Oxime-containing compound and application thereof

Abstract

The invention provides an oxime-containing compound and application thereof. The oxime-containing compound provided by the invention has a structure as shown in a formula (I) or enantiomers, diastereoisomers, racemate, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope labeled compounds or prodrugs of the structure as shown in the formula (I). The oxime-containing compound provided by the invention can be used for preventing and / or treating cancers and other hyperproliferative diseases and diseases related to Hippo pathway dysfunction. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 2023110591740 filed on August 21, 2023, and the entire text of the above-mentioned Chinese patent application is hereby cited as a part of this application. Technical Field

[0003] The present invention relates to the field of medicine, and in particular to an oxime-containing compound and a use thereof. Background Art

[0004] The Hippo pathway has become an effective target for the treatment of hyperproliferative disorders and diseases, especially 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. The 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 homolog 1 (SAV1) can phosphorylate and activate the effector protein, 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 the transcriptional coactivator with a PDZ binding motif (TAZ or WWTR1). When the Hippo pathway is "off", phosphorylated YAP / TAZ is retained 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 TEADNA-binding protein (TEAD1-4). Dysregulation of the Hippo pathway leads to increased activity of YAP / TAZ, which is associated with tumors, hyperproliferation, cell invasion, metastasis, and chemoresistance.

[0005] The TEAD transcription factor family is the final effector of the Hippo pathway, which regulates 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 a variety of solid tumors, including prostate cancer, gastric cancer, breast cancer, germ cell tumors, head and neck squamous cell carcinoma, renal cell carcinoma, etc. Due to its high correlation with clinical pathological parameters of human malignant tumors, TEAD can be used as a prognostic biomarker for solid tumors. As an important anti-tumor target discovered in the past decade, the Hippo pathway is a target for anti-tumor therapy. Compared with the regulators upstream of the Hippo signaling pathway, inhibitors targeting TEAD-YAP may more effectively and directly correct the dysregulated Hippo signaling pathway, thereby achieving the purpose of tumor treatment.

[0006] Therefore, cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction can be prevented and / or treated by targeting YAP, TAZ or TEAD, thereby inhibiting the protein-protein interaction of YAP-TEAD, TAZ-TEAD or other functional proteins with TEAD. Summary of the invention

[0007] In order to solve the above-mentioned technical problems existing in the prior art, the present invention provides an oxime-containing compound, which can prevent and / or treat cancers and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction by targeting YAP, TAZ or TEAD and inhibiting the protein-protein interaction between YAP-TEAD, TAZ-TEAD or other functional proteins and TEAD, and has good drug development prospects.

[0008] In one aspect, the present invention provides a compound having a structure as shown in formula (I), or being an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the structure as shown in formula (I);

[0009]

[0010] Ring A is selected from: 5-10 membered heteroaryl, C 6-10 Aryl, 5-6 membered heterocyclic group;

[0011] Ring B is selected from: C 3-8 Monocyclic alkyl, C 5-12 Bridged bicycloalkyl, C 5-12 Spirobicycloalkyl, C 5-12 Fused bicycloalkyl, C6-10 Aryl, 5-12 membered heteroaryl;

[0012] Z 1 Select from: O or NR z1 ; R z1 Selected from H, deuterium, C 1-6 alkyl;

[0013] R 1 Selected from: -NHS(=O) 2 -R 1a 、-NHC(=O)-R 1a 、-(4-6-membered nitrogen heterocyclic group)-C(=O)-R 1a , -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O) 2 NH-R 1a 、-NH-R 1a , C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)NH-R 1a 、-C(=O)NR 1a R 1b or -C(=O)-R 1a ; where R 1a and R 1b Each independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally, R 1a and R 1b Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring or a 5-12 membered aromatic heterocyclic ring; R 1a and R 1b C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, or R 1a and R 1b , together with the atoms to which they are attached, form a 3-12 membered heterocyclic ring or a 5-12 membered aromatic heterocyclic ring, each independently optionally substituted by 1, 2, 3 or 4 R 1c Replace, each R 1c are independently selected from halogen, oxo, hydroxy, C 1-6 Alkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; R 1c C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently substituted with halogen, oxo, hydroxyl, C 1-6 Alkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Substitution of cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl;

[0014] R 2 C 1-6 alkyl;

[0015] R 4 Each independently selected from: H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein R 4 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily replaced by 1, 2 or 3 selected from C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted; optionally, two R 4 , together with the atoms to which they are attached, form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring;

[0016] R 5 Each independently selected from: halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0017] Optionally, ring A and R 4 , CR 2 Together they form a parallel ring structure;

[0018] m is 0, 1, 2, 3 or 4;

[0019] n is 0, 1, 2, 3 or 4.

[0020] On the other hand, the present invention provides a pharmaceutical composition comprising the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug and at least one pharmaceutically acceptable carrier.

[0021] On the other hand, the present invention provides the use of the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or a combination thereof in the preparation of a medicament for inhibiting the protein-protein interaction between a functional protein and TEAD to prevent and / or treat cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

[0022] On the other hand, the present invention provides the use of the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or composition thereof in inhibiting the protein-protein interaction between functional protein and TEAD to prevent and / or treat cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

[0023] On the other hand, the present invention provides a method for preventing and / or treating cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction by inhibiting the protein-protein interaction between a functional protein and TEAD, comprising administering to a patient an effective amount of a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or a combination thereof.

[0024] Another aspect of the present invention relates to a method for preparing, separating and purifying a compound represented by formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs.

[0025] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical features in other embodiments, as long as they do not conflict.

[0026] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects 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. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0028] definition

[0029] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0030] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0031] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0032] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, 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.

[0033] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0034] The term "subject" refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0035] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0036] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0037] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. 2 O- is equivalent to -OCH 2 -.

[0038] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0039] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0040] The terms "racemate," "racemate" or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0041] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0042] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0043] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely. If the compound contains a double bond, the substituent may be in E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.

[0044] In the compounds of the general formula of the present application, the group Can be used with groups Used interchangeably to cover its Z type, E type and mixtures of the two.

[0045] In the general formula compounds and specific compounds of the present application, the group Can be used with Used interchangeably to cover its Z type, E type and mixtures of the two.

[0046] The stereochemical definitions and rules used in the present invention generally follow SP 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 optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its 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 left-handed. Compounds prefixed with (+) or d are right-handed. 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 a racemate and this may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0047] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain 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 terms of the (R)- or (S)-configuration.

[0048] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0049] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0050] Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. 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, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, 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).

[0051] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. A special example of an N-oxide is an N-oxide of a tertiary amine or an N-oxide of a nitrogen-containing heterocyclic nitrogen atom. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA).

[0052] The term "metabolite" refers to a product obtained by the metabolism of a specific compound or its salt in vivo. The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

[0053] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammals treated therewith. Preferably, the "pharmaceutically acceptable" of the present invention refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.

[0054] The term "pharmaceutically acceptable salt" refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or other methods described in books and literature, such as ion exchange methods, to obtain these salts. More pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts of compounds formed with bases, including, but not limited to, inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C 1-4 alkyl) 4 Salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, choline salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts and tromethamine salts.

[0055] Pharmaceutically acceptable acid addition salts can be formed by the compounds of the present invention and inorganic or organic acid, and pharmaceutically acceptable base addition salts can be formed by the compounds of the present invention and inorganic or organic base. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds, alkaline or acidic moieties. Generally speaking, such salts can be prepared by reacting the free acid forms 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 forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional 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", Stahland Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0056] The term "solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention. The solvent can be water, acetic acid, 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 mixed solvent 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, tert-butanol , sec-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropanol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, isopropylbenzene or a mixture thereof, etc.

[0057] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[0058] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (such as ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can form solvates with pharmaceutically acceptable solvents (including water) inherently or by design; therefore, the present invention is intended to include both solvated and unsolvated forms.

[0059] The term "ester" is represented by the formula -OC(=O)R or -C(=O)OR, wherein R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.

[0060] The term "isotopically labeled compound" means that a compound of the present invention is labeled with an isotope. It is identical to those compounds described herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 Oh, 17 Oh, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0061] Compounds of the present invention containing the aforementioned isotopic labels and / or other isotopic labels of other atoms and pharmaceutically acceptable salts of the compounds are all within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotope-labeled compounds, such as 3 H and 14 C incorporation into the compounds of the present invention can be used for drug and / or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, isotopes with larger mass numbers, such as deuterium, 2 H substitution may offer some therapeutic advantage of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0062] In addition, the substitution of heavier isotopes, particularly deuterium (i.e., 2H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improved therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of compounds of formula I to VI. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0063] The term "prodrug" used in the present invention represents a compound that is converted into a compound shown in Formula I in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to 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.

[0064] Unless explicitly stated otherwise, the descriptions used in the present invention such as "each...is independently" and "...are each independently" and "...are independently" are interchangeable and should be understood in a broad sense, which may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0065] The terms "optional", "optionally" or "arbitrarily", "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted with..." means that the substitution may or may not occur.

[0066] When the term "each independently" is used in combination with "arbitrarily", for example, "each independently arbitrarily replaced by..." means that specific options are replaced by... or not by... without affecting each other.

[0067] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0068] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 alkyl.

[0069] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a 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 the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0070] The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of S, N and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NRT (such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N). In the compounds involved in the present invention, when containing multiple heteroatoms, the compounds composed thereof conform to the covalent rules and composition rules of organic compounds, that is, the compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent rules and composition rules of organic compounds.

[0071] The term "heterocyclyl" or "heterocycle" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms and heteroatoms. The heteroatoms have the meanings as described herein. A heterocyclyl group may be fully saturated or contain one or more unsaturations, but may not have an aromatic ring. In one embodiment, a heterocyclyl group is a 3-6 membered ring, such as a 3-6 membered saturated or partially unsaturated heterocyclyl (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give, for example, SO, SO 2 ,PO,PO 2In one embodiment, the saturated or partially unsaturated heterocyclic group is selected from the group consisting of a saturated monocyclic heterocyclic group, a saturated bicyclic heterocyclic group, a saturated tricyclic heterocyclic group, a partially unsaturated monocyclic heterocyclic group, a partially unsaturated bicyclic heterocyclic group, and a partially unsaturated tricyclic heterocyclic group. Bicyclic heterocyclic groups refer to heterocyclic groups of bicyclic systems. Monocyclic heterocyclic groups refer to heterocyclic groups of monocyclic systems. 5-6 membered heterocyclic groups refer to heterocyclic groups with 5-6 ring atoms. 4-7 membered heterocyclic groups refer to heterocyclic groups with 4-7 ring atoms. 3-6 membered heterocyclic groups refer to heterocyclic groups with 3-6 ring atoms. A nitrogen heterocyclic group refers to a heterocyclic group containing nitrogen.

[0072] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms. The cycloalkyl group may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring. In one embodiment, the cycloalkyl group contains 3 to 8 carbon atoms, such as C 3-8 In one embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, such as C 3-6 Saturated or partially unsaturated cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. 3-8 Monocycloalkyl refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms in the ring. 5-12 The bridged bicyclic alkyl group refers to a bridged bicyclic cycloalkyl group having 5 to 12 carbon atoms in the ring. 5-12 Spirobicycloalkyl refers to a spirobicyclic cycloalkyl group with 5 to 12 carbon atoms in the ring. 5-12 The fused bicycloalkyl group refers to a fused bicyclic cycloalkyl group having 5 to 12 carbon atoms in the ring.

[0073] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic and tricyclic aromatic system containing heteroatoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroatoms have the definition described in the present invention. In some embodiments, the heteroaryl group is a heteroaryl group composed of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-10-membered heteroaryl group; the heteroaryl group is a heteroaryl group composed of 5-8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-8-membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group composed of 5-7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-7-membered heteroaryl group. ; 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.

[0074] The term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". 6-10 membered aryl refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl, naphthyl, etc.

[0075] The term "hydrogen" means 1 H; "deuterium" means 2 H.

[0076] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0077] The term "amino" refers to -NH 2 .

[0078] The term "hydroxy" refers to -OH.

[0079] The term "cyano" refers to -CN.

[0080] The term "nitro" refers to -NO 2 .

[0081] The term "carboxyl" refers to HO(C=O)-.

[0082] The term "oxo" refers to O=, that is, when the substituent is O=, O is connected to the substituted group at a suitable position through a double bond.

[0083] The term "alkyl" or "alkyl group" refers to a saturated, straight-chain or branched hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C 1-3 Alkyl. 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 the like.

[0084] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon group containing carbon atoms, wherein at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, includes "cis" and "tans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-6 carbon atoms, i.e., C 2 -C 6 In another embodiment, the alkenyl group contains 2-4 carbon atoms, i.e., C 2 -C 4 Examples of alkenyl groups include, but are not limited to, vinyl (—CH═CH 2 ), allyl (-CH 2 CH=CH 2 ),etc.

[0085] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing carbon atoms, wherein at least one site of unsaturation, i.e., one carbon-carbon sp triple bond, is present. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms, i.e., C 2 -C 6 In another embodiment, the alkynyl group contains 2-4 carbon atoms, i.e., C 2 -C 4 Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propargyl (—CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 ),etc.

[0086] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C 1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C 1-3 Alkoxy.

[0087] The term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or ingredients from the drug (or, in the case of a method, a step). The phrase "consisting of excludes any element, step, or ingredient not specified in the drug (or, in the case of a method, a step). The phrase "consisting essentially of refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the drug (or, in the case of a method, a step).

[0088] For the sake of brevity, when describing the same part in multiple groups, the same part is extracted and described separately; for example, R y Selected from: -NHS(=O) 2 -C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -S(=O) 2 NH-C 1-4 Alkyl, -NH-C 1-4 Alkyl, C 1-4 Alkyl; when R y C in each option 1-4 When describing an alkyl group, R y C 1-4 Alkyl, which is equivalent to "-NHS(=O) 2 -C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -S(=O) 2 NH-C 1-4 Alkyl, -NH-C 1-4 Alkyl, C 1-4 -C in the alkyl group 1-4 alkyl.

[0089] As described herein, the ring system formed by substituent R connected to the central ring by a bond represents that the substituent R is substituted at any substitutable or any reasonable position on ring A or ring B. For example, formula f represents any possible substituted position on ring A or ring B, as shown in formulas f1-f8:

[0090]

[0091] As described herein, a substituent is connected to a central ring by a bond to form a ring system, such as (R x ) n , represents n substituents R x Substitution can be made at any substitutable position on the ring. For example, formula a represents a benzene ring which can be substituted with n R x replace.

[0092]

[0093] The term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0094] Description of the compounds of the present invention

[0095] The present invention provides a compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which plays an active role in inhibiting the protein-protein interaction between functional protein and TEAD to prevent and / or treat cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

[0096] In one aspect, the present invention provides a compound having a structure as shown in formula (I), or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof;

[0097]

[0098] Ring A is selected from: 5-10 membered heteroaryl, C 6-10 Aryl, 5-6 membered heterocyclic group;

[0099] Ring B is selected from: C 3-8 Monocyclic alkyl, C 5-12 Bridged bicycloalkyl, C 5-12 Spirobicycloalkyl, C 5-12 Fused bicycloalkyl, C 6-10 Aryl, 5-12 membered heteroaryl;

[0100] Z 1 Select from: O or NR z1 ; R z1 Selected from H, deuterium, C 1-6 alkyl;

[0101] R 1 Selected from: -NHS(=O) 2-R 1a 、-NHC(=O)-R 1a 、-(4-6-membered nitrogen heterocyclic group)-C(=O)-R 1a , -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O) 2 NH-R 1a 、-NH-R 1a , C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)NH-R 1a 、-C(=O)NR 1a R 1b or -C(=O)-R 1a ; where R 1a and R 1b Each independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally, R 1a and R 1b Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring or a 5-12 membered aromatic heterocyclic ring; R 1a and R 1b C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, or R 1a and R 1b , together with the atoms to which they are attached, form a 3-12 membered heterocyclic ring or a 5-12 membered aromatic heterocyclic ring, each independently optionally substituted by 1, 2, 3 or 4 R 1c Replace, each R 1c are independently selected from halogen, oxo, hydroxy, C 1-6 Alkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; R 1c C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently substituted with halogen, oxo, hydroxyl, C 1-6 Alkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Substitution of cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl;

[0102] R 2 C 1-6 alkyl;

[0103] R 4 Each independently selected from: H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein R 4 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily replaced by 1, 2 or 3 selected from C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted; optionally, two R 4 , together with the atoms to which they are attached, form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring;

[0104] R 5 Each independently selected from: halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0105] Optionally, ring A and R 4 , CR 2 Together they form a parallel ring structure;

[0106] m is 0, 1, 2, 3 or 4;

[0107] n is 0, 1, 2, 3 or 4.

[0108] In some embodiments, Ring A is selected from: 5-10 membered heteroaryl, C 6-10 Aryl or 5-6 membered heterocyclic group.

[0109] In some embodiments, Ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a phenyl group, or a 6-membered heterocyclyl group.

[0110] In some embodiments, Ring A is # indicates the same as R 1 * indicates the connection with CR 2 The connection point, X 1 N or CR 41 ;X 2 N or CR 42 ;X 3 N or CR 43 ;X 4 N or CR 44 ;X 5 is S, O or NH; R 41 , R 42 , R 43 and R 44 Each independently selected from: H, deuterium, halogen, C 1-6 Alkyl, C 1-6 alkoxy, 5-6 membered heteroaryl or phenyl; wherein R 41 , R 42 , R 43 and R 44 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily replaced by 1, 2 or 3 selected from C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted; optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44 , when in the ortho position, together with the atoms to which they are connected, form a 5-6 membered carbocyclic group, a 5-6 membered heterocyclic group, a phenyl group or a 5-6 membered heteroaryl group.

[0111] In some embodiments, R 41 , R 42 , R 43 and R 44 Each independently selected from: H, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 alkoxy, 5-6 membered heteroaryl or phenyl; wherein R 41 , R 42 , R 43 and R 44 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily substituted by 1, 2 or 3 substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy; optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44, when in the ortho position, together with the atoms to which they are connected, form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group.

[0112] In some embodiments, R 41 , R 42 , R 43 and R 44 Each is independently selected from: H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenyl, Optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44 , when in the adjacent position, together with the atoms to which they are attached, form

[0113] In some embodiments, R 41 , R 42 , R 43 and R 44 are each independently selected from: H, deuterium, fluorine, methyl or methoxy; optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44 , when in the adjacent position, together with the atoms to which they are attached, form

[0114] In some embodiments, Ring A is Where # indicates the same as R 1 Connection, * indicates CR 2 Connection, X 1 , X 2 , X 3 and X 4 Has the definition described in the present invention.

[0115] In some embodiments, Ring A is Among them, # indicates that R 1 Connection, * indicates CR 2 Connection, X 1 , X 2 and X 5 Has the definition described in the present invention.

[0116] In some embodiments, ring A and R 4 , CR 2 Together they form a ring structure, the ring structure being selected from Indicates the connection with N in NO group, # indicates the connection with R1 The position of the bonding; optionally, the hydrogen on the carbon or nitrogen in the ring structure can be selected from deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-4 The alkoxy group is substituted with one or more substituents, wherein the substituted C 1-6 The substituents in the alkyl group are selected from deuterium, fluorine, chlorine, bromine, cyano and hydroxyl.

[0117] In some embodiments, ring A and R 4 , CR 2 Together they form a ring structure, the ring structure being selected from Optionally, the hydrogen on the carbon or nitrogen in the cyclic structure can be selected from deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 The alkoxy group is substituted with one or more substituents, wherein the substituted C 1-4 The substituents in the alkyl group are selected from fluorine, chlorine, bromine, cyano and hydroxy.

[0118] In some embodiments, ring A and R 4 , CR 2 Together they form a ring structure, the ring structure being selected from Optionally, the hydrogen on the carbon or nitrogen in the cyclic structure can be selected from deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 The alkoxy group is substituted with one or more substituents, wherein the substituted C 1-4 The substituents in the alkyl group are selected from deuterium, fluorine, chlorine, bromine, cyano and hydroxyl.

[0119] In some embodiments, ring A and R 4 , CR 2 Together we form In other embodiments, ring A and R 4 , CR 2 Together we form

[0120] In some embodiments, ring A is selected from: phenyl, pyridyl, pyrimidyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, furanyl or thiadiazolyl. In some embodiments, ring A is selected from: phenyl, pyridyl, pyrimidyl, thienyl or thiazolyl. In some embodiments, ring A is selected from: pyridyl, thienyl or thiazolyl.

[0121] In some embodiments, Ring A is selected from: # indicates the same as R 1* indicates the connection with CR 2 connection.

[0122] In some embodiments, Ring A is selected from: # indicates the same as R 1 * indicates the connection with CR 2 connection.

[0123] In some embodiments, Ring B is selected from: C 3-8 Monocyclic alkyl, C 5-12 Bridged bicycloalkyl, C 5-12 Spirobicycloalkyl, C 5-12 Fused bicycloalkyl or C 6-10 In some embodiments, ring B is selected from: C 3-6 Monocyclic alkyl, C 5-10 Bridged bicycloalkyl, C 5-10 Spirobicycloalkyl, C 5-10 Fused bicycloalkyl, phenyl, pyridyl or pyrimidinyl.

[0124] In some embodiments, Ring B is selected from the group consisting of: cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, phenyl, pyridyl,

[0125] In some embodiments, Ring B is selected from the group consisting of: cyclobutyl, cyclohexyl, cyclohexenyl, phenyl, pyridinyl,

[0126] In some embodiments, Ring B is selected from: cyclobutyl, cyclohexyl, or phenyl. In some embodiments, Ring B is cyclobutyl. In some embodiments, Ring B is cyclohexyl. In some embodiments, Ring B is phenyl.

[0127] In some embodiments, Z 1 Select from: O or NR z1 ; R z1 Selected from H, deuterium, C 1-6 In some embodiments, Z 1 Select from: O or NR z1 ; R z1 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, and butyl. 1 Select from: O or NR z1 ; R z1 is selected from H. In some embodiments, Z 1 Selected from: O.

[0128] In some embodiments, R 1 Selected from: -NHS(=O) 2 -R 1a 、-NHC(=O)-R1a 、-(4-6-membered nitrogen heterocyclic group)-C(=O)-R 1a , -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O) 2 NH-R 1a 、-NH-R 1a , C 1-4 Alkyl, C 1-4 Alkoxy, -C(=O)NH-R 1a 、-C(=O)NR 1a R 1b or -C(=O)-R 1a ; where R 1a and R 1b Each independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally, R 1a and R 1b , together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or a 5-10 membered aromatic heterocyclic ring; R 1a and R 1b C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, or R 1a and R 1b , together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or a 5-10 membered aromatic heterocyclic ring, each independently optionally substituted by 1, 2, 3 or 4 R 1c Replace, each R 1c are independently selected from halogen, oxo, hydroxy, C 1-4 Alkyl, halogen, amino, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)(C 1-4 alkyl), -NHC(=O)OC 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; R 1c C 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)(C 1-4 alkyl), -NHC(=O)OC 1-4Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently substituted with halogen, oxo, hydroxyl, C 1-4 Alkyl, halogen, amino, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)(C 1-4 alkyl), -NHC(=O)OC 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 The substituents of the cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are substituted.

[0129] In some embodiments, R 1a and R 1b Not at the same time as hydrogen.

[0130] In some embodiments, R 1b is hydrogen, R 1a Selected from: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, R 1a Optionally 1, 2, 3 or 4 R 1c Replace, each R 1c are independently selected from halogen, oxo, hydroxy, C 1-4 Alkyl, halogen, amino, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)(C 1-4 alkyl), -NHC(=O)OC 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; R 1c C 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)(C 1-4 alkyl), -NHC(=O)OC 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently substituted with halogen, oxo, hydroxyl, C 1-4 Alkyl, halogen, amino, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)(C 1-4alkyl), -NHC(=O)OC 1-4 Alkyl, C 1-4 Alkoxy, phenyl, C 3-6 The substituents of the cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are substituted.

[0131] In some embodiments, R 1b is hydrogen, R 1a Selected from: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, R 1a Optionally substituted by 1, 2, 3 or 4 groups selected from halogen, oxo, fluoro, hydroxy, amino, C 1-4 Hydroxyalkyl, C 1-4 Alkyl, C 1-4 The substituents are substituted by alkoxy and 5-6 membered nitrogen-containing heteroaryl.

[0132] In some embodiments, R 1b is hydrogen, R 1a Selected from: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, R 1a Optionally substituted with 1, 2, 3 or 4 substituents selected from halo, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl.

[0133] In some embodiments, R 1 Selected from: -NHS(=O) 2 -C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(4-6 membered nitrogen heterocyclic group)-C(=O)-C 1-6 Alkyl, -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O) 2 NH-C 1-6 Alkyl, -S(=O) 2 NH-C 2-6 Alkenyl, -S(=O) 2 NH-C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -NH-C 5-6 Cycloalkyl, -NHS(=O) 2 -C 2-6Alkenyl, -NHC(=O)-C 2-6 Alkenyl, -NHS(=O) 2 -C 2-6 Alkynyl, -NHC(=O)-C 2-6 Alkynyl, C 1-6 Alkyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 1-6 Alkoxy, -C(=O)NH-C 3-6 Cycloalkyl or -C(=O)NH-(3-6 membered heterocyclic group); wherein R 1 C 1-6 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from halogen, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 The substituents of the cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are substituted.

[0134] In some embodiments, R 1 Selected from: -NHS(=O) 2 -C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O) 2 NH-C 1-4 Alkyl, -S(=O) 2 NH-C 2-4 Alkenyl, -S(=O) 2 NH-C 2-4 Alkynyl, -NH-C 1-4 Alkyl, -NH-C 5-6 Cycloalkyl, -NHS(=O) 2 -C 2-4 Alkenyl, -NHC(=O)-C 2-4 Alkenyl, -NHS(=O) 2 -C 2-4 Alkynyl, -NHC(=O)-C 2-4Alkynyl, C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkoxy, -C(=O)NH-C 3-6 Cycloalkyl or -C(=O)NH-(3-6 membered heterocyclic group); wherein R 1 C 1-4 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, C 2-4 Alkenyl, C 2-4 Alkynyl, C 5-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl.

[0135] In some embodiments, R 1 C(=O)NR 1a R 1b In some embodiments, R 1 Selected from the group consisting of:

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144] In some embodiments, R 1 Selected from: trifluoromethyl, -NHS(=O) 2 -CH 3 、-S(=O) 2 NH-CH 3 、-NHC(=O)-CH 3 , -C(=O)OH, -NHC(=O)-CH=CH 2 、-NHC(=O)-CF=CH 2 、-NHS(=O)2 -CH=CH 2 、-NHS(=O) 2 -CF=CH 2 、-C(=O)NH-CH(CH 3 )CH 2 OH, -C(=O)NH-CH(CH 3 )CH 2 OCH 3 、-C(=O)NH-CH(CH 3 )-pyridyl, -C(=O)NH-CH(phenyl)-CH 2 OH, -C(=O)NH-cyclobutyl-hydroxy, -C(=O)NH-cyclobutyl-methoxy, -C(=O)NH-tetrahydropyranyl, -C(=O)NHCH 3 、-C(=O)NH-O-CH(CH 3 )CH 2 OH, -C(=O)NH-C(CH 3 ) 2 CH 2 OH, -C(=O)NH-CH(CH 3 )-Pyridinyl-NH 2 、-C(=O)NH-CH(pyridyl)-CH 2 OH, -C(=O)NH-CH(isopropyl)-CH 2 OH, -C(=O)NH-cyclobutyl-CH 2 OH, -C(=O)NH-CH(CH 2 CH 3 )CH 2 OH, -C(=O)NH-fluorocyclobutyl-CH 2 OH,

[0145] In some embodiments, R 1 Selected from: trifluoromethyl, -NHS(=O) 2 -CH 3 、-S(=O) 2 NH-CH 3 、-NHC(=O)-CH=CH 2 、-NHC(=O)-CF=CH 2 、-NHS(=O) 2 -CH=CH 2 、-C(=O)NH-CH(CH 3 )CH 2 OH, -C(=O)NH-CH(CH 3 )CH2 OCH 3 、-C(=O)NH-CH(CH 3 )-pyridinyl, -C(=O)NH-CH(pyridinyl)-CH 2 OH, -C(=O)NH-CH(isopropyl)-CH 2 OH, -C(=O)NH-CH(CH 2 CH 3 )CH 2 OH, -C(=O)NH-C(CH 3 ) 2 CH 2 OH,

[0146] In some embodiments, R 1 Selected from: -C(=O)NH-CH(CH 3 )CH 2 OH, -C(=O)NH-CH(CH 3 )CH 2 OCH 3 、-NHC(=O)-CH=CH 2 、-NHC(=O)-CF=CH 2 、-C(=O)NH-C(CH 3 ) 2 CH 2 OH, -C(=O)NH-CH(isopropyl)-CH 2 OH or

[0147] In some embodiments, R 1 Selected from: -NHC(=O)-CF=CH 2 、-C(=O)NH-C(CH 3 ) 2 CH 2 OH, -C(=O)NH-CH(isopropyl)-CH 2 OH or

[0148] In some embodiments, R 2 C 1-6 In some embodiments, R 2 C 1-4 In some embodiments, R 2 C 1-3 In some embodiments, R 2 is methyl or ethyl. In some embodiments, R 2 It is methyl.

[0149] In some embodiments, R 4 Each independently selected from: H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein R 4 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily replaced by 1, 2 or 3 selected from C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted; optionally, two R 4 , together with the atoms to which they are connected, form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring.

[0150] In some embodiments, R 4 Each independently selected from: H, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein R 4 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily substituted by 1, 2, or 3 substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy, and isopropoxy; optionally, two R in the ortho position 4 , together with the atoms to which they are connected, form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring.

[0151] In some embodiments, R 4 Each is independently selected from: H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenyl, 1-methyl-imidazol-4-yl Optionally, two R in ortho position 4 , together with the atoms to which they are attached, form

[0152] In some embodiments, R 4 Each independently selected from: H, deuterium, fluorine, methyl, methoxy; optionally, two R in ortho position 4 , together with the atoms to which they are attached, form

[0153] In some embodiments, R 5 Each independently selected from: halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 In some embodiments, R 5 Each independently selected from: halogen, halogenated C 1-4 Alkyl, halogenated C 1-4 In some embodiments, R 5 Each is independently selected from: fluorine, trifluoromethyl, trifluoromethoxy. In some embodiments, R 5 In some embodiments, R5 Each is independently selected from: trifluoromethyl and trifluoromethoxy.

[0154] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1.

[0155] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0156] In some specific embodiments, the compound of the present invention has a structure represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or is an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the structure represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX);

[0157]

[0158]

[0159] Among them, R 1a , R 1b , R 2 , R 5 , X 1 , X 2 , X 3 , X 4 , X 5 , p and n have the definitions described in the present invention.

[0160] In some embodiments, in Formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX):

[0161] X 1 N or CR 41 ;X 2 N or CR 42 ;X 3 N or CR 43 ;X 4 N or CR 44 ;X 5 O, S or NH; R 41 , R 42 , R 43 and R44 Each independently selected from: H, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein R 41 , R 42 , R 43 and R 44 The 5-6 membered heteroaryl and phenyl are each independently substituted by 1, 2 or 3 substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy; optionally, in formula III, R 41 and R 44 , together with the atoms to which they are attached, form a 5-6 membered heterocyclyl, a 5-6 membered heteroaryl; or optionally, in Formula IV, R 41 and R 44 , or R 41 and R 42 , together with the atoms to which they are attached, form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl;

[0162] p is each independently 1, 2 or 3; n is each independently 1 or 2;

[0163] R 1a and R 1b The definition of is the same as that of the present invention; R 2 and R 5 The definition of is the same as that of the present invention mentioned above.

[0164] In some embodiments, in Formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX): R 1a and R 1b are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein R 1a and R 1b C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclylphenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl.

[0165] In some embodiments, in Formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX): R 1a and R 1b are independently hydrogen, -CH 3 、-CH=CH 2 、-CF=CH 2 、-CH(CH 3 )CH 2 OH, -CH(CH 3 )CH 2 OCH 3 、-CH(CH 3 )-pyridinyl, -CH(phenyl)-CH 2 OH, -cyclobutyl-hydroxy, -cyclobutyl-methoxy, -tetrahydropyranyl, O-CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH(CH 3 )-Pyridinyl-NH 2 、-CH(pyridyl)-CH 2 OH, -CH(isopropyl)-CH 2 OH, -cyclobutyl-CH 2 OH, -CH(CH 2 CH 3 )CH 2 OH, -fluorocyclobutyl-CH 2 OH.

[0166] In some embodiments, in Formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX): R 1a and R 1b Not hydrogen at the same time.

[0167] In some embodiments, R 1b is hydrogen, R 1a for

[0168] In some embodiments, R 41 , R 42 , R 43 and R 44 Each is independently selected from: H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenyl, 1-methyl-imidazol-4-yl

[0169] In some embodiments, R 41 , R42 , R 43 and R 44 Each is independently selected from: H, deuterium, fluorine, methyl, methoxy.

[0170] In some embodiments, the compounds of the present invention have the structure shown in the above formula (II) or are enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs of the structure shown in the above formula (II).

[0171] In some embodiments, the compounds of the present invention have the structure shown in the above formula (V) or are enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs of the structure shown in the above formula (V).

[0172] In some specific embodiments, the compound of the present invention has a structure represented by formula (I-1) or (I-2), or is an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the structure represented by formula (I-1) or (I-2);

[0173]

[0174] Among them, R 1a , X 2 , R 2 , R 5 , n and p have the same meanings as defined herein before.

[0175] In some embodiments, in formula (I-1), R 1a C 1-4 Alkyl or C 3-6 Cycloalkyl, R 1a C 1-4 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl; X 2 N or CH; R 2 C 1-3 Alkyl, such as methyl, ethyl; R 5 Each independently selected from fluorine, fluorinated C 1-4 Alkyl and fluorinated C 1-4 Alkoxy; n is 1 or 2.

[0176] In some embodiments, in formula (I-1), R 1a for In some embodiments, in formula (I-1), R 2 In some embodiments, in formula (I-1), R 5 Each is independently selected from trifluoromethyl and trifluoromethoxy. In some embodiments, in formula (I-1), n ​​is 1.

[0177] In some embodiments, in formula (I-2), R 1a C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl, where R 1a C 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Each alkynyl group is independently optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl; R 2 C 1-3 Alkyl, for example, methyl or ethyl, R 5 Each independently selected from fluorine, fluorinated C 1-4 Alkyl and fluorinated C 1-4 Alkoxy, preferably fluorine, trifluoromethyl and trifluoromethoxy; p is 1, 2 or 3; n is 1 or 2.

[0178] In some embodiments, in formula (I-2), R 1a Halogenated C 2-4 Alkenyl, e.g. In some embodiments, in formula (I-2), R 2 In some embodiments, in formula (I-2), R 5 Each is independently selected from fluorine, trifluoromethyl and trifluoromethoxy. In some embodiments, in formula (I-2), R 5 In some embodiments, in formula (I-2), p is 1 or 3. In some embodiments, in formula (I-2), n is 2.

[0179] In some specific embodiments, the compound of the present invention has a structure represented by formula (I-3) or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug;

[0180]

[0181] In formula (I-3), X 1 is N or CH; X 2 N or CH; R 2 is selected from methyl or ethyl; R 5 Each is independently selected from fluorine, trifluoromethyl and trifluoromethoxy; n is 1 or 2.

[0182] In some embodiments, in formula (I-3), X 1 CH; X 2 It is N or CH.

[0183] In some embodiments, in formula (I-3), R 2 It is methyl.

[0184] In some embodiments, in formula (I-3), R 5 Each is independently selected from trifluoromethyl and trifluoromethoxy.

[0185] In some embodiments, in formula (I-3), n is 1.

[0186] In some specific embodiments, the compounds of the present invention have the structures shown below or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs;

[0187]

[0188]

[0189]

[0190]

[0191]

[0192] Pharmaceutical compositions and methods of administration

[0193] The present invention relates to a pharmaceutical composition, which comprises the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, labeled compound or prodrug; and at least one pharmaceutically acceptable carrier.

[0194] The present invention relates to a pharmaceutical composition, which comprises the compound or its stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0195] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers and diluents, and further excipients such as excipients, binders, fillers, and additional therapeutic agents. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0196] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0197] The present invention also relates to a pharmaceutical composition comprising as an active ingredient a compound of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or a pharmaceutically acceptable salt thereof, which can be used in particular for the treatment of neoplastic diseases, in particular cancer, as described herein. The composition can be formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or in particular for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (coated where applicable), 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, in particular humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions may contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0198] The compound of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or a pharmaceutically acceptable salt thereof can be processed with a pharmaceutically inert inorganic or organic excipient 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 its derivatives, binders such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, flow agents such as fumed 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, semisolid and liquid polyols and the like.

[0199] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0200] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0201] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0202] The dosage can vary within wide limits and, of course, will be in accordance with individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 1 to 1000 mg of a compound of formula I per person should be appropriate, although the above lower or upper limits may also be exceeded if necessary.

[0203] The compounds of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) may also be used in combination with one or more other pharmacologically active compounds which are also effective against the same disease, preferably using a different mode of action, or which reduce or prevent possible undesirable side effects of the compounds of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX). The combination partners may be administered simultaneously in such treatment, for example by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms, each containing one or more than one combination partner.

[0204] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In a non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, inhibiting, preventing and / or ameliorating cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

[0205] The term "treatment" or "treating" as used herein in the context of treating a disease or disorder generally relates to treatment and therapy of humans or animals (e.g., in veterinary applications), wherein some desired therapeutic effects are obtained, e.g., inhibiting the progression of a disease or disorder, and including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving a disease or disorder, and curing a disease or disorder. Treatment as a preventive measure (i.e., prevention) is also included. For example, patients who have not yet developed the disease or disorder but are at risk of developing the disease or disorder are covered by the term "treatment". For example, treatment includes prevention of cancer, reducing the incidence of cancer, alleviating cancer symptoms, etc.

[0206] In some embodiments, the present invention provides a compound or pharmaceutical composition of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or a pharmaceutically acceptable salt thereof for use in inhibiting protein-protein interaction between functional proteins and TEAD to prevent and / or treat cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

[0207] In some embodiments, the present invention provides a compound or pharmaceutical composition of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or a pharmaceutically acceptable salt thereof for the preparation of a method for inhibiting protein-protein interaction between a functional protein and TEAD to prevent and / or treat cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

[0208] In some embodiments, the present invention provides a method for preventing and / or treating cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction by inhibiting protein-protein interaction between a functional protein and TEAD, the method comprising administering to a patient a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the functional protein includes YAP and / or TAZ.

[0210] In some embodiments, the present invention provides a method of treating cancer and other hyperproliferative disorders and diseases.

[0211] In some embodiments, the cancers described herein include, but are not limited to, carcinoma, sarcoma, leukemia, myeloma, lymphoma, and cancers of the brain and spinal cord.

[0212] In some embodiments, cancers and other hyperproliferative disorders and diseases that can be treated with the compounds of the present invention can include, but are not limited to, breast cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, brain cancer, kidney cancer, testicular cancer, urethral cancer, rectal cancer, fallopian tube cancer, penis cancer, vaginal cancer, stomach cancer, skin cancer, melanoma, liver cancer, gastrointestinal stromal tumors, urothelial cancer, thyroid cancer, parathyroid cancer, adrenal cancer, bone cancer, oral cancer, ovarian cancer, uterine cancer, head and neck squamous cell carcinoma, endometrial cancer, gallbladder cancer, bladder cancer, oropharyngeal cancer, lymph node cancer, glioblastoma, astrocytoma, glioblastoma multiforme, or soft tissue sarcoma, fibrosarcoma, chondrosarcoma, hemangioma, teratoma, lipoma, myxoma, fibroma, rhabdomyoma, teratoma, bile duct cancer, Ewing's sarcoma.

[0213] In some embodiments, examples of leukemias that can be treated with the compounds of the present invention can include, but are not limited to, lymphoblastic T cell leukemia, chronic myelogenous leukemia, acute lymphoblastic T cell leukemia, acute myeloid leukemia, hairy-cell leukemia, chronic neutrophilic leukemia, mantle cell leukemia, acute megakaryocytic leukemia, multiple myeloma, megakaryoblasticleukemia, erythroleukemia, plasmacytoma, promyelocytic leukemia, leukemia, chronic myelomonocytic leukemia, myelodysplastic syndrome, myelofibrosis, chronic myelogenous leukemia, polycythemia vera, thrombocythemia, chronic lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia, Waldenstrom's macroglobulinemia, Castleman's disease, chronic neutrophilic leukemia, immunoblastic large cell leukemia, plasma cell neoplasm, and leukemia in any other part of the body.

[0214] In some embodiments, examples of lymphomas that can be treated with the compounds of the present invention can include, but are not limited to, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt's lymphoma, lymphoblastic T-cell lymphoma, marginal zone lymphoma, cutaneous T cell lymphoma, CNS lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (Peripheral T-cell lymphoma), T-cell lymphoma, anaplastic large cell lymphoma, primary mediastinal lymphoma, mycosis fungoides, small non-cleaved cell lymphoma, lymphoblastic lymphoma, immunoblastic lymphoma, primary effusion lymphoma and HIV-related (or AIDS-related) lymphoma. The above solid tumors can be modeled using the methods and cell lines described in the examples.

[0215] Synthesis method

[0216] Compounds of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) can be synthesized by the methods given below, by the methods given in the experimental section below, or by analogous methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds of formula (I), (I-1), (I-2), (I-3), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX); rather, other techniques known to the skilled chemist may also be used for compound synthesis.

[0217] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or / and 19 F-NMR). 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19 F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvent used was deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD or MeOH-d 4 ) or deuterated dimethyl sulfoxide (DMSO-d6). TMS (0 ppm) or chloroform (7.25 ppm) is used as the reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), brs (broadened singlet). The coupling constant J is expressed in Hertz (Hz).

[0218] Liquid chromatography-mass spectrometry (LC-MS) was detected using an Agilent 1260 mass spectrometer, and HPLC was determined using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0219] The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

[0220] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0221] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0222] It will be appreciated by those skilled in the art of organic synthesis that optimal reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by conventional optimization procedures. In some cases, the order of the following reaction scheme and / or reaction steps may be changed to promote reaction or avoid forming unwanted by-products. In addition, the functional groups present in each position of the molecule must be compatible with the proposed reagent and reaction. This limitation of substituents compatible with reaction conditions is obvious to those skilled in the art, and then alternative methods must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive group in the compound, and it is assumed that such a protecting group (PG) is in the appropriate position when necessary. Conventional protecting groups can be used according to standard practices well known in the art (for explanation, see Greene TW, Wuts PGM, Protective Groups in Organic Synthesis [protective groups in organic synthesis], the 5th edition, publisher: John Wiley & Sons (John Wiley & Sons), 2014). Protective groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or protecting groups can be removed in subsequent reaction steps or post-treatment.

[0223] The following abbreviations are used throughout this invention:

[0224] Pre-HPLC: Preparative High Performance Liquid Chromatography

[0225] Concentration unit M or mol / L: mole per liter

[0226] Volume unit mL: milliliter

[0227] Mass unit g: gram

[0228] The unit of amount of substance is mmol: millimole

[0229] ℃: Celsius

[0230] PPh 3 :Triphenylphosphine

[0231] DIAD: diisopropyl azodicarboxylate

[0232] NCS: n-chlorosuccinimide

[0233] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0234] DIEA: N,N-diisopropylethylamine

[0235] DMAP: 4-dimethylaminopyridine

[0236] Pd(PPh 3 ) 4 :Tetrakis(triphenylphosphine)palladium

[0237] Pd(dppf)Cl 2 :[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0238] CuI: Cuprous iodide

[0239] NaOH: Sodium hydroxide

[0240] FeCl 3 :Ferric chloride

[0241] DMF: N,N-dimethylformamide

[0242] EA: Ethyl acetate

[0243] DCM: dichloromethane

[0244] THF: Tetrahydrofuran

[0245] DMSO: dimethyl sulfoxide

[0246] HOBT: 1-Hydroxybenzotriazole

[0247] EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0248] The following examples are provided to help understand the present invention. However, it should be understood that these examples are only used to illustrate the present invention, but do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention.

[0249] Example 1: (E)-N-(5-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)-6-methoxypyridin-3-yl)methanesulfonamide (001)

[0250]

[0251] Step 1: Synthesis of Compound 1-3

[0252] To a solution of compound 1-2 (3.66 mL, 36.78 mmol) in tetrahydrofuran (100 mL) was added compound 1-1 (5.01 g, 36.78 mmol), PPh 3 (463.06 mg, 1.77 mmol) and DIAD (8.18 g, 40.46 mmol). The reaction mixture was stirred at 50°C for 2.5 hours, quenched with water (40 mL), and extracted with dichloromethane (50 mL×3). The organic phase was washed with saturated sodium chloride solution (30 mL×3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 1-3.

[0253] 1 H NMR (DMSO-d 6 )δ:7.83(s,4H),4.35-4.42(m,1H),2.07-2.23(m,2H),1.83-1.96(m,6H).

[0254] Step 2: Synthesis of Compound 1-4

[0255] To a solution of compound 1-3 (200 mg, 0.71 mmol) in dichloromethane (1.5 mL) and methanol (0.15 mL) was added hydrazine hydrate (69 μL, 1.42 mmol) The reaction mixture was stirred at 25° C. for 2 hours, filtered, and the filtrate was concentrated to obtain compound 1-4.

[0256] Step 3: Synthesis of Compound 1-7

[0257] Compound 1-6 (3.25 g, 9.01 mmol), CuI (0.03 mL, 0.86 mmol) and Pd(PPh) were added to a solution of compound 1-5 (2 g, 8.58 mmol) in xylene (20 mL). 3 ) 4(0.99 g, 0.86 mmol). After the reaction mixture was stirred at 120°C for 4.5 hours, it was cooled to room temperature, 1M hydrochloric acid solution (25 mL) was added, and the reaction mixture was stirred at 25°C for 16 hours. Saturated sodium bicarbonate solution (40 mL) was added to quench, and extracted with dichloromethane (50 mL×3). The organic phase was washed with saturated sodium chloride solution (30 mL×3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 1-7.

[0258] 1 H NMR (DMSO-d 6 )δ:9.28(d,J=2.8Hz,1H),8.69(d,J=2.9Hz,1H),4.16(s,3H),2.65(s,3H).

[0259] Step 4: Synthesis of Compound 1-8

[0260] Compound 1-4 (5.01 g, 36.78 mmol), acetic acid (100 μL) and 4A molecular sieve (200 mg) were added to a solution of compound 1-7 (100 mg, 0.51 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 25 ° C for 16 hours, and then saturated sodium bicarbonate solution was added to adjust the pH to 7, diluted with water (2 mL), and extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (2 mL × 3), dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 1-8.

[0261] Step 5: Synthesis of Compound 1-9

[0262] To a solution of compound 1-8 (73 mg, 0.22 mmol) in ethanol (2 mL) were added activated carbon (26.60 mg, 2.22 mmol), FeCl 3 (7.19 mg, 0.04 mmol) and hydrazine hydrate (14.73 μL, 0.30 mmol). After stirring the reaction mixture at 80°C for 2 hours, water (2 mL) was added to quench it and extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated sodium chloride solution (3 mL×3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 1-9.

[0263] Step 6: Synthesis of Compound 001

[0264] At 0°C, triethylamine (66.69 μL, 0.48 mmol) and methanesulfonyl chloride (40 μL, 0.52 mmol) were added to a solution of compound 1-9 (48 mg, 0.16 mmol) in dichloromethane (5 mL). After the reaction mixture was stirred at room temperature for 1 hour, it was concentrated to dryness under reduced pressure, the residue was dissolved in tetrahydrofuran (1 mL), and 6M NaOH solution (5 mL) was added. After the reaction mixture was stirred at 50°C for 1 hour, saturated ammonium chloride solution was added to quench, and extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated sodium chloride solution (5 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 001 (35.38 mg, 0.09 mmol, yield: 57.48%).

[0265] MS (ESI): m / z = 378.10 [M+H] + .

[0266] 1 H NMR (DMSO-d 6 )δ:9.60(s,1H),8.09(d,J=2.8Hz,1H),7.55(d,J=2.8Hz,1H),4.29-4.35(m,1H),3.89(s,3H),2.98(s,3H),2.14(s,3H),1.80-2.06(m,8H).

[0267] Example 2: (E)-N-(6-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)pyridin-3-yl)methanesulfonamide (002)

[0268]

[0269] Step 1: Synthesis of compound 2-2

[0270] Compound 1-4 (354.84 mg, 2.35 mmol), acetic acid (100 μL) and 4A molecular sieve (30 mg) were added to a solution of compound 2-1 (300 mg, 1.81 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at 25 ° C for 16 hours, and then saturated sodium bicarbonate solution was added to adjust the pH to 7, diluted with water (5 mL), and extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL × 3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 2-2.

[0271] Step 2: Synthesis of compound 2-3

[0272] To a solution of compound 2-2 (200 mg, 0.67 mmol) in ethanol (5 mL) were added activated carbon (80.19 mg, 6.68 mmol), FeCl 3 (16.26 mg, 0.10 mmol) and hydrazine hydrate (0.32 mL, 6.68 mmol). The reaction mixture was stirred at 80 ° C for 2 hours, quenched with water (5 mL), and extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (3 mL × 3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 2-3.

[0273] Step 3: Synthesis of Compound 002

[0274] At 0°C, triethylamine (231.63 μL, 1.67 mmol) and methanesulfonyl chloride (86.21 μL, 1.11 mmol) were added to a solution of compound 2-3 (150 mg, 0.56 mmol) in dichloromethane (5 mL). After the reaction mixture was stirred at room temperature for 1 hour, it was concentrated to dryness under reduced pressure, the residue was dissolved in tetrahydrofuran (1 mL), and 6 M NaOH solution (5 mL) was added. After the reaction mixture was stirred at 50°C for 1 hour, saturated ammonium chloride solution was added to quench, and extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated sodium chloride solution (5 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 002 (150 mg, 0.43 mmol, yield: 77.08%).

[0275] MS (ESI): m / z = 348.0 [M+H] + .

[0276] 1 H NMR (DMSO-d 6 )δ:10.17(s,1H),8.43(d,J=2.4Hz,1H),7.86(d,J=8.6Hz,1H),7.64(dd,J=8. 7,2.7Hz,1H),4.34-4.42(m,1H),3.08(s,3H),2.24(s,3H),1.85-2.03(m,8H).

[0277] Example 3: (E)-N-(6-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)pyridin-3-yl)acrylamide (031)

[0278]

[0279] Step 1: Synthesis of compound 31-2

[0280] Compound 1-4 (354.84 mg, 2.35 mmol), acetic acid (100 μL) and 4A molecular sieve (30 mg) were added to a solution of compound 31-1 (300 mg, 1.81 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at 25 ° C for 16 hours, and then saturated sodium bicarbonate solution was added to adjust the pH to 7, and water (5 mL) was added to dilute it, and it was extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL × 3), dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 31-2.

[0281] Step 2: Synthesis of compound 31-3

[0282] To a solution of compound 31-2 (230 mg, 0.77 mmol) in ethanol (5 mL) were added activated carbon (92.22 mg, 7.69 mmol), FeCl 3 (18.70 mg, 0.12 mmol) and hydrazine hydrate (0.32 mL, 6.68 mmol). The reaction mixture was stirred at 80 ° C for 2 hours, quenched with water (5 mL), and extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (3 mL × 3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 31-3.

[0283] Step 3: Synthesis of compound 031

[0284] At 0°C, DIEA (94.20 μL, 0.57 mmol) and acryloyl chloride (16.50 μL, 0.20 mmol) were added to a solution of compound 31-3 (50 mg, 0.19 mmol) in dichloromethane (3 mL). After the reaction mixture was stirred at room temperature for 0.5 hours, water (3 mL) was added to quench it, and it was extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated sodium chloride solution (3 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 031 (45 mg, 0.14 mmol, yield: 73.91%).

[0285] MS (ESI): m / z = 324.2 [M+H] + .

[0286] 1H NMR(DMSO-d6)δ:10.50(s,1H),8.84(d,J=2.3Hz,1H),8.14(dd,J=8.8,2.5Hz,1H),7.87(d,J=8.8Hz,1H),6.45(dd,J=17.0, 10.0Hz, 1H), 6.31 (dd, J=17.0, 1.9Hz, 1H), 5.83 (dd, J=10.1, 1.9Hz, 1H), 4.35-4.42 (m, 1H), 2.25 (s, 3H), 1.85-2.04 (m, 8H).

[0287] Example 4: (E)-N-(6-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)pyridin-3-yl)-2-fluoroacrylamide (032)

[0288]

[0289] Step 1: Synthesis of compound 032

[0290] At 0°C, HATU (127.07 mg, 0.33 mmol) and DIEA (110.75 μL, 0.67 mmol) were added to a DMF (2 mL) solution of compound 2-fluoroacrylic acid (36.11 mg, 0.40 mmol). After the reaction mixture was stirred at room temperature for 0.5 hours, compound 31-3 (60 mg, 0.22 mmol) was added. After the reaction mixture was stirred at room temperature for 16 hours, water (3 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (5 mL×3). The organic phase was washed with a saturated sodium chloride solution (3 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 032 (49.66 mg, 0.14 mmol, yield: 64.22%).

[0291] MS (ESI): m / z = 342.2 [M+H] + .

[0292] 1 H NMR (DMSO-d 6 )δ:10.65(s,1H),8.92(d,J=1.9Hz,1H),8.17(dd,J=8.8,2.5Hz,1H),7.89(d,J=8.8Hz,1H),5.68-5.85(m,1H),5.50(dd,J=15.6,3.8Hz,1H),4.39(br s,1H),2.25(s,3H),1.86-2.04(m,8H).

[0293] Example 5: (E)-N-(6-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)pyridin-3-yl)ethylenesulfonamide (033)

[0294]

[0295] Step 1: Synthesis of compound 033

[0296] At 0°C, 2,6-dimethylpyridine (25.67 μL, 0.22 mmol) and ethylenesulfonyl chloride (13.49 μL, 0.15 mmol) were added to a solution of compound 31-3 (40 mg, 0.15 mmol) in dichloromethane (7 mL). After the reaction mixture was stirred at room temperature for 0.5 hours, water (3 mL) was added to quench it, and it was extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated sodium chloride solution (3 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 033 (17 mg, 0.047 mmol, yield: 31.60%).

[0297] MS (ESI): m / z = 360.1 [M+H] + .

[0298] 1 H NMR(DMSO-d6)δ:10.45(s,1H),8.38(d,J=2.4Hz,1H),7.84(d,J=8.6Hz,1H),7.57(dd,J=8.8,2.6Hz,1H),6.86(dd,J =16.4,9.9Hz,1H),6.17(d,J=16.4Hz,1H),6.09(d,J=9.9Hz,1H),4.34-4.41(m,1H),2.22(s,3H),1.84-2.04(m,8H).

[0299] Example 7: (E)-4-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide (036)

[0300]

[0301] Step 1: Synthesis of compound 36-2

[0302] Compound 36-1 (2 g, 9.21 mmol) was dissolved in DMSO (5 mL), and then ammonia water (5 mL) was added, and the mixture was stirred at 125°C for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 36-2.

[0303] Step 2: Synthesis of compound 36-3

[0304] Add water (10mL) to the reaction bottle I and place it in an ice bath, then add thionyl chloride (3.4mL) and cuprous iodide (462.49mg, 4.67mmol) and stir in an ice bath for 30 minutes. Dissolve compound 36-2 (1g, 4.67mmol) in water (10mL) in the reaction bottle II, then drop concentrated hydrochloric acid (1.17mL, 14.01mmol) and sodium nitrite (966.88mg, 14.01mmol) and stir in an ice bath for 30 minutes. Then, add the solution in the reaction bottle II to the reaction bottle I, stir at room temperature for 2 hours, and the reaction is completed. Add water and dichloromethane to extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product compound 36-3.

[0305] Step 3: Synthesis of compound 36-4

[0306] Dissolve methylamine ethanol solution (3.39 mL, 25.88 mmol) in tetrahydrofuran (30 mL), add sodium bicarbonate (4.35 g, 51.76 mmol), then add compound 36-3 (770 mg, 2.59 mmol), and stir at room temperature for 12 hours. After the reaction is completed, add water and dichloromethane for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain compound 36-4.

[0307] Step 3: Synthesis of compound 36-5

[0308] Compound 36-4 (200 mg, 0.68 mmol) was dissolved in methanol (5 mL), (4,4-difluorocyclohexyl)amine oxide (155 mg, 1.03 mmol) and acetic acid (0.04 mL) were added, and the mixture was stirred at 60°C for 12 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added to quench the reaction, and water and dichloromethane were added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 36-5.

[0309] Step 4: Synthesis of Compound 036

[0310] Compound 36-5 (265 mg, 0.62 mmol), N-methyl-4-(tri-n-butyltin)imidazole (277.53 mg, 0.75 mmol), tetrakis(triphenylphosphine)palladium (72.01 mg, 0.06 mmol) and cuprous iodide (11.87 mg, 0.06 mmol) were dissolved in DMF (3 mL), nitrogen was replaced three times and nitrogen was protected, and the reaction was stirred at 130°C for 12 hours. After the reaction was completed, potassium fluoride aqueous solution was added to quench the residual tin reagent in the reaction, the precipitate was removed by filtration, and water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 036 (52 mg, 19.57%).

[0311] MS m / z(ESI):427.2[M+H] + .

[0312] 1 H NMR (DMSO-d 6 )δ:8.17(s,1H),7.71(s,1H),7.63(dd,J=1.4,8.0Hz,1H),7.55-7.50(m,1H),7.45(d,J=8.0Hz,1H),7 .20(s,1H),4.35-4.28(m,1H),3.69(s,3H),2.45-2.42(m,3H),2.15-1.95(m,7H),1.89-1.82(m,4H).

[0313] Example 8: (E)-N-methyl-6-(1-(2-(4-(trifluoromethyl)phenyl)hydrazono)ethyl)pyridine-3-sulfonamide

[0314]

[0315] Step 1: Synthesis of compound 37-2

[0316] At 0°C, thionyl chloride (0.27 mL, 3.67 mmol) was dissolved in water (1 mL) solution, stirred at 25°C for 1 hour, and then cuprous chloride (0.73 mg, 0.01 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour to form solution 1. At -5°C, a water (0.1 mL) solution of compound sodium nitrite (304.08 mg, 4.41 mmol) was added dropwise to a solution of compound 39-1 (50 mg, 0.37 mmol) in concentrated hydrochloric acid (0.1 mL), and the reaction mixture was stirred at -5°C for 1 hour to form solution 2. At -5°C, solution 2 was added dropwise to solution 1, stirred at -5°C for 1 hour, quenched with water (5 mL), and extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated sodium chloride solution (5 mL×3), dried, and concentrated to obtain a residue. At 0°C, a solution of 30% methylamine ethanol solution (0.38 mL, 3.64 mmol) in tetrahydrofuran (2 mL) was added with a solution of compound sodium bicarbonate (611.98 mg, 7.28 mmol) in water (2 mL), and the residue was added. After the reaction mixture was stirred at 25°C for 16 hours, water (5 mL) was added to quench it, and it was extracted with dichloromethane (5 mL×3). The organic phase was washed with a saturated sodium chloride solution (3 mL×3), dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 37-2.

[0317] Step 2: Synthesis of Compound 037

[0318] Compound (4-(trifluoromethyl)phenyl)hydrazine (0.03mL, 0.21mmol), acetic acid (100μL) and 4A molecular sieve (80mg) were added to a solution of compound 37-2 (42mg, 0.20mmol) in dichloromethane (1mL). After the reaction mixture was stirred at 25°C for 5 hours, saturated sodium bicarbonate solution was added to adjust the pH to 7, water (5mL) was added to dilute, and dichloromethane (5mL×3) was used for extraction. The organic phase was washed with saturated sodium chloride solution (5mL×3), dried and concentrated, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 037 (51mg, 0.14mmol, yield: 68.88%).

[0319] MS (ESI): m / z = 373.1 [M+H] + .

[0320] 1 H NMR (DMSO-d 6)δ:10.18(s,1H),8.87(d,J=1.9Hz,1H),8.35(d,J=8.5Hz,1H),8.11(dd,J=8.5,2.3Hz,1H),7.68(br d, J=5.0Hz, 1H), 7.58-7.64 (m, J=8.6Hz, 2H), 7.46-7.52 (m, J=8.6Hz, 2H), 2.46-2.48 (m, 3H), 2.41 (s, 3H).

[0321] Example 10: (E)-2-Fluoro-N-(6-(1-(((4-(trifluoromethyl)cyclohexyl)oxy)imino)ethyl)pyridin-3-yl)acrylamide (039)

[0322]

[0323]

[0324] Step 1: Synthesis of compound 39-3

[0325] Compound 39-14-(trifluoromethyl)cyclohexanol (1.5 g, 8.92 mmol), N-hydroxyphthalimide (1.46 g, 8.92 mmol) and triphenylphosphine (2.81 g, 10.70 mmol) were dissolved in THF (20 mL), DIAD (1.95 mL, 9.81 mmol) was slowly added dropwise at 0°C, and the mixture was stirred at 50°C overnight. After the reaction was completed, it was cooled to room temperature, most of the solvent was removed by rotation, and then water (10 mL) was added to dilute, and extracted with EA (10 x 3 mL). The organic phase was washed with saturated brine (5 x 3 mL), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain a mixture of compound 39-3.

[0326] Step 2: Synthesis of compound 39-4

[0327] To a solution of the mixture of compound 39-3 (1.5 g) in ethanol (10 mL) was added hydrazine hydrate (0.26 mL, 5.27 mmol) dropwise, and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was cooled to 0°C, filtered, and the filtrate was collected to obtain a mixture of compound 39-4.

[0328] Step 3: Synthesis of compound 39-6

[0329] 1-(5-aminopyridin-2-yl)ethanone (156.57 mg, 1.15 mmol), acetic acid (150 μL, 2.62 mmol) and 4A molecular sieves (350 mg) were added to a solution of a mixture of compound 39-4 (421 mg) in DCM (5 mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, the filtrate was collected, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 39-6.

[0330] Step 4: Synthesis of Compound 039

[0331] HATU (408.76 mg, 1.07 mmol), DIEA (0.36 mL, 2.15 mmol), DMAP (8.76 mg, 0.07 mmol) and 2-fluoroacrylic acid (64.26 mg, 0.71 mmol) were added to a DMF (3 mL) solution of compound 39-6 (258 mg, 0.86 mmol), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (5 mL) was added to quench, and extracted with EA (5 x 3 mL). The organic phase was washed with saturated brine (5 x 3 mL), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 039 (157 mg, 0.41 mmol, yield: 57.30%).

[0332] MS (ESI): m / z=414.2[M+H]+.

[0333] 1 H NMR (400 MHz, DMSO-d 6 )δ=10.64(br s,1H),8.91(br s,1H),8.16(br d,J=7.1Hz,1H),7.88(br d,J=8.0Hz,1H),5.90-5.64(m,1H),5.49(br d,J=14.8Hz,1H),4.44(br s,1H),2.41(br s,1H),2.31-2.20(m,3H),2.09(br d,J=11.3Hz,2H),1.75-1.58(m,4H),1.58-1.46(m,2H).

[0334] Example 12: (E)-N-(4-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)-2-fluorophenyl)-2-fluoroacrylamide (041)

[0335]

[0336] Step 1: Synthesis of compound 41-2

[0337] Compound 1-4 (222.06 mg, 1.47 mmol), acetic acid (150 μL, 2.62 mmol) and 4A molecular sieve (400 mg) were added to a solution of 4'-amino-3'-fluoroacetophenone (150 mg) in DCM (3 mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, the filtrate was collected, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 41-2.

[0338] Step 2: Synthesis of Compound 041

[0339] HATU (436.62 mg, 1.15 mmol), DIEA (0.38 mL, 2.30 mmol) and 2-fluoroacrylic acid (68.93 mg, 0.77 mmol) were added to a DMF (3 mL) solution of compound 41-2 (263 mg, 0.92 mmol), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (5 mL) was added to quench, and extracted with EA (5 x 3 mL). The organic phase was washed with saturated brine (5 x 3 mL), dried and concentrated, and the resulting residue was purified by silica gel column chromatography and pre-HPLC to obtain compound 041 (94.5 mg, 0.26 mmol, yield: 34.29%).

[0340] MS(ESI): m / z=359.0[M+H]+.

[0341] 1 H NMR (400 MHz, DMSO-d 6 )δ=10.22(br s,1H),7.62-7.49(m,3H),5.80-5.64(m,1H),5.46(dd,J=3.7,15.6Hz,1H),4.37(br d,J=3.1Hz,1H),2.21(s,3H),2.03-1.86(m,8H).

[0342] Example 16: (E)-2-Fluoro-N-(2-fluoro-4-(1-((4-(trifluoromethyl)phenoxy)imino)ethyl)phenyl)acrylamide (046)

[0343]

[0344] Step 1: Synthesis of compound 46-2

[0345] O-[4-(trifluoromethyl)phenyl]hydroxylamine (149.67 mg, 0.845 mmol), acetic acid (100 μL, 1.75 mmol) and 4A molecular sieves (250 mg) were added to a DCM (3 mL) solution of compound 46-1 (100 mg), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, the filtrate was collected, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 46-2.

[0346] Step 2: Synthesis of Compound 046

[0347] HATU (290.88 mg, 0.765 mmol), DIEA (0.25 mL, 1.53 mmol) and 2-fluoroacrylic acid (45.93 mg, 0.51 mmol) were added to a DMF (3 mL) solution of compound 46-2 (193 mg, 0.62 mmol), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (5 mL) was added to quench, and extracted with EA (5 x 3 mL). The organic phase was washed with saturated brine (5 x 3 mL), dried and concentrated, and the resulting residue was purified by silica gel column chromatography and pre-HPLC to obtain compound 046 (58.7 mg, 0.15 mmol, yield: 29.67%).

[0348] MS (ESI): m / z = 385.0 [M+H] + .

[0349] 1 H NMR (400 MHz, DMSO-d 6 )δ=10.30(br s,1H),7.83-7.64(m,5H),7.51(d,J=8.6Hz,2H),5.85-5.66(m,1H),5.49(dd,J=3.8,15.6Hz,1H),2.48(s,3H).

[0350] Example 17: (E)-N-(2-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)pyrimidin-5-yl)-2-fluoroacrylamide (047)

[0351]

[0352] Step 1: Synthesis of compound 47-2

[0353] To a solution of compound 47-1 (200 mg, 1.15 mmol) in tetrahydrofuran (4 mL) at 0°C were added DMAP (1.40 mg, 0.01 mmol), DIEA (0.57 mL, 3.45 mmol), and (Boc)2 O (376.29 mg, 1.72 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with water (4 mL) under ice bath conditions, and extracted with EA (5 mL). The organic phase was washed with saturated sodium chloride solution (4 mL × 3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 47-2.

[0354] Step 2: Synthesis of compound 47-3

[0355] To a solution of compound 47-2 (100 mg, 0.36 mmol) in 1,4-dioxane (1.5 mL) and water (0.5 mL) were added isopropenylboronic acid pinacol ester (0.08 mL, 0.40 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (29.79 mg, 0.04 mmol), cesium fluoride (110.83 mg, 0.73 mmol) and sodium carbonate (77.33 mg, 0.73 mmol). The reaction mixture was stirred at room temperature for 16 hours, quenched with water (4 mL) under ice bath conditions, and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride solution (4 mL × 3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 47-3.

[0356] Step 3: Synthesis of compound 47-4

[0357] Ozone was introduced into a solution of compound 47-3 (60 mg, 0.255 mmol) in methanol (3 mL) at -78°C. The reaction mixture was stirred at -78°C for 5 minutes, and dimethyl sulfide (0.5 mL) was added, followed by concentration under reduced pressure to obtain compound 47-4.

[0358] Step 4: Synthesis of compound 47-5

[0359] To a solution of compound 47-4 (53 mg, 0.223 mmol) in dichloromethane (2 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane (1.675 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain compound 47-5.

[0360] Step 5: Synthesis of compound 47-6

[0361] Compound 1-4 (40.78 mg, 0.270 mmol), acetic acid (20 μL) and 4A molecular sieve (100 mg) were added to a solution of compound 47-5 (37 mg, 0.270 mmol) in dichloromethane (2 mL). After the reaction mixture was stirred at 25 ° C for 16 hours, saturated sodium bicarbonate solution was added to adjust the pH to 7, water (5 mL) was added to dilute, and dichloromethane (5 mL × 3) was used for extraction. The organic phase was washed with saturated sodium chloride solution (5 mL × 3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 47-6 (72 mg, 0.266 mmol, yield: 98.74%).

[0362] MS (ESI): m / z = 271.0 [M+H] + .

[0363] Step 6: Synthesis of Compound 047

[0364] At 0°C, HATU (101.29 mg, 0.266 mmol) and DIEA (44.026 μL, 0.266 mmol) were added to a DMF (2 mL) solution of compound 2-fluoroacrylic acid (23.99 mg, 0.266 mmol). After the reaction mixture was stirred at room temperature for 0.5 hours, compound 47-6 (72 mg, 0.266 mmol) was added. After the reaction mixture was stirred at room temperature for 16 hours, water (3 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (5 mL×3). The organic phase was washed with a saturated sodium chloride solution (3 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 047 (5.14 mg, 0.015 mmol, yield: 5.57%).

[0365] MS (ESI): m / z = 343.1 [M+H] + .

[0366] 1 H NMR (DMSO-d 6 )δ:10.87(br s,1H),9.17(s,2H),5.71-5.89(m,1H),5.55(dd,J=15.5,3.9Hz,1H),4.40-4.46(m,1H),2.28(s,3H),1.82-2.06(m,8H).

[0367] Example 18: (E)-N-(6-(1-((3,3-difluorocyclobutyloxy)imino)ethyl)pyridin-3-yl)-2-fluoroacrylamide (048)

[0368]

[0369] Step 1: Synthesis of compound 48-3

[0370] Triphenylphosphine (964.72 mg, 3.68 mmol), compound 48-2 (0.26 mL, 3.07 mmol) and diisopropyl azodicarboxylate (0.67 mL, 3.37 mmol) were added to a solution of compound 48-1 (500 mg, 3.07 mmol) in tetrahydrofuran (10 mL), and the reaction mixture was stirred at 50 ° C for 15 hours, diluted with water (5 mL), and extracted with EA (100 mL × 2). The organic phase was washed with saturated sodium chloride (5 mL), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 48-3.

[0371] Step 2: Synthesis of compound 48-4

[0372] At 0°C, hydrazine hydrate solution (36.87 μL, 0.61 mmol) was added dropwise to a solution of compound 48-3 (77 mg, 0.30 mmol) in methanol (0.1 mL)\dichloromethane (1 mL). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction mixture was filtered, the filtrate was collected and concentrated, and compound 48-4 was obtained without purification.

[0373] Step 3: Synthesis of compound 48-6

[0374] Compound 48-4 (162.75 mg, 1.32 mmol), acetic acid (0.3 mL, 5.25 mmol) and 4A molecular sieves (500 mg, 1.32 mmol) were added to a solution of compound 48-5 (180 mg, 1.32 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 25 °C for 5 hours, quenched by adding aqueous sodium bicarbonate (5 mL), and extracted with EA (100 mL × 2). The organic phase was washed with saturated sodium chloride (5 mL), dried and concentrated to obtain compound 48-6.

[0375] Step 6: Synthesis of Compound 048

[0376] At 0°C, HATU (494.92 mg, 1.30 mmol) and N,N-diisopropylethylamine (215.68 μL, 1.30 mmol) were added to a solution of 2-fluoroacrylic acid (58.60 mg, 0.65 mmol) in N,N-dimethylformamide (5 mL). Ten minutes later, compound 48-6 (157 mg, 0.65 mmol) was added. After the reaction mixture was stirred at 25°C for 3 hours, water (3 mL) was added to quench the mixture, and the mixture was extracted with EA (25 mL×2). The organic phase was washed with saturated sodium chloride (3 mL). The organic phase was washed with saturated brine, dried, and concentrated, and the resulting residue was pre-purified by column chromatography and then purified by Pre-HPLC (TFA conditions) to obtain compound 048 (85.59 mg, 0.27 mmol, yield: 41.87%).

[0377] MS(ESI): m / z=314.0[M+H]+.

[0378] 1 H NMR (400 MHz, DMSO-d 6 )δ=10.67(br s,1H),8.94(d,J=2.3Hz,1H),8.19(dd,J=2.5,8.8Hz,1H),7.87(d,J=8.8Hz,1H),5.83(d,J=3.8Hz,1H ), 5.50 (dd, J = 3.8, 15.5Hz, 1H), 4.88-4.77 (m, 1H), 3.10-2.97 (m, 2H), 2.86-2.72 (m, 2H), 2.27 (s, 3H).

[0379] Example 24: (E)-2-Fluoro-N-(6-(1-(2-(4-(trifluoromethyl)phenyl)hydrazono)ethyl)pyridin-3-yl)acrylamide (067)

[0380]

[0381] Step 1: Synthesis of compound 67-2

[0382] Under nitrogen protection, 4-(trifluoromethyl)phenyl)hydrazine (72 mg, 0.40 mmol), 4AF molecular sieve (250 mg) were added to a DCM (5 mL) solution of 1-(5-aminopyridin-2-yl)ethane-1-one (50 mg, 0.37 mmol), and 0.2 mL of acetic acid was added dropwise. After the reaction mixture was stirred at room temperature for 4 hours, it was quenched with water (10 mL) and extracted with EA (30 mL). The organic phase was washed with saturated sodium chloride solution (30 mL×3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 67-2 (50 mg).

[0383] Step 4: Synthesis of Compound 067

[0384] Under nitrogen protection, HATU (50 mg, 0.17 mmol) was added to DMF (2 mL), 2-fluoroacrylic acid (13 mg, 0.14 mmol) was added, DIEA (49 μL, 0.28 mmol) was added dropwise, and after stirring at room temperature for half an hour, compound 67-2 (50 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, quenched by adding water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 067 (25 mg, 0.068 mmol, yield: 49%).

[0385] 1 H NMR (DMSO-d 6 ,400MHz)δ10.61(s,1H),9.90(s,1H),8.90(s,1H),8.15(d,2H,J=1.3Hz),7.57(d,2H,J= 8.8Hz), 7.43 (d, 2H, J = 8.6Hz), 5.83 (d, 1H, J = 3.8Hz), 5.71 (d, 1H, J = 3.8Hz), 2.37 (s, 3H).

[0386] MS (ESI): m / z = 367 [M+H] + .

[0387] Example 26: (E)-2-Fluoro-N-(6-(1-((4-(trifluoromethyl)phenoxy)imino)ethyl)pyridin-3-yl)acrylamide (068)

[0388]

[0389] Step 1: Synthesis of compound 68-2

[0390] Compound O-(4-(trifluoromethyl)phenyl)hydroxylamine (130.10 mg, 0.73 mmol), acetic acid (0.2 mL) and 4A molecular sieve (300 mg) were added to a solution of compound 68-1 (100 mg, 0.73 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at 25°C for 3 hours, and then saturated sodium bicarbonate solution was added to adjust the pH to 7, diluted with water (5 mL), and extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated sodium chloride solution (5 mL×3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 68-2.

[0391] Step 2: Synthesis of Compound 068

[0392] At 0°C, HATU (154.53 mg, 0.41 mmol) and DIEA (0.13 mL, 0.81 mmol) were added to a DMF (2 mL) solution of compound 2-fluoroacrylic acid (43.92 mg, 0.49 mmol). After the reaction mixture was stirred at room temperature for 0.5 hours, compound 68-2 (80 mg, 0.27 mmol) was added. After the reaction mixture was stirred at room temperature for 16 hours, water (3 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (5 mL×3). The organic phase was washed with a saturated sodium chloride solution (3 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (neutral conditions) to obtain compound 068 (57 mg, 0.15 mmol, yield: 56.84%).

[0393] MS (ESI): m / z = 368.1 [M+H] + .

[0394] 1 H NMR (DMSO-d 6 )δ:10.74(s,1H),9.02(d,J=2.3Hz,1H),8.28(dd,J=8.8,2.5Hz,1H),8.14(d,J=8.8Hz,1H),7.75 (d,J=8.8Hz,2H),7.53(d,J=8.6Hz,2H),5.71-5.88(m,1H),5.52(dd,J=15.6,3.8Hz,1H),2.51(br s,3H).

[0395] Example 27: (R,E)-4-(1-(4-fluorophenoxy)imino)ethyl)-N-(1-hydroxypropan-2-yl)benzamide (081)

[0396]

[0397] Step 1: Synthesis of compound 81-3

[0398] Compound 81-2 (858 mg, 6.130 mmol), compound 81-1 (500 mg, 3.065 mmol), and cuprous chloride (303.44 mg, 3.065 mmol) were dissolved in 1,2-dichloroethane (15 mL), and then pyridine (272.688 μL, 3.372 mmol) was added to the above stirring system at room temperature, and the reaction was stirred overnight at room temperature after oxygen replacement. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic phase was collected, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%) to obtain compound 81-3 (590 mg, 2.294 mmol, yield 74.84%) as a white solid.

[0399] MS m / z(ESI):258.0[M+1].

[0400] Step 2: Synthesis of compound 81-4

[0401] Compound 81-3 (550 mg, 2.138 mmol) was dissolved in dichloromethane (10 mL) and methanol (1 mL), and then hydrazine hydrate (214 mg, 4.276 mmol) was added to the above system and stirred at room temperature overnight. After the reaction was completed, the solvent was first concentrated under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phase was collected, dried, and concentrated under reduced pressure to obtain compound 81-4 (300 mg, 2.360 mmol) as a white solid. This product was a crude product and could be directly carried out to the next step without purification.

[0402] MS m / z(ESI):128.3[M+1].

[0403] Step 3: Synthesis of compound 81-6

[0404] Compound 81-4 (300 mg, 1.416 mmol) and compound 81-5 (232 mg, 1.416 mmol) were dissolved in dichloromethane (5 mL) and acetic acid (0.5 mL) was slowly added dropwise to the system, and then the reaction was stirred at room temperature for two hours. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether=25%) to obtain compound 81-6 (200 mg, 0.732 mmol, yield 51.69%) as a white solid.

[0405] MS m / z(ESI):274.0[M+1].

[0406] Step 4: Synthesis of Compound 081

[0407] Compound 81-6 (100 mg, 0.366 mmol), (R)-2-amino-1-propanol (28 mg, 0.366 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (208 mg, 0.549 mmol) were dissolved in N,N-dimethylformamide (4 mL), and finally N,N-diisopropylethylamine was slowly added. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: LAIPU-SAC prepHPLC-C18-7um-30×250mm; mobile phase: A: 0.1% formic acid dissolved in water B: acetonitrile, gradient ratio: acetonitrile 50%-85%, flow rate: 20 mL / min) to obtain compound 081 (80.09 mg, 0.242 mmol, yield 66.24%) as a white solid.

[0408] MS m / z(ESI):331.2[M+1].

[0409] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.20(d,J=8.0Hz,1H),7.95-7.92(m,J=8.6Hz,2H),7.90-7.87(m,J=8.6Hz,2H),7.34-7.27(m,2H ),7.21(t,J=8.3Hz,2H),4.98-4.48(m,1H),4.10-3.96(m,1H),3.48(dd,J=5.8,10.6Hz,1H),3.37(br d,J=6.4Hz,1H),2.48-2.44(m,3H),1.14(d,J=6.8Hz,3H).

[0410] Example 28: (R,E)-4-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)-N-(1-hydroxypropyl-2-yl)benzamide (082)

[0411]

[0412]

[0413] Step 1: Preparation of compound 82-2

[0414] Compound 82-1 (100 mg, 1.096 mmol), compound 1-4 (497.24 mg, 3.289 mmol), Molecular sieves (300 mg) were dissolved in 4 mL of tetrahydrofuran, acetic acid (376.612 μL, 6.579 mmol) was added at room temperature, and the reaction was stirred at 70°C overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 82-2 (154 mg, yield: 47.24%).

[0415] MS m / z(ESI):298.0[M+1].

[0416] Step 2: Preparation of Compound 082

[0417] Compound 82-2 (150 mg, 0.505 mmol), EDCI (193.44 mg, 1.009 mmol), and HOBt (136.36 mg, 1.009 mmol) were dissolved in dimethylformamide (3 mL), and a solution of (R)-2-aminopropan-1-ol (75.79 mg, 1.009 mmol) and N,N-diisopropylethylamine (326.06 mg, 2.523 mmol) in dimethylformamide (1 mL) was added, and the reaction was allowed to proceed overnight at room temperature. After concentration under reduced pressure, the product was purified by high performance liquid chromatography (Waters_2545, chromatographic column: Waters-SunFire-C18, 19×250 mm, 10 μm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 25%-95%, flow rate: 20 mL / min) to obtain the cis and trans isomers of compound 082: compound 082-P1 (33 mg, yield: 17.64%) and compound 082-P2 (84.51 mg, yield: 46.64%).

[0418] MS m / z(ESI):355.1[M+1].

[0419] 082-P1: 1 H NMR (400 MHz, DMSO-d 6 ): δ8.15(br d,J=8.1Hz,1H),7.88(d,J=8.3Hz,2H),7.60(d,J=8.4Hz,2H),4.71(t,J=5.8Hz,1H),4.22(br d,J=2.4Hz,1H),4.01(td,J=6.7,13.6Hz,1H),3.46(td,J=5.6,10.8Hz,1H) ,3.38-3.33(m,1H),2.18(s,3H),1.96-1.72(m,8H),1.13(d,J=6.8Hz,3H).

[0420] 082-P2: 1 H NMR (400 MHz, DMSO-d6 ): δ8.14(br d,J=7.9Hz,1H),7.88(br d,J=8.1Hz,2H),7.74(br d,J=8.3Hz,2H),4.73(br s,1H),4.39(br s,1H),4.07-3.96(m,1H),3.52-3.41(m,1H),3.39-3.34(m,1H),2.24(s,3H),2.06-1.83(m,8H),1.13(br d,J=6.6Hz,3H).

[0421] Example 29: (R,E)-5-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)-N-(1-hydroxypropan-2-yl)thiophene-2-carboxamide (092)

[0422]

[0423] Step 1: Synthesis of compound 92-2

[0424] Compound 92-1 (200 mg, 1.175 mmol), compound 1-4 (532.94 mg, 3.526 mmol), Molecular sieves (500 mg) were dissolved in 6 mL of tetrahydrofuran, acetic acid (403.655 μL, 7.051 mmol) was added at room temperature, and the mixture was stirred at 70°C overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 92-2 (338 mg, yield: 94.84%).

[0425] MS m / z(ESI):304.0[M+1].

[0426] Step 2: Synthesis of Compound 092

[0427] Compound 92-2 (380 mg, 1.253 mmol), EDCI (480.32 mg, 2.506 mmol), and HOBt (338.58 mg, 2.506 mmol) were dissolved in dimethylformamide (3 mL), and a solution of (R)-2-aminopropan-1-ol (188.20 mg, 2.506 mmol) and N,N-diisopropylethylamine (1.112 mL, 6.264 mmol) in dimethylformamide (1 mL) was added, and the mixture was reacted at room temperature overnight. The liquid was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters_2545, chromatographic column: Waters-SunFire-C18, 19×250 mm, 10 μm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-95%, flow rate: 20 mL / min) to obtain the cis and trans isomers of compound 092: compound 092-P1 (141 mg, yield: 31.10%) and compound 092-P2 (94 mg, yield: 20.60%).

[0428] MS m / z(ESI):361.1[M+1].

[0429] 092-P1: 1 H NMR (400 MHz, DMSO-d 6 ): δ8.26(d,J=8.0Hz,1H),7.81(d,J=4.1Hz,1H),7.56(d,J=4.1Hz,1H),4.75(t,J=5.7Hz,1H),4.45(br s,1H),3.96(td,J=6.7,13.7Hz,1H),3.45(td,J=5.6,10.8Hz,1H),3.39-3.33(m,1H),2.30(s,3H),2.11-1.86(m,8H),1.13(d,J=6.8Hz,3H).

[0430] 092-P2: 1 H NMR (400 MHz, DMSO-d 6 ): δ8.17(br d,J=7.5Hz,1H),7.72(br d,J=2.6Hz,1H),7.41(br d,J=2.6Hz,1H),4.74(br s,1H),4.32(br s,1H),4.05-3.86(m,1H),3.43(br d,J=4.5Hz,1H),3.32(br d,J=4.5Hz,1H),2.22(s,3H),2.09-1.77(m,8H),1.11(br d,J=6.3Hz,3H).

[0431] Example 30: (S,E)-N-(1-hydroxypropan-2-yl)-5-(1-((4-(trifluoromethyl)phenoxy)imino)ethyl)thiophene-2-carboxamide (093)

[0432]

[0433] Step 1: Synthesis of compound 93-3

[0434] Compound 93-1 (100 mg, 0.59 mmol, Bidex Pharmaceuticals) was dissolved in 3 mL of methanol, and compound 93-2 (79 μL, 0.59 mmol, Bidex Pharmaceuticals), acetic acid (100 μL, 1.75 mmol), tetraisopropyl titanate (0.35 mL, 1.18 mmol) and 4A molecular sieves (200 mg) were added, and the mixture was stirred at 60° C. for 16 hours. After removing part of the molecular sieves by filtration, the mixture was directly concentrated under reduced pressure to obtain a residue containing compound 93-3 (370 mg).

[0435] MS m / z(ESI):329.8[M+1].

[0436] Step 2: Synthesis of compound 093

[0437] The residue containing compound 93-3 (370 mg) was dissolved in tetrahydrofuran (5 mL), and EDCI (349 mg, 1.82 mmol), HOBt (246 mg, 1.82 mmol), N,N-diisopropylethylamine (0.3 mL, 1.82 mmol) and compound 93-4 (85 μL, 1.09 mmol) were added and reacted at room temperature for 16 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B (pure ethyl acetate) and high performance liquid chromatography (Gilson_306_1741, chromatographic column: LAIPU-SAC prep HPLC-C18-7um-30×250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 80%-90%, flow rate: 25 mL / min) to obtain compound 093 (60 mg, yield: 26.2%).

[0438] MS m / z(ESI):386.9[M+1].

[0439] 1H NMR(400MHz,Chloroform-d)δ=7.65-7.55(m,2H),7.52-7.31(m,4H),6.33-6.17(m,1H) ), 4.36-4.20 (m, 1H), 3.87-3.61 (m, 2H), 2.48 (d, J = 13.8Hz, 3H), 1.32 (t, J = 6.7Hz, 3H).

[0440] Example 31: (R,E)-N-(1-hydroxypropan-2-yl)-5-(1-((4-(trifluoromethyl)phenoxy)imino)ethyl)thiophene-2-carboxamide (070)

[0441]

[0442] Step 1: Synthesis of compound 93-3

[0443] Compound 93-1 (200 mg, 1.175 mmol), compound 93-2 (208 mg, 1.175 mmol) and 4A molecular sieve (400 mg, 0.24 mmol) were dissolved in methanol (10 mL) and acetic acid (1 mL), and tetraisopropyl titanate (0.700 mL, 2.350 mmol) was slowly added to the reaction, and the reaction was stirred overnight at 60 degrees Celsius. After the reaction was completed, water and ethyl acetate were added to extract, and the organic phase was collected, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to obtain compound 93-3 (150 mg, 0.456 mmol, yield 38.76%) as a white solid.

[0444] Step 2: Synthesis of Compound 070

[0445] Compound 93-3 (50 mg, 0.152 mmol), compound 93-5 (12 mg, 0.152 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (87 mg, 0.228 mmol) were dissolved in N,N-dimethylformamide, and N,N-diisopropylethylamine (59 μL, 0.364 mmol) was added, and the reaction was stirred at room temperature for three hours. After the reaction was completed, ethyl acetate and water were added for extraction, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: LAIPU-SAC prep HPLC-C18-7um-30×250mm; mobile phase: A: 0.1% formic acid dissolved in water B: acetonitrile, gradient ratio: acetonitrile 60%-65%, flow rate: 30 mL / min) to obtain compound 070 (32.30 mg, 0.084 mmol, yield 55.5%) as a white solid.

[0446] MS m / z(ESI):387.1[M+1].

[0447] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.42-8.17(m,1H),7.91-7.65(m,4H),7.53-7.39(m,2H),4.83-4.71(m,1H),4.08-3 .88(m,1H),3.54-3.41(m,1H),3.39-3.34(m,1H),2.49-2.49(m,3H),1.20-1.08(m,3H).

[0448] Example 32: (S)-4-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)-N-(1-hydroxypropan-2-yl)benzamide (094)

[0449]

[0450] Step 1: Synthesis of compound 94-2

[0451] Compound 94-1 (100 mg, 1.10 mol), acetic acid (395 mg, 6.58 mmol) and 4A molecular sieve (300 mg) were dissolved in 4 mL of tetrahydrofuran, and compound 1-4 (497 mg, 3.29 mmol, Bidex Pharmaceuticals) was added at 0°C. After stirring and reacting at 70°C for 18 hours, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 94-2 (154 mg, yield: 47%).

[0452] MS m / z(ESI):298.0[M+1].

[0453] Step 2: Synthesis of Compound 094

[0454] Compound 94-2 (460 mg, 1.55 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 84-3 (174 mg, 2.32 mmol, Bidex Pharmaceuticals), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (445 mg, 2.32 mmol), 1-hydroxybenzotriazole (418 mg, 3.10 mmol) and N,N-diisopropylethylamine (0.81 mL, 4.64 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the cis and trans isomers of compound 094: compound 094-P1 (11 mg, yield: 5.0%) and compound 094-P2 (183 mg, yield: 35.0%).

[0455] MS m / z(ESI):355.1[M+1].

[0456] 095-P1: 1 H NMR (400 MHz, DMSO-d 6 )δ=8.17-8.12(m,1H),7.88(d,J=8.5Hz,2H),7.60(d,J=8.5Hz,2H),4.71(s,1H),4.26-4.17(m,1H),4.07-3.95 (m,1H),3.46(td,J=5.6,10.9Hz,1H),3.37-3.35(m,1H),2.18(s,3H),2.02-1.78(m,8H),1.13(d,J=6.6Hz,3H).

[0457] 095-P2: 1 H NMR (400 MHz, DMSO-d 6 )δ=8.14(d,J=8.0Hz,1H),7.88(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),4.72(t,J=.8Hz,1H),4.39(br d,J=2.8Hz,1H),4.06-3.97(m,1H),3.46(td,J=5.6,10.8Hz,1H),3.37-3.33(m,1H),2.24(s,3H),2.05-1.86(m,8H),1.13(d,J=6.8Hz,3H).

[0458] Example 33: (S)-4-(1-(((4,4-difluorocyclohexyl)oxy)imino)ethyl)-N-(1-hydroxypropan-2-yl)benzamide (084)

[0459]

[0460]

[0461] Step 1: Synthesis of compound 84-2

[0462] Compound 84-1 (200 mg, 1.18 mol), acetic acid (0.40 mL, 7.05 mmol) and 4A molecular sieve (500 mg) were dissolved in 6 mL of tetrahydrofuran, and compound 1-4 (533 mg, 3.53 mmol, Bidex Pharmaceuticals) was added at 0°C. After stirring and reacting at 70°C for 18 hours, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 84-2 (338 mg, yield: 95%).

[0463] MS m / z(ESI):304.0[M+1].

[0464] Step 2: Synthesis of compound 084

[0465] Compound 84-2 (250 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 84-3 (92.86 mg, 1.24 mmol, Bidex Pharmaceuticals), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (237 mg, 1.24 mmol), 1-hydroxybenzotriazole (223 mg, 1.65 mmol) and N,N-diisopropylethylamine (0.43 mL, 2.47 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the cis and trans isomers of compound 084: compound 084-P1 (65 mg, yield: 23%) and compound 084-P2 (60 mg, yield: 18%).

[0466] MS m / z(ESI):355.1[M+1].

[0467] 084-P1: 1 H NMR (400 MHz, DMSO-d 6)δ=8.26(d,J=8.0Hz,1H),7.81(d,J=4.1Hz,1H),7.56(d,J=4.1Hz,1H),4.75(t,J=5.7Hz,1H),4.45(br s,1H),3.96(td,J=6.6,13.7Hz,1H),3.45(td,J=5.6,10.8Hz,1H),3.38-3.33(m,1H),2.30(s,3H),2.08-1.89(m,8H),1.13(d,J=6.8Hz,3H).

[0468] 084-P2: 1 H NMR (400 MHz, DMSO-d 6 )δ=8.16(d,J=8.1Hz,1H),7.71(d,J=4.0Hz,1H),7.41(d,J=3.9Hz,1H),4.73(t,J=5.7Hz,1H),4.35-4.29(m,1H),3.95(td, J=6.6,13.8Hz,1H),3.43(td,J=5.6,10.8Hz,1H),3.38-3.32(m,1H),2.22(s,3H),2.05-1.83(m,8H),1.11(d,J=6.8Hz,3H).

[0469] Example 34: N-(1-hydroxy-2-methyl-2-propyl)-5-(1-((4-(trifluoromethyl)phenoxy)imino)ethyl)thiophene-2-carboxamide (099)

[0470]

[0471] 1) Preparation of Compound 99-2

[0472] Compound 99-1 (500 mg, 2.938 mmol), O-(4-(trifluoromethyl)phenyl)hydroxylamine (0.434 mL, 3.232 mmol), 4A molecular sieve (1500 mg, 0.880 mmol) were dissolved in a mixed solution of AcOH (1 mL) and MeOH (10 mL), and tetraisopropyl titanate (1.751 mL, 5.876 mmol) was added to the mixture. The mixture was stirred at a temperature of 60° C. for 18 hours. The reaction mixture was cooled to 25° C. and filtered. The filtrate was concentrated, and the reaction mixture was adjusted to pH=3 with 2M hydrochloric acid. The mixture was filtered, and the filter cake was washed with water. Crude compound 99-2 (700 mg) was obtained.

[0473] 2) Step 2 Synthesis of Compound 099

[0474] Compound 99-2 (50 mg, 0.152 mmol) was dissolved in tetrahydrofuran (2 mL), and EDCI (58.22 mg, 0.304 mmol), HOBt (41.04 mg, 0.304 mmol), N,N-diisopropylethylamine (0.100 mL, 0.607 mmol) and 2-amino-2-methyl-1-propanol (20.30 mg, 0.228 mmol) were added respectively, and the mixture was stirred at 25 ° C for 1 h under nitrogen. Saturated aqueous ammonium chloride solution was added to the reaction solution to quench the reaction. EA (25 mL) was added to the mixture for dilution, and the resulting mixture was washed with water (25 mL). The organic phase was separated and washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC to obtain compound 099 (4.39 mg).

[0475] MS m / z(ESI):401.1[M+H] + .

[0476] 1 H NMR(400MHz,CHLOROFORM-d)δ=7.56-7.49(m,2H),7.42-7.35(m,2H),7.30-7.23(m,2H) ),6.08-5.92(m,1H),3.63(d,J=5.4Hz,2H),2.44-2.38(m,3H),1.36(d,J=6.8Hz,6H).

[0477] Example 35 (R)-N-(1-hydroxy-3-methyl-2-butyl)-2-(1-((4-(trifluoromethoxy)phenoxy)imino)ethyl)thiazole-5-carboxamide (119)

[0478]

[0479] 1) Preparation of Compound 119-2

[0480] Compound 119-1 (150 mg, 0.876 mmol) was dissolved in tetrahydrofuran (3 mL) solution, and EDCI (335.98 mg, 1.753 mmol), HOBt (236.83 mg, 1.753 mmol), N,N-diisopropylethylamine (0.579 mL, 3.505 mmol) and (2R)-2-amino-3-methylbutan-1-ol (0.117 mL, 1.052 mmol) were added respectively, and the mixture was stirred at room temperature for 1 h under nitrogen protection. Water (5 mL) was added to the reaction mixture, and it was extracted with EA (25 mL). The organic phase was then washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 119-2 (119.5 mg).

[0481] 2) Step 2 Synthesis of Compound 119

[0482] Compound 119-2 (119 mg, 0.464 mmol), O-(4-(trifluoromethoxy)phenyl)hydroxylamine (90 mg, 0.466 mmol), 4A molecular sieve (120 mg, 0.438 mmol) were dissolved in AcOH (0.2 mL) and tetrahydrofuran (2 mL) solution, and tetraisopropyl titanate (0.28 mL, 0.946 mmol) was added dropwise. The mixture was stirred at 60°C for 3 hours. After the reaction was completed, the reaction mixture was cooled to 25°C and filtered. The filtrate was diluted with EA (25 mL), washed twice with saturated sodium chloride solution (5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 119 (64.62 mg).

[0483] MS m / z(ESI):432.1[M+H] + .

[0484] 1 H NMR (400MHz, DMSO-d6)δ=8.83-8.57(m,1H),8.56-8.34(m,1H),7.53-7.33(m,4H),4.85-4.55(m,1H),3.91-3.72(m,1H),3.69-3.45(m,2H),2.55(br d,J=8.0Hz,3H),2.05-1.85(m,1H),1.05-0.72(m,6H)

[0485] Example 36 N-(1-(Hydroxymethyl)cyclobutyl)-2-(1-((4-(trifluoromethoxy)phenoxy)imino)ethyl)thiazole-5-carboxamide (121)

[0486]

[0487] 1) First step: Synthesis of compound 121-2

[0488] Compound 121-1 (6.3 g, 30.65 mmol) was dissolved in 1,2-dichloroethane (30 mL), and 2-hydroxyisoindole-1,3-dione (2.5 g, 15.32 mmol), 4A molecular sieve (3.8 g, 97.12 mmol), cuprous chloride (1.67 g, 16.85 mmol) and pyridine (1.487 mL, 18.39 mmol) were added. The mixture was stirred at room temperature for 36 h under oxygen atmosphere. After the reaction was completed, the solid was filtered off, water (30 mL) was added to the system, and the mixture was extracted with dichloroethane (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL), and the organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 121-2 (2.4 g).

[0489] 2) Second step: Synthesis of compound 121-3

[0490] Compound 121-2 (500 mg, 1.547 mmol) was dissolved in a mixed solution of dichloromethane (5 mL) and methanol (0.5 mL), and hydrazine hydrate (1 mL) was added. The reaction was stirred at room temperature for 15 h. After the reaction was completed, the solid was filtered off, and the filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 121-3 (230 mg).

[0491] 3) Synthesis of the third step compound 121-5

[0492] Compound 121-4 (100 mg, 0.584 mmol) was dissolved in N,N-dimethylformamide (5 mL), (1-aminocyclobutyl)methanol (101.15 mg, 0.701 mmol), EDCI (223.99 mg, 1.168 mmol), HOBT (157.89 mg, 1.168 mmol), and N,N-diisopropylethylamine (0.305 mL, 1.753 mmol) were added, and the mixture was stirred at room temperature for 1 h under nitrogen protection. Water (5 mL) was added to the system, and the mixture was extracted with dichloromethane (5 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 121-5 (81 mg).

[0493] 4) Synthesis of the fourth step Example 121

[0494] Compound 121-5 (81 mg, 0.319 mmol) was dissolved in 1,2-dichloroethane (5 mL), O-(4-(trifluoromethoxy)phenyl)hydroxylamine (64.52 mg, 0.319 mmol) was added, and tetraisopropyl titanate (0.189 mL, 0.637 mmol) was added dropwise. The temperature was raised to 60°C and stirred for 15 h. After the reaction was completed, water (2 mL) was added to the system, the solid was filtered off, and the filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 121 (54.53 mg).

[0495] MS m / z(ESI):429.9[M+H] + .

[0496] 1 H NMR (DMSO-d 6 ,400MHz)δ8.7-8.8(m,1H),8.70(s,1H),7.4-7.5(m,3H),7.3-7.4(m,1H),4.8- 5.0(m,1H),3.6-3.7(m,2H),2.5-2.6(m,3H),2.1-2.3(m,4H),1.7-1.9(m,2H).

[0497] Example 37 N-(1-(Hydroxymethyl)cyclobutyl)-5-(1-((4-(trifluoromethyl)phenoxy)imino)ethyl)thiophene-2-carboxamide (126)

[0498]

[0499] 1) Preparation of Compound 126-2

[0500] Compound 126-1 (99.4 mg, 0.584 mmol) was dissolved in N,N-dimethylformamide (5 mL), (1-aminocyclobutyl)methanol (101.15 mg, 0.701 mmol), EDCI (223.99 mg, 1.168 mmol), HOBT (157.89 mg, 1.168 mmol), and N,N-diisopropylethylamine (0.305 mL, 1.753 mmol) were added, and the mixture was stirred at room temperature for 1 h under nitrogen protection. Water (5 mL) was added to the system, and the mixture was extracted with dichloromethane (5 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 126-2 (81 mg).

[0501] 2) Second Step Synthesis of Example 126

[0502] Compound 126-2 (81 mg, 0.319 mmol) was dissolved in 1,2-dichloroethane (5 mL) solution, compound O-(4-(trifluoromethoxy)phenyl)hydroxylamine (64.52 mg, 0.319 mmol) was added, and tetraisopropyl titanate (0.189 mL, 0.637 mmol) was added dropwise. The temperature was raised to 60°C and stirred for 15 h. Water (2 mL) was added to the reaction mixture, the solid was filtered off, and the filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 126 (54.53 mg).

[0503] MS m / z(ESI):413.1[M+H] + .

[0504] 1 H NMR (400MHz, METHANOL-d4) δ = 7.78-7.47 (m, 5H), 7.41 (d, J = 8.6Hz, 1H), 3.85 (d,J=5.6Hz,2H),2.50(d,J=6.5Hz,3H),2.41-2.17(m,4H),2.03-1.81(m,2H)

[0505] Biological tests:

[0506] Test Example 1.TEAD reporter gene experiment-MCF7

[0507] Cells: Hippo Pathway / TEAD Luciferase Reporter MCF7 cells (BPS Bioscience, 60618).

[0508] step:

[0509] 1. Before the experiment, preheat the growth medium (BPS Bioscience, 79531) in a 37°C water bath.

[0510] 2. Take out MCF7 cells (BPS Bioscience, 60618) from the 37°C constant temperature incubator and wash once with PBS.

[0511] 3. Add 2 mL of trypsin to a T75 cell culture flask and incubate at 37°C under CO 2 Digest for 3 minutes in an incubator.

[0512] 4. Add 4.5 mL of culture medium to stop digestion, collect cells in a 50 mL centrifuge tube, centrifuge at 1000 rpm for 5 min, discard the supernatant, and resuspend the cells in 10 mL of fresh culture medium.

[0513] 5. Mix 30 μL of cell suspension with 30 μL of trypan blue and count using a cell counter.

[0514] 6. Adjust the cell density to 2.5 x 10 5 / mL, 40 μL of cells were seeded into each well of a white transparent bottom 384-well microplate (Corning, 3765).

[0515] 7. Incubate cells at 37°C, CO 2 Incubate overnight in an incubator.

[0516] 8. Add 40 μL of compound to 384-well microplate using Ehco 650. The final concentration of DMSO in the assay medium is 0.1%.

[0517] 9. At 37°C, CO 2 The cells were cultured in an incubator for 24 hours.

[0518] 10. Add 20 μL ONE-Step to each well TM Luciferase Assay System (BPS, 60690) reagents were stabilized at room temperature for 5 minutes, and the luminescence value was measured using EnVision Xcite Multilabel Reader (PerkinElmer, 2105-0020).

[0519] 11. Data processing:

[0520] %Inhibition={(Signalcompound-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)}×100

[0521] IC50 (nM) calculation: Calculated using the curve fit (Prism 9, non-liner inhibitor, 4 parameter) algorithm in the Prism 9 software Curve fit.

[0522] Signalcompound: signal value of drug-added group;

[0523] SignalAve_PC: average signal value of Yangshen group;

[0524] SignalAve_VC: average signal value of DMSO control group;

[0525] The results are shown in Table 1. The IC 50 The value levels are as follows:

[0526] A: IC 50≤50nM; B:50nM <IC 50 ≤300nM; C: 300nM <IC 50 ≤1000nM; D:IC 50 >1000nM.

[0527] Table 1

[0528] Compound No. <![CDATA[TEAD reporter gene assay IC 50 (nM)]]> 001 C 002 C 031 A 032 A 033 D 036 D 037 D 039 D 041 A 046 B 047 B 048 A 093 A 070 A

[0529] The experimental results show that the compounds of the present application have the ability to inhibit TEAD reporter gene activity.

[0530] Test example 2. Chemiluminescence assay to detect the effect of the compound of the present invention on the viability of NCI-H226 cells

[0531] 1. Preparation before experiment: Corning CellTiter- Detection kit: Promega, catalog number: G7570; iD3 microplate reader.

[0532] 2. NCI-H226 cell culture: NCI-H226 derived from ATCC catalog number: CRL-5826 was cultured in 89% RPMI-1640 + 10% FBS + 1% double antibody in a 5% CO 2 37℃ constant temperature incubator.

[0533] 3. Day 1: When the cell confluence rate reaches 90%, remove the culture medium, add 3 mL PBS to wash the residual culture medium, add 1 mL Trypsin and incubate in the incubator for 5 min. After most of the cells fall off, add 2 mL culture medium to stop digestion. Dilute the cell concentration to 5X10 3 / mL, in 500 cells / well were plated in a 96-well black transparent bottom cell plate, i.e. 100uL was added to each well.

[0534] 4. Administration on the second day: Take out 10mM TEAD inhibitor storage solution and thaw at room temperature to prepare the following concentrations of working solution: 0.0015μM, 0.0046μM, 0.0137μM, 0.0412μM, 0.1235μM, 0.3704μM, 1.1111μM, 3.3333μM, 10μM. 0.6mL complete medium + 1.2μL 10mM storage solution to prepare a 20μM working solution; take 0.2mL of the above solution and add it to 0.4mL complete medium to prepare a 6.6666μM working solution, and prepare other concentrations by 3-fold gradient dilution. Add 100μL of working solution to the 96-well plate with cells.

[0535] 5. Replace the solution with fresh one on the third day after adding the medicine.

[0536] 6. On the 6th day of administration Kit detection: Select the CellTiter-Glo detection program on the microplate reader and read the luminescence value.

[0537] Data processing: cell viability value = 100 × (luminescence value of drug-added well - luminescence value of blank well) / (luminescence value of solvent well - luminescence value of blank well). IC50 calculation: the cell viability value and the corresponding drug concentration value were calculated using the (log (inhibitor) vs. normalized response--Variable slope algorithm in Curve fit of Prism 8 software.

[0538] The selectivity results are shown in Table 2 below. The H226IC 50 Value grade: A:IC 50 ≤100nM; B:100nM <IC 50 ≤500nM; C: 500nM<IC 50 ≤1000nM.

[0539] Table 2

[0540] Compound No. <![CDATA[H226 anti-proliferation IC 50 > 001 C 031 C 032 A 039 C 040 B 042 B 093 B 070 B 075 C 086 B 099 A 114 C 119 A 121 A 124 B 126 A 127 C 131 C 132 B 139 B 140 B 141 B

[0541] The experimental results show that the compounds of the present application can effectively inhibit the proliferation of target-sensitive tumor cells H226.

[0542] Test Example 3. In vivo PK test

[0543] 1. Experimental Animals

[0544] Six ICR mice were divided into two groups, oral and intravenous, with three mice in each group. The mice were fasted for 10-14 hours before administration and had free access to water.

[0545] 2. Preparation of drug preparations

[0546] The compound to be tested is weighed according to the dosage, and prepared into a dosage preparation of appropriate concentration with a solvent (commonly used 5% DMSO + 10% Solutol (polyethylene glycol-15 hydroxystearate) + 85% saline) (the volume of intravenous and oral administration to mice is 5 mL / kg and 10 mL / kg, respectively). The intravenous injection is a clear solution, and the oral dose is a clear solution or a uniform suspension.

[0547] 3. Animal medication and blood sample collection

[0548] Animals were dosed by intravenous injection and oral gavage, and blood samples were collected at 0.033h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after intravenous injection and 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after oral administration. Whole blood was centrifuged at 4°C, 6800g for 6min, and the upper plasma was stored in a -80°C refrigerator for analysis.

[0549] 4. Plasma sample testing

[0550] Take the DMSO stock solution of the test substance and dilute it with methanol or acetonitrile solution to form a series of working solutions, add it to the blank plasma matrix, and prepare the 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 for protein precipitation. Centrifuge all samples at 4℃, 18000g for 10min, and take an appropriate amount of supernatant for LC-MS / MS injection analysis.

[0551] 5. Parameter calculation

[0552] The plasma drug concentration-time curve was drawn according to the test concentration, and WinNonlin software was used to calculate the non-compartmental model, including: half-life (T 1 / 2 ), area under the drug-time curve (AUC 0-t ), peak plasma concentration (C max ) and other pharmacokinetic parameters. The results are shown in Table 3.

[0553] Table 3

[0554]

[0555]

[0556] The experimental results show that the compound of the present application has excellent pharmacokinetic properties.

[0557] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. All technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A compound having a structure represented by formula (I), or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; Ring A is selected from: 5-10 membered heteroaryl, C 6-10 Aryl, 5-6 membered heterocyclic group; Ring B is selected from: C 3-8 Monocyclic alkyl, C 5-12 Bridged bicycloalkyl, C 5-12 Spirobicycloalkyl, C 5-12 Fused bicycloalkyl, C 6-10 Aryl, 5-12 membered heteroaryl; Z 1 Select from: O or NR z1 ; R z1 Selected from H, deuterium, C 1-6 alkyl; R 1 Selected from: -NHS(=O)2-R 1a 、-NHC(=O)-R 1a 、-(4-6-membered nitrogen heterocyclic group)-C(=O)-R 1a , -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O)2NH-R 1a 、-NH-R 1a , C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)NH-R 1a 、-C(=O)NR 1a R 1b or -C(=O)-R 1a ; where R 1a and R 1b Each independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally, R 1a and R 1b Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring or a 5-12 membered aromatic heterocyclic ring; R 1a and R 1b C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, or R 1a and R 1b Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring or a 5-12 membered aromatic heterocyclic ring, each independently optionally substituted by 1, 2, 3 or 4 R 1c Replace, each R 1c are independently selected from halogen, oxo, hydroxy, C 1-6 Alkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; R 1c C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently substituted with halogen, oxo, hydroxyl, C 1-6 Alkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Substitution of cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl; R 2 C 1-6 alkyl; R 4 Each independently selected from: H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein, R 4 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily replaced by 1, 2 or 3 selected from C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted; optionally, two R 4 , together with the atoms to which they are attached, form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring; Optionally, ring A and R 4 , CR 2 Together they form a parallel ring structure; R 5 Each independently selected from: halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein Ring A is a 5-membered heteroaryl group, a 6-membered heteroaryl group, a phenyl group or a 6-membered heterocyclic group; Preferably, ring A is # indicates the same as R 1 * indicates the connection with CR 2 The connection point, X 1 N or CR 41 ; X 2 N or CR 42 ; X 3 N or CR 43 ; X 4 N or CR 44 ; X 5 is S, O or NH; R 41 , R 42 , R 43 and R 44 Each independently selected from: H, deuterium, halogen, C 1-6 Alkyl, C 1-6 alkoxy, 5-6 membered heteroaryl or phenyl; wherein R 41 , R 42 , R 43 and R 44 The 5-6 membered heteroaryl and phenyl are each independently and arbitrarily replaced by 1, 2 or 3 selected from C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted; optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44 , when in the ortho position, together with the atoms to which they are attached, form a 5-6 membered carbocyclic group, a 5-6 membered heterocyclic group, a phenyl group or a 5-6 membered heteroaryl group; Preferably, R 41 , R 42 , R 43 and R 44 Each independently selected from: H, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 alkoxy, 5-6 membered heteroaryl or phenyl; wherein R 41 , R 42 , R 43 and R 44 The 5-6 membered heteroaryl and phenyl are each independently substituted by 1, 2 or 3 substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy; optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44 , when in the ortho position, together with the atoms to which they are connected, form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; Preferably, R 41 , R 42 , R 43 and R 44 Each is independently selected from: H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenyl, Optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44 , when in the adjacent position, together with the atoms to which they are attached, form Preferably, R 41 , R 42 , R 43 and R 44 are each independently selected from: H, deuterium, fluorine, methyl or methoxy; optionally, R 41 and R 42 , or R 42 and R 43 , or R 41 and R 44 , when in the adjacent position, together with the atoms to which they are attached, form Optionally, ring A and R 4 , CR 2 Together they form a ring structure, the ring structure being selected from * indicates the connection with N in NO group, # indicates the connection with R 1 The position of the bonding; optionally, the hydrogen on the carbon or nitrogen in the ring structure can be selected from deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-4 The alkoxy group is substituted with one or more substituents, wherein the substituted C 1-6 The substituents in the alkyl group are selected from deuterium, fluorine, chlorine, bromine, cyano, and hydroxyl; Preferably, ring A is selected from: phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, furanyl or thiadiazolyl; Preferably, ring A is selected from: # indicates the same as R 1 * indicates the connection with CR 2 The connection point; Preferably, ring A is selected from: phenyl, pyridyl, pyrimidinyl, thienyl or thiazolyl; Preferably, ring A is selected from: pyridyl, thienyl or thiazolyl; More preferably, Ring A is selected from: # indicates the same as R 1 * indicates the connection with CR 2 connection.

3. The compound according to claim 1, wherein Ring B is selected from: C 3-8 Monocyclic alkyl, C 5-12 Bridged bicycloalkyl, C 5-12 Spirobicycloalkyl, C 5-12 Fused bicycloalkyl or C 6-10 Aryl; Preferably, ring B is selected from: C 3-6 Monocyclic alkyl, C 5-10 Bridged bicycloalkyl, C 5-10 Spirobicycloalkyl, C 5-10 Fused bicycloalkyl, phenyl, pyridyl or pyrimidyl; Preferably, ring B is selected from: cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, phenyl, pyridyl, Preferably, ring B is selected from: cyclobutyl, cyclohexyl, cyclohexenyl, phenyl, pyridyl, Preferably, ring B is selected from: cyclobutyl, cyclohexyl or phenyl.

4. The compound according to claim 1, wherein Z 1 Select from: O or NR z1 ; R z1 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl or butyl; Preferably, Z 1 Select from: O or NR z1 ; R z1 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl or butyl; Preferably, Z 1 Selected from: O or NH; Preferably, Z 1 Selected from: O.

5. The compound according to claim 1, wherein R 1 Selected from: -NHS(=O)2-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(4-6 membered nitrogen heterocyclic group)-C(=O)-C 1-6 alkyl, -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O)2NH-C 1-6 Alkyl, -S(=O)2NH-C 2-6 Alkenyl, -S(=O)2NH-C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -NH-C 5-6 Cycloalkyl, -NHS(=O)2-C 2-6 Alkenyl, -NHC(=O)-C 2-6 Alkenyl, -NHS(=O)2-C 2-6 Alkynyl, -NHC(=O)-C 2-6 Alkynyl, C 1-6 Alkyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 1-6 Alkoxy, -C(=O)NH-C 3-6 Cycloalkyl or -C(=O)NH-(3-6 membered heterocyclic group); wherein R 1 C 1-6 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from halogen, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, halogen, amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NHC(=O)OC 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-6 Substitution of cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl; Preferably, R 1 Selected from: -NHS(=O)2-C 1-4 Alkyl, -NHC(=O)-C 1-4 alkyl, -C(=O)OH, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, -S(=O)2NH-C 1-4 Alkyl, -S(=O)2NH-C 2-4 Alkenyl, -S(=O)2NH-C 2-4 Alkynyl, -NH-C 1-4 Alkyl, -NH-C 5-6 Cycloalkyl, -NHS(=O)2-C 2-4 Alkenyl, -NHC(=O)-C 2-4 Alkenyl, -NHS(=O)2-C 2-4 Alkynyl, -NHC(=O)-C 2-4 Alkynyl, C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkoxy, -C(=O)NH-C 3-6 Cycloalkyl or -C(=O)NH-(3-6 membered heterocyclic group); wherein R 1 C 1-4 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, C 2-4 Alkenyl, C 2-4 Alkynyl, C 5-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl; Preferably, R 1 Selected from: trifluoromethyl, -NHS(=O)2-CH3, -S(=O)2NH-CH3, -NHC(=O)-CH3, -C(=O)OH, -NHC(=O)-CH=CH2, -NHC(=O)-CF=CH2, -NHS(=O)2-CH=CH2, -NHS(=O)2-CF=CH2, -C(=O)NH-CH(CH3)CH2OH, -C(=O)NH-CH(CH3)CH2OCH3, -C(=O)NH-CH(CH3)-pyridyl, -C(=O)NH-CH(phenyl)-CH2OH, -C(=O)NH-cyclobutyl-hydroxy -C(=O)NH-cyclobutyl-methoxy, -C(=O)NH-tetrahydropyranyl, -C(=O)NHCH3, -C(=O)NH-O-CH(CH3)CH2OH, -C(=O)NH-C(CH3)2CH2OH, -C(=O)NH-CH(CH3)-pyridyl-NH2, -C(=O)NH-CH(pyridyl)-CH2OH, -C(=O)NH-CH(isopropyl)-CH2OH, -C(=O)NH-cyclobutyl-CH2OH, -C(=O)NH-CH(CH2CH3)CH2OH, -C(=O)NH-fluorocyclobutyl-CH2OH, Preferably, R 1 Selected from: trifluoromethyl, -NHS(=O)2-CH3, -S(=O)2NH-CH3, -NHC(=O)-CH=CH2, -NHC(=O)-CF=CH2, -NHS(=O)2-CH=CH2, -C(=O)NH-CH(CH3)CH2OH, -C(=O)NH-CH(CH3)CH2OCH3, -C(=O)NH-CH(CH3)-pyridyl, -C(=O)NH-CH(pyridyl)-CH2OH, -C(=O)NH-CH(isopropyl)-CH2OH, -C(=O)NH-CH(CH2CH3)CH2OH, -C(=O)NH-C(CH3)2CH2OH、 Preferably, R 1 Selected from: -NHC(=O)-CH=CH2, -C(=O)NH-CH(CH3)CH2OH, -C(=O)NH-CH(CH3)CH2OCH3, -NHC(=O)-CF=CH2, -C(=O)NH-C(CH3)2CH2OH, -C(=O)NH-CH(isopropyl)-CH2OH or Preferably, R 1 Selected from: -NHC(=O)-CF=CH2, -C(=O)NH-C(CH3)2CH2OH, -C(=O)NH-CH(isopropyl)-CH2OH or More preferably, R 1 for R 2 Selected from C 1-4 Alkyl; preferably, R 2 is methyl or ethyl; more preferably, R 2 is methyl; R 4 Each independently selected from: H, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein R 4 The 5-6 membered heteroaryl and phenyl are each independently substituted by 1, 2 or 3 substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy; optionally, two R in the ortho position 4 , together with the atoms to which they are attached, form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring; Preferably, R 4 Each is independently selected from: H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenyl, Optionally, two R in ortho position 4 , together with the atoms to which they are attached, form Preferably, R 4 Each independently selected from: H, deuterium, fluorine, methyl, methoxy; optionally, two R in ortho position 4 , together with the atoms to which they are attached, form R 5 Each independently selected from: halogen, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; preferably, R 5 Each is independently selected from: fluorine, trifluoromethyl, trifluoromethoxy; preferably, R 5 Each independently selected from: trifluoromethyl and trifluoromethoxy; m is 0, 1 or 2; preferably, m is 0 or 1; n is 0, 1 or 2; preferably, n is 1 or 2.

6. The compound according to claim 1, wherein The compound has a structure represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or is an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the structure represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX); Among them, X 1 N or CR 41 ; X 2 N or CR 42 ; X 3 N or CR 43 ; X 4 N or CR 44 ; X 5 O, S or NH; R 41 , R 42 , R 43 and R 44 Each independently selected from: H, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl, phenyl; wherein R 41 , R 42 , R 43 and R 44 The 5-6 membered heteroaryl and phenyl are each independently substituted by 1, 2 or 3 substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy; optionally, in formula III, R 41 and R 44 , together with the atoms to which they are attached, form a 5-6 membered heterocyclyl, a 5-6 membered heteroaryl; or optionally, in Formula IV, R 41 and R 44 , or R 41 and R 42 , together with the atoms to which they are attached, form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; p is each independently 1, 2 or 3; n is each independently 1 or 2; R 1a and R 1b The definition of R is the same as that in claim 1; 2 and R 5 The same as defined in any one of claims 1 to 5; Preferably, R 1a and R 1b are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein R 1a and R 1b C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclylphenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl; Preferably, R 1a and R 1b Each is independently hydrogen, -CH3, -CH=CH2, -CF=CH2, -CH(CH3)CH2OH, -CH(CH3)CH2OCH3, -CH(CH3)-pyridyl, -CH(phenyl)-CH2OH, -cyclobutyl-hydroxy, -cyclobutyl-methoxy, -tetrahydropyranyl, O-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH(CH3)-pyridyl-NH2, -CH(pyridyl)-CH2OH, -CH(isopropyl)-CH2OH, -cyclobutyl-CH2OH, -CH(CH2CH3)CH2OH, -fluorocyclobutyl-CH2OH; Preferably, R 1b is hydrogen, R 1a for Preferably, R 41 , R 42 , R 43 and R 44 Each is independently selected from: H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenyl, Preferably, R 41 , R 42 , R 43 and R 44 Each is independently selected from: H, deuterium, fluorine, methyl or methoxy.

7. The compound according to claim 1, wherein The compound has a structure represented by formula (I-1) or (I-2) or is an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the structure represented by formula (I-1) or (I-2); Among them, R 1a , R 2 , R 5 , n is as defined in claim 1, X 2 The definition of is the same as that of claim 2 or 6, and the definition of p is the same as that of claim 6; Preferably, in formula (I-1), R 1a C 1-4 Alkyl or C 3-6 Cycloalkyl, R 1a C 1-4 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl; preferably, R 1a for X 2 N or CH; R 2 C 1-3 Alkyl, preferably methyl or ethyl; R 5 Each independently selected from fluorine, fluorinated C 1-4 Alkyl and fluorinated C 1-4 Alkoxy, preferably fluorine, trifluoromethyl and trifluoromethoxy; n is 1 or 2; Preferably, in formula (I-2), R 1a C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl, where R 1a C 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Each alkynyl group is independently optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, oxo, fluoro, hydroxy, amino, hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy and pyridyl; preferably, R 1a Halogenated C 2-4 Alkenyl, more preferably R 2 C 1-3 Alkyl, preferably methyl or ethyl, R 5 Each independently selected from fluorine, fluorinated C 1-4 Alkyl and fluorinated C 1-4 Alkoxy, preferably fluorine, trifluoromethyl and trifluoromethoxy; p is 1, 2 or 3; n is 1 or 2.

8. The compound according to claim 1, wherein The compound has the structure shown below or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; 9. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 8 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug and at least one pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the composition according to claim 9 in the preparation of a medicament for inhibiting the protein-protein interaction between a functional protein and TEAD to prevent and / or treat cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction, preferably, the functional protein comprises YAP and / or TAZ; Preferably, the cancer and other hyperproliferative disorders and diseases are selected from the group consisting of: breast cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, brain cancer, kidney cancer, testicular cancer, urethral cancer, rectal cancer, fallopian tube cancer, penis cancer, vaginal cancer, stomach cancer, skin cancer, melanoma, liver cancer, gastrointestinal stromal tumors, urothelial cancer, thyroid cancer, parathyroid cancer, adrenal cancer, bone cancer, oral cancer, ovarian cancer, uterine cancer, head and neck squamous cell carcinoma, endometrial cancer, gallbladder cancer, bladder cancer, oropharyngeal cancer, lymph node cancer, glioblastoma, astrocytoma, glioblastoma multiforme or soft tissue sarcoma, fibrosarcoma, chondrosarcoma, hemangioma, teratoma, lipoma, myxoma, fibroma, rhabdomyoma, teratoma, bile duct cancer, Ewing's sarcoma, leukemia, myeloma, lymphoma, spinal cord cancer; Preferably, the cancer is selected from lung cancer, gastric cancer, breast cancer, head and neck squamous cell carcinoma; Preferably, the cancer is lung cancer.

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