Protein tyrosine phosphatase inhibitor, composition, and medical use

Abstract

The present invention provides a compound or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite thereof or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof. Also provided is a composition comprising the compound and a medical use. The compound has good drug preparation prospects in terms of treatment or prevention of diseases or disorders related to PTPN2.

Description

Protein tyrosine phosphatase inhibitors and their compositions and medical uses

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application No. 202311199656.6 filed on September 15, 2023, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present invention relates to the field of medicine, and in particular to protein tyrosine phosphatase inhibitors and compositions thereof, and medical uses thereof. Background Art

[0004] Immune checkpoint inhibitors, such as PD-1 antibodies, have revolutionized the treatment of various cancers, but most patients are unable to benefit from these PD-1 blockade therapies. This situation has prompted several research teams to identify new immunotherapy targets, either to develop novel immunotherapy drugs for cancer patients who do not respond to PD-1 antibodies or to develop therapies that can synergize with PD-1 antibodies to enhance their anti-cancer efficacy.

[0005] PTPN2, short for Tyrosine-protein phosphatase non-receptor type 2, also known as TC-PTP, is a member of the protein tyrosine phosphatase (PTP) family. PTPN2 shares 74% sequence homology and 86% structural similarity with its family member PTPN1 (also known as PTP1B). Members of this family act as signaling factors, participating in the regulation of multiple signaling pathways and cellular processes, including cell growth, differentiation, the mitotic cycle, and oncogenic transformation. The PTPN2 protein contains an N-terminal kinase domain and a C-terminal non-catalytic domain. The nuclear localization signal (NLS) at the C-terminus is involved in the autoregulation of catalytic activity and the determination of isoform localization. Due to selective splicing, PTPN2 has two isoforms, TC45 and TC48. Differences in the C-terminal region result in different localizations of the different isoforms, thus affecting their substrate selection. PTPN2 negatively regulates signaling of some 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 negatively regulates signaling mediated by inflammatory cytokines (IL-2 and interferon) by dephosphorylating JAK1, JAK3, and their substrates, signal transducer and activator of transcription 1 (STAT1).

[0006] Research has shown that inhibiting the PTPN2 immune regulator can promote anti-tumor immunity, thereby clearing tumors. Specifically, deleting the gene expressing PTPN2 from the immune systems (CD8+ T cells) of cancer-bearing mice stimulated the production and adaptation of killer T cells that fight infection and cancer. In one experiment, deleting PTPN2 eliminated colon cancer in all mice. Furthermore, another experiment showed that deleting PTPN2 combined with PD-1 blockade therapy successfully eliminated a quarter of mice carrying extremely aggressive and treatment-resistant melanoma tumors.

[0007] Summary of the Invention

[0008] In order to solve the above-mentioned technical problems existing in the prior art, the present invention provides a novel PTPN2 inhibitor, which has good drug development prospects in treating or preventing diseases or conditions related to PTPN2.

[0009] Specifically,

[0010] In one aspect, the present invention provides a compound having a structure represented by formula (I) or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof;

[0011] in,

[0012] R 1a and R 1b Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy;

[0013] L is selected from NR 1c ,O,S;

[0014] R 1c Selected from hydrogen, C 1-6 alkyl;

[0015] G is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 The carbon atoms that can be substituted on the alkylene-5-10 membered heteroaryl are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR 2a R2b Substituents substituted;

[0016] R 2a and R 2b Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 The carbon atoms that may be substituted on the alkylene-4-10 membered heterocyclic group are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-6 Alkyl, halogenated C 1-6 The substituents of the alkoxy group are substituted.

[0017] On the other hand, the present invention provides a pharmaceutical composition comprising the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug and at least one pharmaceutically acceptable carrier.

[0018] On the other hand, the present invention provides a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or a composition of the present invention, for treating or preventing a disease or condition associated with PTPN2.

[0019] On the other hand, the present invention provides the use of the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the composition of the present invention in the preparation of a medicament for treating or preventing a disease or condition associated with PTPN2.

[0020] In another aspect, the present invention provides a method for treating or preventing a disease or condition associated with PTPN2, comprising administering to a person in need thereof a therapeutically effective amount of a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or the composition of the present invention.

[0021] Another aspect of the present invention relates to methods for preparing, separating and purifying the compounds represented by formula (I), (II), (III) and (IV).

[0022] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.

[0023] The foregoing description only summarizes certain aspects of the present invention, but is not intended to be limiting. These and other aspects will be described in more detail and fully below. All references in this specification are incorporated herein by reference in their entirety. DETAILED DESCRIPTION

[0024] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0025] definition

[0026] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0027] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0028] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0029] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, the chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0030] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0031] The term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to a primate (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0032] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0033] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0034] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0035] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0036] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0037] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0038] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. For example Valence tautomers include interconversions that occur by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion between pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0039] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0040] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely.

[0041] The stereochemical definitions and conventions used herein generally follow those of 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 an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0042] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0043] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0044] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0045] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolution sp. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0046] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where 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-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amines to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0047] The term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0048] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0049] 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 literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed between compounds and acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or these salts are obtained by other methods described in books and literature, such as ion exchange methods. Further pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts formed between compounds and bases, including but not limited to inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed by compounds containing any N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary, and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins)), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, cholinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, and tromethamine salts.

[0050] Pharmaceutically acceptable acid addition salts can be formed by the action of the compounds of this invention with inorganic or organic acids, and pharmaceutically acceptable base addition salts can be formed by the action of the compounds of this invention with inorganic or organic bases. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compound, alkaline or acidic moieties. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences," 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahland Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0051] The term "solvate" refers to an association complex formed by one or more solvent molecules and the compound of the present invention. The solvent can be water, acetic acid, diethyl ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-butanol, 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, isopropyl alcohol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropyl alcohol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, cumene or a mixture thereof, etc.

[0052] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[0053] In addition, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

[0054] The term "ester" is represented by the formula -OC(O)R or -C(O)OR, wherein R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.

[0055] The term "isotopically labeled compound" means a compound of the present invention that is labeled with an isotope. It is identical to those compounds described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0056] Compounds of the present invention containing the aforementioned isotopic labels and / or other isotopic labels of other atoms and pharmaceutically acceptable salts of the compounds are all within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotope-labeled compounds, such as 3 H and 14 C is incorporated into the compounds of the present invention for drug and / or substrate tissue distribution analysis. Due to ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, isotopes with larger mass numbers, such as deuterium, 2 H substitutions may offer therapeutic advantages of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0057] In addition, the substitution of heavier isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages, which are due to the higher metabolic stability. For example, an increase in in vivo half-life or a reduction in dosage requirements or an improvement in therapeutic index are achieved. It should be understood that deuterium in the present invention is considered a substituent of the compounds of formula I to VI. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0058] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound shown in Formula I in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylating the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, 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.

[0059] In this article, solid lines can be used Solid wedge virtual wedge Chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate the presence of the indicated stereoisomers. When present in a racemic mixture, the use of solid and dashed wedges defines relative stereochemistry, not absolute stereochemistry.

[0060] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any ring atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0061] Unless otherwise expressly indicated, when a substituent is described by a conventional chemical formula written from left to right, the substituent includes only its left-to-right form, attached to the structures on the left and right sides of the corresponding group in the general compound structure.

[0062] Unless otherwise expressly stated, the descriptions used in the present invention of "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0063] The terms "optional," "optionally," or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with" means that the substitution may or may not occur.

[0064] When the term "each independently" is used in combination with "optionally", for example, "each independently arbitrarily replaced by..." means that the specific options are either replaced by... or not replaced by... without affecting each other.

[0065] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0066] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0067] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0068] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of S, N, and P; primary, secondary, and tertiary amines and quaternary ammonium salts; or a form in which the hydrogen on the nitrogen atom in a heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl), or NRT (such as NRT in N-substituted pyrrolidinyl, where RT is a substituent on N). Among the compounds involved in the present invention, when containing multiple heteroatoms, the compounds composed thereof conform to the covalent and compositional rules of organic compounds, that is, compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent and compositional rules of organic compounds.

[0069] The term "heterocyclyl" or "heterocycle" refers to an optionally substituted partially or fully saturated non-aromatic cyclic group, for example, a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered tricyclic ring system having at least one heteroatom in at least one of the carbon-containing rings. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also be optionally oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom. In some embodiments, the heterocyclic group is selected from: a monocyclic heterocyclic group, a bicyclic heterocyclic group, a tricyclic heterocyclic group. A 4- to 8-membered heterocyclic group means that the ring atoms consist of 4-8 carbon atoms and heteroatoms. In some embodiments, the monocyclic heterocyclyl is selected from oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothiphenyl, 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl, etc. In some embodiments, the bicyclic heterocyclyl is selected from 7-oxabicyclo[2.2.1]heptyl.

[0070] The term "cycloalkyl" refers to a monovalent or polyvalent saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic system containing carbon atoms. 3-6 Cycloalkyl refers to a cycloalkyl group with 3-6 ring atoms. In some embodiments, the cycloalkyl group is selected from the group consisting of monocyclic cycloalkyl, bicyclic cycloalkyl, and tricyclic cycloalkyl. 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, borneol, 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, tricyclic hydrocarbon groups include adamantyl, and the like.

[0071] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic and tricyclic aromatic system containing heteroatoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroatoms have the definition described in the present invention. In some embodiments, the heteroaryl group is a heteroaryl group composed of 5 to 10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-10 membered heteroaryl group; the heteroaryl group is a heteroaryl group composed of 5 to 8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-8 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group composed of 5 to 7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-7 membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6-membered heteroaryl group; In some embodiments, the heteroaryl group is a 5-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a 6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group.

[0072] The term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring." A 6-10 membered aryl group refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl.

[0073] The term "hydrogen" means 1 H; "deuterium" refers to 2 H.

[0074] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0075] The term "amino" refers to -NH2;

[0076] The term "hydroxyl" refers to -OH;

[0077] The term "cyano" refers to -CN;

[0078] The term "nitro" refers to -NO2;

[0079] The term "carboxyl" refers to HO(C=O)-;

[0080] The term "oxo" refers to O=, that is, when the substituent is O=, O is connected to the substituted group through a double bond.

[0081] The term "alkyl" or "alkyl group" refers to a saturated, straight-chain or branched hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 Alkyl; In another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, ie, C 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0082] The term "alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group containing carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms, i.e., C1-C6 alkylene; in another embodiment, the alkylene group contains 1 to 4 carbon atoms, i.e., C1-C4 alkylene; in another embodiment, the alkylene group contains 1 to 3 carbon atoms, i.e., C1-C3 alkylene.

[0083] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing carbon atoms, wherein at least one site of unsaturation exists, i.e., one carbon-carbon sp2 double bond, including "cis" and "tans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-6 carbon atoms, i.e., C2-C6 alkenyl; in another embodiment, the alkenyl group contains 2-4 carbon atoms, i.e., C2-C4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0084] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkoxy group contains 1-4 carbon atoms, ie, C 1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, ie, C 1-3 Alkoxy.

[0085] The term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or ingredients from the drug (or, in the case of a method, a step). The phrase "consisting of excludes any element, step, or ingredient not specified in the drug (or, in the case of a method, a step). The phrase "consisting essentially of refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the drug (or, in the case of a method, a step).

[0086] The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of the others. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0087] Unless otherwise stated, substituents or group combinations contemplated herein for Markush structures are those that are stable or chemically feasible.

[0088] As used herein, the term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0089] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in a subject that is generally characterized by unregulated cell growth and / or proliferation. Some cancers consist of rapidly dividing cells, while other cancers consist of cells that divide more slowly than normal cells. Examples of types of cancer may include or exclude, for example, carcinomas, lymphomas (e.g., Hodgkin and non-Hodgkin lymphomas), blastomas, sarcomas, and leukemias. More specific examples of such cancers may include or exclude, for example, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, peritoneal cancer, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, leukemias and other lymphoproliferative disorders, and various types of head and neck cancer.

[0090] Description of the compounds of the present invention

[0091] The present invention provides a compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which plays an active role in treating or preventing PTPN2-related diseases or conditions.

[0092] Specifically, the present invention provides a compound having a structure represented by formula (I) or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs;

[0093] in,

[0094] R 1a and R 1b Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy;

[0095] L is selected from NR 1c ,O,S;

[0096] R 1c Selected from hydrogen, C 1-6 alkyl;

[0097] G is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl is each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR2a R 2b Substituents substituted;

[0098] R 2a and R 2b Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 The carbon atoms that may be substituted on the alkylene-4-10 membered heterocyclic group are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-6 Alkyl, halogenated C 1-6 The substituents of the alkoxy group are substituted.

[0099] In some embodiments, R 1a and R 1b Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl and halogenated C 1-3 Alkoxy.

[0100] In some embodiments, R 1a and R 1b Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethoxy, and 2,2-difluoroethoxy.

[0101] In some embodiments, R 1a and R 1b are each independently selected from the group consisting of: hydrogen, deuterium, fluorine and hydroxyl.

[0102] In some embodiments, R 1a and R 1b All are hydrogen.

[0103] In some embodiments, L is selected from NR 1c 、O。

[0104] In some embodiments, L is NR 1c .

[0105] In some embodiments, L is O.

[0106] In some embodiments, R 1c Selected from hydrogen, C 1-3 alkyl.

[0107] In some embodiments, R 1c For hydrogen.

[0108] In some embodiments, L is NH.

[0109] In some embodiments, G is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl is each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, -NR 2a R 2b Substituents substituted;

[0110] R 2a and R 2b Each independently selected from: hydrogen, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 The carbon atoms that may be substituted on the alkylene-4-7 membered heterocyclic group are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C1-3 Alkyl, halogenated C 1-3 The substituents of the alkoxy group are substituted.

[0111] In some embodiments, G is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 The carbon atoms that can be substituted on the alkylene-5-6 membered heteroaryl are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, -NR 2a R 2b Substituents substituted;

[0112] R 2a and R 2b Each independently selected from: hydrogen, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 The carbon atoms that may be substituted on the alkylene-4-7 membered heterocyclic group are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-3 Alkyl, halogenated C 1-3 In some embodiments, G is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5 membered heteroaryl is each independently, optionally substituted by one or more independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, -NR 2a R 2b Substituents substituted;

[0113] R 2a and R 2b are independently selected from: hydrogen, C 1-3 alkyl.

[0114] In some embodiments, G is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-membered heteroaryl; wherein the C 1- 6 alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 The carbon atoms that can be substituted on the alkylene-5-membered heteroaryl are each independently, optionally substituted by one or more independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, -NR 2a R 2b Substituents substituted;

[0115] R 2a and R 2b are independently selected from: hydrogen, C 1-3 In some embodiments, G is selected from C1-6 Alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl, -C 1-4 Alkylene-C 3-6 The substituted carbon atoms on the cycloalkyl group are each independently, optionally substituted by one or more independently selected from halogen, C 1-3 Alkyl, halogenated C 1-3 The alkyl group is substituted with a substituent.

[0116] In some embodiments, G is selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0117] In some embodiments, G is selected from:

[0118] In some embodiments, G is selected from:

[0119] In some embodiments, G is selected from:

[0120] In some embodiments, G is selected from:

[0121] In some embodiments, G is selected from:

[0122] In some embodiments, -LG is selected from:

[0123] In some embodiments, -LG is selected from:

[0124] In some embodiments, -LG is selected from:

[0125] In some embodiments, -LG is selected from:

[0126] In some embodiments, -LG is selected from:

[0127] In some embodiments, the compound has a structure shown in formula (II) or (III),

[0128] Wherein, the G has the definition described in the present invention.

[0129] In some embodiments, the compound has a structure shown in formula (II),

[0130] Wherein, the G has the definition described in the present invention.

[0131] In some embodiments, the compound has a structure shown in formula (III),

[0132] Wherein, the G has the definition described in the present invention.

[0133] In some embodiments, the compound has the structure shown in formula (IV)

[0134] M is selected from a bond or C 1-6 Alkylene; the C 1-6 The alkylene group is optionally substituted by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Substitution of alkyl groups;

[0135] R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR 2a R 2b 、C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are optionally substituted by one or more independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Substitution of alkyl groups;

[0136] R 2a 、R 2b Has the definition described in the present invention.

[0137] In some embodiments, the M is selected from a bond or C 1-6 Alkylene; the C 1-6 The alkylene group is optionally substituted by 1 to 3 groups each independently selected from halogen, hydroxy, cyano, C 1-3 Alkyl, halogenated C 1-3 The alkyl group is substituted with a substituent.

[0138] In some embodiments, the M is selected from C 1-6 Alkylene; the C 1-6 The alkylene group is optionally substituted by 1 to 3 groups each independently selected from halogen, hydroxy, cyano, C 1-3 Alkyl, halogenated C 1-3 The alkyl group is substituted with a substituent.

[0139] In some embodiments, R 3 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR 2a R 2b 、C 3-6 Cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane), 4-7 membered heterocyclic group (e.g., oxolane, oxahene, morpholinyl), phenyl, 5-6 membered heteroaryl (e.g. pyrazolyl, isoxazolyl, oxadiazolyl, triazolyl); wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by one or more independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl substituents substituted; R 2a and R 2b are independently selected from: hydrogen, C 1-3 alkyl.

[0140] In some embodiments, the M is selected from C 1-6 Alkylene; the C 1-6 The alkylene group is optionally substituted with 1 to 3 substituents each independently selected from halogen.

[0141] In some embodiments, R 3 Selected from hydrogen and halogen.

[0142] In some embodiments, as R 3 The optional 4-7 membered heterocyclic group is selected from

[0143] In some embodiments, as R3 The 5-6 membered heteroaryl group of the optional group is a 5 membered heteroaryl group, preferably

[0144] In some embodiments, R 3 Selected from hydrogen, F, bromine, hydroxyl, cyano, methyl, ethyl, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -C(CH3)2OH, -C(CH3)3, -C(CH3)2CF3, -C(CH3)2CN, -C(CF3)2OH, -CH2CH(CH3)(CH2CH3), difluoromethyl, trifluoromethyl, -CH2CF3, -CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CF3, -CH(CH3)OH, -CH2CH(CH3)OH, -CH2CH(CF3)OH, -CH(CF3)2, -N(CH3)2.

[0145] In some embodiments, the compound has the structure shown below:

[0146] In some embodiments, the compound has the structure shown below:

[0147] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0148] The compound represented by formula (I) of the present invention forms a specific bridged ring structure, reduces the chiral center, and is easy to synthesize.

[0149] Pharmaceutical compositions and methods of administration

[0150] The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; and a pharmaceutically acceptable carrier.

[0151] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and diluents. Other components may also include excipients such as excipients, binders, and fillers, as well as additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0152] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, pharmaceutical 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 ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0153] The present invention also relates to a compound of formula (I), (II), (III) or (IV) or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs as active ingredients, or a pharmaceutical composition thereof, which can be used, in particular, for the treatment of neoplastic diseases, in particular cancer, as described herein. The composition can be formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or in particular for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (coated where applicable), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, in particular humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions can comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0154] The compound of formula (I), (II), (III) or (IV) or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically 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, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, flow agents such as fumed silicon dioxide can be used as such 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 are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0155] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0156] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0157] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0158] The dosage can vary within wide limits and, of course, will be adapted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 1 to 1000 mg of a compound of formula I per person should be appropriate, although the above lower or upper limits may also be exceeded if necessary.

[0159] The compounds of formula (I), (II), (III) or (IV) may also be used in combination with one or more other pharmacologically active compounds that are also effective against the same disease, preferably using different modes of action, or that reduce or prevent possible undesirable side effects of the compounds of formula (I), (II), (III) or (IV). The combination partners may be administered simultaneously in such treatments, for example by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms (each containing one or more than one combination partner).

[0160] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, inhibiting, preventing, and / or ameliorating any disease, disorder, or condition involving PTPN2.

[0161] The term "treatment" or "treating" as used herein in the context of treating a disease or disorder generally relates to treatment and therapy for humans or animals (e.g., in veterinary applications), wherein some desired therapeutic effects are obtained, e.g., suppressing the progression of a disease or disorder, and including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving a disease or disorder, and curing a disease or disorder. Also included are treatments (i.e., preventions) as preventive measures. For example, a patient who has not yet developed the disease or disorder but is at risk of developing the disease or disorder is covered by the term "treatment." For example, treatment includes prevention of cancer, reducing the incidence of cancer, alleviating cancer symptoms, etc.

[0162] In some embodiments, the present invention provides a compound represented by (I), (II), (III) or (IV) or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or a pharmaceutical composition thereof, for treating or preventing a disease or condition associated with PTPN2.

[0163] In some embodiments, the present invention provides the use of the compound represented by (I), (II), (III) or (IV) or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, or pharmaceutical compositions thereof, in the preparation of drugs for treating or preventing PTPN2-related diseases or conditions.

[0164] In some embodiments, the present invention provides a method for treating or preventing a PTPN2-related disease or condition, comprising administering a therapeutically effective amount of a compound of (I), (II), (III) or (IV) or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or a pharmaceutical composition thereof.

[0165] In some embodiments, the disease or condition associated with PTPN2 comprises cancer, type 2 diabetes, metabolic syndrome, obesity, or a metabolic disease.

[0166] In some embodiments, the cancer comprises carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, melanoma.

[0167] As used herein, the term "cancer" refers to all types of cancers, neoplasms or malignancies found in mammals, including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions or methods provided herein include lymphomas, sarcomas, bladder cancer, bone cancer, brain tumors, 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 resistance, Herceptin (herceptin) resistance, HER2 positive, doxorubicin (doxorubicin) resistance, tamoxifen resistance, ductal carcinoma, lobular carcinoma, primary, 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 tumor, sarcoma), glioblastoma multiforme, glioma or melanoma. Other examples include thyroid cancer, endocrine system 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, stomach cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, primary macroglobulinemia disease, primary brain tumor, carcinoma, malignant pancreatic insulinoma, malignant carcinoid tumor, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's Disease of the Nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate cancer.

[0168] The term "carcinoma" refers to a malignant neoplasm composed of epithelial cells that tends to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, adenocarcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoma carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bronchoalveolar carcinoma, bronchogenic carcinoma, encephalic carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus carcinoma, cribriform carcinoma, armored carcinoma, cutaneous carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, tubular carcinoma, dural carcinoma, embryonal carcinoma, encephalic carcinoma, epidermoid carcinoma, epithelial gland carcinoma, exophytic carcinoma, preulcerous carcinoma, fibrous carcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematogenous carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, carcinoma), clear carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma carcinoma), large cell carcinoma, lentiform carcinoma, bean-shaped carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanotic carcinoma, nevus carcinoma, myxoid carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucoepidermoid carcinoma, mucinous carcinoma, mucinous adenocarcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, honeycomb cell carcinoma, erosive carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatous carcinoma, Schneider's 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 cell carcinoma, squamous cell carcinoma, linear carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, tubular carcinoma, tubercular carcinoma, verrucous carcinoma, or villous carcinoma.

[0169] The term "sarcoma" generally refers to tumors composed of embryonic connective tissue-like material and generally consists of tightly packed cells embedded in a fibrillary or homogenous substance. 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, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chlorosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, spontaneous multiple colored hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, cell sarcoma), angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, periosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serosal cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0170] The term "leukemia" broadly refers to progressive malignant diseases of the blood-forming organs and is generally characterized by abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on: (1) the duration and characteristics of the disease: acute or chronic; (2) the cell types involved: myeloid (myelogenic), lymphoid (lymphogenic), or monocytic; and (3) whether the number of abnormal cells in the blood is increased or not: leukemic or non-leukemic (meta-leukemic). 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 myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemias, leukocytic leukemias, basophilic leukemias, blast cell leukemias, bovine leukemia, chronic myelogenous leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, adult T-cell leukemia, Hematopoietic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia leukemia), plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, metastatic leukemia, or undifferentiated cell leukemia.

[0171] The term "melanoma" is considered to mean a tumor arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0172] In some embodiments, the cancer includes solid and lymphoid cancers, 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), lymphomas including B acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's lymphomas, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma, leukemias (including AML, ALL, and CML), and / or multiple myeloma.

[0173] In some embodiments, the cancer comprises 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 carcinoma.

[0174] Synthesis method

[0175] Compounds having formula (I), (II), (III) or (IV) can be synthesized by the methods given below, by the methods given in the experimental section below, or by similar methods. The schemes described herein are not intended to be an exhaustive list of methods for preparing compounds having formula (I), (II), (III) or (IV); on the contrary, other techniques known to skilled chemists can also be used for compound synthesis.

[0176] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR and / or 19 F-NMR). 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19F-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD600 NMR spectrometer. The solvents used were deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD or MeOH-d₄), or deuterated dimethyl sulfoxide (DMSO-d₆). TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and brs (broadened singlet). Coupling constants, J, are expressed in Hertz (Hz).

[0177] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC analysis was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).

[0178] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0179] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0180] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0181] It will be appreciated by those skilled in the art of organic synthesis that optimal reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by conventional optimization procedures. In some cases, the order of the following reaction schemes and / or reaction steps may be changed to promote reaction or to avoid forming unwanted by-products. In addition, the functional groups present in various positions of the molecule must be compatible with the proposed reagents and reactions. This limitation of substituents compatible with reaction conditions is apparent to those skilled in the art, and then alternative methods must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive group in the compound, and it is assumed that such a protecting group (PG) is in the appropriate position if necessary. Conventional protecting groups can be used according to standard practices well known in the art (for explanation, see Greene T.W, Wuts P.GM, Protective Groups in Organic Synthesis [protective groups in organic synthesis], 5th edition, publisher: John Wiley & Sons (John Wiley & Sons), 2014). Protective groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or protecting groups can be removed in subsequent reaction steps or post-processing.

[0182] The following abbreviations are used throughout this invention:

[0183] LCMS: liquid chromatography-mass spectrometry;

[0184] M, mol / L: moles per liter;

[0185] ml, mL: milliliter;

[0186] g: grams;

[0187] mmol: millimole;

[0188] ℃: degrees Celsius;

[0189] ACN: propionitrile;

[0190] DMSO: dimethyl sulfoxide;

[0191] FA: formic acid;

[0192] MeCN: acetonitrile.

[0193] The following examples are provided to facilitate understanding of the present invention. However, it should be understood that these examples and accompanying drawings are intended to illustrate the present invention only and are not intended to limit the present invention in any way. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and variations may be made without departing from the spirit of the present invention.

[0194] Preparation Example

[0195] Example 1: Preparation of Compound 1

[0196] Step 1: Dissolve compound 1-2 (25.0 g, 121.93 mmol) in tetrahydrofuran (500 mL) and add n-butyllithium (51.51 mL, 128.78 mmol, 2.5 M solution in n-hexane) at -70°C. After stirring at -70°C for half an hour, slowly add a solution of compound 1-1 (26.0 g, 107.32 mmol) in tetrahydrofuran (10 mL). Allow the reaction to warm to room temperature and stir overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the residue by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:10) to obtain compound 1-3. MS m / z (ESI): 351.1 [M+H-H2O] + . 1 H NMR(400MHz, CDCl3)δ6.83(t,J=1.7Hz,1H),6.80–6.75(m,1H),6.55(td,J=2.4,10.4Hz,1H),5.21–5.04(m,2H), 3.83(s,3H),3.44–3.42(m,1H),3.14–3.09(m,2H),2.88–2.83(m,2H),1.33–1.30(m,6H),1.25(d,J=6.4Hz,6H).

[0197] Step 2: Dissolve compound 1-3 (8.5 g, 23.07 mmol) in trifluoroacetic acid (50 mL) and add triethylsilane (21.92 mL, 135.72 mmol) at 0°C. Stir the reaction mixture at 25°C for 12 hours. Dilute the reaction mixture with dichloromethane (100 mL) and concentrate. Dissolve the residue in ethyl acetate (150 mL) and slowly pour it into a saturated aqueous sodium bicarbonate solution (300 mL) and stir until no bubbles form. Separate the layers and wash the organic phase with saturated brine (200 mL) and dry it over anhydrous sodium sulfate. Filter and concentrate the filtrate. The residue is isolated and purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:10) to obtain compound 1-4. MS m / z (ESI): 353.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ6.59–6.53(m,2H),6.51–6.45(m,1H),5.22–5.02(m,2H),3.81(s,3H),3.65 –3.51(m,1H),2.95–2.83(m,2H),2.70–2.57(m,2H),1.30(d,J=6.4Hz,6H),1.26(d,J=6.4Hz,6H).

[0198] Step 3: Dissolve compound 1-4 (5.6 g, 15.89 mmol) in methanol (20 mL), tetrahydrofuran (20 mL), and water (20 mL), and add potassium hydroxide (3.18 g, 56.75 mmol). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated. The residue was dissolved in water (50 mL) and extracted with methyl tert-butyl ether (20 mL). The aqueous phase was adjusted to pH 6 with 2M aqueous hydrochloric acid solution and then purified by reverse phase column (acetonitrile: water = 1:1) and lyophilized to obtain compound 1-5. MS m / z (ESI): 291.0 [M+Na] + .

[0199] Step 4: Add polyphosphoric acid (80 mL) to compound 1-5 (3.99 g, 14.89 mmol), and stir the reaction mixture at 100°C for 3 hours. Cool the reaction mixture to approximately 60°C, quench it with ice water (300 mL), and extract it with ethyl acetate (100 mL x 4). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Filter the mixture, and concentrate the filtrate. The residue was purified by preparative HPLC (column: C18 150 x 40 mm; flow rate: 60 mL / min, mobile phase: [water (FA)-ACN]; B%: 12%-52%, 9 min) to afford compound 1-6. MS m / z (ESI): 251.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.56(brs,1H),6.87–6.84(m,1H),6.81–6.75(m, 1H),3.86(s,3H),3.28–3.25(m,1H),2.97–2.89(m,2H),2.43–2.37(m,2H).

[0200] Step 5: Compound 1-6 (600 mg, 2.40 mmol) was dissolved in toluene (10 mL). 4A molecular sieves (1000 mg, 0.40 mmol), triethylamine (364 mg, 3.60 mmol), benzyl alcohol (1037 mg, 9.59 mmol), and diphenylphosphoryl azide (990 mg, 3.60 mmol) were added sequentially. The reaction mixture was refluxed at 120°C for 12 hours. The reaction mixture was cooled and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:10) to obtain compound 1-7. MS m / z (ESI): 356.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.68–7.54(m,1H),7.45–7.29(m,5H),6.83(d,J=2.0Hz,1H),6.77(dd,J=2. 0,12.8Hz,1H),5.04(s,2H),3.86(s,3H),3.44–3.37(m,1H),2.97–2.87(m,2H),2.48–2.39(m,2H).

[0201] Step 6: To a solution of compound 1-7 (600 mg, 1.69 mmol) in trifluoroacetic acid (8 mL) was added triethylsilane (5 mL, 30.96 mmol), and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL) and concentrated. The residue was dissolved in ethyl acetate (25 mL), washed with saturated sodium bicarbonate aqueous solution (25 mL), washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 1:10) to obtain compound 1-8. MS m / z (ESI): 342.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:7.86–7.76(m,1H),7.40–7.31(m,5H),6.61–6.53(m,2H),5.03(s,2 H),3.72(s,3H),3.09–3.00(m,1H),2.63–2.56(m,2H),2.99–2.89(m,2H),1.68–1.59(m,2H).

[0202] Step 7: Dissolve compound 1-8 (500 mg, 1.46 mmol) in dichloromethane (8 mL). Add boron tribromide (2 mL, 20.76 mmol) at -70°C. Stir the reaction mixture at 25°C for 16 hours. Slowly pour the reaction mixture into ice water (50 mL) and extract with ethyl acetate (30 mL x 2). The aqueous phase, representing the aqueous solution of compound 1-9, is used directly in the next step.

[0203] Step 8: Solid sodium carbonate was added to an aqueous solution of compound 1-9 (50 mL) until the pH reached 8. Tetrahydrofuran (5 mL) was then added, followed by di-tert-butyl dicarbonate (684 mg, 3.14 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was extracted with ethyl acetate (30 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was isolated and purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:10) to obtain compound 1-10. MS m / z (ESI): 238.3 [M-56+H] + . 1 H NMR (400MHz, CDCl3) δ6.41–6.37(m,2H),5.29–5.17(m,1H),4.96–4.81(m, 1H),3.06–2.96(m,3H),2.83–2.56(m,2H),1.85–1.76(m,2H),1.49(s,9H).

[0204] Step 9: To a mixture of compound 1-10 (400 mg, 1.36 mmol) and cesium carbonate (1333 mg, 4.09 mmol) in anhydrous N,N-dimethylformamide (5 mL) at -30°C was added 1-(chloromethoxy)-2-methoxyethane (423 mg, 3.40 mmol). The reaction mixture was stirred at -30°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was isolated and purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:10) to obtain compound 1-11. MS m / z (ESI): 404.3 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ6.70–6.57(m,2H),5.24(s,2H),4.95–4.80(m,1H),3.89–3.81(m,2H),3.64 –3.54(m,2H),3.40(s,3H),3.07–3.03(m,3H),2.81–2.52(m,2H),1.85–1.78(m,2H),1.48(s,9H).

[0205] Step 10: Dissolve compound 1-11 (350 mg, 0.92 mmol) in tetrahydrofuran (1 mL). Slowly add 2.5 M n-butyllithium (1.84 mL, 4.59 mmol) dropwise at -70°C under a nitrogen atmosphere. Stir the reaction at -70°C for 1 hour. Slowly add a solution of iodine (1168 mg, 4.60 mmol) in tetrahydrofuran (0.5 mL) dropwise at -70°C. Stir the reaction at -70°C for 1 hour. Add a solution of iodine (1168 mg, 4.60 mmol) in tetrahydrofuran (0.5 mL) dropwise at -70°C under a nitrogen atmosphere. Stir the reaction at -78°C for 2 hours. Quench the reaction with saturated ammonium chloride (10 mL) and extract with ethyl acetate (20 mL x 3). Wash the organic phase with aqueous sodium sulfite (20 mL), saturated brine (20 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate. The residue was separated and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 1:5) to obtain compound 1-12. MS m / z (ESI): 530.0 [M+Na] + . 1 H NMR(400MHz, CDCl3)δ6.70(s,1H),5.34–5.30(m,2H),4.87(brs,1H),3.92–3.86(m,2H),3.63–3 .56(m,2H),3.39(s,3H),3.11–3.03(m,3H),2.81–2.52(m,2H),1.85–1.77(m,2H),1.48(s,9H).

[0206] Step 11: Compound 1-12 (420 mg, 0.83 mmol), glycine tert-butyl ester (163 mg, 1.24 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (75 mg, 0.08 mmol), and cesium carbonate (809 mg, 2.48 mmol) were dissolved in dioxane (5 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 95°C for 4 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 1:10) to obtain compound 1-13. MS m / z(ESI):511.2[M+H] + . 1H NMR (400MHz, CDCl3) δ6.66(s,1H),5.32(s,2H),4.85(brs,1H),4.40(brs,1H),3.96(s,2H),3.91–3.82(m,2H),3.65–3. 53(m,2H),3.40(d,J=2.8Hz,3H),3.03(s,2H),2.97–2.94(m,1H),2.64(brs,2H),1.79–1.75(m,2H),1.49–1.44(m,18H).

[0207] Step 12: Under a nitrogen atmosphere at 0°C, to a solution of chlorosulfonic acid isocyanate (164 mg, 1.16 mmol) in dichloromethane (4 mL) was added dropwise allyl alcohol (380 mg, 6.54 mmol), and the reaction solution was stirred at 0°C for 30 minutes. Under a nitrogen atmosphere at 0°C, the reaction solution was added dropwise to a solution of compound 1-13 (295 mg, 0.58 mmol) and triethylamine (0.24 mL, 1.73 mmol) in dichloromethane (4 mL). The reaction solution was stirred for 2 hours under a nitrogen atmosphere at 0°C. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL×3), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to give compound 1-14, which was used directly in the next step. MS m / z(ESI):640.3[M- t Bu+Na] + .

[0208] Step 13: Compound 1-14 (350 mg, 0.52 mmol) was dissolved in methanol (4 mL), and tetrakistriphenylphosphine palladium (30 mg, 0.03 mmol), sodium methoxide (30% methanol solution) (0.58 mL, 3.12 mmol), and 4A molecular sieves (500 mg) were added. The atmosphere was replaced with nitrogen three times, and the reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was filtered, and the filtrate was quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with dichloromethane (10 mL x 3), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and the residue was isolated and purified by silica gel column chromatography (methanol:dichloromethane = 1:10) to obtain compound 1-15. MS m / z (ESI): 538.3 [M+Na] + .

[0209] Step 14: Dissolve compound 1-15 (130 mg, 0.25 mmol) in dichloromethane (1.5 mL), add trifluoroacetic acid (0.5 mL), and stir the reaction at 25°C for 2 hours. The reaction solution was concentrated, and the residue was purified by reverse phase column chromatography (acetonitrile:water = 1:10) to obtain compound 1-16. MS m / z (ESI): 328.2 [M+H] + .

[0210] Step 15: Compound 1-16 (50 mg, 0.15 mmol) was dissolved in methanol (0.4 mL) and dichloromethane (0.66 mL). Triethylamine (0.03 mL, 0.23 mmol) and isovaleraldehyde (0.02 mL, 0.20 mmol) were added, and the reaction mixture was stirred at 20°C for 3 hours. Sodium borohydride (17.3 mg, 0.46 mmol) was added, and the reaction mixture was stirred at 20°C for 30 minutes. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30 mm, 5 μm; flow rate: 30 mL / min; mobile phase: [Water(NH3H2O-NH4HCO3)-MeCN]; B%: 18%-38%) to afford compound 1. MS m / z (ESI): 398.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.30(brs,1H),8.64(brs,1H),6.52(s,1H),3.95(s,2H),3.30–3.25(m,2H),3.14– 3.09(m,1H),3.06(s,2H),2.97–2.92(m,2H),1.73–1.65(m,3H),1.53–1.45(m,2H),0.92(d,J=6.8Hz,6H).

[0211] Example 2: Preparation of Compound 2

[0212] Compound 1-16 (50 mg, 0.15 mmol) was dissolved in methanol (0.5 mL) and dichloromethane (0.5 mL). Triethylamine (0.03 mL, 0.23 mmol) and 4,4,4-trifluorobutyraldehyde (20.8 mg, 0.17 mmol) were added, and the reaction mixture was stirred at 20°C for 3 hours. Sodium borohydride (17.3 mg, 0.46 mmol) was added, and the reaction mixture was stirred at 20°C for 30 minutes. The reaction mixture was concentrated, and the residue was purified by preparative 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%) to obtain compound 2. MS m / z (ESI): 437.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.27(brs,1H),8.66(brs,1H),6.52(s,1H),3.95(s,2H),3.46–3.41(m, 2H),3.13–3.11(m,1H),3.03(brs,4H),2.46–2.34(m,2H),1.86–1.77(m,2H),1.74–1.70(m,2H).

[0213] Other compounds of the present application can be prepared by referring to the above examples and making necessary adjustments as needed.

[0214] Test Example 1: PTPN2 inhibitory activity assay

[0215] The present invention uses an HTRF assay to determine the inhibitory activity of compounds against PTPN2. The specific experimental procedure is as follows: Compounds were transferred to a 384-well plate (PE#6007290) using ECHO. 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 reaction buffer and added (final concentration: 1 nM). The compound was incubated with PTPN2 and the substrate (biotin-(NH-CH2-CH2-O-CH2-CH2-O-CH2-CO)-TRDI-(PY)-ETDYYRKK-NH2) (Genscript) was then added (final concentration: 1 μM). The reaction was incubated at room temperature for 40 minutes, and then the reaction was terminated by adding a quencher. Eu-anti-P(PY20) antibody (Cisbio#AD0066) and 15 nM APC-Streptavidin (Cisbio#AD0201) were added to a final concentration of 10 nM and incubated at room temperature for 1 h. The fluorescence values ​​of the 384-well plate after reaction were read at 620 nm and 665 nm using Envision. The IC values ​​of the inhibition of PTPN2 enzyme activity were fitted by nonlinear regression analysis using a four-parameter logistic equation. 50 Value (PTPN 2IC 50 ).

[0216] Yang ginseng:

[0217] The compounds of the present invention have been tested to have good PTPN2 inhibitory activity. The test results of some representative compounds are shown in Table 1.

[0218] Table 1

[0219] A:IC 50 ≤20nM, B: 20nM <IC 50 ≤100nM, C:100nM <IC 50 ≤500nM, D: 500nM <IC 50 .

[0220] Test Example 2: B16F10 mIFNγ-induced cell growth inhibition experiment

[0221] 40 μL (150 cells / well) of B16F10 cells (source ATCC Cat#CRL-6475) were seeded into 384-well plates. Compounds were transferred to the 384-well plates containing cells using EHCO. One group of cells was treated with 10 μL of complete medium (RPMI 1640 medium + 10% FBS) without mIFNγ, while another group was treated with 10 μL of complete medium containing mIFNγ (source R&D Cat#485-MI / CF, final concentration 25 ng / ml). Different concentrations of compound (DMSO content 0.5%) were added to the reaction system. The cell culture plates were incubated at 37°C, 5% CO2 in a humidified incubator for 96 hours. 25 μL of CTG was added and the reaction was read using Envision. DMSO / mIFNγ served as a negative control. As a positive control, the cell growth inhibition IC was fitted by nonlinear regression analysis using a four-parameter logistic equation. 50 Value (Cell IC 50 ).

[0222] The compounds of the present invention have been tested to have a good inhibitory effect on B16F10 mIFNγ-induced cell growth. The test results of representative compounds are shown in Table 2.

[0223] Table 2

[0224] A:IC 50 ≤1μM, B: 1μM <IC 50 ≤10μM, C:10μM <IC 50 ≤100μM, D: 100μM <IC 50 .

[0225] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. Any technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A compound having a structure represented by formula (I), or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; in, R 1a and R 1b Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 Alkoxy; L is selected from NR 1c , O, S; R 1c Selected from hydrogen, C 1-6 alkyl; G is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 The alkylene-5-10 membered heteroaryl groups are each independently, optionally substituted by one or more groups independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR 2a R 2b Substituents are substituted; R 2a and R 2b Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 The carbon atoms that may be substituted on the alkylene-4-10 membered heterocyclic group are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-6 Alkyl, halogenated C 1-6 The substituents of the alkoxy group are substituted.

2. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; in, R 1a and R 1b Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl and halogenated C 1-3 Alkoxy; Preferably, R 1a and R 1b each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethoxy, and 2,2-difluoroethoxy; More preferably, R 1a and R 1b Each independently selected from: hydrogen, deuterium, fluorine and hydroxyl; More preferably, R 1a and R 1b All are hydrogen.

3. The compound of claim 1 or 2, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; in, L is selected from NR 1c , O; Preferably, L is NR 1c ; Preferably, R 1c Selected from hydrogen, C 1-3 alkyl; More preferably, R 1c For hydrogen.

4. The compound according to any one of claims 1 to 3, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; in, G is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl; wherein the C 1-6 alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 The alkylene-5-6 membered heteroaryl groups are each independently, optionally substituted by one or more groups independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, -NR 2a R 2b Substituents are substituted; R 2a and R 2b Each independently selected from: hydrogen, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 The carbon atoms that may be substituted on the alkylene-4-7 membered heterocyclic group are each independently, optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, C 1-3 Alkyl, halogenated C 1-3 Substitution of alkoxy groups; Preferably, G is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-7 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 The alkylene-5-membered heteroaryl groups are each independently, optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, -NR 2a R 2b Substituents are substituted; R 2a and R 2b Each independently selected from: hydrogen, C 1-3 alkyl; Preferably, G is selected from C 1-6 Alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl, -C 1-4 Alkylene-C 3-6 The substituted carbon atoms on the cycloalkyl group are each independently, optionally substituted by one or more independently selected from halogen, C 1-3 Alkyl, halogenated C 1-3 Substitution of alkyl groups; More preferably, G is selected from C 1-6 Alkyl or C 1-6 Haloalkyl; Preferably, G is selected from: More preferably, G is selected from: More preferably, G is selected from: More preferably, G is selected from:

5. A compound according to any one of claims 1 to 4, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof, wherein: -LG is selected from: Preferably, -LG is selected from: Further preferably, -LG is selected from: More preferably, -LG is selected from:

6. The compound according to any one of claims 1 to 5, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; in, The compound has a structure shown in formula (II) or (III), The definition of G is as defined in any one of claims 1 to 5.

7. The compound according to any one of claims 1 to 6, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; in, The compound has a structure shown in formula (IV) M is selected from a bond or C 1-6 Alkylene; said C 1-6 The alkylene group is optionally substituted by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Substitution of alkyl groups; R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR 2a R 2b , C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are optionally substituted by one or more independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Substitution of alkyl groups; R 2a , R 2b as defined in any one of claims 1 to 6; Preferably, the M is selected from a bond or C 1-6 Alkylene; said C 1-6 The alkylene group is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxy, cyano, C 1-3 Alkyl, halogenated C 1-3 Substitution of alkyl groups; Preferably, the M is selected from C 1-6 Alkylene; said C 1-6 The alkylene group is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxy, cyano, C 1-3 Alkyl, halogenated C 1-3 Substitution of alkyl groups; Preferably, R 3 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR 2a R 2b , C 3-6 Cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane), 4-7 membered heterocyclic group (e.g., oxolane, oxacyclohexane, morpholinyl), phenyl, 5-6 membered heteroaryl (e.g. pyrazolyl, isoxazolyl, oxadiazolyl, triazolyl); wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by one or more independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl substituents are substituted; R 2a and R 2b Each independently selected from: hydrogen, C 1-3 alkyl; More preferably, the M is selected from C 1-6 Alkylene; said C 1-6 The alkylene group is optionally substituted with 1 to 3 substituents each independently selected from halogen; More preferably, R 3 is selected from hydrogen and halogen; More preferably, as R 3 The optional 4-7 membered heterocyclic group is selected from As R 3 The 5-6 membered heteroaryl group of the optional group is a 5 membered heteroaryl group, preferably Preferably, R 3 Selected from hydrogen, F, bromine, hydroxyl, cyano, methyl, ethyl, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -C(CH3)2OH, -C(CH3)3, -C(CH3)2CF3, -C(CH3)2CN, -C(CF3)2OH, -CH2CH(CH3)(CH2CH3), difluoromethyl, trifluoromethyl, -CH2CF3, -CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CF3, -CH(CH3)OH, -CH2CH(CH3)OH, -CH2CH(CF3)OH, -CH(CF3)2, -N(CH3)2.

8. A compound according to any one of claims 1 to 7, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; wherein, The compound is selected from 9. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 8 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug and at least one pharmaceutically acceptable carrier.

10. A compound according to any one of claims 1 to 8 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the composition of claim 9, for use in treating or preventing a disease or condition associated with PTPN2.

11. Use of a compound according to any one of claims 1 to 8 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the composition of claim 9 in the preparation of a medicament for treating or preventing a disease or condition associated with PTPN2.

12. A method for treating or preventing a disease or condition associated with PTPN2, comprising administering to a person in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 8 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or the composition of claim 9.

13. The use according to claim 11, the method according to claim 12, wherein: The disease or condition associated with PTPN2 includes cancer, type 2 diabetes, metabolic syndrome, obesity or metabolic disease; preferably, the cancer includes: carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, melanoma; preferably, the cancer includes: solid and lymphoma, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer (including liver tumors), lymphoma, including B acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (non-Hodgkin's lymphomas) (such as Burkitt's lymphoma (Burkitt's Preferably, the cancer comprises 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 carcinoma.

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