[go: up one dir, main page]

WO2025011570A1 - 蛋白酪氨酸磷酸酶抑制剂及其组合物、医药用途 - Google Patents

蛋白酪氨酸磷酸酶抑制剂及其组合物、医药用途 Download PDF

Info

Publication number
WO2025011570A1
WO2025011570A1 PCT/CN2024/104645 CN2024104645W WO2025011570A1 WO 2025011570 A1 WO2025011570 A1 WO 2025011570A1 CN 2024104645 W CN2024104645 W CN 2024104645W WO 2025011570 A1 WO2025011570 A1 WO 2025011570A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkylene
alkyl
cycloalkyl
hydrogen
independently
Prior art date
Application number
PCT/CN2024/104645
Other languages
English (en)
French (fr)
Inventor
牟剑锋
段新丽
俞清方
王童
董广平
胡晨明
谷正松
鄂镜雯
王绍晖
陈斌
张佩宇
Original Assignee
深圳众格生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳众格生物科技有限公司 filed Critical 深圳众格生物科技有限公司
Publication of WO2025011570A1 publication Critical patent/WO2025011570A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicine, and in particular to a protein tyrosine phosphatase inhibitor and a composition thereof, and medical uses thereof.
  • Immune checkpoint inhibitors represented by PD-1 antibodies have changed the treatment of many cancers, but most patients cannot benefit from this type of PD-1 blocking therapy. This situation has prompted some research teams to focus on finding new immunotherapy targets to develop new immunotherapy drugs that can be used for cancer patients who do not respond to PD-1 antibodies, or therapies that can synergize with PD-1 antibodies to improve their anti-cancer efficacy.
  • PTPN2 the full name of which is Tyrosine-protein phosphatase non-receptor type 2, also known as TC-PTP, is a member of the protein tyrosine phosphatase (PTP) family.
  • PTP1B family protein tyrosine phosphatase
  • members of this family participate in regulating a variety of signaling pathways and cellular processes, including cell growth, differentiation, 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) in the C-terminus participates in the automatic regulation of catalytic activity and the determination of subtype localization. Due to selective splicing, PTPN2 has two isomers, namely TC45 and TC48. The difference in the C-terminal region causes different subtypes to be located differently, thus affecting their substrate selection.
  • PTPN2 negatively regulates the signals of some receptor protein tyrosine kinases (including INSR, EGFR, CSF1R, PDGFR), non-receptor protein tyrosine kinases (such as JAK1, JAK2, JAK3), transcription factors (STAT1, STAT3 and STAT6) and Src family kinases (Fyn, Lck).
  • PTPN2 can negatively regulate the signal transduction mediated by inflammatory cytokines (IL-2 and interferon) through dephosphorylation of JAK1, JAK3 and their substrates signal transducer and activator of transcription 1 (STAT1).
  • deleting the gene expressing PTPN2 from the immune system (CD8+T cells) of cancer-bearing mice can stimulate the production and adaptability of killer T cells that fight infection and cancer.
  • deleting PTPN2 eliminated colon cancer in all mice.
  • 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.
  • the present invention provides a novel PTPN2 inhibitor, which has good drug development prospects in treating or preventing diseases or conditions related to PTPN2.
  • the present invention provides a compound having a structure represented by formula (I-1) or (I-2) 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;
  • R 1a and R 1b are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy;
  • R 1c and R 1d are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 2b is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, -N(R a )(R b ) and -N(R a )-N(R b )-C(O)-phenyl;
  • R 3 , R 3a and R 3b are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl);
  • X1 is selected from O, S, NRf and C(R e )(R d );
  • Ra and Rb are each independently selected from: hydrogen and C1-6 alkyl; optionally, the C1-6 alkyl is substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl;
  • R c is selected from the group consisting of: hydroxy, C 1-6 alkyl and phenyl;
  • Re and Rd are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 halocycloalkyl, amino, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl); optionally, Re and R3a , together with the atoms to which they are attached, form a 3-7 membered carbocyclic ring; or, Re and R2b , together with the atoms to which they are attached, form a 3-7 membered carbocyclic ring;
  • Rf is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl; optionally, Rf and R3a , together with the atoms to which they are attached, form a 3-7 membered heterocyclic ring; or, Rf and R2b , together with the atoms to which they are attached, form a 3-7 membered heterocyclic ring;
  • Rg is each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, nitro, oxo, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkyl, and C 1-6 haloalkyl;
  • R h is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl;
  • n is selected from: 0 or 1;
  • p is selected from: 0, 1, 2 or 3;
  • q is selected from: 0, 1, 2, 3 or 4;
  • w is selected from: 1 or 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug and at least one pharmaceutically acceptable carrier.
  • 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,
  • the ester, solvate, hydrate, isotope-labeled compound or prodrug, or the composition of the present invention is used for treating or preventing diseases or disorders associated with PTPN2.
  • 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.
  • 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 the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the composition of the present invention.
  • the present invention relates to methods for preparing, separating and purifying compounds represented by formula (I-1), (I-2), (II-0), (II-1), (II-2), (III-0), (III-1), (III-2), (IV-1), (IV-2), (V), (V-1), (VI-0), and (VI-1).
  • any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict.
  • any technical feature can be applied to the technical features in other embodiments, as long as they do not conflict.
  • subject refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to humans.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • enantiomers refers to two non-superimposable isomers of a compound that are mirror images of each other.
  • 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.
  • racemate refers to an equimolar mixture of two enantiomers devoid of optical activity.
  • 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.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
  • the prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are right-handed.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate and this may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • 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.
  • 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.
  • the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
  • racemate of the resulting final product or intermediate can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the obtained diastereomeric salts thereof.
  • the racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • 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, E. L.
  • nitrogen oxide means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings.
  • the corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • oxidizing agents such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), in which, for example, the amine compound is reacted
  • metabolite refers to a product obtained by the metabolism of a specific compound or its salt in vivo.
  • the metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammals treated therewith.
  • pharmaceutically acceptable refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.
  • 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 by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates
  • organic acid salts such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate
  • 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
  • Pharmaceutically acceptable salts also include salts formed by compounds with bases, including but not limited to, inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • 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 any compound containing a group of N. 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, C1-8 sulfonates and aromatic sulfonates.
  • Organic base salts e.g., primary, secondary, and tertiary amine salts, substituted amines (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts
  • certain organic amine salts include, for example, isopropylamine salts, benzathine salts, cholinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, and tromethamine salts.
  • Pharmaceutically acceptable acid addition salts can be formed by the compounds of the present invention and inorganic or organic acid
  • pharmaceutically acceptable base addition salts can be formed by the compounds of the present invention and inorganic or organic base
  • Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds, alkaline or acidic moieties. Generally speaking, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid.
  • a suitable base such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K
  • solvate refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • the solvent can be water, acetic acid, ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-but
  • hydrate refers to an association of one or more water molecules with a compound of the present invention.
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of containing their solvents (such as ethanol, DMSO, etc.) for their crystallization.
  • the compounds disclosed in the present invention can form solvates with pharmaceutically acceptable solvents (including water) inherently or by design; therefore, the present invention is intended to include both solvated and unsolvated forms.
  • esters 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.
  • isotopically labeled compound means that the compounds of the present invention are labeled with an isotope. They are identical to those compounds described herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the natural common atomic mass or mass number.
  • isotopes that may also be introduced 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.
  • Isotope-labeled compounds of the invention such as radioactive isotope-labeled compounds, such as 3 H and 14 C incorporated into the compounds of the invention can be used for drug and/or substrate tissue distribution analysis. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred due to ease of preparation and detection.
  • substitution with isotopes with larger mass numbers, such as deuterium, i.e., 2 H, can provide some therapeutic advantages of greater metabolic stability, For example, increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferred in some circumstances.
  • isotopes particularly deuterium (i.e., 2H or D)
  • deuterium in the present invention is regarded as a substituent of compounds of formula I to VI.
  • concentration of such heavier isotopes, particularly deuterium can be defined by an isotopic enrichment factor.
  • isotopic enrichment factor used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent of a compound of the invention is designated as deuterium
  • the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.
  • prodrug used in the present invention represents a compound that is converted into a compound shown in Formula I in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug compound of the present invention can be an ester.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • phosphate esters such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • prodrugs please refer to the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. 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.
  • Solid wedge Virtual wedge Chemical bonds of the compounds of the 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 stereoisomers shown.
  • the use of solid and dashed wedges is to define relative stereochemistry, rather than absolute stereochemistry.
  • each independently is used in combination with “arbitrarily”, for example, "each independently arbitrarily replaced by" means that the specific options are replaced by... or not by... without affecting each other.
  • C 1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is linked.
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of S, N and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NRT (such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N).
  • N such as N in 3,4-dihydro-2H-pyrrolyl
  • NH such as NH in pyrrolidinyl
  • NRT such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N.
  • the compounds composed thereof conform to the covalent rules and composition rules of organic compounds, that is, the compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent rules and composition rules of organic compounds.
  • heterocyclic group refers to an optionally substituted partially or fully saturated non-aromatic cyclic group, for example, a 4-7-membered monocyclic, 7-12-membered bicyclic or 10-15-membered tricyclic system, wherein the group has at least one heteroatom in at least one ring containing carbon atoms.
  • 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 nitrogen and sulfur heteroatoms may also be optionally oxidized.
  • the heterocyclic group may be connected at a heteroatom or a carbon atom.
  • the heterocyclic group is selected from: a monocyclic heterocyclic group, a bicyclic heterocyclic group, a tricyclic heterocyclic group.
  • a 4-8-membered heterocyclic group indicates that the ring atoms are composed of 4-8 carbon atoms and heteroatoms.
  • the heterocyclic group includes fused rings, spirocycles, bridged rings and combinations thereof.
  • 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.
  • the bicyclic heterocyclyl is selected from 7-oxabicyclo[2.2.1]heptyl.
  • carrier refers to a saturated (i.e., "cycloalkyl” and “cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., “cycloalkenyl” and “cycloalkenylene”) and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6, 4-6 or 5-6) ring carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
  • the carbon ring includes a fused ring,
  • cycloalkyl refers to a monovalent or polyvalent saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic system containing carbon atoms.
  • C 3-6 cycloalkyl refers to a cycloalkyl group with 3-6 carbon atoms in the ring.
  • the cycloalkyl group is selected from: monocyclic cycloalkyl, bicyclic cycloalkyl, tricyclic cycloalkyl.
  • monocyclic cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • bicyclic cycloalkyl includes but is 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, bicyclo[2.2.2]octyl, etc.
  • tricyclic hydrocarbon groups include adamantyl and the like.
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic, bicyclic and tricyclic aromatic system containing a heteroatom
  • heteroaryl can be used interchangeably with the term “heteroaromatic ring” or “heteroaromatic compound”, wherein the heteroatom has the definition described in the present invention.
  • the heteroaryl group is a heteroaryl group consisting of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-10 membered heteroaryl group;
  • the heteroaryl group is a heteroaryl group consisting of 5-8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-8 membered heteroaryl group;
  • the heteroaryl group is a heteroaryl group consisting of 5-7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-7 membered heteroaryl group;
  • the heteroaryl group is a heteroaryl group consisting of 5-6 atoms containing 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
  • aryl or "aromatic ring” refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system.
  • aryl can be used interchangeably with the term “aromatic ring” or “aromatic ring”.
  • 6-10 membered aryl refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl, naphthyl, etc.
  • halogen and halo refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • amino refers to -NH 2 ;
  • hydroxyl refers to -OH
  • cyano refers to -CN
  • nitro refers to -NO 2 ;
  • alkyl refers to a saturated, straight or branched hydrocarbon group containing carbon atoms.
  • the alkyl group contains 1-6 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, i.e., C 1-3 alkyl.
  • 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.
  • alkylene refers to a saturated, straight-chain or branched divalent hydrocarbon group containing carbon atoms.
  • the alkylene group contains 1-6 carbon atoms, i.e., C 1 -C 6 alkylene; in another embodiment, the alkylene group contains 1-4 carbon atoms, i.e., C 1 -C 4 alkylene; in another embodiment, the alkylene group contains 1-3 carbon atoms, i.e., C 1 -C 3 alkylene.
  • alkenyl refers to a straight or branched monovalent hydrocarbon group containing carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, including “cis” and “tans” positioning, or “E” and “Z” positioning.
  • 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.
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein.
  • the alkoxy group contains 1-6 carbon atoms, i.e., C 1-6 alkoxy; in another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C 1-4 alkoxy; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C 1-3 alkoxy.
  • 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 substituent R is connected to the central ring by a bond to form a ring system (as shown below) representing the substituent R at any substitutable or any reasonable position on the A ring.
  • formula f represents any possible substituted position on the A ring, as shown in formulas f1-f4:
  • a substituent is connected to a central ring by a bond to form a ring system, such as (R x ) n , which means that n substituents R x can be substituted at any substitutable position on the ring.
  • formula a represents a benzene ring that can be substituted by n R x generation.
  • substituted refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent.
  • the specific substituent is a substituent described above, or a substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues.
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer refers to or describe a physiological condition in a subject that is typically 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.
  • types of cancer may include or exclude, for example, carcinomas, lymphomas (e.g., Hodgkin and non-Hodgkin lymphomas), blastomas, sarcomas, and leukemias.
  • cancers may include or exclude, for example, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, 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 cancer or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, leukemia and other lymphoproliferative disorders, and various types of head and neck cancer.
  • squamous cell carcinoma small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, peritoneal cancer, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian
  • 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 disorders.
  • the present invention provides a compound having a structure represented by formula (I-1) or (I-2) 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;
  • R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 3a , R 3b , X 1 , n, p and q have the same meanings as those defined in the present invention.
  • R 1a and R 1b are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkyl, and halo-substituted C 1-6 alkoxy.
  • R 1a and R 1b are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, and halo-substituted C 1-4 alkoxy.
  • R 1a and R 1b are 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.
  • R 1a and R 1b are each independently selected from the group consisting of: hydrogen, deuterium, fluorine, and hydroxyl.
  • R 1a and R 1b are both hydrogen.
  • R 1c and R 1d are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and halogenated C 1-6 alkyl.
  • R 1c and R 1d are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, and halogenated C 1-4 alkyl.
  • R 1c and R 1d are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, and difluoromethyl.
  • R 1c and R 1d are each independently selected from: hydrogen, deuterium, fluorine.
  • R 1c and R 1d are each independently selected from: hydrogen, fluorine.
  • R 2a is selected from: -OC 1-6 alkyl, -OC 1-4 alkylene-C 3-6 cycloalkyl, -OC 1-4 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-(4-8 membered heterocyclyl), -N(R a )-C( ⁇ O)-C 1-6 alkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -N(R a )-C 1-4 alkylene-phenyl, -C 1-4 alkylene-C 3-6 cyclo
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-(4-8 membered heterocyclyl), -N(R a )-C( ⁇ O)-C 1-6 alkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -N(R a )-C 1-4 alkylene-phenyl; wherein the substitutable carbon atoms in the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ;
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 1-6 haloalkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl.
  • R 2a is selected from the following groups:
  • R 2a is selected from the following groups:
  • R 2a is selected from the following groups:
  • R 2a is selected from the following groups:
  • R 2a is selected from the following groups:
  • R 2a is
  • R 2b is selected from the group consisting of: hydrogen, deuterium, hydroxyl, halogen, -N( Ra )( Rb ), and -N( Ra )-N( Rb )-C(O)-phenyl.
  • R 2b is selected from the group consisting of: hydrogen, deuterium, hydroxy, fluoro, chloro, and bromo.
  • R 2b is selected from the group consisting of: hydrogen and deuterium.
  • R 2b is hydrogen
  • R 3 , R 3a and R 3b are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, amino, -NH ( C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl).
  • R 3 , R 3a and R 3b are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy , C 3-6 cycloalkyl, C 3-6 halocycloalkyl, amino, -NH (C 1-4 alkyl), -N(C 1-4 alkyl)(C 1-4 alkyl).
  • R 3 , R 3a and R 3b are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl.
  • R 3 , R 3a and R 3b are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, trifluoromethyl, difluoromethyl.
  • R 3 , R 3a and R 3b are each independently selected from the group consisting of: hydrogen, deuterium, fluorine, and hydroxyl.
  • R 3 , R 3a and R 3b are each independently selected from the group consisting of: hydrogen, fluoro, and hydroxy.
  • X 1 is selected from O, S, NR f and C(R e )(R d ).
  • Ra and Rb are each independently selected from: hydrogen and C1-6 alkyl; optionally, the C1-6 alkyl is substituted with one or more substituents selected from halogen, cyano, oxo, and hydroxy.
  • Ra and Rb are each independently selected from: hydrogen and C1-4 alkyl; optionally, the C1-4 alkyl is substituted with one or more substituents selected from halogen, cyano, oxo, and hydroxy.
  • Ra and Rb are each independently selected from: hydrogen, methyl.
  • R c is selected from the group consisting of: hydroxy, C 1-6 alkyl, and phenyl.
  • R c is selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and phenyl.
  • Re and Rd are each independently selected from: hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 halocycloalkyl, amino, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl); optionally, Re and R3a , together with the atoms to which they are attached, form a 3-7 membered carbocyclic ring; or, Re and R2b , together with the atoms to which they are attached, form a 3-7 membered carbocyclic ring.
  • Re and Rd are each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, C3-6 halocycloalkyl, amino, -NH( C1-4 alkyl), -N( C1-4 alkyl)( C1-4 alkyl); optionally, Re and R3a , together with the atoms to which they are attached, form a 3-6 membered carbocyclic ring; or, Re and R2b , together with the atoms to which they are attached, form a 3-6 membered carbocyclic ring.
  • Rf is selected from: hydrogen, C1-6 alkyl, C1-6 haloalkyl; optionally, Rf and R3a together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, or, Rf and R2b together with the atoms to which they are attached form a 3-7 membered heterocyclic ring.
  • Rf is selected from: hydrogen, C1-4 alkyl, C1-4 haloalkyl; optionally, Rf and R3a together with the atoms to which they are attached form a 3-6 membered heterocyclic ring, or, Rf and R2b together with the atoms to which they are attached form a 3-6 membered heterocyclic ring.
  • Rg is each independently selected from: hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, oxo, amino, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl), C1-6 alkyl, and C1-6 haloalkyl.
  • Rg is each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, nitro, oxo, amino, -NH( C1-4 alkyl), -N( C1-4 alkyl)( C1-4 alkyl), C1-4 alkyl, and C1-4 haloalkyl.
  • each Rg is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, nitro, oxo, amino, -NH- CH3 , -N( CH3 )( CH3 ), methyl, ethyl, trifluoromethyl, and difluoromethyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.
  • R h is selected from the group consisting of: hydrogen, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.
  • n is selected from: 0 or 1.
  • p is selected from: 0, 1, 2 or 3.
  • q is selected from: 0, 1, 2, 3 or 4.
  • w is selected from: 1 or 2.
  • the compound of the structure shown in formula (I-1) is not
  • R 1a and R 1b are each independently selected from hydrogen and deuterium, preferably R 1a and R 1b are selected from hydrogen.
  • R 1c and R 1d are each independently selected from hydrogen, deuterium, and halogen.
  • R 1c and R 1d are each independently selected from hydrogen and halogen. More preferably, one of R 1c and R 1d is selected from hydrogen, and the other is selected from halogen.
  • p is selected from 0 or 1, preferably p is selected from 0.
  • n is selected from 0.
  • R 3 is selected from hydrogen, deuterium, halogen, preferably R 3 is selected from hydrogen and halogen, more preferably R 3 is selected from hydrogen.
  • q is selected from 0, 1 or 2, preferably q is selected from 0.
  • X 1 is selected from O, S, NR f and C( Re )(R d ), preferably X 1 is selected from C( Re )(R d ).
  • Re and Rd are each independently selected from: hydrogen, deuterium, halogen, hydroxyl or, Re and R2b , together with the atoms to which they are attached, form a 3-7 membered carbocyclic ring, preferably Re and Rd are each independently selected from: hydrogen, halogen, hydroxyl or, Re and R2b , together with the atoms to which they are attached, form a 3-6 membered carbocyclic ring (e.g., C3-6 cycloalkyl), more preferably Re and Rd are selected from hydrogen.
  • R 2b is selected from hydrogen or, R 2b and Re , together with the atoms to which they are attached, form a 3-6 membered carbocyclic ring (eg, C 3-6 cycloalkyl).
  • R 2b is selected from hydrogen.
  • R 2a is selected from -N(R a )-C 1-8 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-6 alkylene-(5-6 membered heteroaryl), -N( R a )-C 1-6 alkylene-phenyl, -OC 1-8 alkyl, -OC 1-6 alkylene-(4-8 membered heterocyclyl), -OC 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-(4-8 membered heterocyclyl), -C 1-6 alkylene-N(R a )-C 1-8 alkyl, -C 1-6 alkylene-N(R a
  • R is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -N(R a )-C 1-4 alkylene-phenyl, -OC 1-6 alkyl, -OC 1-4 alkylene-(4-7 membered heterocyclyl), -OC 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-(4-7 membered heterocyclyl), -C 1-4 alkylene-N(R a )-C 1-6 alkyl, -C 1-4 alkylene-N(R a )-
  • R 2a is selected from -N(R a )-C 1-8 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-6 alkylene-(5-6 membered heteroaryl), -N( R a )-C 1-6 alkylene-phenyl, -OC 1-8 alkyl, -OC 1-6 alkylene-(4-8 membered heterocyclyl), -C 1-6 alkylene-N(R a )-C 1-8 alkyl, -C 1-6 alkylene-N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-N(R a )-N(R
  • R is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -N(R a )-C 1-4 alkylene-phenyl, -OC 1-6 alkyl, -OC 1-4 alkylene-(4-7 membered heterocyclyl), -C 1-4 alkylene-N(R a )-C 1-6 alkyl, -C 1-4 alkylene-N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-N(R a )-C 3-6 cyclo
  • R 2a is selected from -N(R a )-C 1-8 alkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-6 alkylene-phenyl, -C 1-6 alkylene-N(R a )-C 1-8 alkyl; wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -N(R a )-C 1-4 alkylene-phenyl, -C 1-4 alkylene-N(R a )-C 1-6 alkyl; wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • R 2a is selected from -N(R a )-C 1-8 alkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl), -C 1-6 alkylene-N(R a )-C 1-8 alkyl; wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -C 1-4 alkylene-N(R a )-C 1-6 alkyl; wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • each Rg is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl), C1-6 alkyl, and C1-6 haloalkyl.
  • each Rg is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -NH( C1-4 alkyl), -N( C1-4 alkyl)( C1-4 alkyl), C1-4 alkyl, and C1-4 haloalkyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, C 1-4 alkyl, and C 1-4 haloalkyl.
  • Ra and Rb are each independently selected from: hydrogen and C1-6 alkyl; optionally, the C1-6 alkyl is substituted with one or more halogens.
  • Ra and Rb are each independently selected from: hydrogen and C1-4 alkyl; optionally, the C1-4 alkyl is substituted with one or more halogens.
  • the compound has a structure shown in formula (II-0):
  • the compound has a structure shown in formula (II-1) or (II-2):
  • R 1a , R 1b , R 1c , R 1d , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 3 , R 3a , R 3b , X 1 , X 2 , n, p and q have the same meanings as those defined in the present invention.
  • R 2c , R 2d , R 2e and R 2f are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, C 1-6 alkyl and halogenated C 1-6 alkyl; optionally, R 2c and R 2d , or R 2e and R 2f form oxo.
  • R 2c , R 2d , R 2e and R 2f are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, C 1-4 alkyl and halogenated C 1-4 alkyl; optionally, R 2c and R 2d , or R 2e and R 2f form oxo.
  • R 2c , R 2d , R 2e and R 2f are each independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, trifluoromethyl; optionally, R 2c and R 2d , or R 2e and R 2f form oxo.
  • R 2g is selected from: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl); the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl are each independently and arbitrarily substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 haloalkyl.
  • R 2g is selected from: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl); the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl are each independently and arbitrarily substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, cyano, methyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl.
  • R 2g is selected from: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl); the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl are each independently and arbitrarily substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, cyano, methyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl.
  • R 2g is selected from: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl; the C 1-4 alkyl, C 3-6 cycloalkyl , 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl are each independently optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 haloalkyl.
  • R 2g is selected from: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, said C 1-4 alkyl
  • the C 3-6 cycloalkyl group and the 4-7 membered heterocyclic group are each independently optionally substituted by one or more substituents selected from halogen.
  • R 2g is selected from: hydrogen, methyl, trifluoromethyl, difluoromethyl, tert-butyl, -CH 2 OH, -N(CH 3 ) 2 , or the following groups:
  • R 2g is selected from: hydrogen, methyl, trifluoromethyl, difluoromethyl, tert-butyl, -N(CH 3 ) 2 or the following groups:
  • R 2g is selected from the group consisting of: hydrogen, methyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyran-2-yl.
  • X2 is NH or O.
  • X 2 is NH
  • the compound has a structure shown in formula (III-0):
  • the compound has a structure shown in formula (III-1) or (III-2):
  • R 1c , R 1d , R 2b , R 2c , R 2d , R 2g , R 3 , X 1 , X 2 , p and q have the same definitions as those described in the present invention.
  • the compound has a structure shown in formula (IV-1) or (IV-2):
  • R 1c , R 1d , R 2b , R 2c , R 2h , R 3 , X 1 , p and q have the same definitions as those described in the present invention.
  • R 2h is selected from: C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-(4-7 membered heterocyclyl), -C 1-4 alkylene-(5-6 membered heteroaryl), -C 1-4 alkylene-phenyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , the C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-(4-7 membered heterocyclyl), -C 1-4 alkylene-(5-6 membered heteroaryl), -C 1-4 alkyl,
  • R 2h is selected from: C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-(4-7 membered heterocyclyl), -C 1-2 alkylene-(5-6 membered heteroaryl), -C 1-2 alkylene-phenyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , the C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-(4-7 membered heterocyclyl), -C 1-2 alkylene-(5-6 membered heteroaryl), -C 1-2 alkyl,
  • R 2h is selected from: C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl , 4-7 membered heterocyclyl are each independently optionally substituted by one or more halogens.
  • R 2h is selected from: C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.
  • R 2h is selected from: methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-hydroxy-propan-2-yl, 2-cyano-propan-2-yl, -N(CH 3 ) 2 ,
  • R 2h is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 2h is selected from: isopropyl, tert-butyl, trifluoromethyl, 2-(1,1,1-trifluoromethyl)-propan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyran-2-yl.
  • the compound has a structure shown in Formula (V):
  • R 1a , R 1b , R 2a , R 2b , R 3 and q have the same definitions as those described in the present invention.
  • R 1a and R 1b are each independently selected from the group consisting of: hydrogen, deuterium, fluorine, and hydroxyl.
  • R 1a and R 1b are hydrogen.
  • R 2a is selected from: -N(R a )-C 1-8 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-(4-8 membered heterocyclyl), -N(R a )-C( ⁇ O)-C 1-8 alkyl, -N(R a )-C( ⁇ O)-OC 1-8 alkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-Si(R c ) 3 , -N(R a )-(C ⁇ N(R b ))-C 1-8 alkyl, -N(R a )-S( ⁇ O) w -C 1-8 alkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl),
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-(4-8 membered heterocyclyl), -N(R a )-C( ⁇ O)-C 1-6 alkyl, -N(R a )-C( ⁇ O)-OC 1-8 alkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-Si(R c ) 3 , -N(R a )-(C ⁇ N(R b ))-C 1-6 alkyl, -N(R a )-S( ⁇ O) w -C 1-6 alkyl, -N(R a )-C 1-4 alkylene-(4-8 membered heterocyclyl), -N(R
  • R 2a is selected from: -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -N(R a )-C 1-4 alkylene-phenyl, -OC 1-6 alkyl, -OC 1-4 alkylene-(4-8 membered heterocyclyl); wherein the substitutable carbon atoms in the optional group of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; R g are each independently selected from: hydrogen, fluorine, hydroxyl, cyano, -N(CH 3 )(CH
  • R 2a is selected from -N(R a )-C 1-8 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-6 alkylene-(5-6 membered heteroaryl), -N( R a )-C 1-6 alkylene-phenyl, -OC 1-8 alkyl, -OC 1-6 alkylene-(4-8 membered heterocyclyl), -OC 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-(4-8 membered heterocyclyl); wherein the substitutable carbon atoms in the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -N( R a )-C 1-4 alkylene-phenyl, -OC 1-6 alkyl, -OC 1-4 alkylene-(4-7 membered heterocyclyl), -OC 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-(4-7 membered heterocyclyl); wherein the substitutable carbon atoms in the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected
  • R 2a is selected from -N(R a )-C 1-8 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl), -N(R a )-C 1-6 alkylene-(5-6 membered heteroaryl), -N( R a )-C 1-6 alkylene-phenyl, -OC 1-8 alkyl, -OC 1-6 alkylene-(4-8 membered heterocyclyl); wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituor
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -N( R a )-C 1-4 alkylene-phenyl, -OC 1-6 alkyl, -OC 1-4 alkylene-(4-7 membered heterocyclyl); wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituor
  • R 2a is selected from -N(R a )-C 1-8 alkyl, -N(R a )-C 1-6 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-6 alkylene-(4-8 membered heterocyclyl); wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • R 2a is selected from -N(R a )-C 1-6 alkyl, -N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl); wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • each Rg is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl), C1-6 alkyl, and C1-6 haloalkyl.
  • each Rg is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, -NH( C1-4 alkyl), -N( C1-4 alkyl)( C1-4 alkyl), C1-4 alkyl, and C1-4 haloalkyl.
  • each Rg is independently selected from the group consisting of hydrogen, fluoro, hydroxy, cyano, -N( CH3 ) 2 , methyl, ethyl, trifluoromethyl, and difluoromethyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R h is selected from the group consisting of: hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, and 2,2-difluoroethyl.
  • Ra is selected from the group consisting of hydrogen and C1-6 alkyl; optionally, the C1-6 alkyl is substituted with one or more substituents selected from halogen, cyano, oxo, and hydroxy.
  • Ra is selected from the group consisting of hydrogen and C1-4 alkyl; optionally, the C1-4 alkyl is substituted with one or more substituents selected from halogen, cyano, oxo, and hydroxy.
  • Ra is hydrogen
  • R 2b is selected from the group consisting of: hydrogen, deuterium, hydroxy, fluoro, chloro, and bromo.
  • R 2b is hydrogen
  • R 3 is selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl.
  • R 3 is selected from: hydrogen, fluorine.
  • q is selected from: 0, 1, 2.
  • the compound has a structure shown in formula (V-1):
  • R 2c and R 2d are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, C 1-6 alkyl and halogenated C 1-6 alkyl; optionally, R 2c and R 2d form an oxo group;
  • R 2g is selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl); the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are each independently and arbitrarily substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-4 alkyl, and halogenated C 1-4 alkyl;
  • X2 is NH or O.
  • X 2 is NH
  • R 2c and R 2d are each independently selected from the group consisting of hydrogen, fluoro, cyano, hydroxy, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • R 2c and R 2d are each independently selected from the group consisting of hydrogen, fluoro, cyano, hydroxy, methyl, ethyl, trifluoromethyl.
  • R 2g is selected from: hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl (e.g., pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl); the C 1-3 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are each independently and arbitrarily substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • substituents selected from halogen, hydroxyl, cyano, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • R 2g is selected from: hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl (e.g., pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl); the C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are each independently and arbitrarily substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • substituents selected from halogen, hydroxyl, cyano, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • R 2g is selected from the group consisting of: hydrogen, F, methyl, ethyl, -CH(CH 3 ) 2 , -CH 2 OH, difluoromethyl, trifluoromethyl, -CH 2 -CHF 2 , cyclopropyl, Cyclobutyl, Cyclopentyl, cyclohexyl,
  • R 2c and R 2d are hydrogen and R 2g is difluoromethyl.
  • the compound has a structure shown in formula (VI-0):
  • R 2a is selected from -C 1-4 alkylene-N(R a )-C 1-6 alkyl, -C 1-4 alkylene-N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -C 1-4 alkylene-N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -C 1-4 alkylene -N(R a )-C 1-4 alkylene-phenyl, -C 1-4 alkylene-OC 1-6 alkyl, -C 1-4 alkylene-OC 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OC 1-4 alkylene-(4-7 membered heterocyclyl), -C( ⁇ O)—N(R a )-C 1-6 alkyl,
  • R2a is selected from -C1-2 alkylene-N(R a ) -C1-6 alkyl, -C1-2 alkylene-N(R a ) -C1-4 alkylene-C 3-6 cycloalkyl, -C1-2 alkylene-N(R a ) -C1-4 alkylene-(4-7 membered heterocyclyl), -C1-2 alkylene-N(R a ) -C1-4 alkylene-(5-6 membered heteroaryl), -C1-2 alkylene -N(R a )-C1-4 alkylene-phenyl, -C1-2 alkylene-OC1-6 alkyl, -C1-2 alkylene - OC1-4 alkylene - C 3-6 cycloalkyl, -C1-2 alkylene- OC1-4 alkylene-(4-7 membered heterocyclyl), -C( ⁇ O)—N(R a ) -C1-6 alkyl, -C R
  • R 2a is selected from -C 1-2 alkylene-N(R a )-C 1-6 alkyl, -C 1-2 alkylene-N(R a )-C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-N(R a )-C 1-4 alkylene-(4-7 membered heterocyclyl), -C 1-2 alkylene-N(R a )-C 1-4 alkylene-(5-6 membered heteroaryl), -C 1-2 alkylene-N(R a )-C 1-4 alkylene-phenyl; wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • R 2a is selected from -C 1-2 alkylene-N(R a )-C 1-6 alkyl; wherein the substitutable carbon atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R g ; and/or, the substitutable ring nitrogen atoms on the optional groups of R 2a are each independently and optionally substituted with one or more substituents each independently selected from R h .
  • Rg is each independently selected from: hydrogen, deuterium, halogen (e.g., fluorine, chlorine, bromine), hydroxyl, cyano, amino, -NH( C1-4 alkyl), -N( C1-4 alkyl)( C1-4 alkyl), C1-4 alkyl and C1-4 haloalkyl.
  • halogen e.g., fluorine, chlorine, bromine
  • R h is selected from the group consisting of: hydrogen, deuterium, C 1-4 alkyl, and C 1-4 haloalkyl.
  • Ra and Rb are each independently selected from: hydrogen and C1-4 alkyl; optionally, the C1-4 alkyl is substituted with one or more halogens.
  • the compound has a structure shown in formula (VI-1):
  • the compound has the structure shown below:
  • the compound has the structure shown below:
  • the compound has the structure shown below:
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • compositions and methods of administration are provided.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its enantiomers, diastereoisomers, isomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, labeled compound or prodrug thereof; and a pharmaceutically acceptable carrier.
  • pharmaceutical composition refers to a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically/pharmaceutically acceptable carriers and diluents, and further excipients such as excipients, binders, fillers, and additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents.
  • additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • the term "pharmaceutically acceptable carrier” refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).
  • the present invention also relates to a compound having formula I-1, I-2, II-1, II-2, III-1, III-2, IV-1, IV-2 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 a pharmaceutical composition thereof, which can be particularly used for the treatment of neoplastic diseases, especially 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 especially for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (suitably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, especially humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles.
  • These compositions can contain the active ingredient alone, or preferably, together with a pharmaceutically acceptable carrier.
  • the compounds of formula I-1, I-2, II-1, II-2, III-1, III-2, IV-1, IV-2 or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen 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, semisolid and liquid polyols, etc.
  • 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.
  • Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.
  • 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.
  • the dosage can vary within wide limits and, of course, will be in accordance with individual requirements in each particular case.
  • 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.
  • Compounds of formula I-1, I-2, II-1, II-2, III-1, III-2, IV-1, IV-2 can also be used in combination with one or more other pharmacologically active compounds, which are also effective against the same disease, preferably using different modes of action, or reducing or preventing possible undesirable side effects of compounds of formula I-1, I-2, II-1, II-2, III-1, III-2, IV-1, IV-2.
  • Combination partners can be administered simultaneously in this treatment, for example by incorporating them into a single pharmaceutical formulation, or by administering two or more different dosage forms (each containing one or more than one combination partner) and continuously.
  • terapéuticaally effective amount of a compound of the present invention refers to an amount of a compound of the present invention that will cause a biological or medical response in a subject (e.g., 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.).
  • 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 improving any disease, disorder or condition associated with PTPN2.
  • treatment or “treating” as used herein in the context of treating a disease or disorder generally relates to treatment and therapy of humans or animals (e.g., in veterinary applications), wherein some desired therapeutic effects are obtained, e.g., inhibiting the progression of a disease or disorder, and including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving a disease or disorder, and curing a disease or disorder.
  • Treatment as a preventive measure i.e., prevention
  • treatment includes prevention of cancer, reducing the incidence of cancer, alleviating cancer symptoms, etc.
  • the present invention provides compounds shown in I-1, I-2, II-1, II-2, III-1, III-2, IV-1, IV-2 or their 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, which are used to treat or prevent diseases or conditions associated with PTPN2.
  • the present invention provides the use of compounds shown in I-1, I-2, II-1, II-2, III-1, III-2, IV-1, IV-2 or their 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.
  • the present invention provides a method for treating or preventing PTPN2-related diseases or disorders, the method comprising administering a therapeutically effective amount of a compound shown as I-1, I-2, II-1, II-2, III-1, III-2, IV-1, IV-2 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.
  • a disease or condition associated with PTPN2 comprises cancer, type 2 diabetes, metabolic syndrome, obesity, or a metabolic disease.
  • the cancer comprises: carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, melanoma.
  • cancer refers to all types of cancers, neoplasms or malignancies found in mammals, including leukemia, lymphoma, carcinoma and sarcoma.
  • Exemplary cancers that can be treated with the compounds, pharmaceutical compositions or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain 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
  • thyroid cancer cancer of the endocrine system
  • 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
  • primary blood Hypercalcemia primary macroglobulinemia, primary brain tumor, cancer, 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
  • carcinoma refers to a malignant neoplasm composed of epithelial cells that tends to infiltrate surrounding tissues and cause metastasis.
  • 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, bronchial carcinoma, bronchogenic carcinoma, brain-like carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine body carcinoma, cribriform carcinoma, armored carcinoma, Thyroid carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, tubular carcinoma, dural carcinoma, embryo
  • sarcoma generally refers to a tumor composed of embryonic connective tissue-like material and is generally composed of tightly packed cells embedded in a fibrillary or homogenous material.
  • Sarcomas that can be treated with the compounds, pharmaceutical compositions or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy'ssarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green sarcoma, 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, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, extraperiosteal sarcoma, reticular cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.
  • leukemia refers broadly to progressive malignancies 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 clinically classified based on: (1) the duration and characteristics of the disease: acute or chronic; (2) the type of cells 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).
  • 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 leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic Leukemia, lymphogenic leukemia, lymphocytic leuk
  • melanoma is considered to mean a tumor arising from the melanocytic 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.
  • 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 (such as Burkitt's lymphomas, small cell lymphomas and large cell lymphomas), Hodgkin's lymphoma, leukemias (including AML, ALL and CML) and/or multiple myeloma.
  • solid and lymphoid cancers including B acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (such as Burkitt's lymphomas, small cell lymphomas and large cell lymphomas), Hodgkin's lymphoma, leukemias (including AML, ALL and CML
  • 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.
  • the structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or/and 19 F-NMR).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR were measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD600 NMR spectrometer, and the measurement solvents were deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD or MeOH-d 4 ) or deuterated dimethyl sulfoxide (DMSO-d6).
  • TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), brs (broadened singlet).
  • the coupling constant J is expressed in Hertz (Hz).
  • LC-MS Liquid chromatography-mass spectrometry
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • 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.
  • 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], the 5th edition, publisher: John Wiley & Sons (John Wiley & Sons), 2014). Protective groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or protective groups can be removed in subsequent reaction steps or post-treatment.
  • Step 1 Add tert-butyldimethylsilyl chloride (11.3 g, 74.97 mmol) to a solution of compound 1-1 (15.7 g, 71.61 mmol) and imidazole (14.7 g, 215.92 mmol) in dichloromethane (200 mL) at 0°C. The reaction solution was stirred at 0°C for 2 hours. The reaction solution was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with 1M dilute hydrochloric acid (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-2.
  • Step 2 At 0°C, sodium borohydride (8.3 g, 219.40 mmol) was added to a mixture of compound 1-2 (27 g, 72.86 mmol) and calcium chloride (16.2 g, 145.97 mmol) in tetrahydrofuran (200 mL) and ethanol (100 mL). The mixture was stirred at 15°C for 12 hours. The reaction solution was slowly poured into water (300 mL) and diluted with ethyl acetate (200 mL).
  • Step 3 Under nitrogen protection, at 0°C, add dichlorothionyl (6.7 mL, 92.37 mmol) dropwise to a solution of imidazole (19.5 g, 286.43 mmol) and triethylamine (21.7 mL, 156.55 mmol) in dichloromethane (100 mL). After the mixture was stirred at 0°C for 30 minutes, a solution of compound 1-3 (21.7 g, 71.03 mmol) in dichloromethane (100 mL) was added dropwise. The reaction solution was stirred at 0°C for 1 hour.
  • reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-4, which was directly used in the next step.
  • Step 4 Add ruthenium trichloride (0.93 g, 3.56 mmol) and sodium periodate (22.8 g, 106.60 mmol) to a solution of compound 1-4 (25 g, 71.12 mmol) in dichloromethane (120 mL) and water (120 mL). The reaction solution was stirred at 15 ° C for 12 hours. After filtering the reaction solution with diatomaceous earth, the filtrate was extracted with dichloromethane (100 mL x3). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 5 Under nitrogen protection, potassium tert-butoxide solution (105 mL, 105.00 mmol, 1M tetrahydrofuran solution) was added dropwise to a solution of compound 1-6 (23.5 g, 98.74 mmol) and benzyl alcohol (10.8 mL, 103.87 mmol) in tetrahydrofuran (450 mL) at -50 °C. Under nitrogen protection, the mixture was stirred at -50 °C for 20 minutes. The reaction solution was quenched with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (200 mL x3).
  • Step 6 Add saturated ammonium chloride solution (120 mL) to a solution of compound 1-7 (23 g, 70.53 mmol) and zinc powder (14 g, 214.13 mmol) in tetrahydrofuran (230 mL) and methanol (230 mL). The reaction solution was stirred at 20 ° C for 2 hours. The reaction solution was diluted with ethyl acetate (200 mL) and filtered with diatomaceous earth. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-8, which was directly used in the next step reaction.
  • Step 7 Trifluoroacetic anhydride (12.3 mL, 88.43 mmol) was added dropwise to a solution of compound 1-8 (20.2 g, 68.21 mmol) and pyridine (9 mL, 111.50 mmol) in acetonitrile (200 mL) at 20°C. The reaction mixture was stirred at 20°C. Stir for 1 hour. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 8 Under nitrogen protection, lithium diisopropylamide (55 mL, 110.00 mmol, 2M tetrahydrofuran solution) was added dropwise to a solution of compound 1-9 (18.5 g, 47.18 mmol) in tetrahydrofuran (100 mL) at -70 ° C. After the reaction solution was stirred at -70 ° C for 30 minutes, a solution of compound 1-5 (15 g, 42.67 mmol) in tetrahydrofuran (100 mL) was added dropwise at -70 ° C. The reaction solution was stirred at -70 ° C for 2 hours.
  • Step 9 Under nitrogen protection, 1,1-bis(diphenylphosphine)dibrominated iron palladium dichloride (1 g, 1.37 mmol) was added to a mixture of compound 1-10 (15 g, 26.53 mmol), potassium ethylene trifluoroborate (11 g, 82.12 mmol) and potassium carbonate (11 g, 79.59 mmol) in 1,4-dioxane (150 mL) and water (15 mL). Under nitrogen protection, the reaction solution was stirred at 100°C for 12 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3).
  • Step 10 Under nitrogen protection, add a solution of sulfur trioxide pyridine (14.6g, 91.73mmol) in dimethyl sulfoxide (80mL) to a solution of compound 1-11 (7.8g, 15.22mmol) and triethylamine (12.7mL, 91.62mmol) in dimethyl sulfoxide (80mL) at 0°C. Under nitrogen protection, the reaction solution was stirred at 0°C for 1 hour. After the reaction solution was poured into a saturated sodium bicarbonate solution (200mL), it was extracted with dichloromethane (100mL x3).
  • Step 11 Under nitrogen protection, sodium hydrogen (1.3 g, 32.50 mmol) was added to a solution of methyltriphenylphosphine bromide (12 g, 33.59 mmol) in tetrahydrofuran (30 mL) at 0°C. After the reaction solution was stirred at 0°C for 30 minutes, a solution of compound 1-12 (4.8 g, 9.40 mmol) in tetrahydrofuran (30 mL) was added to the reaction solution. The reaction solution was stirred at 60°C for 12 hours. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3).
  • Step 12 Add methyl bromoacetate (0.66 mL, 6.95 mmol) to a solution of compound 1-13 (2.5 g, 4.92 mmol) and potassium carbonate (2.05 g, 14.83 mmol) in N,N-dimethylformamide (30 mL). Stir the reaction mixture at 60°C for 2 hours. Dilute the reaction mixture with water (100 mL) and extract with ethyl acetate (50 mL x 3). Combine the organic phases and use The crude product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 13 Under nitrogen protection, 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl[2-(isopropoxy-5-(N,N-dimethylaminosulfonyl)phenyl]methylruthenium dichloride (0.71 g, 0.96 mmol) was added to a solution of compound 1-14 (2.8 g, 4.82 mmol) in dichloromethane (160 mL). The reaction solution was stirred at 40°C in the dark for 6 hours. The reaction solution was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3).
  • Step 14 Under nitrogen protection, a solution of diethylzinc (1.10 mL, 1.10 mmol, 1M hexane solution) in dichloromethane (1 mL) was added dropwise at 0°C. After the reaction solution was stirred at 0°C for 15 minutes, a solution of compound 1-15 (250 mg, 0.45 mmol) in dichloromethane (1 mL) was added dropwise. The reaction solution was stirred at 20°C for 30 minutes. The reaction solution was diluted with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL x3).
  • Step 15 Add sodium methoxide (110 mg, 2.04 mmol) to a solution of compound 1-16 (280 mg, 0.49 mmol) in methanol (3 mL). Stir the reaction solution at 60°C for 2 hours. The solvent was dried by rotary evaporation to obtain crude compound 1-17, which was directly used in the next step.
  • Step 17 Add tert-butyl alcohol (73 ⁇ L, 0.77 mmol) to a solution of chlorosulfonyl isocyanate (65 ⁇ L, 0.75 mmol) in dichloromethane (0.2 mL). After the reaction solution was stirred at 20°C for 15 minutes, a solution of compound 1-18 (150 mg, 0.32 mmol) and triethylamine (135 ⁇ L, 0.97 mmol) in dichloromethane (0.2 mL) was added dropwise. The reaction solution was stirred at 20°C for another hour. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3).
  • Step 18 Add trifluoroacetic acid to a solution of compound 1-19 (107 mg, 0.16 mmol) in dichloromethane (1 mL). Acid (500 ⁇ L, 6.71mmol). After the reaction solution was stirred at 25°C for 1 hour, the solvent was dried by rotary evaporation, and the crude compound was dissolved in dichloromethane (5mL), and triethylamine (110 ⁇ L, 0.79mmol) and di-tert-butyl dicarbonate (170 ⁇ L, 0.79mmol) were added. After the reaction solution was stirred at 25°C for another 30 minutes, the solvent was dried by rotary evaporation.
  • Step 19 Add sodium methoxide (25 mg, 0.46 mmol) to a solution of compound 1-20 (117 mg, 0.21 mmol) in methanol (2 mL). The reaction solution was stirred at 60°C for 20 minutes. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-21. MS m/z (ESI): 540.2 [M+Na] + .
  • Step 20 Add trifluoroacetic acid (500 ⁇ L, 6.71 mmol) to a solution of compound 1-21 (94 mg, 0.18 mmol) in dichloromethane (2 mL). Stir the reaction solution at 25°C for 1 hour. The solvent was dried by rotary evaporation to obtain crude compound 1-22, which was directly used in the next step. MS m/z (ESI): 416.1 [MH] - .
  • Step 21 Sodium cyanoborohydride (35 mg, 0.56 mmol) was added to a solution of compound 1-22 (75.8 mg, 0.18 mmol) and isovaleraldehyde (20 ⁇ L, 0.19 mmol) in methanol (0.3 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated and the crude product was purified by reverse phase column (C18, 5-50% acetonitrile/0.1% ammonium bicarbonate aqueous solution) to obtain compound 1-23. MS m/z (ESI): 488.2 [M+H] + .
  • Step 22 Add 10% wet palladium carbon (10 mg) to a solution of compound 1-23 (60 mg, 0.12 mmol) in methanol (2 mL). Under the protection of hydrogen (15 psi), the reaction solution was stirred at 25°C for 4 hours. After the reaction solution was filtered through diatomaceous earth, the filtrate was dried by rotary evaporation, and the crude product was purified by preparative HPLC (C18, acetonitrile/0.1% aqueous ammonium bicarbonate solution) to obtain compound 1. MS m/z (ESI): 396.1 [MH] - .
  • Compound 1 was prepared by SFC chiral separation (Column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: A:CO 2 B:methanol(0.05% DEA)Isocratic:50% B; Flow Rate(ml/min): 80; Column temp.: 35°C; ABPR: 1500psi) to obtain compound 2 (isomer 1, first peak, retention time of 1.301 minutes) and compound 3 (isomer 2, second peak, retention time of 1.936 minutes).
  • Step 1 Dissolve compound 4-1 (15.0 g, 58.53 mmol) in ethanol (200 mL), add isoamylamine hydrochloride (15 g, 58.53 mmol) and paraformaldehyde (19.31 g, 585.30 mmol). Stir the reaction solution at 95°C for 12 hours. After cooling the reaction solution to room temperature, filter it and wash the filter cake with ethanol. Dry the filter cake under reduced pressure to obtain compound 4-2. MS m/z (ESI): 356.1 [M+H] + .
  • Step 2 Dissolve compound 4-2 (14.0 g, 39.39 mmol) in tetrahydrofuran (100 mL), add triethylamine (11.96 g, 118.16 mmol) and Boc anhydride (9.46 g, 43.33 mmol). The reaction solution was stirred at 25 ° C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate.
  • Step 3 Dissolve compound 4-3 (15.0 g, 32.93 mmol) in methanol (500 mL), and slowly add 10% wet palladium carbon (3.50 g) to the reaction solution under a nitrogen atmosphere. Replace the hydrogen three times, and stir the reaction solution under a hydrogen atmosphere (30 psi) at room temperature for 12 hours. The reaction solution is filtered through diatomaceous earth, and the filter residue is washed with methanol. The filtrate is concentrated to obtain compound 4-4, which is directly used in the next step.
  • Step 4 Compound 4-4 (8.5 g, 23.26 mmol) was dissolved in N,N-dimethylformamide (100 mL), cesium carbonate (22.73 g, 69.78 mmol) was added to the reaction solution under nitrogen atmosphere, 2-methoxyethoxymethyl chloride (5.3 mL, 46.52 mmol) was added dropwise at -30°C, and the reaction solution was stirred at -30°C for 30 minutes. The reaction solution was quenched with water (300 mL) and extracted with ethyl acetate (300 mL ⁇ 3). The organic phase was washed with brine (100 mL) and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated.
  • Step 5 Dissolve (fluoromethyl)triphenylphosphine tetrafluoroborate (12.63 g, 33.07 mmol) in tetrahydrofuran (150 mL), slowly add potassium tert-butoxide (3.71 g, 33.07 mmol) at 0°C under a nitrogen atmosphere, and stir the reaction solution at 0°C for 30 minutes.
  • Dissolve compound 4-5 (5 g, 11.02 mmol) in 20 mL of tetrahydrofuran and slowly add it dropwise to the reaction solution at 0°C. The reaction solution was stirred at room temperature for 2 hours.
  • Step 6 Dissolve compound 4-6 (4.3 g, 9.16 mmol) in tetrahydrofuran (50 mL), slowly add 2.5 M n-butyl lithium (18.31 mL, 45.79 mmol) at -78 ° C under nitrogen atmosphere, and stir the reaction solution at -78 ° C for 30 minutes.
  • Dissolve iodine (6.97 g, 27.47 mmol) in tetrahydrofuran (20 mL), slowly add it to the reaction solution at -78 ° C, and stir the reaction solution at -78 ° C for 2 hours.
  • reaction solution is quenched with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (100 mL x3).
  • the organic phase is washed with sodium sulfite aqueous solution (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate.
  • Step 7 Compound 4-7 (5.0 g, 8.40 mmol), glycine tert-butyl ester (1.65 g, 12.60 mmol), methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (0.76 g, 0.84 mmol) and cesium carbonate (8.21 g, 25.19 mmol) were dissolved in dioxane (50 mL), replaced with nitrogen three times, and the reaction solution was stirred at 95 ° C for 4 hours.
  • methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amin
  • Step 8 Take three-necked flask A, dissolve chlorosulfonyl isocyanate (1.65g, 11.69mmol) in dichloromethane (50mL), add allyl alcohol (0.95g, 16.36mmol) dropwise at 0°C nitrogen atmosphere, and stir the reaction solution at 0°C for 1 hour.
  • Take three-necked flask B dissolve compound 4-8 (3.5g, 5.85mmol) in dichloromethane (50mL), and add triethylamine (2.4mL, 17.54mmol) dropwise. Add the solution in three-necked flask A to B at 0°C. Stir the reaction solution at 0°C nitrogen atmosphere for 2 hours.
  • reaction solution is diluted with water (50mL), extracted with ethyl acetate (50mL x3), and the organic phase is washed with brine (30mL) and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain compound 4-9.
  • Step 9 Compound 4-9 (3.0 g, 3.94 mmol) was dissolved in methanol (60 mL), and tetrakistriphenylphosphine palladium (0.23 g, 0.20 mmol), sodium methoxide (1.3 mL, 23.63 mmol, 30% methanol solution) and 4A molecular sieves (3.0 g) were added, and nitrogen was replaced three times. The reaction solution was stirred at 60°C for 12 hours.
  • Step 10 Compound 4-11 (600 mg, 0.99 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2.0 mL, 26.84 mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the residue was prepared by HPLC (column: Phenomenex Gemini NX 150 ⁇ 30 mm, 5 ⁇ m; flow rate: 60 mL/min; mobile phase: [Water (ammonia hydroxide v/v)-ACN]; B%: 9%-49%, 9 min) to obtain compound 4.
  • HPLC columnumn: Phenomenex Gemini NX 150 ⁇ 30 mm, 5 ⁇ m; flow rate: 60 mL/min; mobile phase: [Water (ammonia hydroxide v/v)-ACN]; B%: 9%-49%, 9 min
  • Compound 4 was prepared by SFC chiral separation (Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Condition : CO2- EtOH (0.1% NH3H2O ) Begin B: 35% End B: 35%; Flow Rate (ml/min): 80) to obtain compound 5 (isomer 1, first peak, retention time 1.062 minutes) and compound 6 (isomer 2, second peak, retention time 1.486 minutes).
  • Step 1 Compound 4-10 (400 mg, 0.66 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.3 mL, 17.44 mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the residue was prepared by HPLC (column: Phenomenex Gemini NX 150 ⁇ 30 mm, 5 ⁇ m; flow rate: 60 mL/min; mobile phase: [Water (ammonia hydroxide v/v)-ACN]; B%: 6%-46%, 9 min) to obtain compound 7. MS m/z (ESI): 416.0 [M+H] + .
  • Step 2 Under nitrogen protection, add 10% wet palladium carbon (10 mg) to a solution of compound 8-1 (30 mg, 56.87 ⁇ mol) in ethanol (2 mL). Stir the reaction solution at 25°C for 12 hours under a hydrogen atmosphere (15 psi). Filter the reaction solution through diatomaceous earth, spin dry the filtrate, and purify the crude product by preparative HPLC (C18, 0.05% ammonium bicarbonate solution/acetonitrile) to obtain compound 8. MS m/z (ESI): 438.1 [M+H] + .
  • Step 1 Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.8g, 23.14mmol) and triethylamine (7.4mL, 53.38mmol) to a solution of compound 9-1 (3.0g, 17.63mmol) and N,O-dimethylhydroxylamine hydrochloride (3.5g, 35.88mmol) in N,N-dimethylformamide (30mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was diluted with water (100mL) and extracted with ethyl acetate (50mL x3).
  • Step 2 At 0°C, lithium aluminum hydride (0.56 mL, 1.4 mmol, 2.5 M tetrahydrofuran solution) was added dropwise to a solution of compound 9-2 (200 mg, 0.94 mmol) in tetrahydrofuran (5 mL). After the addition was completed, the reaction solution was stirred at 0°C for 2 hours. The reaction solution was quenched with sodium sulfate decahydrate, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 9-3.
  • Step 3 Sodium cyanoborohydride (10 mg, 159.13 ⁇ mol) was added to a methanol (1 mL) solution of compound 1-22 (22 mg, 52.70 ⁇ mol) and compound 9-3 (1.44 mL, 158.1 ⁇ mol). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (C18, 0.05% ammonium bicarbonate solution/acetonitrile) to obtain compound 9-4. MS m/z (ESI): 556.4 [M+H] + .
  • Step 4 Under nitrogen protection, add 10% wet palladium carbon (5 mg) to a solution of compound 9-4 (24 mg, 43.20 ⁇ mol) in tetrahydrofuran (3 mL). Stir the reaction solution at 25°C for 12 hours under a hydrogen atmosphere (15 psi). Filter the reaction solution through diatomaceous earth, spin dry the filtrate, and purify the crude product by preparative HPLC (C18, 0.05% ammonium bicarbonate solution/acetonitrile) to obtain compound 9. MS m/z (ESI): 466.1 [M+H] + .
  • Example 10 The synthesis of compound 10 refers to Example 4, except that 3,3-dimethylbutyraldehyde was used as the raw material to replace 4,4,4-trifluorobutyraldehyde in Example 4, and compound 10 was prepared using the same method as Example 4.
  • Example 11 The synthesis of compound 11 refers to Example 4, except that 2-cyclohexyl acetaldehyde is used as the raw material to replace 4,4,4-trifluorobutyraldehyde in Example 4, and compound 11 is prepared using the same method as Example 4.
  • Step 1 Add Dess-Martin reagent (980 mg, 2.31 mmol) to a solution of compound 12-1 (200 mg, 2.08 mmol) in dichloromethane (4 mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was diluted to 10 mL with dichloromethane to obtain a solution of compound 12-2 which was directly used in the next step.
  • 1 H NMR 400 MHz, CDCl 3
  • Step 2 Sodium cyanoborohydride (75 mg, 1.19 mmol) was added to a methanol (2 mL) solution of compound 1-22 (400 mg, 0.60 mmol) and compound 12-2 (4.0 mL, 0.84 mmol, dichloromethane solution). The reaction solution was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (C18, 0.05% ammonium bicarbonate solution/acetonitrile) to obtain compound 12-3. MS m/z (ESI): 496.2 [M+H] + .
  • Step 3 Under nitrogen protection, at -70°C, add boron trichloride (1.5 mL, 1.5 mmol, 1 M n-hexane solution) to a solution of compound 12-3 (160 mg, 0.32 mmol) and pentamethylbenzene (96 mg, 0.65 mmol) in dichloromethane (5 mL). The reaction solution was stirred at -70°C for 1 hour. The reaction solution was quenched with methanol (2 mL) at -70°C, the mixed solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (C18, 0.05% ammonium bicarbonate solution/acetonitrile) to obtain compound 12.
  • Compound 12 was separated by SFC (Instrument: WATERS150preparative SFC (SFC-26); Column: ChiralPak IC, 250 ⁇ 30mm ID, 10 ⁇ m; Mobile phase: A for CO2 and B for Methanol (0.1% NH3H2O); Gradient: B 40%; Flow rate: 150mL/min; Back pressure: 100bar; Column temperature: 38°C; Wavelength: 220nm; Cycle time: ⁇ 8min), and the first peak (retention time: 1.543 minutes) was obtained, which was compound 13, MS m/z (ESI): 405.9 [M+H] + .
  • SFC Streparative SFC
  • Example 8 The synthesis of compound 15 was carried out by referring to Example 8, except that the raw material 2-cyclopropylethanol was used to replace compound 12-1 in Example 8, and compound 15 was prepared by the same method as Example 8.
  • Example 16 The synthesis of compound 16 was performed by referring to Example 4, except that the raw material tetrahydropyran-2-carboxaldehyde was used to replace the 4,4,4-trifluorobutyraldehyde in Example 4, and the same method as Example 4 was used to prepare compound 16.
  • Test Example 1 PTPN2 Inhibitory Activity Assay
  • the present invention adopts HTRF assay to determine the characteristics of the inhibitory activity of the compound on PTPN2.
  • the specific experimental process is as follows: the compound is transferred to a 384-well plate (PE#6007290) by ECHO, and an enzymatic reaction buffer (50mM HEPES pH7.5, 10mM EDTA, 0.01% Tween 20, 2mM DTT) is prepared.
  • an enzymatic reaction buffer 50mM HEPES pH7.5, 10mM EDTA, 0.01% Tween 20, 2mM DTT
  • PTPN2 (Sino biological #10570-H20B) is diluted in the reaction buffer, PTPN2 (final concentration 1nM) is added and incubated with the compound at room temperature for 10min, and then the substrate (final concentration 1 ⁇ M) (biotin-(NH- CH2 - CH2 -O-CH2- CH2 - O -CH2 - CO)-TRDI-(PY)-ETDYYRKK- NH2 ) (Genscript) is added, and the reaction is terminated by adding a quencher after incubation at room temperature for 40min.
  • Eu-anti-P(PY20) antibody (Cisbio#AD0066) and 15 nM APC-Streptavidin (Cisbio#AD0201) were added at a final concentration of 10 nM and incubated at room temperature for 1 h.
  • the fluorescence values of the 384-well plate after the reaction were read at 620 nm and 665 nm using Envision.
  • the IC 50 value (PTPN 2IC 50 ) for inhibiting PTPN2 enzyme activity was fitted by nonlinear regression analysis using a four-parameter logistic equation.
  • the compounds of the present invention have good PTPN2 inhibitory activity after testing.
  • the test results of some representative compounds are shown in Table 1.
  • Table 1 A IC 50 ⁇ 20nM
  • B 20nM ⁇ IC 50 ⁇ 100nM
  • C 100nM ⁇ IC 50 ⁇ 500nM
  • D 500nM ⁇ IC 50 .
  • Test Example 2 B16F10 mIFN ⁇ -induced cell growth inhibition experiment
  • B16F10 cells (source ATCC Cat#CRL-6475) were inoculated into a 384-well plate. The compound was transferred to the 384-well plate containing cells using EHCO. One group of cells was added with 10 ⁇ L of complete medium without mIFN ⁇ (RPMI 1640 medium + 10% FBS), and one group was added with 10 ⁇ L of complete medium containing mIFN ⁇ (source R&D Cat#485-MI/CF, final concentration 25 ng/ml). Different concentrations of compounds (DMSO content 0.5%) were added to the reaction system.
  • the cell culture plate was placed in a 37°C, 5% CO 2 incubator for 96 hours, 25 ⁇ L CTG was added, and Envision was used for reading.
  • DMSO/mIFN ⁇ was used as a negative control.
  • the cell growth inhibition IC 50 value (Cell IC 50 ) was fitted by nonlinear regression analysis with a four-parameter Logistic equation.
  • Table 2 A IC 50 ⁇ 1 ⁇ M
  • B 1 ⁇ M ⁇ IC 50 ⁇ 10 ⁇ M
  • C 10 ⁇ M ⁇ IC 50 ⁇ 100 ⁇ M
  • D 100 ⁇ M ⁇ IC 50 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明提供了一种化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药；还提供了含有该化合物的组合物及医药用途，该化合物在治疗或预防与PTPN2相关的疾病或病症方面具有较好的成药前景。

Description

蛋白酪氨酸磷酸酶抑制剂及其组合物、医药用途
相关申请的引用
本申请要求2023年07月11日提交的中国专利申请CN202310857115.1和2023年09月12日提交的中国专利申请CN202311171624.5的优先权，通过援引加入的方式将其内容整体并入本申请，并用于所有目的。
技术领域
本发明涉及医药领域，具体涉及蛋白酪氨酸磷酸酶抑制剂及其组合物、医药用途。
背景技术
以PD-1抗体为代表的免疫检查点抑制剂已改变多种癌症的治疗方式，但是大部分患者无法获益于这类PD-1阻断疗法。这一现状促使一些研究团队致力于寻找新的免疫疗法靶点，以开发可用于对PD-1抗体不响应的癌症患者的新型免疫治疗药物，或可协同PD-1抗体提高其抗癌疗效的疗法。
PTPN2，全称为Tyrosine-protein phosphatase non-receptor type 2，又名TC-PTP，是蛋白酪氨酸磷酸酶(PTP)家族的一员。PTPN2与同家族蛋白PTPN1(又名PTP1B)拥有74％的序列同源性和86％的结构相似性。该家族成员作为信号因子，参与调节多种信号通路和细胞进程，包括细胞生长、分化、有丝分裂周期和致癌转化。PTPN2蛋白包含N端激酶结构域和C端非催化结构域，在C端中的核定位信号(Nuclear localization signal,NLS)参与催化活性的自动调节和亚型定位的确定。PTPN2由于选择性剪切，拥有两种异构体，分别是TC45和TC48，在C端区域的差异，使不同亚型定位不同，从而影响它们的底物选择。PTPN2负向调节部分受体蛋白酪氨酸激酶(包括INSR、EGFR、CSF1R、PDGFR)、非受体蛋白酪氨酸激酶(如JAK1、JAK2、JAK3)、转录因子(STAT1、STAT3和STAT6)以及Src家族激酶(Fyn,Lck)的信号。PTPN2能够通过JAK1、JAK3及其底物信号传导与转录激活子1(Signal transducer and activator of transcription,STAT1)的去磷酸化，负向调节炎症细胞因子(IL-2和干扰素)介导的信号传导。
有关研究表明，抑制PTPN2免疫调节因子可促进抗肿瘤免疫力，从而可以清除肿瘤。具体来说，从患癌小鼠的免疫系统(CD8+T细胞)中删除表达PTPN2的基因，可刺激对抗感染和癌症的杀伤性T细胞的产生和适应性。在其中一项实验中，删除PTPN2消除了所有小鼠的结肠癌。此外，另一项实验显示，删除PTPN2结合PD-1阻断疗法成功消除了四分之一携带极具侵袭性且对治疗耐药的小鼠黑色素瘤。
发明内容
为了解决现有技术中存在的上述技术问题，本发明提供了一种新颖PTPN2抑制剂，该化合物在治疗或预防与PTPN2相关的疾病或病症方面具有较好的成药前景。
具体的，
一方面，本发明提供了具有式(I-1)或(I-2)所示的结构的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药；
其中，R1a和R1b各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基；
R1c和R1d各自独立地选自：氢、氘、卤素、C1-6烷基和卤代C1-6烷基；
R2a选自：氢、氘、羟基、氨基、C1-8烷基、C2-8烯基、C3-6环烷基、5-6元杂芳基、4-8元杂环基、-O-C1-8烷基、-O-C1-6亚烷基-C3-6环烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C(＝O)-N(Ra)-C1-8烷基、-O-C(＝O)-N(Ra)-苯基、-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-8烷基、–N(Ra)-C(＝O)-O-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-Si(Rc)3、-N(Ra)-(C＝N(Rb))-C1-8烷基、-N(Ra)-S(＝O)w-C1-8烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)(Rb)、-C1-6亚烷基-N(Ra)-C(＝O)-O-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-C3- 6环烷基、-C1-6亚烷基-N(Ra)-C(＝O)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-O-C1-8烷基、-C1-6亚烷基-O-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-O-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-O-C1-6亚烷基-N(Ra)(Rb)、-S(＝O)w-C1-8烷基、-C(＝O)-N(Ra)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
R2b选自：氢、氘、羟基、卤素、-N(Ra)(Rb)和-N(Ra)-N(Rb)-C(O)-苯基；
R3、R3a和R3b各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；
X1选自O、S、NRf和C(Re)(Rd)；
Ra和Rb各自独立地选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代；
Rc选自：羟基、C1-6烷基和苯基；
Re和Rd各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；任选地，Re和R3a，与它们相连的原子一起形成3-7元碳环；或，Re和R2b，与它们相连的原子一起形成3-7元碳环；
Rf选自：氢、C1-6烷基、C1-6卤代烷基；任选地，Rf和R3a，与它们相连的原子一起形成3-7元杂环；或，Rf和R2b，与它们相连的原子一起形成3-7元杂环；
Rg各自独立地选自：氢、氘、卤素、羟基、氰基、硝基、氧代、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基；
Rh选自：氢、氘、C1-6烷基和C1-6卤代烷基；
n选自：0或1；
p选自：0、1、2或3；
q选自：0、1、2、3或4；
w选自：1或2。
另一方面，本发明提供了一种药物组合物，其包含本发明所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药和至少一种药学上可接受的载体。
另一方面，本发明提供了本发明所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、 酯、溶剂化物、水合物、同位素标记化合物或前药，或本发明所述组合物，其用于治疗或预防与PTPN2相关的疾病或病症。
另一方面，本发明提供了本发明所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，或本发明所述组合物，在制备药物中的用途，所述药物用于治疗或预防与PTPN2相关的疾病或病症。
另一方面，本发明提供了一种治疗或预防与PTPN2相关的疾病或病症的方法，其包括向需要其的人施用治疗有效量的本发明所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，或本发明所述组合物。
本发明另一方面涉及式(I-1)、(I-2)、(II-0)、(II-1)、(II-2)、(III-0)、(III-1)、(III-2)、(IV-1)、(IV-2)、(V)、(V-1)、(VI-0)、(VI-1)所示的化合物的制备、分离和纯化的方法。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。本说明书中的所有参考文献通过整体引用于此。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步的详细说明。此处所描述的具体实施例仅用于解释本发明，并不用于构成对本发明的任何限制。此外，在以下说明中，省略了对公知结构和技术的描述，以避免不必要地混淆本公开的概念。这样的结构和技术在许多出版物中也进行了描述。
定义
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考“OrganicChemistry”,ThomasSorrell,UniversityScienceBooks,Sausalito:1999,和“March'sAdvancedOrganicChemistry”byMichaelB.SmithandJerryMarch,JohnWiley&Sons,NewYork:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分 被考虑在所述实施方案的实施方式中采用或使用。
术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。
术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
术语“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
术语“消旋体”、“外消旋物”或“外消旋混合物”是指缺少光学活性的两个对映异构体的等摩尔混合物。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergybarrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropictautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。再例如价键互变异构体(valencetautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。
术语“几何异构体”也称“顺反异构体”，因双键(包括烯烃的双键、C＝N双键和N＝N双键)或环碳原子的单健不能自由旋转而引起的异构体。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.,McGraw-HillDictionaryofChemicalTerms(1984)McGraw-HillBookCompany,NewYork；andEliel,E.andWilen,S,“StereochemistryofOrganicCompounds”,JohnWiley&Sons,Inc,NewYork,1994。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racematesand Resolutions(WileyInterscience,NewYork,1981)；Principles of Asymmetric Synthesis(2ndEd.RobertE.Gawley,JeffreyAube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agentsand Optical Resolutionsp.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,WileyInterscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂，例如二氯甲烷中，使胺化合物与间-氯过苯甲酸(MCPBA)反应。
术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。优选地，本发明所述的“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可药典上列举的在动物中、特别是人体中使用的。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Bergeetal.,J.PharmaceuticalSciences,66：1-19,1977所记载的。药学上可接受的盐包括化合物与酸形成的盐，包括但并不限于，无机酸盐(如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，硝酸盐，高氯酸盐)和有机酸盐(如乙酸盐，羟基乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，富马酸盐，扁桃酸盐，磺基水杨酸盐)，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。更多的药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙 酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。药学上可接受的盐还包括化合物与碱形成的盐，包括但不限于，无机碱盐(如碱金属盐，碱土金属盐，铵盐和N+(C1-4烷基)4盐)，碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。有机碱盐(如伯胺盐、仲胺盐和叔胺盐，取代的胺(包括天然存在的取代的胺、环状胺、碱性离子交换树脂)盐)，某些有机胺盐包括，例如，异丙胺盐、苄星青霉素(benzathine)盐、胆碱盐(cholinate)、二乙醇胺盐、二乙胺盐、赖氨酸盐、葡甲胺(meglumine)盐、哌嗪盐和氨丁三醇盐。
可药用的酸加成盐可由本发明化合物与无机酸或有机酸作用形成，可药用碱加成盐可由本发明化合物与无机碱或有机碱作用形成。本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington’s Pharmaceutical Sciences”，第20版，MackPublishingCompany,Easton,Pa.,(1985)；和“药用盐手册：性质、选择和应用(HandbookofPharmaceuticalSalts:Properties,Selection,andUse)”，StahlandWermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。所述溶剂可以是水、乙酸、乙醚、异丙醚、石油醚、甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸正丙酯、乙酸异丁酯、乙酸正丁酯、甲基叔丁基醚(MTBE)、正庚烷、体积比为10:90～90:10的乙醇和水的混合溶剂、丙酮、甲基异丁基甲酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、乙二醇、正丁醇、叔丁醇、仲丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、正己烷、环己烷、正庚烷、体积比为1:5～5:1的正庚烷和乙酸乙酯的混合溶剂、异丙醇、甲醇、丁酮、l-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、正丙醇、异丙醇、2-丙酮、4-甲基-2戊酮、吡啶、四氢呋喃、甲乙酮、甲苯、二甲苯、异丙苯或它们的混合物等等。
术语“水合物”是指一个或多个水分子与本发明的化合物所形成的缔合物。
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
术语“酯”通过式-OC(O)R或者-C(O)OR表示，其中R可为本发明所述的烷基、环烷基、烯基、环烯基、炔基、环炔基、芳基或者杂芳基。
术语“同位素标记化合物”是指本发明化合物用同位素标记。其除以下事实外与本发明所述的那些化合物相同：一个或多个原子被原子质量或质量数不同于天然常见原子质量或质量数的原子代替。还可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如2H，3H，13C，14C，15N，16O，17O，31P，32P，36S，18F和37Cl。
包含前述同位素标记和/或其他原子的其他同位素标记的本发明化合物以及所述化合物的药学上可接受的盐都包括在本发明范围内。同位素标记的本发明化合物，例如放射性同位素标记化合物，如3H和14C掺入到本发明化合物中可用于药物和/或底物组织分布分析。由于易于制备以及检测，氚代的，即，3H，以及碳-14，即14C，同位素特别优选。此外，用质量数较大的同位素，如氘，即2H取代，可提供一些更大的代谢稳定性的治疗上的优势， 例如增加的体内半衰期或减少的剂量需求。因此，在一些情形下可能是优选的。
此外，较重同位素特别是氘(即，2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式I至VI化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式I所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：Higuchietal.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Rocheetal.,Bioreversible Carriers in Drug Design,American Pharmaceutical Associationand Pergamon Press,1987；Rautioetal.,Prodrugs:Designand Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Heckeretal.,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345。
本文中可使用实线实楔形虚楔形描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键旨在表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键旨在表明存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。
当取代基的键显示为穿过环中连接两个原子的键(“漂浮键”)时，则这样的取代基可键连至该可取代的环中的任一成环原子，除非另有说明。在显示可用环成员携带可取代的氢原子的情况下，当该漂浮键键连至该可用环成员时，该可取代氢原子实质上已被取代(即，不存在)。
除非以其他方式明确指出，当通过从左向右书写的常规化学式描述取代基时，该取代基仅包括其从左向右书写的形式，分别与通式化合物结构中对应基团的左右两边的结构相连。
除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
术语“任选”、“任选地”或“任意、“任意地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。例如，“任选地被……取代”是指该取代可以存在或可以不存在。
术语“各自独立的”与“任意地”组合使用时，例如，“各自独立的任意地被…取代”表示具体选项之间互相不影响的被…或者不被…取代。
术语“不饱和”或“不饱和的”表示部分含有一个或多个不饱和度。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1- 6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“杂原子”是指O、S、N、P和Si，包括S，N和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NRT(像N-取代的吡咯烷基中的NRT，RT为N上的取代基)。在本发明涉及的化合物中，当含有多个杂原子时，其组成的化合物是符合有机化合物的共价规则和组成规则，即含多个杂原子的化合物应当是排除了不符合有机化合物共价规则和组成规则的化合物。
术语“杂环基”或“杂环”指任选被取代的部分或完全饱和的非芳香族环状基团，例如该基团是4至7元单环、7至12元二环或10至15元三环系统，该基团在至少一个含有碳原子的环中具有至少一个杂原子。含有杂原子的杂环基团的各环可以具有1、2或3个选自氮原子、氧原子和硫原子的杂原子，其中氮和硫杂原子还可以任选被氧化。杂环基团可以在杂原子或碳原子处连接。在一些实施方案中，所述杂环基选自：单环杂环基、双环杂环基、三环杂环基。4-8元杂环基表示环原子由4-8个碳原子和杂原子组成。所述杂环基包括稠环、螺环、桥环及其组合形式。在一些实施方案中，单环杂环基选自氧杂环丁基、吡咯烷基、四氢呋喃基、哌嗪基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜、1，3-二氧戊环和四氢-1，1-二氧代噻吩基、1，1，4-三氧代-1，2，5-噻二唑烷-2-基等。在一些实施方案中，双环杂环基选自7-氧杂双环[2.2.1]庚基。
术语“碳环”指具有例如3-10个(适合地具有3-8个，更适合地具有3-7、3-6、4-6或5-6个)环碳原子的饱和(即，“环烷基”和“亚环烷基”)或部分不饱和的(即在环内具有一个或多个双键(即，“环烯基”和“亚环烯基”)和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环丁烯基(环)、(亚)环戊烯基(环)、(亚)环己烯基(环)、(亚)环庚烯基(环)、(亚)环辛烯基(环)、(亚)环壬烯基(环)等。所述碳环包括稠环、螺环、桥环及其组合形式。
术语“环烷基”表示含有碳原子的，单价或多价的饱和或部分不饱和的单环，双环或三环的非芳香体系。C3-6环烷基表示环原子为3-6个碳的环烷基。在一些实施方案中，所述环烷基选自：单环环烷基、双环环烷基、三环环烷基。在一些实施方案中，单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基等。在一些实施方案中，双环环烷基包括但不限于龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6，6-二甲基二环[3.1.1]庚基、2，6，6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基等。在一些实施方案中，三环烃基包括金刚烷基等。
术语“杂芳基”或“杂芳环”表示含杂原子的单环、双环和三环的芳香性体系，术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。其中杂原子具有本发明所述的定义。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个原子组成的杂芳基，即5-10元杂芳基；杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个原子组成的杂芳基，即5-8元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-7个原子组成的杂芳基，即5-7元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个原子组成的杂芳基，即5-6元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选 自O，S和N的杂原子的5个原子组成的杂芳基，即5元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的6个原子组成的杂芳基，即6元杂芳基。
术语“芳基”或“芳环”表示单环、双环、三环的芳香性碳环体系。术语“芳基”可以和术语“芳环”或“芳香环”交换使用。6-10元芳基表示含有6-10个环原子的芳基基团。其实例包括但不限于：苯基，萘基等。
术语“氢”是指1H；“氘”是指2H。
术语“卤素”和“卤代”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“氨基”是指-NH2；
术语“羟基”是指-OH；
术语“氰基”是指-CN；
术语“硝基”是指-NO2；
术语“羧基”是指HO(C＝O)-；
术语“氧代”是指O＝，即当取代基为O＝时，O通过双键与被取代基团相连。
术语“烷基”或“烷基基团”，表示含碳原子、饱和的直链或支链烃基基团。在一实施方案中，烷基基团含有1-6个碳原子，即C1-6烷基；在又一实施方案中，烷基基团含有1-4个碳原子，即C1-4烷基；还在一实施方案中，烷基基团含有1-3个碳原子，即C1-3烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。
术语“亚烷基”表示含碳原子、饱和的直链或支链二价烃基。在一实施方案中，亚烷基基团含有1-6个碳原子，即C1-C6亚烷基；在又一实施方案中，亚烷基基团含有1-4个碳原子，即C1-C4亚烷基；还在一实施方案中，亚烷基基团含有1-3个碳原子，即C1-C3亚烷基。
术语“烯基”表示含有碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其包括“cis”和“tans”的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-6个碳原子，即C2-C6烯基；在又一实施方案中，烯基基团包含2-4个碳原子，即C2-C4烯基。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)，等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。在一实施方案中，烷氧基基团含有1-6个碳原子，即C1-6烷氧基；在另一实施方案中，烷氧基基团含有1-4个碳原子，即C1-4烷氧基；在又一实施方案中，烷氧基基团含有1-3个碳原子，即C1-3烷氧基。
术语“包含”与“包括”、“含有”或“特征在于”同义，其是包容性的或开放式的，并且不从药物(或在方法的情况为步骤)中排除另外的未提及的元素或成分。短语“由……组成”不包括未在药物(或在方法的情况为步骤)中指明的任何元素、步骤或成分。短语“基本上由……组成”是指指明的材料和那些不实质影响药物(或在方法的情况为步骤)的基本和新颖特性的材料。
像本文所描述的，取代基R由一个键连接到中心的环上形成的环体系(如下图所示)代表取代基R在A环上任何可取代或任何合理的位置进行取代。例如，式f代表A环上任何可能被取代的位置，如式f1-f4所示：
如本文所描述，取代基由一个键连接到中心的环上形成的环体系，如(Rx)n，代表n个取代基Rx可以在所在的环上任何可取代的位置进行取代。例如，式a代表苯环可被n个Rx取 代。
术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的，即各个取代之间是相互独立地。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。
除非特别说明，本文涉及马库什结构的取代或基团组合是那些稳定的或化学上可实现的取代或组合。
本文所用的术语“肿瘤”是指所有赘生性细胞生长和增殖，无论是恶性的还是良性的，以及所有癌前期和癌性细胞和组织。术语“癌症”、“癌性”、“细胞增殖性病症”、“增殖性病症”和“肿瘤”在本文中提及时并不相互排斥。
本文所用的术语“癌症”和“癌性”是指或描述受试者的生理状况，其通常以不受调节的细胞生长和/或增殖为特征。一些癌症由快速分裂的细胞组成，而另一些癌症则由分裂比正常细胞更慢的细胞组成。癌症实例的类型可以包括或排除例如癌(carcinoma)、淋巴瘤(例如，霍奇金和非霍奇金淋巴瘤)、母细胞瘤、肉瘤和白血病。此类癌症的更具体的实例可以包括或排除例如鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状癌、腹膜癌、肝细胞癌(hepatocellular cancer)、胃肠癌、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞癌(hepatoma)、乳腺癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)、白血病和其他淋巴细胞增生性病症，以及各种类型的头颈癌。
本发明化合物的描述
本发明提供了一种化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，在治疗或预防PTPN2相关的疾病或病症中发挥着积极的作用。
具体的说，本发明提供了具有式(I-1)或(I-2)所示的结构的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药；
其中，R1a、R1b、R1c、R1d、R2a、R2b、R3、R3a、R3b、X1、n、p、q具有本发明所述的定义。
在一些实施例中，本发明的化合物不是在一些实施例中，R1a和R1b各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基。
在一些实施例中，R1a和R1b各自独立地选自：氢、氘、卤素、羟基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基和卤代C1-4烷氧基。
在一些实施例中，R1a和R1b各自独立地选自：氢、氘、氟、氯、溴、羟基、甲基、乙基、甲氧基、乙氧基、三氟甲基、二氟甲基、2,2-二氟乙基、三氟甲氧基和2,2-二氟乙氧基。
在一些实施例中，R1a和R1b各自独立地选自：氢、氘、氟和羟基。
在一些实施例中，R1a和R1b均为氢。
在一些实施例中，R1c和R1d各自独立地选自：氢、氘、卤素、C1-6烷基和卤代C1-6烷基。
在一些实施例中，R1c和R1d各自独立地选自：氢、氘、卤素、C1-4烷基和卤代C1-4烷基。
在一些实施例中，R1c和R1d各自独立地选自：氢、氘、氟、氯、溴、甲基、乙基、三氟甲基和二氟甲基。
在一些实施例中，R1c和R1d各自独立地选自：氢、氘、氟。
在一些实施例中，R1c和R1d各自独立地选自：氢、氟。
在一些实施例中，R2a选自：氢、氘、羟基、氨基、C1-8烷基、C2-8烯基、C3-6环烷基、5-6元杂芳基、4-8元杂环基、-O-C1-8烷基、-O-C1-6亚烷基-C3-6环烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C(＝O)-N(Ra)-C1-8烷基、-O-C(＝O)-N(Ra)-苯基、-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-8烷基、–N(Ra)-C(＝O)-O-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-Si(Rc)3、-N(Ra)-(C＝N(Rb))-C1-8烷基、-N(Ra)-S(＝O)w-C1-8烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)(Rb)、-C1-6亚烷基-N(Ra)-C(＝O)-O-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-N(Ra)-C(＝O)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-O-C1-8烷基、-C1-6亚烷基-O-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-O-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-O-C1-6亚烷基-N(Ra)(Rb)、-S(＝O)w-C1-8烷基、-C(＝O)-N(Ra)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自：氢、氘、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基、5-6元杂芳基、4-8元杂环基、-O-C1-6烷基、-O-C1-4亚烷基-C3-6环烷基、-O-C1-4亚烷基-(4-8元杂环基)、-O-C(＝O)-N(Ra)-C1-6烷基、-O-C(＝O)-N(Ra)-苯基、-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-6烷基、–N(Ra)-C(＝O)-O-C1-8烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-Si(Rc)3、-N(Ra)-(C＝N(Rb))-C1-6烷基、-N(Ra)-S(＝O)w-C1-6烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基- N(Ra)(Rb)、-C1-4亚烷基-N(Ra)-C(＝O)-O-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-S(O)w-C1-6烷基、-C(＝O)-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自：-O-C1-6烷基、-O-C1-4亚烷基-C3-6环烷基、-O-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-N(Ra)(Rb)、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-S(＝O)w-C1-6烷基、-C(＝O)-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-6卤代烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基。
在一些实施例中，R2a选自以下基团：

在一些实施例中，R2a选自以下基团：

在一些实施例中，R2a选自以下基团：
在一些实施例中，R2a选自以下基团：
在一些实施例中，R2a选自以下基团：
在一些实施例中，R2a为
在一些实施例中，R2b选自：氢、氘、羟基、卤素、-N(Ra)(Rb)和-N(Ra)-N(Rb)-C(O)-苯基。
在一些实施例中，R2b选自：氢、氘、羟基、氟、氯和溴。
在一些实施例中，R2b选自：氢和氘。
在一些实施例中，R2b为氢。
在一些实施例中，R3、R3a和R3b各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1- 6烷基)、-N(C1-6烷基)(C1-6烷基)。
在一些实施例中，R3、R3a和R3b各自独立地选自：氢、氘、卤素、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1- 4烷基)、-N(C1-4烷基)(C1-4烷基)。
在一些实施例中，R3、R3a和R3b各自独立地选自：氢、氘、氟、氯、溴、羟基、C1-4烷基、C1-4卤代烷基。
在一些实施例中，R3、R3a和R3b各自独立地选自：氢、氘、氟、氯、溴、羟基、甲基、乙基、三氟甲基、二氟甲基。
在一些实施例中，R3、R3a和R3b各自独立地选自：氢、氘、氟和羟基。
在一些实施例中，R3、R3a和R3b各自独立地选自：氢、氟和羟基。
在一些实施例中，X1选自O、S、NRf和C(Re)(Rd)。
在一些实施例中，Ra和Rb各自独立地选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代。
在一些实施例中，Ra和Rb各自独立地选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代。
在一些实施例中，Ra和Rb各自独立地选自：氢、甲基。
在一些实施例中，Rc选自：羟基、C1-6烷基和苯基。
在一些实施例中，Rc选自：羟基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基和苯基。
在一些实施例中，Re和Rd各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；任选地，Re和R3a，与它们相连的原子一起形成3-7元碳环；或，Re和R2b，与它们相连的原子一起形成3-7元碳环。
在一些实施例中，Re和Rd各自独立地选自：氢、氘、氟、氯、溴、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1- 4烷基)、-N(C1-4烷基)(C1-4烷基)；任选地，Re和R3a，与它们相连的原子一起形成3-6元碳环；或，Re和R2b，与它们相连的原子一起形成3-6元碳环。
在一些实施例中，Rf选自：氢、C1-6烷基、C1-6卤代烷基；任选地，Rf和R3a与和它们相连的原子一起形成3-7元杂环，或，Rf和R2b与和它们相连的原子一起形成3-7元杂环。
在一些实施例中，Rf选自：氢、C1-4烷基、C1-4卤代烷基；任选地，Rf和R3a与和它们相连的原子一起形成3-6元杂环，或，Rf和R2b与和它们相连的原子一起形成3-6元杂环。
在一些实施例中，Rg各自独立地选自：氢、氘、卤素、羟基、氰基、硝基、氧代、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基。
在一些实施例中，Rg各自独立地选自：氢、氘、氟、氯、溴、羟基、氰基、硝基、氧代、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Rg各自独立地选自：氢、氘、氟、氯、溴、羟基、氰基、硝基、氧代、氨基、-NH-CH3、-N(CH3)(CH3)、甲基、乙基、三氟甲基和二氟甲基。
在一些实施例中，Rh选自：氢、氘、C1-6烷基和C1-6卤代烷基。
在一些实施例中，Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Rh选自：氢、氘、甲基、三氟甲基、二氟甲基和2,2-二氟乙基。
在一些实施例中，Rh选自：氢、甲基、三氟甲基、二氟甲基和2,2-二氟乙基。
在一些实施例中，n选自：0或1。
在一些实施例中，p选自：0、1、2或3。
在一些实施例中，q选自：0、1、2、3或4。
在一些实施例中，w选自：1或2。
在一些实施例中，式(I-1)所示的结构的化合物不是
在一些实施例中，R1a和R1b各自独立地选自氢和氘，优选R1a和R1b选自氢。
在一些实施例中，R1c和R1d各自独立地选自氢、氘、卤素，优选R1c和R1d各自独立地选自氢和卤素，更优选R1c和R1d其中一者选自氢，另一者选自卤素。
在一些实施例中，p选自0或1，优选p选自0。
在一些实施例中，n选自0。
在一些实施例中，R3选自氢、氘、卤素，优选R3选自氢和卤素，更优选R3选自氢。
在一些实施例中，q选自0、1或2，优选q选自0。
在一些实施例中，X1选自O、S、NRf和C(Re)(Rd)，优选X1选自C(Re)(Rd)。
在一些实施例中，Re和Rd各自独立地选自：氢、氘、卤素、羟基或，Re和R2b，与它们相连的原子一起形成3-7元碳环，优选Re和Rd各自独立地选自：氢、卤素、羟基或，Re和R2b，与它们相连的原子一起形成3-6元碳环(例如C3-6环烷基)，更优选Re和Rd选自氢。
在一些实施例中，R2b选自氢或，R2b和Re，与它们相连的原子一起形成3-6元碳环(例如C3-6环烷基)，优选R2b选自氢。
在一些实施例中，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C1-6亚烷基-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-O-C1-8烷基、-C1-6亚烷基-O-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-O-C1-6亚烷基-(4-8元杂环基)、-C(＝O)-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C(＝O)-C1-8烷基、-C1-6亚烷基-N(Ra)(Rb)、-C1-6亚烷基-O-C1-6亚烷基-N(Ra)(Rb)、-N(Ra)-C(＝O)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)、-O-C1-4亚烷基-C3-6环烷基、-N(Ra)-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)(Rb)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-N(Ra)-C(＝O)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可 被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-O-C1-8烷基、-C1-6亚烷基-O-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-O-C1-6亚烷基-(4-8元杂环基)、-C(＝O)-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C(＝O)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-N(Ra)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，Rg各自独立地选自：氢、氘、卤素、羟基、氰基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基。
在一些实施例中，Rg各自独立地选自：氢、氘、卤素、羟基、氰基、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Rh选自：氢、氘、C1-6烷基和C1-6卤代烷基。
在一些实施例中，Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Ra和Rb各自独立地选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个卤素取代。
在一些实施例中，Ra和Rb各自独立地选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个卤素取代。
在一些实施例中，所述化合物具有式(II-0)所示的结构：
在一些实施例中，所述化合物具有式(II-1)或(II-2)所示的结构：
其中，R1a、R1b、R1c、R1d、R2b、R2c、R2d、R2e、R2f、R2g、R3、R3a、R3b、X1、X2、n、p、q具有本发明所述的定义。
在一些实施例中，R2c、R2d、R2e和R2f各自独立地选自：氢、氘、氟、氯、氰基、羟基、C1-6烷基和卤代C1-6烷基；任选地，R2c和R2d，或R2e和R2f形成氧代。
在一些实施例中，R2c、R2d、R2e和R2f各自独立地选自：氢、氘、氟、氯、氰基、羟基、C1-4烷基和卤代C1-4烷基；任选地，R2c和R2d，或R2e和R2f形成氧代。
在一些实施例中，R2c、R2d、R2e和R2f各自独立地选自：氢、氘、氟、氯、氰基、羟基、甲基、乙基、三氟甲基；任选地，R2c和R2d，或R2e和R2f形成氧代。
在一些实施例中，R2g选自：氢、C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；所述的C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基各自独立地任意地被1个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代。
在一些实施例中，R2g选自：氢、C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；所述的C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基各自独立地任意地被1个或多个选自氟、氯、溴、羟基、氰基、甲基、三氟甲基、二氟甲基、2,2-二氟乙基取代基取代。
在一些实施例中，R2g选自：氢、C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；所述的C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基各自独立地任意地被1个或多个选自氟、氯、溴、羟基、氰基、甲基、三氟甲基、二氟甲基、2,2-二氟乙基取代基取代。
在一些实施例中，R2g选自：氢、C1-4烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基；所述C1-4烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基各自独立地任选被1个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代。
在一些实施例中，R2g选自：氢、C1-4烷基、C3-6环烷基、4-7元杂环基，所述C1-4烷 基、C3-6环烷基、4-7元杂环基各自独立地任选被1个或多个选自卤素的取代基取代。
在一些实施例中，R2g选自：氢、甲基、三氟甲基、二氟甲基、叔丁基、-CH2OH、-N(CH3)2或以下基团：
在一些实施例中，R2g选自：氢、甲基、三氟甲基、二氟甲基、叔丁基、-N(CH3)2或以下基团：
在一些实施例中，R2g选自：氢、甲基、叔丁基、三氟甲基、环丙基、环戊基、环己基、四氢吡喃-2-基。
在一些实施例中，X2为NH或O。
在一些实施例中，X2为NH。
在一些实施例中，所述化合物具有式(III-0)所示的结构：
在一些实施例中，所述化合物具有式(III-1)或(III-2)所示的结构：
其中，R1c、R1d、R2b、R2c、R2d、R2g、R3、X1、X2、p、q具有本发明所述的定义。
在一些实施例中，所述化合物具有式(IV-1)或(IV-2)所示的结构：
其中，R1c、R1d、R2b、R2c、R2h、R3、X1、p、q具有本发明所述的定义。
在一些实施例中，R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-(5-6元杂芳基)、-C1- 4亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2，所述C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2各自独立地任选地被一个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代。
在一些实施例中，R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-C1-2亚烷基-(4-7元杂环基)、-C1-2亚烷基-(5-6元杂芳基)、-C1- 2亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2，所述C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-C1-2亚烷基-(4-7元杂环基)、-C1-2亚烷基-(5-6元杂芳基)、-C1-2亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2各自独立地任选地被一个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代。在一些实施例中，R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-N(C1-6烷基)2，所述C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-N(C1-6烷基)2各自独立地任选地被一个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代。
在一些实施例中，R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基；所述C1-6烷基、C3- 6环烷基、4-7元杂环基各自独立地任选地被一个或多个卤素取代。
在一些实施例中，R2h选自：C1-6烷基、C1-6卤代烷基、C3-6环烷基。
在一些实施例中，R2h选自：甲基、乙基、异丙基、叔丁基、二氟甲基、三氟甲基、2-(1,1,1-三氟甲基)-丙-2-基、环丙基、环丁基、环戊基、环己基、苯基、2-羟基-丙-2-基、2-氰基-丙-2-基、-N(CH3)2、
在一些实施例中，R2h选自：甲基、乙基、异丙基、叔丁基、二氟甲基、三氟甲基、2-(1,1,1-三氟甲基)-丙-2-基、环丙基、环丁基、环戊基和环己基。
在一些实施例中，R2h选自：异丙基、叔丁基、三氟甲基、2-(1,1,1-三氟甲基)-丙-2-基、环丙基、环戊基、环己基、四氢吡喃-2-基。
在一些实施例中，所述化合物具有式(V)所示的结构：
其中，R1a、R1b、R2a、R2b、R3、q具有本发明所述的定义。
在一些实施例中，R1a和R1b各自独立地选自：氢、氘、氟和羟基。
在一些实施例中，R1a和R1b为氢。
在一些实施例中，R2a选自：-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-8烷基、–N(Ra)-C(＝O)-O-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-Si(Rc)3、-N(Ra)-(C＝N(Rb))-C1-8烷基、-N(Ra)-S(＝O)w-C1-8烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-C3-6环烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C(＝O)-N(Ra)-C1-8烷基、-O-C(＝O)-N(Ra)-苯基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；Rg各自独立地选自：氢、氘、卤素、羟基、氰基、硝基、氧代、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基；w选自：1或2；Ra和Rb各自独立地选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-6烷基、–N(Ra)-C(＝O)-O-C1-8烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-Si(Rc)3、-N(Ra)-(C＝N(Rb))-C1-6烷基、-N(Ra)-S(＝O)w-C1-6烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-C3-6环烷基、-O-C1-4亚烷基-(4-8元杂环基)、-O-C(＝O)-N(Ra)-C1-6烷基、-O-C(＝O)-N(Ra)-苯基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；Rg各自独立地选自：氢、氘、氟、氯、溴、羟基、 氰基、硝基、氧代、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基；w选自：1或2；Ra和Rb各自独立地选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代。
在一些实施例中，R2a选自：-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-8元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；Rg各自独立地选自：氢、氟、羟基、氰基、-N(CH3)(CH3)、甲基、乙基、三氟甲基和二氟甲基；Ra为氢。
在一些实施例中，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C1-6亚烷基-C3-6环烷基、-N(Ra)-(4-8元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)、-O-C1-4亚烷基-C3-6环烷基、-N(Ra)-(4-7元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，Rg各自独立地选自：氢、氘、卤素、羟基、氰基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基。
在一些实施例中，Rg各自独立地选自：氢、氘、氟、氯、溴、羟基、氰基、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Rg各自独立地选自：氢、氟、羟基、氰基、-N(CH3)2、甲基、乙基、三氟甲基和二氟甲基。
在一些实施例中，Rh选自：氢、氘、C1-6烷基和C1-6卤代烷基。
在一些实施例中，Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Rh选自：氢、氘、甲基、三氟甲基、二氟甲基和2,2-二氟乙基。
在一些实施例中，Ra选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代。
在一些实施例中，Ra选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代。
在一些实施例中，Ra为氢。
在一些实施例中，R2b选自：氢、氘、羟基、氟、氯和溴。
在一些实施例中，R2b为氢。
在一些实施例中，R3选自：氢、氘、卤素、羟基。
在一些实施例中，R3选自：氢、氟。
在一些实施例中，q选自：0、1、2。
在一些实施例中，所述化合物具有式(V-1)所示的结构：
其中，R2c和R2d各自独立地选自：氢、氘、氟、氯、氰基、羟基、C1-6烷基和卤代C1-6烷基；任选地，R2c和R2d形成氧代；
R2g选自：氢、C1-4烷基、C3-6环烷基、4-8元杂环基、苯基、5-6元杂芳基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；所述的C1-4烷基、C3-6环烷基、4-8元杂环基、苯基、5-6元杂芳基各自独立地任意地被1个或多个选自卤素、羟基、氰基、C1-4烷基、卤代C1-4烷基的取代基取代；
X2为NH或O。
在一些实施例中，X2为NH。
在一些实施例中，R2c和R2d各自独立地选自：氢、氟、氰基、羟基、C1-3烷基和卤代C1-3烷基。
在一些实施例中，R2c和R2d各自独立地选自：氢、氟、氰基、羟基、甲基、乙基、三氟甲基。
在一些实施例中，R2g选自：氢、C1-3烷基、C3-6环烷基、4-8元杂环基、苯基、5-6元杂芳基(例如吡唑基、异噁唑基、三唑基、噁二唑基)；所述的C1-3烷基、C3-6环烷基、4-8元杂环基、苯基、5-6元杂芳基各自独立地任意地被1个或多个选自卤素、羟基、氰基、C1-3烷基、卤代C1-3烷基的取代基取代。
在一些实施例中，R2g选自：氢、C1-3烷基、C3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基(例如吡唑基、异噁唑基、三唑基、噁二唑基)；所述的C1-3烷基、C3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基各自独立地任意地被1个或多个选自卤素、羟基、氰基、C1-3烷基、卤代C1-3烷基的取代基取代。
在一些实施例中，R2g选自：氢、F、甲基、乙基、-CH(CH3)2、-CH2OH、二氟甲基、 三氟甲基、-CH2-CHF2、环丙基、环丁基、环戊基、环己基、
在一些实施例中，R2c和R2d为氢，R2g为二氟甲基。
在一些实施例中，所述化合物具有式(VI-0)所示的结构：
在一些实施例中，R2a选自-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)(Rb)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-N(Ra)-C(＝O)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-C1-2亚烷基-N(Ra)-C1-6烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-2亚烷基-O-C1-6烷基、-C1-2亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-2亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-2亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-2亚烷基-O-C1-4亚烷基-N(Ra)(Rb)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-C1-2亚烷基-N(Ra)-C1-6烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-苯基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，R2a选自-C1-2亚烷基-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代。
在一些实施例中，Rg各自独立地选自：氢、氘、卤素(例如氟、氯、溴)、羟基、氰基、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基。
在一些实施例中，Ra和Rb各自独立地选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个卤素取代。
在一些实施例中，所述化合物具有式(VI-1)所示的结构：
在一些实施例中，所述化合物具有如下所示的结构：


在一些实施例中，所述化合物具有如下所示的结构：


在一些实施例中，所述化合物具有如下所示的结构：

本发明涵盖对各个实施方案进行任意组合所得的化合物。
药物组合物和施用方法
本发明涉及一种药物组合物，其包含本发明所述的化合物或其对映异构体、非对映异 构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物标记化合物或前药；和药学上可接受的载体。
术语“药物组合物”表示一种或多种本文所述化合物或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体、稀释剂，更进一步的还可包含赋形剂、粘合剂、填充剂等辅料，以及抗糖尿病试剂、抗高血糖试剂、抗肥胖症试剂、抗高血压试剂、抗血小板试剂、抗动脉粥样硬化试剂或者降脂试剂等附加治疗剂。药物组合物的目的是促进化合物对生物体的给药。
如本文所用，术语“药学上可接受的载体”是指可用于制备或使用药物组合物的物质，并且包括例如合适的稀释剂、溶剂、分散介质、表面活性剂、抗氧化剂、防腐剂、等渗剂、缓冲剂、乳化剂、吸收延迟剂、盐、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、润湿剂、甜味剂、矫味剂、染料，以及它们的组合，如本领域技术人员已知的(参见例如RemingtonTheScienceandPracticeofPharmacy[雷明顿：药物科学与实践]，第22版，PharmaceuticalPress[药物出版社]，2013年，第1049至1070页)。
本发明还涉及包含作为活性成分的具有式I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，或其药物组合物，其可尤其用于治疗肿瘤性疾病，特别是癌症，如本文所述。可以将组合物配制用于非肠胃外施用，例如鼻、口腔、直肠、肺、阴道、舌下、局部、透皮、眼，或尤其用于口服施用，例如以口服固体剂型的形式，例如颗粒剂、丸剂、粉剂、片剂、薄膜衣片剂或糖衣片剂、泡腾片剂、硬胶囊剂和软胶囊剂或羟丙基甲基纤维素(HPMC)胶囊剂(适用地进行包衣)、口腔崩解片剂、口服溶液、脂质乳剂或悬浮液，或用于肠胃外施用，比如静脉内、肌内或皮下、鞘内、皮内或硬膜外施用至哺乳动物，特别是人，例如以溶液、脂质乳剂或含有微粒或纳米颗粒的悬浮液的形式。这些组合物可以包含单独的活性成分，或优选地，连同药学上可接受的载体。
具有式I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药可以用药学惰性的无机或有机赋形剂加工，以用于生产口服固体剂型，例如颗粒剂、丸剂、粉剂、片剂、薄膜衣片剂或糖衣片剂、泡腾片剂、硬胶囊剂或HPMC胶囊剂或口腔崩解片剂。填充剂例如乳糖、纤维素、甘露糖醇、山梨醇、磷酸钙、淀粉或其衍生物，粘合剂例如纤维素、淀粉、聚乙烯吡咯烷酮或其衍生物，助流剂例如滑石、硬脂酸或其盐，流动剂例如煅制二氧化硅，可以用作这类赋形剂，用于配制和制造口服固体剂型，例如颗粒剂、丸剂、粉剂、片剂、薄膜衣片剂或糖衣片剂、泡腾片剂、硬胶囊剂或HPMC胶囊剂或口腔崩解片剂。软胶囊剂的合适赋形剂是例如植物油、蜡、脂肪、半固体和液体多元醇等。
用于制造口服溶液、脂质乳剂或悬浮液的合适的赋形剂例如是水、醇、多元醇、蔗糖、转化糖、葡萄糖等。
用于肠胃外配制品的合适的赋形剂例如是水、醇、多元醇、甘油、植物油、卵磷脂、表面活性剂等。
此外，药物制剂可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。药物制剂还可以含有其他治疗上有价值的物质。
剂量可以在宽范围内变化，并且当然，在每种特定情况下都符合个体要求。通常，在口服施用的情况下，每日约1至1000mg具有通式I的化合物/人的剂量应该是适当的，尽管也可以在必要时超出上述下限或上限。
具有式I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2所示化合物还可以与一种或多种其他具有药理学活性的化合物组合使用，这些其他化合物也有效对抗同一疾病，优选使用不同作用方式，或者减少或预防具有式I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2所示化合物的可能的不希望的副作用。组合伴侣可以在这种治疗中例如通过将它们掺入单一药物配制品中而同时施用，或通过施用两种或更多种不同的剂型(每种剂型含有一种或多于一种组合伴侣)而连续施用。
术语“治疗有效量”的本发明化合物是指将引起受试者的生物或医学应答(例如，酶或蛋白活性的减小或抑制，或改善症状、缓解病症、减缓或延迟疾病进展或预防疾病等)的本发明化合物的量。在一个非限制性实施例中，术语“治疗有效量”是指本发明化合物的如下量，所述量当被施用至受试者时有效地至少部分缓解、抑制、预防和/或改善涉及PTPN2相关的任何疾病、病症或状况。
如本文在治疗疾病或障碍的上下文中所使用的术语“治疗(treatment或treating)”总体上涉及人或动物(例如在兽医应用)的治疗和疗法，其中获得一些希望的治疗效果，例如，抑制疾病或障碍的进展，并且包括降低进展的速率、停止进展的速率、缓解疾病或障碍的症状、改善疾病或障碍、以及治愈疾病或障碍。也包括作为预防措施的治疗(即，预防)。例如，用于尚未发展出该疾病或障碍、但处于发展该疾病或障碍风险的患者被术语“治疗”涵盖。例如，治疗包括癌症的预防、降低癌症发病率、缓解癌症症状等。
在一些实施方案中，本发明提供了I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2所示化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，或其药物组合物，其用于治疗或预防与PTPN2相关的疾病或病症。
在一些实施方案中，本发明提供了I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2所示化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，或其药物组合物，在制备用于治疗、或预防PTPN2的相关的疾病或病症的药物中的用途。
在一些实施方案中，本发明提供了一种治疗或预防PTPN2的相关疾病或病症的方法，该方法包括施用治疗有效量的I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2所示化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，或其药物组合物。
在一些实施方案中，PTPN2的相关疾病或病症包括癌症、2型糖尿病、代谢综合征、肥胖症或代谢疾病。
在一些实施方案中，所述癌症包括：癌瘤、肉瘤、腺癌、淋巴瘤、白血病、黑素瘤。
如本文所用，术语“癌症”是指在哺乳动物中发现的所有类型的癌症、赘瘤或恶性肿瘤，包括白血病、淋巴瘤、癌瘤和肉瘤。可以用本文提供的化合物、药物组合物或方法治疗的示例性癌症包括淋巴瘤、肉瘤、膀胱癌、骨癌、脑肿瘤、宫颈癌、结肠癌、食道癌、胃癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、白血病、前列腺癌、乳腺癌(例如ER阳性、ER阴性、化疗抗性、赫赛汀(herceptin)抗性、HER2阳性、阿霉素(doxorubicin)抗性、它莫西芬抗性、导管癌、小叶癌、原发性、转移性)、卵巢癌、胰腺癌、肝癌(例如肝细胞癌)、肺癌(例如非小细胞肺癌、鳞状细胞肺癌、腺癌、大细胞肺癌、小细胞肺癌、类癌瘤、肉瘤)、多形性成胶质细胞瘤、神经胶质瘤或黑素瘤。其他实例包括甲状腺癌、内分泌系统癌、脑癌、乳腺癌、宫颈癌、结肠癌、头颈癌、肝癌、肾癌、肺癌、非小细胞肺癌、黑素瘤、间皮瘤、卵巢癌、肉瘤、胃癌、子宫癌或髓母细胞瘤、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、成神经细胞瘤、神经胶质瘤、多形性成胶质细胞瘤、卵巢癌、横纹肌肉瘤、原发性血 小板增多症、原发性巨球蛋白血病、原发性脑肿瘤、癌症、恶性胰脏胰岛素瘤、恶性类癌瘤、膀胱癌、恶变前皮肤病变、睾丸癌、淋巴瘤、甲状腺癌、成神经细胞瘤、食道癌、生殖泌尿道癌、恶性高钙血症、子宫内膜癌、肾上腺皮层癌、内分泌或外分泌胰脏赘瘤、髓样甲状腺癌、髓样甲状腺癌瘤、黑素瘤、结肠直肠癌、乳头状甲状腺癌、肝细胞癌、柏哲德氏乳头病(Paget's Disease of the Nipple)、叶状肿瘤、小叶癌瘤、导管癌瘤、胰脏星形细胞癌、肝脏星形细胞癌或前列腺癌。
术语“癌瘤”是指倾向于浸润周围组织并引起转移的由上皮细胞组成的恶性新生物。可以用本文提供的化合物、药物组合物或方法治疗的示例性癌瘤包括例如甲状腺髓样癌、家族性甲状腺髓样癌、腺癌、腺泡癌、腺囊性癌、腺样囊性癌、腺瘤癌、肾上腺皮质癌、肺泡癌、肺泡细胞癌、基底细胞癌、基底细胞癌、基底样癌、基底鳞状细胞癌、支气管肺泡癌、支气管癌、支气管原性癌、脑状癌、胆管细胞癌、绒毛膜癌、胶样癌、粉刺癌、子宫体癌、筛状癌、铠甲状癌、皮肤癌、柱状癌、柱状细胞癌、管癌、管状癌、硬膜癌、胚胎癌、脑样癌、表皮样癌、上皮腺癌、外生性癌、溃疡前癌、纤维状癌、胶样癌、胶状癌、巨细胞癌、巨细胞癌、腺癌、粒层细胞癌、毛发基质癌、血样癌、肝细胞癌、许特莱氏细胞癌(Hurthle cell carcinoma)、透明癌、肾上腺样癌、婴儿胚胎癌、原位癌、表皮内癌、上皮内癌、克罗姆佩切氏癌(Krompecher'scarcinoma)、库尔奇基氏细胞癌(Kulchitzky-cell carcinoma)、大细胞癌、扁豆状癌、豆状癌、脂肪瘤性癌、小叶癌、淋巴上皮癌、髓质癌、髓样癌、黑素癌、黑痣癌、粘液样癌、粘液癌、粘液细胞癌、粘液表皮样癌、粘液性癌、粘液腺癌、粘液瘤样癌、鼻咽癌、燕麦细胞癌、骨化性癌、骨样癌、乳头状癌、门静脉周癌、侵袭前癌、蜂状上皮细胞癌、糜烂性癌、肾脏肾细胞癌、储备细胞癌、肉瘤癌、施奈德氏癌、硬化癌、阴囊癌、印戒细胞癌、单纯性癌、小细胞癌、马铃薯状癌、球状细胞癌、梭形细胞癌、海绵状癌、鳞状癌、鳞状细胞癌、线状癌、毛细血管扩张性癌、毛细血管扩张癌、移行细胞癌、结节性癌、管状癌、结节性癌、疣状癌或绒毛状癌。
术语“肉瘤”一般是指由胚胎结缔组织样物质组成的肿瘤，而且一般由包埋在纤丝状或同质物质中的紧密堆积细胞构成。可以用本文提供的化合物、药物组合物或方法治疗的肉瘤包括软骨肉瘤、纤维肉瘤、淋巴肉瘤、黑素肉瘤、粘液肉瘤、骨肉瘤、阿贝美西氏肉瘤(Abemethy'ssarcoma)、脂肉瘤、脂肪肉瘤、肺泡状软部肉瘤、釉母细胞肉瘤、葡萄样肉瘤、绿色肉瘤、绒膜癌瘤、胚胎性肉瘤、威尔姆斯瘤肉瘤(Wilms'tumor sarcoma)、子宫内膜肉瘤、基质肉瘤、尤因氏肉瘤(Ewing'ssarcoma)、筋膜肉瘤、成纤维细胞肉瘤、巨细胞肉瘤、粒细胞肉瘤、霍奇金氏肉瘤、自发多发性有色出血性肉瘤、B细胞性成免疫细胞肉瘤、淋巴瘤、T细胞性成免疫细胞肉瘤、詹森氏肉瘤(Jensen's sarcoma)、卡波西氏肉瘤(Kaposi's sarcoma)、枯氏细胞肉瘤(Kupffer cell sarcoma)、血管肉瘤、白血病性肉瘤、恶性间叶瘤肉瘤、骨膜外肉瘤、网状细胞肉瘤、劳斯氏肉瘤(Rous sarcoma)、浆液囊性肉瘤、滑膜肉瘤或毛细管扩张肉瘤。
术语“白血病”广义上是指血液形成器官的渐进性恶性病，而且一般以血液和骨髓中的白细胞及其前驱细胞的畸态增殖和发育为特征。白血病在临床上一般基于以下各项进行分类：(1)疾病的持续时间和特征：急性或慢性；(2)所涉及的细胞类型：骨髓(骨髓原性)、淋巴(淋巴原性)或单核细胞性；以及(3)血液中的异常细胞数目增加或不增加：白血性或非白血性(亚白血性)。可以用本文提供的化合物、药物组合物或方法治疗的示例性白血病包括例如急性非淋巴细胞白血病、慢性淋巴细胞性白血病、急性粒细胞性白血病、慢性粒细胞性白血病、急性前骨髓细胞性白血病、成人T细胞白血病、非白血性白血病、白细胞性白血病、嗜碱性白血病、母细胞白血病、牛白血病、慢性髓细胞性白血病、皮肤白血病、胚胎性白血病、嗜酸性粒细胞性白血病、格罗斯氏白血病(Gross'leukemia)、毛细胞性白血病、成血细胞性白血病、血胚细胞性白血病、组织细胞性白血病、干细胞性白血病、急性单核细胞性白血病、白细胞减少性白血病、淋巴性白血病、成淋巴细胞性白血病、淋巴细胞性 白血病、淋巴原性白血病、淋巴细胞样白血病、淋巴肉瘤细胞性白血病、肥大细胞性白血病、巨核细胞性白血病、成小髓细胞性白血病、单核细胞性白血病、成髓细胞性白血病、骨髓性白血症、骨髓粒细胞性白血病、骨髓单核细胞性白血病、内格利氏白血病(Naegeli leukemia)、浆细胞性白血病、多发性骨髓瘤、浆细胞性白血病、前髓细胞性白血病、里德尔细胞性白血病(Rieder cell leukemia)、希林氏白血病(Schilling's leukemia)、干细胞性白血病、亚白血性白血病或未分化细胞性白血病。
术语“黑素瘤”被视为意指由皮肤和其他器官的黑素细胞系统产生的肿瘤。可以用本文提供的化合物、药物组合物或方法治疗的黑素瘤包括例如肢端雀斑样痣黑素瘤、无黑素性黑素瘤、良性青少年性黑素瘤、克劳德曼氏黑素瘤(Cloudman's melanoma)、S91黑素瘤、哈-帕二氏黑素瘤(Harding-Passey melanoma)、青少年性黑素瘤、恶性雀斑样痣黑素瘤、恶性黑素瘤、结节性黑素瘤、甲下黑素瘤或浅表扩散性黑素瘤。
在一些实施方案中，所述癌症包括：实体和淋巴癌、肾癌、乳腺癌、肺癌、膀胱癌、结肠癌、卵巢癌、前列腺癌、胰腺癌、胃癌、脑癌、头颈癌、皮肤癌、子宫癌、睾丸癌、神经胶质瘤、食道癌、肝癌(包括肝肿瘤)、淋巴瘤，包括B急性成淋巴细胞性淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin's lymphomas)(例如伯基特氏淋巴瘤(Burkitt's lymphomas)、小细胞淋巴瘤和大细胞淋巴瘤)、霍奇金氏淋巴瘤、白血病(包括AML、ALL和CML)和/或多发性骨髓瘤。
在一些实施方案中，所述癌症包括肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、前列腺癌、转移性癌症或癌瘤。
合成方法
具有式I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2所示化合物可以通过下面给出的方法、通过下面实验部分给出的方法或通过类似方法合成。本文所述的方案不旨在呈现用于制备具有式I-1、I-2、II-1、II-2、III-1、III-2、IV-1、IV-2所示化合物的方法的详尽列表；相反，熟练的化学家知道的其他技术也可以用于化合物合成。
化合物的结构是通过核磁共振(1H-NMR、13C-NMR或/和19F-NMR)来确定的。1H-NMR、13C-NMR、19F-NMR化学位移(δ)以百万分之一(ppm)的单位给出。1H-NMR、13C-NMR、19F-NMR的测定是用BrukerUltrashield-400核磁共振谱仪和BrukerAvanceIIIHD600核磁共振谱仪，测定溶剂为氘代氯仿(CDCl3)、氘代甲醇(CD3OD或MeOH-d4)或者氘代二甲基亚砜(DMSO-d6)。用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet,单峰)，d(doublet,双峰)，t(triplet,三重峰)，m(multiplet,多重峰)，br(broadened,宽峰)，dd(doubletofdoublets,双二重峰)，dt(doubletoftriplets,双三重峰)，td(tripletofdoublets,三双重峰)，brs(broadenedsinglet,宽单峰)。偶合常数J，单位用赫兹(Hz)表示。
液质联用色谱(LC-MS)是使用Agilent1260质谱仪检测的。HPLC的测定使用Agilent1100高压色谱仪(Microsorb5micronC18100x3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
有机合成领域的技术人员应理解，最佳反应条件可随所用的特定反应物或溶剂而变化，但这些条件可通过常规优化程序确定。在一些情况下，可以改变进行以下反应方案和/或反 应步骤的顺序以促进反应或避免形成不需要的副产物。此外，存在于分子各个位置的官能团必须与所提出的试剂和反应相容。对与反应条件相容的取代基的这种限制对于本领域技术人员来说是显而易见的，并且然后必须使用替代方法。此外，在本文提到的一些反应中，可能需要或希望保护化合物中的任何敏感基团，并且假定必要时这样的保护基团(PG)在适当的位置。常规保护基团可根据本领域熟知的标准实践使用(关于说明，参见GreeneT.W,WutsP.G.M,ProtectiveGroupsinOrganicSynthesis[有机合成中的保护基团],第5版,出版商:约翰·威利父子出版公司(JohnWiley&Sons),2014)。可以使用本领域熟知的常规技术在合成中的任何方便的阶段除去保护基团，或者可以在后续反应步骤或后处理中除去保护基团。
下列简写词的使用贯穿本发明
LCMS：液质联用色谱
M、mol/L：摩尔每升
ml、mL：毫升
g：克
mmol：毫摩尔
℃：摄氏度
下面提供实施例可以帮助理解本发明。但应理解，这些实施例和附图仅用于说明本发明，但不构成任何限制。本发明的实际保护范围在权利要求书中进行阐述。应理解，在不脱离本发明精神的情况下，可以进行任何修改和改变。
制备实施例
实施例1：化合物1、2和3的制备

步骤1：在0℃下向化合物1-1(15.7g,71.61mmol)和咪唑(14.7g,215.92mmol)的二氯甲烷(200mL)的溶液中加入叔丁基二甲基氯硅烷(11.3g,74.97mmol)。反应液在0℃下搅拌2小时。将反应液用水(200mL)稀释，并用二氯甲烷(100mL x3)萃取。合并有机相分别用1M稀盐酸(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩得到化合物1-2。1H NMR(400MHz,CDCl3)δ5.32(d,J＝8.4Hz,1H),4.38-4.30(m,1H),4.03(dd,J＝2.8,10.0Hz,1H),3.81(dd,J＝2.8,10.0Hz,1H),3.73(s,3H),1.45(s,9H),0.86(s,9H),0.02(d,J＝5.2Hz,6H)。
步骤2：在0℃下，向化合物1-2(27g,72.86mmol)和氯化钙(16.2g,145.97mmol)的四氢呋喃(200mL)和乙醇(100mL)的混合物中加入硼氢化钠(8.3g,219.40mmol)。混合物于15℃下搅拌12小时。将反应液缓慢倒入水(300mL)中，并用乙酸乙酯(200mL)稀释。该混合物经硅藻土过滤，滤液用乙酸乙酯(200mL x3)萃取，合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩得到化合物1-3。1H NMR(400MHz,CDCl3)δ5.13(s,1H),3.91–3.73(m,3H),3.73–3.56(m,2H),2.69(s,1H),1.45(s,9H),0.90(s,9H),0.07(s,6H)。
步骤3：在氮气保护下，在0℃下，向咪唑(19.5g,286.43mmol)和三乙胺(21.7mL,156.55mmol)的二氯甲烷(100mL)溶液中逐滴加入二氯亚砜(6.7mL,92.37mmol)。混合物于0℃下搅拌30分钟后，滴入化合物1-3(21.7g,71.03mmol)的二氯甲烷(100mL)溶液。反应液在0℃下搅拌1小时。反应液用水(200mL)稀释后，并用乙酸乙酯(100mL x3)萃取。合并有机相用食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩得到化合物1-4，直接用于下一步反应。
步骤4：向化合物1-4(25g,71.12mmol)的二氯甲烷(120mL)和水(120mL)的溶液中加入三氯化钌(0.93g,3.56mmol)和高碘酸钠(22.8g,106.60mmol)。反应液于15℃下搅拌12小时。将反应液用硅藻土过滤后，滤液用二氯甲烷(100mL x3)萃取。合并有机相，用食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1:5)纯化，得到化合物1-5。1H NMR(400MHz,CDCl3)δ4.65–4.55(m,2H),4.30-4.23(m,1H),3.87(dd,J＝4.0,10.0Hz,1H),3.78(dd,J＝8.0,10.0Hz,1H),1.55(s,9H),0.89(s,9H),0.09(d,J＝2.8Hz,6H)。
步骤5：在氮气保护下，在-50℃下向化合物1-6(23.5g,98.74mmol)和苯甲醇(10.8mL,103.87mmol)的四氢呋喃(450mL)溶液中滴入叔丁醇钾溶液(105mL，105.00mmol，1M四氢呋喃溶液)。在氮气保护下，混合物在-50℃搅拌20分钟。反应液用饱和氯化铵溶液(300mL)淬灭，并用乙酸乙酯(200mL x3)萃取。合并有机相并用食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1：20)纯化，得到化合物1-7。1H NMR(400MHz,DMSO-d6)δ7.63(t,J＝1.6Hz,1H),7.59(dd,J＝9.2,1.6Hz,1H),7.47–7.33(m,5H),5.36(s,2H)。
步骤6：向化合物1-7(23g,70.53mmol)和锌粉(14g,214.13mmol)的四氢呋喃(230mL)和甲醇(230mL)溶液中加入饱和氯化铵溶液(120mL)。反应液在20℃下搅拌2小时。反应液用乙酸乙酯(200mL)稀释后，用硅藻土过滤。滤液加水(300mL)稀释后，用乙酸乙酯(100mL x3)萃取。合并有机相并用食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩得到化合物1-8，直接用于下一步反应。
步骤7：在20℃下向化合物1-8(20.2g,68.21mmol)和吡啶(9mL,111.50mmol)的乙腈(200mL)溶液中逐滴加入三氟乙酸酐(12.3mL,88.43mmol)。反应液在20℃下搅 拌1小时。反应液用水(300mL)稀释后，用乙酸乙酯(100mL x3)萃取。合并有机相并用食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1:10)纯化，得到化合物1-9。1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.48–7.27(m,7H),5.24(s,2H)。
步骤8：在氮气保护下，在-70℃下向化合物1-9(18.5g，47.18mmol)的四氢呋喃(100mL)溶液中逐滴加入二异丙基氨基锂(55mL,110.00mmol，2M的四氢呋喃溶液)。反应液在-70℃下搅拌30分钟后，在-70℃下逐滴加入化合物1-5(15g,42.67mmol)的四氢呋喃(100mL)溶液。反应液在-70℃下搅拌2小时。向反应液中逐滴加入3M稀盐酸(86mL)后，反应液在15℃下再搅拌12小时。反应液用水(200mL)稀释后，用乙酸乙酯(100mL x3)萃取。合并有机相并用食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝4：5)纯化，得到化合物1-10。MS m/z(ESI):465.2[M-Boc+H]+。1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.44–7.34(m,6H),6.44(d,J＝9.2Hz,1H),5.19(s,2H),4.83-4.66(m,1H),3.79–3.69(m,1H),3.43-3.38(m,1H),2.90–2.73(m,2H),1.28(s,9H)。
步骤9：在氮气保护下，向化合物1-10(15g,26.53mmol)、乙烯三氟硼酸钾(11g,82.12mmol)和碳酸钾(11g,79.59mmol)的1,4-二氧六环(150mL)和水(15mL)的混合物中加入1,1-双(二苯基膦)二荗铁二氯化钯(1g,1.37mmol)。在氮气保护下，反应液在100℃下搅拌12小时。反应液用水(200mL)稀释后，用乙酸乙酯(100mL x3)萃取。合并有机相并用食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝2:5)纯化，得到化合物1-11。MS m/z(ESI):535.4[M+Na]+。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.47–7.41(m,2H),7.41–7.35(m,2H),7.35–7.31(m,1H),7.19(s,1H),7.13(dd,J＝17.2,10.8Hz,1H),6.51(d,J＝8.4Hz,1H),6.05–5.77(m,1H),5.42(d,J＝11.2Hz,1H),5.22(s,2H),4.70(t,J＝6.0Hz,1H),3.59–3.49(m,1H),3.31–3.26(m,2H),2.83–2.78(m,1H),2.71-2.63(m,1H),1.31(s,9H)。
步骤10：在氮气保护下，在0℃下向化合物1-11(7.8g,15.22mmol)和三乙胺(12.7mL,91.62mmol)的二氯甲烷(80mL)和二甲基亚砜(80mL)溶液中加入三氧化硫吡啶(14.6g,91.73mmol)的二甲基亚砜(80mL)溶液。在氮气保护下，反应液在0℃下搅拌1小时。反应液倒入饱和碳酸氢钠溶液(200mL)后，用二氯甲烷(100mL x3)萃取。合并有机相并用1.0M稀盐酸溶液(200mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。粗品用石油醚/乙酸乙酯的混合溶液(100mL，体积比10/1)打浆，得到化合物1-12。MS m/z(ESI):533.2[M+Na]+。1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.47(s,1H),7.53–7.26(m,6H),7.19(s,1H),6.93(dd,J＝10.8,17.2Hz,1H),5.86(d,J＝17.2Hz,1H),5.42(d,J＝11.2Hz,1H),5.23(s,2H),3.87–3.73(m,1H),3.13–3.08(m,1H),2.99–2.85(m,1H),1.34(s,9H)。
步骤11：在氮气保护下，在0℃下向甲基三苯基溴化膦(12g,33.59mmol)的四氢呋喃(30mL)溶液中加入钠氢(1.3g,32.50mmol)。反应液在0℃下搅拌30分钟后，向反应液中加入化合物1-12(4.8g,9.40mmol)的四氢呋喃(30mL)溶液。反应液在60℃下搅拌12小时。反应液用水(100mL)淬灭后，用乙酸乙酯(50mL x3)萃取。合并有机相并用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1：10)纯化，得到化合物1-13。MS m/z(ESI):531.2[M+Na]+。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.50–7.26(m,5H),7.18(s,1H),7.13–6.83(m,2H),5.87(d,J＝17.2Hz,1H),5.80–5.64(m,1H),5.44(d,J＝11.2Hz,1H),5.22(s,2H),5.04–4.80(m,2H),4.17–3.95(m,1H),2.90-2.71(m,2H),1.33(s,9H)。
步骤12：向化合物1-13(2.5g,4.92mmol)和碳酸钾(2.05g,14.83mmol)的N,N-二甲基甲酰胺(30mL)溶液中加入溴乙酸甲酯(0.66mL,6.95mmol)。反应液在60℃下搅拌2小时。反应液用水(100mL)稀释后，用乙酸乙酯(50mL x3)萃取。合并有机相并用 饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1：5)纯化，得到化合物1-14。MS m/z(ESI):603.4[M+Na]+。1H NMR(400MHz,DMSO-d6)δ7.52–7.29(m,5H),7.24(d,J＝7.6Hz,1H),7.20–6.85(m,2H),5.94(dd,J＝11.2,17.2Hz,1H),5.83-5.60(m,1H),5.51(dd,J＝4.8,11.2Hz,1H),5.35–5.15(m,2H),5.00–4.81(m,2H),4.50(dd,J＝2.8,16.8Hz,1H),4.29–4.13(m,1H),4.12-4.05(m,1H),3.61(s,3H),2.86–2.72(m,2H),1.43-1.25(m,9H)。
步骤13：在氮气保护下，向化合物1-14(2.8g,4.82mmol)的二氯甲烷(160mL)溶液中加入1,3-双(2,4,6-三甲基苯基)-4,5-二氢咪唑-2-基[2-(异丙氧-5-(N,N-二甲胺磺酰)苯基]甲基二氯化钌(0.71g,0.96mmol)。反应液在40℃下避光搅拌6小时。反应液用水(200mL)稀释后，用二氯甲烷(100mL x3)萃取。合并有机相并用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1：3)纯化，得到化合物1-15。MS m/z(ESI):575.2[M+Na]+。1H NMR(400MHz,DMSO-d6)δ7.49–7.11(m,6H),7.01(s,1H),6.53(d,J＝9.6Hz,1H),6.12–5.96(m,1H),5.28–5.07(m,2H),4.51(dd,J＝5.6,16.8Hz,1H),4.35–4.26(m,2H),3.61(d,J＝2.8Hz,3H),3.00–2.85(m,1H),2.64–2.53(m,1H),1.40(s,9H)。
步骤14：在氮气保护下，在0℃下向二乙基锌(1.10mL,1.10mmol,1M正己烷溶液)的二氯甲烷(1mL)溶液中逐滴加入二碘甲烷(0.18mL,2.23mmol)的二氯甲烷(1mL)溶液。反应液在0℃下搅拌15分钟后，逐滴加入化合物1-15(250mg,0.45mmol)的二氯甲烷(1mL)溶液。反应液在20℃下搅拌30分钟。反应液用饱和氯化铵溶液(20mL)稀释后，用乙酸乙酯(30mL x3)萃取。合并有机相并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1：3)纯化，得到化合物1-16。MS m/z(ESI):589.4[M+Na]+。1H NMR(400MHz,DMSO-d6)δ7.44–7.38(m,4H),7.37–7.30(m,1H),7.12(s,1H),7.08–7.02(m,1H),5.27–5.07(m,2H),4.49(dd,J＝5.2,16.8Hz,1H),4.20(dd,J＝8.0,16.8Hz,1H),3.91–3.71(m,1H),3.60(s,3H),2.88–2.77(m,1H),2.20–2.00(m,2H),1.78–1.65(m,1H),1.42(s,9H),1.04–0.89(m,2H)。
步骤15：向化合物1-16(280mg,0.49mmol)的甲醇(3mL)溶液中加入甲醇钠(110mg,2.04mmol)。反应液在60℃下搅拌2小时。溶剂旋干，得到粗品化合物1-17，直接用于下一步反应。
步骤16：向化合物1-17(222mg,0.46mmol)的N,N-二甲基甲酰胺(4mL)溶液中加入碘甲烷(0.04mL,0.64mmol)。反应液在15℃下搅拌3小时。反应液用水(20mL)稀释后，用乙酸乙酯(30mL x3)萃取。合并有机相并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝3：20)纯化，得到化合物1-18。MS m/z(ESI):571.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ7.47(d,J＝7.2Hz,2H),7.40(t,J＝7.2Hz,2H),7.34(t,J＝7.2Hz,1H),6.97(d,J＝8.4Hz,1H),6.79(s,1H),5.11(s,2H),4.86–4.74(m,1H),4.02–3.93(m,2H),3.81-3.67(m,1H),3.58(s,3H),2.82-2.78(m,1H),1.99–1.86(m,2H),1.61-1.51(m,1H),1.41(s,9H),0.84–0.71(m,2H)。
步骤17：向氯磺酰异氰酸酯(65μL,0.75mmol)的二氯甲烷(0.2mL)溶液中加入叔丁醇(73μL,0.77mmol)。反应液在20℃下搅拌15分钟后，滴入化合物1-18(150mg,0.32mmol)和三乙胺(135μL,0.97mmol)的二氯甲烷(0.2mL)溶液。反应液在20℃下再搅拌1小时。反应液用水(30mL)稀释后，用乙酸乙酯(20mL x3)萃取。合并有机相并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1：4)纯化，得到化合物1-19。MS m/z(ESI):672.4[M+Na]+。1H NMR(400MHz,DMSO-d6)δ11.21(d,J＝5.6Hz,1H),7.47(d,J＝7.6Hz,2H),7.39(t,J＝7.6Hz,2H),7.32(t,J＝7.2Hz,1H),7.03(t,J＝7.6Hz,1H),6.88(s,1H),5.20(q,J＝13.2Hz,2H),4.67(dd,J＝7.2,17.6Hz,1H),4.34(d,J＝18.4Hz,1H),3.85–3.69(m,1H),3.55(s,3H),2.87–2.74(m,1H),2.08–2.00(m,2H),1.72–1.61(m,1H),1.42(s,9H),1.34–1.28(m,9H),0.96–0.80(m,2H).
步骤18：向化合物1-19(107mg,0.16mmol)的二氯甲烷(1mL)溶液中加入三氟乙 酸(500μL,6.71mmol)。反应液在25℃下搅拌1小时后，溶剂旋干，得到的粗品化合物溶解在二氯甲烷(5mL)中，加入三乙胺(110μL,0.79mmol)和二碳酸二叔丁酯(170μL,0.79mmol)。反应液在25℃下再搅拌30分钟后，溶剂旋干。粗品经硅胶柱层析(乙酸乙酯：石油醚＝2：3)纯化，得到化合物1-20。MS m/z(ESI):572.4[M+Na]+。1H NMR(400MHz,DMSO-d6)δ7.51(d,J＝7.6Hz,2H),7.39(t,J＝7.6Hz,2H),7.32(t,J＝7.2Hz,1H),7.07–7.00(m,1H),6.94(s,1H),6.88(s,2H),5.15(s,2H),4.36(dd,J＝4.0,17.6Hz,1H),4.18(dd,J＝3.2,17.6Hz,1H),3.83–3.75(m,1H),3.55(s,3H),2.87–2.80(m,1H),2.10–1.99(m,2H),1.74–1.59(m,1H),1.42(s,9H),0.97–0.84(m,2H)。
步骤19：向化合物1-20(117mg,0.21mmol)的甲醇(2mL)溶液中加入甲醇钠(25mg,0.46mmol)。反应液在60℃下搅拌20分钟。反应液用水(30mL)稀释后，用乙酸乙酯(20mL x3)萃取。有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，浓缩，得到化合物1-21。MS m/z(ESI):540.2[M+Na]+。1H NMR(400MHz,DMSO-d6)δ7.50(d,J＝6.8Hz,2H),7.35(t,J＝6.8Hz,2H),7.30(d,J＝7.2Hz,1H),7.02(d,J＝7.6Hz,1H),6.92(s,1H),5.14(s,2H),4.00–3.89(m,2H),3.86–3.75(m,1H),2.88–2.75(m,1H),2.07–1.99(m,2H),1.72–1.60(m,1H),1.42(s,9H),0.94–0.81(m,2H)。
步骤20：向化合物1-21(94mg,0.18mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(500μL,6.71mmol)。反应液在25℃下搅拌1小时。溶剂旋干，得到粗品化合物1-22，直接用于下一步反应。MS m/z(ESI):416.1[M-H]-。
步骤21：向化合物1-22(75.8mg,0.18mmol)和异戊醛(20μL,0.19mmol)的甲醇(0.3mL)溶液中加入氰基硼氢化钠(35mg,0.56mmol)。反应液在25℃下搅拌1小时。反应液浓缩，粗品经反相柱(C18,5-50％乙腈/0.1％碳酸氢铵水溶液)纯化，得到化合物1-23。MS m/z(ESI):488.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.50(d,J＝7.6Hz,2H),7.35(t,J＝7.6Hz,2H),7.30(d,J＝7.2Hz,1H),6.98(s,1H),5.16(s,2H),3.93(s,2H),3.66(s,1H),3.22-3.00(m,4H),2.29-2.15(m,2H),1.95-1.83(m,1H),1.74–1.61(m,1H),1.58-1.48(m,2H),1.14-1.01(m,2H),0.93(d,J＝6.4Hz,6H)。
步骤22：向化合物1-23(60mg,0.12mmol)的甲醇(2mL)溶液中加入10％湿钯碳(10mg)。在氢气(15psi)保护下，反应液在25℃下搅拌4小时。反应液经硅藻土过滤后，滤液旋干，粗品经制备HPLC(C18,乙腈/0.1％碳酸氢铵水溶液)纯化，得到化合物1。MS m/z(ESI):396.1[M-H]-。1H NMR(400MHz,DMSO-d6)δ9.28(br s,1H),8.51(br s,1H),6.69(s,1H),3.91(s,2H),3.65(s,1H),3.30–2.96(m,4H),2.25–2.08(m,2H),1.90–1.78(m,1H),1.74–1.60(m,1H),1.57–1.46(m,2H),1.11–0.98(m,2H),0.92(d,J＝6.4Hz,6H)。
化合物1经SFC手性分离制备(Column：Chiralpak IC-3 100*4.6mm I.D.,3um；Mobile phase:A:CO2 B:methanol(0.05％ DEA)Isocratic:50％ B；Flow Rate(ml/min)：80；Column temp.:35℃；ABPR:1500psi)得到化合物2(异构体1，第一个峰，保留时间为1.301分钟)和化合物3(异构体2，第二个峰，保留时间为1.936分钟)。
化合物2：MS m/z(ESI):398.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.27(br s,1H),8.50(br s,1H),6.69(s,1H),3.92(s,2H),3.67–3.60(m,1H),3.30–3.04(m,4H),2.22–2.13(m,2H),1.89–1.82(m,1H),1.75–1.64(m,1H),1.53(q,J＝7.3Hz,2H),1.08–1.00(m,2H),0.93(d,J＝6.6Hz,6H)。
化合物3：MS m/z(ESI):398.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.27(br s,1H),8.50(br s,1H),6.69(s,1H),3.92(s,2H),3.67–3.60(m,1H),3.30–3.04(m,4H),2.22–2.13(m,2H),1.89–1.82(m,1H),1.75–1.64(m,1H),1.53(q,J＝7.3Hz,2H),1.08–1.00(m,2H),0.93(d,J＝6.6Hz,6H)。
实施例2：化合物4、5和6的制备
步骤1：将化合物4-1(15.0g,58.53mmol)溶于乙醇(200mL)中，加入异戊胺盐酸盐(15g,58.53mmol)和多聚甲醛(19.31g,585.30mmol)。反应液于95℃搅拌12小时。反应液冷却至室温后过滤，滤饼用乙醇洗涤。滤饼减压干燥后得到化合物4-2。MS m/z(ESI)：356.1[M+H]+。
步骤2：将化合物4-2(14.0g,39.39mmol)溶于四氢呋喃(100mL)，加入三乙胺(11.96g,118.16mmol)和Boc酸酐(9.46g,43.33mmol)。反应液于25℃搅拌3小时。反应液用水(100mL)稀释，乙酸乙酯(200mL)萃取。有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经硅胶柱层析(四氢呋喃：石油醚＝1:4)分离纯化，得到化合物4-3。1H NMR(400MHz,DMSO-d6)δ7.50–7.34(m,5H),7.06(s,1H),6.88(br d,J＝10.4Hz,1H),5.30–5.17(m,2H),3.52–3.35(m,2H),3.50–3.10(m,3H),2.99(br s,1H),2.89(br s,1H),1.55–1.44(m,1H),1.43–1.27(m,11H),0.87(d,J＝6.4Hz,6H)。
步骤3：将化合物4-3(15.0g,32.93mmol)溶于甲醇(500mL)中，氮气氛围下向反应液中缓慢加入10％湿钯碳(3.50g)。氢气置换三次，反应液在室温氢气氛围(30psi)搅拌12小时。反应液经硅藻土过滤，滤渣用甲醇洗涤。滤液浓缩，得到化合物4-4，直接用于下一步。
步骤4：将化合物4-4(8.5g,23.26mmol)溶于N,N-二甲基甲酰胺(100mL)中，氮气氛围下向反应液中加入碳酸铯(22.73g,69.78mmol)，-30℃滴加2-甲氧基乙氧基甲基氯(5.3mL,46.52mmol)，反应液在-30℃搅拌30分钟。反应液用水(300mL)淬灭，乙酸乙酯(300mL×3)萃取。有机相用食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩。残留物经硅胶柱层析(四氢呋喃：石油醚＝3：7)分离纯化，得到化合物4-5。MS m/z(ESI):354.2[M+H-Boc]+。1H NMR(400MHz,DMSO-d6)δ7.03(s,1H),6.85(br d,J＝11.2Hz,1H),5.39(s,2H),3.78–3.70(m,2H),3.51–3.42(m,4H),3.22(s,3H),3.14(br s,2H),2.99(br s,1H),2.86(br s,1H),1.48(td,J＝6.4,13.2Hz,1H),1.43–1.22(m,12H),0.87(d,J＝6.4Hz,6H)。
步骤5：将(氟甲基)三苯基膦四氟硼酸盐(12.63g,33.07mmol)溶于四氢呋喃(150mL)中，0℃在氮气氛围下缓慢加入叔丁醇钾(3.71g,33.07mmol)，反应液0℃搅拌30分钟。用20mL四氢呋喃溶解化合物4-5(5g,11.02mmol)，0℃将其缓慢滴加至反应液中。反应液在室温搅拌2小时。反应液用饱和氯化铵水溶液(300mL)淬灭，乙酸乙酯(300mL x3)萃取，有机相用食盐水(200mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩得到粗产品， 残留物经硅胶柱层析(四氢呋喃:石油醚＝1:10)分离纯化，得到化合物4-6。MS m/z(ESI):492.2[M+Na]+。
步骤6：将化合物4-6(4.3g,9.16mmol)溶于四氢呋喃中(50mL)，-78℃氮气氛围下缓慢滴加2.5M正丁基锂(18.31mL,45.79mmol)，反应液在-78℃搅拌30分钟。用四氢呋喃(20mL)溶解碘(6.97g，27.47mmol),-78℃将其缓慢滴加至反应液中,反应液在-78℃下搅拌2小时。反应液用饱和氯化铵(300mL)淬灭，乙酸乙酯(100mL x3)萃取。有机相用亚硫酸钠水溶液(100mL)洗涤，食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩。残留物经硅胶柱层析(四氢呋喃：石油醚＝3：10)分离纯化，得到化合物4-7。MS m/z(ESI):540.1[M+H-56]+。
步骤7：将化合物4-7(5.0g,8.40mmol)、甘氨酸叔丁酯(1.65g,12.60mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(0.76g,0.84mmol)和碳酸铯(8.21g,25.19mmol)溶于二氧六环(50mL)中，氮气置换三次，反应液在95℃搅拌4小时。反应液用水(300mL)和乙酸乙酯(300mL x3)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩得到粗产品，残留物经硅胶柱层析(四氢呋喃：石油醚＝3：10)分离纯化，得到化合物4-8。MS m/z(ESI):599.3[M+H]+。
步骤8：取三口烧瓶A，将氯磺酰异氰酸酯(1.65g,11.69mmol)溶于二氯甲烷中(50mL)，0℃氮气氛围下滴加丙烯醇(0.95g,16.36mmol)，反应液在0℃下搅拌1小时。取三口烧瓶B，将化合物4-8(3.5g,5.85mmol)溶于二氯甲烷(50mL)，滴加三乙胺(2.4mL,17.54mmol)。0℃将三口烧瓶A的溶液滴加至B中。反应液0℃氮气氛围中搅拌2小时。反应液用水(50mL)稀释，乙酸乙酯(50mL x3)萃取，有机相用食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩，得到化合物4-9。MS m/z(ESI):760.3[M-H]-。
步骤9：将化合物4-9(3.0g,3.94mmol)溶于甲醇(60mL)中，加入四三苯基磷钯(0.23g,0.20mmol)、甲醇钠(1.3mL,23.63mmol,30％甲醇溶液)和4A分子筛(3.0g)，氮气置换三次，反应液60℃搅拌12小时。反应液用饱和氯化铵水溶液(100mL)淬灭，乙酸乙酯(300mL x3)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩，粗品经HPLC制备(柱子:C18 150×40mm；流速:60mL/min,流动相：[Water(NH3H2O+NH4HCO3)-ACN]；B％:20％-60％乙腈,9min)得到化合物4-10(第一个峰,保留时间2.64分钟)和4-11(第二个峰,保留时间2.76分钟)。化合物4-10：MS m/z(ESI):602.2[M-H]-。化合物4-11：MS m/z(ESI):602.2[M-H]-。
步骤10：将化合物4-11(600mg,0.99mmol)溶于二氯甲烷(6mL)中，加入三氟乙酸(2.0mL,26.84mmol)，反应液于25℃搅拌12小时。反应液浓缩，残留物经HPLC制备(柱子：Phenomenex Gemini NX 150×30mm,5μm；流速：60mL/min；流动相：[Water(ammonia hydroxide v/v)-ACN]；B％:9％-49％,9min)得到化合物4。化合物4经SFC手性分离制备(Column：DAICEL CHIRALPAK IG(250mm*30mm,10um)；Condition：CO2-EtOH(0.1％NH3H2O)Begin B：35％ End B：35％；Flow Rate(ml/min)：80)，得到化合物5(异构体1，第一个峰,保留时间1.062分钟)和化合物6(异构体2，第二个峰,保留时间1.486分钟)。
化合物4：MS m/z(ESI):416.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.63(br s,1H),8.23(s,1H),7.68–7.23(m,1H),6.66(s,1H),4.01–3.88(m,2H),3.63(br s,1H),3.30–3.11(m,2H),3.10–3.05(m,1H),3.05–2.85(m,4H),1.68–1.56(m,1H),1.52–1.41(m,2H),0.89(d,J＝6.4Hz,6H)。
化合物5：MS m/z(ESI):416.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.63(br s,1H),8.23(s,1H),7.68–7.23(m,1H),6.66(s,1H),4.01–3.88(m,2H),3.63(br s,1H),3.30–3.11(m,2H),3.10–3.05(m,1H),3.05–2.85(m,4H),1.68–1.56(m,1H),1.52–1.41(m,2H),0.89(d,J＝6.4Hz,6H)。
化合物6：MS m/z(ESI):416.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.53(br s,1H),8.18(br s,1H),7.58–7.28(m,1H),6.66(s,1H),4.01–3.88(m,2H),3.63(br s,1H),3.20–3.03(m,3H),3.02–2.85(m,4H),1.68–1.56(m,1H),1.54–1.43(m,2H),0.89(d,J＝6.4Hz,6H)。
实施例3：化合物7的制备
步骤1：将化合物4-10(400mg,0.66mmol)溶于二氯甲烷(4mL)中，加入三氟乙酸(1.3mL,17.44mmol)，反应液在25℃搅拌12小时。反应液浓缩，残留物经HPLC制备(柱子：Phenomenex Gemini NX 150×30mm,5μm；流速：60mL/min；流动相：[Water(ammonia hydroxide v/v)-ACN]；B％:6％-46％,9min)得到化合物7。MS m/z(ESI):416.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.25(br s,1H),6.95(br d,J＝82.0Hz,1H),6.67(s,1H),3.94(s,2H),3.22–2.96(m,4H),2.95–2.88(m,3H),2.77(br d,J＝16.0Hz,1H),1.61(td,J＝6.4,13.2Hz,1H),1.54–1.44(m,2H),0.89(d,J＝6.4Hz,6H)。
实施例4：化合物8的制备
步骤1：向化合物1-22(24mg,57.49μmol)和4,4,4-三氟丁醛(7μL,66.62μmol)的甲醇(0.2mL)溶液中加入氰基硼氢化钠(6mg,95.48μmol)。反应液在25℃下搅拌2小时。反应液减压浓缩，粗品经硅胶柱层析(甲醇：二氯甲烷＝1：10)纯化，得到化合物8-1。MS m/z(ESI):528.2[M+H]+。
步骤2：在氮气保护下，向化合物8-1(30mg,56.87μmol)的乙醇(2mL)溶液中加入10％湿钯碳(10mg)。在氢气(15psi)氛围下，反应液在25℃下搅拌12个小时。反应液经硅藻土过滤，滤液旋干，粗品经制备HPLC(C18,0.05％碳酸氢铵溶液/乙腈)纯化，得到化合物8。MS m/z(ESI):438.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.25(br s,1H),8.63(br s,1H),6.69(s,1H),3.90(s,2H),3.67(br s,1H),3.26–2.92(m,4H),2.47–2.36(m,2H),2.26–2.05(m,2H),1.95–1.71(m,3H),1.13–0.94(m,2H)。
实施例5：化合物9的制备
步骤1：向化合物9-1(3.0g,17.63mmol)和N,O-二甲基羟胺盐酸盐(3.5g,35.88mmol)的N,N-二甲基甲酰胺(30mL)溶液中加2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(8.8g,23.14mmol)和三乙胺(7.4mL,53.38mmol)。反应液在25℃下搅拌12小时。反应液加水(100mL)稀释后用乙酸乙酯(50mL x3)萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并过滤，滤液减压浓缩。粗品经硅胶柱层析(乙酸乙酯：石油醚＝1：10)纯化，得到化合物9-2。MS m/z(ESI):214.0[M+H]+。1H NMR(400MHz,CDCl3)δ3.69(s,3H),3.19(s,3H),2.60(s,2H),1.29(s,6H)。
步骤2：在0℃下，向化合物9-2(200mg,0.94mmol)的四氢呋喃(5mL)溶液中滴加入氢化铝锂(0.56mL,1.4mmol,2.5M四氢呋喃溶液)。加料完毕后，反应液在0℃下搅拌2个小时。反应液用十水合硫酸钠淬灭，混合物经硅藻土过滤，滤液减压浓缩得到化合物9-3。1H NMR(400MHz,CDCl3)δ9.75-9.73(m,1H),2.47(d,J＝2.4Hz,2H),1.22(s,6H)。
步骤3：向化合物1-22(22mg,52.70μmol)和化合物9-3(1.44mL,158.1μmol)的甲醇(1mL)溶液中加入氰基硼氢化钠(10mg,159.13μmol)。反应液在25℃下搅拌12小时。反应液减压浓缩，粗品经反相柱层析(C18,0.05％碳酸氢铵溶液/乙腈)纯化，得到化合物9-4。MS m/z(ESI):556.4[M+H]+。
步骤4：在氮气保护下，向化合物9-4(24mg,43.20μmol)的四氢呋喃(3mL)溶液中加入10％湿钯碳(5mg)。在氢气(15psi)氛围下，反应液在25℃下搅拌12个小时。反应液经硅藻土过滤，滤液旋干，粗品经制备HPLC(C18,0.05％碳酸氢铵溶液/乙腈)纯化，得到化合物9。MS m/z(ESI):466.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.41(s,1H),6.69(s,1H),3.91(s,2H),3.78-3.56(m,1H),3.47–3.38(m,1H),3.19–3.06(m,3H),2.25-2.08(m,2H),1.96–1.70(m,3H),1.15(s,6H),1.08-0.92(m,2H)。
实施例6：化合物10的制备
化合物10的合成参考实施例4，使用原料3,3-二甲基丁醛替换实施例4的4,4,4-三氟丁醛，采用与实施例4相同的方法进行化合物10的制备。
化合物10：MS m/z(ESI):412.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.29(s,1H),6.75–6.62(m,1H),3.94–3.88(m,2H),3.70–3.59(m,1H),3.27–2.80(m,4H), 2.25–1.98(m,2H),1.92–1.79(m,1H),1.59–1.51(m,1H),1.45(t,J＝8.8Hz,1H),1.17–0.97(m,2H),0.96–0.86(m,9H)。
实施例7：化合物11的制备
化合物11的合成参考实施例4，使用原料2-环己基乙醛替换实施例4的4,4,4-三氟丁醛，采用与实施例4相同的方法进行化合物11的制备。
化合物11：MS m/z(ESI):438.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.25(brs,1H),8.33(brs,1H),6.76–6.63(m,1H),3.94–3.87(m,2H),3.68–3.62(m,1H),3.20–2.84(m,4H),2.25–1.94(m,2H),1.90–1.78(m,1H),1.78–1.57(m,5H),1.56–1.49(m,1H),1.48–1.39(m,1H),1.28–0.78(m,8H)。
实施例8：化合物12、13和14的制备
步骤1：向化合物12-1(200mg,2.08mmol)的二氯甲烷(4mL)溶液中加入戴斯-马丁试剂(980mg,2.31mmol)。反应液在25℃下搅拌12小时。反应液经硅藻土过滤，滤液用二氯甲烷稀释到10mL，得到化合物12-2的溶液直接用于下一步反应。1H NMR(400MHz,CDCl3)δ9.79(s,1H),6.24(t,J＝50.4Hz,1H),3.10–2.96(m,2H)。
步骤2：向化合物1-22(400mg,0.60mmol)和化合物12-2(4.0mL,0.84mmol,二氯甲烷溶液)的甲醇(2mL)溶液中加入氰基硼氢化钠(75mg,1.19mmol)。反应液在25℃下搅拌3小时。反应液减压浓缩，粗品经反相柱层析(C18,0.05％碳酸氢铵溶液/乙腈)纯化，得到化合物12-3。MS m/z(ESI):496.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.80(brs,1H),7.53–7.47(m,2H),7.40–7.32(m,2H),7.32–7.26(m,1H),6.98(s,1H),6.26(tt,J＝4.0,56.0Hz,1H),5.16(s,2H),3.94(d,J＝2.0Hz,2H),3.82–3.66(m,1H),3.30–3.24(m,2H),3.20–3.08(m,2H),2.39–2.14(m,4H),1.95–1.81(m,1H),1.16–1.01(m,2H)。
步骤3：在氮气保护，-70℃下，向化合物12-3(160mg,0.32mmol)和五甲基苯(96mg,0.65mmol)的二氯甲烷(5mL)溶液中加入三氯化硼(1.5mL,1.5mmol,1M正己烷溶液)。反应液在-70℃下搅拌1个小时。反应液在-70℃下用甲醇(2mL)淬灭，混合液减压浓缩，粗品经制备HPLC(C18,0.05％碳酸氢铵溶液/乙腈)纯化，得到化合物12。MS  m/z(ESI):406.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.76(brs,1H),6.69(s,1H),6.25(tt,J＝4.0,56.0Hz,1H),3.91(s,2H),3.82–3.66(m,1H),3.30–3.24(m,2H),3.20–3.08(m,2H),2.39–2.16(m,4H),1.87–1.79(m,1H),1.07–1.02(m,2H)。
化合物12经过SFC拆分(Instrument:WATERS150preparative SFC(SFC-26)；Column:ChiralPak IC,250×30mm I.D.,10μm；Mobile phase:A for CO2 and B for Methanol(0.1％NH3H2O)；Gradient:B 40％；Flow rate:150mL/min；Back pressure:100bar；Column temperature:38℃；Wavelength:220nm；Cycle time:～8min)后得到第一个峰(保留时间：1.543分钟)为化合物13，MS m/z(ESI):405.9[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.76(brs,1H),6.69(s,1H),6.25(tt,J＝4.0,56.0Hz,1H),3.91(s,2H),3.82–3.66(m,1H),3.30–3.24(m,2H),3.20–3.08(m,2H),2.39–2.16(m,4H),1.87–1.79(m,1H),1.07–1.02(m,2H)。得到第二个峰(保留时间：1.978分钟)为化合物14，MS m/z(ESI):405.9[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.76(brs,1H),6.69(s,1H),6.25(tt,J＝4.0,56.0Hz,1H),3.91(s,2H),3.82–3.66(m,1H),3.30–3.24(m,2H),3.20–3.08(m,2H),2.39–2.16(m,4H),1.87–1.79(m,1H),1.07–1.02(m,2H)。
实施例9：化合物15的制备
化合物15的合成参考实施例8，使用原料2-环丙基乙醇替换实施例8的化合物12-1，采用与实施例8相同的方法进行化合物15的制备。
化合物15：MS m/z(ESI):495.9[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.25(brs,1H),8.50(brs,1H),6.76–6.62(m,1H),3.97–3.85(m,2H),3.69–3.62(m,1H),3.20–2.87(m,4H),2.28–1.96(m,2H),1.89–1.75(m,1H),1.61–1.38(m,2H),1.16–0.89(m,2H),0.87–0.64(m,1H),0.53–0.37(m,2H),0.19–0.00(m,2H)。
实施例10：化合物16的制备
化合物16的合成参考实施例4，使用原料四氢吡喃-2-甲醛替换实施例4的4,4,4-三氟丁醛，采用与实施例4相同的方法进行化合物16的制备。
化合物16：MS m/z(ESI):426.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.73(brs,1H),6.68(s,1H),4.02–3.94(m,1H),3.90(s,2H),3.72–3.53(m,2H),3.47–3.40(m,1H),3.26–3.17(m,1H),3.14–3.00(m,2H),2.29–2.11(m,2H),1.92–1.77(m,2H),1.68–1.59(m,1H),1.56–1.45(m,3H),1.29–1.21(m,2H),1.12–0.98(m,2H)。
实施例11：化合物17的制备
化合物17的合成参考实施例8，使用原料2-环戊基乙醇替换实施例8的化合物12-1，采用与实施例8相同的方法进行化合物17的制备。
化合物17：MS m/z(ESI):424.6[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.25(brs,1H),8.49(brs,1H),6.69(s,1H),3.91(s,2H),3.73–3.60(m,1H),3.16–3.00(m,3H),2.24–2.12(m,2H),1.89–1.72(m,4H),1.70–1.47(m,6H),1.18–1.08(m,2H),1.08–1.01(m,2H)。
实施例12：化合物18的制备
化合物18的合成参考实施例8，使用原料3-溴-5-羟基苯甲醇替换实施例8的化合物12-1，采用与实施例8相同的方法进行化合物18的制备。
化合物18：MS m/z(ESI):511.8[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),7.28(d,J＝8.0Hz,1H),7.08–6.99(m,2H),6.67(s,1H),4.17(q,J＝13.6Hz,2H),3.90(d,J＝2.0Hz,2H),3.57–3.50(m,1H),3.14–3.02(m,1H),2.24–2.09(m,2H),1.87–1.78(m,1H),1.11–0.95(m,2H)。
测试例1：PTPN2抑制活性测定实验
本发明采用HTRF assay测定化合物对PTPN2抑制活性的特性，具体实验过程如下：利用ECHO将化合物转移至384孔板(PE#6007290)，准备酶学反应缓冲液(50mM HEPES pH7.5,10mM EDTA,0.01％ Tween 20,2mM DTT)。将PTPN2(Sino biological#10570-H20B)稀释在反应缓冲液中，加入PTPN2(终浓度1nM)与化合物在室温下孵育10min，随后加入底物(终浓度1μM)(biotin-(NH-CH2-CH2-O-CH2-CH2-O-CH2-CO)-T-R-D-I-(PY)-E-T-D-Y-Y-R-K-K-NH2)(Genscript)，室温孵育40min后加入淬灭剂终止反应。加入终浓度为10nM Eu-anti-P(PY20)antibody(Cisbio#AD0066)和15nM APC-Streptavidin(Cisbio#AD0201)，室温孵育1h，将反应后的384孔板使用Envision在620nm和665nm处读取荧光值，通过非线性回归分析四参数Logistic方程拟合抑制PTPN2酶活性IC50值(PTPN 2IC50)。
阳参：
经检测，本发明的化合物具有较好的PTPN2抑制活性，部分代表性化合物的测试结果如表1所示。
表1


A：IC50≤20nM，B：20nM<IC50≤100nM，C：100nM<IC50≤500nM，D：500nM<IC50。
测试例2：B16F10 mIFNγ诱导的细胞生长抑制实验
将40μL(150cells/well)B16F10细胞(来源ATCC Cat#CRL-6475)接种到384孔板中，利用EHCO将化合物转移至含细胞的384板中，一组细胞加入10μL不含mIFNγ的完全培养基(RPMI 1640medium+10％FBS)，一组加入10μL含mIFNγ(来源R&D Cat#485-MI/CF，终浓度25ng/ml)的完全培养基，反应体系中加入不同浓度的化合物(DMSO含量0.5％)。将细胞培养板置于37℃，5％ CO2培养箱孵育96h，加入25μL CTG，使用Envision进行读数，以DMSO/mIFNγ作为阴性对照，为阳性对照，通过非线性回归分析四参数Logistic方程拟合细胞生长抑制IC50值(Cell IC50)。
经检测，本发明的化合物对B16F10 mIFNγ诱导的细胞生长具有较好的抑制作用，代表性化合物的检测结果如表2所示。
表2

A：IC50≤1μM，B：1μM<IC50≤10μM，C：10μM<IC50≤100μM，D：100μM<IC50。
本发明的技术方案不限于上述具体实施例的限制，凡是根据本发明的技术方案做出的技术变形，均落入本发明的保护范围之内。

Claims (19)

  1. 具有式(I-1)或(I-2)所示的结构的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药；
    其中，
    R1a和R1b各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基；
    优选地，R1a和R1b各自独立地选自：氢、氘、卤素、羟基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基和卤代C1-4烷氧基；
    优选地，R1a和R1b各自独立地选自：氢、氘、氟、氯、溴、羟基、甲基、乙基、甲氧基、乙氧基、三氟甲基、二氟甲基、2,2-二氟乙基、三氟甲氧基和2,2-二氟乙氧基；
    优选地，R1a和R1b各自独立地选自：氢、氘、氟和羟基；
    R1c和R1d各自独立地选自：氢、氘、卤素、C1-6烷基和卤代C1-6烷基；
    优选地，R1c和R1d各自独立地选自：氢、氘、卤素、C1-4烷基和卤代C1-4烷基；
    优选地，R1c和R1d各自独立地选自：氢、氘、氟、氯、溴、甲基、乙基、三氟甲基和二氟甲基；
    优选地，R1c和R1d各自独立地选自：氢、氘、氟；
    R2a选自：氢、氘、羟基、氨基、C1-8烷基、C2-8烯基、C3-6环烷基、5-6元杂芳基、4-8元杂环基、-O-C1-8烷基、-O-C1-6亚烷基-C3-6环烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C(＝O)-N(Ra)-C1-8烷基、-O-C(＝O)-N(Ra)-苯基、-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-8烷基、–N(Ra)-C(＝O)-O-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-Si(Rc)3、-N(Ra)-(C＝N(Rb))-C1-8烷基、-N(Ra)-S(＝O)w-C1-8烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)(Rb)、-C1-6亚烷基-N(Ra)-C(＝O)-O-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-C3- 6环烷基、-C1-6亚烷基-N(Ra)-C(＝O)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-O-C1-8烷基、-C1-6亚烷基-O-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-O-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-O-C1-6亚烷基-N(Ra)(Rb)、-S(＝O)w-C1-8烷基、-C(＝O)-N(Ra)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自：氢、氘、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基、5-6元杂芳基、4-8元杂环基、-O-C1-6烷基、-O-C1-4亚烷基-C3-6环烷基、-O-C1-4亚烷基-(4-8元杂环基)、-O-C(＝O)-N(Ra)-C1-6烷基、-O-C(＝O)-N(Ra)-苯基、-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-6烷基、–N(Ra)-C(＝O)-O-C1-8烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-Si(Rc)3、-N(Ra)-(C＝N(Rb))-C1-6烷基、-N(Ra)-S(＝O)w-C1-6烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚 烷基-苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-N(Ra)(Rb)、-C1-4亚烷基-N(Ra)-C(＝O)-O-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-S(O)w-C1-6烷基、-C(＝O)-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自：-O-C1-6烷基、-O-C1-4亚烷基-C3-6环烷基、-O-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-N(Ra)(Rb)、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-C1- 4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-8元杂环基)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-S(＝O)w-C1-6烷基、-C(＝O)-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-N(Ra)-C(＝O)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-8元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；
    优选地，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-6卤代烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基；
    优选地，R2a选自以下基团：

    优选地，R2a选自以下基团：
    优选地，R2a选自以下基团：
    优选地，R2a选自以下基团：
    优选地，R2a为
    R2b选自：氢、氘、羟基、卤素、-N(Ra)(Rb)和-N(Ra)-N(Rb)-C(O)-苯基；
    优选地，R2b选自：氢、氘、羟基、氟、氯和溴；
    优选地，R2b选自：氢和氘；R3、R3a和R3b各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；
    优选地，R3、R3a和R3b各自独立地选自：氢、氘、卤素、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)；
    优选地，R3、R3a和R3b各自独立地选自：氢、氘、氟、氯、溴、羟基、C1-4烷基、C1-4卤代烷基；
    优选地，R3、R3a和R3b各自独立地选自：氢、氘、氟、氯、溴、羟基、甲基、乙基、三氟甲基、二氟甲基；
    优选地，R3、R3a和R3b各自独立地选自：氢、氘、氟和羟基；X1选自O、S、NRf和C(Re)(Rd)；
    Ra和Rb各自独立地选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代；
    优选地，Ra和Rb各自独立地选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代；
    优选地，Ra和Rb各自独立地选自：氢、甲基；
    Rc选自：羟基、C1-6烷基和苯基；
    优选地，Rc选自：羟基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基和苯基；
    Re和Rd各自独立地选自：氢、氘、卤素、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；任选地，Re和R3a，与它们相连的原子一起形成3-7元碳环；或，Re和R2b，与它们相连的原子一起形成3-7元碳环；
    优选地，Re和Rd各自独立地选自：氢、氘、氟、氯、溴、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-6环烷基、C3-6卤代环烷基、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)；任选地，Re和R3a，与它们相连的原子一起形成3-6元碳环；或，Re和R2b，与它们相连的原子一起形成3-6元碳环；
    Rf选自：氢、C1-6烷基、C1-6卤代烷基；任选地，Rf和R3a与和它们相连的原子一起形成3-7元杂环，或，Rf和R2b与和它们相连的原子一起形成3-7元杂环；
    优选地，Rf选自：氢、C1-4烷基、C1-4卤代烷基；任选地，Rf和R3a与和它们相连的原子一起形成3-6元杂环，或，Rf和R2b与和它们相连的原子一起形成3-6元杂环；
    Rg各自独立地选自：氢、氘、卤素、羟基、氰基、硝基、氧代、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基；
    优选地，Rg各自独立地选自：氢、氘、氟、氯、溴、羟基、氰基、硝基、氧代、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基；
    优选地，Rg各自独立地选自：氢、氘、氟、氯、溴、羟基、氰基、硝基、氧代、氨基、-NH-CH3、-N(CH3)(CH3)、甲基、乙基、三氟甲基和二氟甲基；
    Rh选自：氢、氘、C1-6烷基和C1-6卤代烷基；
    优选地，Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基；
    优选地，Rh选自：氢、氘、甲基、三氟甲基、二氟甲基和2,2-二氟乙基；
    n选自：0或1；
    p选自：0、1、2或3；
    q选自：0、1、2、3或4；
    w选自：1或2；
    条件是：化合物不是
  2. 如权利要求1所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其中：
    R1a和R1b各自独立地选自氢和氘，优选R1a和R1b选自氢；和/或
    R1c和R1d各自独立地选自氢、氘、卤素，优选R1c和R1d各自独立地选自氢和卤素，更优选R1c和R1d其中一者选自氢，另一者选自卤素；和/或
    p选自0或1，优选p选自0；和/或
    n选自0；和/或
    R3选自氢、氘、卤素，优选R3选自氢和卤素，更优选R3选自氢；和/或
    q选自0、1或2，优选q选自0；和/或
    X1选自O、S、NRf和C(Re)(Rd)，优选X1选自C(Re)(Rd)；和/或
    Re和Rd各自独立地选自：氢、氘、卤素、羟基或，Re和R2b，与它们相连的原子一起形成3-7元碳环，优选Re和Rd各自独立地选自：氢、卤素、羟基或，Re和R2b，与它们相连的原子一起形成3-6元碳环(例如C3-6环烷基)，更优选Re和Rd选自氢；
    R2b选自氢或，R2b和Re，与它们相连的原子一起形成3-6元碳环(例如C3-6环烷基)，优选R2b选自氢。
  3. 如权利要求1或2所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其中：
    R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C1-6亚烷基-C3-6环烷基、-N(Ra)-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-O-C1-8烷基、-C1-6亚烷基-O-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-O-C1-6亚烷基-(4-8元杂环基)、-C(＝O)-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C(＝O)-C1-8烷基、-C1-6亚烷基-N(Ra)(Rb)、-C1-6亚烷基-O-C1-6亚烷基-N(Ra)(Rb)、-N(Ra)-C(＝O)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)、-O-C1-4亚烷基-C3-6环烷基、-N(Ra)-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)(Rb)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-N(Ra)-C(＝O)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-C1-6亚烷基-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-O-C1-8烷基、-C1-6亚烷基-O-C1-6亚烷基-C3-6环烷基、-C1-6亚烷基-O-C1-6亚烷基-(4-8元杂环基)、-C(＝O)-N(Ra)-C1-8烷基、-C1-6亚烷基-N(Ra)-C(＝O)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、- N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-苯基、-C1-6亚烷基-N(Ra)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    更优选R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-C1-6亚烷基-N(Ra)-C1-8烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    更优选R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；和/或
    Rg各自独立地选自：氢、氘、卤素、羟基、氰基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基；
    优选Rg各自独立地选自：氢、氘、卤素、羟基、氰基、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基；和/或
    Rh选自：氢、氘、C1-6烷基和C1-6卤代烷基；
    优选Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基；和/或
    Ra和Rb各自独立地选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个卤素取代，优选Ra和Rb各自独立地选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个卤素取代。
  4. 如权利要求1-3任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有式(II-0)或(II-2)所示的结构；
    其中，
    R2c、R2d、R2e和R2f各自独立地选自：氢、氘、氟、氯、氰基、羟基、C1-6烷基和卤代C1-6烷基；任选地，R2c和R2d，或R2e和R2f形成氧代；
    优选地，R2c、R2d、R2e和R2f各自独立地选自：氢、氘、氟、氯、氰基、羟基、C1-4烷基和卤代C1-4烷基；任选地，R2c和R2d，或R2e和R2f形成氧代；
    优选地，R2c、R2d、R2e和R2f各自独立地选自：氢、氘、氟、氯、氰基、羟基、甲基、乙基、三氟甲基；任选地，R2c和R2d，或R2e和R2f形成氧代；
    R2g选自：氢、C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；所述的C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基各自独立地任意地被1个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代；
    优选地，R2g选自：氢、C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)；所述的C1-4烷基、C3-6环烷基、4-8元杂环基、5-6元杂芳基、苯基各自独立地任意地被1个或多个选自氟、氯、溴、羟基、氰基、甲基、三氟甲基、二氟甲基、2,2-二氟乙基取代基取代；
    优选地，R2g选自：氢、C1-4烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基；所述C1-4烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基各自独立地任选被1个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代；
    优选地，R2g选自：氢、C1-4烷基、C3-6环烷基、4-7元杂环基，所述C1-4烷基、C3-6环烷基、4-7元杂环基各自独立地任选被1个或多个选自卤素的取代基取代；
    优选地，R2g选自：氢、甲基、三氟甲基、二氟甲基、叔丁基、-CH2OH、-N(CH3)2或以下基团：
    优选地，R2g选自：氢、甲基、叔丁基、三氟甲基、环丙基、环戊基、环己基、四氢吡喃-2-基；
    X2为NH或O，优选X2为NH；
    优选地，所示式(II-0)具有式(II-1)所示结构：
  5. 如权利要求1-4任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有式(III-0)或(III-2)所示的结构：
    优选所述式(III-0)具有式(III-1)所示结构：
  6. 如权利要求1-5任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有式(IV-1)或(IV-2)所示的结构
    其中，R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2，所述C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2各自独立地任选地被一个或多个选自卤素、 羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代；
    优选R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-C1-2亚烷基-(4-7元杂环基)、-C1-2亚烷基-(5-6元杂芳基)、-C1-2亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2，所述C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-C1-2亚烷基-(4-7元杂环基)、-C1-2亚烷基-(5-6元杂芳基)、-C1-2亚烷基-苯基、-NH(C1-6烷基)、-N(C1-6烷基)2各自独立地任选地被一个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代；
    优选R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-N(C1-6烷基)2，所述C1-6烷基、C3-6环烷基、4-7元杂环基、5-6元杂芳基、苯基、-C1-2亚烷基-C3-6环烷基、-N(C1-6烷基)2各自独立地任选地被一个或多个选自卤素、羟基、氰基、C1-4烷基、C1-4卤代烷基的取代基取代；
    优选R2h选自：C1-6烷基、C3-6环烷基、4-7元杂环基；所述C1-6烷基、C3-6环烷基、4-7元杂环基各自独立地任选地被一个或多个卤素取代；
    优选地，R2h选自：甲基、乙基、异丙基、叔丁基、二氟甲基、三氟甲基、2-(1,1,1-三氟甲基)-丙-2-基、环丙基、环丁基、环戊基、环己基、苯基、2-羟基-丙-2-基、2-氰基-丙-2-基、-N(CH3)2、
    优选地，R2h选自：异丙基、叔丁基、三氟甲基、2-(1,1,1-三氟甲基)-丙-2-基、环丙基、环戊基、环己基、四氢吡喃-2-基。
  7. 如权利要求1-3任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有式(V)所示的结构
  8. 如权利要求7所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，
    其中：R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)、-O-C1-6亚烷基-C3-6环烷基、-N(Ra)-(4-8元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)、-O-C1-4亚烷基-C3-6环烷基、-N(Ra)-(4-7元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)、-N(Ra)-C1-6亚烷基-(5-6元杂芳基)、-N(Ra)-C1-6亚烷基-苯基、-O-C1-8烷基、-O-C1-6亚烷基-(4-8元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C3-6环烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-N(Ra)-C1-4亚烷基-苯基、-O-C1-6烷基、-O-C1-4亚烷基-(4-7元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-N(Ra)-C1-8烷基、-N(Ra)-C1-6亚烷基-C3-6环烷基、-N(Ra)-C1-6亚烷基-(4-8元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-N(Ra)-C1-6烷基、-N(Ra)-C1-4亚烷基-C3-6环烷基、-N(Ra)-C1-4亚烷基-(4-7元杂环基)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；和/或
    Rg各自独立地选自：氢、氘、卤素、羟基、氰基、氨基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、C1-6烷基和C1-6卤代烷基；
    优选地，Rg各自独立地选自：氢、氘、氟、氯、溴、羟基、氰基、氨基、-NH(C1-4烷 基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基；
    优选地，Rg各自独立地选自：氢、氟、羟基、氰基、-N(CH3)2、甲基、乙基、三氟甲基和二氟甲基；和/或
    Rh选自：氢、氘、C1-6烷基和C1-6卤代烷基；
    优选地，Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基；
    优选地，Rh选自：氢、氘、甲基、三氟甲基、二氟甲基和2,2-二氟乙基；和/或
    Ra选自：氢和C1-6烷基；任选地，所述C1-6烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代；
    优选地，Ra选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个选自卤素、氰基、氧代、羟基的取代基取代；
    优选地，Ra为氢。
  9. 如权利要求1-5、7-8任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有式(V-1)所示的结构
  10. 如权利要求9所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，X2为NH；
    优选地，R2c和R2d各自独立地选自：氢、氟、氰基、羟基、C1-3烷基和卤代C1-3烷基；
    进一步优选地，R2c和R2d各自独立地选自：氢、氟、氰基、羟基、甲基、乙基、三氟甲基；
    优选地，R2g选自：氢、C1-3烷基、C3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基(例如吡唑基、异噁唑基、三唑基、噁二唑基)；所述的C1-3烷基、C3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基各自独立地任意地被1个或多个选自卤素、羟基、氰基、C1-3烷基、卤代C1-3烷基的取代基取代。
  11. 如权利要求1-3任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有式(VI-0)所示的结构：
  12. 如权利要求11所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其中：
    R2a选自-C1-4亚烷基-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-4亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-4亚烷基-O-C1-6烷基、-C1-4亚烷基-O-C1-4亚烷基-C3- 6环烷基、-C1-4亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-4亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-4亚烷基-N(Ra)(Rb)、-C1-4亚烷基-O-C1-4亚烷基-N(Ra)(Rb)、-N(Ra)-C(＝O)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-C1-2亚烷基-N(Ra)-C1-6烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-苯基、-C1-2亚烷基-O-C1-6烷基、-C1-2亚烷基-O-C1-4亚烷基-C3-6环烷基、-C1-2亚烷基-O-C1-4亚烷基-(4-7元杂环基)、-C(＝O)-N(Ra)-C1-6烷基、-C1-2亚烷基-N(Ra)-C(＝O)-C1-6烷基、-C1-2亚烷基-O-C1-4亚烷基-N(Ra)(Rb)；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    优选地，R2a选自-C1-2亚烷基-N(Ra)-C1-6烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-C3-6环烷基、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(4-7元杂环基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-(5-6元杂芳基)、-C1-2亚烷基-N(Ra)-C1-4亚烷基-苯基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；
    更优选地，R2a选自-C1-2亚烷基-N(Ra)-C1-6烷基；其中R2a的可选基团上可被取代的碳原子，各自独立地、任选地被1个或多个各自独立地选自Rg的取代基取代；和/或，R2a的可选基团上的可被取代的环氮原子，各自独立地、任选被1个或多个各自独立地选自Rh的取代基取代；和/或
    Rg各自独立地选自：氢、氘、卤素(例如氟、氯、溴)、羟基、氰基、氨基、-NH(C1-4烷基)、-N(C1-4烷基)(C1-4烷基)、C1-4烷基和C1-4卤代烷基；和/或
    Rh选自：氢、氘、C1-4烷基和C1-4卤代烷基；和/或
    Ra和Rb各自独立地选自：氢和C1-4烷基；任选地，所述C1-4烷基被1个或多个卤素取代。
  13. 如权利要求1-5任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有式(VI-1)所示的结构：
  14. 如权利要求1-13任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，其特征在于，所述化合物具有如下所示的结构：


  15. 一种药物组合物，其包含如权利要求1-14任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药和至少一种药学上可接受的载体。
  16. 如权利要求1-14任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药，或权利要求15的组合物，其用于治疗或预防与PTPN2相关的疾病或病症。
  17. 如权利要求1-14任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药或权利要求15的组合物，在制备药物中的用途，所述药物用于治疗或预防与PTPN2相关的疾病或病症。
  18. 一种治疗或预防与PTPN2相关的疾病或病症的方法，其包括向需要其的人施用治疗 有效量的如权利要求1-14任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药或权利要求15的组合物。
  19. 如权利要求17所述的用途、权利要求18所述的方法，其中，所述与PTPN2相关的疾病或病症包括癌症、2型糖尿病、代谢综合征、肥胖症或代谢疾病；优选地，所述癌症包括：癌瘤、肉瘤、腺癌、淋巴瘤、白血病、黑素瘤；优选地，所述癌症包括：实体和淋巴癌、肾癌、乳腺癌、肺癌、膀胱癌、结肠癌、卵巢癌、前列腺癌、胰腺癌、胃癌、脑癌、头颈癌、皮肤癌、子宫癌、睾丸癌、神经胶质瘤、食道癌、肝癌(包括肝肿瘤)、淋巴瘤，包括B急性成淋巴细胞性淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin's lymphomas)(例如伯基特氏淋巴瘤(Burkitt's lymphomas)、小细胞淋巴瘤和大细胞淋巴瘤)、霍奇金氏淋巴瘤、白血病(包括AML、ALL和CML)和/或多发性骨髓瘤；优选地，所述癌症包括肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、前列腺癌、转移性癌症或癌瘤。
PCT/CN2024/104645 2023-07-11 2024-07-10 蛋白酪氨酸磷酸酶抑制剂及其组合物、医药用途 WO2025011570A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202310857115.1 2023-07-11
CN202310857115 2023-07-11
CN202311171624 2023-09-12
CN202311171624.5 2023-09-12

Publications (1)

Publication Number Publication Date
WO2025011570A1 true WO2025011570A1 (zh) 2025-01-16

Family

ID=94214689

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/104645 WO2025011570A1 (zh) 2023-07-11 2024-07-10 蛋白酪氨酸磷酸酶抑制剂及其组合物、医药用途

Country Status (1)

Country Link
WO (1) WO2025011570A1 (zh)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008067527A1 (en) * 2006-12-01 2008-06-05 Novartis Ag Inhibitors of protein tyrosine phosphatase for the treatment of muscle atrophy and related disorders
CN101326173A (zh) * 2005-12-08 2008-12-17 诺瓦提斯公司 作为抗糖尿病剂的噻二唑衍生物
CN101336235A (zh) * 2005-12-08 2008-12-31 诺瓦提斯公司 作为ptp-酶抑制剂的1-邻氟苯基取代的1,2,5-噻唑烷二酮衍生物
CN101547694A (zh) * 2006-12-01 2009-09-30 诺瓦提斯公司 用于促进生理性心脏肥大的蛋白酪氨酸磷酸酶抑制剂
CN114025844A (zh) * 2019-03-14 2022-02-08 卡里科生命科学有限责任公司 蛋白酪氨酸磷酸酶抑制剂及其使用方法
WO2022056281A1 (en) * 2020-09-11 2022-03-17 Calico Life Sciences Llc Protein tyrosine phosphatase inhibitors and methods of use thereof
WO2022192598A1 (en) * 2021-03-11 2022-09-15 Kumquat Biosciences Inc. Heterocycles and uses thereof
WO2023150150A1 (en) * 2022-02-02 2023-08-10 Nerio Therapeutics, Inc. Protein tyrosine phosphatase inhibitors and uses thereof
WO2024141015A1 (en) * 2022-12-30 2024-07-04 Insilico Medicine Ip Limited Protein tyrosine phosphatase inhibitors and uses thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101326173A (zh) * 2005-12-08 2008-12-17 诺瓦提斯公司 作为抗糖尿病剂的噻二唑衍生物
CN101336235A (zh) * 2005-12-08 2008-12-31 诺瓦提斯公司 作为ptp-酶抑制剂的1-邻氟苯基取代的1,2,5-噻唑烷二酮衍生物
WO2008067527A1 (en) * 2006-12-01 2008-06-05 Novartis Ag Inhibitors of protein tyrosine phosphatase for the treatment of muscle atrophy and related disorders
CN101547694A (zh) * 2006-12-01 2009-09-30 诺瓦提斯公司 用于促进生理性心脏肥大的蛋白酪氨酸磷酸酶抑制剂
CN114025844A (zh) * 2019-03-14 2022-02-08 卡里科生命科学有限责任公司 蛋白酪氨酸磷酸酶抑制剂及其使用方法
WO2022056281A1 (en) * 2020-09-11 2022-03-17 Calico Life Sciences Llc Protein tyrosine phosphatase inhibitors and methods of use thereof
WO2022192598A1 (en) * 2021-03-11 2022-09-15 Kumquat Biosciences Inc. Heterocycles and uses thereof
WO2023150150A1 (en) * 2022-02-02 2023-08-10 Nerio Therapeutics, Inc. Protein tyrosine phosphatase inhibitors and uses thereof
WO2024141015A1 (en) * 2022-12-30 2024-07-04 Insilico Medicine Ip Limited Protein tyrosine phosphatase inhibitors and uses thereof

Similar Documents

Publication Publication Date Title
TWI871397B (zh) Ｋｒａｓ突變蛋白抑制劑
CN107735399B (zh) 作为蛋白质激酶的调节剂的手性二芳基大环
AU2014298051B2 (en) Novel quinazolinones as bromodomain inhibitors
US20230271935A1 (en) Ire1 small molecule inhibitors
ES2526981T3 (es) N-sulfonilbenzamidas como inhibidores de canales de sodio dependientes de voltaje
US10676438B2 (en) KCNQ2-5 channel activator
ES2982890T3 (es) Antagonistas del receptor muscarínico de acetilcolina M4
JPWO2010074193A1 (ja) 新規２環性複素環化合物
BR112015023279B1 (pt) compostos para inibição de fasn
WO2021238827A1 (zh) Egfr抑制剂、其制备方法及用途
US20230257383A1 (en) Compound serving as btk inhibitor, preparation method therefor, and use thereof
JP2020189852A (ja) キナーゼ阻害活性を有するベンズヒドロール−ピラゾール誘導体及びその使用
JP2020537692A (ja) ヘテロ環式化合物、ヘテロ環式化合物を含む組成物、及びその使用方法
WO2021249533A1 (zh) 雌激素受体调节剂化合物及其用途
US10501466B2 (en) WDR5 inhibitors and modulators
WO2025011445A1 (zh) 一种嘧啶胺类nuak抑制剂及其制备方法和用途
US20220356186A1 (en) Perk inhibiting pyrrolopyrimidine compounds
JP7546780B2 (ja) アザヘテロアリール化合物、その調製方法及び使用
US20220348583A1 (en) Perk inhibiting imidazolopyrazine compounds
JP2012031152A (ja) 新規２環性複素環化合物からなる医薬
US11555031B2 (en) Compounds and methods for regulating insulin secretion
WO2025011570A1 (zh) 蛋白酪氨酸磷酸酶抑制剂及其组合物、医药用途
JP6248048B2 (ja) キナーゼ阻害活性を有するトリプトリン誘導体及びその使用
WO2022171139A1 (zh) 一种巨环化合物、药物组合物以及其用途
TW202341987A (zh) 一種Polθ抑制劑

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24838822

Country of ref document: EP

Kind code of ref document: A1