of elements in the array.

[0354] In some implementations, E 1 Selected from NH, O, and S.

[0355] In some implementations, n1 is 0.

[0356] In some implementations, c1 and c2 are 0.

[0357] In some implementations, p is 0 or 1.

[0358] In some implementations, m is 0 or 1.

[0359] In some implementations, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0360] In some implementations, each R b Independently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl.

[0361] In some implementations, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0362] In some implementations... Selected from the following structures:

[0363] In some implementations... Selected from the following structures:

[0364] In some implementations... Selected from the following structures:

[0365] In some implementations... Selected from the following structures:

[0366] In some implementations... Selected from the following structures:

[0367] In some implementations... Selected from the following structures:

[0368] In some implementations... Selected from the following structures:

[0369] In some implementations... Selected from the following structures:

[0370] In some implementations... for

[0371] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl.

[0372] In some implementations, p1 is independently selected from 0, 1, and 2.

[0373] In some implementations, p1 is selected from 0 or 1.

[0374] In some implementations, p1 is 0.

[0375] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl.

[0376] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0377] In some implementations, R aa Selected from

[0378] In some implementations, each R aaIndependently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0379] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, or methoxy.

[0380] In some implementations, R aa Each is independently selected from hydrogen or C1-C4 alkyl (e.g., methyl).

[0381] In some embodiments, the compound has any of the following structural formulas:

[0382] Among them, R 1 R 2 R 3 R b L 1 L 2 L 3 p, m have the definitions described in this article;

[0383] n1 is 0, 1, or 2;

[0384] R a Each is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl;

[0385] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0386] c1 and c2 are each independently selected from 0 and 1.

[0387] In some implementations, p is 0 or 1.

[0388] In some implementations, m is 0 or 1.

[0389] In some implementations, n1 is 0.

[0390] In some implementations, each R a Independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0391] In some implementations, R a Each is independently selected from hydrogen or C1-C6 alkyl groups.

[0392] In some embodiments, the compound has any of the following structural formulas:

[0393] Among them, R 1 R 2 R 3 R b E 4 E 5 R Y1 R Y2 L 1 L 2 L 3 p, p1 have the definitions described herein;

[0394] n1 is 0, 1, or 2;

[0395] R aEach is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy C1-C6 alkoxy groups substituted with alkyl, cyano, hydroxyl, and cyclopropyl groups; C1-C6 alkoxy groups substituted with cyano and cyclopropyl groups; C1-C6 alkoxy groups substituted with C1-C6 alkylamino groups; C1-C6 alkoxy groups substituted with cyano; -NHC(O)C1-C6 alkyl groups substituted with hydroxyl groups; -NHC(O)C1-C6 alkyl groups substituted with cyano; or two adjacent Ra groups linked together to form a C4-C6 saturated cycloalkyl group;

[0396] R aa Each is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl;

[0397] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0398] c1 and c2 are each independently selected from 0 and 1.

[0399] In some implementations, n1 is 0.

[0400] In some implementations, both c1 and c2 are 0.

[0401] In some implementations, R Y1 Selected from hydrogen, methyl, or ethyl.

[0402] In some implementations, R Y2 Selected from hydrogen, methyl, or ethyl.

[0403] In some implementations, Ra Each is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl.

[0404] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl.

[0405] In some implementations, two adjacent R a They can be linked together to form cyclopentyl or cyclohexyl groups.

[0406] In some implementations, R a Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0407] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0408] In some implementations, R a Selected from:

[0409] In some implementations, R a Each is independently selected from hydrogen or C1-C6 alkyl groups.

[0410] In some implementations, each R a Independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0411] In some implementations, each R aa Independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0412] In some implementations, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0413] In some implementations, R bEach is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0414] In some implementations, R b Each is independently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl.

[0415] In some implementations, R Y1 Selected from hydrogen, methyl, or ethyl.

[0416] In some implementations, R Y2 Selected from hydrogen, methyl, or ethyl.

[0417] In some implementations, R 1 R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), C1-C4 alkoxy, and O=.

[0418] In some implementations, R 1 R 2 R 3 Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino.

[0419] In some embodiments, the compound has any of the following structural formulas:

[0420] Among them, R b L 1 L 2 L 3 p and m have the definitions described in this article;

[0421] n1 is 0, 1, or 2;

[0422] R aEach is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl;

[0423] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0424] c1 and c2 are each independently selected from 0 and 1.

[0425] In some implementations, p is 0 or 1.

[0426] In some implementations, m is 0 or 1.

[0427] In some implementations, n1 is 0.

[0428] In some embodiments, the compound has any of the following structural formulas:

[0429] Among them, R b R Y1 R Y2 L 1 L 2 L 3 p, p1 have the definitions described herein;

[0430] n1 is 0, 1, or 2;

[0431] R aEach is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl; or two adjacent R a They connect to form C4-C6 saturated cycloalkyl groups;

[0432] R aa Each is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl;

[0433] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;

[0434] c1 and c2 are each independently selected from 0 and 1.

[0435] In some implementations, two adjacent R a They connect to form C4-C6 saturated cycloalkyl groups.

[0436] In some implementations, R aEach is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl.

[0437] In some implementations, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl.

[0438] In some implementations, R a Selected from hydrogen or C1-C4 alkyl.

[0439] In some implementations, R a Selected from hydrogen or methyl.

[0440] In some implementations, R a Selected from hydrogen.

[0441] In some implementations, two adjacent R a They can be linked together to form cyclopentyl or cyclohexyl groups.

[0442] In some implementations, R aEach is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0443] In some implementations, R a Selected from

[0444] In some implementations, each R a Independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0445] In some implementations, each R aa Independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0446] In some implementations, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0447] In some implementations, R b Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;

[0448] In some implementations, R b Selected from C1-C6 haloalkyl and C1-C6 haloalkoxy groups.

[0449] In some implementations, R b Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0450] In some implementations, R b Each is independently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl.

[0451] In some implementations, R b Selected from trifluoromethyl, -OCF3.

[0452] In some implementations, R Y1 Selected from hydrogen, methyl, or ethyl.

[0453] In some implementations, R Y2 Selected from hydrogen, methyl, or ethyl.

[0454] In some implementations, R 1 R 2 R 3 Each group is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl and C1-C4 alkoxy groups are optionally independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), C1-C4 alkoxy, and O, for example: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino.

[0455] In some embodiments, the compound has a structure as shown in formula a, b, c, d, or e:

[0456] In equations a, b, c, d, and e, R a R b L 1 L 2 L 3 It has the definition described in this article.

[0457] In some embodiments, the compound has the structure shown in formula f, g, h, i, or j:

[0458] Among them, R a R b L 1 L 2 L 3 It has the definition described in this article.

[0459] In some implementations, R a Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0460] In some implementations, R a Selected from:

[0461] In some implementations, each R a Independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino,

[0462] In some implementations, R b Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0463] In some implementations, R b Each is independently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl.

[0464] In some implementations, L 1 Selected from key; L 2 Selected from key; L 3 Selected from key.

[0465] In some embodiments, the compounds of this application have the structure shown below or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs.

[0466] Pharmaceutical Compositions and Administration

[0467] This application relates to a pharmaceutical composition comprising the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, hydrates, isotopically labeled compounds or prodrugs; and a pharmaceutically acceptable carrier or diluent.

[0468] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutical acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutical acceptable carriers, diluents, and further excipients such as excipients, binders, fillers, etc., as well as additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0469] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, all of which are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.

[0470] This application also relates to pharmaceutical compositions comprising the compound provided herein or a pharmaceutically acceptable salt thereof as an active ingredient, which may be used, in particular, to treat neoplastic diseases, especially cancer, as described herein. The compositions may be formulated for non-parenteral administration, such as nasal, oral, rectal, lung, vaginal, sublingual, topical, transdermal, ocular, or especially for oral administration, for example in oral solid dosage forms such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules and soft capsules or hydroxypropyl methylcellulose (HPMC) capsules (suitably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, particularly humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions may contain a single active ingredient, or preferably, together with a pharmaceutically acceptable carrier.

[0471] The compounds provided in this application, or their pharmaceutically acceptable salts, can be processed with pharmaceutically inert inorganic or organic excipients for the production of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or derivatives thereof, binders such as cellulose, starch, polyvinylpyrrolidone or derivatives thereof, flow aids such as talc, stearic acid or salts thereof, and flow agents such as calcined silica can be used as such excipients for the formulation and manufacture of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols.

[0472] Suitable excipients for manufacturing oral solutions, lipid emulsions or suspensions include, for example, water, alcohol, polyol, sucrose, invert sugar, glucose, etc.

[0473] Suitable excipients for parenteral preparations include water, alcohol, polyol, glycerin, vegetable oil, lecithin, surfactant, etc.

[0474] In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may also contain other substances of therapeutic value.

[0475] Dosage can vary over a wide range, and of course, it is individualized in each specific case. Generally, in the case of oral administration, a dose of about 1 to 1000 mg of a compound of general formula (I) per person per day should be appropriate, although it may be necessary to exceed the lower or upper limits mentioned above.

[0476] The compounds provided in this application can also be used in combination with one or more other pharmacologically active compounds that are also effective against the same disease, preferably using different modes of action, or to reduce or prevent possible undesirable side effects of the compounds provided in this application. Combination partners can be administered simultaneously in such treatment, for example, by incorporating them into a single pharmaceutical formulation, or by administering two or more different dosage forms (each containing one or more combination partners) consecutively.

[0477] The compounds provided according to this application, as described above, or pharmaceutically acceptable salts thereof, are particularly useful for treating neoplastic diseases, such as cancer, especially carcinoma, sarcoma, leukemia, myeloma, and lymphoma, as well as cancers of the brain and spinal cord, for example, when administered in a therapeutically effective amount. According to some embodiments, cancer treated with the compounds of this application is mediated by modulating the interaction between YAP / TAZ and TEAD. According to some embodiments, the compounds of this application can treat cancer by modulating the interaction between YAP / TAZ and TEAD. According to some embodiments, the compounds of this application can inhibit the interaction between YAP / TAZ and TEAD. According to some embodiments, the cancer is a solid tumor. According to some embodiments, the cancer is a hematologic malignancy. In some cases, the solid tumor is a sarcoma or carcinoma. According to some embodiments, the solid tumor is a sarcoma. In some cases, the solid tumor is carcinoma.

[0478] Examples of proliferative disorders and diseases include, but are not limited to, epithelial tumors, squamous cell tumors, basal cell tumors, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, appendage and skin appendage tumors, mucoepidermoid tumors, cystic tumors, mucinous and serous tumors, ductal, lobular and medullary tumors, acinar cell tumors, complex epithelial tumors, specialized adenomas, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatosis tumors, myxomatous tumors, lipomatous tumors, myomatous tumors, and complex... Mixed stromal tumors, fibroepithelial tumors, synovial tumors, mesothelial tumors, germ cell tumors, trophoblastic tumors, mesonephrosomas, hemangiomas, lymphangiomas, osteochondromatosis, giant cell tumors, miscellaneous bone tumors, odontogenic tumors, gliomas, neuroepithelial tumors and neuroendocrine tumors, meningiomas, schwannomas, granulosa cell tumors and alveolar soft tissue sarcomas, Hodgkin and non-Hodgkin lymphomas, B-cell lymphomas, T-cell lymphomas, pilocellular lymphomas, Burkitt's lymphoma and other lymphoreticular tissue tumors, plasmacytomas, mast cell tumors, immunoproliferative disorders, leukemia, miscellaneous myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0479] Examples of cancers affecting body organs and sites include, but are not limited to, breast, cervix, ovary, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal glands, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematologic malignancies (such as lymphoma, leukemia, myeloma, or lymphoma), bladder, urinary tract, kidney, skin, thyroid, brain, head, neck, prostate, and testes. Preferably, the cancers are selected from the group consisting of: breast cancer, prostate cancer, cervical cancer, ovarian cancer, stomach cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, bladder cancer, mesothelioma, hematologic malignancies, melanoma, and sarcoma.

[0480] As used herein in the context of treating a disease or disorder, the term "treatment" generally refers to the treatment and therapy of humans or animals (e.g., in veterinary applications) in which some desired therapeutic effect is achieved, such as inhibiting the progression of the disease or disorder, and includes reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of the disease or disorder, improving the disease or disorder, and curing the disease or disorder. It also includes treatment as a preventative measure (i.e., prevention). For example, treatment for patients who have not yet developed the disease or disorder but are at risk of developing it is covered by the term "treatment." For example, treatment includes cancer prevention, reducing cancer incidence, alleviating cancer symptoms, etc.

[0481] As used herein, the term "therapeutic effective amount" refers to the amount of a compound, or a material, composition, or dosage form containing that compound, which, when administered according to the desired treatment regimen, is effective in producing some desired therapeutic effect in proportion to a reasonable benefit / risk ratio.

[0482] Synthesis method

[0483] The compounds provided in this application can be synthesized by the methods given below, by the methods given in the experimental section below, or by similar methods. The methods described herein are not intended to present an exhaustive list of methods for preparing the compounds provided in this application; rather, other techniques known to a skilled chemist may also be used for the synthesis of these compounds.

[0484] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 400M NMR spectrometer, with deuterated DMSO as the solvent and tetramethylsilane (TMS) as the internal standard.

[0485] MS was determined using a SHIMADZU LC-2030plus / LCMS-2020 liquid chromatography-mass spectrometry system (manufacturer: SHIMADZU, MS model: LCMS-2020).

[0486] High performance liquid chromatography (HPLC) analysis was performed using a SHIMADZU LC-2030plus liquid chromatograph.

[0487] Thin-layer chromatography silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.

[0488] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0489] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0490] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0491] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0492] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: petroleum ether / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0493] Those skilled in the art of organic synthesis will understand that optimal reaction conditions can vary depending on the specific reactants or solvents used, but these conditions can be determined through conventional optimization procedures. In some cases, the order of the reaction scheme and / or reaction steps can be altered to promote the reaction or avoid the formation of unwanted byproducts. Furthermore, functional groups present at various positions in the molecule must be compatible with the proposed reagents and reactions. This limitation on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods must then be employed. Additionally, in some of the reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups in the compound, and it is assumed that such protecting groups (PGs) are in the appropriate positions if necessary. Conventional protecting groups can be used according to standard practices well known in the art (for details, see Greene TW, Wuts PGM, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, 2014). Protecting groups can be removed at any convenient stage of the synthesis using conventional techniques well known in the art, or they can be removed in subsequent reaction steps or post-treatments.

[0494] The following abbreviations are used throughout this application: LCMS: Liquid chromatography-mass spectrometry; HPLC: High performance liquid chromatography; M, mol / L: Moles per liter; mmol: Millimoles; μM: Micromoles per liter; ml, mL: Milliliters; μL: Microliters; g: Grams; mg: Milligrams; ℃: Degrees Celsius; min: Minutes; FA: Formic acid; TFA: Trifluoroacetic acid; DMF: N,N-Dimethylformamide; 1,2-DCE: 1,2-Dichloroethane; HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; SEM-Cl: 2-(Trimethylsilyl)ethoxymethylchloro; DMAP: 4-Dimethylaminopyridine; HOBT: 1-Hydroxybenzotriazole; EDCI: 1-(3-Dimethylaminopropyl)-3-Ethylcarbodiimide

[0495] The following embodiments are provided to aid in understanding this application. However, it should be understood that these embodiments are for illustrative purposes only and do not constitute any limitation. The actual scope of protection of this application is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of this application.

[0496] Example 1: Preparation of Compound 1

[0497] 2-Fluoro-1-(3-(pyridin-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0498] 1) Preparation of compound 1c in the first step

[0499] Compound 1a (1.0 g, 6.3 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (6.3 mL, 9.5 mmol) was slowly added at -78 °C. The mixture was stirred for 30 minutes, and then compound 1b (1.9 g, 7.5 mmol) was added. The mixture was then heated to room temperature and stirred overnight. Hydrochloric acid (10 mL, 3 M) and water (10 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 4 / 1) to give compound 1c (800 mg).

[0500] 2) Preparation of compound 1d in the second step

[0501] Compound 1c (200 mg, 0.76 mmol) was dissolved in 1,2-DCE (10 mL), and O-(4-(trifluoromethyl)phenyl)hydroxylamine (156 mg, 0.19 mmol), tetraisopropyl titanate (0.4 mL, 1.5 mmol), acetic acid (250 μL, 0.07 mmol) and... Molecular sieve (200 mg) was stirred overnight at 80 °C. Water (20 mL) was added to the reaction solution, and ethyl acetate (20 mL * 3) was used for extraction. The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 1d (140 mg).

[0502] 3) Preparation of compound 1f in the third step

[0503] Compound 1d (140 mg, 0.33 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.2 mL) was slowly added dropwise. The mixture was stirred at 25 °C for 1 hour. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (5 mL), and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue (90 mg) containing compound 1f.

[0504] 4) Preparation of Compound 1 in the fourth step

[0505] Compound 1f (90 mg, 0.27 mmol) was dissolved in DMF (3 mL), and HATU (212 mg, 0.55 mmol), DIEA (83 μL, 0.54 mmol), and 2-fluoroacrylic acid (43 mg, 0.48 mmol) were added. The mixture was stirred at room temperature for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (instrument: Gilson 306 1741, column: Waters-CORTECS-C18-2.7 μm-4.6 x 30 mm; mobile phase: A: 0.05% TFA / H2O, B: ACN, gradient ratio: acetonitrile 5-95, flow rate: 35 mL / min) to obtain compound 1 (10 mg).

[0506] MS m / z(ESI): 394.1 [M+1] + .

[0507] 1 H NMR (400MHz, DMSO-d6) δ = 8.73 (d, J = 4.8Hz, 1H), 8.07-7.96 (m, 2H), 7.75 (d, J = 8.8Hz, 2H), 7.59 -7.49(m,1H),7.45(d,J=8.8Hz,2H),5.56-5.26(m,2H),4.74-4.51(m,2H),4.42-4.11(m,3H).

[0508] Example 2 Preparation of Compound 2

[0509] 2-Fluoro-1-(3-(pyridin-3-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)propyl-2-yl-1-one

[0510] 1) Preparation of compound 2c in the first step

[0511] Under a nitrogen atmosphere at -78°C, 2.97 mL of butyllithium (4.7 mmol) was added dropwise to 10 mL of tetrahydrofuran containing compound 2a (500 mg, 3.2 mmol), and the mixture was stirred at -78°C for 1 hour. Then, compound 1b (1.1 g, 4.8 mmol) was added, and the reaction mixture was slowly brought to room temperature and stirred overnight. Hydrochloric acid (10 mL, 3 M) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 2c (185 mg).

[0512] 2) Preparation of compound 2d in the second step

[0513] Compound 2c (185 mg, 0.70 mmol) was dissolved in 1,2-DCE (3 mL), and then compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (114 μL, 0.85 mmol), acetic acid (200 μL, 3.5 mmol), tetraisopropyl titanate (0.63 mL, 2.1 mmol) and... Molecular sieve (300 mg) was stirred at 60 °C for 16 hours. The mixture was filtered, and the filtrate was extracted with water (10 mL) and ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 2d (146 mg).

[0514] 3) Preparation of compound 2f in the third step

[0515] Compound 2d (146 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (5 mL), and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue (111 mg) containing compound 2f.

[0516] 4) Preparation of compound 2 in the fourth step

[0517] The residue containing compound 2f (111 mg) was dissolved in tetrahydrofuran (5 mL), and EDCI hydrochloride (111.4 mg, 0.58 mmol), HOBT (78.5 mg, 0.58 mmol), DIEA (96 μL, 0.58 mmol), and 2-fluoroacrylic acid (6 mg, 0.07 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 2 (53.32 mg).

[0518] MS m / z(ESI): 394.4 [M+1] + .

[0519] 1 H NMR (400MHz, DMSO-d6) δ = 8.81 (d, J = 1.8Hz, 1H), 8.72 (dd, J = 1.5, 4.8Hz, 1H), 7.99 (td, J = 1.8, 7.9Hz, 1H),7.78-7.70(m,2H),7.56-7.44(m,3H),5.56-5.37(m,1H),5.28(dd,J=3.6,16.6Hz,1H),4.81(br d,J=4.0Hz,1H),4.53-4.39(m,3H),4.07(br d,J=8.8Hz,1H).

[0520] Example 3: Preparation of a mixture of compounds 3 and 4

[0521] 2-Fluoro-1-(3-(pyrazin-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)propyl-2-yl-1-one

[0522] 1) Preparation of compound 3c in the first step

[0523] Under a nitrogen atmosphere at -78°C, n-butyllithium (3.0 mL, 4.7 mmol, 1.6 M) was added dropwise to tetrahydrofuran (10 mL) containing compound 3a (500 mg, 3.1 mmol), and the mixture was stirred at -78°C for 1 hour. Then, compound 1b (0.92 g, 3.8 mmol) was added, and the reaction mixture was slowly brought to room temperature and stirred overnight. Hydrochloric acid (10 mL, 3 M) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 3c (196 mg).

[0524] 2) Preparation of compound 3d in the second step

[0525] Compound 3c (185 mg, 0.74 mmol) was dissolved in 1,2-DCE (3 mL), and then compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (120 μL, 0.9 mmol), acetic acid (200 μL, 3.5 mmol), tetraisopropyl titanate (0.66 mL, 2.2 mmol) and... Molecular sieve (300 mg) was stirred at 60 °C for 16 hours. The mixture was filtered, and the filtrate was extracted with water (10 mL) and ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 3d (69 mg).

[0526] 3) Preparation of compound 3f in the third step

[0527] Compound 3d (69 mg) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate solution (5 mL), and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue (50 mg) containing compound 3f.

[0528] 4) Preparation of the mixture of compound 3 and compound 4 in step four

[0529] The residue (50 mg) containing compound 3f was dissolved in tetrahydrofuran (2 mL), and HATU (74 mg, 0.19 mmol), DIEA (43 μL, 0.26 mmol), and 2-fluoroacrylic acid (12 mg, 0.13 mmol) were added. The mixture was stirred at room temperature for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to obtain a mixture of compounds 3 and 4.

[0530] MS m / z(ESI): 395.3 [M+1] + .

[0531] 1 H NMR (400MHz, DMSO-d6) δ = 9.36-9.23 (m, 1H), 8.85-8.73 (m, 2H), 7.77 (dd, J = 6.5, 8.5Hz, 2H), 7.56-7.48(m,2H),5.57-5.40(m,1H),5.30(ddd,J=3.5,6.6,16.7Hz,1H),4.80-4.21(m,5H).

[0532] Example 4: Preparation of Compound 4

[0533] The mixture of compound 3 and compound 4 prepared in Example 3 was purified by high performance liquid chromatography (Gilson 306 1741, column: Puningtech-Pntulips-C18-10μm-30*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 25mL / min) to obtain compound 4 (4.2mg).

[0534] MS m / z(ESI): 395.3 [M+1] + .

[0535] 1 H NMR (400MHz, DMSO-d6) δ=9.34(s,1H),8.89–8.68(m,2H),7.76(br d,J=8.5Hz,2H),7.56–7.46(m,2H),5.57–5.39(m,1H),5.31(br dd,J=3.1,16.6Hz,1H),4.66(br s,2H),4.43–4.17(m,3H).

[0536] Example 5 Preparation of Compound 9

[0537] 2-Fluoro-1-(3-(thiazolyl-5-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0538] 1) Preparation of compound 9c in the first step

[0539] Under a nitrogen atmosphere at -78°C, 10 mL of tetrahydrofuran containing compound 9a (600 mg, 3.7 mmol) was added dropwise with n-butyllithium (3.43 mL, 5.5 mmol, 2.5 M), and the mixture was stirred at -78°C for 1 hour. Then, compound 1b (1.07 g, 4.4 mmol) was added, and the reaction mixture was slowly brought to room temperature and stirred overnight. Hydrochloric acid (10 mL, 3 M) was added to the reaction mixture, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 9c (246 mg).

[0540] MS m / z(ESI):269.0[M+1].

[0541] 2) Preparation of compounds 9d-1 and 9d-2 in the second step

[0542] Compound 9c (246 mg, 0.92 mmol) was dissolved in 1,2-DCE (5 mL), and then compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (135 μL, 1.0 mmol), acetic acid (300 μL, 5.7 mmol), tetraisopropyl titanate (0.82 mL, 2.8 mmol) and... Molecular sieve (500 mg) was stirred at 60 °C for 16 hours. The mixture was filtered, and the filtrate was extracted with water (10 mL) and ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compounds 9d-1 (131.5 mg) and 9d-2 (174.5 mg).

[0543] MS m / z(ESI):428.2[M+1].

[0544] 3) Preparation of compound 9f in the third step

[0545] Compound 9d-1 (131.5 mg, 0.31 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (5 mL), and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue (85 mg) containing compound 9f.

[0546] MS m / z(ESI): 328.7 [M+1].

[0547] 4) Preparation of compound 9 in the fourth step

[0548] The residue (85 mg) containing compound 9f was dissolved in tetrahydrofuran (2 mL), and EDCI hydrochloride (83 mg, 0.43 mmol), HOBT (58 mg, 0.43 mmol), DIEA (75 μL, 0.43 mmol), and 2-fluoroacrylic acid (12 mg, 0.13 mmol) were added. The mixture was reacted at room temperature for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 9 (7.02 mg, yield: 8.12%).

[0549] MS m / z(ESI):400.0[M+1].

[0550] 1 H NMR (400MHz, DMSO-d6) δ = 8.07 (d, J = 3.3Hz, 1H), 7.97 (d, J = 3.3Hz, 1H), 7.82 (d, J = 8.2Hz, 2H), 7.44 (d, J = 8.5Hz, 2H),5.58-5.43(m,1H),5.31(dd,J=3.6,16.6Hz,1H),4.83-4.72(m,2H),4.69-4.60(m,1H),4.48-4.37(m,2H).

[0551] Example 6 Preparation of Compound 10

[0552] 2-Fluoro-1-(3-(thiazolyl-5-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0553] 1) Preparation of compound 10f in the first step

[0554] Compound 9d-2 (174.5 mg, 0.41 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was slowly added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was slowly added dropwise to a saturated sodium bicarbonate solution (5 mL), and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue (85 mg) containing compound 10f.

[0555] MS m / z(ESI): 328.7 [M+1].

[0556] 2) Preparation of compound 10 in the second step

[0557] The residue (85 mg) containing compound 10f was dissolved in tetrahydrofuran (2 mL), and EDCI hydrochloride (83 mg, 0.43 mmol), HOBT (58 mg, 0.43 mmol), DIEA (75 μL, 0.43 mmol), and 2-fluoroacrylic acid (12 mg, 0.13 mmol) were added. The mixture was stirred at room temperature for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 10 (42.5 mg).

[0558] MS m / z(ESI):400.0[M+1].

[0559] 1 H NMR (400MHz, DMSO-d6) δ=8.30(d,J=3.3Hz,1H),8.21(d,J=3.3Hz,1H),7.84(d,J=8.8Hz,2H),7.63(d,J=8.5H z,2H),5.58-5.42(m,1H),5.31(dd,J=3.6,16.6Hz,1H),4.78(dt,J=4.0,9.1Hz,1H),4.71-4.63(m,1H),4.55 -4.36(m,3H).

[0560] Example 7 Preparation of Compounds 11 and 122

[0561] (2-Fluoro-1-(3-(oxazol-5-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0562] 1) Preparation of compound 11c in the first step

[0563] Compound 11b (1300 mg, 4.60 mmol) and lithium chloride (292 mg, 6.9 mmol) were dissolved in tetrahydrofuran (15 mL). Isopropyl magnesium chloride (3.4 mL, 6.8 mmol, 2 M) was slowly added at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1 hour. Then, compound 11a (530 mg, 5.5 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour. Then, saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL). The mixture was separated and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 11c (853 mg).

[0564] 2) Preparation of compound 11d in the second step

[0565] Compound 11c (853 mg, 3.29 mmol) was dissolved in dichloromethane (15 mL), and compound Dys-Martin oxidant (2.10 g, 4.95 mmol) was slowly added at 0 °C. The mixture was heated to 25 °C and stirred for 1.5 hours. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 11d (649 mg).

[0566] 3) Preparation of compound 11e in the third step

[0567] At 0℃, 11 days (640mg, 2.54mmol) were used. Molecular sieve (640 mg) and O-(4-(trifluoromethyl)phenyl)hydroxylamine (0.41 mL, 0.80 mmol) were added to a solution of acetic acid (2 mL) and 1,2-DCE (10 mL), followed by the addition of tetraisopropyl titanate (1.5 mL, 5.1 mmol). The mixture was stirred at 80 °C for 18 hours. After the reaction solution was brought to room temperature, it was filtered, and the filtrate was extracted with water (10 mL) 1,1 and then with ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 3 / 1) to give compound 11e (602 mg).

[0568] 4) Preparation of compound 11f in the fourth step

[0569] Compound 11e (543 mg, 0.98 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL, 13.06 mmol) was added dropwise. The mixture was stirred at 25 °C for 0.5 hours. Then, saturated sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 11f (330 mg).

[0570] 5) Preparation of compounds 11 and 122 in step five

[0571] 2-Fluoroacrylate (161 mg, 1.79 mmol), HOBT (322 mg, 2.38 mmol), EDCI hydrochloride (457 mg, 2.38 mmol), and DIEA (0.60 mL, 3.63 mmol) were dissolved in tetrahydrofuran (3 mL). A tetrahydrofuran (3 mL) solution of compound 11f (390 mg, 1.19 mmol) was added. The reaction mixture was stirred at 25 °C under nitrogen for 1 hour. Then, water (20 mL) was added, and the mixture was extracted with ethyl acetate (25 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by liquid chromatography (Gilson 306 1741, column: Puningtech-Pntulips-C18-10μm-30*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-60%, flow rate: 30 mL / min) to obtain compound 11 (24.47 mg) and compound 122 (39.07 mg).

[0572] MS m / z(ESI): 384.0 [M+H] +

[0573] Compound 11: 1 H NMR (400MHz, DMSO-d6) δ = 8.65 (s, 1H), 7.80 (s, 2H), 7.77 (s, 1H), 7.41 (d, J = 8.8Hz, 2H), 5. 60-5.44(m,1H),5.33(dd,J=3.6,16.6Hz,1H),4.83-4.73(m,1H),4.72-4.62(m,1H),4.46 -4.30(m,3H).

[0574] Compound 122: 1H NMR (400MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.42 (s, 1H), 7.79 (d, J = 9.0Hz, 2H), 7.69 (d, J = 8.8Hz, 2H), 5.57 -5.43(m,1H),5.32(dd,J=3.5,16.5Hz,1H),4.80-4.64(m,2H),4.40-4.32(m,2H),4.32-4.23(m,1H).

[0575] Example 8 Preparation of Compound 12

[0576] 1-(3-((1H-pyrazol-3-yl)((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)-2-fluoroprop-2-en-1-one

[0577] 1) Preparation of compound 12b in the first step

[0578] At 0 °C, NaH (272.2 mg, 6.8 mmol) was added to a dichloromethane (10 mL) solution of compound 12a (500 mg, 3.4 mmol), and the mixture was stirred for 15 minutes. SEM-Cl (0.90 mL, 5.1 mmol) was slowly added, and the mixture was stirred at 30 °C for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 12b (940 mg).

[0579] 2) Preparation of compound 12c in the second step

[0580] Under a nitrogen atmosphere at -78°C, a tetrahydrofuran solution of n-butyllithium (0.52 mL, 1.3 mmol, 2.5 M) was added to a tetrahydrofuran solution of compound 12b (300 mg, 1.1 mmol) in 5 mL. The mixture was stirred at -78°C for 1 hour, and then compound 1b (290.8 mg, 1.2 mmol) was slowly added. The temperature was slowly raised to 25°C and stirred for 1 hour. A saturated ammonium chloride solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 12c (120 mg).

[0581] 3) Preparation of compound 12d in the third step

[0582] At 0 °C, compound 12c (90 mg, 0.24 mmol), Molecular sieve (120 mg / L) and O-(4-(trifluoromethyl)phenyl)hydroxylamine (38 μL, 0.28 mmol) were added to a mixture of acetic acid (0.1 mL) and 1,2-DCE (0.5 mL). Tetraisopropyl titanate (1.0 mL, 3.4 mmol) was added to the mixture, and the mixture was heated to 60 °C and stirred for 8 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was extracted with water (5 mL) and ethyl acetate (25 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 10 / 1) to give compound 12d (24 mg).

[0583] 4) Preparation of compound 12e in the fourth step

[0584] At 0 °C, trifluoroacetic acid (0.3 mL, 3.9 mmol) was added dropwise to a solution of compound 12d (24 mg, 0.044 mmol) in dichloromethane (1 mL). The reaction mixture was heated to 25 °C and stirred for 0.5 hours. A saturated sodium bicarbonate solution (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL x 2). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 12e (10 mg).

[0585] 5) Preparation of compound 12 in step 5

[0586] At 0 °C, 2-fluoroacrylic acid (3.5 mg, 0.039 mmol), HATU (18.4 mg, 0.048 mmol), and DIEA (11.2 μL, 0.064 mmol) were dissolved in DMF (0.5 mL). After stirring for 10 minutes, a DMF (0.5 mL) solution of compound 12e (10 mg, 0.032 mmol) was added. The mixture was heated to 25 °C and stirred for 0.5 hours. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 12 (2.28 mg).

[0587] MS m / z (ESI): 383.1 [M+H] + .

[0588] 1H NMR(400MHz, DMSO-d6)δ=13.60-13.31(m,1H),8.01-7.72(m,3H),7.61-7.40(m, 2H),7.29-6.74(m,1H),5.60-5.40(m,1H),5.35-5.24(m,1H),4.83-4.28(m,5H).

[0589] Example 9: Preparation of Compounds 13 and 86

[0590] 1-(3-((1H-imidazol-2-yl)((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)-2-fluoroprop-2-en-1-one

[0591] 1) Preparation of compound 13b in the first step

[0592] At 0 °C, DMAP (24.9 mg, 0.20 mmol), DIEA (1.0 mL, 6.1 mmol), and SEM-Cl (0.36 mL, 2.04 mmol) were slowly added to a 12 mL solution of dichloromethane containing 300 mg (2.0 mmol). The mixture was heated to 25 °C and stirred for 18 hours. A saturated sodium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 13b (289 mg).

[0593] 2) Preparation of compound 13c in the second step

[0594] At 0 °C, ethyl magnesium bromide (0.40 mL, 1.2 mmol, 3 M) was added to a tetrahydrofuran (10 mL) solution of compound 13b (280 mg, 1.010 mmol), and the mixture was stirred for 0.5 h. Compound 1b (271.4 mg, 1.1 mmol) was slowly added to the reaction mixture, and the temperature was slowly raised to 25 °C, and the mixture was stirred for 0.5 h. Hydrochloric acid (5 mL, 3 M) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compound 13c (269 mg).

[0595] 3) Preparation of compound 13d in the third step

[0596] At 0°C, compound 13c (269 mg, 0.71 mmol) was subjected to treatment. Molecular sieve (270 mg, 0.80 mmol) and O-(4-(trifluoromethyl)phenyl)hydroxylamine (0.11 mL, 0.85 mmol) were placed in a mixture of acetic acid (0.5 mL) and 1,2-DCE (3 mL). Tetraisopropyl titanate (0.42 mL, 1.41 mmol) was added to the mixture. The mixture was heated to 60 °C and stirred for 8 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with water (10 mL) and ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 10 / 1) to give compound 13d (218 mg).

[0597] 4) Preparation of compound 13e in the fourth step

[0598] At 0 °C, trifluoroacetic acid (0.5 mL, 6.53 mmol) was added dropwise to a dichloromethane (3 mL) solution of compound 13d (166 mg, 0.31 mmol). The reaction mixture was heated to 25 °C and stirred for 1 hour. Saturated sodium bicarbonate (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 13e (90 mg).

[0599] 5) Preparation of compounds 13 and 86 in step five

[0600] At 0 °C, 2-fluoroacrylic acid (31.34 mg, 0.35 mmol), HATU (165.4 mg, 0.44 mmol), and DIEA (154.5 μL, 0.87 mmol) were dissolved in DMF (1 mL). After stirring for 10 minutes, a DMF (1 mL) solution of compound 13e (90 mg, 0.29 mmol) was added. The mixture was heated to 25 °C and stirred for 1 hour. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 13 (9.29 mg) and compound 86 (8.4 mg).

[0601] MS m / z(ESI): 383.0 [M+H] + .

[0602] Compound 13: 1H NMR(400MHz,DMSO-d6)δ=12.91(br s,1H),7.78(d,J=8.8Hz,2H),7.58(d,J=8.8Hz,2H),7.39(s,1H),7.16(s,1H),5.57-5.43(m,1H),5.31(dd,J=3.5,16.5Hz,1H),4.83(br d,J=7.5Hz,1H),4.75(br d,J=4.0Hz,1H),4.61-4.36(m,3H).

[0603] Compound 86: 1 H NMR(400MHz,DMSO-d6)δ=12.65(br s,1H),7.80(d,J=9.0Hz,2H),7.72(d,J=8.8Hz,2H),7.52(d,J=1.5Hz,1H),7.26(s,1H) ,5.56-5.41(m,1H),5.30(dd,J=3.5,16.8Hz,1H),4.73(dt,J=4.3,8.9Hz,1H),4.61(br s,1H),4.43-4.34(m,1H),4.34-4.27(m,2H).

[0604] Example 10 Preparation of Compound 14

[0605] 2-Fluoro-1-(3-(thiazo-4-yl((4-trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0606] 1) Preparation of compound 14b in the first step

[0607] Under a nitrogen atmosphere at -78°C, 10 mL of tetrahydrofuran containing compound 14a (600 mg, 3.7 mmol) was slowly added to n-butyllithium (2.19 mL, 5.5 mmol, 2.5 M), and the reaction was stirred at -78°C for 1 hour. Then, compound 1b (1.07 g, 4.4 mmol) was added, and the reaction mixture was slowly brought to room temperature and stirred overnight. The reaction mixture was quenched with hydrochloric acid (10 mL, 3 M), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated sodium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 14c (320 mg).

[0608] MS m / z(ESI):269.0[M+1].

[0609] 2) Preparation of compounds 14d-1 and 14d-2 in the second step

[0610] Compound 14c (320 mg, 1.2 mmol) was dissolved in 1,2-DCE (6 mL), and then compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (168 μL, 1.3 mmol), acetic acid (500 μL, 8.7 mmol), tetraisopropyl titanate (1.06 mL, 3.6 mmol) and... Molecular sieve (600 mg) was stirred at 60 °C for 16 hours. After filtration, water (10 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compounds 14d-1 (149 mg) and 14d-2 (223 mg).

[0611] MS m / z(ESI):427.9[M+1].

[0612] 3) Preparation of compound 14f in the third step

[0613] Compound 14d-1 (149 mg, 0.35 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution (5 mL), and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue (164 mg) containing compound 14f.

[0614] MS m / z(ESI): 328.2 [M+1].

[0615] 4) Preparation of compound 14 in step four

[0616] The residue containing compound 14f (164 mg) was dissolved in tetrahydrofuran (2 mL), and EDCI hydrochloride (160 mg, 0.83 mmol), HOBT (113 mg, 0.83 mmol), DIEA (291 μL, 1.7 mmol) and 2-fluoroacrylic acid (38 mg, 0.42 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) and high performance liquid chromatography (Gilson_306_1741, column: Puningtech-Pntulips-C18-10μm-30*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 25 mL / min) to obtain compound 14 (28.24 mg, yield: 16.94%).

[0617] MS m / z(ESI): 399.9 [M+1].

[0618] 1 H NMR (400MHz, DMSO-d6) δ = 8.07 (d, J = 3.3Hz, 1H), 7.97 (d, J = 3.0Hz, 1H), 7.82 (d, J = 8.2Hz, 2H), 7.45 (d, J = 8.8Hz, 2H),5.57-5.43(m,1H),5.31(dd,J=3.6,16.6Hz,1H),4.83-4.75(m,2H),4.69-4.61(m,1H),4.49-4.38(m,2H).

[0619] Example 11 Preparation of Compound 15

[0620] 2-Fluoro-1-(3-(thiazo-4-yl((4-trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0621] 1) Preparation of compound 15f in the first step

[0622] Compound 14d-2 (223 mg, 0.55 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (5 mL), and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue (304 mg crude) containing compound 15f.

[0623] MS m / z(ESI): 328.2 [M+1].

[0624] 2) Preparation of compound 15 in the second step

[0625] The residue containing compound 15f (304 mg) was dissolved in tetrahydrofuran (3 mL), and EDCI hydrochloride (192 mg, 1.6 mmol), HOBT (209 mg, 1.6 mmol), DIEA (539 μL, 3.1 mmol) and 2-fluoroacrylic acid (70 mg, 0.77 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) and high performance liquid chromatography (Gilson_306_1741, column: Puningtech-Pntulips-C18-10μm-30*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 25 mL / min) to obtain compound 15 (81.82 mg, yield: 26.47%).

[0626] MS m / z(ESI): 399.9 [M+1].

[0627] 1 H NMR (400MHz, DMSO-d6) δ = 8.31 (d, J = 3.0Hz, 1H), 8.22 (d, J = 3.3Hz, 1H), 7.84 (d, J = 9.0Hz, 2H), 7.64 (d, J = 8.8Hz, 2 H), 5.50 (s, 1H), 5.31 (dd, J = 3.6, 16.6Hz, 1H), 4.79 (dt, J = 4.0, 9.3Hz, 1H), 4.71-4.64 (m, 1H), 4.54-4.36 (m, 3H).

[0628] Example 12 Preparation of Compound 18

[0629] 2-Fluoro-1-(3-((4-methoxypyridin-3-yl)((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0630] The synthesis of Example 11 follows the same steps as in Example 2.

[0631] MS m / z(ESI): 424.1 [M+1] + .

[0632] 1 H NMR(400MHz, DMSO-d6)δ=8.64-8.42(m,2H),7.77-7.66(m,2H),7.46-7.22(m,3 H),5.56-5.23(m,2H),4.86-4.54(m,2H),4.41-4.18(m,3H),3.93-3.85(m,3H).

[0633] Example 13 Preparation of Compound 41

[0634] 2-Fluoro-1-(3-((6-methoxypyrazin-2-yl)((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0635] 1) Preparation of compound 41c in the first step

[0636] Under a nitrogen atmosphere, compound 41a (500 mg, 2.7 mmol), compound 1b (646 mg, 2.7 mmol), and n-butyllithium (1.59 mL, 4.0 mmol, 2.5 M) were dissolved in tetrahydrofuran (8 mL) and stirred at -78 °C for 3 hours. Water (30 mL) and ethyl acetate (10 mL x 3) were added to the reaction mixture for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 41c (127 mg).

[0637] 2) Preparation of compound 41e in the second step

[0638] Compound 41c (100 mg, 0.34 mmol) was dissolved in acetic acid (0.5 mL) and 1,2-DCE (5 mL), and then added... Molecular sieve (70 mg), compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (0.054 mL, 0.41 mmol), and tetraisopropyl titanate (0.2 mL, 0.68 mmol) were stirred overnight at 60 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL * 3), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compound 41e (123 mg).

[0639] 3) Preparation of compound 41f in the third step

[0640] Compound 41e (10 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL) at room temperature, and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was quenched with saturated sodium carbonate solution (3 mL). The mixture was then extracted with ethyl acetate (1 mL). The organic phase was concentrated under reduced pressure to give crude compound 41f (7.79 mg).

[0641] 4) Preparation of compound 41 in step four

[0642] At room temperature, compound 41f (34 mg, 0.097 mmol), DIEA (50 mg, 0.39 mmol), EDCI hydrochloride (37 mg, 0.19 mmol), and HOBT (26.08 mg, 0.19 mmol) were dissolved in tetrahydrofuran (1 mL). 2-fluoroacrylic acid (10 mg, 0.12 mmol) was added to the reaction mixture, and the mixture was stirred for 2 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (4 mL). The organic phase was separated, washed with saturated sodium chloride solution (4 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 41 (10 mg).

[0643] MS m / z(ESI): 425.4 [M+1] + .

[0644] 1H NMR (400MHz, DMSO-d6) δ=8.72-9.15(m,1H),8.31(s,1H),7.63(d,J=8.8Hz,2H),7.31-7.41(m,2H),5.5 6-5.75(m,1H),5.12(dd,J=15.8,3.0Hz,1H),4.71-4.92(m,2H),4.42-4.63(m,3H),3.92-4.00(m,3H).

[0645] Example 14 Preparation of Compounds 64 and 123

[0646] 2-Fluoro-1-(3-(oxazol-4-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0647] 1) Preparation of compound 64c in the first step

[0648] Under a nitrogen atmosphere at -78°C, 35 mL of n-butyllithium (87.50 mmol, 2.5 M) was slowly added to a solution of 65a (5.0 g, 72.40 mmol) in tetrahydrofuran (55 mL), and the mixture was stirred at -78°C for 0.5 h. Then, 16.9 mL of compound 64b (108.60 mmol) was added, and the mixture was stirred at -78°C for 1 h. A saturated ammonium chloride solution (50 mL) was then added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 64c (13.24 g).

[0649] 2) Preparation of compound 64d in the second step

[0650] At 0 °C, a solution of 64c (13.2 g, 31.2 mmol) in dichloromethane (50 mL) was added with Dys-Martin oxidant (20 g, 47.2 mmol), and the mixture was heated to 30 °C and stirred for 1.5 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (100 mL * 3), and the combined organic phases were washed with saturated sodium chloride solution (50 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 64d (9.2 g).

[0651] 3) Preparation of compound 64e in the third step

[0652] Compound 64d (5.0 g, 19.8 mmol) was dissolved in 1,2-DCE (50 mL), and compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (3 mL, 17.8 mmol), acetic acid (5 mL, 87.3 mmol), tetraisopropyl titanate (14.5 mL, 49.0 mmol) and... Molecular sieve (8 g) was stirred at 60 °C for 16 hours. After filtration, water (60 mL) and ethyl acetate (60 mL * 3) were added to the filtrate for extraction. The combined organic phases were washed with saturated sodium chloride solution (50 mL), separated, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 64e (6.6 g).

[0653] 4) Preparation of compound 64f in step four

[0654] To a solution of 64e (200 mg, 0.49 mmol) in dichloromethane (2 mL), 0.2 mL of trifluoroacetic acid was slowly added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then slowly added dropwise to a saturated sodium bicarbonate solution (5 mL), and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 64f (150 mg).

[0655] 5) Preparation of compounds 64 and 123 in step five

[0656] Compound 64f (150 mg) was dissolved in tetrahydrofuran (2 mL), and EDCI hydrochloride (115 mg, 0.60 mmol), HOBT (81 mg, 0.60 mmol), DIEA (140 μL, 0.80 mmol) and 2-fluoroacrylic acid (36 mg, 0.40 mmol) were added. The mixture was stirred at room temperature for 1 hour. Then, water (5 mL) and ethyl acetate (5 mL * 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) and high performance liquid chromatography (Gilson_306_1741, column: Puningtech-Pntulips-C18-10μm-30*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 30 mL / min) to obtain compound 64 (41.6 mg) and compound 123 (37.4 mg).

[0657] MS m / z(ESI): 384.1 [M+1]+ .

[0658] Compound 64: 1 H NMR (400MHz, DMSO-d6) δ = 8.72 (s, 1H), 8.61 (s, 1H), 7.78-7.74 (m, J = 8.8Hz, 2H), 7.45-7.41 (m, J = 8.8Hz, 2H), 5 .56-5.42(m,1H),5.31(dd,J=3.5,16.5Hz,1H),4.80-4.70(m,1H),4.70-4.62(m,1H),4.50-4.36(m,2H),4.31 -4.24(m,1H).

[0659] Compound 123: 1 H NMR (400MHz, DMSO-d6) δ = 9.29 (d, J = 1.0Hz, 1H), 8.64 (d, J = 0.8Hz, 1H), 7.81-7.76 (m, J = 8.8Hz, 2H), 7.71 -7.67(m,J=8.8Hz,2H),5.57-5.42(m,1H),5.30(dd,J=3.5,16.8Hz,1H),4.80-4.69(m,1H),4.61(br dd,J=3.8,8.8Hz,1H),4.38-4.25(m,3H).

[0660] Example 15 Preparation of Compound 65

[0661] 2-Fluoro-1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0662] 1) Preparation of compound 65c in the first step

[0663] Under a nitrogen atmosphere at -78°C, n-butyllithium (4.34 mL, 411 mmol, 2.5 M) was added dropwise to a tetrahydrofuran (20 mL) solution of compound 65a (500 mg, 7.2 mmol), and the mixture was stirred at -78°C for 3 hours. Compound 1b (1.94 g, 8.0 mmol) was added to the reaction mixture, and the mixture was slowly brought to room temperature and stirred overnight. A saturated ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compound 65c (385.6 mg).

[0664] 2) Preparation of compound 65d-1 in the second step

[0665] Compound 65c (534 mg, 1.5 mmol) was dissolved in 1,2-DCE (5 mL) and tetrahydrofuran (2 mL), and then compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (246 μL, 1.8 mmol), acetic acid (0.5 mL, 8.7 mmol), tetraisopropyl titanate (1.36 mL, 4.9 mmol) and... Molecular sieve (700 mg) was stirred at 65 °C for 16 hours. After filtration, water (10 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compounds 65d-1 (223 mg) and 65d-2 (306 mg).

[0666] 3) Preparation of compound 65e in the third step

[0667] Compound 65d-1 (223 mg, 0.54 mmol) was dissolved in dichloromethane (4 mL), and trimethylsilyl trifluoromethanesulfonate (245 μL, 1.4 mmol) and 2,4-dimethylpyridine (189 μL, 1.6 mmol) were slowly added. The mixture was stirred at room temperature for 1.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (8 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 65e (127 mg).

[0668] 4) Preparation of compound 65 in step four

[0669] The crude compound 65e (127 mg) was dissolved in tetrahydrofuran (3 mL), and EDCI hydrochloride (98 mg, 0.51 mmol), HOBT (69 mg, 0.51 mmol), DIEA (120 μL, 0.68 mmol) and 2-fluoroacrylic acid (31 mg, 0.64 mmol) were added. The mixture was stirred at room temperature for 1 hour. Add water (5 mL) to the reaction solution, extract with ethyl acetate (5 mL * 3), wash the combined organic phases with saturated sodium chloride solution (10 mL), separate the layers, dry the organic phases with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) and high performance liquid chromatography (SHIMADZU_LC-20AP_SPD-20A, column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 45-55%, flow rate: 25 mL / min) to obtain compound 65 (68.75 mg).

[0670] MS m / z(ESI): 384.1 [M+1] + .

[0671] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (s, 1H), 7.80 (br d, J = 8.8Hz, 2H), 7.54 (s, 1H), 7.46 (br d,J=8.5Hz,2H),5.58-5.42(m,1H),5.31(dd,J=3.4,16.6Hz,1H),4.84-4.71(m,2H),4.58-4.38(m,3H).

[0672] Example 16 Preparation of Compound 66

[0673] 2-Fluoro-1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0674] 1) Preparation of compound 66e in the first step

[0675] Compound 65d-2 (306 mg, 0.74 mmol) was dissolved in dichloromethane (4 mL), and trimethylsilyl trifluoromethanesulfonate (337 μL, 1.9 mmol) and 2,4-dimethylpyridine (259 μL, 2.2 mmol) were slowly added. The mixture was stirred at room temperature for 1.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (8 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 66e (226 mg).

[0676] 2) Preparation of compound 66 in the second step

[0677] The crude compound 66e (226 mg) was dissolved in tetrahydrofuran (3 mL), and EDCI hydrochloride (174 mg, 0.91 mmol), HOBT (123 mg, 0.91 mmol), DIEA (211 μL, 1.2 mmol) and 2-fluoroacrylic acid (55 mg, 0.64 mmol) were added. The mixture was stirred at room temperature for 1 hour. Add water (5 mL) to the reaction solution, extract with ethyl acetate (5 mL * 3), wash the combined organic phases with saturated sodium chloride solution (10 mL), separate the layers, dry the organic phases with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) and high performance liquid chromatography (SHIMADZU_LC-20AP_SPD-20A, column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 45-55%, flow rate: 25 mL / min) to obtain compound 66 (143.8 mg).

[0678] MS m / z(ESI): 384.1 [M+1] + .

[0679] 1 H NMR (400MHz, DMSO-d6) δ=8.49(s,1H),7.82-7.76(m,J=8.8Hz,2H),7.62(s,1H),7.54-7.49(m,J=8 .8Hz,2H),5.57-5.41(m,1H),5.31(dd,J=3.6,16.6Hz,1H),4.76-4.65(m,2H),4.39-4.28(m,3H).

[0680] Example 17 Preparation of Compound 70

[0681] 2-Fluoro-1-(4-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)piperidin-1-yl)prop-2-en-1-one

[0682] 1) Preparation of compound 70b in the first step

[0683] Under a nitrogen atmosphere at -78°C, 105 mg, 1.5 mmol of tetrahydrofuran (8 mL) was slowly added to a solution of 65a (8 mL), and the mixture was stirred at -78°C for 0.5 hours. Then, 70a (497 mg, 1.8 mmol) was added, and the mixture was brought to room temperature and stirred overnight. Hydrochloric acid (5 mL, 3 M) and water (5 mL) were added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compound 70b (106 mg).

[0684] 2) Preparation of compound 70c in the second step

[0685] Dissolve 70b (106 mg, 0.38 mmol) in 1,2-DCE (1 mL), add O-(4-(trifluoromethyl)phenyl)hydroxylamine (61 μL, 0.45 mmol), tetraisopropyl titanate (135 μL, 0.46 mmol), acetic acid (100 μL), and... Molecular sieve (110 mg) was stirred overnight at 60 °C. Then, water (10 mL) and ethyl acetate (30 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give compounds 70c-1 (32 mg) and 70c-2 (38 mg).

[0686] 3) Preparation of compound 70d-1 in the third step

[0687] Trifluoroacetic acid (20 μL, 0.26 mmol) was slowly added dropwise to a solution of 70c-1 (32 mg, 0.07 mmol) in dichloromethane (1 mL). The mixture was stirred at 25 °C for 0.5 hours. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate solution (3 mL). The mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with a saturated sodium chloride solution (50 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure to obtain compound 70d-1 (23 mg).

[0688] 4) Preparation of compound 70 in step four

[0689] Compound 70d-1 (18 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL), and EDCI hydrochloride (20 mg, 0.10 mmol), HOBT (14 mg, 0.10 mmol), DIEA (34 μL, 0.21 mmol), and 2-fluoroacrylic acid (6 mg, 0.07 mmol) were added. The mixture was stirred at room temperature for 0.5 hours, and then water (5 mL) and ethyl acetate (5 mL * 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 70 (5.6 mg).

[0690] MS m / z(ESI): 412.1 [M+1] + .

[0691] 1 H NMR (400MHz, DMSO-d6) δ = 8.33 (s, 1H), 7.80 (d, J = 8.8Hz, 2H), 7.54-7.47 (m, 3H), 5.33-5.13 (m, 2H), 4.41 (br s, 1H), 4.01 (br s,1H),3.97-3.89(m,1H),2.90(br s,1H),2.28-2.15(m,2H),1.86(br d,J=12.3Hz,2H),0.95-0.74(m,1H).

[0692] Example 18 Preparation of Compound 124

[0693] 2-Fluoro-1-(4-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)piperidin-1-yl)prop-2-en-1-one

[0694] 1) Preparation of compound 70d-2 in the first step

[0695] To a solution of 70c-2 (38 mg, 0.09 mmol) in dichloromethane (1 mL), trifluoroacetic acid (20 μL, 0.26 mmol) was slowly added dropwise. The mixture was stirred at 25 °C for 0.5 hours. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate solution (3 mL). The mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure to obtain compound 70d-2 (27 mg).

[0696] 2) Preparation of compound 124 in the second step

[0697] Compound 70d-2 (20 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL), and EDCI hydrochloride (22 mg, 0.12 mmol), HOBT (16 mg, 0.12 mmol), DIEA (40 μL, 0.24 mmol), and 2-fluoroacrylic acid (6 mg, 0.07 mmol) were added. The mixture was stirred at room temperature for 1 hour. Then, water (5 mL) and ethyl acetate (5 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 124 (5.18 mg).

[0698] MS m / z(ESI): 412.1 [M+1] + .

[0699] 1 H NMR (400MHz, DMSO-d6) δ = 8.47 (s, 1H), 7.76 (d, J = 8.8Hz, 2H), 7.62 (s, 1H), 7.44 (d, J = 8.5 Hz,2H),5.31-5.12(m,2H),4.51-4.21(m,1H),4.21-3.85(m,1H),3.48-3.42(m,1H),3.04 -2.84(m,1H),2.07(br d,J=11.8Hz,2H),1.69(br d,J=11.5Hz,2H),0.92-0.79(m,1H).

[0700] Example 19 Preparation of Compound 87

[0701] 2-Fluoro-1-(3-(pyridin-3-yl((4-(trifluoromethoxy)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0702] Referring to the synthesis process of Example 2, Example 87 (13.2 mg) was obtained by multi-step synthesis from starting material compound 87a.

[0703] MS m / z(ESI): 410.1 [M+1] + .

[0704] 1H NMR (400MHz, DMSO-d6) δ = 79 (d, J = 2.0Hz, 1H), 8.72-8.67 (m, 1H), 8.04-7.95 (m, 1H), 7.59-7.51 (m, 1H), 7.42-7.2 9(m,4H),5.57-5.38(m,1H),5.34-5.25(m,1H),4.83-4.58(m,1H),4.49-4.39(m,2H),4.30-4.18(m,1H),4.06(br d,J=8.3Hz,1H).

[0705] Example 20 Preparation of Compound 89

[0706] 1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)ethyl-1-one

[0707] 1) Preparation of compound 89 in the first step

[0708] At room temperature, acetic anhydride (11 μL, 0.12 mmol) was added to a tetrahydrofuran (1 mL) solution of 65e (30 mg, 0.10 mmol) and DIEA (25 μL, 0.14 mmol), and the mixture was stirred at room temperature for 1 hour. Then, water (5 mL) and ethyl acetate (5 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 89 (16.7 mg).

[0709] MS m / z(ESI): 354.0 [M+1] + .

[0710] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (s, 1H), 7.81 (d, J = 8.8Hz, 2H), 7.54 (s, 1H), 7.46 (d, J = 8.8Hz, 2H), 4.57-4.43 (m, 3H), 4.30-4.21 (m, 2H), 1.79 (s, 3H).

[0711] Example 21 Preparation of Compound 125

[0712] 1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)ethyl-1-one

[0713] 1) Preparation of compound 125 in the first step

[0714] The residue containing compound 66e (25 mg, 0.08 mmol) was dissolved in tetrahydrofuran (0.5 mL), and acetic anhydride (10 μL, 0.11 mmol) and DIEA (20 μL, 0.11 mmol) were added. The mixture was stirred at room temperature for 3 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) and high performance liquid chromatography (Gilson_GX281, column: Welch-Xtimate-C18-7um-30*250nm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 35-75%, flow rate: 35 mL / min) to obtain compound 125 (15.4 mg).

[0715] MS m / z(ESI): 354.0 [M+1] + .

[0716] 1 H NMR (400MHz, DMSO-d6) δ = 8.50 (s, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.63 (s, 1H), 7.51 (d, J = 8.8Hz, 2H), 4.49-4.41 (m, 2H), 4.24-4.16 (m, 3H), 1.79 (s, 3H).

[0717] Example 22 Preparation of Compound 90

[0718] (1-(methylsulfonyl)azacyclobutane-3-yl)(oxazol-2-yl)methyl ketone O-(4-(trifluoromethyl)phenyl)oxime

[0719] 1) Preparation of compound 90 in the first step

[0720] At room temperature, methanesulfonic anhydride (87 mg, 0.50 mmol) and DIEA (73 μL, 0.42 mmol) were added to a 1 mL solution of 66e (100 mg) tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 90 (21.43 mg).

[0721] MS m / z(ESI): 389.9 [M+1] + .

[0722] 1 H NMR (400MHz, DMSO-d6) δ = 8.51-8.49 (m, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.63 (d, J = 0.8Hz, 1H), 7.54 (d, J = 8.5Hz, 2H), 4.32-4.18 (m, 5H), 3.07 (s, 3H).

[0723] Example 23 Preparation of Compound 126

[0724] (1-(methylsulfonyl)azacyclobutane-3-yl)(oxazol-2-yl)methyl ketone O-(4-(trifluoromethyl)phenyl)oxime

[0725] 1) Preparation of compound 126 in the first step

[0726] At room temperature, methanesulfonic anhydride (34 mg, 0.20 mmol) and DIEA (42 μL, 0.24 mmol) were added to a 1 mL solution of 65e (30 mg) tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. Then, water (3 mL) and ethyl acetate (3 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 126 (15.7 mg).

[0727] MS m / z(ESI): 390.0 [M+1] + .

[0728] 1 H NMR (400MHz, DMSO-d6) δ = 8.37 (s, 1H), 7.80 (d, J = 8.8Hz, 2H), 7.54 (s, 1H), 7.51 (d, J = 8.8Hz, 2H), 4.40-4.33 (m, 3H), 4.26-4.20 (m, 2H), 3.02 (s, 3H).

[0729] Example 24 Preparation of Compounds 91 and 127

[0730] Oxazo-2-yl(1-(vinylsulfonyl)azacyclobutane-3-yl)methyl ketone O-(4-(trifluoromethyl)phenyl)oxime

[0731] 1) Preparation of compounds 91 and 127 in the first step

[0732] At room temperature, a mixture (100 mg) containing compounds 65e and 66e was dissolved in tetrahydrofuran (3 mL), and vinyl sulfonyl chloride (183 μL, 0.96 mmol) and DIEA (73 μL, 0.42 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water (5 mL) and ethyl acetate (5 mL * 3) were added to the reaction solution for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) and high performance liquid chromatography (Gilson GX281 column: Welch-Xtimate-C18-7um-30*250nm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 45%-85%, flow rate: 35 mL / min) to obtain compound 91 (18.33 mg) and compound 127 (16.72 mg).

[0733] MS m / z(ESI): 402.0 [M+1] + .

[0734] Compound 91: 1 H NMR (400MHz, DMSO-d6) δ=8.51-8.48(m,1H),7.81(d,J=8.8Hz,2H),7.62(s,1H),7.51(d,J=8.5Hz,2H),7.11(d d,J=10.0,16.5Hz,1H),6.34(d,J=10.3Hz,1H),6.25(d,J=16.5Hz,1H),4.29-4.20(m,3H),4.19-4.13(m,2H).

[0735] Compound 127: 1 H NMR (400MHz, DMSO-d6) δ=8.37(s,1H),7.80(d,J=9.0Hz,2H),7.54(s,1H),7.52-7.48(m,2H),7.05(dd,J= 10.0,16.5Hz,1H),6.27(d,J=10.0Hz,1H),6.19(d,J=16.5Hz,1H),4.45-4.34(m,1H),4.30-4.22(m,4H).

[0736] Example 25 Preparation of Compound 92

[0737] 1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)but-2-yn-1-one

[0738] 1) Preparation of compound 92 in the first step

[0739] The residue (100 mg) containing compound 65e was dissolved in tetrahydrofuran (1 mL), and 2-butynyl chloride (33 μL, 0.38 mmol) and DIEA (73 μL, 0.42 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (5 mL) and ethyl acetate (5 mL * 3) were added to the reaction solution for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) and high performance liquid chromatography (Gilson GX281 column: Welch-Xtimate-C18-7um-30*250nm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 35%-75%, flow rate: 35 mL / min) to obtain compound 92 (45.95 mg).

[0740] MS m / z(ESI): 378.0 [M+1] + .

[0741] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (d, J = 0.8Hz, 1H), 7.81 (d, J = 8.8Hz, 2H), 7.55 (d, J = 0. 8Hz,1H),7.47(d,J=8.8Hz,2H),4.62-4.49(m,3H),4.39-4.26(m,2H),2.01(s,3H).

[0742] Example 26 Preparation of Compound 128

[0743] 1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)but-2-yn-1-one

[0744] 1) Preparation of compound 128 in the first step

[0745] The residue containing compound 66e (50 mg) was dissolved in tetrahydrofuran (1 mL), and EDCI hydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole (33 mg, 0.24 mmol), DIEA (42 μL, 0.24 mmol), and 2-butynedic acid (14 mg, 0.17 mmol) were added. The mixture was stirred at room temperature for 3 hours. Add 5 mL of water to the reaction solution and extract with ethyl acetate (5 mL * 3). Wash the combined organic phases with saturated sodium chloride solution (10 mL), separate the layers, dry the organic phases with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) and high performance liquid chromatography (Gilson_GX281, column: Welch-Xtimate-C18-7um-30*250nm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 35%-75%, flow rate: 35 mL / min) to obtain compound 128 (26 mg).

[0746] MS m / z(ESI): 378.0 [M+1] + .

[0747] 1 H NMR (400MHz, DMSO-d6) δ = 8.50 (s, 1H), 7.82-7.78 (m, J = 8.8Hz, 2H), 7.63 (s, 1 H), 7.51 (d, J = 8.8Hz, 2H), 4.52-4.43 (m, 2H), 4.30-4.22 (m, 3H), 2.02 (s, 3H).

[0748] Example 27 Preparation of Compounds 93 and 129

[0749] 1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0750] 1) Preparation of compounds 93 and 129 in the first step

[0751] A mixture containing 65e and 66e (100 mg) was dissolved in tetrahydrofuran (2 mL), and acryloyl chloride (31 μL, 0.38 mmol) and DIEA (73 μL, 0.42 mmol) were added. The mixture was stirred at room temperature for 1 hour. Then, water (3 mL) and ethyl acetate (3 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compound 93 (35.8 mg) and compound 129 (37.9 mg).

[0752] MS m / z(ESI): 366.0 [M+H] +

[0753] Compound 93: 1 H NMR (400MHz, DMSO-d6) δ=8.36(s,1H),7.81(d,J=8.5Hz,2H),7.54(s,1H),7.46(d,J=8.8Hz,2H),6.36(dd,J=10.4,16.9Hz,1 H), 6.14 (dd, J = 2.1, 16.9Hz, 1H), 5.69 (dd, J = 2.3, 10.3Hz, 1H), 4.65 (d, J = 8.3Hz, 2H), 4.55-4.47 (m, 1H), 4.43-4.30 (m, 2H).

[0754] Compound 129: 1 H NMR (400MHz, DMSO-d6) δ = 8.50 (s, 1H), 8.36 (s, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.63 (s, 1H), 7.54-7.49 (m, 2H), 6.36 ( dd,J=10.3,17.0Hz,1H),6.12(dd,J=2.3,17.0Hz,1H),5.71-5.66(m,1H),4.63-4.51(m,2H),4.31-4.25(m,3H).

[0755] Example 28 Preparation of Compounds 94 and 130

[0756] (2E)-1-(3-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)but-2-en-1-one

[0757] 1) Preparation of compounds 94 and 130 in the first step

[0758] A mixture containing 65e and 66e (100 mg) was dissolved in tetrahydrofuran (1 mL), and trans-butenoyl chloride (40 μL, 0.42 mmol) and DIEA (291 μL, 1.67 mmol) were added. The mixture was stirred at room temperature for 1 hour. Then, water (3 mL) and ethyl acetate (3 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting system: petroleum ether / ethyl acetate = 3 / 1) to give compounds 94 (48.3 mg) and 130 (16.9 mg).

[0759] MS m / z(ESI): 380.0 [M+1] + .

[0760] Compound 94: 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (s, 1H), 7.80 (d, J = 8.8Hz, 2H), 7.54 (s, 1H), 7.46 (d, J = 8.6Hz, 2H), 6.75-6.61 (m, 1H), 6.05 (dd,J=1.6,15.3Hz,1H),4.61(d,J=8.1Hz,2H),4.49(quin,J=8.1Hz,1H),4.40-4.23(m,2H),1.83(dd,J=1.4,6.8Hz,3H).

[0761] Compound 130: 1 H NMR (400MHz, DMSO-d6) δ = 8.50 (s, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.62 (s, 1H), 7.51 (d, J = 8.8Hz, 2H), 6.7 1-6.62(m,1H),6.08-6.02(m,1H),4.57-4.46(m,2H),4.28-4.19(m,3H),1.83(dd,J=1.6,6.9Hz,3H).

[0762] Example 29 Preparation of Compounds 100 and 131

[0763] 2-Fluoro-1-(3-(furan-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0764] 1) Preparation of compound 100b in the first step

[0765] Compound 11b (655 μL, 3.8 mmol) and lithium chloride (200 mg, 4.7 mmol) were dissolved in tetrahydrofuran (2 mL). Isopropyl magnesium bromide (2.4 mL, 3.1 mmol, 1.3 M) was added dropwise at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 1 hour. Then, compound 100a (0.40 mL, 5.2 mmol) in tetrahydrofuran (1 mL) was added dropwise at -78 °C. The mixture was slowly brought to room temperature and stirred for 18 hours. Then, saturated ammonium chloride aqueous solution (5 mL) and ethyl acetate (5 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 100b (82 mg).

[0766] 2) Preparation of compound 100c in the second step

[0767] Compound 100b (154 mg, 0.50 mmol) was dissolved in dichloromethane (2 mL) at 0 °C, and Dys-Martin oxidant (387 mg, 0.91 mmol) was added. The mixture was heated to 25 °C and stirred for 1 hour. Saturated sodium bicarbonate aqueous solution (2 mL) was added to the reaction solution, followed by extraction with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 100c (81 mg).

[0768] 3) Preparation of compound 100d in the third step

[0769] Compound 100c (81 mg, 0.32 mmol) was dissolved in 1,2-DCE (1.5 mL), and then added... Molecular sieve (1510 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (61 μL, 0.36 mmol), acetic acid (56 μL, 0.98 mmol), and tetraisopropyl titanate (285 μL, 0.96 mmol) were stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 100d (74.6 mg).

[0770] 4) Preparation of compound 100e in the fourth step

[0771] Compound 100d (74.6 mg, 0.18 mmol), {[dioxo(trifluoromethyl)-λ6-thioalkyl]oxy}trimethylsilane (82 μL, 0.45 mmol), and 2,4-dimethylpyridine (63 μL, 0.55 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. The reaction solution was slowly added dropwise to a saturated ammonium chloride solution (3 mL), and extracted with dichloromethane (3 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 100e (46.5 mg).

[0772] 5) Preparation of compounds 100 and 131 in step five

[0773] 100e (50 mg, 0.15 mmol), 2-fluoroacrylic acid (15 mg, 0.17 mmol), EDCI hydrochloride (46 mg, 0.24 mmol), HOBT (33 mg, 0.24 mmol), and DIEA (42 μL, 0.24 mmol) were dissolved in tetrahydrofuran (1.5 mL). The mixture was stirred at room temperature for 18 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Gilson_GX281; Cell: Welch-Xtimate-C18-7um-30*250nm; Mobile phase: A: 0.1% FA / H2O; B: ACN; Gradient: 45%-85% in 10 min; Flow rate: 35 mL / min; UV wavelength: 220 / 254nm) to obtain compounds 100 (9.11 mg) and 131 (18.46 mg).

[0774] MS m / z(ESI): 383.1 [M+1] + .

[0775] Compound 100: 1H NMR (400MHz, DMSO-d6) δ = 7.94 (d, J = 1.3Hz, 1H), 7.77 (d, J = 8.8Hz, 2H), 7.40 (d, J = 8.5Hz, 2H), 7.09 (d, J = 3.5Hz ,1H),6.71(dd,J=1.8,3.5Hz,1H),5.61-5.43(m,1H),5.33(dd,J=3.5,16.8Hz,1H),4.82-4.73(m,1H),4.66(br s,1H),4.45-4.30(m,3H).

[0776] Compound 131: 1 H NMR (400MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.81-7.73 (m, 3H), 7.61 (br d,J=8.5Hz,2H),6.85-6.80(m,1H),5.57-5.42(m,1H),5.36-5.27(m,1H),4.75(br s,1H),4.67-4.59(m,1H),4.37-4.24(m,3H).

[0777] Example 30 Preparation of Compound 101

[0778] 2-Fluoro-1-(3-(furan-3-yl(4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0779] 1) Preparation of compound 101b in the first step

[0780] Compound 11b (1.5 mL, 8.64 mmol) and lithium chloride (470 mg, 11.1 mmol) were dissolved in tetrahydrofuran (2 mL). Isopropyl magnesium bromide (2.0 mL, 4.0 mmol, 2 M) was added dropwise under a nitrogen atmosphere at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, 1 mL of tetrahydrofuran (0.40 mL, 5.2 mmol) of 101a was added dropwise to the reaction mixture at -78 °C, and the mixture was stirred at -78 °C for 2 hours. Saturated ammonium chloride aqueous solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 101b (220 mg).

[0781] 2) Preparation of compound 101c in the second step

[0782] At 0 °C, a solution of compound 101b (220 mg, 0.87 mmol) in dichloromethane (2 mL) was added with Dys-Martin oxidant (553 mg, 1.3 mmol), and the mixture was heated to 25 °C and stirred for 1 hour. A saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 101c (162.5 mg).

[0783] 3) Preparation of compound 101d in the third step

[0784] Compound 101c (162.5 mg, 0.65 mmol) was dissolved in 1,2-DCE (2 mL), and then added... Molecular sieve (300 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (133 μL, 0.78 mmol), acetic acid (185 μL, 3.23 mmol), and tetraisopropyl titanate (575 μL, 1.94 mmol) were stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting system: petroleum ether / ethyl acetate = 5 / 1) to give compounds 101d-1 (96 mg) and 101d-2 (152 mg).

[0785] 4) Preparation of compound 101e in the fourth step

[0786] Compound 101d-1 (96 mg, 0.23 mmol), {[dioxo(trifluoromethyl)-λ6-thioalkyl]oxy}trimethylsilane (105 μL, 0.58 mmol), and 2,4-dimethylpyridine (80 μL, 0.70 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a saturated ammonium chloride solution (4 mL), extracted with dichloromethane (5 mL x 3), and the combined organic phases were washed with a saturated sodium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 101e (70 mg).

[0787] 5) Preparation of compound 101 in step 5

[0788] Compound 101e (70 mg, 0.23 mmol), 2-fluoroacrylic acid (21 mg, 0.23 mmol), EDCI hydrochloride (65 mg, 0.34 mmol), HOBT (46 mg, 0.34 mmol), and DIEA (59 μL, 0.34 mmol) were dissolved in tetrahydrofuran (2 mL). The mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 101 (35.4 mg).

[0789] MS m / z(ESI): 383.1 [M+1] + .

[0790] 1 H NMR (400MHz, DMSO-d6) δ=8.18-8.15(m,1H),7.82(t,J=1.6Hz,1H),7.73(d,J=8.8Hz,2H),7.39(d,J=8.5Hz,2 H),6.86(dd,J=0.8,1.9Hz,1H),5.56-5.41(m,1H),5.30(dd,J=3.5,16.6Hz,1H),4.80-4.70(m,1H),4.58(br t,J=6.3Hz,1H),4.44-4.35(m,1H),4.33-4.20(m,2H).

[0791] Example 31 Preparation of Compound 132

[0792] 2-Fluoro-1-(3-(furan-3-yl(4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0793] 1) Preparation of compound 132a in the first step

[0794] Compound 101d-2 (152 mg, 0.37 mmol), {[dioxo(trifluoromethyl)-λ6-thioalkyl]oxy}trimethylsilane (168 μL, 0.93 mmol), and 2,4-dimethylpyridine (128 μL, 1.11 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a saturated ammonium chloride solution (4 mL) and extracted with dichloromethane (5 mL * 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 132a (110 mg).

[0795] 2) Preparation of compound 132 in the second step

[0796] Compound 132a (110 mg, 0.36 mmol), 2-fluoroacrylic acid (35 mg, 0.39 mmol), EDCI hydrochloride (102 mg, 0.53 mmol), HOBT (72 mg, 0.53 mmol), and DIEA (93 μL, 0.53 mmol) were dissolved in tetrahydrofuran (2 mL). The mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 132 (55.12 mg).

[0797] MS m / z(ESI): 383.1 [M+1] + .

[0798] 1 H NMR (400MHz, DMSO-d6) δ=8.72(s,1H),7.90(s,1H),7.79-7.74(m,J=8.8Hz,2H),7.64-7.59(m,J=8 .8Hz,2H),6.93(d,J=1.8Hz,1H),5.58-5.42(m,1H),5.35-5.28(m,1H),4.80-4.72(m,1H),4.60(br s,1H),4.42-4.34(m,1H),4.31-4.15(m,2H).

[0799] Example 32 Preparation of Compound 102

[0800] 2-Fluoro-1-(3-(thiophene-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0801] 1) Preparation of compound 102b in the first step

[0802] Compound 11b (465 μL, 2.7 mmol) and lithium chloride (170 mg, 4.0 mmol) were dissolved in tetrahydrofuran (2 mL). Isopropyl magnesium bromide (2.0 mL, 4.0 mmol, 2 M) was added dropwise under a nitrogen atmosphere at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, 102a (250 μL, 2.7 mmol) in tetrahydrofuran (3 mL) was added dropwise to the reaction mixture at -78 °C, and the mixture was slowly heated to room temperature and stirred for 18 hours. The reaction mixture was extracted with saturated ammonium chloride aqueous solution (5 mL) and ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 102b (496 mg).

[0803] 2) Preparation of compound 102c in the second step

[0804] At 0 °C, a solution of compound 102b (496 mg, 1.693 mmol) in dichloromethane (5 mL) was added with Dys-Martin oxidant (1.17 g, 2.8 mmol), and the mixture was heated to 25 °C and stirred for 1 hour. The reaction mixture was then extracted with saturated sodium bicarbonate aqueous solution (5 mL) and ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 102c (236 mg).

[0805] 3) Preparation of compound 102d in the third step

[0806] Compound 102c (236 mg, 0.88 mmol) was dissolved in 1,2-DCE (3 mL), and then added... Molecular sieve (500 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (166 μL, 0.97 mmol), acetic acid (100 μL, 1.8 mmol), and tetraisopropyl titanate (785 μL, 2.7 mmol) were stirred at 65 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting system: petroleum ether / ethyl acetate = 5 / 1) to give compounds 102d-1 (53 mg) and 102d-2 (119 mg).

[0807] 4) Preparation of compound 102e in the fourth step

[0808] Compound 102d-1 (52.6 mg, 0.11 mmol), {[dioxo(trifluoromethyl)-λ6-thioalkyl]oxy}trimethylsilane (55 μL, 0.30 mmol), and 2,4-dimethylpyridine (42 μL, 0.37 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was added dropwise to a saturated ammonium chloride solution (2 mL), extracted with dichloromethane (3 mL x 3), and the combined organic phases were washed with a saturated sodium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 102e (40 mg).

[0809] 5) Preparation of compound 102 in step five

[0810] 102e (40 mg, 0.11 mmol), 2-fluoroacrylic acid (11 mg, 0.12 mmol), EDCI hydrochloride (35 mg, 0.18 mmol), HOBT (25 mg, 0.19 mmol), and DIEA (32 μL, 0.18 mmol) were dissolved in tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 1 hour. Water (3 mL) and ethyl acetate (3 mL x 3) were added to the reaction mixture for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 102 (18.4 mg).

[0811] MS m / z(ESI): 399.0 [M+1] + .

[0812] 1 H NMR (400MHz, DMSO-d6) δ=7.80-7.75(m,3H),7.49(dd,J=1.0,3.8Hz,1H),7.37(d,J=8.5Hz,2H),7.21(dd,J=3.8,5.3Hz,1H), 5.59-5.45(m,1H),5.33(dd,J=3.6,16.6Hz,1H),4.85-4.77(m,1H),4.71-4.64(m,1H),4.51-4.42(m,2H),4.38-4.29(m,1H).

[0813] Example 33 Preparation of compound 133

[0814] 2-Fluoro-1-(3-(thiophene-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0815] 1) Preparation of compound 133a in the first step

[0816] Compound 102d-2 (52.6 mg, 0.11 mmol), {[dioxo(trifluoromethyl)-λ6-thioalkyl]oxy}trimethylsilane (55 μL, 0.30 mmol), and 2,4-dimethylpyridine (42 μL, 0.37 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was added dropwise to a saturated ammonium chloride solution (2 mL), extracted with dichloromethane (3 mL x 3), and the combined organic phases were washed with a saturated sodium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 133a (40 mg).

[0817] 2) Preparation of compound 133 in the second step

[0818] Compound 133a (40 mg, 0.11 mmol), 2-fluoroacrylic acid (11 mg, 0.12 mmol), EDCI hydrochloride (35 mg, 0.18 mmol), HOBT (25 mg, 0.19 mmol), and DIEA (32 μL, 0.18 mmol) were dissolved in tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 133 (64.5 mg).

[0819] MS m / z(ESI): 399.0 [M+1] + .

[0820] 1 H NMR (400MHz, DMSO-d6) δ=8.08(dd,J=0.9,5.1Hz,1H),7.83-7.78(m,J=8.8Hz,2H),7.66(dd,J=0.9,3.9Hz,1H),7.60-7.54(m,J=8.8Hz,2H ),7.29(dd,J=3.9,5.1Hz,1H),5.58-5.43(m,1H),5.32(dd,J=3.5,16.5Hz,1H),4.87-4.78(m,1H),4.71-4.61(m,1H),4.47-4.30(m,3H).

[0821] Example 34 Preparation of Compound 103

[0822] 2-Fluoro-1-(3-(thiophene-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0823] 1) Preparation of compound 103b in the first step

[0824] The intermediate compound 103a was synthesized following the same synthetic route as intermediate 102d-1 of compound 102.

[0825] Compound 103a (216 mg, 0.51 mmol), {[dioxo(trifluoromethyl)-λ6-thioalkyl]oxy}trimethylsilane (230 μL, 1.3 mmol), and 2,4-dimethylpyridine (175 μL, 1.5 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a saturated sodium bicarbonate solution (3 mL), extracted with ethyl acetate (3 mL * 2), and the combined organic phases were washed with a saturated sodium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 103b (46.5 mg).

[0826] 2) Preparation of compound 103 in the second step

[0827] 103b (150 mg, 0.46 mmol), 2-fluoroacrylic acid (42 mg, 0.47 mmol), EDCI hydrochloride (132 mg, 0.69 mmol), HOBT (93 mg, 0.69 mmol), and DIEA (120 μL, 0.69 mmol) were dissolved in tetrahydrofuran (2 mL). The mixture was stirred at room temperature for 1.5 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Gilson_GX281; Cell: Welch-Xtimate-C18-7um-30*250nm; Mobile phase: A: 0.1% FA / H2O; B: ACN; Gradient: 45%-85% in 10 min; Flow rate: 35 mL / min; UV wavelength: 220 / 254nm) to obtain compound 103 (103.6 mg).

[0828] MS m / z(ESI): 399.0 [M+1] + .

[0829] 1H NMR (400MHz, DMSO-d6) δ = 8.45 (dd, J = 1.3, 2.8 Hz, 1H), 7.95 ( dd, J = 1.3, 2.8 Hz, 1H), 7.80-7.69 ( m, 6H), 7.64 ( dd, J = 1.3, 5.0 Hz, 1H), 7.55 ( d, J =8.8Hz,2H),7.48(dd,J=1.1,5.1Hz,1H),7.42(d,J=8.8Hz,2H),5.58-5.41(m,2H),5.31(td,J=3.7,16.6Hz,2H),4.84-4.70(m,2H),4.57(br d,J=6.0Hz,2H),4.48-4.18(m,6H).

[0830] Example 35 Preparation of Compounds 104 and 134

[0831] 2-Fluoro-1-(3-(isoxazo-5-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0832] 1) Preparation of compounds 104 and 134 in the first step

[0833] The intermediate compound 104a was synthesized following the same synthetic route as intermediate 102d.

[0834] Compound 104a (30 mg, 0.10 mmol) was dissolved in tetrahydrofuran (1 mL), and EDCI hydrochloride (28 mg, 0.15 mmol), HOBT (20 mg, 0.15 mmol), DIEA (25 μL, 0.14 mmol), and 2-fluoroacrylic acid (9 mg, 0.10 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 104 (21.6 mg) and compound 134 (18.0 mg).

[0835] MS m / z(ESI): 384.0 [M+1] + .

[0836] Compound 104: 1H NMR (400MHz, DMSO-d6) δ = 8.93 (d, J = 2.0Hz, 1H), 7.81 (d, J = 8.8Hz, 2H), 7.69-7.65 (m, 3H), 5.58-5.42 (m, 1H), 5.32 (dd, J = 3.6, 16.6Hz, 1H), 4.78 (br s,1H),4.70(br s,1H),4.37(s,3H).

[0837] Compound 134: 1 H NMR (400MHz, DMSO-d6) δ = 8.81 (d, J = 2.0Hz, 1H), 7.80 (d, J = 8.8Hz, 2H), 7.46 (d, J = 8.5Hz, 2H), 7. 10(d,J=2.0Hz,1H),5.59-5.44(m,1H),5.32(dd,J=3.6,16.6Hz,1H),4.82–4.75(m,1H),4.66(br t,J=6.4Hz,1H),4.50–4.39(m,2H),4.34–4.27(m,1H).

[0838] Example 36 Preparation of Compound 105

[0839] 2-Fluoro-1-(3-(isoxazo-4-yl(4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0840] 1) Preparation of compound 105b in the first step

[0841] Compound 11b (320 mg, 1.13 mmol) and lithium chloride (66 mg, 1.56 mmol) were dissolved in tetrahydrofuran (7 mL). Isopropyl magnesium bromide (1.2 mL, 1.56 mmol, 1.3 M) was added dropwise under a nitrogen atmosphere at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, 105a (100 mg, 1.03 mmol) in tetrahydrofuran (7 mL) was added dropwise to the reaction mixture at -78 °C, and the mixture was slowly brought to room temperature and stirred for 1 hour. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 105b (176 mg).

[0842] 2) Preparation of compound 105c in the second step

[0843] At 0 °C, a solution of compound 105b (176 mg, 0.69 mmol) in dichloromethane (2 mL) was added with Dys-Martin oxidant (440 mg, 1.0 mmol), and the mixture was heated to 25 °C and stirred for 1.5 hours. The reaction mixture was then extracted with saturated sodium bicarbonate aqueous solution (5 mL) and ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compound 105c (136 mg).

[0844] 3) Preparation of compound 105d in the third step

[0845] Compound 105c (136 mg, 0.54 mmol) was dissolved in 1,2-DCE (5 mL), and then added... Molecular sieve (140 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (110 μL, 0.82 mmol), acetic acid (1 mL), and tetraisopropyl titanate (320 μL, 1.08 mmol) were stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with water (5 mL) and ethyl acetate (25 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 10 / 1) to give compound 105d (190 mg).

[0846] 4) Preparation of compound 105e in the fourth step

[0847] Compound 105d (190 mg, 0.45 mmol) and trifluoroacetic acid (1 mL, 13.1 mmol) were dissolved in dichloromethane (5 mL) at 0 °C, and stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a saturated sodium bicarbonate solution (3 mL), extracted with ethyl acetate (20 mL * 2), and the combined organic phases were washed with a saturated sodium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 105e (139 mg).

[0848] 5) Preparation of compound 105 in step five

[0849] 2-Fluoroacrylate (50 mg, 0.56 mmol), HBTU (255 mg, 0.67 mmol), and DIEA (0.23 mL, 1.39 mmol) were dissolved in DMF (1 mL), followed by the addition of 105e (50 mg, 0.15 mmol). The mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Gilson_GX281; Cell: Welch-Xtimate-C18-7um-30*250nm; Mobile phase: A: 0.1% FA / H2O B: ACN; Gradient: 45%-85% in 10 min; Flow rate: 35 mL / min; UV wavelength: 220 / 254nm) to obtain compound 105 (21.61 mg).

[0850] MS m / z(ESI): 384.0 [M+1] + .

[0851] 1 H NMR (400MHz, DMSO-d6) δ=9.93-9.43(m,1H),9.22-9.08(m,1H),7.77(t,J=9.6Hz,2H),7.68(d,J=8.8Hz,1H),7.46(d,J=8.8Hz,1 H),5.58-5.43(m,1H),5.32(td,J=3.2,16.6Hz,1H),4.78(dt,J=3.8,8.9Hz,1H),4.68-4.57(m,1H),4.45-4.38(m,1H),4.33(br dd,J=8.6,16.1Hz,1H),4.28-4.21(m,1H).

[0852] Example 37 Preparation of Compound 106

[0853] 2-Fluoro-1-(3-(isoxazo-3-yl(4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0854] 1) Preparation of compound 106b in the first step

[0855] Under a nitrogen atmosphere at -78°C, a solution of compound 11b (320 mg, 1.1 mmol) and lithium chloride (66 mg, 1.6 mmol) in tetrahydrofuran (5 mL) was added dropwise with isopropyl magnesium bromide (1.2 mL, 1.6 mmol), and the mixture was stirred at -78°C for 1 hour. Then, a solution of 106a (100 mg, 1.0 mmol) in tetrahydrofuran (3 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour. A saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 106b (146 mg).

[0856] 2) Preparation of compound 106c in the second step

[0857] Compound 106b (146 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL) at 0 °C, and Dys-Martin oxidant (210 mg, 0.50 mmol) was added. The mixture was stirred at 25 °C for 1.5 hours. Saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 106c (69 mg).

[0858] 3) Preparation of compound 106d in the third step

[0859] Compound 106c (69 mg, 0.27 mmol) was dissolved in 1,2-DCE (2 mL), and then added... Molecular sieve (70 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (55 μL, 0.41 mmol), acetic acid (0.4 mL), and tetraisopropyl titanate (170 μL, 0.57 mmol) were stirred at 80 °C for 18 hours. The mixture was filtered, and the filtrate was extracted with water (5 mL) and ethyl acetate (25 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 10 / 1) to give compound 106d (106 mg).

[0860] 4) Preparation of compound 106e in the fourth step

[0861] Compound 106d (106 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.1 mL, 1.3 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate solution (3 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 106e (75 mg).

[0862] 5) Preparation of compound 106 in step five

[0863] Dissolve 2-fluoroacrylic acid (25 mg, 0.28 mmol), HBTU (135 mg, 0.36 mmol), and DIEA (0.12 mL, 0.73 mmol) in DMF (1 mL) solution, and add 106e (75 mg, 0.23 mmol) of DMF (1 mL) solution dropwise at room temperature. Stir at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Gilson 306 1741, column: Puningtech-Pntulips-C18-10μm-30*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 25 mL / min) to obtain compound 106 (27.86 mg).

[0864] MS m / z(ESI): 384.0 [M+1] + .

[0865] 1 H NMR (400MHz, DMSO-d6) δ=9.29-9.10(m,1H),7.79(dd,J=3.1,8.9Hz,2H),7.60(d,J=8.5Hz,1H),7.51(d,J=8.5Hz ,1H),7.44-7.10(m,1H),5.57-5.42(m,1H),5.32(dd,J=3.6,16.6Hz,1H),4.80-4.64(m,2H),4.62-4.28(m,3H).

[0866] Example 38 Preparation of Compound 108

[0867] 2-Fluoro-1-(3-(thiazo-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0868] 1) Preparation of compound 108b in the first step

[0869] Compound 11b (1.30 g, 4.6 mmol) and lithium chloride (175 mg, 4.1 mmol) were dissolved in tetrahydrofuran (20 mL). Isopropyl magnesium bromide (3.3 mL, 6.6 mmol) was added dropwise under a nitrogen atmosphere at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, 108a (0.39 mL, 4.44 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction mixture at -78 °C, and the mixture was stirred at -78 °C for another 1 hour. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 108b (766 mg).

[0870] 2) Preparation of compound 108c in the second step

[0871] At 0 °C, a solution of compound 108b (766 mg, 2.8 mmol) in dichloromethane (12 mL) was added with Dys-Martin oxidant (1.65 g, 3.9 mmol), and the mixture was heated to 25 °C and stirred for 1.5 hours. The reaction mixture was then extracted with saturated sodium bicarbonate aqueous solution (5 mL) and ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) to give compound 108c (434 mg).

[0872] 3) Preparation of compound 108d in the third step

[0873] Compound 108c (434 mg, 1.6 mmol) was dissolved in 1,2-DCE (5 mL), and then added... Molecular sieve (150 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (0.25 mL, 1.9 mmol), acetic acid (1 mL), and tetraisopropyl titanate (0.7 mL, 2.4 mmol) were stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with water (5 mL) and ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 108d (401 mg).

[0874] 4) Preparation of compound 108e in the fourth step

[0875] Compound 108d (401 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (0.25 mL, 3.3 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (3 mL), and extracted with ethyl acetate (20 mL * 2). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 108e (280 mg).

[0876] 5) Preparation of compound 108 in step five

[0877] Dissolve 2-fluoroacrylic acid (95 mg, 1.6 mmol), HBTU (490 mg, 1.3 mmol), and DIEA (0.45 mL, 2.7 mmol) in DMF (5 mL) at room temperature, and then add dropwise a DMF (5 mL) solution of 118e (280 mg, 0.86 mmol). Stir at room temperature for 0.5 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Gilson 306 1741; Cloumn: Puningtech-Pntulips-C18-10μm-30*250mm; Mobile phase: A: 0.05% TFA / H2O B: ACN; Gradient: 20%-60% in 10 min; Flow rate: 30 mL / min; UV wavelength: 220 nm) to obtain compound 108 (14.9 mg).

[0878] MS m / z(ESI): 400.1 [M+1] + .

[0879] 1 H NMR (400MHz, DMSO-d6) δ = 8.32-7.95 (m, 2H), 7.87-7.80 (m, 2H), 7.67-7.41 (m, 2H), 5.57-5.41 (m, 1H ), 5.31 (dd, J = 3.5, 16.5 Hz, 1H), 4.79 (dt, J = 4.0, 9.1 Hz, 1H), 4.72-4.61 (m, 1H), 4.60-4.34 (m, 3H).

[0880] Example 39 Preparation of Compounds 109 and 135

[0881] 2-Fluoro-1-(6-(oxazol-2-yl((4-(trifluoromethyl)phenoxy)imino)methyl)-2-azaspiro[3.3]heptane-2-yl)prop-2-en-1-one

[0882] 1) Preparation of compound 109b in the first step

[0883] Compound 109a (1.0 g, 4.7 mmol) and p-toluenesulfonyl hydrazine (1.06 g, 5.7 mmol) were added to acetonitrile (10 mL). The mixture was stirred at 90 °C under a nitrogen atmosphere for 18 hours. Water (10 mL) and ethyl acetate (50 mL x 2) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (20 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compound 109b (1.0 g).

[0884] 2) Preparation of compound 109d in the second step

[0885] Compounds 109b (1.0 g, 2.3 mmol), 109c (330 mg, 3.4 mmol), and cesium carbonate (1.47 g, 4.5 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 100 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and water (10 mL) was added. Extraction was performed with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 109d (70 mg).

[0886] 3) Preparation of compound 109f in the third step

[0887] Compound 109d (136 mg, 0.54 mmol) was dissolved in 1,2-DCE (5 mL), and then added... Molecular sieve (140 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (110 μL, 0.82 mmol), acetic acid (1 mL), and tetraisopropyl titanate (320 μL, 1.1 mmol) were stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with water (5 mL) and ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 10 / 1) to give compound 109f (190 mg).

[0888] 4) Preparation of compound 109g in step four

[0889] Compound 109f (190 mg, 0.45 mmol) and trifluoroacetic acid (0.25 mL, 3.3 mmol) were dissolved in dichloromethane (1 mL) at 0 °C, and stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a saturated sodium bicarbonate solution (3 mL), extracted with ethyl acetate (20 mL * 2), and the combined organic phases were washed with a saturated sodium chloride solution (5 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 109 g (20 mg).

[0890] 5) Preparation of compounds 109 and 135 in step five

[0891] 2-Fluoroacrylate (7 mg, 0.08 mmol), HBTU (35 mg, 0.09 mmol), and DIEA (30 μL, 0.18 mmol) were dissolved in DMF (0.5 mL), and 109 g (20 mg, 0.06 mmol) of DMF (0.5 mL) solution was added. The mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1) to give compounds 109 (7.96 mg) and 135 (4.1 mg).

[0892] MS m / z(ESI): 424.2 [M+1] + .

[0893] Compound 109: 1 H NMR (400MHz, DMSO-d6) δ=8.33(s,1H),7.79(d,J=8.8Hz,2H),7.52(s,1H),7.46(d,J=8.5Hz,2H),5.53-5.36(m,1H),5.27(ddd,J=3 .5,9.3,16.5Hz,1H),4.53(d,J=3.3Hz,1H),4.31(d,J=3.3Hz,1H),4.15(s,1H),4.05-3.97(m,1H),3.94(s,1H),2.83-2.66(m,4H).

[0894] Compound 135: 1H NMR (400MHz, DMSO-d6) δ = 8.45 (s, 1H), 7.78 (br d,J=7.8Hz,2H),7.59(s,1H),7.47(d,J=8.5Hz,2H),5.53-5.36(m,1H),5.33-5.24(m,1H),4.50(d,J= 3.3Hz, 1H), 4.32 (d, J = 3.0Hz, 1H), 4.12 (s, 1H), 3.94 (s, 1H), 3.75 (q, J = 8.4Hz, 1H), 2.62-2.55 (m, 4H).

[0895] Example 40 Preparation of Compounds 118 and 136

[0896] 1-(3-((1H-imidazol-4-yl)((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutane-1-yl)-2-fluoroprop-2-en-1-one

[0897] 1) Preparation of compound 118b in the first step

[0898] Compound 11b (680 mg, 2.4 mmol) and lithium chloride (140 mg, 3.3 mmol) were dissolved in tetrahydrofuran (10 mL). Isopropyl magnesium bromide (2.5 mL, 3.3 mmol, 1.3 M) was added dropwise under a nitrogen atmosphere at -78 °C. The mixture was stirred at -78 °C for 1 hour. Then, a tetrahydrofuran (5 mL) solution of compound 118a (485 mg, 2.1 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour. Then, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 118b (447 mg).

[0899] 2) Preparation of compound 118c in the second step

[0900] Compound 118b (447 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL), and Dys-Martin oxidant (325 mg, 0.77 mmol) was added at 0 °C. The mixture was heated to 25 °C and stirred for 2 hours. Saturated sodium bicarbonate solution (5 mL) and ethyl acetate (50 mL * 2) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 12 / 1) to obtain compound 118c (124 mg).

[0901] 3) Preparation of compound 118d in the third step

[0902] Compound 118c (124 mg, 0.33 mmol) was dissolved in 1,2-DCE (3 mL), and then added... Molecular sieve (130 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (65 μL, 0.50 mmol), acetic acid (0.5 mL), and tetraisopropyl titanate (193 μL, 0.65 mmol) were heated to 80 °C and stirred for 18 hours. The reaction solution was then cooled to room temperature and filtered. The filtrate was added with water (10 mL) and extracted with ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 10 / 1) to give compound 118d (136 mg).

[0903] 4) Preparation of compound 118e in the fourth step

[0904] Compound 118d (136 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.25 mL, 3.3 mmol) was slowly added. The mixture was stirred at room temperature for 18 hours. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate solution (3 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 118e (60 mg).

[0905] 5) Preparation of compounds 118 and 136 in step five

[0906] Dissolve 2-fluoroacrylic acid (25 mg, 0.28 mmol), HBTU (110 mg, 0.29 mmol), and DIEA (0.1 mL, 0.61 mmol) in DMF (1 mL) solution, and add 118e (60 mg, 0.19 mmol) of DMF (1 mL) solution dropwise. The mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL * 2). The combined organic phases were washed with saturated sodium chloride (5 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by high performance liquid chromatography (Gilson 306 1741; Cell: Puningtech-Pntulips-C18-10μm-30*250mm; Mobile phase: A: 0.1% FA / H2O B: ACN; Gradient: 30%-70% in 10 min; Flow rate: 30 mL / min; UV wavelength: 220 nm) to obtain compounds 118 (16.66 mg) and 136 (10.56 mg).

[0907] MS m / z(ESI): 383.1 [M+1] + .

[0908] Compound 118: 1 H NMR(400MHz,DMSO-d6)δ=12.81(br s,1H),8.29(s,1H),7.87(s,1H),7.76(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H),5.56-5.41(m ,1H),5.29(dd,J=3.5,16.8Hz,1H),4.77-4.68(m,1H),4.63-4.53(m,1H),4.40-4.24(m,3H).

[0909] Compound 136: 1 H NMR(400MHz,DMSO-d6)δ=8.87(br s,1H),8.01(s,1H),7.79(d,J=8.9Hz,2H),7.52(d,J=8.6Hz,1H),5.61-5.43(m,1H),5.33(dd,J=3.6,16.7Hz,1H),4.77(br d,J=4.9Hz,1H),4.68(br d,J=3.4Hz,1H),4.44-4.31(m,3H).

[0910] Example 41 Preparation of compounds 119 and 137

[0911] 2-Fluoro-1-(3-((1-methyl-1H-imidazol-4-yl)((4-(trifluoromethyl)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0912] 1) Preparation of compound 119b in the first step

[0913] Compound 11b (850 mg, 3.0 mmol) and lithium chloride (175 mg, 4.1 mmol) were dissolved in tetrahydrofuran (15 mL). Isopropyl magnesium bromide (2.0 mL, 4.0 mmol, 2 M) was slowly added dropwise at -78 °C under an atmospheric atmosphere. The mixture was stirred at -78 °C for 1 hour. A tetrahydrofuran solution of compound 119a (300 mg, 3.1 mmol) (15 mL) was added. The mixture was stirred at -78 °C for 1 hour. The mixture was then brought to room temperature. Water (10 mL) and ethyl acetate (50 mL x 2) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography (eluting system: ethyl acetate) to obtain compound 119b (276 mg).

[0914] 2) Preparation of compound 119c in the second step

[0915] Compound 119b (276 mg, 1.0 mmol) was dissolved in dichloromethane (3 mL) at 0 °C, and Dys-Martin oxidant (600 mg, 1.4 mmol) was added. The mixture was heated to 25 °C and stirred for 1.5 hours. The mixture was extracted with saturated sodium bicarbonate solution (3 mL) and ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give compound 119c (151 mg).

[0916] 3) Preparation of compound 119d in the third step

[0917] Compound 119c (150 mg, 0.52 mmol) was dissolved in 1,2-DCE (10 mL), and then added... Molecular sieve (440 mg), O-(4-(trifluoromethyl)phenyl)hydroxylamine (0.24 mL, 1.8 mmol), acetic acid (2 mL), and tetraisopropyl titanate (0.9 mL, 3.0 mmol) were mixed and stirred at 80 °C for 18 hours. The reaction mixture was brought to room temperature, filtered, and the filtrate was extracted with ethyl acetate (35 mL * 2) after adding water (10 mL). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 3 / 1) to give compound 119d (180 mg).

[0918] 4) Preparation of compound 119e in the fourth step

[0919] Compound 119d (180 mg, 0.42 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.25 mL, 3.3 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. Then, saturated sodium bicarbonate (3 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 119e (120 mg).

[0920] 5) Preparation of compounds 119 and 137 in step five

[0921] Dissolve 2-fluoroacrylic acid (40 mg, 0.44 mmol), HBTU (210 mg, 0.55 mmol), and DIEA (0.2 mL, 1.2 mmol) in DMF (3 mL), and add dropwise 119e (15 mg, 0.03 mmol) in DMF (2 mL). Stir at room temperature for 0.5 hours. Add water (3 mL) to the reaction solution, extract with ethyl acetate (25 mL * 2), wash the combined organic phases with saturated sodium chloride solution (10 mL), separate the liquids, dry the organic phases with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by high performance liquid chromatography (Gilson 306 1741; Cell: Puningtech-Pntulips-C18-10μm-30*250mm; Mobile phase: A: 0.1% FA / H2O B: ACN; Gradient: 20%-60% in 10 min; Flow rate: 30 mL / min; UV wavelength: 220 nm) to obtain compounds 119 (16.29 mg) and 137 (30.25 mg).

[0922] MS m / z(ESI): 397.2 [M+1] + .

[0923] Compound 119: 1 H NMR (400MHz, DMSO-d6) δ = 8.34 (d, J = 1.0Hz, 1H), 7.81-7.75 (m, 3H), 7.63 (d, J = 8.5Hz, 2H), 5.56-5.39 (m, 1H), 5.29 (dd, J = 3.5, 16.5Hz, 1H), 4.76-4.68 (m, 1H), 4.59-4.53 (m, 1H), 4.35-4.26 (m, 3H), 3.79 (s, 3H).

[0924] Compound 137: 1 H NMR (400MHz, DMSO-d6) δ = 7.82 (s, 1H), 7.77-7.72 (m, 3H), 7.40 (d, J = 8.8Hz, 2H), 5.56-5.41 (m, 1H), 5.2 9(dd,J=3.5,16.5Hz,1H),4.80-4.67(m,2H),4.48(quin,J=8.3Hz,1H),4.41-4.30(m,2H),3.73(s,3H).

[0925] Example 42 Preparation of Compounds 120 and 138

[0926] 2-Fluoro-1-(3-(oxazol-4-yl((4-(trifluoromethoxy)phenoxy)imino)methyl)azacyclobutan-1-yl)prop-2-en-1-one

[0927] 1) Preparation of compound 120a in the first step

[0928] Compound 64d (340 mg, 1.1 mmol) was dissolved in 1,2-DCE (4 mL) and tetrahydrofuran (1 mL), and then O-(4-(trifluoromethoxy)phenyl)hydroxylamine (285 mg, 1.3 mmol), acetic acid (0.5 mL, 8.7 mmol), tetraisopropyl titanate (1.20 mL, 4.0 mmol) and... Molecular sieve (600 mg) was stirred at 65 °C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 5 / 1) to give compound 120a (66 mg).

[0929] 2) Preparation of compound 120b in the second step

[0930] Compound 120a (66 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), and trimethylsilyl trifluoromethanesulfonate (70 μL, 0.39 mmol) and 2,4-dimethylpyridine (53 μL, 0.46 mmol) were slowly added. The mixture was stirred at room temperature for 1 hour. Water (5 mL) was slowly added dropwise to the reaction solution, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 120b (50 mg).

[0931] 3) Preparation of compound 120 in the third step

[0932] Compound 120b (50 mg) was dissolved in tetrahydrofuran (1 mL), and EDCI hydrochloride (44 mg, 0.23 mmol), HOBT (31 mg, 0.23 mmol), DIEA (53 μL, 0.30 mmol) and 2-fluoroacrylic acid (14 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 1 hour. Add water (5 mL) to the reaction solution and extract with ethyl acetate (5 mL * 3). Wash the combined organic phases with saturated sodium chloride solution (10 mL), separate the layers, dry the organic phases with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent system: petroleum ether / ethyl acetate = 2 / 1) and high performance liquid chromatography (Gilson_306_1741, column: Puningtech-Pntulips-C18-10μm-30*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 30 mL / min) to obtain compounds 120 (13.4 mg) and 138 (7.6 mg).

[0933] MS m / z(ESI): 400.1 [M+1] +

[0934] Compound 120: 1 H NMR (400MHz, DMSO-d6) δ = 8.69 (d, J = 1.0Hz, 1H), 8.59 (d, J = 1.0Hz, 1H), 7.41-7.31 (m, 4H), 5.57-5.41 (m, 1H) ,5.30(dd,J=3.6,16.6Hz,1H),4.79-4.70(m,1H),4.70-4.61(m,1H),4.49-4.35(m,2H),4.32-4.23(m,1H).

[0935] Compound 138: 1H NMR (400MHz, DMSO-d6) δ = 9.25 (d, J = 0.8Hz, 1H), 8.63 (d, J = 0.8Hz, 1H), 7.58 (d, J = 8.1Hz, 2H), 7.42 (d, J = 8.8Hz, 2H),5.56-5.41(m,1H),5.30(dd,J=3.5,16.8Hz,1H),4.79-4.67(m,1H),4.63-4.56(m,1H),4.37-4.23(m,3H).

[0936] Biological evaluation

[0937] Test Example 1. Chemiluminescence assay to detect the effect of TEAD inhibitors on the viability of NCI-H226 and MSTO-211H cells

[0938] 1. Preparation before the experiment: Corning Pore-filled black transparent bottom cell plate, Corning, part number: #3603; Test kit: Promega, catalog number: G7570; Model of ELISA reader.

[0939] 2. Cell Culture

[0940] NCI-H226 cell culture: NCI-H226 cells derived from ATCC catalog number CRL-5826 were cultured in 89% RPMI-1640 + 10% FBS + 1% double antibiotics and placed in a 37°C constant temperature incubator containing 5% CO2.

[0941] MSTO-211H cell culture: MSTO-211H cells derived from ATCC catalog number CRL-2081 were cultured in 89% RPMI-1640 + 10%...

[0942] FBS + 1% double antibiotics, placed in a 37°C constant temperature incubator containing 5% CO2.

[0943] 3. Day 1: Once the cell confluence reaches 90%, aspirate the culture medium, add 3 mL of PBS to wash away any remaining medium, add 1 mL of Trypsin, and incubate for 5 min. After most cells have detached, add 2 mL of culture medium to stop digestion. Dilute the cell concentration to 5 × 10⁻⁶. 3 Cells / mL, at Corning Use a black transparent bottom cell plate, seed 500 cells / well, that is, add 100μL to each well.

[0944] 4. Day 2 Dosing: Thaw the 10mM TEAD inhibitor stock solution (DMSO solution of the compound) at room temperature and prepare working solutions of the following concentrations: 0.0015μM, 0.0046μM, 0.0137μM, 0.0412μM, 0.1235μM, 0.3704μM, 1.1111μM, 3.3333μM, 10μM. Prepare a 20μM working solution by adding 1.2μL of the 10mM stock solution to 0.6mL of complete culture medium; add 0.2mL of the above solution to 0.4mL of complete culture medium to prepare a 6.6666μM working solution, and repeat this 3-fold serial dilution to prepare other concentrations. Add 100μL of the working solution to a pre-coated 96-well plate.

[0945] 5. Replace with fresh medication on the 3rd day after adding the medication.

[0946] 6. Use on the 6th day of administration. Test with the kit. Select the CellTiter-Glo detection program on the microplate reader and read the luminescence value.

[0947] Data processing: Cell viability value = 100 × (Crystal emission value of drug-treated wells - Crystal emission value of blank wells) / (Crystal emission value of solvent-treated wells - Crystal emission value of blank wells), IC50 50 Calculation: The cell viability value and the corresponding drug concentration value were calculated using the (log(inhibitor) vs. normalized response--Variable slope) algorithm in the Curve fit of Prism 8 software.

[0948] The activity results are shown in Table 1 below. The NCI-H226 antiproliferative IC50 of the compound is shown in Table 1. 50 Value level: A: IC 50 ≤10nM; B: 10nM <IC 50 ≤100nM; C:IC 50 >100nM; MSTO-211H anti-proliferative IC 50 The rating is: A:IC 50 ≤50nM; B: 50nM <IC 50 ≤500nM; C:IC 50 >500nM.

[0949] Table 1

[0950] Experimental results showed that the compounds in this application could inhibit the proliferation of target-sensitive tumor cells NCI-H226 and MSTO-211H. Some test results are shown in Table 1. The inhibitory activity of some compounds on NCI-H226 cell proliferation was significantly better than that of the control compound BPI-460372.

[0951] The structural formula for BPI-460372 is as follows:

[0952] Test Example 2. Detection of the effect of TEAD inhibitors on YAP / TEAD transcriptional activity in NCI-H226 or MSTO-211H cells using real-time quantitative nucleic acid amplification detection system (qPCR).

[0953] 1. Reagents and Cells

[0954] NCI-H226 cell culture: NCI-H226 cells derived from ATCC catalog number CRL-5826 were cultured in 89% RPMI-1640 + 10% FBS + 1% penicillin antibiotics and incubated at 37°C in a 5% CO2 incubator. RNA extraction kit (Tiangen, DP430, stored at room temperature). SYBR dye (Kangwei Century, CW0957M, stored at -20°C).

[0955] MSTO-211H cell culture: MSTO-211H cells derived from ATCC catalog number CRL-2081 were cultured in 89% RPMI-1640 + 10% FBS + 1% penicillin antibiotics and incubated at 37°C in a 5% CO2 incubator. RNA extraction kit (Tiangen, DP430, stored at room temperature). SYBR dye (Kangwei Century, CW0957M, stored at -20°C).

[0956] 2. RNA extraction procedure

[0957] 2.1 After treating cells with 0.5 μM or 1 μM drug (DMSO solution of the compound) for 24 h, collect the cells (the cell count should not exceed 1 × 10⁻⁶). 7 Remove the cell culture supernatant, wash once with PBS, remove the PBS, and immediately proceed to step 2: lysis step.

[0958] 2.2 Cell lysis

[0959] Prepare lysis buffer: Add β-mercaptoethanol to RL to a final concentration of 1%, such as adding 10 μL of β-mercaptoethanol to 1 mL of RL; Lysis: Add an appropriate amount of lysis buffer RL, transfer the cell lysis buffer to a centrifuge tube, and vortex to mix.

[0960] Table 2

[0961] 2.3 Transfer all solutions to the CS filter column (place the CS filter column in the collection tube), centrifuge at 12000 rpm (~13400×g) for 2 min, and collect the filtrate.

[0962] 2.4 Add 1 volume of 70% ethanol (usually 350 μL or 600 μL) to the filtrate, mix well, and transfer the resulting solution and precipitate together into the adsorption column CR3. Centrifuge at 12000 rpm (~13400×g) for 30-60 seconds, discard the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

[0963] 2.5 Add 350 μL of protein removal solution RW1 to the adsorption column CR3, centrifuge at 12000 rpm (13400×g) for 30-60 seconds, discard the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

[0964] 2.6 Preparation of DNase I working solution: Take 10 μL of DNase I stock solution and put it into a new RNase-Free centrifuge tube. Add 70 μL of RDD buffer and mix gently.

[0965] 2.7 Add 80 μL of DNase I working solution to the center of the adsorption column CR3 and let it stand at room temperature for 15 min.

[0966] 2.8 Add 350 μL of protein removal solution RW1 to the adsorption column CR3, centrifuge at 12000 rpm (~13400×g) for 30-60 seconds, discard the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

[0967] 2.9 Add 500 μL of washing buffer RW to the adsorption column CR3, let it stand at room temperature for 2 min, centrifuge at 12000 rpm (~13400×g) for 30-60 sec, discard the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

[0968] 2.10 Repeat step 9.

[0969] 2.11 Centrifuge at 12000 rpm (~13400×g) for 2 min, and discard the waste liquid. Place the adsorption column CR3 at room temperature for 3-5 minutes to thoroughly dry any residual washing liquid in the adsorption material.

[0970] 2.12 Transfer the adsorption column CR3 into a new RNase-Free centrifuge tube, add 30-100 μL of RNase-Free ddH2O, incubate at room temperature for 2 min, and centrifuge at 12000 rpm (~13400×g) for 2 min to obtain the RNA solution.

[0971] 2.13 The concentration of the extracted RNA was detected using Nanodrop.

[0972] 3 Reverse transcription operation steps

[0973] 3.1 Place the RNA sample to be reverse transcribed and the reagents of the reverse transcription kit (thermo, 4368814, -20°C) on ice to completely dissolve.

[0974] 3.2 Prepare 2×RT master mixes according to the kit instructions.

[0975] 3.3 Gently tap the bottom of the prepared 2×RT master mix tube to mix evenly, then shake it lightly with a handheld centrifuge and place it on ice for later use.

[0976] 3.4 First, calculate the volume required to aspirate 500 ng of RNA for each sample based on the extracted RNA concentration. Then, calculate the volume of RNase-free H2O to be added according to a 10 μL system. Number the 8-tube PCR tubing for RNase. First, add RNase-free H2O to the corresponding number, then add the corresponding volume of 500 ng RNA. Mix by pipetting several times, then add 10 μL of 2×RT master mix. Gently tap the bottom of the tube to mix thoroughly, then shake it lightly with a handheld centrifuge and place it on ice.

[0977] 3.5 Place the PCR tube into the PCR instrument, tighten the cap, and set the PCR program according to the following conditions. The reaction volume is 20 μL.

[0978] 3.6 Store the reversed cDNA at -20°C for later use.

[0979] 4. qPCR procedure

[0980] 4.1 Dissolve the forward and reverse primers (specific primer sequences are shown in Table 3) of the genes 36B4, CTGF and CYR61 to be detected, along with the sample cDNA and SYBR green on ice and mix thoroughly.

[0981] Table 3

[0982] 4.2 Diluting the primers

[0983] Dissolve and mix the synthesized forward primer and reverse primer in ddH2O according to the volume specified in the tube (typically at a concentration of 100 μM). Take 2.5 μL of the 100 μM primer stock and add it to an EP tube containing 47.5 μL of ddH2O to dilute it to 5 μM. Then mix equal volumes of the 5 μM forward primer and reverse primer to form a 2.5 μM F / R primer mixture.

[0984] 4.3 Dilution of cDNA

[0985] After the reverse transcribed cDNA is completely dissolved on ice, mix it thoroughly. Add 4 μL of cDNA to each well of the 384QPCR plate for each experiment, and perform 3 replicates. Calculate the required sample volume, take out the PCR 8-tube strip, dilute the cDNA 20 times with ddH2O, gently tap the bottom of the tube to mix it thoroughly, shake it on a handheld centrifuge, and place it on ice for later use.

[0986] 4.4 Prepare the SYBR and primer mixture in a 1.5 mL centrifuge tube, gently tap the bottom of the tube to mix thoroughly, shake it on a handheld centrifuge, and place it on ice for later use.

[0987] 4.5 After loading all wells, use a pipette to aspirate 6 μL of the corresponding gene's SYBR and 2.5 μM F / R primer mixture. After loading, affix the sealing film and press firmly on all four sides. Centrifuge for 5 min before PCR to ensure all liquid is at the bottom of the plate. Set the qPCR reaction program. The pre-denaturation reaction with Kangwei Century SYBR dye must be completed at 95℃ for 10 min, with a reaction volume of 20 μL and 40 cycles. Save the data for analysis.

[0988] Some experimental results are shown in Figures 1 to 9. Some compounds in this application exhibit significant inhibitory effects on YAP / TEAD transcriptional activity in NCI-H226 cells. For example, compounds 2 and 3 showed better inhibitory effects on downstream target genes of YAP in NCI-H226 cells than the control compound VT103. Compounds 92 and 129 showed better inhibitory effects on downstream target genes of YAP in NCI-H226 cells than the control compound BPI-460372.

[0989] The structural formula of the reference compound VT103 is as follows:

[0990] Test Example 3. In vivo PK test

[0991] 1. Laboratory animals

[0992] Six ICR mice were divided into two groups: one receiving oral administration and the other receiving intravenous administration, with three mice in each group. The mice were fasted for 10-14 hours before administration, but had free access to water.

[0993] 2. Preparation of drug formulations

[0994] Weigh the test compound according to the dosage and prepare an appropriate concentration of the drug formulation with a solvent (10 mL / kg for both intravenous and oral administration to mice). The intravenous injection is a clear solution, and the oral formulation is a clear solution or a homogeneous suspension.

[0995] 3. Animal drug administration and blood sample collection

[0996] Animals were administered the drug via intravenous injection and oral gavage. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at the same time after oral administration. Whole blood was centrifuged at 6800g for 6 minutes at 4°C, and the supernatant plasma was collected and stored at -80°C for analysis.

[0997] 4. Plasma sample testing

[0998] Dilute the DMSO stock solution of the analyte with methanol or acetonitrile to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of methanol or acetonitrile containing internal standard according to the response to precipitate proteins. Centrifuge all samples at 4°C, 18000g for 10 min, and take an appropriate amount of supernatant for LC-MS / MS analysis.

[0999] 5. Parameter Calculation

[1000] Based on the tested concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software, the curve was calculated using a non-compartmental model, including: half-life (T0). 1 / 2 ), Area under the curve (AUC) 0-t Pharmacokinetic parameters such as bioavailability (F) were analyzed. The results are shown in Table 4 below.

[1001] Table 4

[1002] Experimental results show that some compounds in this application have excellent pharmacokinetic properties.

[1003] Test Example 4. Detection of the inhibitory activity of TEAD on YAP / TEAD transcription in vivo using the MSTO-211H nude mouse xenograft model.

[1004] 1. Establishment of the MSTO-211H CDX nude mouse model

[1005] MSTO-211H cells, derived from ATCC catalog number CRL-2081, were cultured in 89% RPMI-1640 + 10% FBS + 1% penicillin-streptomycin in a 37°C incubator containing 5% CO2. In 15cm culture dishes, once cell confluence reached 90%, the culture medium was aspirated, and 5mL of PBS was added to wash away any remaining medium. Then, 3mL of Trypsin was added, and the cells were incubated for 5 minutes. After most cells detached, 6mL of culture medium was added to stop the digestion. MSTO-211H cells were collected, washed twice with 50mL of PBS, and diluted to 4×10⁻⁶ cells with PBS. 7Add 1 volume of Matrigel (Corning) to each cell suspension at a concentration of 100 μL / mL and mix well. Inject 100 μL of the cell suspension subcutaneously into the right anterior axilla of nude mice (2 × 10⁶ cells / mL). 6 Each cell.

[1006] 2. Administration

[1007] Drug preparation: Solvent: 8.5 mL physiological saline + 1 mL Solutol, dissolve the drug in DMSO to a concentration of 20 mg / mL for storage. Working solution: Add 35 μL of drug storage solution to 665 μL of solvent to prepare a 10 mg / kg TEAD inhibitor.

[1008] The tumor to be transplanted is 100 mm in size. 3 The patient was given 10 mg / kg of TEAD inhibitor and corresponding solvent by gavage once a day for 3 consecutive days. On the morning of the fourth day, the transplanted tumor was removed and flash-frozen in liquid nitrogen.

[1009] 3. Total RNA extraction from xenograft tumors

[1010] 3.1 Label the modules, cap, and grinding tubes of the tissue homogenizer and pre-cool them in a -80°C freezer. Before use, immerse the modules in liquid nitrogen. Place the tumor tissue, which has been flash-frozen in liquid nitrogen, into the homogenizer. Run at 60Hz for 30 seconds, then stop for 30 seconds. Repeat this process 5 times, removing the tissue each time and immersing it in liquid nitrogen for 30 seconds to ensure the low temperature.

[1011] 3.2 After grinding, place on ice and add 600 μL of lysis buffer (thermos, Purelink) to each tube. Mix the mini kit (12183025) with 1% β-mercaptoethanol and vortex to dissolve. Let stand on ice for 5 minutes. Transfer the supernatant to an enzyme-free EP tube and centrifuge at 12,000 rpm for 10 minutes at 4°C. Transfer the supernatant to a new enzyme-free EP tube and add an equal volume of 70% ethanol. Vortex to mix.

[1012] 3.3 Transfer the mixed liquid to the adsorption column, centrifuge at 12,000 rpm for 1 min at room temperature, discard the waste liquid, a maximum of 700 μL can be transferred, and the remaining liquid can be added back for centrifugation.

[1013] 3.4 Add 350 μL of wash buffer I to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, and discard the waste liquid.

[1014] 3.5 DNase I digestion: Take 10 μL of DNase I stock solution and place it into a new RNase-Free centrifuge tube. Add 70 μL of RDD buffer and mix gently. Add 80 μL of DNase I working solution to the center of the adsorption column for each sample and incubate at room temperature for 15 min.

[1015] 3.6 After digestion, add 350 μL of wash buffer I to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, and discard the waste liquid.

[1016] 3.7 Add 500 μL of wash buffer II to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, and discard the waste liquid. Repeat once.

[1017] 3.8 Place the adsorption column in a centrifuge and centrifuge at 12,000 rpm for 2 minutes at room temperature. Then, place the adsorption column at room temperature for 5 minutes to thoroughly dry any residual washing solution in the adsorption material.

[1018] 3.9 Transfer the adsorption column to a new RNase-Free centrifuge tube, add 30-100 μL of RNase-Free ddH2O, incubate at room temperature for 2 min, and centrifuge at 12000 rpm (~13400×g) for 2 min to obtain the RNA solution.

[1019] 3.10 The concentration of the extracted RNA was detected using Nanodrop.

[1020] 4. The reverse transcription and qPCR steps are the same as those in Method 4 of Test Example 3.

[1021] Some experimental results are shown in Figures 10 and 11. Some compounds of this application showed significant inhibitory effects on downstream target genes of YAP when administered to MSTO-211H cell tumor model mice under subcutaneous transplantation for a short period of time.

[1022] Test Example 5. Long-term efficacy experiment of drugs in nude mouse xenograft tumors

[1023] 1. NCI-H226 Cell Culture: NCI-H226 cells, derived from ATCC catalog number CRL-5826, were cultured in 89% RPMI-1640 + 10% FBS + 1% penicillin and streptomycin in a 37°C incubator containing 5% CO2. In 15cm culture dishes, when cell confluence reached 90%, the culture medium was aspirated, and 5mL of PBS was added to wash away any remaining medium. 3mL of Trypsin was added, and the cells were incubated for 5 minutes. After most cells detached, 6mL of culture medium was added to stop digestion. NCI-H226 cells were collected, washed twice with 50mL of PBS, and diluted to 2×10⁻⁶ cells with PBS. 8 Add 1 volume of Matrigel (Corning) to each cell suspension at a concentration of 100 μL / mL and mix well. Inject 100 μL of the cell suspension subcutaneously into the right anterior axilla of nude mice, i.e., 1 × 10⁶ cells / mL. 7 Each cell.

[1024] 2. Approximately one and a half months later, when the transplanted tumor has grown to 100mm... 3 Five mice were divided into groups of approximately 5 to receive the drug. Body weight, tumor length, and width were recorded. Drug preparation: a stock solution of 85% saline + 10% Solutol + 5% DMSO was administered to each nude mouse via gavage at a dose of 200 μL per day. Body weight, tumor length, and width were recorded weekly.

[1025] 3. Once the transplanted tumor has grown to a suitable size, nude mice are anesthetized with 4% chloral hydrate, and blood is collected from the heart. After euthanizing the mice with CO2, the following tissues are collected: transplanted tumor, lung, heart, kidney, pancreas, spleen, stomach, liver, duodenum, jejunum, cecum, ileum, rectum, and colon. The transplanted tumor is flash-frozen in liquid nitrogen, and the remaining tissues are fixed in 4% paraformaldehyde.

[1026] The experimental results are shown in Figure 12. Some of the compounds in this application can effectively inhibit tumor growth in the NCI-H226 cell mouse subcutaneous xenograft model, and the weight of the mice does not change.

[1027] Test Example 6. Effects of TEAD inhibitors on cellular-level TEAD1 / 2 / 3 / 4 palmitoylation

[1028] 1. Cell plating: 293T cells were plated in 10cm cell culture dishes (1 minute 5 seconds). The cell density reached approximately 40% on the second day.

[1029] 2. Cell transfection: 1 dish of cells was not transfected and served as a blank control. 4 dishes of cells were transfected with TEAD-myc-Flag plasmid (8 μg plasmid per dish). The transfection procedure was the same as the lipo2000 transfection protocol. The medium was changed 6 hours after transfection.

[1030] 3. Acylation reaction: 24 hours after transfection, Palmitic Acid Alkyne (working concentration 100 μM) and TEAD inhibitor were added to the cells and incubated overnight. The experimental groups were set as follows: blank control; negative control group (DMSO + TEAD + PAA-); control group (DMSO + TEAD + PAA+); positive control (positive control drug + TEAD + PAA+); negative control group (negative control drug + TEAD + PAA+); and drug-added group (test drug + TEAD + PAA+).

[1031] 4. Protein collection: 48 h after transfection, lyse cells to collect protein (1 mL RIPA lysis buffer per dish of cells), sonicate (20% power for 4 seconds, stop for 9 seconds, 5 times), centrifuge at 12000 rpm for 10 min, take 90 μL of supernatant as input sample, and perform IP on the remainder.

[1032] 5. IP and Elution of Proteins: IP was performed using FLAG-tagged antibody magnetic beads. Before incubation, the magnetic beads (Beyotime or Thermofisher Beads) were pre-washed with RIPA lysis buffer, using 40 μL of magnetic beads per tube (refer to the manufacturer's instructions). After pre-washing, the magnetic beads were resuspended in the lysed sample and pre-incubated at 4°C for 1 hour. The supernatant was collected using a magnetic rack, and 1 μg of FLAG peptide (150 μg / ml) was added and incubated overnight at 4°C.

[1033] 6. Click chemistry: After IP binding in step 5, the magnetic beads were washed three times with lysis buffer and resuspended in ddHO. Then, the reaction solution from the click chemistry kit was added sequentially: azido-biotin (100 μM), CuSO4 (1 mM), Tris-(benzyltriazolylmethyl)amine (100 μM), and Tris-carboxyethylphosphine (1 mM). The mixture was vortexed until the solution turned orange, and the magnetic bead suspension was incubated at room temperature for 30 minutes. After the reaction was complete, the magnetic beads were collected, and 40 μL of 2× loading buffer was added. The mixture was boiled at 70°C for 10 minutes, followed by Western blot analysis.

[1034] 7. The sample was analyzed using the standard Western blotting procedure, and the palmitoylation level was finally detected by chemiluminescence using Streptavidin-HRP.

[1035] Some experimental results are shown in Figure 13. Some compounds in this application (e.g., compound 65) are pan-TEAD inhibitors, and under the same administration concentration, their inhibition of YAP / TEAD interaction is significantly better than that of the control compound VT103.

[1036] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. A compound having the structure shown in Formula I or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof; Ring A is selected from: bond, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, phenyl; Ring B is selected from: C4-C8cycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C5-C6cycloalkyl and phenyl, C5-C6cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocyclyl and phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl; preferably, Ring B is selected from phenyl, pyridyl, cyclohexyl; The ring C is selected from: C4-C6 cycloalkyl, 4-6 heterocyclic, 5-12 bridged cycloalkyl, 5-12 spirocyclic, 5-12 fused cycloalkyl, 5-10 heteroaryl, C6-C 10 Aryl; R 1 , R 2 , R 3 each independently is selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy; wherein said C1-C6alkyl, C1-C6alkoxy are optionally each independently substituted with 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6alkylamino, C1-C6alkoxy, O=; Each R a Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, C 3-6 Substitution of cycloalkyl groups; or two adjacent R groups. a The components are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, and O=. Preferably; each R a Independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from 1-3 of the following: deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C 3-6 Substitution of cycloalkyl groups; or two adjacent R groups. a The compounds are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1, 2, or 3 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, and O=. Each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, SF5; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally each independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, and O; preferably, each R b Independently selected from: C1-C6 alkyl, C1-C6 alkoxy, SF5; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1-6 substituents selected from deuterium and halogen; Each R c Independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=; preferably, each R c Independently selected from: hydrogen, deuterium, and halogens; Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-, -N(R) Y1 )-、-P(=O)(R Y1 )-;in, Each R Y1 Whether the same or different, each is independently selected from: hydrogen, C1-C4 alkyl; Y 2 is selected from the group consisting of: a bond, -C(=0)-, -S(=0)2-, -N(R Y2 )-, -Ci-C4alkylene-; wherein R Y2 is selected from the group consisting of: hydrogen, Ci-C4alkyl; L 1 is selected from: a bond, -N(R L1 )-, -C1-C4alkylene-; wherein R L1 is selected from: hydrogen, C1-C4alkyl; L 2 is selected from: a bond, -N(R L2 )-, -C1-C4alkylene-; wherein R L2 is selected from: hydrogen, C1-C4alkyl; L 3 is selected from: a bond, -N(R L3 )-, -C1-C4alkylene-; wherein R L3 is selected from: hydrogen, C1-C4alkyl; Indicates a triple bond, double bond, or key; when When representing a triple bond, R 2 and R 3 Does not exist; when When representing a key, structural unit express n, m, and p are each independently selected from: 0, 1, 2, 3, 4, and 5.

2. The compound according to claim 1, characterized in that, Ring A is selected from: 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenyl; Ring B is selected from: 5-10 membered heteroaryl, C 6-10 aryl, C5-C6cycloalkyl and phenyl, C5-C6cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocyclyl and phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl; preferably, Ring B is selected from phenyl; The ring C is selected from: C4-C6 cycloalkyl, 4-6 heterocyclic, 5-12 bridged cycloalkyl, 5-12 spirocyclic, 5-12 fused cycloalkyl, 5-10 heteroaryl, C6-C 10 Aryl; R 1 R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, and O; Each R a Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, C 3-6 Substitution of cycloalkyl groups; or two adjacent R groups. a The components are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, and O=. Preferably; each R a Independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally each independently selected from 1-3 of the following: deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C 3-6 Substitution of cycloalkyl groups; or two adjacent R groups. a The compounds are linked together to form C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl; wherein the C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl are optionally and independently substituted by 1, 2, or 3 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, and O=. Each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, SF5; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally each independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, and O; preferably, each R b Independently selected from: C1-C6 alkyl, C1-C6 alkoxy, SF5; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally each independently substituted by 1-6 substituents selected from deuterium and halogen; Each R c Independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=; preferably, each R c Independently selected from: hydrogen, deuterium, and halogens; Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-; Y 2 Selected from: key, -N(R) Y2 )-、-C1-C4 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl; L 1 Selected from: key, -N(R) L1 )-、-C1-C4 alkylene-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl; L 2 Selected from: key, -N(R) L2 )-、-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl; L 3 Selected from: key, -N(R) L3 )-、-C1-C4 alkylene-; wherein R L3 Selected from: hydrogen, C1-C4 alkyl; Indicates a triple bond or a double bond; when When representing a triple bond, R 2 and R 3 It does not exist; n, m, and p are each independently selected from: 0, 1, 2, 3, 4, and 5.

3. The compound according to claim 1, characterized in that, Ring A is selected from 5-6 membered heteroaryl, 5-6 membered saturated heterocyclic group, 5-6 membered partially unsaturated heterocyclic group, and phenyl; Preferably, ring A is selected from phenyl or 5-6-membered heteroaryl; the heteroatom of the 5-6-membered heteroaryl is selected from N, O and S, and the number of heteroatoms is selected from 1, 2 and 3; Preferably, ring A is selected from 5-6-membered heteroaryl groups; the heteroatoms of the 5-6-membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is selected from 1 and 2. Preferably, ring A is selected from 5-6-membered heteroaryl groups; the 5-6-membered heteroaryl group has 1 or 2 N heteroatoms and 0 or 1 heteroatoms selected from O and S; Preferably, It has the following structure: in, X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 Each is independently selected from: CH, N; E 1 E 2 E 3 E 4 E 5 E 6 Each is independently selected from: CH2, NH, O, S; Preferably, It has the following structure: in, X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 Each is independently selected from: CH, N; E 1 E 2 Each is independently selected from: CH2, NH, O, S.

4. The compound according to any one of claims 1-3, characterized in that, It has the following structure: Wherein, p' is selected from: 0, 1, 2, 3 or 4; preferably, p and p' are each independently selected from 0 or 1; more preferably, p and p' are both selected from 0; Preferably, It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Wherein, p' is selected from: 0, 1, 2, 3 or 4; preferably, p and p' are each independently selected from 0 or 1; more preferably, p and p' are both selected from 0.

5. The compound according to any one of claims 1-4, characterized in that, It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Among them, R aa Each is independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl; p1 is independently selected from 0, 1, and 2; preferably, p1 is selected from 0 or 1; more preferably, p1 is 0; Preferably, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl; Preferably, R aa Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R aa Each is independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R aa Each is independently selected from: hydrogen, deuterium, or methoxy.

6. The compound according to any one of claims 1-5, characterized in that, The ring C is C4-C6 saturated cycloalkyl, 4-6 membered saturated heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-12 membered bridged carbocyclic group, 5-12 membered spirocarbocyclic group, 5-12 membered fused carbocyclic group, 5-12 membered bridged heterocyclic group, 5-12 membered spiroheterocyclic group, 5-12 membered fused heterocyclic group, 5-10 membered heteroaryl group, C6-C 10 Aryl group; preferably, the ring C is a C4-C6 saturated cycloalkyl group, a 4-6 membered saturated heterocyclic group, a C4-C6 partially unsaturated cycloalkyl group, a 4-6 membered partially unsaturated heterocyclic group, a 5-12 membered bridged carbocyclic group, a 5-12 membered bridged heterocyclic group, a 5-12 membered spirocyclic group, a 5-12 membered fused heterocyclic group, a 5-10 membered heteroaryl group, or a C6-C 10 Aryl group; preferably, the ring C is selected from 4-6 membered saturated heterocyclic groups, 5-12 membered spiroheterocyclic groups, 5-10 membered heteroaryl groups, C6-C... 10 Aryl; Preferably, the ring C is selected from 4-6 membered saturated heterocyclic groups, 5-10 membered heteroaryl groups, and C6-C... 10 Aryl, 7-11 membered spiroheterocyclic groups; Preferably, the ring C is selected from 4-6 membered saturated heterocyclic groups, 5-6 membered heteroaryl groups, phenyl groups, and 7-9 membered spiroheterocyclic groups; Preferably, the ring C is selected from 4-6 member saturated heterocyclic groups, and the heteroatom is selected from nitrogen; Preferably, It has the following structure: in, c1 and c2 are each independently selected from: 0 and 1; c3, c4, c5, and c6 are each independently selected from: 0, 1, and 2; c7, c8, c9, and c10 are each independently selected from: 1 and 2; Preferably, It has the following structure: in, c1 and c2 are each independently selected from: 0 and 1; c7, c8, c9, and c10 are each independently selected from: 1 and 2; Preferably, It has the following structure:

7. The compound according to any one of claims 1-6, characterized in that, It has the following structure: Preferably, Selected from Preferably, for Among them, R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; n1 is independently selected from: 0, 1, 2; Preferably, R cc Each of the following elements is independently selected from: hydrogen, deuterium, fluorine, methyl, preferably hydrogen or deuterium; n1 is independently selected from: 0, 1, 2; preferably, n1 is 0; Preferably, Selected from The key marked with "1" is connected to Y. 2 The key marked with "2" is connected to L. 3 ; Preferably, Selected from Preferably, for 8. The compound according to any one of claims 1-7, characterized in that, Cycle B is selected from 5-10 heteroaryl groups, C 6-10 Aryl, C 4-8 cycloalkyl; Preferably, ring B is selected from 5-6 membered heteroaryl groups, C 6-8 Aryl, C 5-7 cycloalkyl; Preferably, ring B is selected from 6-membered nitrogen-containing aryl, phenyl, and cyclohexyl groups; Preferably, It has the following structure: Preferred Preferably, It has the following structure: Preferably, for Preferably, R b Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; Preferably, R b Selected from C1-C6 haloalkyl and C1-C6 haloalkoxy groups; Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; Preferably, each R b Independently selected from: trifluoromethyl, -SF5, -OCF3, -CF2Cl, -OCF2Cl; Preferably, each R b Independently selected from: trifluoromethyl, -OCF3, preferably trifluoromethyl; Preferably, m is 0, 1 or 2, and more preferably, m is 1.

9. The compound according to any one of claims 1-8, characterized in that, R 1 R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl, C1-C4 alkoxy are optionally independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, or O. Each R a Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino; wherein the -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino are optionally each independently separated by 1-3 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, O=, C 3-6 Cycloalkyl substitution; or two adjacent Rs a The groups are linked to form C4-C6 saturated cycloalkyl groups, 4-6 membered saturated heterocyclic groups, C4-C6 partially unsaturated cycloalkyl groups, 4-6 membered partially unsaturated heterocyclic groups, 5-6 membered heteroaryl groups, and phenyl groups; wherein the C4-C6 saturated cycloalkyl groups, 4-6 membered saturated heterocyclic groups, C4-C6 partially unsaturated cycloalkyl groups, 4-6 membered partially unsaturated heterocyclic groups, 5-6 membered heteroaryl groups, and phenyl groups are optionally and independently substituted with 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, or O; preferably, each R a Independently selected from: hydrogen, deuterium, halogen, cyano, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino; wherein the -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino are optionally each independently substituted by 1-3 deuterium, halogen, hydroxyl, cyano, C1-C4 alkylamino groups; or two adjacent R groups. a They can be linked together to form C4-C6 saturated cycloalkyl groups, 4-6 membered saturated heterocyclic groups, C4-C6 partially unsaturated cycloalkyl groups, 4-6 membered partially unsaturated heterocyclic groups, 5-6 membered heteroaryl groups, and phenyl groups; Each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, SF5; wherein the C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino are optionally each independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, or O; preferably, each R b Independently selected from: C1-C4 alkyl, C1-C4 alkoxy, SF5; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally each independently substituted with 1-6 deuterium or halogen; Each R c Independently selected from: hydrogen, deuterium, halogen, C1-C4 alkyl; wherein the C1-C4 alkyl is optionally substituted with 1-6 deuterium, halogen, amino, hydroxyl, cyano, or O=; Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-; Y 2 Selected from: key, -N(R) Y2 )-、-C1-C2 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl; L 1 Selected from key; L 2 Selected from key; L 3 Selected from key.

10. The compound according to any one of claims 1-9, characterized in that, The compound has the structure shown in formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13 or II-14; in, X 1 X 2 X 3 X 4 Each is independently selected from: CH, N; preferably, X 1 X 4 Let N, X 2 X 3 For CH, or X 1 X 2 X 3 For CH, X 4 Let N be the number of people in the group. X 9 X 10 Each is independently selected from: CH, N; E 1 and E 3 Each is independently selected from: CH2, NH, O, S; preferably, E 1 Selected from NH, O, and S; E 2 E 4 and E 5 Independently selected from: CH, N; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2; preferably, n1 is 0; c1 and c2 are each independently selected from: 0 and 1; c7, c8, c9, and c10 are each independently selected from: 1 and 2; Other symbols such as R 1 R 2 R 3 L 1 L 2 L 3 Y 1 Y 2 R a R b The definitions of m and p are the same as those in Equation I; Preferably, p is 0 or 1; Preferably, m is 0 or 1; Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

11. The compound according to any one of claims 1-10, characterized in that, The compound has the structure shown in formula iii-1, iii-2, iii-3, iii-4, iii-5, iii-6, iii-7, iii-8, iii-9, iii-10, iii-11, iii-12, iii-13, iii-14, iii-15, iii-16, iii-17, iii-18, iii-19, iii-20 or iii-21; in, X 1 X 2 X 3 X 4 Each is independently selected from: CH, N; preferably, X 1 X 4 Let N, X 2 X 3 For CH, or X 1 X 2 X 3 For CH, X 4 Let N be the number of people in the group. X 9 X 10 Each is independently selected from: CH, N; E 1 and E 3 Each is independently selected from: CH2, NH, O, S; preferably, E 1 Selected from NH, O, and S; E 2 E 4 and E 5 Independently selected from: CH, N; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2; preferably, n1 is 0; c1 and c2 are each independently selected from 0 and 1; preferably, c1 and c2 are 0. c7, c8, c9, and c10 are each independently selected from: 1 and 2; Other symbols such as R 1 R 2 R 3 L 1 L 2 L 3 R Y1 R Y2 R a R b The definitions of p and p are the same as those in Equation I; Preferably, p is 0 or 1; Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

12. The compound according to claim 10 or 11, characterized in that, in, Selected from the following structures: Preferably, Selected from the following structures: Preferably, Selected from the following structures: Selected from the following structures: Preferably, Selected from the following structures: Preferably, Selected from the following structures: Preferably, Selected from the following structures: Preferably, for Among them, R aa Each is independently selected from: hydrogen, deuterium, halogen, amino, hydroxyl, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl; p1 is independently selected from 0, 1, and 2; preferably, p1 is selected from 0 or 1; more preferably, p1 is 0; Preferably, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl; Preferably, R aa Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R aa Each is independently selected from: hydrogen, fluorine, chlorine, amino, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R aa Each is independently selected from: hydrogen, deuterium, or methoxy; preferably, R aa Each is independently selected from hydrogen or C1-C4 alkyl (e.g., methyl).

13. The compound according to any one of claims 1-12, characterized in that, The compound has any of the following structural formulas: Among them, R 1 R 2 R 3 R b E 4 E 5 R Y1 R Y2 L 1 L 2 L 3 The definitions of p, p1 and p1 are the same as those in any one of claims 1-11; n1 is 0, 1, or 2; preferably, n1 is 0. R a Each is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl; or two adjacent R a They connect to form C4-C6 saturated cycloalkyl groups; Preferably, R a Each is independently selected from hydrogen or C1-C6 alkyl groups; R aa Each is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; c1 and c2 are each independently selected from 0 and 1; preferably, both c1 and c2 are 0. Preferably, R Y1 Selected from hydrogen, methyl, or ethyl; Preferably, R Y2 Selected from hydrogen, methyl, or ethyl; Preferably, R 1 R 2 R 3 Each is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally each independently substituted by 1 to 6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), C1-C4 alkoxy, and O; Preferably, p is 0 or 1; Preferably, R a Each is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxyl-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted The C1-C4 alkoxy, hydroxyl and cyclopropyl substituted C1-C4 alkoxy, cyano and cyclopropyl substituted C1-C4 alkoxy, C1-C4 alkylamino substituted C1-C4 alkoxy, cyano substituted -NHC(O)C1-C4 alkyl, hydroxyl substituted -NHC(O)C1-C4 alkyl, cyano substituted -C(O)NHC1-C4 alkyl; or two adjacent Ra linked together to form cyclopentyl or cyclohexyl; Preferably, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl; Preferably, R a Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R aa Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl; Preferably, R b Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

14. The compound according to any one of claims 1-13, characterized in that, The compound has any of the following structural formulas: Among them, R b R Y1 R Y2 L 1 L 2 L 3 The definitions of p, p1 and p1 are the same as those in any one of claims 1-13; n1 is 0, 1, or 2; preferably, n1 is 0. R a Each is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl; or two adjacent R a They connect to form C4-C6 saturated cycloalkyl groups; R aa Each is independently selected from: hydrogen, deuterium, halogen, amino, -C(O)NHC1-C6 alkyl, -NHC(O)C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), C1-C6 alkoxy, O=, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkoxy. Amino-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, hydroxyl and cyclopropyl-substituted C1-C6 alkoxy, cyano and cyclopropyl-substituted C1-C6 alkoxy, C1-C6 alkylamino-substituted C1-C6 alkoxy, cyano-substituted -NHC(O)C1-C6 alkyl, hydroxyl-substituted -NHC(O)C1-C6 alkyl, cyano-substituted -C(O)NHC1-C6 alkyl; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; Preferably, R Y1 Selected from hydrogen, methyl, or ethyl; Preferably, R Y2 Selected from hydrogen, methyl, or ethyl; Preferably, R 1 R 2 R 3 Each group is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl and C1-C4 alkoxy groups are optionally independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), C1-C4 alkoxy, and O, for example: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino. Preferably, p is 0 or 1; Preferably, R a Each is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl; or two adjacent R a They connect to form cyclopentyl or cyclohexyl groups; Preferably, R aa Each is independently selected from: hydrogen, deuterium, cyano, halogen, amino, -C(O)NHC1-C4 alkyl, -NHC(O)C1-C4 alkyl, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino (e.g., di(C1-C4 alkyl)amino), halo-C1-C4 alkyl, halo-C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy, cyano-substituted C1-C4 alkoxy, hydroxy and cyclopropyl-substituted C1-C4 alkoxy, cyano and cyclopropyl-substituted C1-C4 alkoxy, C1-C4 alkylamino-substituted C1-C4 alkoxy, cyano-substituted -NHC(O)C1-C4 alkyl, hydroxy-substituted -NHC(O)C1-C4 alkyl, cyano-substituted -C(O)NHC1-C4 alkyl; Preferably, R a Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R aa Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl; Preferably, R b Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

15. The compound according to any one of claims 1-14, characterized in that, The compound has the structure shown in formulas a, b, c, d, e, f, g, h, i, or j: In equations a, b, c, d, e, f, g, h, i, and g, R a R b L 1 L 2 L 3 The definition is as defined in any one of claims 1-13; Preferably, R a Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)CH2CH3, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, 1-hydroxy-cyclopropylmethoxy, 1-cyano-cyclopropylmethoxy, dimethylamino, Preferably, R a Selected from hydrogen or C1-C4 alkyl (e.g., methyl); more preferably, R a Selected from hydrogen; Preferably, R b Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; preferably, R b Selected from C1-C6 haloalkyl (e.g., -CF3), C1-C6 haloalkoxy (e.g., -OCF3), more preferably, R b Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; Preferably, L 1 Selected from key; L 2 Selected from key; L 3 Selected from key.

16. The compound according to claim 1, characterized in that, The compound is selected from the group consisting of the following compounds:

17. A pharmaceutical composition comprising the compound of any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof; and a pharmaceutically acceptable carrier or diluent.

18. Use of any compound of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or pharmaceutical composition of claim 17 for the preparation of a medicament for treating cancer; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

19. Use of the compound of any one of claims 1-16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or the pharmaceutical composition of claim 17, for the preparation of a medicament for inhibiting cancer progression.

20. The use of any compound of claims 1-16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition of claim 17, for the preparation of a medicament for treating a disease or condition associated with increased TEAD expression.

21. The use of any compound of claims 1-16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition of claim 17, for the preparation of a medicament for treating a disease or condition associated with increased TEAD activity.

22. The use of any compound of claims 1-16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition of claim 17, for the preparation of a medicament for treating a disease or condition related to TEAD activity; wherein, Inhibiting TEAD activity would be beneficial for the aforementioned disease or condition.

23. Use of the compound of any one of claims 1-16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or the pharmaceutical composition of claim 17, in the preparation of a medicament for treating diseases or conditions related to the Hippo pathway; wherein, Inhibition of the Hippo pathway will be beneficial to the disease or condition.

24. The use according to any one of claims 18-23, wherein the disease or condition is a proliferative disease; preferably, the proliferative disease is cancer.

25. The use according to any one of claims 18-24, wherein the cancer is a cancer in which YAP is confined to the cell nucleus.

26. The use according to any one of claims 18-25, wherein the TEAD overexpression, increased TEAD expression, or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression, or increased TEAD1 activity; and / or The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD2 overexpression, increased TEAD2 expression, or increased TEAD2 activity; and / or The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD3 overexpression, increased TEAD3 expression, or increased TEAD3 activity; and / or The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD4 overexpression, increased TEAD4 expression, or increased TEAD4 activity.

27. Use of the compound of any one of claims 1-16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or the pharmaceutical composition of claim 17, for the preparation of a medicament having the activity of binding to TEAD and blocking the interaction between YAP / TEAD.

28. The use of any compound of claims 1-16, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites, pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, or prodrugs, or the pharmaceutical composition of claim 17, for the preparation of a medicament for treating a disease or condition; wherein the disease or condition is a disease or condition related to a protein that interacts with TEAD; preferably, the disease or condition related to the protein that interacts with TEAD includes, but is not limited to, cancer, metabolic diseases, inflammatory diseases, or neurodegenerative diseases; more preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelial carcinoma, etc. Tumors, melanomas, fibrosarcomas, bladder cancer, rectal cancer, lymphomas, cervical cancer, head and neck cancer, brain cancer, upper respiratory and digestive tract cancers, colorectal cancer, urinary tract cancer, or colon cancer; preferably, the cancers are selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, stomach cancer, breast cancer, or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, or undifferentiated carcinoma; even more preferably, the brain cancers include, but are not limited to, gliomas; head and neck cancers include, but are not limited to, head and neck squamous cell carcinoma; lung cancers include, but are not limited to, lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma, or non-small cell lung cancer; stomach cancers include, but are not limited to, gastric adenocarcinoma; breast cancers include, but are not limited to, ductal breast cancer, breast cancer, or HR+ breast cancer; prostate cancers include, but are not limited to, prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.

29. A method for inhibiting the interaction between TEAD and YAP; or for preventing and / or treating diseases mediated by the nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to antitumor drugs; or for reversing tumor cell resistance to antitumor drugs, comprising contacting the cells with or administering to the subject a compound as claimed in any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or a pharmaceutical composition as claimed in claim 17; Preferably, the subject is a mammal, more preferably a human.

30. The use of any compound of claims 1-16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition of claim 17, for inhibiting the interaction between TEAD and YAP; or for preventing and / or treating diseases mediated by the nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to antitumor drugs; or for reversing tumor cell resistance to antitumor drugs.

31. A method of treating cancer in a patient, comprising administering to the patient a compound of any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition as described in claim 17; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

32. A method for inhibiting cancer progression in a patient, comprising administering to the patient a compound of any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition as described in claim 17; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

33. A method of treating a patient with a disease or condition associated with increased TEAD expression, comprising administering to the patient a compound of any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition as described in claim 17.

34. A method of treating a patient suffering from a disease or condition associated with increased TEAD activity, comprising administering to the patient a compound of any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition as described in claim 16.

35. A method of treating a disease or condition in which inhibition of TEAD activity would be beneficial to said disease or condition, comprising administering to a patient a compound of any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition as described in claim 17.

36. A method of treating a disease or condition in which inhibition of the Hippo pathway would be beneficial to said disease or condition, comprising administering to a patient a compound of any one of claims 1-16 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug, or a pharmaceutical composition as described in claim 17.

37. The method according to any one of claims 31-36, wherein the disease or condition is a proliferative disease; preferably, the proliferative disease is cancer.

38. The method according to any one of claims 31-37, wherein the cancer is a cancer in which YAP is confined to the cell nucleus.

39. The method according to any one of claims 31-38, wherein the TEAD overexpression, increased TEAD expression, or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression, or increased TEAD1 activity; and / or The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD2 overexpression, increased TEAD2 expression, or increased TEAD2 activity; and / or The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD3 overexpression, increased TEAD3 expression, or increased TEAD3 activity; and / or The TEAD overexpression, increased TEAD expression, or increased TEAD activity refers to TEAD4 overexpression, increased TEAD4 expression, or increased TEAD4 activity.

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