Protein tyrosine phosphatase inhibitors, compositions containing the same, and their medical use

Abstract

The present invention provides compounds or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitric oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, as well as compositions containing such compounds and their medical uses. The compounds have good pharmaceutically promising embodiments for treating or preventing diseases or disorders related to PTPN2.

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application Publication No. CN202310857115.1 filed on 11 July 2023 and Chinese Patent Application Publication No. CN202311171624.5 filed on 12 September 2023, the contents of which are incorporated herein by reference in whole and for all purposes.

[0002] This invention relates to the medical field, and more particularly to protein tyrosine phosphatase inhibitors and compositions thereof, and their pharmaceutical use. [Background technology]

[0003] Immune checkpoint inhibitors represented by PD-1 antibodies have revolutionized the treatment of many cancers, yet the majority of patients do not benefit from these PD-1 blocking therapies. This situation has prompted some research teams to work on finding new immunotherapy targets—developing novel immunotherapeutic agents that can be used for cancer patients who do not respond to PD-1 antibodies, or therapies that can work in conjunction with PD-1 antibodies to enhance their anti-cancer efficacy.

[0004] PTPN2, also known by its full name TC-PTP, is a protein tyrosine phosphatase nonreceptor type 2 and a member of the protein tyrosine phosphatase (PTP) family. PTPN2 shares 74% sequence homology and 86% structural similarity with its congener family protein, PTPN1 (also known as PTP1B). As signaling factors, members of this family are involved in regulating various signaling pathways and cellular processes, including cell growth, differentiation, mitotic cycles, and oncogenic transformation. The PTPN2 protein contains an N-terminal kinase domain and a C-terminal non-catalytic domain, and the nuclear localization signal (NLS) at the C-terminus is involved in the autoregulation of catalytic activity and the determination of subtype localization. Due to alternative splicing, PTPN2 has two isoforms, TC45 and TC48, and differences in the C-terminal region cause different subtypes to be positioned at different locations, thereby affecting their substrate selection. PTPN2 negatively modulates the signaling of certain receptor protein tyrosine kinases (including INSR, EGFR, CSF1R, and PDGFR), non-receptor protein tyrosine kinases (such as JAK1, JAK2, and JAK3), transcription factors (STAT1, STAT3, and STAT6), and Src family kinases (Fyn and Lck). PTPN2 may also negatively modulate inflammatory cytokine (IL-2 and interferon) mediated signaling via dephosphorylation of JAK1 and JAK3 and their substrate signaling and transcriptional activator 1 (STAT1).

[0005] Related studies have shown that inhibiting the PTPN2 immunomodulatory factor promotes anti-tumor immunity, thereby enabling the elimination of tumors. Specifically, by deleting the gene that expresses PTPN2 from the immune system (CD8+ T cells) of cancer-bearing mice, the production and adaptability of killer T cells that fight infection and cancer can be stimulated. In one experiment, deleting PTPN2 eliminated colon cancer in all mice. Additionally, in another experiment, it was shown that deletion of PTPN2 in combination with PD-1 blockade therapy successfully eliminated one-fourth of melanomas in mice with highly invasive and treatment-resistant cancers. Summary of the Invention Means for Solving the Problems

[0006] (Gist of the Invention) To solve the above technical problems existing in the prior art, the present invention provides a novel PTPN2 inhibitor that has good prospects for drug development in the treatment or prevention of diseases or disorders related to PTPN2.

[0007] Specifically, On the one hand, the present invention relates to formula (I-1) or (I-2)

[0008] [Chemical Formula] (In the formula, R , 1~6 , 2a and R 1b are each independently selected from H, D, halogen, -OH, C​​​​​​​​​​​​​​​​​​​​​​1~8 Alkyl, C 2~8 Alkenil, C 3~6 Cycloalkyl, 5-6 member heteroaryl, 4-8 member heterocyclyl, -OC 1~8 Alkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-(4-8 member heterocyclyl),-OC(=O)-N(R) a )-C 1~8 Alkyl, -OC(=O)-N(R a )-phenyl, -N(R a )-C 1~8 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl), -N(R a )-C(=O)-C 1~8 Alkyl, -N(R a )-C(=O)-OC 1~8 Alkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-Si(R c )3, -N(R a )-(C=N(R b ))-C 1~8 Alkyl, -N(R a )-S(=O) w -C 1~8 Alkyl, -N(R a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~6 Alkylene-phenyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkilen-(4-8 member heterocyclyl),-C 1~6 Alkylene-N(R) a )(R b ), -C1~6 Alkylene-N(R a )-C(=O)-O-C 1~8 Alkyl, -C 1~6 Alkylene-N(R a )-C 1~8 Alkyl, -C 1~6 Alkylene-N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkylene-N(R a )-C(=O)-C 1~8 Alkyl, -C 1~6 Alkylene-N(R a )-C 1~6 Alkylene-(4- to 8-membered heterocyclyl), -C 1~6 Alkylene-N(R a )-C 1~6 Alkylene-(5- to 6-membered heteroaryl), -C 1~6 Alkylene-N(R a )-C 1~6 Alkylene-phenyl, -C 1~6 Alkylene-O-C 1~8 Alkyl, -C 1~6 Alkylene-O-C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkylene-O-C 1~6 Alkylene-(4- to 8-membered heterocyclyl), -C 1~6 Alkylene-O-C 1~6 Alkylene-N(R a )(R b )、-S(=O) w -C 1~8 Alkyl and -C(=O)-N(R a )-C 1~8 selected from alkyl, where the replaceable carbon atoms of R 2a are each independently and optionally substituted by one or more substituents independently selected from R g ; and / or the replaceable nitrogen atoms on the ring of R 2a are each independently and optionally substituted by one or more substituents independently selected from R h ; R 2b is selected from H, D, -OH, halogen, -N(R a )(R b ) and -N(R a )-N(R b )-C(O)-phenyl; R 3 , R 3a and R 3b are each independently selected from H, D, halogen, -OH, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 3~6 cycloalkyl, C 3~6 halocycloalkyl, -NH2, -NH(C 1~6 alkyl) and -N(C 1~6 alkyl)(C 1~6 alkyl); X 1 is selected from O, S, NR f and C(R e )(R d ); R a and R b are each independently selected from H and C 1~6 ]>alkyl; optionally, C 1~6 alkyl is substituted with one or more substituents selected from halogen, -CN, oxo and -OH; R<000-0121>is selected from -OH, C 1~6 alkyl and phenyl; R e and R d are each independently selected from H, D, halogen, -OH, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 3~6 cycloalkyl, C 3~6 halocycloalkyl, -NH2, -NH(C 1~6 alkyl) and -N(C 1~6 1~6 alkyl); optionally, R​e and R 3a They, together with the atoms they connect to, form a 3- to 7-membered carbocyclic ring; or R e and R 2b These, together with the atoms they connect to, form a 3- to 7-membered carbon-cyclic ring; R f H, C 1~6 Alkyl and C 1~6 Selected from haloalkyls; optionally, R f and R 3a These, together with the atoms they connect to, form a heterocyclic ring of 3 to 7 members; or R f and R 2b These, together with the atoms they connect to, form a heterocyclic ring of 3 to 7 members; Each R g H, D, halogen, -OH, -CN, nitro, oxo, -NH2, -NH(C) 1~6 Alkyl), -N(C 1~6 Alkyl)(C 1~6 Alkyl), C 1~6 Alkyl and C 1~6 Independently selected from haloalkyl groups; R h H, D, C 1~6 Alkyl and C 1~6 Selected from haloalkyl; n is selected from 0 or 1; p is selected from 0, 1, 2, or 3; q is selected from 0, 1, 2, 3, or 4; w is selected from 1 or 2. The present invention provides compounds having a structure represented by [the given formula], or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs.

[0009] On the other hand, the present invention provides a pharmaceutical composition comprising the compound according to the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, and at least one pharmaceutically acceptable carrier.

[0010] On the other hand, the present invention provides compounds or enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs thereof, or compositions according to the present invention, for treating or preventing diseases or disorders related to PTPN2.

[0011] On the other hand, the present invention provides the use of compounds according to the present invention or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, or compositions according to the present invention, in the preparation / manufacturing of pharmaceuticals for treating or preventing diseases or disorders related to PTPN2.

[0012] On the other hand, the present invention provides a method for treating or preventing a disease or disorder related to PTPN2, comprising administering a therapeutically effective amount of a compound according to the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or composition according to the present invention, to a person in need.

[0013] On the other hand, the present invention relates to methods for preparing, separating, and purifying compounds represented by formulas (I-1), (I-2), (II-0), (II-1), (II-2), (III-0), (III-1), (III-2), (IV-1), (IV-2), (V), (V-1), (VI-0), and (VI-1).

[0014] Any embodiment of any aspect of the present invention may be combined with another embodiment, provided they do not conflict. Furthermore, any technical feature in any embodiment of any aspect of the present invention may be applied to a technical feature in another embodiment, provided they do not conflict.

[0015] The foregoing description summarizes only certain aspects of the present invention, but is not limited to these aspects. The contents of these and other aspects are described more specifically and completely below. All references in this specification are incorporated herein by reference in their entirety. [Modes for carrying out the invention]

[0016] To make the object, technical solution, and advantages of the present invention clearer and more understandable, the present invention is described in further detail in conjunction with embodiments in the following section. The specific embodiments described herein are used solely for the purpose of illustrating the present invention and are not intended to constitute any limitation of the invention. Furthermore, in the following description, descriptions of well-known structures and techniques have been omitted to avoid unnecessary confusion of the concepts of this disclosure. Such structures and techniques are also described in numerous publications.

[0017] definition Certain embodiments of the present invention are described in detail herein, examples of which are illustrated by the accompanying structural and chemical formulas. The present invention is intended to encompass all substitutions, modifications and equivalent technical solutions, all of which fall within the scope of the present invention as defined by the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used in practicing the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more combined documents, patents and similar materials differ from or conflict with this application (including, but not limited to, defined terms, application of terms, described science and technology, etc.), this application shall prevail.

[0018] For clarity, it should be further recognized that certain features of the present invention described in multiple separate embodiments may, as an alternative, be provided in combination in a single embodiment. Conversely, various features of the present invention, described in a single embodiment for simplicity, may, as an alternative, be provided individually or in any suitable secondary combination.

[0019] Unless otherwise specified, all technical terms used in this invention have the same meaning as those commonly understood by those skilled in the art. All patents and publications relating to this invention are incorporated herein by reference in their entirety.

[0020] Unless otherwise indicated, the following definitions as used herein apply. For the purposes of this invention, chemical elements are consistent with the CAS version of the periodic table 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 contents of which are incorporated herein by reference.

[0021] Unless otherwise indicated or there is a clear contrast in context, the parts of speech "a," "an," and "the," as used herein, are intended to include "at least one" or "one or more." Therefore, as used herein, these parts of speech refer to one or more (i.e., at least one) objects. For example, "component" refers to one or more components, i.e., there may be more than one component intended for adoption or use in the practice of the embodiments described.

[0022] The term "subject" refers to an animal. Typically, the animal is a mammal. The subject may also refer to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In one particular embodiment, the subject is a primate. In another embodiment, the subject is a human.

[0023] The term “patient” refers to a human being (including adults and children) or another animal. In some embodiments, “patient” refers to a human being.

[0024] The terms “comprise(s),” “comprising,” “include(s),” “included,” “including,” “encompass,” “contain(s),” or “containing” are open expressions that include the content specified in the present invention but do not exclude other content.

[0025] When substituents are described by a conventional chemical formula written from left to right, the substituents include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0026] The term "enantiomer" refers to two incompatible isomers of a compound that are mirror images of each other.

[0027] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Diastereomer mixtures can be separated by electrophoresis and chromatography, such as HPLC, which are high-resolution analytical procedures.

[0028] The terms "racemate," "racemi," or "racemic mixture" refer to an equimolar mixture of two enantiomers that lack optical activity.

[0029] The term "tautomer" or "tautomer form" refers to structural isomers that have different energies and can be converted to each other across low-energy barriers. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) are involved in interconversions carried out by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. In another example,

[0030] [ka] Valence tautomers are involved in interconversion that occurs through the rearrangement of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypenta-3-en-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 indicated, all tautomer forms of the compounds of the present invention are within the scope of the present invention.

[0031] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the way their atoms or groups are arranged in space. Examples of stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and atropisomers.

[0032] The term "geometric isomer" is also called "cis-trans isomer," which refers to isomers caused by double bonds (including olefin double bonds, C=N double bonds, and N=N double bonds) or single bonds of ring carbon atoms that cannot rotate freely.

[0033] The stereochemical definitions and rules used in this 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, i.e., 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 stereochemistry of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols used to identify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory, and the prefix (+) or d indicates that the compound is dextrorotatory. Certain stereoisomers are enantiomers, and mixtures of such isomers are called enantiomer mixtures. A mixture of enantiomers in a 50:50 ratio is called a racemic mixture or racemate, which can result from a lack of stereoselectivity or stereospecificity in a chemical reaction or process.

[0034] Any chiral atom (e.g., carbon) of the compounds disclosed by the present invention may exist in racemic or enantiomerically enriched forms, for example, in (R), (S), or (R,S) configurations. In certain embodiments, each chiral atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in terms of the (R) or (S) configuration.

[0035] Depending on the selection of starting materials and processes, the compounds according to the present invention may exist in the form of one or a mixture thereof of its possible isomers, for example, racemates and diastereomer mixtures (depending on the number of chiral carbon atoms). Optically active (R) or (S) isomers can be prepared using chiral synthons or chiral reagents, or can be divided using the prior art. If the compound contains a double bond, the substituent may have an E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration.

[0036] Any mixture of the resulting stereoisomers can be separated, for example, by chromatography and / or fractional crystallization into pure or substantially pure geometric isomers, enantiomers, or diastereomers based on differences in the physicochemical properties of their constituent components.

[0037] Any resulting racemic final product or intermediate can be separated into optical enantiomers by methods familiar to those skilled in the art, for example, by separation of the diastereomer salts obtained as they are. Alternatively, the racemic product can be separated by chiral chromatography, for example, by high-performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis; see, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd edition, Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolution sp.268 (ELEliel, editor, Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G., editor, Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim, Germany, 2007).

[0038] The term "nitrogen oxide" or "N-oxide" refers to the fact that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amines can form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pp. 509-514) by treatment with an oxidized form, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). In particular, N-oxides can be prepared by the method of LWDeady (Syn.Comm. 1977, 7, 509-514), where, for example, the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0039] The term "metabolite" refers to a product obtained by the metabolism of a particular compound or a salt thereof in vivo. Metabolites of compounds can be identified by techniques well known in the art, and their activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by complete contact of the compounds of the present invention with mammals for a certain period of time.

[0040] The term “pharmaceutically acceptable” means that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or with the mammals it treats. Preferably, “pharmaceutically acceptable” in this invention means that it is approved by a federal regulatory agency or a central government, or that it is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly humans.

[0041] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the reference: SMBerge et al., J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts (such as hydrochlorides, hydrobroms, phosphates, sulfates, nitrates, and perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, and sulfosalicylates), or salts formed by the compounds with acids, including salts obtained by other methods described in books and literature, such as ion exchange methods. More pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-H. Examples include droxyethyl 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, and valerate. Pharmaceutically acceptable salts include, but are not limited to, inorganic base salts (alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4Salts formed by compounds with a base, including alkyl(4) salts, are also mentioned, and alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. The present invention also intends to include quaternary ammonium salts formed by any compound containing an N group. Water-soluble, oil-soluble, or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts include suitable and non-toxic ammonium, quaternary ammonium salts, and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1~8 Further examples include sulfonates and aromatic sulfonates. Examples of organic base salts (e.g., primary, secondary and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins)) and certain organic amine salts include, for example, isopropylamine salt, benzathine salt, corinate salt, diethanolamine salt, diethylamine salt, lysine salt, meglumine salt, piperazine salt, and tromethamine salt.

[0042] pharmaceutically acceptable acid addition salts can be formed by the compounds of the present invention together with an inorganic or organic acid, and pharmaceutically acceptable base addition salts can be formed by the compounds of the present invention together with an inorganic or organic base. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, alkaline or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. These reactions are usually carried out in water, an organic solvent, or a mixture of the two. Generally, where appropriate, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable additional salts can be found, for example, in 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).

[0043] The term "solvate" refers to an association formed by one or more solvent molecules and the compounds of the present invention. The solvents include 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, and sec-butyl ether. These may include ethanol, 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, 1-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 mixtures thereof.

[0044] The term "hydrate" refers to an aggregate formed by one or more water molecules and the compound of the present invention.

[0045] In addition, the compounds disclosed in this invention, including their salts, can be obtained, alternatively, in the form of their hydrates, or in forms containing their solvents (such as ethanol or DMSO) for their crystallization. The compounds disclosed in this invention can form solvates with pharmaceutically acceptable solvents (including water), either essentially or by design. Therefore, this invention is intended to include both solvated and non-solvated forms.

[0046] The term "ester" is represented by the formula -OC(O)R or -C(O)OR, where R may be an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, cycloalkynyl group, aryl group or heteroaryl group as described herein.

[0047] The term "isotope-labeled compound" refers to the compounds of the present invention that are labeled with isotopes. These compounds are identical to those described herein, except that one or more atoms are replaced by atoms having a mass or mass number different from that of the naturally occurring common atoms. Exemplary isotopes that may be introduced into the compounds of the present invention include: 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl.

[0048] The compounds of the present invention, including the isotopic labels and / or other isotopic labels of other atoms described above, and pharmaceutically acceptable salts of said compounds, all fall within the scope of the present invention. Examples of isotopic-labeled compounds of the present invention include, 3 H and 14 Radioisotope-labeled compounds such as 13C can be incorporated into the compounds of the present invention and used for drug and / or substrate tissue distribution analysis. Due to the ease of preparation and detection, deuterated, i.e., 3 H and carbon 14, that is 14 C isotopes are particularly preferred. In addition, deuterium, i.e. 2 Substitutions using isotopes with higher mass numbers, such as 1H, can offer greater therapeutic benefits in some aspects of metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, this may be preferable in some cases.

[0049] In addition, heavier isotopes, especially deuterium (i.e., 2 Substitutions of H or D can provide certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, or improved therapeutic index. In this invention, deuterium should be understood as a substituent of the compounds of formulas I through VI. The concentrations of these heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. As used in this invention, the term “isotopic enrichment factor” refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent of the compound of the present invention is specified as deuterium, the compound has an isotopic enrichment coefficient for each specified deuterium atom of at least 3500 (52.5% deuterium incorporation for each specified 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). Examples of pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent can be isotope-substituted, such as D2O, acetone-d6, and DMSO-d6.

[0050] When used in the present invention, the term "prodrug" refers to the in vivo conversion of a compound to a compound of formula I. Such conversions are influenced by hydrolysis of the prodrug in blood or enzymatic conversion of the prodrug in blood or tissue to the parent structure. The prodrug compound of the present invention may be an ester, and esters that can be used as prodrugs in existing inventions include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, the compounds of the present invention contain a hydroxyl group, which can be acylated to obtain the compound in prodrug form. Other prodrug forms include phosphate esters, such as phosphate ester compounds obtained by phosphorylation of a 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, ACS Symposium 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.

[0051] Solid line (-), black wedge (

[0052] [ka] ) and dashed wedge (

[0053] [ka] ) can be used herein to illustrate the chemical bonding of the compounds of the present invention. The use of solid lines to illustrate bonds attached to a chiral carbon atom is intended to indicate the presence of all possible stereoisomers at that carbon atom (e.g., specific enantiomers and racemic mixtures). The use of black fills or dashed wedges to illustrate bonds attached to a chiral carbon atom is intended to indicate the presence of the stereoisomers shown. In the presence of racemic mixtures, black fills and dashed wedges are used to define relative stereochemistry rather than absolute stereochemistry.

[0054] When a substituent is shown to be bonded through a bond connecting two ring atoms ("floating bond"), such substituent may be bonded to any ring atom in the substituteable ring, unless otherwise indicated. When an available ring member is shown to possess a substituteable hydrogen atom, and a floating bond is bonded to an available ring member, the substituteable hydrogen atom is substantially substituted (i.e., absent).

[0055] Unless otherwise explicitly stated, when substituents are described by conventional chemical formulas written from left to right, the substituents include only those forms written from left to right, respectively, where they are connected to the left and right sides of the corresponding group in the structure of the compound in the general formula.

[0056] Unless otherwise explicitly stated, the descriptions used in this invention, such as "each independently," "each independently," and "independently," are interchangeable and should be broadly understood to mean that certain options represented by the same symbol in different bases do not affect each other, or that certain options represented by the same symbol in the same base do not affect each other.

[0057] The terms “optional,” “optionally,” or “at will” mean that the event or situation described thereafter may or may not occur, and that description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, “optionally substituted by…” means that the substitution may or may not exist.

[0058] The term "independently" is used in combination with "optionally," for example, "independently and optionally substituted by..." means that certain options are either independently substituted by... or not substituted by...

[0059] The terms "unsaturated" or "unsaturated" refer to a portion containing a degree of unsaturation of 1 or more.

[0060] In various parts of this specification, substituents of the compounds of the present invention are disclosed with respect to the type or range of the group. It is of particular note that the present invention includes each independent secondary combination of individual members of these types and ranges of groups. For example, "C 1~6 The term "alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl as independently disclosed.

[0061] In various parts of the present invention, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definitions for the variables list "alkyl" or "aryl", then "alkyl" or "aryl" should be understood to represent the linked alkylene group or arylene group, respectively.

[0062] The term "heteroatom" refers to O, S, N, P, and Si, and includes any oxidation state of S, N, and P; primary, secondary, and tertiary amines and quaternary ammonium salts; or heterocyclic rings in which hydrogen on the nitrogen atom is substituted, e.g., 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, where RT is a substituent on N). When a compound involved in the present invention contains multiple heteroatoms, the compound composed of multiple heteroatoms conforms to the covalent bonding rules and compositional rules of organic compounds; that is, compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent bonding rules and compositional rules of organic compounds.

[0063] The term “heterocyclyl” or “heterocyclic” refers to a selectively substituted, partially or fully saturated non-aromatic cyclic group having at least one heteroatom in at least one of the carbon-carbon-containing rings, e.g., a 4- to 7-membered monocyclic system, a 7- to 12-membered bicyclic system, or a 10- to 15-membered tricyclic system. Each ring of a heterocyclyl containing heteroatoms may have one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also be selectively oxidized. Heterocyclyls may be linked by heteroatoms or carbon atoms. In some embodiments, heterocyclyls are selected from: monocyclic heterocyclyls, bicyclic heterocyclyls, and tricyclic heterocyclyls. A 4- to 8-membered heterocyclic group indicates that the ring atoms consist of 4- to 8 carbon atoms and heteroatoms. Heterocyclic groups include fused rings, spiro rings, bridging rings, and combinations thereof. In some embodiments, the monocyclic heterocyclil is selected from oxetanil, pyrrolidinil, tetrahydrofuranil, piperazinil, tetrahydropyranil, morpholinil, thiomorpholinil, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothiophenyl, 1,1,4-trioxo-1,2,5-thiadiazolidine-2-yl, and the like. In some embodiments, the bicyclic heterocyclil is selected from 7-oxabicyclo[2.2.1]heptyl.

[0064] The term "carbocyclic ring" refers to a saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (preferably 3 to 8, more preferably 3 to 7, 3 to 6, 4 to 6, or 5 to 6) ring carbon atoms, and is not limited to the following: This includes rhozpropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclobutenyl(ene)(ring), cyclopentenyl(ene)(ring), cyclohexenyl(ene)(ring), cycloheptenyl(ene)(ring), cyclooctenyl(ene)(ring), cyclononenyl(ene)(ring), etc. As for carbocyclic rings, examples include fused rings, spirorings, bridging rings, and combinations thereof.

[0065] The term "cycloalkyl" refers to monovalent or polyvalent saturated or partially unsaturated monocyclic, bicyclic, or tricyclic non-aromatic systems containing carbon atoms. 3~6 A cycloalkyl group refers to a cycloalkyl group having 3 to 6 ring carbon atoms. In some embodiments, the cycloalkyl group is selected from: monocyclic cycloalkyl groups, bicyclic cycloalkyl groups, and tricyclic cycloalkyl groups. In some embodiments, monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. In some embodiments, bicyclic cycloalkyl groups include, but are not limited to, bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, and bicyclo[2.2.2]octyl. In some embodiments, a tricyclic hydrocarbon group includes adamantyl.

[0066] The terms “heteroaryl” or “heteroaromatic ring” refer to monocyclic, bicyclic, and tricyclic aromatic systems containing heteroatoms. The term “heteroaryl” can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound.” Heteroatoms have the definitions set forth in this invention. In some embodiments, a heteroaryl is a heteroaryl consisting of 5 to 10 atoms containing one, two, three, or four heteroatoms independently selected from O, S, and N, i.e., a 5 to 10-membered heteroaryl; a heteroaryl is a heteroaryl consisting of 5 to 8 atoms containing one, two, three, or four heteroatoms independently selected from O, S, and N, i.e., a 5 to 8-membered heteroaryl; in some embodiments, a heteroaryl is a heteroaryl consisting of 5 to 7 atoms containing one, two, three, or four heteroatoms independently selected from O, S, and N, i.e., a 5 to 7-membered heteroaryl; In some embodiments, the heteroaryl is a heteroaryl composed of 5 to 6 atoms containing one, two, three or four heteroatoms independently selected from O, S, and N, i.e., a 5 to 6-membered heteroaryl; in some embodiments, the heteroaryl is a heteroaryl composed of 5 atoms containing one, two, three or four heteroatoms independently selected from O, S, and N, i.e., a 5-membered heteroaryl; and in some embodiments, the heteroaryl is a heteroaryl composed of 6 atoms containing one, two, three or four heteroatoms independently selected from O, S, and N, i.e., a 6-membered heteroaryl.

[0067] The terms "aryl" or "aryl ring" refer to monocyclic, bicyclic, or tricyclic aromatic carbocyclic systems. The term "aryl" is interchangeable with the terms "aryl ring" or "aromatic ring." A 6- to 10-membered aryl refers to an aromatic group containing 6 to 10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl.

[0068] The term "hydrogen" is 1 H refers to H; "deuterium" is, 2 It refers to H.

[0069] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0070] The term "amino" refers to -NH2.

[0071] The term "hydroxyl" refers to the -OH group.

[0072] The term "cyano" refers to -CN.

[0073] The term "nitro" refers to -NO2.

[0074] The term "carboxyl" refers to HO(C=O)-.

[0075] The term "oxo" refers to O=, meaning that when the substituent is O=, O is connected to the group that is substituted by a double bond.

[0076] The term "alkyl" or "alkyl group" refers to a saturated, linear, or branched hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1~6 It is alkyl; in another embodiment, the alkyl group contains 1 to 4 carbon atoms, i.e., C 1~4 It is alkyl; in another embodiment, the alkyl group contains 1 to 3 carbon atoms, i.e., C 1~3 It is an alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.

[0077] The term "alkylene" refers to a saturated, linear, or branched divalent hydrocarbon group containing carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms, i.e., a C1-C6 alkylene; in another embodiment, the alkylene group contains 1 to 4 carbon atoms, i.e., a C1-C4 alkylene; and in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms, i.e., a C1-C3 alkylene.

[0078] The term "alkenyl" includes the positioning of "cis" and "trans" or "E" and "Z" and refers to at least one unsaturated site, i.e., carbon-carbon sp 2 This refers to a monovalent hydrocarbon group, either linear or branched, containing a carbon atom along with a double bond. In one embodiment, the alkenyl group contains 2 to 6 carbon atoms, i.e., a C2-C6 alkenyl; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms, i.e., a C2-C4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2) and allyl (-CH2CH=CH2).

[0079] The term "alkoxy" refers to an alkyl group connected to the rest of the molecule via an oxygen atom, where alkyl group has the meaning described in this invention. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, i.e., C 1~6 It is an alkoxy; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, i.e., C 1~4 It is an alkoxy; in another embodiment, the alkoxy group contains 1 to 3 carbon atoms, i.e., C 1~3 It is an alkoxy.

[0080] The term “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended, and does not exclude any additional undescribed elements or components from the drug (or, in the case of a method, a step). The phrase “consisting of…” does not include any elements, steps, or components not specified in the drug (or, in the case of a method, a step). The phrase “essential from…” refers to materials that do not substantially affect the basic and novel characteristics of the specified materials and the drug (or, in the case of a method, a step).

[0081] As described herein, a ring system formed by substituents R connected to the center of the ring by a bond (as shown in the figure below) represents the substitution of substituent R at any substitutable or any reasonable position on ring A. For example, formula f is given by formulas f1 to f4:

[0082] [ka] As shown, this represents any possible substituted position in ring A.

[0083] As described herein, a ring system formed by substituents connected to the center of the ring by a bond, for example, n substituents R x (R x ) n The can be substituted at any substitutable position on the ring. For example, equation a can be substituted with n R x It represents a benzene ring that may be substituted by [a specific substituted element].

[0084] [ka]

[0085] The term "substituted" refers to one or more hydrogen atoms on a particular group that are replaced by a particular substituent. The particular substituent is one of the substituents described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group has substituents selected from the particular group at any of the substitutable sites of the group, and the substituents may be identical or different at each position; that is, each substitution is independent of the others. It should be understood by those skilled in the art that the substituent combinations intended in the present invention are stable or chemically feasible.

[0086] Unless otherwise specified, the substituents or group combinations involved herein with respect to the Markush structures are stable or chemically feasible.

[0087] The term “tumor,” as used herein, refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, and to all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “proliferative disorder,” “proliferative disorder,” and “tumor,” as used herein, are not mutually exclusive.

[0088] When used herein, the terms “cancer” and “malignant” refer to or describe a physiological condition in an object typically characterized by unregulated cell growth and / or proliferation. Some cancers consist of rapidly dividing cells, while others consist of cells that divide more slowly than normal cells. Examples of cancer types may or may not include, for example, carcinoma, lymphoma (e.g., Hodgkin and non-Hodgkin lymphoma), blastoma, sarcoma, and leukemia. More specific examples of these cancers may include, but may be excluded, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, leukemia and other lymphoproliferative disorders, as well as various types of head and neck cancer.

[0089] Description of the compound of the present invention The present invention provides compounds, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs, that play an active role in treating or preventing PTPN2-related diseases or disorders.

[0090] In detail, the present invention relates to formula (I-1) or (I-2)

[0091] [ka] (In the formula, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 3a , R 3b , X 1n, p, and q have the definitions described in this invention. The present invention provides compounds having a structure represented by [the given formula], or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs.

[0092] In some embodiments, the compounds of the present invention are

[0093] [ka] No. In some embodiments, R 1a and R 1b H, D, halogen, -OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 Each is independently selected from the haloalkoxys.

[0094] In some embodiments, R 1a and R 1b H, D, halogen, -OH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 Each is independently selected from the haloalkoxys.

[0095] In some embodiments, R 1a and R 1b Each of these is independently selected from H, D, F, Cl, Br, -OH, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethoxy, and 2,2-difluoroethoxy.

[0096] In some embodiments, R 1a and R 1b Each of these is independently selected from H, D, F, and -OH.

[0097] In some embodiments, R 1a and R 1b Both are H.

[0098] In some embodiments, R 1c and R 1d H, D, halogen, C 1~6 Alkyl and C 1~6 Each is independently selected from the haloalkyl groups.

[0099] In some embodiments, R 1c and R 1d H, D, halogen, C 1~4 Alkyl and C 1~4 Each is independently selected from the haloalkyl groups.

[0100] In some embodiments, R 1c and R 1d Each of these is independently selected from H, D, F, Cl, Br, methyl, ethyl, trifluoromethyl, and difluoromethyl.

[0101] In some embodiments, R 1c and R 1d These are selected independently from H, D, and F.

[0102] In some embodiments, R 1c and R 1d These are selected independently from H and F.

[0103] In some embodiments, R 2a H, D, -OH, -NH2, C 1~8 Alkyl, C 2~8 Alkenil, C 3~6 Cycloalkyl, 5-6 member heteroaryl, 4-8 member heterocyclyl, -OC 1~8 Alkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-(4-8 member heterocyclyl),-OC(=O)-N(R)a )-C 1~8 Alkyl, -OC(=O)-N(R a )-phenyl, -N(R a )-C 1~8 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl), -N(R a )-C(=O)-C 1~8 Alkyl, -N(R a )-C(=O)-OC 1~8 Alkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-Si(R c )3, -N(R a )-(C=N(R b ))-C 1~8 Alkyl, -N(R a )-S(=O) w -C 1~8 Alkyl, -N(R a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~6 Alkylene-phenyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkilen-(4-8 member heterocyclyl),-C 1~6 Alkylene-N(R) a )(R b ), -C 1~6 Alkylene-N(R) a )-C(=O)-OC 1~8 Alkyl, -C 1~6 Alkylene-N(R) a )-C 1~8 Alkyl, -C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -C1~6 Alkylene-N(R) a )-C(=O)-C 1~8 Alkyl, -C 1~6 Alkylene-N(R) a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-(5-6 member heteroaryl),-C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-phenyl, -C 1~6 Alkylene-OC 1~8 Alkyl, -C 1~6 Alkylene-OC 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkylene-OC 1~6 Alkilen-(4-8 member heterocyclyl),-C 1~6 Alkylene-OC 1~6 Alkylene-N(R) a )(R b ), -S(=O) w -C 1~8 Alkyl and -C(=O)-N(R a )-C 1~8 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0104] In some embodiments, R 2a H, D, -OH, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 3~6 Cycloalkyl, 5-6 member heteroaryl, 4-8 member heterocyclyl, -OC 1~6 Alkyl, -OC 1~4Alkylene-C 3~6 Cycloalkyl, -OC 1~4 Alkylene-(4-8 member heterocyclyl),-OC(=O)-N(R) a )-C 1~6 Alkyl, -OC(=O)-N(R a )-phenyl, -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl), -N(R a )-C(=O)-C 1~6 Alkyl, -N(R a )-C(=O)-OC 1~8 Alkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-Si(R c )3, -N(R a )-(C=N(R b ))-C 1~6 Alkyl, -N(R a )-S(=O) w -C 1~6 Alkyl, -N(R a )-C 1~4 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~4 Alkylene-phenyl, -C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkilen-(4-8 member heterocyclyl),-C 1~4 Alkylene-N(R) a )(R b ), -C 1~4 Alkylene-N(R) a )-C(=O)-OC 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C 1~6 Alkyl, -C1~4 Alkylene-N(R) a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-N(R) a )-C(=O)-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkilen-(4-8 member heterocyclyl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-(5-6 member heteroaryl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-phenyl, -C 1~4 Alkylene-OC 1~6 Alkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-OC 1~4 Alkilen-(4-8 member heterocyclyl),-C 1~4 Alkylene-OC 1~4 Alkylene-N(R) a )(R b ), -S(=O) w -C 1~6 Alkyl and -C(=O)-N(R a )-C 1~6 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0105] In some embodiments, R 2a is, -OC 1~6 Alkyl, -OC 1~4 Alkylene-C 3~6Cycloalkyl, -OC 1~4 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl), -N(R a )-C(=O)-C 1~6 Alkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~4 Alkylene-phenyl, -C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkilen-(4-8 member heterocyclyl),-C 1~4 Alkylene-N(R) a )(R b ), -C 1~4 Alkylene-N(R) a )-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-N(R) a )-C(=O)-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkilen-(4-8 member heterocyclyl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-(5-6 member heteroaryl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-phenyl, -C 1~4 Alkylene-OC 1~6Alkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-OC 1~4 Alkilen-(4-8 member heterocyclyl),-C 1~4 Alkylene-OC 1~4 Alkylene-N(R) a )(R b ), -S(=O) w -C 1~6 Alkyl and -C(=O)-N(R a )-C 1~6 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0106] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl), -N(R a )-C(=O)-C 1~6 Alkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl) and -N(R a )-C 1~4 Selected from alkylene-phenyl, where R 2a The replaceable carbon atoms are R gEach molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0107] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 1~6 Haloalkyl and -N(R) a )-C 1~4 Alkylene-C 3~6 Selected from cycloalkyl groups.

[0108] In some embodiments, R 2a The following is the basis:

[0109] [ka] JPEG2026525318000010.jpg134150 Selected from.

[0110] In some embodiments, R 2a The following is the basis:

[0111] [ka] JPEG2026525318000012.jpg127150 Selected from.

[0112] In some embodiments, R 2a The following is the basis:

[0113] [ka] Selected from.

[0114] In some embodiments, R 2a The following is the basis:

[0115] [ka] Selected from.

[0116] In some embodiments, R 2a The following is the basis:

[0117] [ka] Selected from.

[0118] In some embodiments, R 2a teeth,

[0119] [ka] That is the case.

[0120] In some embodiments, R 2b H, D, -OH, halogen, -N(R) a )(R b ) and -N(R a )-N(R b Selected from )-C(O)-phenyl.

[0121] In some embodiments, R 2b The element is selected from H, D, -OH, F, Cl, and Br.

[0122] In some embodiments, R 2b This is selected from H and D.

[0123] In some embodiments, R 2b H is H.

[0124] In some embodiments, R 3 , R 3a and R 3b H, D, halogen, -OH, C 1~6Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, C 3~6 Halocycloalkyl, -NH2, -NH(C) 1~6 Alkyl) and -N(C 1~6 Alkyl)(C 1~6 Each is independently selected from alkyl groups.

[0125] In some embodiments, R 3 , R 3a and R 3b H, D, halogen, -OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~6 Cycloalkyl, C 3~6 Halocycloalkyl, -NH2, -NH(C) 1~4 Alkyl) and -N(C 1~4 Alkyl)(C 1~4 Each is independently selected from alkyl groups.

[0126] In some embodiments, R 3 , R 3a and R 3b These are H, D, F, Cl, Br, -OH, C 1~4 Alkyl and C 1~4 Each is independently selected from the haloalkyl groups.

[0127] In some embodiments, R 3 , R 3a and R 3b Each of these is independently selected from H, D, F, Cl, Br, -OH, methyl, ethyl, trifluoromethyl, and difluoromethyl.

[0128] In some embodiments, R 3 , R 3a and R 3b Each of these is independently selected from H, D, F, and -OH.

[0129] In some embodiments, R 3 , R 3a and R 3b Each of these is independently selected from H, F, and -OH.

[0130] In some embodiments, X 1 O, S, NR f and C(R e )(R d ) will be selected from.

[0131] In some embodiments, R a and R b H and C 1~6 Each alkyl group is independently selected; optionally, C 1~6 The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH.

[0132] In some embodiments, R a and R b H and C 1~4 Each alkyl group is independently selected; optionally, C 1~4 The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH.

[0133] In some embodiments, R a and R b The atoms are independently selected from H and methyl.

[0134] In some embodiments, R c is -OH, C 1~6 Selected from alkyl and phenyl.

[0135] In some embodiments, R c The compound is selected from -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and phenyl.

[0136] In some embodiments, R e and Rd H, D, halogen, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, C 3~6 Halocycloalkyl, -NH2, -NH(C) 1~6 Alkyl) and -N(C 1~6 Alkyl)(C 1~6 Each is independently selected from alkyl; optionally, R e and R 3a They, together with the atoms they connect to, form a 3- to 7-membered carbocyclic ring; or R e and R 2b These atoms, together with the atoms they connect to, form a 3- to 7-membered carbocyclic ring.

[0137] In some embodiments, R e and R d These are H, D, F, Cl, Br, -OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~6 Cycloalkyl, C 3~6 Halocycloalkyl, -NH2, -NH(C) 1~4 Alkyl) and -N(C 1~4 Alkyl)(C 1~4 Each is independently selected from alkyl; optionally, R e and R 3a They, together with the atoms they connect to, form a 3-6 membered carbocyclic ring; or R e and R 2b These atoms, together with the atoms they connect to, form a 3- to 6-membered carbocyclic ring.

[0138] In some embodiments, R f H, C 1~6 Alkyl and C 1~6 Selected from haloalkyls; optionally, R f and R 3aThese, together with the atoms they connect to, form a heterocyclic ring of 3 to 7 members; or R f and R 2b These atoms, together with the atoms they connect to, form a heterocyclic ring with 3 to 7 members.

[0139] In some embodiments, R f H, C 1~4 Alkyl and C 1~4 Selected from haloalkyls; optionally, R f and R 3a They, together with the atoms they connect to, form a 3-6 member heterocyclic ring; or R f and R 2b These atoms, together with the atoms they connect to, form a heterocyclic ring with 3 to 6 members.

[0140] In some embodiments, R g H, D, halogen, -OH, -CN, nitro, oxo, -NH2, -NH(C) 1~6 Alkyl), -N(C 1~6 Alkyl)(C 1~6 Alkyl), C 1~6 Alkyl and C 1~6 It is independently selected from haloalkyl groups.

[0141] In some embodiments, R g H, D, F, Cl, Br, -OH, -CN, nitro, oxo, -NH2, -NH(C) 1~4 Alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), C 1~4 Alkyl and C 1~4 It is independently selected from haloalkyl groups.

[0142] In some embodiments, R g The following are independently selected from H, D, F, Cl, Br, -OH, -CN, nitro, oxo, -NH2, -NH-CH3, -N(CH3)(CH3), methyl, ethyl, trifluoromethyl, and difluoromethyl.

[0143] In some embodiments, R h H, D, C 1~6 Alkyl and C 1~6 Selected from haloalkyl groups.

[0144] In some embodiments, R h H, D, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0145] In some embodiments, R h This is selected from H, D, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.

[0146] In some embodiments, R h This is selected from H, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.

[0147] In some embodiments, n is selected from 0 or 1.

[0148] In some embodiments, p is selected from 0, 1, 2, or 3.

[0149] In some embodiments, q is selected from 0, 1, 2, 3, or 4.

[0150] In some embodiments, w is selected from 1 or 2.

[0151] In some embodiments, compounds having the structure represented by formula (I-1) are

[0152] [ka] No.

[0153] In some embodiments, R 1a and R 1b is independently selected from H and D, preferably R1a and R 1b It is selected from H.

[0154] In some embodiments, R 1c and R 1d The elements are independently selected from H, D, and halogens, and preferably R 1c and R 1d is independently selected from H and halogen, and more preferably R 1c and R 1d One of them is selected from H, and the other is selected from halogens.

[0155] In some embodiments, p is selected from 0 or 1, preferably from 0.

[0156] In some embodiments, n is selected from 0.

[0157] In some embodiments, R 3 The halogen is selected from H, D, and halogen, preferably R 3 is selected from H and halogen, more preferably R 3 It is selected from H.

[0158] In some embodiments, q is selected from 0, 1, or 2, and preferably q is selected from 0.

[0159] In some embodiments, X 1 O, S, NR f and C(R e )(R d ) is selected from, preferably X 1 C(R e )(R d ) will be selected from.

[0160] In some embodiments, R e and R d These are independently selected from H, D, halogens, and -OH, or R e and R 2bThese, together with the atoms they connect to, form a 3- to 7-membered carbocyclic ring; preferably, R e and R d is independently selected from H, halogen and OH, or R e and R 2b These, together with the atoms they connect to, form a 3-6 membered carbocyclic ring (C 3~6 Forms cycloalkyl groups, etc., and more comfortably, R e and R d It is selected from H.

[0161] In some embodiments, R 2b is selected from H, or R 2b and R e These, together with the atoms they connect to, form a 3-6 membered carbocyclic ring (C 3~6 Forms cycloalkyl groups, etc., and more comfortably, R 2b It is selected from H.

[0162] In some embodiments, R 2a is -N(R a )-C 1~8 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~6 Alkylene-phenyl, -OC 1~8 Alkyl, -OC 1~6 Alkilen-(4-8 member heterocyclyl),-OC 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl),-C 1~6 Alkylene-N(R) a )-C 1~8 Alkyl, -C1~6 Alkylene-N(R) a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkylene-N(R) a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-(5-6 member heteroaryl),-C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-phenyl, -C 1~6 Alkylene-OC 1~8 Alkyl, -C 1~6 Alkylene-OC 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkylene-OC 1~6 Alkylene-(4-8 member heterocyclyl),-C(=O)-N(R) a )-C 1~8 Alkyl, -C 1~6 Alkylene-N(R) a )-C(=O)-C 1~8 Alkyl, -C 1~6 Alkylene-N(R) a )(R b ), -C 1~6 Alkylene-OC 1~6 Alkylene-N(R) a )(R b ) and -N(R a )-C(=O)-C 1~8 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0163] In some embodiments, R 2ais -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~4 Alkylene-phenyl, -OC 1~6 Alkyl, -OC 1~4 Alkilen-(4-7 member heterocyclyl), -OC 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-(4-7 member heterocyclyl), -C 1~4 Alkylene-N(R) a )-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-(5-6 member heteroaryl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-phenyl, -C 1~4 Alkylene-OC 1~6 Alkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) a )-C 1~6 Alkyl, -C1~4 Alkylene-N(R) a )-C(=O)-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )(R b ), -C 1~4 Alkylene-OC 1~4 Alkylene-N(R) a )(R b ) and -N(R a )-C(=O)-C 1~6 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0164] In some embodiments, R 2a is -N(R a )-C 1~8 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~6 Alkylene-phenyl, -OC 1~8 Alkyl, -OC 1~6 Alkilen-(4-8 member heterocyclyl),-C 1~6 Alkylene-N(R) a )-C 1~8 Alkyl, -C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6Alkylene-N(R) a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-(5-6 member heteroaryl),-C 1~6 Alkylene-N(R) a )-C 1~6 Alkylene-phenyl, -C 1~6 Alkylene-OC 1~8 Alkyl, -C 1~6 Alkylene-OC 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkylene-OC 1~6 Alkylene-(4-8 member heterocyclyl),-C(=O)-N(R) a )-C 1~8 Alkyl and -C 1~6 Alkylene-N(R) a )-C(=O)-C 1~8 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0165] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl),-N(R a )-C1~4 Alkylene-phenyl, -OC 1~6 Alkyl, -OC 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~4 Alkylene-N(R) a )-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-(5-6 member heteroaryl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-phenyl, -C 1~4 Alkylene-OC 1~6 Alkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) a )-C 1~6 Alkyl and -C 1~4 Alkylene-N(R) a )-C(=O)-C 1~6 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0166] In some embodiments, R 2a is -N(R a )-C 1~8Alkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-(4- to 8-membered heterocyclyl), -N(R a )-C 1~6 Alkylene-phenyl and -C 1~6 Alkylene-N(R a )-C 1~8 Selected from alkyl, wherein the replaceable carbon atoms of R 2a are each independently and optionally substituted by one or more substituents independently selected from R g ; and / or the replaceable nitrogen atoms on the ring of R 2a are each independently and optionally substituted by one or more substituents independently selected from R h .

[0167] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-(4- to 7-membered heterocyclyl), -N(R a )-C 1~4 Alkylene-phenyl and -C 1~4 Alkylene-N(R a )-C 1~6 Selected from alkyl, wherein the replaceable carbon atoms of R 2a are each independently and optionally substituted by one or more substituents independently selected from R g ; and / or the replaceable nitrogen atoms on the ring of R 2a are each independently and optionally substituted by one or more substituents independently selected from R h .

[0168] In some embodiments, R 2ais -N(R a )-C 1~8 Alkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-(4-8 member heterocyclyl) and -C 1~6 Alkylene-N(R) a )-C 1~8 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0169] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-(4-7 member heterocyclyl) and -C 1~4 Alkylene-N(R) a )-C 1~6 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0170] In some embodiments, R g H, D, halogen, -OH, -CN, -NH2, -NH(C) 1~6 Alkyl), -N(C1~6 Alkyl)(C 1~6 Alkyl), C 1~6 Alkyl and C 1~6 It is independently selected from haloalkyl groups.

[0171] In some embodiments, R g H, D, halogen, -OH, -CN, -NH2, -NH(C) 1~4 Alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), C 1~4 Alkyl and C 1~4 It is independently selected from haloalkyl groups.

[0172] In some embodiments, R h H, D, C 1~6 Alkyl and C 1~6 Selected from haloalkyl groups.

[0173] In some embodiments, R h H, D, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0174] In some embodiments, R a and R b H and C 1~6 Each alkyl group is independently selected; optionally, C 1~6 The alkyl group is substituted with one or more substituents selected from halogens.

[0175] In some embodiments, R a and R b H and C 1~4 Each alkyl group is independently selected; optionally, C 1~4 The alkyl group is substituted with one or more substituents selected from halogens.

[0176] In some embodiments, the compound is of formula (II-0):

[0177] [Chemistry] It has a structure represented by.

[0178] In some embodiments, the compound is of formula (II-1) or (II-2):

[0179] [Chemistry] (wherein R 1a , R 1b , R 1c , R 1d , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 3 , R 3a , R 3b , X 1 , X 2 , n, p and q have the definitions described in the present invention.) It has a structure represented by.

[0180] In some embodiments, R 2c , R 2d , R 2e and R 2f are each independently selected from H, D, F, Cl, -CN, -OH, C [[ID=6」 1~6 alkyl and C 1~6 haloalkyl; optionally, R 2c and R 』 2d form oxo, or R 2e and R 2f form oxo.

[0181] [[ID=7」 In some embodiments, R 2c , R 2d , R 2e and R 2f are each independently selected from H, D, F, Cl, -CN, -OH, C 1~4 alkyl and C 1~4 haloalkyl; optionally, R2c and R 2d It forms an oxo, or R 2e and R 2f It forms an oxo.

[0182] In some embodiments, R 2c , R 2d , R 2e and R 2f is independently selected from H, D, F, Cl, -CN, -OH, methyl, ethyl, and trifluoromethyl; optionally, R 2c and R 2d It forms an oxo, or R 2e and R 2f It forms an oxo.

[0183] In some embodiments, R 2g H, C 1~4 Alkyl, C 3~6 Cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -NH2, -NH(C 1~6 Alkyl) and -N(C 1~6 Alkyl)(C 1~6 Selected from alkyl; C 1~4 Alkyl, C 3~6 Cycloalkyls, 4-8 membered heterocyclyls, 5-6 membered heteroaryls, and phenyls are halogens, -OH, -CN, C 1~4 Alkyl and C 1~4 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups.

[0184] In some embodiments, R 2g H, C 1~4 Alkyl, C 3~6 Cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -NH2, -NH(C 1~6 Alkyl) and -N(C 1~6 Alkyl)(C 1~6 Selected from alkyl; C 1~4 Alkyl, C 3~6Cycloalkyls, 4- to 8-membered heterocyclines, 5- to 6-membered heteroaryls, and phenyls are each independently and optionally substituted with one or more substituents selected from F, Cl, Br, -OH, -CN, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.

[0185] In some embodiments, R 2g H, C 1~4 Alkyl, C 3~6 Cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, -NH2, -NH(C 1~6 Alkyl) and -N(C 1~6 Alkyl)(C 1~6 Selected from alkyl; C 1~4 Alkyl, C 3~6 Cycloalkyls, 4- to 8-membered heterocyclyls, and 5- to 6-membered heteroaryls are each independently and optionally substituted with one or more substituents selected from F, Cl, Br, -OH, -CN, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.

[0186] In some embodiments, R 2g H, C 1~4 Alkyl, C 3~6 Selected from cycloalkyls, 4-7 membered heterocyclines, 5-6 membered heteroaryls, and phenyls; C 1~4 Alkyl, C 3~6 Cycloalkyls, 4-7 membered heterocyclyls, 5-6 membered heteroaryls, and phenyls are halogens, -OH, -CN, C 1~4 Alkyl and C 1~4 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups.

[0187] In some embodiments, R 2g H, C 1~4 Alkyl, C 3~6 Selected from cycloalkyl and 4- to 7-membered heterocyclyl groups; C 1~4 Alkyl, C 3~6Cycloalkyl and 4- to 7-membered heterocyclyls are each independently and optionally substituted with one or more substituents selected from halogens.

[0188] In some embodiments, R 2g This includes H, methyl, trifluoromethyl, difluoromethyl, tert-butyl, -CH2OH, -N(CH3)2, or the following groups:

[0189] [ka] Selected from.

[0190] In some embodiments, R 2g This includes H, methyl, trifluoromethyl, difluoromethyl, tert-butyl, -CH2OH, -N(CH3)2, or the following groups:

[0191] [ka] Selected from.

[0192] In some embodiments, R 2g This is selected from H, methyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, and tetrahydropyran-2-yl.

[0193] In some embodiments, X 2 It is either NH or O.

[0194] In some embodiments, X 2 It is NH.

[0195] In some embodiments, the compound is of formula (III-0):

[0196] [ka] It has a structure represented by [this].

[0197] In some embodiments, the compound is of formula (III-1) or (III-2):

[0198] [ka] (In the formula, R 1c , R 1d , R 2b , R 2c , R 2d , R 2g , R 3 , X 1 , X 2 (p and q have the definitions described in this invention.) It has a structure represented by [this].

[0199] In some embodiments, the compound is of formula (IV-1) or (IV-2):

[0200] [ka] (In the formula, R 1c , R 1d , R 2b , R 2c , R 2h , R 3 , X 1 (p and q have the definitions described in this invention.) It has a structure represented by [this].

[0201] In some embodiments, R 2h C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~4 Alkylene-(5-6 member heteroaryl),-C1~4 Alkylene-phenyl, -NH(C) 1~6 Alkyl) and -N(C 1~6 Selected from alkyl)2; C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~4 Alkylene-(5-6 member heteroaryl),-C 1~4 Alkylene-phenyl, -NH(C) 1~6 Alkyl) and -N(C 1~6 Alkyl)2 is a halogen, -OH, -CN, C 1~4 Alkyl and C 1~4 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups.

[0202] In some embodiments, R 2h C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1~2 Alkylene-C 3~6 Cycloalkyl, -C 1~2 Alkilen-(4-7 member heterocyclyl),-C 1~2 Alkylene-(5-6 member heteroaryl),-C 1~2 Alkylene-phenyl, -NH(C) 1~6 Alkyl) and -N(C 1~6 Selected from alkyl)2; C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1~2 Alkylene-C 3~6 Cycloalkyl, -C 1~2 Alkilen-(4-7 member heterocyclyl),-C 1~2 Alkylene-(5-6 member heteroaryl),-C 1~2 Alkylene-phenyl, -NH(C) 1~6Alkyl) and -N(C 1~6 Alkyl)2 is a halogen, -OH, -CN, C 1~4 Alkyl and C 1~4 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups.

[0203] In some embodiments, R 2h C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1~2 Alkylene-C 3~6 Cycloalkyl and -N(C 1~6 Selected from alkyl)2; C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1~2 Alkylene-C 3~6 Cycloalkyl and -N(C 1~6 Alkyl)2 is a halogen, -OH, -CN, C 1~4 Alkyl and C 1~4 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups.

[0204] In some embodiments, R 2h C 1~6 Alkyl, C 3~6 Selected from cycloalkyl and 4- to 7-membered heterocyclyl groups; C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 7-membered heterocyclyls are each independently and optionally substituted with one or more substituents selected from halogens.

[0205] In some embodiments, R 2h C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 Selected from cycloalkyl groups.

[0206] In some embodiments, R2h Methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-hydroxy-propan-2-yl, 2-cyano-propan-2-yl, -N(CH3)2,

[0207] [ka] Selected from.

[0208] In some embodiments, R 2h The compound is selected from methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0209] In some embodiments, R 2h The isopropyl, tert-butyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, and tetrahydropyran-2-yl.

[0210] In some embodiments, the compound is of formula (V):

[0211] [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , R 3 (and q have the definitions described in this invention.) It has a structure represented by [this].

[0212] In some embodiments, R 1a and R1b Each of these is independently selected from H, D, F, and -OH.

[0213] In some embodiments, R 1a and R 1b H is H.

[0214] In some embodiments, R 2a is -N(R a )-C 1~8 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl), -N(R a )-C(=O)-C 1~8 Alkyl, -N(R a )-C(=O)-OC 1~8 Alkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-Si(R c )3, -N(R a )-(C=N(R b ))-C 1~8 Alkyl, -N(R a )-S(=O) w -C 1~8 Alkyl, -N(R a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~6 Alkylene-phenyl, -OC 1~8 Alkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-(4-8 member heterocyclyl),-OC(=O)-N(R) a )-C 1~8 Alkyl, -OC(=O)-N(R a ) Selected from phenyl, where R 2aThe replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; R g H, D, halogen, -OH, -CN, nitro, oxo, -NH2, -NH(C) 1~6 Alkyl), -N(C 1~6 Alkyl)(C 1~6 Alkyl), C 1~6 Alkyl and C 1~6 Independently selected from haloalkyl groups; w is selected from 1 or 2; R a and R b H and C 1~6 Each alkyl group is independently selected; optionally, C 1~6 The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH.

[0215] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-(4-8 member heterocyclyl), -N(R a )-C(=O)-C 1~6 Alkyl, -N(R a )-C(=O)-OC 1~8 Alkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-Si(R c )3, -N(R a )-(C=N(R b ))-C 1~6 Alkyl, -N(R a )-S(=O) w -C 1~6 Alkyl, -N(R a )-C 1~4 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~4Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~4 Alkylene-phenyl, -OC 1~6 Alkyl, -OC 1~4 Alkylene-C 3~6 Cycloalkyl, -OC 1~4 Alkylene-(4-8 member heterocyclyl),-OC(=O)-N(R) a )-C 1~6 Alkyl and -OC(=O)-N(R a ) Selected from phenyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; R g H, D, F, Cl, Br, -OH, -CN, nitro, oxo, -NH2, -NH(C) 1~4 Alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), C 1~4 Alkyl and C 1~4 Independently selected from haloalkyl groups; w is selected from 1 or 2; R a and R b H and C 1~4 Each alkyl group is independently selected; optionally, C 1~4 The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH.

[0216] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl),-N(R a )-C1~4 Alkylene-phenyl, -OC 1~6 Alkyl and -OC 1~4 Selected from alkylenes (4-8 member heterocyclines), where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and R g R is independently selected from H, F, -OH, -CN, -N(CH3)(CH3), methyl, ethyl, trifluoromethyl, and difluoromethyl; a H is H.

[0217] In some embodiments, R 2a is -N(R a )-C 1~8 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~6 Alkylene-phenyl, -OC 1~8 Alkyl, -OC 1~6 Alkilen-(4-8 member heterocyclyl),-OC 1~6 Alkylene-C 3~6 Cycloalkyl and -N(R a )-(4-8 member heterocyclyl) are selected, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0218] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~4 Alkylene-phenyl, -OC 1~6 Alkyl, -OC 1~4 Alkilen-(4-7 member heterocyclyl), -OC 1~4 Alkylene-C 3~6 Cycloalkyl and -N(R a )-(4-7 member heterocyclyl) are selected, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0219] In some embodiments, R 2a is -N(R a )-C 1~8 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~6 Alkilen-(4-8 member heterocyclyl),-N(R a )-C 1~6 Alkylene-(5-6 member heteroaryl),-N(R a )-C1~6 Alkylene-phenyl, -OC 1~8 Alkyl and -OC 1~6 Selected from alkylenes (4-8 member heterocyclines), where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0220] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -N(R a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-N(R a )-C 1~4 Alkylene-(5-6 member heteroaryl),-N(R a )-C 1~4 Alkylene-phenyl, -OC 1~6 Alkyl and -OC 1~4 Selected from alkylenes (4-7 member heterocyclines), where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0221] In some embodiments, R 2a is -N(R a )-C 1~8 Alkyl, -N(Ra )-C 1~6 Alkylene-C 3~6 Cycloalkyl and -N(R a )-C 1~6 Selected from alkylenes (4-8 member heterocyclines), where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0222] In some embodiments, R 2a is -N(R a )-C 1~6 Alkyl, -N(R a )-C 1~4 Alkylene-C 3~6 Cycloalkyl and -N(R a )-C 1~4 Selected from alkylenes (4-7 member heterocyclines), where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0223] In some embodiments, R g H, D, halogen, -OH, -CN, -NH2, -NH(C) 1~6 Alkyl), -N(C 1~6 Alkyl)(C 1~6 Alkyl), C 1~6 Alkyl and C 1~6 It is independently selected from haloalkyl groups.

[0224] In some embodiments, R gH, D, F, Cl, Br, -OH, -CN, -NH2, -NH(C 1~4 Alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), C 1~4 Alkyl and C 1~4 It is independently selected from haloalkyl groups.

[0225] In some embodiments, R g The compound is independently selected from H, F, -OH, -CN, -N(CH3)2, methyl, ethyl, trifluoromethyl, and difluoromethyl.

[0226] In some embodiments, R h H, D, C 1~6 Alkyl and C 1~6 Selected from haloalkyl groups.

[0227] In some embodiments, R h H, D, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0228] In some embodiments, R h This is selected from H, D, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.

[0229] In some embodiments, R a H and C 1~6 Selected from alkyl groups; optionally, C 1~6 The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH.

[0230] In some embodiments, R a H and C 1~4 Selected from alkyl groups; optionally, C 1~4 The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH.

[0231] In some embodiments, R a H is H.

[0232] In some embodiments, R 2b The element is selected from H, D, -OH, F, Cl, and Br.

[0233] In some embodiments, R 2b H is H.

[0234] In some embodiments, R 3 This is selected from H, D, halogens, and -OH.

[0235] In some embodiments, R 3 This is selected from H and F.

[0236] In some embodiments, q is selected from 0, 1, and 2.

[0237] In some embodiments, the compound is of formula (V-1):

[0238] [ka] (In the formula, R 2c and R 2d These are H, D, F, Cl, -CN, -OH, C 1~6 Alkyl and C 1~6 Each is independently selected from the haloalkyl groups; optionally, R 2c and R 2d It forms an oxo; R 2g H, C 1~4 Alkyl, C 3~6 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -NH2, -NH(C 1~6 Alkyl) and -N(C 1~6 Alkyl)(C 1~6 Selected from alkyl; C 1~4 Alkyl, C 3~6Cycloalkyl groups, 4-8 membered heterocyclyl groups, phenyl groups, and 5-6 membered heteroaryl groups are associated with halogens, -OH groups, -CN groups, and C groups. 1~4 Alkyl and C 1~4 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups; X 2 (It is either NH or O.) It has a structure represented by [this].

[0239] In some embodiments, X 2 It is NH.

[0240] In some embodiments, R 2c and R 2d H, F, -CN, -OH, C 1~3 Alkyl and C 1~3 Each is independently selected from the haloalkyl groups.

[0241] In some embodiments, R 2c and R 2d Each of these is independently selected from H, F, -CN, -OH, methyl, ethyl, and trifluoromethyl.

[0242] In some embodiments, R 2g H, C 1~3 Alkyl, C 3~6 Selected from cycloalkyls, 4-8 membered heterocyclyls, phenyls, and 5-6 membered heteroaryls (such as pyrazolyl, isoxazolyl, triazolyl, and oxadiazolyl); C 1~3 Alkyl, C 3~6 Cycloalkyls, 4- to 8-membered heterocyclyls, phenyls, and 5- to 6-membered heteroaryls are halogens, -OH, -CN, and C 1~3 Alkyl and C 1~3 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups.

[0243] In some embodiments, R 2g H, C 1~3 Alkyl, C 3~6Selected from cycloalkyls, 4-7 membered heterocyclyls, phenyls, and 5-6 membered heteroaryls (such as pyrazolyl, isoxazolyl, triazolyl, and oxadiazolyl); C 1~3 Alkyl, C 3~6 Cycloalkyl groups, 4-7 membered heterocyclyl groups, phenyl groups, and 5-6 membered heteroaryl groups are associated with halogens, -OH groups, -CN groups, and C groups. 1~3 Alkyl and C 1~3 Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups.

[0244] In some embodiments, R 2g H, F, methyl, ethyl, -CH(CH3)2, -CH2OH, difluoromethyl, trifluoromethyl, -CH2-CHF2, cyclopropyl,

[0245] [ka] Cyclobutyl,

[0246] [ka] Cyclopentyl, cyclohexyl,

[0247] [ka] Selected from.

[0248] In some embodiments, R 2c and R 2d H is R 2g It is difluoromethyl.

[0249] In some embodiments, the compound is of formula (VI-0):

[0250] [ka] It has a structure represented by [this].

[0251] In some embodiments, R 2a is -C 1~4 Alkylene-N(R) a )-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-N(R) a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-(5-6 member heteroaryl),-C 1~4 Alkylene-N(R) a )-C 1~4 Alkylene-phenyl, -C 1~4 Alkylene-OC 1~6 Alkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~4 Alkylene-OC 1~4 Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) a )-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )-C(=O)-C 1~6 Alkyl, -C 1~4 Alkylene-N(R) a )(R b ), -C 1~4 Alkylene-OC 1~4 Alkylene-N(R) a )(R b ) and -N(R a )-C(=O)-C 1~6 Selected from alkyl, where R 2a The replaceable carbon atoms are R gEach of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0252] In some embodiments, R 2a is -C 1~2 Alkylene-N(R) a )-C 1~6 Alkyl, -C 1~2 Alkylene-N(R) a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~2 Alkylene-N(R) a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~2 Alkylene-N(R) a )-C 1~4 Alkylene-(5-6 member heteroaryl),-C 1~2 Alkylene-N(R) a )-C 1~4 Alkylene-phenyl, -C 1~2 Alkylene-OC 1~6 Alkyl, -C 1~2 Alkylene-OC 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~2 Alkylene-OC 1~4 Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) a )-C 1~6 Alkyl, -C 1~2 Alkylene-N(R) a )-C(=O)-C 1~6 Alkyl and -C 1~2 Alkylene-OC 1~4 Alkylene-N(R) a )(R b ) is selected, and here, R 2a The replaceable carbon atoms are R gEach of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0253] In some embodiments, R 2a is -C 1~2 Alkylene-N(R) a )-C 1~6 Alkyl, -C 1~2 Alkylene-N(R) a )-C 1~4 Alkylene-C 3~6 Cycloalkyl, -C 1~2 Alkylene-N(R) a )-C 1~4 Alkilen-(4-7 member heterocyclyl),-C 1~2 Alkylene-N(R) a )-C 1~4 Alkylene-(5-6 member heteroaryl) and -C 1~2 Alkylene-N(R) a )-C 1~4 Selected from alkylene-phenyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2a The substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0254] In some embodiments, R 2a is -C 1~2 Alkylene-N(R) a )-C 1~6 Selected from alkyl, where R 2a The replaceable carbon atoms are R g Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R 2aThe substituteable nitrogen atoms on the ring are R h Each molecule is independently and optionally substituted by one or more substituents, each independently selected from the others.

[0255] In some embodiments, R g These include H, D, halogens (F, Cl and Br, etc.), -OH, -CN, -NH2, -NH(C 1~4 Alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), C 1~4 Alkyl and C 1~4 It is independently selected from haloalkyl groups.

[0256] In some embodiments, R h H, D, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0257] In some embodiments, R a and R b H and C 1~4 Each alkyl group is independently selected; optionally, C 1~4 The alkyl group is substituted with one or more substituents selected from halogens.

[0258] In some embodiments, the compound is of formula (VI-1):

[0259] [ka] It has a structure represented by [this].

[0260] In some embodiments, the compound has the following structure:

[0261] [ka] JPEG2026525318000034.jpg200148 JPEG2026525318000035.jpg99150 It holds.

[0262] In some embodiments, the compound has the following structure:

[0263] [ka] JPEG2026525318000037.jpg201150 JPEG2026525318000038.jpg43149 It holds.

[0264] In some embodiments, the compound has the following structure:

[0265] [ka] JPEG2026525318000040.jpg39148 It holds.

[0266] The present invention encompasses compounds obtained by any combination of various embodiments.

[0267] Pharmaceutical composition and administration method The present invention relates to a pharmaceutical composition comprising the compound or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, labeled compounds or prodrugs; and a pharmaceutically acceptable carrier.

[0268] The term "pharmaceutical composition" refers to a mixture of one or more compounds, or physiologically / pharmaceutically acceptable salts or prodrugs, described herein, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and diluents, as well as adjuvants, such as excipients, binders and fillers, and additional therapeutic agents, such as antidiabetic agents, antihyperglycemic agents, anti-obesity agents, antihypertensive agents, antiplatelet agents, anti-atherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate the administration of compounds to a living organism.

[0269] As used herein, the term “pharmaceutically acceptable carrier” means a substance that can be used to prepare or use a pharmaceutical composition, including, for example, suitable diluents, solvents, dispersions, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption inhibitors, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2013, pp. 1049–1070).

[0270] The present invention also relates in particular to compounds having formula I-1, I-2, II-1, II-2, III-1, III-2, IV-1 or IV-2 as an active ingredient, or to enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs thereof, or to pharmaceutical compositions thereof, which can be used for the treatment of neoplasms, especially cancer as described herein. The composition can be formulated for parenteral administration, such as nasal, oral, rectal, lung, vaginal, sublingual, topical, transdermal, or ophthalmic administration, or especially 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 hydroxypropyl methylcellulose (HPMC) capsules (appropriately coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions; or for parenteral administration, such as intravenous, intramuscular or subcutaneous, subarachnoid, intradermal or epidural administration, for example, in the form of solutions, lipid emulsions or suspensions containing fine particles or nanoparticles. These compositions may contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0271] Compounds having formulas I-1, I-2, II-1, II-2, III-1, III-2, IV-1, or IV-2, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs can be processed with pharmaceutically inert inorganic or organic excipients to produce 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, polyvinylpyrrolidone or its derivatives; flow enhancers, such as talc, stearic acid or its salts; and flowables, such as fuming silica, can be used as excipients for the preparation 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 include, for example, vegetable oils, waxes, fats, semi-solids, and liquid polyols.

[0272] Suitable excipients for the preparation of oral solutions, lipid emulsions, or suspensions include, for example, water, alcohol, polyol, sucrose, invert sugar, and glucose.

[0273] Suitable excipients for parenteral formulations include, for example, water, alcohol, polyol, glycerol, vegetable oil, lecithin, and surfactants.

[0274] In addition, the pharmaceutical preparation may contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparation may also contain other therapeutically beneficial substances.

[0275] Dosage can vary within a wide range, and naturally, each specific case will meet individual requirements. Generally, for oral administration, a daily dose of approximately 1 to 1000 mg of a compound having general formula I per person should be appropriate, although the above lower or upper limits may be exceeded if necessary.

[0276] Compounds having formulas I-1, I-2, II-1, II-2, III-1, III-2, IV-1, or IV-2 may also be used in combination with one or more other pharmacologically active compounds that are effective against the same disease, preferably using different modes of action or reducing or preventing possible undesirable side effects of compounds having formulas I-1, I-2, II-1, II-2, III-1, III-2, IV-1, or IV-2. Combination chaperones 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 combination chaperones).

[0277] The term "therapeutic dose" of the compound of the present invention refers to the amount of the compound of the present invention that elicits a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement, alleviation, slowing or delaying disease progression, or prevention of disease). In a non-limiting embodiment, the term "therapeutic dose" refers to the amount of the compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, inhibiting, preventing, and / or improving any disease, disorder, or condition associated with PTPN2.

[0278] The terms “treatment” or “to treat” as used herein in the context of treating a disease or disorder generally refer to treatment and therapy of humans or animals (e.g., in veterinary use), and hereby include certain desired therapeutic effects, such as inhibiting the progression of a disease or disorder, slowing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving the condition for a disease or disorder, and curing a disease or disorder. It also includes treatment as a preventive measure (i.e., prevention). For example, patients who have not yet developed a disease or disorder but are at risk of developing one are included by the term “treatment.” For example, treatment includes cancer prevention, reducing the incidence of cancer, and alleviating cancer symptoms.

[0279] In some embodiments, the present invention provides compounds having formulas I-1, I-2, II-1, II-2, III-1, III-2, IV-1, or IV-2, or enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs, or pharmaceutical compositions thereof, for use in the treatment or prevention of diseases or disorders related to PTPN2.

[0280] In some embodiments, the present invention provides the use of compounds having I-1, I-2, II-1, II-2, III-1, III-2, IV-1, or IV-2, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs, or pharmaceutical compositions thereof, in the manufacture of pharmaceuticals for treating or preventing diseases or disorders related to PTPN2.

[0281] In some embodiments, the present invention provides a method for treating or preventing PTPN2-related diseases or disorders, comprising administering a therapeutically effective amount of a compound having I-1, I-2, II-1, II-2, III-1, III-2, IV-1 or IV-2, or an enantiomer, diastereomer, racemic mixture, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or a pharmaceutical composition thereof.

[0282] In some embodiments, diseases or disorders associated with PTPN2 include cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disorders.

[0283] In some embodiments, cancers include: carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, and melanoma.

[0284] As used herein, the term “cancer” means all types of cancer, neoplasms, or malignant tumors found in mammals, including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, Herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-resistant, tubular carcinoma, lobular carcinoma, primary and metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid tumors, and sarcoma), glioblastoma multiforme, glioma, or melanoma. Other examples include thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic cancer Examples include thyroid gland tumors, malignant carcinoid tumors, bladder cancer, pre-malignant skin diseases, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, tubular carcinoma, pancreatic astrocellular carcinoma, hepatic astrocellular carcinoma, or prostate cancer.

[0285] The term "cancer" refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, adenocarcinoma, acinar carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal carcinoid carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchial carcinoma, bronchogenic lung cancer, brain cancer, cholangiocarcinoma, choriocarcinoma, colloidal carcinoma, Comedo carcinoma, endometrial cancer, cribriform carcinoma, armor-like carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, tubular carcinoma, dural carcinoma, embryonic carcinoma, brain cancer, epidermoid carcinoma, epithelial adenocarcinoma, exophytic carcinoma, preulcer carcinoma, fibrous carcinoma, coroi Decarcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatric carcinoma, hematogenous carcinoma, hepatocellular carcinoma, Hersl cell carcinoma, lucid carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ (carcinoma) in situ), intraepithelial carcinoma, intraepithelial carcinoma Carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, bean-shaped carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, medullary carcinoma, melanoma, nevus carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucoepidermal carcinoma, mucinous carcinoma, mucinous adenocarcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, bee-shaped cell carcinoma, erosive carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcoma, Schneiderian carcinoma, sclerosing carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous carcinoma, squamous cell carcinoma, linear carcinoma, peripheral telangiectatic carcinoma, peripheral telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma Examples include carcinoma, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or choriocarcinoma.

[0286] The term "sarcoma" generally refers to a tumor consisting of embryonic connective tissue-like material and generally of tightly packed cells embedded in fibrous or homogeneous material. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, staphyloid sarcoma, green sarcoma, choriocarcinoma, embryonic sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, and fascia. Examples include sarcomas, fibroblastic sarcomas, giant cell sarcomas, granulocytic sarcomas, Hodgkin's sarcomas, spontaneously occurring multiple colored hemorrhagic sarcomas, B-cell immunoblastic sarcomas, lymphomas, T-cell immunoblastic sarcomas, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, extraperiosteal sarcoma, reticular sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or peripheral telangiectatic sarcoma.

[0287] The term "leukemia" broadly refers to progressive malignancies of the hematopoietic organs, generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on: (1) the duration and characteristics of the disease: acute or chronic; (2) the cell type involved: myeloid, lymphoid, or monocytic; and (3) an increase or absence of an increase in the number of abnormal cells in the blood: leukemia or non-leukemia (subleukemia). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocyte leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, and stem cell leukemia. Leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphotropic leukemia, lymphocyticoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, or anaplastic cell leukemia.

[0288] The term "melanoma" is understood to mean a tumor arising from the melanocyte system of the skin and other organs. Examples of melanomas that can be treated with the compounds, pharmaceutical compositions or methods provided herein include acral lentiginous melanoma, achromocytic melanoma, benign juvenile melanoma, Crowdmann melanoma, S91 melanoma, Harding-Passé melanoma, juvenile melanoma, lentigo malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0289] In some embodiments, cancers include: solid and lymphoid cancers, kidney cancers, breast cancers, lung cancers, bladder cancers, colon cancers, ovarian cancers, prostate cancers, pancreatic cancers, stomach cancers, brain cancers, head and neck cancers, skin cancers, uterine cancers, testicular cancers, gliomas, esophageal cancers, liver cancers (including liver tumors), lymphomas, e.g., acute lymphoblastic lymphoma, non-Hodgkin lymphomas (e.g., Burkitt lymphoma, small cell lymphoma and large cell lymphoma), Hodgkin lymphoma, leukemias (including AML, ALL and CML), and / or multiple myeloma.

[0290] Some types of cancer include lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or cancer.

[0291] Synthesis method Compounds having formulas I-1, I-2, II-1, II-2, III-1, III-2, IV-1, or IV-2 can be synthesized by the methods shown below, by the methods shown in the experimental section below, or by similar methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds having formulas I-1, I-2, II-1, II-2, III-1, III-2, IV-1, or IV-2; conversely, other techniques known to skilled chemists can also be used for compound synthesis.

[0292] The structure of the compound is related to nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR and / or 19 Determined by 1F-NMR. 1 H-NMR, 13 C-NMR and 19 The chemical shift (δ) of F-NMR is expressed in parts per million (ppm). 1 H-NMR, 13 C-NMR and 19F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD600 NMR spectrometer, with deuterated chloroform (CDCl3), deuterated methanol (CD3OD or MeOH-d4), or deuterated dimethyl sulfoxide (DMSO-d6) as the measurement solvent. TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiple peaks appeared, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and brs (broad singlet). The coupling constant J is expressed in Hertz (Hz).

[0293] Liquid chromatography-mass spectroscopy (LC-MS) was performed using an Agilent 1260 mass spectrometer, and HPLC was used to determine the results using an Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100 × 3.0 mm column).

[0294] Qingdao GF254 silica gel plates are used as thin-layer chromatography silica gel plates, with 0.15-0.20 mm plates used for TLC and 0.4-0.5 mm plates used for preparative thin-layer chromatography. For column chromatography, Qingdao silica gel 200-300 mesh silica gel is commonly used as the support.

[0295] The starting materials in the embodiments of the present invention are all known and commercially available, or can be synthesized using or in accordance with literature data reported in the art.

[0296] Unless otherwise specified, all reactions of the present invention are carried out under the protection of a dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperature is always in degrees Celsius.

[0297] Optimal reaction conditions can vary depending on the specific reactants or solvents used, but it should be understood by those skilled in organic synthesis that these conditions can be determined by conventional optimization procedures. In some cases, the following reaction scheme and / or order of reaction steps can be altered to facilitate the reaction or avoid the formation of undesirable by-products. In addition, functional groups present at each position of the molecule must be compatible with the proposed reagents and reaction. This restriction on substituents compatible with the reaction conditions is obvious to those skilled in the art, and alternative methods should then be used. Furthermore, in some reactions described herein, protecting any sensitive groups in the compound may be necessary or desirable, and such protecting groups (PGs) are assumed to be in appropriate positions if necessary. Conventional protecting groups can be used according to standard methods well known in the art (see Greene TW, Wuts PGM, Protective Groups in Organic Synthesis, 5th edition, publisher: John Wiley & Sons, 2014 for illustration). The protecting group can be removed at any convenient stage in the synthesis using prior art well known in the art, or it can be removed in a subsequent reaction step or post-treatment.

[0298] The following abbreviations will be used throughout this invention. LCMS: Liquid Chromatography Mass Spectroscopy M, mol / L: moles per liter ml, mL: milliliter g: grams mmol: millimoles ℃: Celsius

[0299] The following examples are provided to aid in understanding the present invention. However, it should be understood that these examples and figures are used only to illustrate the invention and do not constitute any limitation. The actual scope of protection of the present invention is described in the claims. It should be understood that any modifications and changes may be made without departing from the spirit of the invention. [Examples]

[0300] Preparation example [Example 1] Preparation of compounds 1, 2 and 3

[0301] [ka]

[0302] Step 1: Tert-butyldimethylsilyl chloride (11.3 g, 74.97 mmol) was added at 0°C to a 200 mL solution of compound 1-1 (15.7 g, 71.61 mmol) and imidazole (14.7 g, 215.92 mmol) in dichloromethane. The reaction solution was stirred at 0°C for 2 hours, diluted with water (200 mL), and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with 100 mL of 1 M diluted hydrochloric acid and 100 mL of saturated brine, respectively, dehydrated on anhydrous sodium sulfate, and concentrated to obtain compound 1-2. 1 H NMR (400 MHz, CDCl3) δ 5.32 (d, J = 8.4 Hz, 1 H), 4.38 - 4.30 (m, 1 H), 4.03 (dd, J = 2.8, 10.0 Hz, 1 H), 3.81 (dd, J = 2.8, 10.0 Hz, 1 H), 3.73 (s, 3 H), 1.45 (s, 9 H), 0.86 (s, 9 H), 0.02 (d, J = 5.2 Hz, 6 H).

[0303] Step 2: Sodium borohydride (8.3 g, 219.40 mmol) was added at 0°C to a mixture of compound 1-2 (27 g, 72.86 mmol) and calcium chloride (16.2 g, 145.97 mmol) in tetrahydrofuran (200 mL) and ethanol (100 mL). The mixture was stirred at 15°C for 12 hours. The reaction solution was slowly poured into water (300 mL) and diluted with ethyl acetate (200 mL). The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dehydrated on anhydrous sodium sulfate, and concentrated to obtain compound 1-3. 1 H NMR (400 MHz, CDCl3) δ 5.13 (s, 1 H), 3.91 - 3.73 (m, 3 H), 3.73 - 3.56 (m, 2 H), 2.69 (s, 1 H), 1.45 (s, 9 H), 0.90 (s, 9 H), 0.07 (s, 6 H).

[0304] Step 3: Thionyl chloride (6.7 mL, 92.37 mmol) was added dropwise to a 100 mL solution of imidazole (19.5 g, 286.43 mmol) and triethylamine (21.7 mL, 156.55 mmol) in dichloromethane under a nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes, and then a 100 mL solution of compound 1-3 (21.7 g, 71.03 mmol) in dichloromethane was added dropwise. The reaction solution was stirred at 0°C for 1 hour. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dehydrated on anhydrous sodium sulfate, and concentrated to obtain compound 1-4, which was used directly in the next step.

[0305] Step 4: Ruthenium(III) chloride (0.93 g, 3.56 mmol) and sodium periodate (22.8 g, 106.60 mmol) were added to a solution of compound 1-4 (25 g, 71.12 mmol) in dichloromethane (120 mL) and water (120 mL). The reaction solution was stirred at 15°C for 12 hours. The reaction solution was filtered through Celite, and the filtrate was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with brine (100 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compounds 1-5 were obtained by purifying the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:5). 1 H NMR (400 MHz, CDCl3) δ 4.65 - 4.55 (m, 2 H), 4.30 - 4.23 (m, 1 H), 3.87 (dd, J = 4.0, 10.0 Hz, 1 H), 3.78 (dd, J = 8.0, 10.0 Hz, 1 H), 1.55 (s, 9 H), 0.89 (s, 9 H), 0.09 (d, J = 2.8 Hz, 6 H).

[0306] Step 5: Potassium tert-butoxide solution (105 mL, 105.00 mmol, 1 M tetrahydrofuran solution) was added dropwise to a solution of compound 1-6 (23.5 g, 98.74 mmol) and benzyl alcohol (10.8 mL, 103.87 mmol) in tetrahydrofuran (450 mL) under a nitrogen atmosphere at -50°C. The mixture was stirred under a nitrogen atmosphere at -50°C for 20 minutes. The reaction solution was quenched with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with brine (200 mL), dehydrated on anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:20) to obtain compound 1-7. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (t, J = 1.6 Hz, 1 H), 7.59 (dd, J = 9.2, 1.6 Hz, 1 H), 7.47 - 7.33 (m, 5 H), 5.36 (s, 2 H).

[0307] Step 6: A saturated ammonium chloride solution (120 mL) was added to a solution of compound 1-7 (23 g, 70.53 mmol) and zinc powder (14 g, 214.13 mmol) in tetrahydrofuran (230 mL) and methanol (230 mL). The reaction solution was stirred at 20°C for 2 hours. The reaction solution was diluted with ethyl acetate (200 mL) and filtered through Celite. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine (100 mL), dehydrated on anhydrous sodium sulfate, and concentrated to obtain compound 1-8, which was used directly in the next step.

[0308] Step 7: Trifluoroacetic anhydride (12.3 mL, 88.43 mmol) was added dropwise at 20°C to a solution of compound 1-8 (20.2 g, 68.21 mmol) and pyridine (9 mL, 111.50 mmol) in acetonitrile (200 mL). The reaction solution was stirred at 20°C for 1 hour. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine (200 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-9 was obtained by purifying the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10). 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1 H), 7.48 - 7.27 (m, 7 H), 5.24 (s, 2 H).

[0309] Step 8: A 2M tetrahydrofuran solution of lithium diisopropylamide was added dropwise to a 100mL solution of tetrahydrofuran containing compound 1-9 (18.5g, 47.18 mmol) under a nitrogen atmosphere at -70°C. The reaction solution was stirred at -70°C for 30 minutes, and then a 100mL solution of tetrahydrofuran containing compound 1-5 (15g, 42.67 mmol) was added dropwise at -70°C. The reaction solution was stirred at -70°C for 2 hours. 86mL of 3M diluted hydrochloric acid was added dropwise to the reaction solution, and the reaction solution was stirred at 15°C for a further 12 hours. The reaction solution was diluted with water (200mL) and extracted with ethyl acetate (100mL x 3). The organic phases were combined, washed with brine (100mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-10 was obtained by purifying the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 4:5). MS m / z (ESI): 465.2 [M-Boc+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1 H), 7.44 - 7.34 (m, 6 H), 6.44 (d, J = 9.2 Hz, 1 H), 5.19 (s, 2 H), 4.83 - 4.66 (m, 1 H), 3.79 - 3.69 (m, 1 H), 3.43 - 3.38 (m, 1 H), 2.90 - 2.73 (m, 2 H), 1.28 (s, 9 H).

[0310] Step 9: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1 g, 1.37 mmol) was added under a nitrogen atmosphere to a mixture of compound 1-10 (15 g, 26.53 mmol), potassium vinyltrifluoroborate (11 g, 82.12 mmol), and potassium carbonate (11 g, 79.59 mmol) in 1,4-dioxane (150 mL) and water (15 mL). The reaction solution was stirred under a nitrogen atmosphere at 100 °C for 12 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine (100 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-11 was obtained by purification of the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 2:5). MS m / z (ESI): 535.4 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1 H), 7.47 - 7.41 (m, 2 H), 7.41 - 7.35 (m, 2 H), 7.35 - 7.31 (m, 1 H), 7.19 (s, 1 H), 7.13 (dd, J = 17.2, 10.8 Hz, 1 H), 6.51 (d, J = 8.4 Hz, 1 H), 6.05 - 5.77 (m, 1 H), 5.42 (d, J = 11.2 Hz, 1 H), 5.22 (s, 2 H), 4.70 (t, J = 6.0 Hz, 1 H), 3.59 - 3.49 (m, 1 H), 3.31 - 3.26 (m, 2 H), 2.83 - 2.78 (m, 1 H), 2.71 - 2.63 (m, 1 H), 1.31 (s, 9 H).

[0311] Step 10: A solution of pyridine sulfur trioxide (14.6 g, 91.73 mmol) in dimethyl sulfoxide (80 mL) was added to a solution of compound 1-11 (7.8 g, 15.22 mmol) and triethylamine (12.7 mL, 91.62 mmol) in dichloromethane (80 mL) and dimethyl sulfoxide (80 mL) at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C under a nitrogen atmosphere for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with 1.0 M diluted hydrochloric acid solution (200 mL) and saturated brine (100 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-12 was obtained by slurring the crude product with a mixed solution of petroleum ether / ethyl acetate (100 mL, v / v ratio 10 / 1). MS m / z (ESI): 533.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1 H), 9.47 (s, 1 H), 7.53 - 7.26 (m, 6 H), 7.19 (s, 1 H), 6.93 (dd, J = 10.8, 17.2 Hz, 1 H), 5.86 (d, J = 17.2 Hz, 1 H), 5.42 (d, J = 11.2 Hz, 1 H), 5.23 (s, 2 H), 3.87 - 3.73 (m, 1 H), 3.13 - 3.08 (m, 1 H), 2.99 - 2.85 (m, 1 H), 1.34 (s, 9 H).

[0312] Step 11: Sodium hydrogen (1.3 g, 32.50 mmol) was added to a solution of methyltriphenylphosphonium bromide (12 g, 33.59 mmol) in tetrahydrofuran (30 mL) at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C for 30 minutes, and then a solution of compound 1-12 (4.8 g, 9.40 mmol) in tetrahydrofuran (30 mL) was added to the reaction solution. The reaction solution was stirred at 60°C for 12 hours. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-13 was obtained by purification of the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10). MS m / z (ESI): 531.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1 H), 7.50 - 7.26 (m, 5 H), 7.18 (s, 1 H), 7.13 - 6.83 (m, 2 H), 5.87 (d, J = 17.2 Hz, 1 H), 5.80 - 5.64 (m, 1 H), 5.44 (d, J = 11.2 Hz, 1 H), 5.22 (s, 2 H), 5.04 - 4.80 (m, 2 H), 4.17 - 3.95 (m, 1 H), 2.90 - 2.71 (m, 2 H), 1.33 (s, 9 H).

[0313] Step 12: Methyl bromoacetate (0.66 mL, 6.95 mmol) was added to a solution of compounds 1-13 (2.5 g, 4.92 mmol) and potassium carbonate (2.05 g, 14.83 mmol) in N,N-dimethylformamide (30 mL). The reaction solution was stirred at 60°C for 2 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compounds 1-14 were obtained by purifying the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:5). MS m / z (ESI): 603.4 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.29 (m, 5 H), 7.24 (d, J = 7.6 Hz, 1H), 7.20 - 6.85 (m, 2 H), 5.94 (dd, J = 11.2, 17.2 Hz, 1 H), 5.83 - 5.60 (m, 1 H), 5.51 (dd, J = 4.8, 11.2 Hz, 1 H), 5.35 - 5.15 (m, 2 H), 5.00 - 4.81 (m, 2 H), 4.50 (dd, J = 2.8, 16.8 Hz, 1 H), 4.29 - 4.13 (m, 1 H), 4.12 - 4.05 (m, 1 H), 3.61 (s, 3 H), 2.86 - 2.72 (m, 2 H), 1.43 - 1.25 (m, 9 H).

[0314] Step 13: 1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (0.71 g, 0.96 mmol) was added to a solution of compound 1-14 (2.8 g, 4.82 mmol) in dichloromethane (160 mL) under a nitrogen atmosphere. The reaction solution was stirred in the dark at 40°C for 6 hours. The reaction solution was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-15 was obtained by purifying the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:3). MS m / z (ESI): 575.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.11 (m, 6 H), 7.01 (s, 1 H), 6.53 (d, J = 9.6 Hz, 1 H), 6.12 - 5.96 (m, 1 H), 5.28 - 5.07 (m, 2 H), 4.51 (dd, J = 5.6, 16.8 Hz, 1 H), 4.35 - 4.26 (m, 2 H), 3.61 (d, J = 2.8 Hz, 3 H), 3.00 - 2.85 (m, 1 H), 2.64 - 2.53 (m, 1 H), 1.40 (s, 9 H).

[0315] Step 14: A solution of diiodomethane (0.18 mL, 2.23 mmol) in dichloromethane (1 mL) was added dropwise to a solution of diethylzinc (1.10 mL, 1.10 mmol, 1 M hexane solution) in dichloromethane (1 mL) at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C for 15 minutes, and then compound 1-15 (250 mg, 0.45 mmol) in dichloromethane (1 mL) was added dropwise. The reaction solution was stirred at 20°C for 30 minutes. The reaction solution was diluted with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-16 was obtained by purification of the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:3). MS m / z (ESI): 589.4 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.38 (m, 4 H), 7.37 - 7.30 (m, 1 H), 7.12 (s, 1 H), 7.08 - 7.02 (m, 1 H), 5.27 - 5.07 (m, 2 H), 4.49 (dd, J = 5.2, 16.8 Hz, 1 H), 4.20 (dd, J = 8.0, 16.8 Hz, 1 H), 3.91 - 3.71 (m, 1 H), 3.60 (s, 3 H), 2.88 - 2.77 (m, 1 H), 2.20 - 2.00 (m, 2 H), 1.78 - 1.65 (m, 1H), 1.42 (s, 9 H), 1.04 - 0.89 (m, 2 H).

[0316] Step 15: Sodium methoxide (110 mg, 2.04 mmol) was added to a methanol (3 mL) solution of compound 1-16 (280 mg, 0.49 mmol). The reaction solution was stirred at 60°C for 2 hours. The solvent was dried by rotary evaporation to obtain crude compound 1-17, which was used directly in the next step.

[0317] Step 16: Iodomethane (0.04 mL, 0.64 mmol) was added to a solution of compound 1-17 (222 mg, 0.46 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 15°C for 3 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-18 was obtained by purification of the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 3:20). MS m / z (ESI): 571.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 7.2 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.34 (t, J = 7.2 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.79 (s, 1 H), 5.11 (s, 2 H), 4.86 - 4.74 (m, 1 H), 4.02 - 3.93 (m, 2 H), 3.81 - 3.67 (m, 1 H), 3.58 (s, 3 H), 2.82 - 2.78 (m, 1 H), 1.99 - 1.86 (m, 2 H), 1.61 - 1.51 (m, 1 H), 1.41 (s, 9 H), 0.84 - 0.71 (m, 2 H).

[0318] Step 17: Tert-butanol (73 μL, 0.77 mmol) was added to a solution of chlorosulfonyl isocyanate (65 μL, 0.75 mmol) in dichloromethane (0.2 mL). The reaction solution was stirred at 20°C for 15 minutes, after which compound 1-18 (150 mg, 0.32 mmol) and a solution of triethylamine (135 μL, 0.97 mmol) in dichloromethane (0.2 mL) were added dropwise. The reaction solution was stirred at 20°C for a further 1 hour. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dehydrated on anhydrous sodium sulfate, and concentrated. Compound 1-19 was obtained by purification of the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:4). MS m / z (ESI): 672.4 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (d, J = 5.6 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.88 (s, 1 H), 5.20 (q, J = 13.2 Hz, 2 H), 4.67 (dd, J = 7.2, 17.6 Hz, 1 H), 4.34 (d, J = 18.4 Hz, 1 H), 3.85 - 3.69 (m, 1 H), 3.55 (s, 3 H), 2.87 - 2.74 (m, 1 H), 2.08 - 2.00 (m, 2 H), 1.72 - 1.61 (m, 1 H), 1.42 (s, 9 H), 1.34 - 1.28 (m, 9 H), 0.96 - 0.80 (m, 2 H).

[0319] Step 18: Trifluoroacetic acid (500 μL, 6.71 mmol) was added to a solution of compound 1-19 (107 mg, 0.16 mmol) in dichloromethane (1 mL). The reaction solution was stirred at 25°C for 1 hour, and the solvent was dried by rotary evaporation. The crude compound was dissolved in dichloromethane (5 mL) with the addition of triethylamine (110 μL, 0.79 mmol) and di-tert-butyl dicarbonate (170 μL, 0.79 mmol). The reaction solution was stirred at 25°C for a further 30 minutes, and the solvent was dried by rotary evaporation. Compound 1-20 was obtained by purification of the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 2:3). MS m / z (ESI): 572.4 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.07 - 7.00 (m, 1 H), 6.94 (s, 1 H), 6.88 (s, 2 H), 5.15 (s, 2 H), 4.36 (dd, J = 4.0, 17.6 Hz, 1 H), 4.18 (dd, J = 3.2, 17.6 Hz, 1 H), 3.83 - 3.75 (m, 1 H), 3.55 (s, 3 H), 2.87 - 2.80 (m, 1 H), 2.10 - 1.99 (m, 2 H), 1.74 - 1.59 (m, 1 H), 1.42 (s, 9 H), 0.97 - 0.84 (m, 2 H).

[0320] Step 19: Sodium methoxide (25 mg, 0.46 mmol) was added to a methanol (2 mL) solution of compound 1-20 (117 mg, 0.21 mmol). The reaction solution was stirred at 60°C for 20 minutes. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dehydrated over anhydrous sodium sulfate, and concentrated to obtain compound 1-21. MS m / z (ESI): 540.2 [M+Na] + .1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 6.8 Hz, 2 H), 7.35 (t, J = 6.8 Hz, 2 H), 7.30 (d, J = 7.2 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 1 H), 6.92 (s, 1 H), 5.14 (s, 2 H), 4.00 - 3.89 (m, 2 H), 3.86 - 3.75 (m, 1 H), 2.88 - 2.75 (m, 1 H), 2.07 - 1.99 (m, 2 H), 1.72 - 1.60 (m, 1 H), 1.42 (s, 9 H), 0.94 - 0.81 (m, 2 H).

[0321] Step 20: Trifluoroacetic acid (500 μL, 6.71 mmol) was added to a solution of compound 1-21 (94 mg, 0.18 mmol) in dichloromethane (2 mL). The reaction solution was stirred at 25°C for 1 hour. The solvent was dried by rotary evaporation to obtain crude compound 1-22, which was used directly in the next step. MS m / z (ESI): 416.1 [MH] - .

[0322] Step 21: Sodium borohydride (35 mg, 0.56 mmol) was added to a methanol (0.3 mL) solution of compound 1-22 (75.8 mg, 0.18 mmol) and isovaleraldehyde (20 μL, 0.19 mmol). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated, and the crude product was purified by reverse-phase column chromatography (C18, 5-50% acetonitrile / 0.1% ammonium bicarbonate aqueous solution) to obtain compound 1-23. MS m / z (ESI): 488.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1 H), 7.50 (d, J = 7.6 Hz, 2 H), 7.35 (t, J = 7.6 Hz, 2 H), 7.30 (d, J = 7.2 Hz, 1 H), 6.98 (s, 1 H), 5.16 (s, 2 H), 3.93 (s, 2 H), 3.66 (s, 1 H), 3.22 - 3.00 (m, 4 H), 2.29 - 2.15 (m, 2 H), 1.95 - 1.83 (m, 1 H), 1.74 - 1.61 (m, 1 H), 1.58 - 1.48 (m, 2 H), 1.14 - 1.01 (m, 2 H), 0.93 (d, J = 6.4 Hz, 6 H).

[0323] Step 22: 10% wet palladium-carbon (10 mg) was added to a methanol (2 mL) solution of compound 1-23 (60 mg, 0.12 mmol). The reaction solution was stirred at 25°C for 4 hours under the protection of hydrogen (15 psi). The reaction solution was filtered through Celite, and the filtrate was dried by rotary evaporation. Compound 1 was obtained by preparative HPLC (C18, acetonitrile / 0.1% ammonium bicarbonate aqueous solution). MS m / z (ESI): 396.1 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (br s, 1 H), 8.51 (br s, 1H), 6.69 (s, 1 H), 3.91 (s, 2 H), 3.65 (s, 1 H), 3.30 - 2.96 (m, 4 H), 2.25 - 2.08 (m, 2 H), 1.90 - 1.78 (m, 1 H), 1.74 - 1.60 (m, 1 H), 1.57 - 1.46 (m, 2 H), 1.11 - 0.98 (m, 2 H), 0.92 (d, J = 6.4 Hz, 6 H).

[0324] Separating compound 1 using SFC chiral separation (column: Chiralpak IC-3 100) *By separating the compounds using a 4.6mm ID, 3um mobile phase (A: CO2 B: methanol (0.05% DEA) Isocratic: 50% B), flow rate (ml / min): 80, column temperature: 35°C, ABPR: 1500 psi, compound 2 (isomer 1, first peak, retention time 1.301 min) and compound 3 (isomer 2, second peak, retention time 1.936 min). Compound 2:MS m / z(ESI): 398.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (br s, 1 H), 8.50 (br s, 1 H), 6.69 (s, 1 H), 3.92 (s, 2 H), 3.67 - 3.60 (m, 1 H), 3.30 - 3.04 (m, 4 H), 2.22 - 2.13 (m, 2 H), 1.89 - 1.82 (m, 1 H), 1.75 - 1.64 (m, 1 H), 1.53 (q, J = 7.3 Hz, 2 H), 1.08 - 1.00 (m, 2 H), 0.93 (d, J = 6.6 Hz, 6 H). Compound 3:MS m / z(ESI): 398.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (br s, 1 H), 8.50 (br s, 1 H), 6.69 (s, 1 H), 3.92 (s, 2 H), 3.67 - 3.60 (m, 1 H), 3.30 - 3.04 (m, 4 H), 2.22 - 2.13 (m, 2 H), 1.89 - 1.82 (m, 1 H), 1.75 - 1.64 (m, 1 H), 1.53 (q, J = 7.3 Hz, 2 H), 1.08 - 1.00 (m, 2 H), 0.93 (d, J = 6.6 Hz, 6 H).

[0325] [Example 2] Preparation of compounds 4, 5 and 6

[0326] [ka]

[0327] Step 1: Compound 4-1 (15.0 g, 58.53 mmol) was dissolved in ethanol (200 mL), and isopentylamine hydrochloride (15 g, 58.53 mmol) and paraformaldehyde (19.31 g, 585.30 mmol) were added. The reaction solution was stirred at 95°C for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol. Compound 4-2 was obtained by drying the filter cake under reduced pressure. MS m / z (ESI): 356.1 [M+H] + .

[0328] Step 2: Compound 4-2 (14.0 g, 39.39 mmol) was dissolved in tetrahydrofuran (100 mL), and triethylamine (11.96 g, 118.16 mmol) and Boc anhydrous (9.46 g, 43.33 mmol) were added. The reaction solution was stirred at 25°C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dehydrated on anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:4) to obtain compound 4-3. 1 H NMR (400MHz, DMSO-d6) δ 7.50 - 7.34 (m, 5 H), 7.06 (s, 1 H), 6.88 (br d, J = 10.4 Hz, 1 H), 5.30 - 5.17 (m, 2 H), 3.52 - 3.35 (m, 2 H), 3.50 - 3.10 (m, 3 H), 2.99 (br s, 1 H), 2.89 (br s, 1 H), 1.55 - 1.44 (m, 1 H), 1.43 - 1.27 (m, 11 H), 0.87 (d, J = 6.4 Hz, 6 H).

[0329] Step 3: Compound 4-3 (15.0 g, 32.93 mmol) was dissolved in methanol (500 mL), and 10% wet palladium carbon (3.50 g) was slowly added to the reaction solution under a nitrogen atmosphere. Hydrogen was replaced three times, and the reaction solution was stirred at room temperature under a hydrogen atmosphere (30 psi) for 12 hours. The reaction solution was filtered through Celite, and the filtrate was washed with methanol. Compound 4-4 was obtained by concentrating the filtrate and used directly in the next step.

[0330] Step 4: Compound 4-4 (8.5 g, 23.26 mmol) was dissolved in N,N-dimethylformamide (100 mL). Cesium carbonate (22.73 g, 69.78 mmol) was added to the reaction solution under a nitrogen atmosphere, and 2-methoxyethoxymethyl chloride (5.3 mL, 46.52 mmol) was added dropwise at -30°C. The reaction solution was stirred at -30°C for 30 minutes. The reaction solution was quenched with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with brine (100 mL), dehydrated on anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Compound 4-5 was obtained by purifying the residue by silica gel column chromatography (tetrahydrofuran:petroleum ether = 3:7). MS m / z (ESI): 354.2 [M+H-Boc] + . 1 H NMR (400MHz, DMSO-d6) δ 7.03 (s, 1 H), 6.85 (br d, J = 11.2 Hz, 1 H), 5.39 (s, 2 H), 3.78 - 3.70 (m, 2 H), 3.51 - 3.42 (m, 4 H), 3.22 (s, 3 H), 3.14 (br s, 2 H), 2.99 (br s, 1 H), 2.86 (br s, 1 H), 1.48 (td, J = 6.4, 13.2 Hz, 1 H), 1.43 - 1.22 (m, 12 H), 0.87 (d, J = 6.4 Hz, 6 H).

[0331] Step 5: (Fluoromethyl)triphenylphosphonium tetrafluoroborate (12.63 g, 33.07 mmol) was dissolved in tetrahydrofuran (150 mL), and potassium tert-butoxide (3.71 g, 33.07 mmol) was slowly added at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C for 30 minutes. Compound 4-5 (5 g, 11.02 mmol) was dissolved in tetrahydrofuran (20 mL) and slowly added dropwise to the reaction solution at 0°C. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (300 mL), extracted with ethyl acetate (300 mL x 3), the organic phase was washed with brine (200 mL), dehydrated on anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, and the crude product was purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:10) to obtain compound 4-6. MS m / z(ESI):492.2[M+Na] + .

[0332] Step 6: Compound 4-6 (4.3 g, 9.16 mmol) was dissolved in tetrahydrofuran (50 mL), and 2.5 M n-butyllithium (18.31 mL, 45.79 mmol) was added dropwise under a nitrogen atmosphere at -78°C, and the reaction solution was stirred at -78°C for 30 minutes. Iodine (6.97 g, 27.47 mmol) was dissolved in tetrahydrofuran (20 mL), and slowly added dropwise to the reaction solution at -78°C, and the reaction solution was stirred at -78°C for 2 hours. The reaction solution was quenched with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with aqueous sodium sulfite solution (100 mL), washed with brine (100 mL), and dehydrated on anhydrous sodium sulfate. The solution was filtered and concentrated. Compound 4-7 was obtained by purifying the residue by silica gel column chromatography (tetrahydrofuran:petroleum ether = 3:10). MS m / z (ESI): 540.1 [M+H-56] + .

[0333] Step 7: Compound 4-7 (5.0 g, 8.40 mmol), tert-butylglycinate (1.65 g, 12.60 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.76 g, 0.84 mmol), and cesium carbonate (8.21 g, 25.19 mmol) were dissolved in dioxane (50 mL), the mixture was replaced with nitrogen three times, and the reaction solution was stirred at 95°C for 4 hours. The reaction solution was extracted with water (300 mL) and ethyl acetate (300 mL x 3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was then purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 3:10) to obtain compounds 4-8. MS m / z (ESI): 599.3 [M+H] + .

[0334] Step 8: Take three-necked flask A, dissolve chlorosulfonyl isocyanate (1.65 g, 11.69 mmol) in dichloromethane (50 mL), add allyl alcohol (0.95 g, 16.36 mmol) dropwise under a nitrogen atmosphere at 0°C, and stir the reaction solution at 0°C for 1 hour. Take three-necked flask B, dissolve compound 4-8 (3.5 g, 5.85 mmol) in dichloromethane (50 mL), and add triethylamine (2.4 mL, 17.54 mmol) dropwise. Add the solution from three-necked flask A to three-necked flask B at 0°C. Stir the reaction solution at 0°C under a nitrogen atmosphere for 2 hours. Dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL x 3), wash the organic phase with brine (30 mL), dehydrate over anhydrous sodium sulfate, and filter. Concentrate the filtrate to obtain compound 4-9. MS m / z (ESI): 760.3 [MH] - .

[0335] Step 9: Compound 4-9 (3.0 g, 3.94 mmol) was dissolved in methanol (60 mL), tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol), sodium methoxide (1.3 mL, 23.63 mmol, 30% methanol solution) and 4A molecular sieve (3.0 g) were added, the nitrogen atmosphere was changed three times, and the reaction solution was stirred at 60°C for 12 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (300 mL x 3), the organic phase was washed with saturated brine (100 mL), dehydrated on anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was prepared by HPLC (column: C18 150×40 mm; flow rate: 60 mL / min; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 20%~60% acetonitrile, 9 min) to obtain compounds 4-10 (first peak, retention time 2.64 min) and 4-11 (second peak, retention time 2.76 min). Compound 4-10: MS m / z (ESI): 602.2 [MH] - . Compound 4-11:MS m / z(ESI):602.2[MH] - .

[0336] Step 10: Compound 4-11 (600 mg, 0.99 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2.0 mL, 26.84 mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the residue was prepared by HPLC (column: Phenomenex Gemini NX 150 × 30 mm, 5 μm; flow rate: 60 mL / min; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 9%~49%, 9 min) to obtain compound 4. Compound 4 was subjected to SFC chiral separation (column: DAISEL CHIRALPAK IG (250 mm)). * Compound 5 (isomer 1, first peak, retention time 1.062 min) and compound 6 (isomer 2, second peak, retention time 1.486 min) were obtained by preparation under the following conditions: 30 mm, 10 μm; CO2-EtOH (0.1% NH3H2O) start B: 35% end B: 35%; flow rate (ml / min): 80. Compound 4: MS m / z (ESI): 416.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (br s, 1 H), 8.23 (s, 1 H), 7.68 - 7.23 (m, 1 H), 6.66 (s, 1 H), 4.01 - 3.88 (m, 2 H), 3.63 (br s, 1 H), 3.30 - 3.11 (m, 2 H), 3.10 - 3.05 (m, 1 H), 3.05 - 2.85 (m, 4 H), 1.68 - 1.56 (m, 1 H), 1.52 - 1.41 (m, 2 H), 0.89 (d, J = 6.4 Hz, 6 H). Compound 5: MS m / z (ESI): 416.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (br s, 1 H), 8.23 (s, 1 H), 7.68 - 7.23 (m, 1 H), 6.66 (s, 1 H), 4.01 - 3.88 (m, 2 H), 3.63 (br s, 1 H), 3.30 - 3.11 (m, 2 H), 3.10 - 3.05 (m, 1 H), 3.05 - 2.85 (m, 4 H), 1.68 - 1.56 (m, 1 H), 1.52 - 1.41 (m, 2 H), 0.89 (d, J = 6.4 Hz, 6 H). Compound 6: MS m / z (ESI): 416.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (br s, 1 H), 8.18 (br s, 1 H), 7.58 - 7.28 (m, 1 H), 6.66 (s, 1 H), 4.01 - 3.88 (m, 2 H), 3.63 (br s, 1 H), 3.20 - 3.03 (m, 3 H), 3.02 - 2.85 (m, 4 H), 1.68 - 1.56 (m, 1 H), 1.54 - 1.43 (m, 2 H), 0.89 (d, J = 6.4 Hz, 6 H).

[0337] [Example 3] Preparation of Compound 7

[0338] [ka]

[0339] Step 1: Compound 4-10 (400 mg, 0.66 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.3 mL, 17.44 mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the residue was prepared by HPLC (column: Phenomenex Gemini NX 150 × 30 mm, 5 μm; flow rate: 60 mL / min; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 6%~46%, 9 min) to obtain compound 7. MS m / z (ESI): 416.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1 H), 8.25 (br s, 1 H), 6.95 (br d, J = 82.0 Hz, 1 H), 6.67 (s, 1 H), 3.94 (s, 2 H), 3.22 - 2.96 (m, 4 H), 2.95 - 2.88 (m, 3 H), 2.77 (br d, J = 16.0 Hz, 1 H), 1.61 (td, J = 6.4, 13.2 Hz, 1 H), 1.54 - 1.44 (m, 2 H), 0.89 (d, J = 6.4 Hz, 6 H).

[0340] [Example 4] Preparation of Compound 8

[0341] [ka]

[0342] Step 1: Sodium borohydride (6 mg, 95.48 μmol) was added to a methanol (0.2 mL) solution of compound 1-22 (24 mg, 57.49 μmol) and 4,4,4-trifluorobutyraldehyde (7 μL, 66.62 μmol). The reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:10) to obtain compound 8-1. MS m / z (ESI): 528.2 [M+H] + .

[0343] Step 2: 10% wet palladium-carbon (10 mg) was added under a nitrogen atmosphere to a solution of compound 8-1 (30 mg, 56.87 μmol) in ethanol (2 mL). The reaction solution was stirred at 25°C for 12 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered through Celite, and the filtrate was dried by rotary evaporation. The crude product was purified by preparative HPLC (C18, 0.05% ammonium bicarbonate solution / acetonitrile) to obtain compound 8. MS m / z (ESI): 438.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (br s, 1 H), 8.63 (br s, 1 H), 6.69 (s, 1 H), 3.90 (s, 2 H), 3.67 (br s, 1 H), 3.26 - 2.92 (m, 4 H), 2.47 - 2.36 (m, 2 H), 2.26 - 2.05 (m, 2 H), 1.95 - 1.71 (m, 3 H), 1.13 - 0.94 (m, 2 H).

[0344] [Example 5] Preparation of Compound 9

[0345] [ka]

[0346] Step 1: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.8 g, 23.14 mmol) and triethylamine (7.4 mL, 53.38 mmol) were added to a solution of compound 9-1 (3.0 g, 17.63 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.5 g, 35.88 mmol) in N,N-dimethylformamide (30 mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dehydrated on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 9-2 was obtained by purifying the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10). MS m / z (ESI): 214.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 3.69 (s, 3 H), 3.19 (s, 3 H), 2.60 (s, 2 H), 1.29 (s, 6 H).

[0347] Step 2: Lithium aluminum hydride (0.56 mL, 1.4 mmol, 2.5 M tetrahydrofuran solution) was added dropwise to a solution of compound 9-2 (200 mg, 0.94 mmol) in tetrahydrofuran (5 mL) at 0°C. After the addition was complete, the reaction solution was stirred at 0°C for 2 hours. The reaction solution was quenched with sodium sulfate decahydrate, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 9-3. 1 H NMR (400 MHz, CDCl3) δ 9.75 - 9.73 (m, 1 H), 2.47 (d, J = 2.4 Hz, 2 H), 1.22 (s, 6 H).

[0348] Step 3: Sodium borohydride cyanohydride (10 mg, 159.13 μmol) was added to a methanol (1 mL) solution of compound 1-22 (22 mg, 52.70 μmol) and compound 9-3 (1.44 mL, 158.1 μmol). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (C18, 0.05% ammonium bicarbonate solution / acetonitrile) to obtain compound 9-4. MS m / z (ESI): 556.4 [M+H] + .

[0349] Step 4: 10% wet palladium-carbon (5 mg) was added under a nitrogen atmosphere to a solution of compound 9-4 (24 mg, 43.20 μmol) in tetrahydrofuran (3 mL). The reaction solution was stirred at 25°C for 12 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered through Celite, and the filtrate was dried by rotary evaporation. The crude product was purified by preparative HPLC (C18, 0.05% ammonium bicarbonate solution / acetonitrile) to obtain compound 9. MS m / z (ESI): 466.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1 H), 8.41 (s, 1 H), 6.69 (s, 1 H), 3.91 (s, 2 H), 3.78 - 3.56 (m, 1 H), 3.47 - 3.38 (m, 1 H), 3.19 - 3.06 (m, 3 H), 2.25 - 2.08 (m, 2 H), 1.96 - 1.70 (m, 3 H), 1.15 (s, 6 H), 1.08 - 0.92 (m, 2 H).

[0350] [Example 6] Preparation of Compound 10

[0351] [ka]

[0352] Compound 10 was synthesized by referring to Example 4, except that 3,3-dimethylbutyraldehyde was used as a raw material to replace 4,4,4-trifluorobutyraldehyde in Example 4, and compound 10 was prepared by the same method as in Example 4. Compound 10:MS m / z (ESI): 412.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1 H), 8.29 (s, 1 H), 6.75 - 6.62 (m, 1 H), 3.94 - 3.88 (m, 2 H), 3.70 - 3.59 (m, 1 H), 3.27 - 2.80 (m, 4 H), 2.25 - 1.98 (m, 2 H), 1.92 - 1.79 (m, 1 H), 1.59 - 1.51 (m, 1 H), 1.45 (t, J = 8.8 Hz, 1 H), 1.17 - 0.97 (m, 2 H), 0.96 - 0.86 (m, 9 H).

[0353] [Example 7] Preparation of Compound 11

[0354] [ka]

[0355] Compound 11 was synthesized by referring to Example 4, except that 2-cyclohexylacetaldehyde was used as a starting material to replace 4,4,4-trifluorobutyraldehyde in Example 4, and compound 11 was prepared by the same method as in Example 4. Compound 11:MS m / z (ESI): 438.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.25 (brs, 1 H), 8.33 (brs, 1 H), 6.76 - 6.63 (m, 1 H), 3.94 - 3.87 (m, 2 H), 3.68 - 3.62 (m, 1 H), 3.20 - 2.84 (m, 4 H), 2.25 - 1.94 (m, 2 H), 1.90 - 1.78 (m, 1 H), 1.78 - 1.57 (m, 5 H), 1.56 - 1.49 (m, 1 H), 1.48 - 1.39 (m, 1 H), 1.28 - 0.78 (m, 8 H).

[0356] [Example 8] Preparation of compounds 12, 13 and 14

[0357] [ka]

[0358] Step 1: Dess-Martin reagent (980 mg, 2.31 mmol) was added to a solution of compound 12-1 (200 mg, 2.08 mmol) in dichloromethane (4 mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was filtered through Celite, and the filtrate was diluted with dichloromethane (10 mL) to obtain a solution of compound 12-2, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, 1 H), 6.24 (t, J = 50.4 Hz, 1 H), 3.10 - 2.96 (m, 2 H).

[0359] Step 2: Sodium borohydride (75 mg, 1.19 mmol) was added to a methanol (2 mL) solution of compound 1-22 (400 mg, 0.60 mmol) and compound 12-2 (4.0 mL, 0.84 mmol, dichloromethane solution). The reaction solution was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (C18, 0.05% ammonium bicarbonate solution / acetonitrile) to obtain compound 12-3. MS m / z (ESI): 496.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (brs, 1 H), 7.53 - 7.47 (m, 2 H), 7.40 - 7.32 (m, 2 H), 7.32 - 7.26 (m, 1 H), 6.98 (s, 1 H), 6.26 (tt, J = 4.0, 56.0 Hz, 1 H), 5.16 (s, 2 H), 3.94 (d, J = 2.0 Hz, 2 H), 3.82 - 3.66 (m, 1 H), 3.30 - 3.24 (m, 2 H), 3.20 - 3.08 (m, 2 H), 2.39 - 2.14 (m, 4 H), 1.95 - 1.81 (m, 1 H), 1.16 - 1.01 (m, 2 H).

[0360] Step 3: Boron trichloride (1.5 mL, 1.5 mmol, 1 M n-hexane solution) was added to a solution of compound 12-3 (160 mg, 0.32 mmol) and pentamethylbenzene (96 mg, 0.65 mmol) in dichloromethane (5 mL) under a nitrogen atmosphere at -70°C. The reaction solution was stirred at -70°C for 1 hour. The reaction solution was quenched with methanol (2 mL) at -70°C, the mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (C18, 0.05% ammonium bicarbonate solution / acetonitrile) to obtain compound 12. MS m / z (ESI): 406.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1 H), 8.76 (brs, 1 H), 6.69 (s, 1 H), 6.25 (tt, J = 4.0, 56.0 Hz, 1 H), 3.91 (s, 2 H), 3.82 - 3.66 (m, 1 H), 3.30 - 3.24 (m, 2 H), 3.20 - 3.08 (m, 2 H), 2.39 - 2.16 (m, 4 H), 1.87 - 1.79 (m, 1 H), 1.07 - 1.02 (m, 2 H). Compound 12 was separated by SFC (instrument: WATERS 150 fraction SFC (SFC-26); column: ChiralPak IC, 250 × 30 mm ID, 10 μm; mobile phase: A for CO2 and B for methanol (0.1% NH3H2O); gradient: B 40%; flow rate: 150 mL / min; back pressure: 100 bar; column temperature: 38 °C; wavelength: 220 nm; cycle time: approximately 8 min). The first peak (retention time: 1.543 min) was compound 13, MS m / z (ESI): 405.9 [M+H]. + . 1 ¹H NMR (400 MHz, DMSO-d6) δ values: 9.31 (s, 1 H), 8.76 (brs, 1 H), 6.69 (s, 1 H), 6.25 (tt, J = 4.0, 56.0 Hz, 1 H), 3.91 (s, 2 H), 3.82 - 3.66 (m, 1 H), 3.30 - 3.24 (m, 2 H), 3.20 - 3.08 (m, 2 H), 2.39 - 2.16 (m, 4 H), 1.87 - 1.79 (m, 1 H), 1.07 - 1.02 (m, 2 H). The second peak (retention time: 1.978 mins) was compound 14. MS m / z (ESI): 405.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1 H), 8.76 (brs, 1 H), 6.69 (s, 1 H), 6.25 (tt, J = 4.0, 56.0 Hz, 1 H), 3.91 (s, 2 H), 3.82 - 3.66 (m, 1 H), 3.30 - 3.24 (m, 2 H), 3.20 - 3.08 (m, 2 H), 2.39 - 2.16 (m, 4 H), 1.87 - 1.79 (m, 1 H), 1.07 - 1.02 (m, 2 H).

[0361] [Example 9] Preparation of Compound 15

[0362] [ka]

[0363] Compound 15 was synthesized by referring to Example 8, except that 2-cyclopropylethanol was used as a raw material to replace compound 12-1 in Example 8, and compound 15 was prepared by the same method as in Example 8. Compound 15:MS m / z (ESI): 495.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (brs, 1 H), 8.50 (brs, 1 H), 6.76 - 6.62 (m, 1 H), 3.97 - 3.85 (m, 2 H), 3.69 - 3.62 (m, 1 H), 3.20 - 2.87 (m, 4 H), 2.28 - 1.96 (m, 2 H), 1.89 - 1.75 (m, 1 H), 1.61 - 1.38 (m, 2 H), 1.16 - 0.89 (m, 2 H), 0.87 - 0.64 (m, 1 H), 0.53 - 0.37 (m, 2 H), 0.19 - 0.00 (m, 2 H).

[0364] [Example 10] Preparation of Compound 16

[0365] [ka]

[0366] Compound 16 was synthesized by referring to Example 4, except that tetrahydropyran-2-carboxyaldehyde was used as a starting material to replace 4,4,4-trifluorobutyraldehyde in Example 4, and compound 16 was prepared by the same method as in Example 4. Compound 16:MS m / z (ESI): 426.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1 H), 8.73 (brs, 1 H), 6.68 (s, 1 H), 4.02 - 3.94 (m, 1 H), 3.90 (s, 2 H), 3.72 - 3.53 (m, 2 H), 3.47 - 3.40 (m, 1 H), 3.26 - 3.17 (m, 1 H), 3.14 - 3.00 (m, 2 H), 2.29 - 2.11 (m, 2 H), 1.92 - 1.77 (m, 2 H), 1.68 - 1.59 (m, 1 H), 1.56 - 1.45 (m, 3 H), 1.29 - 1.21 (m, 2 H), 1.12 - 0.98 (m, 2 H).

[0367] [Example 11] Preparation of Compound 17

[0368] [ka]

[0369] Compound 17 was synthesized by referring to Example 8, except that 2-cyclopentylethanol was used as a starting material to replace compound 12-1 in Example 8, and compound 17 was prepared by the same method as in Example 8. Compound 17:MS m / z (ESI): 424.6 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.25 (brs, 1 H), 8.49 (brs, 1 H), 6.69 (s, 1 H), 3.91 (s, 2 H), 3.73 - 3.60 (m, 1 H), 3.16 - 3.00 (m, 3 H), 2.24 - 2.12 (m, 2 H), 1.89 - 1.72 (m, 4 H), 1.70 - 1.47 (m, 6 H), 1.18 - 1.08 (m, 2 H), 1.08 - 1.01 (m, 2 H).

[0370] [Example 12] Preparation of Compound 18

[0371] [ka]

[0372] Compound 18 was synthesized by referring to Example 8, except that 3-bromo-5-hydroxybenzyl alcohol was used as a starting material to replace compound 12-1 in Example 8, and compound 18 was prepared by the same method as in Example 8. Compound 18:MS m / z (ESI): 511.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.08 - 6.99 (m, 2 H), 6.67 (s, 1 H), 4.17 (q, J = 13.6 Hz, 2 H), 3.90 (d, J = 2.0 Hz, 2 H), 3.57 - 3.50 (m, 1 H), 3.14 - 3.02 (m, 1 H), 2.24 - 2.09 (m, 2 H), 1.87 - 1.78 (m, 1 H), 1.11 - 0.95 (m, 2 H).

[0373] [Experimental Example 1] PTPN2 Inhibitory Activity Assay This invention utilizes an HTRF assay to characterize the inhibitory activity of compounds against PTPN2. The specific experimental procedure was as follows: Using ECHO, the compounds were transferred to a 384-well plate (PE#6007290) and an enzyme reaction buffer (50 mM HEPES pH 7.5, 10 mM EDTA, 0.01% Tween 20, 2 mM DTT) was prepared. PTPN2 (Sino biological #10570-H20B) was diluted in the reaction buffer, and PTPN2 (final concentration 1 nM) was added. The compound was incubated at room temperature for 10 minutes, then the substrate (final concentration 1 μM) (biotin-(NH-CH2-CH2-O-CH2-CH2-O-CH2-CO)-TRDI-(PY)-ETDYYRK- K-NH2) (Genscript) was added, and the reaction was stopped by adding a quencher after incubation at room temperature for 40 minutes. The final concentrations of 10 nM Eu anti-P (PY20) antibody (Cisbio #AD0066) and 15 nM APC-streptavidin (Cisbio #AD0201) were added and incubated at room temperature for 1 hour. Fluorescence values ​​of the reacted 384-well plates were read at 620 nm and 665 nm using Envision, and IC50 values ​​inhibiting PTPN2 enzyme activity (PTPN2 IC50) were fitted by 4-parameter logistic regression analysis.

[0374] Positive reference material:

[0375] [ka]

[0376] During testing, the compounds of the present invention exhibited better PTPN2 inhibitory activity, and the test results for some representative compounds are shown in Table 1.

[0377] [Table 1] [Experimental Example 2] B16F10 mIFNγ-induced cell growth inhibition assay 40 μL (150 cells / well) of B16F10 cells (source ATCC Cat#CRL-6475) were seeded into a 384-well plate, and the compound was transferred to the 384-well plate containing the cells using EHCO. One group of cells was added with 10 μL of complete medium (RPMI 1640 medium + 10% FBS) without mIFNγ, and the other group was added with 10 μL of complete medium containing mIFNγ (source R&D Cat#485-MI / CF, final concentration 25 ng / ml), and different concentrations of the compound (DMSO content 0.5%) were added to the reaction system. The cell culture plates were incubated at 37°C in 5% CO2 for 96 hours. 25 μL of CTG was added, and Envision was used for reading, with DMSO / mIFNγ as a negative control, and

[0378] [ka] Using a four-parameter logistic regression equation with a positive control, the cell growth inhibition IC50 value (cellular IC50) was fitted by nonlinear regression analysis.

[0379] During the tests, the compounds of the present invention showed better inhibitory effects on B16F10 mIFNγ-induced cell growth, and the results for representative compounds are shown in Table 2.

[0380] [Table 2]

[0381] The technical solutions of the present invention are not limited to the specific embodiments described above. All technical variations made in accordance with the technical solutions of the present invention fall within the scope of protection of the present invention.

Claims

1. Formula (I-1) or (I-2) 【Chemistry 1】 (In the formula, R １ａ and R １ｂ H, D, halogen, -OH, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl and C １～６ Each is independently selected from the haloalkoxys; Preferably, R １ａ and R １ｂ are each independently selected from H, D, halogen, -OH, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl and C １～４ haloalkoxy; Preferably, R １ａ and R １ｂ Each of these is independently selected from H, D, F, Cl, Br, -OH, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethoxy, and 2,2-difluoroethoxy; Preferably, R １ａ and R １ｂ These are independently selected from H, D, F, and -OH; R １ｃ and R １ｄ H, D, halogen, C １～６ Alkyl and C １～６ Each is independently selected from the haloalkyl groups; Preferably, R １ｃ and R １ｄ H, D, halogen, C １～４ Alkyl and C １～４ Each is independently selected from the haloalkyl groups; Preferably, R １ｃ and R １ｄ is independently selected from H, D, F, Cl, Br, methyl, ethyl, trifluoromethyl, and difluoromethyl; Preferably, R １ｃ and R １ｄ These are selected independently from H, D, and F; R ２ａ H, D, -OH, -NH ２ , C １～８ Alkyl, C ２～８ Alkenil, C ３～６ Cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, -O-C １～８ Alkyl, -O-C １～６ Alkylene-C ３～６ Cycloalkyl, -O-C １～６ Alkylene-(4-8 member heterocyclyl),-O-C(=O)-N(R) ａ )-C １～８ Alkyl, -O-C(=O)-N(R ａ )-phenyl,-N(R ａ )-C １～８ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-(4-8 member heterocyclyl),-N(R ａ ) - C (= O) - C １～８ Alkyl, -N(R) ａ )-C(=O)-OC １～８ Alkyl, -N(R) ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-Si(R ｃ ) ３ , -N(R ａ ) - (C = N(R ｂ ))-C １～８ Alkyl, -N(R) ａ ) - S (= O) ｗ -C １～８ Alkyl, -N(R) ａ )-C １～６ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～６ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～６ Alkylene-phenyl, -C １～６ Alkylene-C ３～６ Cycloalkyl, -C １～６ Alkilen-(4-8 member heterocyclyl),-C １～６ alkylene-N(R ａ )(R ｂ ), -C １～６ alkylene-N(R ａ )-C(=O)-O-C １～８ alkyl, -C １～６ alkylene-N(R ａ )-C １～８ alkyl, -C １～６ alkylene-N(R ａ )-C １～６ alkylene-C ３～６ cycloalkyl, -C １～６ alkylene-N(R ａ )-C(=O)-C １～８ alkyl, -C １～６ alkylene-N(R ａ )-C １～６ alkylene-(4- to 8-membered heterocyclyl), -C １～６ alkylene-N(R ａ )-C １～６ alkylene-(5- to 6-membered heteroaryl), -C １～６ alkylene-N(R ａ )-C １～６ alkylene-phenyl, -C １～６ alkylene-O-C １～８ alkyl, -C １～６ alkylene-O-C １～６ alkylene-C ３～６ cycloalkyl, -C １～６ alkylene-O-C １～６ alkylene-(4- to 8-membered heterocyclyl), -C １～６ alkylene-O-C １～６ alkylene-N(R ａ )(R ｂ ), -S(=O) ｗ -C １～８ alkyl and -C(=O)-N(R ａ )-C １～８ alkyl, where the replaceable carbon atoms of R ２ａ are each independently and optionally substituted by one or more substituents each independently selected from R ｇ ; and / or the replaceable nitrogen atoms on the ring of R ２ａ are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ H, D, -OH, -NH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ３～６ Cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, -O-C １～６ Alkyl, -O-C １～４ Alkylene-C ３～６ Cycloalkyl, -O-C １～４ Alkylene-(4-8 member heterocyclyl),-O-C(=O)-N(R) ａ )-C １～６ Alkyl, -O-C(=O)-N(R ａ )-phenyl,-N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-(4-8 member heterocyclyl),-N(R ａ ) - C (= O) - C １～６ Alkyl, -N(R) ａ )-C(=O)-OC １～８ Alkyl, -N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-Si(R ｃ ) ３ , -N(R ａ ) - (C = N(R ｂ ))-C １～６ Alkyl, -N(R) ａ ) - S (= O) ｗ -C １～６ Alkyl, -N(R) ａ )-C １～４ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～４ Alkylene-phenyl, -C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkilen-(4-8 member heterocyclyl),-C １～４ Alkylene-N(R) ａ ) (Caution ｂ ), -C １～４ Alkylene-N(R) ａ )-C(=O)-OC １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-N(R) ａ ) - C (= O) - C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkilen-(4-8 member heterocyclyl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-phenyl, -C １～４ Alkylene-OC １～６ Alkyl, -C １～４ Alkylene-OC １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-OC １～４ Alkilen-(4-8 member heterocyclyl),-C １～４ Alkylene-OC １～４ Alkylene-N(R) ａ ) (Caution ｂ ), -S (=O) ｗ -C １～６ Alkyl and -C(=O)-N(R ａ )-C １～６ Selected from alkyl, where R ２ａ The substitutable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituteable nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ is, -O-C １～６ Alkyl, -O-C １～４ Alkylene-C ３～６ Cycloalkyl, -O-C １～４ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～６ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-(4-8 member heterocyclyl),-N(R ａ ) - C (= O) - C １～６ Alkyl, -N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～４ Alkylene-phenyl, -C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkilen-(4-8 member heterocyclyl),-C １～４ Alkylene-N(R) ａ ) (Caution ｂ ), -C １～４ Alkylene-N(R) ａ )-C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-N(R) ａ ) - C (= O) - C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkilen-(4-8 member heterocyclyl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-phenyl, -C １～４ Alkylene-OC １～６ Alkyl, -C １～４ Alkylene-OC １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-OC １～４ Alkilen-(4-8 member heterocyclyl),-C １～４ Alkylene-OC １～４ Alkylene-N(R) ａ ) (Caution ｂ ), -S (=O) ｗ -C １～６ Alkyl and -C(=O)-N(R ａ )-C １～６ Selected from alkyl, where R ２ａ The substitutable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituteable nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ is -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-(4-8 member heterocyclyl),-N(R ａ ) - C (= O) - C １～６ Alkyl, -N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl) and -N(R) ａ )-C １～４ Selected from alkylene-phenyl, where R ２ａ The substitutable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ is -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C １～６ Haloalkyl and -N(R) ａ )-C １～４ Alkylene-C ３～６ Selected from cycloalkyl; Preferably, R ２ａ The following is the basis: 【Chemistry 2】 【change】 Selected from; Preferably, R ２ａ The following is the basis: 【Transformation 3】 Selected from; Preferably, R ２ａ The following is the basis: 【Chemistry 4】 Selected from; Preferably, R ２ａ The following is the basis: 【Transformation 5】 Selected from; Preferably, R ２ａ teeth, 【Transformation 6】 And; R ２ｂ H, D, -OH, halogen, -N(R) ａ ) (Caution ｂ ) and -N(R ａ )-N(R ｂ Selected from )-C(O)-phenyl; Preferably, R ２ｂ is selected from H, D, -OH, F, Cl, and Br; Preferably, R ２ｂ is selected from H and D; R ３ , R ３ａ and R ３ｂ H, D, halogen, -OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, C ３～６ Halocycloalkyl, -NH ２ ,-NH(C １～６ Alkyl) and -N(C １～６ (Alkyl) (C １～６ Each is independently selected from alkyl; Preferably, R ３ , R ３ａ and R ３ｂ H, D, halogen, -OH, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～６ Cycloalkyl, C ３～６ Halocycloalkyl, -NH ２ ,-NH(C １～４ Alkyl) and -N(C １～４ (Alkyl) (C １～４ Each is independently selected from alkyl; Preferably, R ３ , R ３ａ and R ３ｂ H, D, F, Cl, Br, -OH, C １～４ Alkyl and C １～４ Each is independently selected from the haloalkyl groups; Preferably, R ３ , R ３ａ and R ３ｂ Each of these is independently selected from H, D, F, Cl, Br, -OH, methyl, ethyl, trifluoromethyl, and difluoromethyl; Preferably, R ３ , R ３ａ and R ３ｂ is independently selected from H, D, F, and -OH; X １ O, S, NR ｆ and C(R ｅ ) (Caution ｄ ) are selected from; R ａ and R ｂ H and C １～６ Each alkyl group is independently selected; optionally, C １～６ The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH; Preferably, R ａ and R ｂ H and C １～４ Each alkyl group is independently selected; optionally, C １～４ The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH; Preferably, R ａ and R ｂ is independently selected from H and methyl; R ｃ is -OH, C １～６ Selected from alkyl and phenyl; Preferably, R ｃ is selected from -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and phenyl; R ｅ and R ｄ H, D, halogen, -OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, C ３～６ Halocycloalkyl, -NH ２ ,-NH(C １～６ Alkyl) and -N(C １～６ (Alkyl) (C １～６ Each is independently selected from alkyl; optionally, R ｅ and R ３ａ They, together with the atoms they connect to, form a 3- to 7-membered carbocyclic ring; or R ｅ and R ２ｂ These, together with the atoms they connect to, form a 3- to 7-membered carbocyclic ring; Preferably, R ｅ and R ｄ H, D, F, Cl, Br, -OH, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～６ Cycloalkyl, C ３～６ Halocycloalkyl, -NH ２ ,-NH(C １～４ Alkyl) and -N(C １～４ (Alkyl) (C １～４ Each is independently selected from alkyl; optionally, R ｅ and R ３ａ They, together with the atoms they connect to, form a 3- to 6-membered carbocyclic ring; or R ｅ and R ２ｂ These, together with the atoms they connect to, form a 3- to 6-membered carbocyclic ring; R ｆ H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups; optionally, R ｆ and R ３ａ They, together with the atoms they connect to, form a heterocyclic ring of 3 to 7 members; or R ｆ and R ２ｂ These, together with the atoms they connect to, form a heterocyclic ring of 3 to 7 members; Preferably, R ｆ H, C １～４ Alkyl and C １～４ Selected from haloalkyl groups; optionally, R ｆ and R ３ａ They, together with the atoms they connect to, form a 3- to 6-membered heterocyclic ring; or R ｆ and R ２ｂ These, together with the atoms they connect to, form a heterocyclic ring of 3 to 6 members; Each R ｇ H, D, halogen, -OH, -CN, nitro, oxo, -NH ２ ,-NH(C １～６ Alkyl), -N(C １～６ (Alkyl) (C １～６ Alkyl), C １～６ Alkyl and C １～６ Selected independently from haloalkyl groups; Preferably, each R ｇ H, D, F, Cl, Br, -OH, -CN, nitro, oxo, -NH ２ ,-NH(C １～４ Alkyl), -N(C １～４ (Alkyl) (C １～４ Alkyl), C １～４ Alkyl and C １～４ Selected independently from haloalkyl groups; Preferably, each R ｇ H, D, F, Cl, Br, -OH, -CN, nitro, oxo, -NH ２ ,-NH-CH ３ , -N(CH ３ ) (CH ３ ), independently selected from methyl, ethyl, trifluoromethyl and difluoromethyl; R ｈ H, D, C １～６ Alkyl and C １～６ Selected from haloalkyls; Preferably, R ｈ H, D, C １～４ Alkyl and C １～４ Selected from haloalkyls; Preferably, R ｈ This is selected from H, D, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl; n is selected from 0 or 1; p is selected from 0, 1, 2, or 3; q is selected from 0, 1, 2, 3, or 4; w is selected from 1 or 2. A compound having a structure represented by, however, 【Transformation 7】 Compounds that are not [specifically] compounds, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs.

2. R １ａ and R １ｂ However, H and D are selected independently, preferably R １ａ and R １ｂ However, selected from H; and / or R １ｃ and R １ｄ However, each is independently selected from H, D, and halogen, preferably R １ｃ and R １ｄ However, H and halogen are selected independently, and more preferably R １ ｃ and R １ｄ One of them is selected from H, and the other is selected from halogens; and / or p is selected from 0 or 1, preferably p is selected from 0; and / or n is selected from 0; and / or R ３ However, it is selected from H, D and halogen, preferably R ３ However, it is selected from H and halogen, more preferably R ３ However, selected from H; and / or q is selected from 0, 1 or 2, preferably q is selected from 0; and / or X １ However, O, S, NR ｆ and C(R ｅ ) (Caution ｄ ) is selected from, preferably X １ However, C(R ｅ ) (Caution ｄ ) selected from; and / or R ｅ and R ｄ However, each can be independently selected from H, D, halogen and -OH, or R ｅ and R ２ｂ However, together with the atoms they connect to, they form a 3- to 7-membered carbocyclic ring, preferably R ｅ and R ｄ However, H, halogen and -OH are selected independently, or R ｅ and R ２ｂ However, together with the atoms they connect to, they form a 3-6 membered carbocyclic ring (C ３～６ Forms a cycloalkyl group, more preferably R ｅ and R ｄ However, it was selected from H; R ２ｂ However, selected from H, or R ２ｂ and R ｅ However, together with the atoms they connect to, they form a 3-6 membered carbocyclic ring (C ３～６ Forms a cycloalkyl group, preferably R ２ｂ However, it is selected from H. The compound described in claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug.

3. R ２ａ However, -N(R ａ )-C １～８ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～６ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～６ Alkylene-phenyl, -O-C １～８ Alkyl, -O-C １～６ Alkylene-(4-8 member heterocyclyl),-O-C １～６ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-(4-8 member heterocyclyl),-C １～６ Alkylene-N(R) ａ )-C １～８ Alkyl, -C １～６ Alkylene-N(R) ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -C １～６ Alkylene-N(R) ａ )-C １～６ Alkilen-(4-8 member heterocyclyl),-C １～６ Alkylene-N(R) ａ )-C １～６ Alkylene-(5-6 member heteroaryl),-C １～６ Alkylene-N(R) ａ )-C １～６ Alkylene-phenyl, -C １～６ Alkylene-OC １～８ Alkyl, -C １～６ Alkylene-OC １～６ Alkylene-C ３～６ Cycloalkyl, -C １～６ Alkylene-OC １～６ Alkylene-(4-8 member heterocyclyl),-C(=O)-N(R) ａ )-C １～８ Alkyl, -C １～６ Alkylene-N(R) ａ ) - C (= O) - C １～８ Alkyl, -C １～６ Alkylene-N(R) ａ ) (Caution ｂ ), -C １～６ Alkylene-OC １～６ Alkylene-N(R) ａ ) (Caution ｂ ) and -N(R ａ ) - C (= O) - C １～８ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～４ Alkylene-phenyl, -O-C １～６ Alkyl, -O-C １～４ Alkylene-(4-7 member heterocyclyl),-O-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-(4-7 member heterocyclyl),-C １～４ Alkylene-N(R) ａ )-C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-phenyl, -C １～４ Alkylene-OC １～６ Alkyl, -C １～４ Alkylene-OC １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-OC １～４ Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) ａ )-C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ ) - C (= O) - C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ ) (Caution ｂ ), -C １～４ Alkylene-OC １～４ Alkylene-N(R) ａ ) (Caution ｂ ) and -N(R ａ ) - C (= O) - C １～６ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～８ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～６ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～６ Alkylene-phenyl, -O-C １～８ Alkyl, -O-C １～６ Alkilen-(4-8 member heterocyclyl),-C １～６ Alkylene-N(R) ａ )-C １～８ Alkyl, -C １～６ Alkylene-N(R) ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -C １～６ Alkylene-N(R) ａ )-C １～６ Alkilen-(4-8 member heterocyclyl),-C １～６ Alkylene-N(R) ａ )-C １～６ Alkylene-(5-6 member heteroaryl),-C １～６ Alkylene-N(R) ａ )-C １～６ Alkylene-phenyl, -C １～６ Alkylene-OC １～８ Alkyl, -C １～６ Alkylene-OC １～６ Alkylene-C ３～６ Cycloalkyl, -C １～６ Alkylene-OC １～６ Alkylene-(4-8 member heterocyclyl),-C(=O)-N(R) ａ )-C １～８ Alkyl and -C １～６ Alkylene-N(R) ａ ) - C (= O) - C １～８ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～４ Alkylene-phenyl, -O-C １～６ Alkyl, -O-C １～４ Alkylene-(4-7 member heterocyclyl),-C １～４ Alkylene-N(R) ａ )-C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-phenyl, -C １～４ Alkylene-OC １～６ Alkyl, -C １～４ Alkylene-OC １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-OC １～４ Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) ａ )-C １～６ Alkyl and -C １～４ Alkylene-N(R) ａ ) - C (= O) - C １～６ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～８ Alkyl, -N(R) ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～６ Alkylene-phenyl and -C １～６ Alkylene-N(R) ａ )-C １～８ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-phenyl and -C １～４ Alkylene-N(R) ａ )-C １～６ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; More specifically, R ２ａ However, -N(R ａ )-C １～８ Alkyl, -N(R) ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-(4-8 member heterocyclyl) and -C １～６ Alkylene-N(R) ａ )-C １～８ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; More specifically, R ２ａ However, -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-7 member heterocyclyl) and -C １～４ Alkylene-N(R) ａ )-C １～６ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or Each R ｇ However, H, D, halogen, -OH, -CN, -NH ２ ,-NH(C １～６ Alkyl), -N(C １～６ (Alkyl) (C １～６ Alkyl), C １～６ Alkyl and C １～６ Selected independently from haloalkyl groups; Preferably, each R ｇ However, H, D, halogen, -OH, -CN, -NH ２ ,-NH(C １～４ Alkyl), -N(C １～４ (Alkyl) (C １～４ Alkyl), C １～４ Alkyl and C １～４ Independently selected from haloalkyl groups; and / or R ｈ However, H, D, C １～６ Alkyl and C １～６ Selected from haloalkyls; Preferably, R ｈ However, H, D, C １～４ Alkyl and C １～４ Selected from haloalkyls; and / or R ａ and R ｂ However, H and C １～６ Each alkyl group is independently selected; optionally, C １～６ The alkyl group is substituted with one or more substituents selected from halogens, preferably R ａ and R ｂ However, H and C １～４ Each alkyl group is independently selected; optionally, C １～４ The alkyl group is substituted with one or more substituents selected from halogens. The compound according to claim 1 or 2, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug.

4. The compound is of formula (II-0) or (II-2): 【Transformation 8】 (In the formula, R ２ｃ , R ２ｄ , R ２ｅ and R ２ｆ H, D, F, Cl, -CN, -OH, C １～６ Alkyl and C １～６ Each is independently selected from haloalkyl groups; optionally, R ２ｃ and R ２ｄ It forms an oxo, or R ２ｅ and R ２ｆ It forms an oxo; Preferably, R ２ｃ , R ２ｄ , R ２ｅ and R ２ｆ H, D, F, Cl, -CN, -OH, C １～４ Alkyl and C １～４ Each is independently selected from haloalkyl groups; optionally, R ２ｃ and R ２ｄ It forms an oxo, or R ２ｅ and R ２ｆ It forms an oxo; Preferably, R ２ｃ , R ２ｄ , R ２ｅ and R ２ｆ is independently selected from H, D, F, Cl, -CN, -OH, methyl, ethyl, and trifluoromethyl; optionally, R ２ｃ and R ２ｄ It forms an oxo, or R ２ｅ and R ２ｆ It forms an oxo; R ２ｇ H, C １～４ Alkyl, C ３～６ Cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -NH ２ ,-NH(C １～６ Alkyl) and -N(C １～６ (Alkyl) (C １～６ Selected from alkyl; C １～４ Alkyl, C ３～６ Cycloalkyls, 4- to 8-membered heterocyclyls, 5- to 6-membered heteroaryls, and phenyls are halogens, -OH, -CN, C １～４ Alkyl and C １～４ Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups; Preferably, R ２ｇ H, C １～４ Alkyl, C ３～６ Cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -NH ２ ,-NH(C １～６ Alkyl) and -N(C １～６ (Alkyl) (C １～６ Selected from alkyl; C １～４ Alkyl, C ３～６ Cycloalkyls, 4- to 8-membered heterocyclyls, 5- to 6-membered heteroaryls, and phenyls are each independently and optionally substituted with one or more substituents selected from F, Cl, Br, -OH, -CN, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl; Preferably, R ２ｇ H, C １～４ Alkyl, C ３～６ Selected from cycloalkyls, 4-7 membered heterocyclines, 5-6 membered heteroaryls, and phenyls; C １～４ Alkyl, C ３～６ Cycloalkyls, 4- to 7-membered heterocyclyls, 5- to 6-membered heteroaryls, and phenyls are halogens, -OH, -CN, and C １～４ Alkyl and C １～４ Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups; Preferably, R ２ｇ H, C １～４ Alkyl, C ３～６ Selected from cycloalkyl and 4- to 7-membered heterocyclyl; C １～４ Alkyl, C ３～６ The cycloalkyl and 4- to 7-membered heterocyclyls are each independently and optionally substituted with one or more substituents selected from halogens; Preferably, R ２ｇ H, methyl, trifluoromethyl, difluoromethyl, tert-butyl, -CH ２ OH, -N(CH ３ ) ２ , or the following basis: 【Chemistry 9】 Selected from; Preferably, R ２ｇ This is selected from H, methyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, and tetrahydropyran-2-yl; X ２ is NH or O, preferably X ２ (This is NH.) It has a structure represented by, Preferably, formula (II-0) is formula (II-1): 【Chemistry 10】 Having a structure represented by, A compound according to any one of claims 1 to 3, or an enantiomer, diastereomer, racemic mixture, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof.

5. The compound is of formula (III-0) or (III-2): 【Chemistry 11】 It has a structure represented by, Preferably, formula (III-0) becomes formula (III-1): 【Chemistry 12】 A compound according to any one of claims 1 to 4, having a structure represented by , or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof.

6. The compound is of formula (IV-1) or (IV-2): 【Chemistry 13】 (In the formula, R ２ｈ C １～６ Alkyl, C ３～６ Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-(4-7 member heterocyclyl),-C １～４ Alkylene-(5-6 member heteroaryl),-C １～４ Alkylene-phenyl,-NH(C) １～６ Alkyl) and -N(C １～６ Alkyl) ２ Selected from; C １～６ Alkyl, C ３～６ Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-(4-7 member heterocyclyl),-C １～４ Alkylene-(5-6 member heteroaryl),-C １～４ Alkylene-phenyl,-NH(C) １～６ Alkyl) and -N(C １～６ Alkyl) ２ is halogen, -OH, -CN, C １～４ Alkyl and C １～４ Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups; Preferably, R ２ｈ C １～６ Alkyl, C ３～６ Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C １～２ Alkylene-C ３～６ Cycloalkyl, -C １～２ Alkylene-(4-7 member heterocyclyl),-C １～２ Alkylene-(5-6 member heteroaryl),-C １～２ Alkylene-phenyl,-NH(C) １～６ Alkyl) and -N(C １～６ Alkyl) ２ Selected from; C １～６ Alkyl, C ３～６ Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C １～２ Alkylene-C ３～６ Cycloalkyl, -C １～２ Alkylene-(4-7 member heterocyclyl),-C １～２ Alkylene-(5-6 member heteroaryl),-C １～２ Alkylene-phenyl,-NH(C) １～６ Alkyl) and -N(C １～６ Alkyl) ２ is halogen, -OH, -CN, C １～４ Alkyl and C １～４ Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups; Preferably, R ２ｈ is selected from C １～６ alkyl, C ３～６ cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, phenyl, -C １～２ alkylene-C ３～６ cycloalkyl and -N(C １～６ alkyl); C ２ alkyl, C １～６ cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, phenyl, -C ３～６ alkylene-C １～２ cycloalkyl and -N(C ３～６ alkyl) are each independently and optionally substituted by one or more substituents selected from halogen, -OH, -CN, C １～４ alkyl and C ２ haloalkyl; １～４ alkyl and C １～４ haloalkyl; Preferably, R ２ｈ is selected from C １～６ alkyl, C ３～６ cycloalkyl, and 4- to 7-membered heterocyclyl; C １～６ alkyl, C ３～６ cycloalkyl, and 4- to 7-membered heterocyclyl are each independently and optionally substituted by one or more substituents selected from halogen; Preferably, R ２ｈ Methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-hydroxy-propan-2-yl, 2-cyano-propan-2-yl, -N(CH ３ ) ２ , 【Chemistry 14】 Selected from; Preferably, R ２ｈ (These are selected from isopropyl, tert-butyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, and tetrahydropyran-2-yl.) A compound according to any one of claims 1 to 5, having a structure represented by , or an enantiomer, diastereomer, racemic mixture, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof.

7. The compound is given by formula (V): 【Chemistry 15】 A compound according to any one of claims 1 to 3, having a structure represented by , or an enantiomer, diastereomer, racemic mixture, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof.

8. R ２ａ However, -N(R ａ )-C １～８ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～６ Alkylene-(4-8 member heterocyclyl),-N(R) ａ )-C １～６ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～６ Alkylene-phenyl, -O-C １～８ Alkyl, -O-C １～６ Alkylene-(4-8 member heterocyclyl),-O-C １～６ Alkylene-C ３～６ Cycloalkyl and -N(R) ａ ) - Selected from (4-8 member heterocyclyl), where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～４ Alkylene-phenyl, -O-C １～６ Alkyl, -O-C １～４ Alkylene-(4-7 member heterocyclyl),-O-C １～４ Alkylene-C ３～６ Cycloalkyl and -N(R) ａ ) - Selected from (4-7 member heterocyclyl), where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ is -N(R ａ )-C １～８ alkyl, -N(R ａ )-C ３～６ cycloalkyl, -N(R ａ )-C １～６ alkylene-C ３～６ cycloalkyl, -N(R ａ )-C １～６ alkylene-(4- to 8-membered heterocyclyl), -N(R ａ )-C １～６ alkylene-(5- to 6-membered heteroaryl), -N(R ａ )-C １～６ alkylene-phenyl, -O-C １～８ alkyl and -O-C １～６ alkylene-(4- to 8-membered heterocyclyl), where the replaceable carbon atoms of R ２ａ are each independently and optionally substituted by one or more substituents independently selected from R ｇ ; and / or the replaceable nitrogen atoms on the ring of R ２ａ are each independently and optionally substituted by one or more substituents independently selected from R ｈ ; Preferably, R ２ａ However, -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -N(R ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-N(R ａ )-C １～４ Alkylene-phenyl, -O-C １～６ Alkyl and -O-C １～４ Selected from alkylenes (4-7 member heterocyclines), where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～８ Alkyl, -N(R) ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl and -N(R) ａ )-C １～６ Selected from alkylenes (4-8 member heterocyclines), where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -N(R ａ )-C １～６ Alkyl, -N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl and -N(R) ａ )-C １～４ Selected from alkylenes (4-7 member heterocyclines), where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or Each R ｇ However, H, D, halogen, -OH, -CN, -NH ２ ,-NH(C １～６ Alkyl), -N(C １～６ (Alkyl) (C １～６ Alkyl), C １～６ Alkyl and C １～６ Selected independently from haloalkyl groups; Preferably, each R ｇ However, H, D, F, Cl, Br, -OH, -CN, -NH ２ ,-NH(C １～４ Alkyl), -N(C １～４ (Alkyl) (C １～４ Alkyl), C １～４ Alkyl and C １～４ Selected independently from haloalkyl groups; Preferably, each R ｇ However, H, F, -OH, -CN, -N(CH ３ ) ２ , independently selected from methyl, ethyl, trifluoromethyl and difluoromethyl; and / or R ｈ However, H, D, C １～６ Alkyl and C １～６ Selected from haloalkyls; Preferably, R ｈ However, H, D, C １～４ Alkyl and C １～４ Selected from haloalkyls; Preferably, R ｈ but selected from H, D, methyl, trifluoromethyl, difluoromethyl and 2,2-difluoroethyl; and / or R ａ However, H and C １～６ Selected independently of alkyl; optionally, C １～６ The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH; Preferably, R ａ However, H and C １～４ Selected independently of alkyl; optionally, C １～４ The alkyl group is substituted with one or more substituents selected from halogens, -CN, oxo, and -OH; Preferably, R ａ H is The compound described in claim 7, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug.

9. The aforementioned compound is of formula (V-1): 【Chemistry 16】 A compound according to any one of claims 1 to 5 and 7 to 8, having the structure represented by , or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof.

10. X ２ is NH; Preferably, R ２ｃ and R ２ｄ However, H, F, -CN, -OH, C １～３ Alkyl and C １～３ Each is independently selected from the haloalkyl groups; More specifically, R ２ｃ and R ２ｄ However, each is independently selected from H, F, -CN, -OH, methyl, ethyl, and trifluoromethyl; Preferably, R ２ｇ However, H, C １～３ Alkyl, C ３～６ Selected from cycloalkyl, 4-7 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl (e.g., pyrazolyl, isoxazolyl, triazolyl, and oxadiazolyl); C １～３ Alkyl, C ３～６ Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halogen, -OH, -CN, C １～３ Alkyl and C １～３ Each substituent is independently and optionally substituted by one or more substituents selected from haloalkyl groups. The compound described in claim 9, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug.

11. The compound is given by formula (VI-0): 【Chemistry 17】 A compound according to any one of claims 1 to 3, having a structure represented by , or an enantiomer, diastereomer, racemic mixture, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof.

12. R ２ａ However, -C １～４ Alkylene-N(R) ａ )-C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-C １～４ Alkylene-N(R) ａ )-C １～４ Alkylene-phenyl, -C １～４ Alkylene-OC １～６ Alkyl, -C １～４ Alkylene-OC １～４ Alkylene-C ３～６ Cycloalkyl, -C １～４ Alkylene-OC １～４ Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) ａ )-C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ ) - C (= O) - C １～６ Alkyl, -C １～４ Alkylene-N(R) ａ ) (Caution ｂ ), -C １～４ Alkylene-OC １～４ Alkylene-N(R) ａ ) (Caution ｂ ) and -N(R ａ ) - C (= O) - C １～６ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -C １～２ Alkylene-N(R) ａ )-C １～６ Alkyl, -C １～２ Alkylene-N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～２ Alkylene-N(R) ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-C １～２ Alkylene-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl),-C １～２ Alkylene-N(R) ａ )-C １～４ Alkylene-phenyl, -C １～２ Alkylene-OC １～６ Alkyl, -C １～２ Alkylene-OC １～４ Alkylene-C ３～６ Cycloalkyl, -C １～２ Alkylene-OC １～４ Alkylene-(4-7 member heterocyclyl),-C(=O)-N(R) ａ )-C １～６ Alkyl, -C １～２ Alkylene-N(R) ａ ) - C (= O) - C １～６ Alkyl and -C １～２ Alkylene-OC １～４ Alkylene-N(R) ａ ) (Caution ｂ ) is selected, and here, R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; Preferably, R ２ａ However, -C １～２ Alkylene-N(R) ａ )-C １～６ Alkyl, -C １～２ Alkylene-N(R) ａ )-C １～４ Alkylene-C ３～６ Cycloalkyl, -C １～２ Alkylene-N(R) ａ )-C １～４ Alkylene-(4-7 member heterocyclyl),-C １～２ Alkylene-N(R) ａ )-C １～４ Alkylene-(5-6 member heteroaryl) and -C １～２ Alkylene-N(R) ａ )-C １～４ Selected from alkylene-phenyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; More specifically, R ２ａ However, -C １～２ Alkylene-N(R) ａ )-C １～６ Selected from alkyl, where R ２ａ The replaceable carbon atoms are R ｇ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or R ２ａ The substituted nitrogen atoms on the ring are R ｈ Each of them is independently and optionally substituted by one or more substituents independently selected from each of them; and / or Each R ｇ However, H, D, halogens (F, Cl, Br, etc.), -OH, -CN, -NH ２ ,-NH(C １～４ Alkyl), -N(C １～４ (Alkyl) (C １～４ Alkyl), C １～４ Alkyl and C １～４ Independently selected from haloalkyl groups; and / or R ｈ However, H, D, C １～４ Alkyl and C １～４ Selected from haloalkyls; and / or R ａ and R ｂ However, H and C １～４ Each alkyl group is independently selected; optionally, C １～４ The alkyl group is substituted with one or more substituents selected from halogens. The compound according to claim 11, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug.

13. The aforementioned compound is of formula (VI-1): [Chemistry 18] A compound according to any one of claims 1 to 5, having a structure represented by , or an enantiomer, diastereomer, racemic mixture, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof.

14. The above compound has the following structure: 【Chemistry 19】 【change】 【change】 A compound according to any one of claims 1 to 13, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug having the above.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, and at least one pharmaceutically acceptable carrier.

16. A compound according to any one of claims 1 to 14, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, used for use in the treatment or prevention of diseases or disorders related to PTPN2, or a pharmaceutical composition according to claim 15.

17. Use of a compound according to any one of claims 1 to 14 or its enantiomer, diastereomer, racemic mixture, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition according to claim 15, in the manufacture of a pharmaceutical product used for the treatment or prevention of a disease or disorder related to PTPN2.

18. A method for treating or preventing a disease or disorder related to PTPN2, comprising administering to a person in need a therapeutically effective amount of a compound according to any one of claims 1 to 14, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug, or the pharmaceutical composition according to claim 15.

19. Diseases or disorders associated with PTPN2 include cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic diseases; preferably, cancer includes carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, and melanoma; preferably, cancer includes solid and lymphoma, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer (including liver tumors), lymphoma (B-cell acute lymphoblastic lymphoma), non-Hodgkin lymphoma (non-Hodgkin The use according to claim 17 or the method according to claim 18, which preferably includes leukemia (including AML, ALL, and CML) and / or multiple myeloma; and preferably includes lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or cancer.

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